Science.gov

Sample records for chronic cyclosporine nephropathy

  1. Delayed treatment with oleanolic acid attenuates tubulointerstitial fibrosis in chronic cyclosporine nephropathy through Nrf2/HO-1 signaling

    PubMed Central

    2014-01-01

    Background Nuclear factor erythroid-2-related factor-2 (Nrf2) is known to protect against tissue injury by orchestrating antioxidant and detoxification responses to oxidative stress. This study investigated whether upregulation of Nrf2-dependent signaling by oleanolic acid (OA), which is known to activate Nrf2, could attenuate renal inflammation and fibrosis in cyclosporine (CsA)-induced kidney injury. Methods Male ICR mice were divided into four treatment groups: Vehicle (VH, n = 6), VH + OA (n = 6), CsA (n = 8), and CsA + OA (n = 8). For the OA-treated groups, OA (25 mg/kg/day) was administered by intraperitoneal injection for the final week of the 4-week experimental period. Renal function, morphologies and signaling were evaluated at the end of the study. Results Treatment with CsA resulted in decreased kidney function and urine osmolality and increased urine volume and urinary albumin levels. The CsA-induced changes were improved by OA treatment. Specifically, administration of OA decreased tubulointerstitial fibrosis and inflammation scores that were increased in CsA-treated mice. Furthermore, OA treatment decreased urinary 8-hydroxy-2′-deoxyguanosine (8-OHdG) and 8-epi-prostaglandin F2α (8-iso-PGF2α) levels. The beneficial effects of OA were attributed to an increased ratio of nuclear/total Nrf2 and subsequently enhanced expression of heme oxygenase (HO)-1, as well as a stable level of Kelch-like ECH-associated protein 1 (Keap1) expression, indicating that OA enhanced nuclear translocation of Nrf2. Increased apoptotic cell death and a high ratio of B cell leukaemia/lymphoma 2 (Bcl-2)-associated X protein (Bax) to Bcl-2 in CsA-treated mice were also significantly ameliorated by OA treatment. Conclusion Our results suggest that OA activates Nrf2/HO-1 signaling in chronic CsA nephropathy, which may have beneficial effects on inflammation and oxidative stress. PMID:24559268

  2. Cyclosporine nephrotoxicity.

    PubMed

    Grinyó, J M; Cruzado, J M

    2004-03-01

    The polypeptide immunosuppressant cyclosporine is a prodrug that binds an intracellular immunophilin. The complex cyclosporine-cyclophilin binds and inhibits the phosphatase activity of calcineurin interfering with the dephosphorilation of members of the nuclear factor of activated T cells, which is involved in the regulation of genes encoding many cytokines. However, calcineurin is not exclusive from T cells; it is also present in many organs, such as the kidney, and their inhibition accounts for both the immunosuppressive and the nephrotoxic effects of cyclosporine. In renal transplantation, it was shown that graft survival improved progressively between 1998 to 1996, mainly due to reduction of acute rejection episodes. There is no doubt that cyclosporine contributed to that success. After 20 years, cyclosporine targets for maintenance immunosuppression have not been defined and the magnitude of chronic cyclosporine nephrotoxicity in renal allografts is not known, in part by the limitations of histologic classification of chronic allograft nephropathy. In the future, the new technology based on DNA microarrays can be a valuable tool to separate chronic drug toxicity from other causes of graft deterioration. On the other hand, in the cyclosporine era, chronic renal failure has emerged as a frequent adverse event after transplantation of nonrenal organs and it is associated with increased risk of death. Although there is not yet enough evidence to support a generalization of calcineurin-free immunosuppression, we should open our minds to the upcoming new concepts on immunosuppression. PMID:15041345

  3. Minimizing the risk of chronic allograft nephropathy.

    PubMed

    Weir, Matthew R; Wali, Ravinder K

    2009-04-27

    Chronic allograft nephropathy, now defined as interstital fibrosis and tubular atrophy not otherwise specified, is a near universal finding in transplant kidney biopsies by the end of the first decade posttransplantation. After excluding death with functioning graft, caused by cardiovascular disease or malignancy, chronic allograft nephropathy is the leading cause of graft failure. Original assumptions were that this was not a modifiable process but inexorable, likely due to past kidney injuries. However, newer understandings suggest that acute or subacute processes are involved, and with proper diagnosis, appropriate interventions can be instituted. Our method involved a review of the primary and secondary prevention trials in calcineurin inhibitor withdrawal. Some of the more important causes of progressive graft deterioration include subclinical cellular or humoral rejection, and chronic calcineurin inhibitor toxicity. Early graft biopsy, assessment of histology, and changes in immunosuppression may be some of the most important measures available to protect graft function. The avoidance of clinical inertia in pursuing subtle changes in graft function is critical. Modification in maintenance immunosuppression may benefit many patients with early evidence of graft deterioration. PMID:19384181

  4. Chronic hypokalemic nephropathy: a clinical study.

    PubMed

    Bock, K D; Cremer, W; Werner, U

    1978-01-01

    Description of 23 patients (21 women, 2 men) with an average age of 36.6 (19--68) years, who were hypokalemic during 6.5 years on the average (range 1/2--16 years). The cause of the potassium depletion was malnutrition (anorexia nervosa, vomiting) and/or abuse of laxatives and/or diuretics. With increasing duration of potassium depletion renal function deteriorated; in two cases terminal renal failure developed. Histology of the kidneys (9 cases) showed the picture of chronic abacterial interstitial nephritis. Urinalysis was negative or non-specific. The blood pressure levels were normal or low, hypertensive values being exceptional. Aside of hypokalemia a tendency to hyponatriemia, hypochloremia and metabolic alcalosis was observed, the latter turning into hypokalemic normochloremic acidosis with advancing renal insufficiency. Plasma renin activity and aldosterone concentration or excretion frequently were elevated, but no close correlation was found between these parameters or with the blood pressure. Bacterial infection of the urinary tract occured, if at all, in the late phase and seems to be complication rather than the cause of the kidney disease. The discussion of other possible pathogenetic factors leads to the conclusion that the term "chronic kaliopenic nephropathy" is justified. Some diagnostic and therapeutic consequences are mentioned. PMID:732256

  5. Treatment of chronic dry eye: focus on cyclosporine

    PubMed Central

    Kymionis, George D; Bouzoukis, Dimitrios I; Diakonis, Vassilios F; Siganos, Charalambos

    2008-01-01

    To review the current treatment of chronic dry eye syndrome, focusing on cyclosporine A (CsA), a systematic literature search was performed using PubMed databases in two steps. The first step was oriented to articles published for dry eye. The second step was focused on the use of CsA in dry eye. A manual literature search was also undertaken based on citations in the published articles. The knowledge on the pathogenesis of dry eye syndrome has changed dramatically during the last few years. Inflammation and the interruption of the inflammatory cascade seem to be the main focus of the ophthalmologic community in the treatment of dry eye, giving the anti-inflammatory therapy a new critical role. The infiltration of T-cells in the conjuctiva tissue and the presence of cytokines and proteasis in the tear fluid were the main reason introducing the use of immunomodulator agents such as corticosteroids, cyclosporine, and doxycicline in order to treat dry eye syndrome. CsA emulsion is approved by the FDA for the treatment of dry eye, while clinical trials of this agent have demonstrated efficacy and safety of CsA. CsA seems to be a promising treatment against dry eye disease. New agents focused on the inflammatory pathogenesis of this syndrome in combination with CsA may be the future in the quest of treating dry eye. More studies are needed to determine the efficacy, safety, timing, and relative cost/effect of CsA. PMID:19668437

  6. Viper bites complicate chronic agrochemical nephropathy in rural Sri Lanka

    PubMed Central

    2014-01-01

    Snakebite is a common occupational health hazard among Sri Lankan agricultural workers, particularly in the North Central Province. Viperine snakes, mainly Russell’s viper envenomation, frequently lead to acute renal failure. During the last two decades, an agrochemical nephropathy, a chronic tubulointerstitial disease has rapidly spread over this area leading to high morbidity and mortality. Most of the epidemiological characteristics of these two conditions overlap, increasing the chances of co-occurrence. Herein, we describe four representative cases of viperine snakebites leading to variable clinical presentations, in patients with chronic agrochemical nephropathy, including two patients presented with acute and delayed anuria. These cases suggest the possibility of unusual manifestations of snakebite in patients with Sri Lankan agrochemical nephropathy, of which the clinicians should be aware. It could be postulated that the existing scenario in the Central America could also lead to similar clinical presentations. PMID:25136354

  7. Cyclosporin-A efficacy in chronic idiopathic urticaria.

    PubMed

    Di Leo, E; Nettis, E; Aloia, A M; Moschetta, M; Carbonara, M; Dammacco, F; Vacca, A

    2011-01-01

    Common drugs in the therapy of chronic idiopathic urticaria (CIU) include antihistamines alone or combined with corticosteroids, but severe unresponsive patients require alternative treatments. This retrospective study aims to evaluate clinical response and safety of low-dose and long-term oral Cyclosporin-A (CyA) in unresponsive patients. One hundred and ten CIU patients, unresponsive to a previous treatment (antihistamines plus prednisone 0.2 mg/kg/day), received additional oral CyA 1–3 mg/kg/day for 6 months. The patients were subdivided into three groups (A, B, C) according to the different CyA doses. Parameters of clinical efficacy including pruritus, and size and number of wheals were evaluated at baseline, after three and six months. All adverse events were recorded. The mean total symptom severity score decreased by 63% in Group A, 76% in Group B, and 85% in Group C after 6 months. Total disappearance of the symptoms was recorded in 43 patients (39.1%): 7 (28%) of Group A; 12 (37.5%) of Group B and 24 (45%) of Group C. After a mean of 2 months from CyA suspension, 14 patients (11%) had recurrence of symptoms. Minor side effects were noted in 8 patients (7%). Our study indicates that low-dose, long-term CyA therapy is efficacious and safe in severe unresponsive CIU. PMID:21496403

  8. Cyclosporin A-mediated cholestasis in patients with chronic hepatitis after heart transplantation.

    PubMed

    Myara, A; Cadranel, J F; Dorent, R; Lunel, F; Bouvier, E; Gerhardt, M; Bernard, B; Ghoussoub, J J; Cabrol, A; Gandjbakhch, I; Opolon, P; Trivin, F

    1996-03-01

    Viral chronic hepatitis often occurs in heart transplant recipients receiving cyclosporin. This essential immunosuppressive drug may induce cholestasis. We investigated the effect of treatment with cyclosporin on serum conjugated bile acids in patients with chronic hepatitis developing after heart transplantation. Fifty-nine patients were studied: 17 with chronic hepatitis, 15 heart transplant patients with normal alanine aminotransferase activity, and 27 heart transplant patients with chronic hepatitis, the last two groups receiving cyclosporin. Hepatic biochemical tests and total bile acid concentration were determined on fasting blood samples. The individual glyco- and tauroconjugated bile acids were quantified by high-performance liquid chromatography and direct spectrometry. In patients taking cyclosporin the bilirubin concentration and the alkaline phosphatase activity were increased only when hepatitis was present, in association with a slight increase in cholic acid level (5.13 microM vs. 0.68 microM; P < 0.01). Conjugated lithocholate concentration was dramatically higher when hepatitis and immunosuppression with cyclosporin were associated (1.17 microM vs. 0.03 and 0.04 microM; P < 0.01). Chenodeoxycholate was the main circulating bile acid only in the heart transplant patients treated with cyclosporin but without hepatitis. These results suggest that the mechanisms which explain the cyclosporin-associated modifications of the bile acid pool are different according to the presence or absence of hepatitis. The occurrence of hepatitis in patients on cyclosporin led to an increase in serum lithocholate and primary bile acid concentrations. Further studies are required to assess the effect of ursodeoxycholic acid for this cholestasis. PMID:8724029

  9. Smad7 protects against chronic aristolochic acid nephropathy in mice

    PubMed Central

    Huang, Xiao-Ru; Fu, Ping; Lan, Hui-Yao

    2015-01-01

    Chronic Aristolochic Acid Nephropathy (AAN) is a progressive chronic kidney disease related to herb medicine. However, treatment for chronic AAN remains ineffective. We report here that Smad7 is protective and has therapeutic potential for chronic AAN. In a mouse model of chronic AAN, progressive renal injury was associated with a loss of renal Smad7 and disruption of Smad7 largely aggravated the severity of chronic AAN as demonstrated by a significant increase in levels of 24-hour urinary protein excretion, serum creatinine, and progressive renal fibrosis and inflammation. In contrast, restored Smad7 locally in the kidneys of Smad7 knockout mice prevented the progression of chronic AAN. Further studies revealed that worsen chronic AAN in Smad7 knockout mice was associated with enhanced activation of TGF-β/Smad3 and NF-κB signaling pathways, which was reversed when renal Smad7 was restored. Importantly, we also found that overexpression of Smad7 locally in the kidneys with established chronic AAN was capable of attenuating progressive chronic AAN by inactivating TGF-β/Smad3-medated renal fibrosis and NF-κB-driven renal inflammation. In conclusion, Smad7 plays a protective role in the pathogenesis of chronic AAN and overexpression of Smad7 may represent a novel therapeutic potential for chronic AAN. PMID:25883225

  10. Oxidative Stress in Diabetic Nephropathy with Early Chronic Kidney Disease.

    PubMed

    Miranda-Díaz, Alejandra Guillermina; Pazarín-Villaseñor, Leonardo; Yanowsky-Escatell, Francisco Gerardo; Andrade-Sierra, Jorge

    2016-01-01

    The increase in the prevalence of diabetes mellitus (DM) and the secondary kidney damage produces diabetic nephropathy (DN). Early nephropathy is defined as the presence of microalbuminuria (30-300 mg/day), including normal glomerular filtration rate (GFR) or a mildly decreased GFR (60-89 mL/min/1.73 m(2)), with or without overt nephropathy. The earliest change caused by DN is hyperfiltration with proteinuria. The acceptable excretion rate of albumin in urine is <30 mg/day. Albuminuria represents the excretion of >300 mg/day. Chronic kidney disease (CKD) is characterized by abnormalities in renal function that persist for >3 months with health implications. Alterations in the redox state in DN are caused by the persistent state of hyperglycemia and the increase in advanced glycation end products (AGEs) with ability to affect the renin-angiotensin system and the transforming growth factor-beta (TGF-β), producing chronic inflammation and glomerular and tubular hypertrophy and favoring the appearance of oxidative stress. In DN imbalance between prooxidant/antioxidant processes exists with an increase in reactive oxygen species (ROS). The overproduction of ROS diminishes expression of the antioxidant enzymes (manganese superoxide dismutase, glutathione peroxidase, and catalase). The early detection of CKD secondary to DN and the timely identification of patients would permit decreasing its impact on health. PMID:27525285

  11. Oxidative Stress in Diabetic Nephropathy with Early Chronic Kidney Disease

    PubMed Central

    Andrade-Sierra, Jorge

    2016-01-01

    The increase in the prevalence of diabetes mellitus (DM) and the secondary kidney damage produces diabetic nephropathy (DN). Early nephropathy is defined as the presence of microalbuminuria (30–300 mg/day), including normal glomerular filtration rate (GFR) or a mildly decreased GFR (60–89 mL/min/1.73 m2), with or without overt nephropathy. The earliest change caused by DN is hyperfiltration with proteinuria. The acceptable excretion rate of albumin in urine is <30 mg/day. Albuminuria represents the excretion of >300 mg/day. Chronic kidney disease (CKD) is characterized by abnormalities in renal function that persist for >3 months with health implications. Alterations in the redox state in DN are caused by the persistent state of hyperglycemia and the increase in advanced glycation end products (AGEs) with ability to affect the renin-angiotensin system and the transforming growth factor-beta (TGF-β), producing chronic inflammation and glomerular and tubular hypertrophy and favoring the appearance of oxidative stress. In DN imbalance between prooxidant/antioxidant processes exists with an increase in reactive oxygen species (ROS). The overproduction of ROS diminishes expression of the antioxidant enzymes (manganese superoxide dismutase, glutathione peroxidase, and catalase). The early detection of CKD secondary to DN and the timely identification of patients would permit decreasing its impact on health. PMID:27525285

  12. [DIABETIC NEPHROPATHY AS A CAUSE OF CHRONIC KIDNEY DISEASE].

    PubMed

    Kos, Ivan; Prkačin, Ingrid

    2014-12-01

    Diabetic nephropathy is the leading cause of end-stage chronic kidney disease in most developed countries. Hyperglycemia, hypertension and genetic predisposition are the main risk factors for the development of diabetic nephropathy. Elevated serum lipids, smoking habits, and the amount and origin of dietary protein also seem to play a role as risk factors. Clinical picture includes a progressive increase in albuminuria, decline in glomerular filtration, hypertension, and a high risk of cardiovascular morbidity and mortality. Screening for albuminuria should be performed yearly, starting 5 years after diagnosis in type 1 diabetes or earlier in the presence of adolescence or poor metabolic control. In patients with type 2 diabetes, screening should be performed at diagnosis and yearly thereafter. Patients with albuminuria should undergo evaluation regarding the presence of associated comorbidities, especially retinopathy and macrovascular disease. Achieving the best metabolic control (HbA1c < 7%), treating hypertension (target blood pressure < 140/85 mm Hg), using drugs with blockade effect on the renin-angiotensin-aldosterone system, treating dyslipidemia and anemia are effective strategies for preventing the development of albuminuria, delaying the progression to more advanced stages of nephropathy and reducing cardiovascular mortality in patients with type 1 and type 2 diabetes. PMID:26285470

  13. Safety and Efficacy of Cyclosporine in the Treatment of Chronic Dry Eye

    PubMed Central

    Schultz, Clyde

    2014-01-01

    Dry-eye syndrome (DES) is a multifactorial disease affecting millions of individuals worldwide. Various factors, including age, hormonal status, genetics, sex, immune status, innervation status, nutrition, pathogens, and environmental stress, can alter the cellular and molecular structure or function of components of the ocular surface system. The resulting imbalance increases susceptibility to desiccation and epithelial damage, leading to a vicious circle in which inflammation amplifies and sustains further damage by chronic deregulation of the system. Lubricating agents and steroids have been used as treatment options. However, as the causes of the disease become better elucidated, the more chemically complex cyclosporine A has become an increasingly useful treatment option and in the United States is currently the only Food and Drug Administration (FDA)-approved prescription drug for the treatment of dry eye. The safety and efficacy of cyclosporine have been shown in numerous studies. PMID:25002818

  14. Assessment of the Siksika chronic disease nephropathy-prevention clinic

    PubMed Central

    Ward, David R.R.; Novak, Ellen; Scott-Douglas, Nairne; Brar, Sony; White, Melvin; Hemmelgarn, Brenda R.

    2013-01-01

    Objective To determine if a community-based multifactorial intervention clinic led by a nurse practitioner would improve management of First Nations people at risk of developing chronic kidney disease. Design Qualitative descriptive study. Setting A nephropathy-prevention clinic in Siksika Nation, Alta. Participants First Nations people with diabetes, hypertension, or dyslipidemia who were referred to the clinic. Main outcome measures Changes in blood pressure (BP), hemoglobin A1c, and low-density lipoprotein levels, as well as in use of antiplatelet therapy, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker medications, and statin therapy. Results Members of the Siksika Nation were treated according to clinical practice guidelines. A total of 78 patients had at least 2 visits to the clinic and were included in this analysis (61.5% were women; mean age 56 years). Among those initially above target, a significant reduction was achieved in mean hemoglobin A1c (0.96%; P < .01), systolic BP (15.84 mm Hg; P < .05), diastolic BP (7.16 mm Hg; P < .001), and low-density lipoprotein (0.62 mmol/L; P < .01) levels. There was a significant increase in the proportion of patients with clinical indications who were treated with acetylsalicylic acid (42.4%; P < .01), angiotensin-converting enzyme inhibitor or angiotensin receptor blocker medications (35.9%; P < .01), or statin therapy (35.9%; P < .01). Conclusion A community-based, nurse practitioner–led clinic can improve many clinically relevant factors in patients at risk of developing chronic kidney disease. Studies have shown that achieving treatment targets is associated with a reduced risk of early death and cardiovascular events; the effect in the First Nations population on these hard clinical end points remains to be determined. PMID:23341675

  15. Chronic cyclosporin A nephrotoxicity, P-glycoprotein overexpression, and relationships with intrarenal angiotensin II deposits.

    PubMed Central

    del Moral, R. G.; Andujar, M.; Ramírez, C.; Gómez-Morales, M.; Masseroli, M.; Aguilar, M.; Olmo, A.; Arrebola, F.; Guillén, M.; García-Chicano, M. J.; Nogales, F. F.; O'Valle, F.

    1997-01-01

    P-glycoprotein (P-gp) expels hydrophobic substances from the cell, including chemotherapeutic agents and immunosuppressants such as cyclosporin A (CsA) and FK506. Exposure of cultured renal tubular cells to CsA induces P-gp overexpression in cell membranes. Angiotensin II has recently been implicated as the principal factor responsible for progression of interstitial fibrosis induced by CsA. To investigate the in vivo relationships between histological lesions, P-gp overexpression, and intrarenal angiotensin II deposits, we developed a model of chronic CsA toxicity in Sprague-Dawley rats treated with 25 mg/kg/day CsA for 28 and 56 days and fed either a standard maintenance diet or a low-salt diet. Immunohistochemical methods were used to study the expression of P-gp in renal tubular cells and the appearance of intrarenal angiotensin II deposits. Rats treated with CsA developed chronic nephrotoxicity lesions that were more evident in the group fed the low-salt diet. Treatment with CsA induced overexpression of P-gp in tubular cells of the kidney that increased with time. We found that immunohistochemical expression of P-gp was slightly more severe in rats fed a low-salt diet. Intrarenal deposits of angiotensin II were more evident in rats treated with CsA; these deposits also increased with time. This finding was also more relevant in rats given the low-salt diet. The up-regulation of P-gp was inversely related to the incidence of hyaline arteriopathy (r = -0.65; P < 0.05), periglomerular (r = -0.58; P < 0.05) and peritubular fibrosis (r = -0.63; P < 0.05), and intrarenal angiotensin H deposits in animals with severe signs of nephrotoxicity (r = -0.65; P < 0.05). These results support the hypothesis that the role of P-gp as a detoxicant in renal cells may be related to mechanisms that control the cytoplasmic removal of both toxic metabolites from CsA and those originating from the catabolism of signal transduction proteins (methylcysteine esters), which are produced

  16. Posing the Question Again: Does Chronic Uric Acid Nephropathy Exist?

    PubMed Central

    2010-01-01

    The question of whether hyperuricemia can induce chronic direct renal injury has been argued for many decades. Despite continued efforts and strong motivations to seek an answer, the current evidence still cannot definitively prove or refute the hypothesis. Recent data in rodents do favor causality between hyperuricemia and renal disease. Human epidemiologic data are quite varied, but positive studies do exist. Pathophysiologic models of biology for this entity are sparse in animals and nonexistent in humans. PMID:19729442

  17. Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy.

    PubMed

    Falger, Jutta C; Mueller, Thomas; Arbeiter, Klaus; Boehm, Michael; Regele, Heinz; Balzar, Egon; Aufricht, Christoph

    2006-06-01

    Chronic allograft nephropathy is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non-nephrotoxic alternative to calcineurin inhibitors. In the present study, effects of a conversion protocol were investigated in pediatric chronic allograft nephropathy with declining glomerular filtration rate (GFR), defined by a Schwartz formula clearance below 60 mL/1.73 m(2)/min, steadily increasing serum creatinine and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kg bodyweight (BW), followed by 0.2 mg/kgBW/day, aimed at trough levels of 15-20 ng/mL. Calcineurin inhibitors were reduced to 50% at the start of sirolimus and discontinued at median 7 days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (-2.9 vs. +0.4 mL/min/1.73 m(2)/month, p = 0.025). Individual GFR increased in five out of eight patients (p = 0.026), and only one child exhibited unaltered progression of graft failure. In the responders, mean serum creatinine improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, or on time post-transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, and serum lipids increased transiently. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from calcineurin inhibitors to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy-proven chronic allograft nephropathy. PMID:16712606

  18. Cyclosporine Ophthalmic

    MedlinePlus

    Ophthalmic cyclosporine is used to increase tear production in people with dry eye disease. Cyclosporine is in a class of medications called immunomodulators. It works by decreasing swelling in the eye ...

  19. [Analgesic nephropathy].

    PubMed

    Pintér, I; Nagy, J

    1998-11-22

    Analgesic nephropathy is a slowly progressive disease caused by the chronic abuse of analgesic mixtures containing two analgesic components combined with potentially addictive substances (coffeine and/or codeine). Pathologically, the nephropathy is characterized by renal papillary necrosis with calcification and chronic interstitial nephritis sometimes in association with transitional-cell carcinoma of the uroepithelium. In the early stage, the clinical characteristics are polyuria, sterile pyuria, sometimes renal colic and haematuria. With further progression of the disease, there are the nonspecific symptoms of advanced renal failure. The incidence of classic analgesic nephropathy among Hungarian patients on chronic renal replacement therapy has proven. There is an urgent need for the estimation of analgesic nephropathy among patients with chronic renal disease and among patients with chronic pain presumably regularly taking analgesics in Hungary. As long as analgesic mixtures containing phenacetin or paracetamol and/or nonsteroidal antiinflammatory drugs and addictive substances are available "over-the-counter", analgesic nephropathy will continue to be a problem also in our country. PMID:9846064

  20. Effect of nephrotoxic drugs on the development of radiation nephropathy after bone marrow transplantation

    SciTech Connect

    Lawton, C.A.; Fish, B.L.; Moulder, J.E. )

    1994-03-01

    Chronic renal failure is a significant cause of late morbidity in bone marrow transplant patients whose conditioning regimen includes total body irradiation (TBI). Radiation is a major cause of this syndrome (bone marrow transplant nephropathy), but it may not be the only cause. These studies use a rat syngeneic bone marrow transplant model to determine whether nephrotoxic agents used in conjunction with bone marrow transplantation (BMT) could be enhancing or accelerating the development of radiation nephropathy. Rats received 11-17 Gy TBI in six fractions over 3 days followed by syngeneic bone marrow transplant. In conjunction with the bone marrow transplants, animals received either no drugs, cyclosporine, amphotericin, gentamicin, or busulfan. Drugs were given in schedules analogous to their use in clinical bone marrow transplantation. Drug doses were chosen so that the drug regimen alone caused detectable acute nephrotoxicity. Animals were followed for 6 months with periodic renal function tests. Gentamicin had no apparent interactions with TBI. Amphotericin increased the incidence of engraftment failure, but did not enhance radiation nephropathy. Cyclosporin with TBI caused late morbidity that appeared to be due to neurological problems, but did not enhance radiation nephropathy. Busulfan resulted in a significant enhancement of radiation nephropathy. Of the nephrotoxins used in conjunction with bone marrow transplantation only radiation and busulfan were found to be risk factors for bone marrow transplant nephropathy. 34 refs., 4 figs., 2 tabs.

  1. [Topical administration of cyclosporin in psoriasis vulgaris].

    PubMed

    Bunse, T; Schulze, H J; Mahrle, G

    1990-06-01

    Two groups of patients with chronic plaque psoriasis were topically treated either with 10% cyclosporin in a jelly base or with 5% cyclosporin in an ointment base under occlusion. We found that cyclosporin penetrates into the lower epidermis and the dermis, when it is applied under occlusion. Obviously, the target cells are neutrophil granulocytes, since they decrease in number under cyclosporin, whereas the other inflammatory cells as well as the epidermal proliferation remain unchanged. In contrast to systemic application of cyclosporin, we did not observe any clinical differences between plaques treated with cyclosporin and those treated with placebo. PMID:2202163

  2. Targeting c-fms kinase attenuates chronic aristolochic acid nephropathy in mice.

    PubMed

    Dai, Xiao Y; Huang, Xiao R; Zhou, Li; Zhang, Lin; Fu, Ping; Manthey, Carl; Nikolic-Paterson, David J; Lan, Hui Y

    2016-03-01

    Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by some Chinese herbal medicines, but treatment remains ineffective. Macrophage accumulation is an early feature in human and experimental AAN; however, the role of macrophages in chronic AAN is unknown. We report here that targeting macrophages with fms-I, a selective inhibitor of the tyrosine kinase activity of the macrophage colony-stimulating factor receptor, suppressed disease progression in a mouse model of chronic AAN. Treatment with fms-I (10mg/kg/BID) from day 0 to 28 (prevention study) or from day 14 to 28 (intervention study) substantially inhibited macrophage accumulation and significantly improved renal dysfunction including a reduction in proteinuria and tubular damage. Progressive interstitial fibrosis (myofibroblast accumulation and collagen deposition) and renal inflammation (increased expression of MCP-1, MIF, and TNF-α) were also attenuated by fms-I treatment. These protective effects involved inhibition of TGF-β/Smad3 and NF-kB signaling. In conclusion, the present study establishes that macrophages are key inflammatory cells that exacerbates progressive tubulointerstitial damage in chronic AAN via mechanisms associated with TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Targeting macrophages via a c-fms kinase inhibitor may represent a novel therapy for chronic AAN. PMID:26909597

  3. Targeting c-fms kinase attenuates chronic aristolochic acid nephropathy in mice

    PubMed Central

    Zhou, Li; Zhang, Lin; Fu, Ping; Manthey, Carl; Nikolic-Paterson, David J.; Lan, Hui Y.

    2016-01-01

    Aristolochic acid nephropathy (AAN) is a progressive kidney disease caused by some Chinese herbal medicines, but treatment remains ineffective. Macrophage accumulation is an early feature in human and experimental AAN; however, the role of macrophages in chronic AAN is unknown. We report here that targeting macrophages with fms-I, a selective inhibitor of the tyrosine kinase activity of the macrophage colony-stimulating factor receptor, suppressed disease progression in a mouse model of chronic AAN. Treatment with fms-I (10mg/kg/BID) from day 0 to 28 (prevention study) or from day 14 to 28 (intervention study) substantially inhibited macrophage accumulation and significantly improved renal dysfunction including a reduction in proteinuria and tubular damage. Progressive interstitial fibrosis (myofibroblast accumulation and collagen deposition) and renal inflammation (increased expression of MCP-1, MIF, and TNF-α) were also attenuated by fms-I treatment. These protective effects involved inhibition of TGF-β/Smad3 and NF-kB signaling. In conclusion, the present study establishes that macrophages are key inflammatory cells that exacerbates progressive tubulointerstitial damage in chronic AAN via mechanisms associated with TGF-β/Smad3-mediated renal fibrosis and NF-κB-driven renal inflammation. Targeting macrophages via a c-fms kinase inhibitor may represent a novel therapy for chronic AAN. PMID:26909597

  4. Nephropathy in dietary hyperoxaluria: A potentially preventable acute or chronic kidney disease

    PubMed Central

    Glew, Robert H; Sun, Yijuan; Horowitz, Bruce L; Konstantinov, Konstantin N; Barry, Marc; Fair, Joanna R; Massie, Larry; Tzamaloukas, Antonios H

    2014-01-01

    Hyperoxaluria can cause not only nephrolithiasis and nephrocalcinosis, but also renal parenchymal disease histologically characterized by deposition of calcium oxalate crystals throughout the renal parenchyma, profound tubular damage and interstitial inflammation and fibrosis. Hyperoxaluric nephropathy presents clinically as acute or chronic renal failure that may progress to end-stage renal disease (ESRD). This sequence of events, well recognized in the past in primary and enteric hyperoxalurias, has also been documented in a few cases of dietary hyperoxaluria. Estimates of oxalate intake in patients with chronic dietary hyperoxaluria who developed chronic kidney disease or ESRD were comparable to the reported average oxalate content of the diets of certain populations worldwide, thus raising the question whether dietary hyperoxaluria is a primary cause of ESRD in these regions. Studies addressing this question have the potential of improving population health and should be undertaken, alongside ongoing studies which are yielding fresh insights into the mechanisms of intestinal absorption and renal excretion of oxalate, and into the mechanisms of development of oxalate-induced renal parenchymal disease. Novel preventive and therapeutic strategies for treating all types of hyperoxaluria are expected to develop from these studies. PMID:25374807

  5. Serum Hepcidin Predicts Uremic Accelerated Atherosclerosis in Chronic Hemodialysis Patients with Diabetic Nephropathy

    PubMed Central

    Li, Han; Feng, Su-Juan; Su, Lu-Lu; Wang, Wei; Zhang, Xiao-Dong; Wang, Shi-Xiang

    2015-01-01

    Background: Hepcidin, as a regulator of body iron stores, has been recently discovered to play a critical role in the pathogenesis of anemia of chronic disease. Atherosclerotic cardiovascular disease is the most common complication and the leading cause of death in chronic hemodialysis (CHD) patients. In the current study, we aimed to explore the relationship between serum hepcidin and uremic accelerated atherosclerosis (UAAS) in CHD patients with diabetic nephropathy (CHD/DN). Methods: A total of 78 CHD/DN and 86 chronic hemodialyzed nondiabetic patients with chronic glomerulonephritis (CHD/non-DN) were recruited in this study. The level of serum hepcidin-25 was specifically measured by liquid chromatography-tandem mass spectrometry. Serum levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. Results: High serum level of hepcidin-25 was seen in CHD patients. Serum hepcidin-25 in CHD/DN was significantly higher than that in CHD/non-DN patients. Serum hepcidin-25 was positively correlated with ferritin, high-sensitivity C-reactive protein (hs-CRP), TNF-α, and IL-6 in CHD/DN patients. CHD/DN patients exhibited higher common carotid artery intima media thickness (CCA-IMT), hs-CRP, and hepcidin-25 levels than that in CHD/non-DN patients. Moreover, in CHD/DN patients, CCA-IMT was positively correlated with serum hepcidin, hs-CRP, and low-density lipoprotein-cholesterol. On multiple regression analysis, serum hepcidin and hs-CRP level exhibited independent association with IMT in CHD/DN patients. Conclusions: These findings suggest possible linkage between iron metabolism and hepcidin modulation abnormalities that may contribute to the development of UAAS in CHD/DN patients. PMID:25963357

  6. The protective effect of vildagliptin in chronic experimental cyclosporine A-induced hepatotoxicity.

    PubMed

    El-Sherbeeny, Nagla A; Nader, Manar A

    2016-03-01

    The study examined the effect of dipeptidyl peptidase-4 (DPP-4) inhibitor, vildagliptin, in cyclosporine (CsA)-induced hepatotoxicity. Rats were divided into 4 groups treated for 28 days: control (vehicle), vildagliptin (10 mg/kg, orally), CsA (20 mg/kg, s.c.), and CsA-vildagliptin group. Liver function was assessed by measuring serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma glutamyltransferase (γGT), lactate dehydrogenase (LDH), and albumin, and histopathological changes of liver were examined. Oxidative stress markers were evaluated. Assessment of nuclear factor-kappa B (NF-κB) activity in hepatic nuclear extract, serum DPP-4, and expression of Bax and Bcl2 were also done. CsA-induced hepatotoxicity was evidenced by increase in serum levels of AST, ALT, and γGT; a decrease in serum albumin; and a significant alteration in hepatic architecture. Also, significant increase in thiobarbituric acid reactive substance (TBARS) and decrease in superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), and glutathione (GSH) levels, increased expression Bax proteins with deceased expression of Bcl2, and increased hepatic activity of NF-κB and serum DPP-4 level were observed upon CsA treatment. Vildagliptin significantly improved all altered parameters induced by CsA administration. Vildagliptin has the potential to protect the liver against CsA-induced hepatotoxicity by reducing oxidative stress, DPP-4 activity, apoptosis, and inflammation. PMID:26632647

  7. Cyclosporine Ophthalmic

    MedlinePlus

    ... used to increase tear production in people with dry eye disease. Cyclosporine is in a class of medications ... Be sure to mention other eye drops for dry eye disease.if you are using artificial tears, instill ...

  8. Hepcidin as a Biomarker of Impaired Renal Function in Rat Models for Chronic Allograft Nephropathy.

    PubMed

    Xue, Dong; Zhou, Cuixing; Shi, Yunbo; Lu, Hao; He, Xiaozhou

    2016-01-01

    BACKGROUND To explore the use of hepcidin as a marker of impaired renal function in a rat model for chronic allograft nephropathy (CAN). MATERIAL AND METHODS Twenty-four models were developed and 20 models were included in this study, using Fisher (F344) rats (donors) and Lewis rats (recipients). Renal function tests were performed preoperatively and postoperatively. Hepcidin, interleukin-6 (IL-6), and erythropoietin levels in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). To observe pathological changes in the kidneys, 10 rats each were sacrificed at 2 months and 4 months after surgery. RESULTS After transplantation, the serum hepcidin and IL-6 levels increased, while urine hepcidin levels decreased. Erythropoietin levels showed a similar trend; all P<0.05. Serum creatinine (SCr) and blood urea nitrogen significantly increased post-operatively, with SCr positively correlating with serum hepcidin. Serum hepcidin positively correlated with IL-6 and negatively correlated with EPO. Histopathological results were consistent with CAN, after transplantation. CONCLUSIONS Hepcidin may be considered as a potential marker of impaired renal function. PMID:26907911

  9. Hepcidin as a Biomarker of Impaired Renal Function in Rat Models for Chronic Allograft Nephropathy

    PubMed Central

    Xue, Dong; Zhou, Cuixing; Shi, Yunbo; Lu, Hao; He, Xiaozhou

    2016-01-01

    Background To explore the use of hepcidin as a marker of impaired renal function in a rat model for chronic allograft nephropathy (CAN). Material/Methods Twenty-four models were developed and 20 models were included in this study, using Fisher (F344) rats (donors) and Lewis rats (recipients). Renal function tests were performed preoperatively and postoperatively. Hepcidin, interleukin-6 (IL-6), and erythropoietin levels in serum and urine were measured by enzyme-linked immunosorbent assay (ELISA). To observe pathological changes in the kidneys, 10 rats each were sacrificed at 2 months and 4 months after surgery. Results After transplantation, the serum hepcidin and IL-6 levels increased, while urine hepcidin levels decreased. Erythropoietin levels showed a similar trend; all P<0.05. Serum creatinine (SCr) and blood urea nitrogen significantly increased post-operatively, with SCr positively correlating with serum hepcidin. Serum hepcidin positively correlated with IL-6 and negatively correlated with EPO. Histopathological results were consistent with CAN, after transplantation. Conclusions Hepcidin may be considered as a potential marker of impaired renal function. PMID:26907911

  10. Corticosteroids in Patients with IgA Nephropathy and Severe Chronic Renal Damage

    PubMed Central

    Pozzi, Claudio; Ferrario, Francesca; Visciano, Bianca; Del Vecchio, Lucia

    2012-01-01

    Little is known about the utility of treating patients with advanced IgA nephropathy (IgAN). From 2001 to 2005, four patients came to our observation because of serum creatinine higher than 3 mg/dL, proteinuria ranging from 1.8 to 5.1 g/day, and a histological picture of diffuse sclerotic lesions. A corticosteroid course of 12 months was given. Patients were observed for a mean follow up of 84 months. At the end of the steroid course, proteinuria lowered quickly below 1 g/day in two patients, whereas the other two experienced a slower and less persistent decrease of proteinuria. Despite similar lesion severity at renal biopsy, renal function stabilized only in these two ones. In conclusion, these preliminary observations suggest a possible efficacy of corticosteroids in slowing down the progression of renal disease and in postponing the need of dialysis in IgAN patients with stage IV CKD and severe chronic histological lesions. PMID:24533200

  11. Low-dose and short-term cyclosporine treatment in patients with chronic idiopathic urticaria: a clinical and immunological evaluation.

    PubMed

    Serhat Inaloz, H; Ozturk, Savas; Akcali, Cenk; Kirtak, Necmettin; Tarakcioglu, Mehmet

    2008-05-01

    The present study aimed to evaluate the effectiveness of 2.5 mg/kg/day cyclosporin (CsA) treatment in patients with severe chronic idiopathic urticaria (CIU) and the impact of CsA treatment on several cytokines involved in the etiopathogenesis of CIU. Twenty-seven CIU patients and 24 healthy control subjects were included in the study. The autologous serum skin test (ASST) for autoantibodies and urticaria activity scoring (UAS) were measured for the evaluation of the clinical severity and the response to therapy, and the serum levels of interleukin (IL)-6, IL-8, IL-2 receptor, IL-1beta, tumor necrosis factor (TNF)-alpha and IL-5 were measured. The mean UAS score was 32.07 +/- 7.05 and 6.22 +/- 3.84 before and after CsA treatment, respectively. The serum IL-2 receptor, TNF-alpha and IL-5 levels of patients before CsA treatment were statistically higher than those of the control group (P = 0.001), and after 4 weeks of CsA therapy the mean IL-2R, TNF-alpha and IL-5 levels were significantly decreased. The data from this study demonstrate that CsA therapy is efficient and safe for CIU patients. Increase in clinical efficacy and marked decreases in serum cytokine levels suggest that inhibition of cytokine generation is involved in the action of the drug in this clinical setting. PMID:18477227

  12. Ocular surface and tear functions after topical cyclosporine treatment in dry eye patients with chronic graft-versus-host disease.

    PubMed

    Wang, Y; Ogawa, Y; Dogru, M; Kawai, M; Tatematsu, Y; Uchino, M; Okada, N; Igarashi, A; Kujira, A; Fujishima, H; Okamoto, S; Shimazaki, J; Tsubota, K

    2008-02-01

    We investigated the effect of 0.05% topical cyclosporine (Cys) on the ocular surface and tear functions in dry eye patients with chronic GVHD (cGVHD) in a prospective comparative study. Thirty eyes of 15 patients refractory to baseline treatment were recruited and the patients assigned for topical Cys treatment group (14 eyes of 7 patients) and control group (12 eyes of 6 patients) respectively. Two patients dropped out because of intolerable irritation while using topical Cys eye drops. Visual analog scale symptom scores, corneal sensitivity, Schirmer I test value, tear film break-up time (TBUT), tear evaporation rate and ocular surface vital staining scores were recorded at baseline and at the end of the following one month. Conjunctival impression and brush cytology were performed before and after the treatment. After topical Cys treatment, significant improvements were found in symptom scores, corneal sensitivity, tear evaporation rate, TBUT, vital staining scores, goblet cells density, conjunctival squamous metaplasia grade, inflammatory cell numbers and the MUC5AC expression. Our study suggests that 0.05% topical Cys may be an effective treatment for dry eye patients with cGVHD. The improvements in the ocular surface and tear functions resulted presumably from the decreased inflammation, increased goblet cell density and MUC5AC mRNA expression. Bone Marrow Transplantation (2008) 41, 293-302; doi:10.1038/sj.bmt.1705900; published online 5 November 2007. PMID:17982500

  13. Campath, calcineurin inhibitor reduction and chronic allograft nephropathy (3C) study: background, rationale, and study protocol

    PubMed Central

    2013-01-01

    Background Kidney transplantation is the best treatment for patients with end-stage renal failure, but uncertainty remains about the best immunosuppression strategy. Long-term graft survival has not improved substantially, and one possible explanation is calcineurin inhibitor (CNI) nephrotoxicity. CNI exposure could be minimized by using more potent induction therapy or alternative maintenance therapy to remove CNIs completely. However, the safety and efficacy of such strategies are unknown. Methods/Design The Campath, Calcineurin inhibitor reduction and Chronic allograft nephropathy (3C) Study is a multicentre, open-label, randomized controlled trial with 852 participants which is addressing two important questions in kidney transplantation. The first question is whether a Campath (alemtuzumab)-based induction therapy strategy is superior to basiliximab-based therapy, and the second is whether, from 6 months after transplantation, a sirolimus-based maintenance therapy strategy is superior to tacrolimus-based therapy. Recruitment is complete, and follow-up will continue for around 5 years post-transplant. The primary endpoint for the induction therapy comparison is biopsy-proven acute rejection by 6 months, and the primary endpoint for the maintenance therapy comparison is change in estimated glomerular filtration rate from baseline to 2 years after transplantation. The study is sponsored by the University of Oxford and endorsed by the British Transplantation Society, and 18 centers for adult kidney transplant are participating. Discussion Late graft failure is a major issue for kidney-transplant recipients. If our hypothesis that minimizing CNI exposure with Campath-based induction therapy and/or an elective conversion to sirolimus-based maintenance therapy can improve long-term graft function and survival is correct, then patients should experience better graft function for longer. A positive outcome could change clinical practice in kidney transplantation. Trial

  14. [Membranous nephropathy].

    PubMed

    Mercadal, Lucile

    2013-12-01

    Membranous nephropathy is characterized by immune complex deposits on the outer side of the glomerular basement membrane. Activation of complement and of oxidation lead to basement membrane lesions. The most frequent form is idiopathic. At 5 and 10 years, renal survival is around 90 and 65% respectively. A prognostic model based on proteinuria, level and duration, progression of renal failure in a few months can refine prognosis. The urinary excretion of C5b-9, β2 and α1 microglobuline and IgG are strong predictors of outcome. Symptomatic treatment is based on anticoagulation in case of nephrotic syndrome, angiotensin conversion enzyme inhibitors, angiotensin II receptor blockers and statins. Immunosuppressive therapy should be discussed for patients having a high risk of progression. Corticoids alone has no indication. Treatment should include a simultaneous association or more often alternating corticoids and alkylant agent for a minimum of 6 months. Adrenocorticoid stimulating hormone and steroids plus mycophenolate mofetil may be equally effective. Steroids plus alkylant decrease the risk of end stage renal failure. Cyclosporine and tacrolimus decrease proteinuria but are associated with a high risk of recurrence at time of withdrawal and are nephrotoxic. Rituximab evaluated on open studies needs further evaluations to define its use. PMID:24315535

  15. Silica nephropathy.

    PubMed

    Ghahramani, N

    2010-07-01

    Occupational exposure to heavy metals, organic solvents and silica is associated with a variety of renal manifestations. Improved understanding of occupational renal disease provides insight into environmental renal disease, improving knowledge of disease pathogenesis. Silica (SiO2) is an abundant mineral found in sand, rock, and soil. Workers exposed to silica include sandblasters, miners, quarry workers, masons, ceramic workers and glass manufacturers. New cases of silicosis per year have been estimated in the US to be 3600-7300. Exposure to silica has been associated with tubulointerstitial disease, immune-mediated multisystem disease, chronic kidney disease and end-stage renal disease. A rare syndrome of painful, nodular skin lesions has been described in dialysis patients with excessive levels of silicon. Balkan endemic nephropathy is postulated to be due to chronic intoxication with drinking water polluted by silicates released during soil erosion. The mechanism of silica nephrotoxicity is thought to be through direct nephrotoxicity, as well as silica-induced autoimmune diseases such as scleroderma and systemic lupus erythematosus. The renal histopathology varies from focal to crescentic and necrotizing glomerulonephritis with aneurysm formation suggestive of polyarteritis nodosa. The treatment for silica nephrotoxicity is non-specific and depends on the mechanism and stage of the disease. It is quite clear that further research is needed, particularly to elucidate the pathogenesis of silica nephropathy. Considering the importance of diagnosing exposure-related renal disease at early stages, it is imperative to obtain a thorough occupational history in all patients with renal disease, with particular emphasis on exposure to silica, heavy metals, and solvents. PMID:23022796

  16. Topical cyclosporine to control ocular surface disease in patients with chronic glaucoma after long-term usage of topical ocular hypotensive medications

    PubMed Central

    Saini, M; Dhiman, R; Dada, T; Tandon, R; Vanathi, M

    2015-01-01

    Purpose To evaluate changes in ocular surface and central corneal sub-basal nerve fiber layer (SBNFL) after topical cyclosporin therapy in chronic glaucoma patients on long-term topical antiglaucoma therapy. Methods A prospective comparative study of ocular surface evaluation of chronic glaucoma patients on long-term topical therapy treated concurrently with a topical cyclosporine 0.05% twice daily for 6 months and controls was done. The study parameters evaluated at recruitment and at the 6-month follow-up included details of topical antiglaucoma medications, visual acuity, intraocular pressure, ocular surface evaluation parameters (TBUT, Schirmers I, ocular surface staining scores and ocular surface disease (OSD) index score (OSDI)), central corneal sensation (Cochet Bonnett aesthesiometer), and central confocal microscopy to study the SBNFL density (SBNFLD). Results Thirty-two eyes of 16 patients with chronic glaucoma and 30 eyes of 15 normal subjects as controls were studied. Mean TBUT, pre/post CsA treatment was 8.67±3.01/12.24±1.83 s (P=0.007). Mean conjunctival/corneal staining scores pre/post CsA treatment were 3.38±1.93/1.50±0.718 (P=0.00) /5.19±1.82/1.81±0.78 (P=0.098), respectively. Mean OSDI pre/post CsA treatment scores were 30.63±14.61/14.76±6.06 (P=0.007). Mean corneal sensations scores pre/post CsA treatment were 4.64±0.46/4.94±0.39 (P=0.002). Central corneal SBNFLD pre and post CsA treatment was 8811.35±2985.29/10335.13±4092.064 μm/mm2 (P=0.0001). Conclusions Schirmer's test, ocular surface staining scores, OSDI, corneal sensations, and corneal SBNFLD showed a statistically significant improvement following a 6-month concurrent topical CsA therapy. PMID:25857609

  17. Kaliopenic nephropathy revisited.

    PubMed

    Elitok, Saban; Bieringer, Markus; Schneider, Wolfgang; Luft, Friedrich C

    2016-08-01

    In the 'older' literature, a definitive renal pathology was described in patients with long-standing hypokalaemia and depletion of the body's potassium reserves. The topic is relevant because possibly a quite cheaply reversible element in the course of chronic kidney disease progression could be addressed. Earlier, pathologists drew attention to vacuolar changes in renal tubular epithelium accompanied by inflammatory interstitial changes in patients with potassium losses. The diagnostic term 'kaliopenic nephropathy' was coined to describe such patients. Kaliopenic nephropathy now receives less emphasis than in earlier times. However, with eating disorders, laxative abuse and other potential causes, we suggest that the syndrome should be resurrected. PMID:27478593

  18. Influence of cyclosporine A on glomerular growth and the effect of mizoribine and losartan on cyclosporine nephrotoxicity in young rats

    PubMed Central

    Kim, Ji Hong; Lee, Yeon Hee; Lim, Beom Jin; Jeong, Hyeon Joo; Kim, Pyung Kil; Shin, Jae Il

    2016-01-01

    The aim of this study was to evaluate the influence of cyclosporine A (CsA) on glomerular growth and the effect of mizoribine (MZR) and losartan (LSAR) on CsA-induced nephropathy in young rats. Six-week-old male Sprague-Dawley rats maintained on a low salt diet were given CsA (15 mg/kg), CsA and LSRT (30 mg/kg/day), CsA and MZR (5 mg/kg), or a combination of CsA, LSRT, and MZR for 4 and 7 weeks (two experiments) and compared with control group (olive oil-treated). Histopathology and glomerular size, inflammatory and fibrotic factors were studied. The score of acute CsA toxicity significantly decreased in the CsA + MZR group compared to the CsA group (p < 0.01). MZR and MZR + LSRT reduced tubulointerstitial fibrosis and TGF-β1 mRNA expression at 7 weeks. Osteopontin (OPN) mRNA expression was decreased at 7 weeks in MZR + LSRT (p < 0.01). Glomerular area decreased CsA group and recovered in MZR (p < 0.01) and MZR + LSRT (p < 0.01) at 7weeks. This study demonstrated that MZR and LSRT had suppressive effects on inflammatory process in chronic CsA nephropathy and led to improvement of tubular damage, tubulointerstitial fibrosis and arteriolopathy by down regulation of OPN and TGF-β1 and glomerular size contraction. PMID:26947764

  19. Membranous nephropathy

    MedlinePlus

    ... to reduce cholesterol and triglyceride levels (most often statins) may be recommended. A low-salt diet may ... of membranous nephropathy Your symptoms get worse or don't go away You develop new symptoms You have ...

  20. Diabetic nephropathy – complications and treatment

    PubMed Central

    Lim, Andy KH

    2014-01-01

    Diabetic nephropathy is a significant cause of chronic kidney disease and end-stage renal failure globally. Much research has been conducted in both basic science and clinical therapeutics, which has enhanced understanding of the pathophysiology of diabetic nephropathy and expanded the potential therapies available. This review will examine the current concepts of diabetic nephropathy management in the context of some of the basic science and pathophysiology aspects relevant to the approaches taken in novel, investigative treatment strategies. PMID:25342915

  1. Neoral: the new cyclosporine.

    PubMed

    Corbett, J; Ross, K

    1998-02-01

    Neoral is an improved formulation of cyclosporine which, through microemulsion technology, provides a more consistent rate of absorption and exposure. If patients are able to take less Neoral and still maintain the same cyclosporine level, there will also be a cost savings involved. A dose reduction of 30% yields pharmacoeconomic savings. With a more consistent rate of absorption, the risks of nephrotoxicity may be reduced. PMID:9543913

  2. The urine albumin-to-creatinine ratio is a reliable indicator for evaluating complications of chronic kidney disease and progression in IgA nephropathy in China

    PubMed Central

    Huan, Lu; Yuezhong, Luo; Chao, Wang; HaiTao, Tu

    2016-01-01

    OBJECTIVE: This study investigated the correlation between the albumin-to-creatinine ratio in the urine and 24-hour urine proteinuria and whether the ratio can predict chronic kidney disease progression even more reliably than 24-hour proteinuria can, particularly in primary IgA nephropathy. METHODS: A total of 182 patients with primary IgA nephropathy were evaluated. Their mean urine albumin-to-creatinine ratio and 24-hour proteinuria were determined during hospitalization. Blood samples were also analyzed. Follow-up data were recorded for 44 patients. A cross-sectional study was then conducted to test the correlation between these parameters and their associations with chronic kidney disease complications. Subsequently, a canonical correlation analysis was employed to assess the correlation between baseline proteinuria and parameters of the Oxford classification. Finally, a prospective observational study was performed to evaluate the association between proteinuria and clinical outcomes. Our study is registered in the Chinese Clinical Trial Registry, and the registration number is ChiCTR-OCH-14005137. RESULTS: A strong correlation (r=0.81, p<0.001) was found between the ratio and 24-hour proteinuria except in chronic kidney disease stage 5. First-morning urine albumin-to-creatinine ratios of ≥125.15, 154.44 and 760.31 mg/g reliably predicted equivalent 24-hour proteinuria ‘thresholds’ of ≥0.15, 0.3 and 1.0 g/24 h, respectively. In continuous analyses, the albumin-to-creatinine ratio was significantly associated with anemia, acidosis, hypoalbuminemia, hyperphosphatemia, hyperkalemia, hypercholesterolemia and higher serum cystatin C. However, higher 24-hour proteinuria was only associated with hypoalbuminemia and hypercholesterolemia. Higher tubular atrophy and interstitial fibrosis scores were also associated with a greater albumin-to-creatinine ratio, as observed in the canonical correlation analysis. Finally, the albumin-to-creatinine ratio and 24-hour

  3. [Selected work-related nephropathies].

    PubMed

    Wołyniec, Wojciech; Renke, Marcin; Wójcik-Stasiak, Małgorzata; Renke, Joanna

    2015-01-01

    Infections, high temperature and many of the toxic substances can cause kidney damage. Acute kidney injury is a well known complication of some work-related diseases, e.g., lead intoxication. Chronic kidney disease can also be caused by some occupational factors. Three work-related nephropathies, in which causal connection with work has been proved, are discussed in this article. There are different risk factors of nephrolithiasis, lead nephropathy and silica nephropathy, but each of them can cause chronic kidney disease. Prevention of these nephropaties seems to be relatively simple. The principles of protection from the toxic effects of heavy metals and silica dust are very specific. The most important prevention of kidney stones is correct fluid intake. In addition to providing adequate quantities of drinking water, it is also important to educate exposed workers and assure enough rest breaks at work. PMID:26536975

  4. IgA nephropathy and psoriatic arthritis that improved with steroid pulse therapy and mizoribine in combination with treatment for chronic tonsillitis and epipharyngitis.

    PubMed

    Kaneko, Tomohiro; Mii, Akiko; Fukui, Megumi; Nagahama, Kiyotaka; Shimizu, Akira; Tsuruoka, Shuichi

    2015-01-01

    A 65-year-old man was admitted to our hospital with edema and renal dysfunction. He had received a diagnosis of psoriatic arthritis at 50 years of age. As a renal biopsy showed IgA nephropathy (IgAN), bilateral tonsillectomy was performed, and one course of steroid pulse therapy with an oral steroid and mizoribine were subsequently administered. The patient's proteinuria gradually reduced in association with an improvement in the renal function. In addition, the rash and arthralgia were ameliorated. In this case, adding treatment for chronic epipharyngitis accelerated the curative effects, and focal infection therapy consisting of immunosuppressive drugs was effective for both IgAN and psoriatic arthritis. PMID:25948353

  5. Thrombocytopenia and Anemia with Anti-c-Mpl antibodies Effectively Treated with Cyclosporine in a Patient with Rheumatoid Arthritis and Chronic Renal Failure.

    PubMed

    Hashimoto, Akari; Kanisawa, Yuji; Fujimi, Akihito; Nakajima, Chisa; Hayasaka, Naotaka; Yamada, Shota; Okuda, Toshinori; Minami, Shinya; Yamauchi, Natsumi; Iwasaki, Sari; Suzuki, Akira; Kato, Junji

    2016-01-01

    A 61-year-old woman with rheumatoid arthritis who was undergoing hemodialysis for end-stage renal failure was transferred to our hospital due to severe thrombocytopenia and anemia. A bone marrow biopsy showed the complete absence of megakaryocytes and erythroblasts. Cyclosporine treatment resulted in the improvement of her megakaryocyte and erythroblast levels, and a decrease in her serum level of anti-c-Mpl (thrombopoietin receptor) antibodies. After this initial improvement, her anemia progressively worsened, despite the continuous administration of immunosuppressive therapy with cyclosporine. Her platelet and leukocyte counts remained stable. This is the first report of a probable case of anti-c-Mpl antibody-associated pure red cell aplasia and acquired amegakaryocytic thrombocytopenic purpura. PMID:26984091

  6. Cyclosporine and tacrolimus.

    PubMed

    Vaden, S L

    1997-08-01

    Cyclosporine and tacrolimus are potent immunosuppressant agents that have been used extensively in humans, primarily for prevention of transplant rejection but also for the treatment of autoimmune disorders. Both agents have similar mechanisms of action and pharmacokinetic profiles. However, the expected toxicity of the agents is dissimilar. Although cyclosporine usage in veterinary medicine is limited, it has been used enough for therapeutic guidelines to be established. Tacrolimus, however, has undergone limited use in veterinary medicine. The drug is too toxic in dogs for its use to be recommended in most clinical situations. This article reviews the mechanism of action, pharmacokinetics, expected drug interactions and toxicities, and clinical usage of cyclosporine and tacrolimus in veterinary medicine. PMID:9283240

  7. Kaliopenic nephropathy revisited

    PubMed Central

    Elitok, Saban; Bieringer, Markus; Schneider, Wolfgang; Luft, Friedrich C.

    2016-01-01

    In the ‘older’ literature, a definitive renal pathology was described in patients with long-standing hypokalaemia and depletion of the body's potassium reserves. The topic is relevant because possibly a quite cheaply reversible element in the course of chronic kidney disease progression could be addressed. Earlier, pathologists drew attention to vacuolar changes in renal tubular epithelium accompanied by inflammatory interstitial changes in patients with potassium losses. The diagnostic term ‘kaliopenic nephropathy’ was coined to describe such patients. Kaliopenic nephropathy now receives less emphasis than in earlier times. However, with eating disorders, laxative abuse and other potential causes, we suggest that the syndrome should be resurrected. PMID:27478593

  8. [Cyclosporin A--dermatologic indications].

    PubMed

    Mahrle, G; Schulze, H J

    1990-01-01

    The pharmacology, the biological action, as well as the clinical indications for systemic or topical application of cyclosporin A (CSA) is reviewed. Our studies yielded the following results: In chronic stationary psoriasis, systemic treatment with CSA in very low doses (2.5 mg/kg/d, 13 patients, 10 weeks) led to a 75% reduction of the PASI score without any side reactions. After topical application of CSA (40 patients, 1/5/10% gel and ointment), we observed a subclinical effect. CSA permeated into the deeper layers of the skin and accumulated up to a concentration of 3.880 ng/g (80-39.000 ng/g, polyclonal RIA); these quantities correspond with those found after systemic administration. In spite of this, CSA was not measurable in the blood. Topical CSA reduced the neutrophils in psoriatic skin both selectively and significantly, but did not affect the epidermal synthesis of DNA. PMID:2183505

  9. Non-Proteinuric Diabetic Nephropathy

    PubMed Central

    Robles, Nicolas Roberto; Villa, Juan; Hernandez Gallego, Roman

    2015-01-01

    Diabetic nephropathy patients traditionally show significant macroalbuminuria prior to the development of renal impairment. However, this clinical paradigm has recently been questioned. Epidemiological surveys confirm that chronic kidney disease (CKD) diagnosed by a low glomerular filtration rate (GFR) is more common in diabetic patients than in the non-diabetic population but a low number of patients had levels of proteinuria above that which traditionally defines overt diabetic nephropathy (>500 mg/g). The large number of patients with low levels of proteinuria suggests that the traditional clinical paradigm of overt diabetic nephropathy is changing since it does not seem to be the underlying renal lesion in most of diabetic subjects with CKD. PMID:26371050

  10. Association between the presence of anti-HLA antibodies with acute rejection and chronic allograft nephropathy in the first year after kidney transplantation.

    PubMed

    Toresan, R; Manfro, R C; Proença, M C C; Veronese, F J V; Salim, P H; da Silva, D M; Ribeiro, A R; Edelweiss, M I A; Pegas, K L; Jobim, L F J

    2008-04-01

    The clinical relevance of anti-HLA antibodies following kidney transplantation has been a recent focus of research. Patients who present anti-HLA antibodies in the posttransplantation period have shown higher incidences of acute rejection episodes (ARE) and chronic allograft nephropathy (CAN). The objective of this study was to evaluate the presence of anti-HLA antibodies during the first year after kidney transplantation and their association with the occurrence of ARE and CAN. Eighty-eight kidney transplant recipients were evaluated for the presence of IgG anti-HLA antibodies using an enzyme-linked immunosorbent assay (LAT-M and LAT-1240, One Lambda Inc, Calif, United States). Protocol kidney biopsies were performed in consenting patients. ARE and CAN were diagnosed by clinical, laboratory, and histopathological criteria. Anti-HLA antibodies were observed in 20 (22.7%) patients. At 1 year follow-up, 26.1% presented ARE and 51.2% developed CAN. Nine patients (45%) with antibodies developed ARE as opposed to 20.6% without antibodies and 64.7% developed CAN as opposed to 47.8% of those without antibodies. In the histological analysis, the anti-HLA antibodies were associated with Banff IIA ARE (P = .001) and Banff grade II CAN (P = .012). Routine posttransplantation search for antibodies may identify cases at higher risk for acute and chronic rejection, and perhaps help to tailor the immunosuppressive regimen. PMID:18454996

  11. Chronic Running Exercise Alleviates Early Progression of Nephropathy with Upregulation of Nitric Oxide Synthases and Suppression of Glycation in Zucker Diabetic Rats

    PubMed Central

    Ito, Daisuke; Cao, Pengyu; Kakihana, Takaaki; Sato, Emiko; Suda, Chihiro; Muroya, Yoshikazu; Ogawa, Yoshiko; Hu, Gaizun; Ishii, Tadashi; Ito, Osamu; Kohzuki, Masahiro; Kiyomoto, Hideyasu

    2015-01-01

    Exercise training is known to exert multiple beneficial effects including renal protection in type 2 diabetes mellitus and obesity. However, the mechanisms regulating these actions remain unclear. The present study evaluated the effects of chronic running exercise on the early stage of diabetic nephropathy, focusing on nitric oxide synthase (NOS), oxidative stress and glycation in the kidneys of Zucker diabetic fatty (ZDF) rats. Male ZDF rats (6 weeks old) underwent forced treadmill exercise for 8 weeks (Ex-ZDF). Sedentary ZDF (Sed-ZDF) and Zucker lean (Sed-ZL) rats served as controls. Exercise attenuated hyperglycemia (plasma glucose; 242 ± 43 mg/dL in Sed-ZDF and 115 ± 5 mg/dL in Ex-ZDF) with increased insulin secretion (plasma insulin; 2.3 ± 0.7 and 5.3 ± 0.9 ng/mL), reduced albumin excretion (urine albumin; 492 ± 70 and 176 ± 11 mg/g creatinine) and normalized creatinine clearance (9.7 ± 1.4 and 4.5 ± 0.8 mL/min per body weight) in ZDF rats. Endothelial (e) and neuronal (n) NOS expression in kidneys of Sed-ZDF rats were lower compared with Sed-ZL rats (p<0.01), while both eNOS and nNOS expression were upregulated by exercise (p<0.01). Furthermore, exercise decreased NADPH oxidase activity, p47phox expression (p<0.01) and α-oxoaldehydes (the precursors for advanced glycation end products) (p<0.01) in the kidneys of ZDF rats. Additionally, morphometric evidence indicated renal damage was reduced in response to exercise. These data suggest that upregulation of NOS expression, suppression of NADPH oxidase and α-oxoaldehydes in the kidneys may, at least in part, contribute to the renal protective effects of exercise in the early progression of diabetic nephropathy in ZDF rats. Moreover, this study supports the theory that chronic aerobic exercise could be recommended as an effective non-pharmacological therapy for renoprotection in the early stages of type 2 diabetes mellitus and obesity. PMID:26379244

  12. Use of Contrast-Enhanced Ultrasonography to Evaluate Chronic Allograft Nephropathy in Rats and Correlations between Time-Intensity Curve Parameters and Allograft Fibrosis.

    PubMed

    Zhang, Qiang; Yu, Zexing; Xu, Yue; Zeng, Song; Zhang, Zijian; Xue, Wenrui; Wang, Wei; Zhang, Xiaodong; Hu, Xiaopeng

    2016-07-01

    This study quantitatively analyzed changes in the hemodynamic characteristics of renal allografts at different stages in a rat chronic allograft nephropathy (CAN) model as well as the relationship between hemodynamic parameters and renal allograft fibrosis using contrast-enhanced ultrasonography (CEUS). The experimental group used a CAN rat model (n = 30), and the control group used an orthotopic syngeneic renal transplant model (n = 30). After surgery, creatinine clearance rates were regularly monitored every 2 wk. The checking times were set at 4, 12 and 24 wk after surgery, which represent early, middle and late stage of CAN, respectively. At different stages of CAN, eight rats from each group were randomly selected for CEUS examination. Time-intensity curve (TIC) parameters, including rise time, peak intensity, mean transit time, area under the curve, wash-in slope, time-to-peak and α-smooth muscle actin (α-SMA) expression; Vimentin expression; and chronic allograft damage index scores were evaluated by linear correlation analysis. Before the creatinine clearance rate showed significant abnormalities, the renal allografts in the experimental group had already presented pathologic changes associated with CAN. In the early stage after surgery, compared to the TIC curve of the control group, the experimental group showed increased rise time, mean transit time, area under the curve and time-to-peak, and decreased wash-in slope (p < 0.05). Chronic allograft damage index scores and the expression levels of α-SMA and Vimentin proteins in renal allografts were correlated with TIC parameters (p < 0.05). Compared to creatinine clearance rate, CEUS can detect CAN at earlier stages. The correlations between TIC-related parameters and the expression levels of α-SMA and Vimentin in renal allografts indicate that CEUS is a feasible way to assess the degree of renal allograft fibrosis quantitatively. PMID:27056611

  13. Retinoids, methotrexate and cyclosporine.

    PubMed

    Dubertret, Louis

    2009-01-01

    Acitretin alone is efficient (PASI 90: 40%). In responders, it is the best long-term maintenance treatment (up to 29 years of continuous treatment). The main side effect is its teratogenicity in females. It is necessary to begin retinoid treatment at low doses (10 mg/day), increasing the dose step by step, looking for the maximum well-tolerated dose (usually defined as a mild cheilitis). Doses higher than the highest well-tolerated dose are frequently responsible for the Kobner phenomenon. In children, retinoids are very efficient and nearly always well tolerated, but it seems important to never give more than 0.5 mg/kg/day. Methotrexate is the best treatment for severe psoriasis. Given at low doses once a week, it is a safe, cheap, convenient and efficient treatment, if carefully monitored. The main problem is the possible long-term liver toxicity of methotrexate. The risk is very low in patients not at risk (no liver disease). In these cases, liver biopsies are dangerous and useless. In the other cases, the need for liver biopsy is very rare, decided only by the hepatologist, and should be replaced by FibroTest and FibroScan. The old American guidelines should not be followed, and new guidelines are needed. Cyclosporine at low doses is an outstanding emergency treatment. It was first used as the last possible systemic treatment, but long-term continuous treatments are seldom possible due to alterations in kidney functions. A careful follow-up of kidney functions, with measurement of the glomerular filtration rate after each year of cumulative treatment, is necessary. The cyclosporine dose must be calculated according to the theoretical body weight in obese patients to avoid overdosage. Cyclosporine is mainly used now as a short-term treatment that is very efficient for young people, who find this illness particularly difficult. Cyclosporine is not contraindicated during pregnancy. PMID:19710551

  14. Reflux nephropathy

    MedlinePlus

    ... and there may be signs and symptoms of chronic kidney disease. Blood and urine tests will be done, and ... infections. If needed, people will be treated for chronic kidney disease. Outlook (Prognosis) Outcome varies, depending on the severity ...

  15. Percutaneous coronary intervention for chronic total occlusion improved prognosis in patients with renal insufficiency at high risk of contrast-induced nephropathy

    PubMed Central

    Liu, Yong; Liu, Yuanhui; Li, Hualong; Zhou, Yingling; Guo, Wei; Duan, Chongyang; Chen, Shiqun; Chen, Pingyan; Tan, Ning; Chen, Jiyan

    2016-01-01

    We investigated whether attempted percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) would improve the prognosis in patients with renal insufficiency at high risk of contrast-induced nephropathy (CIN). We analyzed 2,330 consecutive patients with renal insufficiency with or without CTOs who underwent coronary angiography or PCI from prospectively collected data. The long-term death and risk of CIN were evaluated among three groups: patients without CTOs (group A, n = 1,829), patients with un-attempted PCI for CTOs (group B, n = 142), and patients who underwent attempted PCI for CTOs (group C, n = 359). Overall, group B and group C (successful rate, 89%) patients had similar renal function and were not significantly associated with an increased risk of CIN (adjusted odds ratio [OR] = 0.88, 95% confidence interval [CI]: 0.41–1.93, P = 0.758). During a 2.33-year period (median), multivariate analysis demonstrated that attempted PCI for CTOs was independently associated with lower mortality (adjusted hazard ratio for death: 0.38, 95% CI: 0.18–0.83; P = 0.015). Attempted PCI for CTOs improved the long-term prognosis in patients with high-risk renal insufficiency and did not increase the risk of CIN. PMID:26899017

  16. Juvenile nephropathy in two related Pembroke Welsh corgi puppies.

    PubMed

    McKay, L W; Seguin, M A; Ritchey, J W; Levy, J K

    2004-11-01

    Juvenile nephropathy has been documented in many breeds. Two related Pembroke Welsh corgi puppies presented at three and five months of age, respectively, for evaluation of lethargy, diarrhoea, poor body condition, polyuria and proteinuria. Based upon the clinical presentation, urinalysis and serum biochemistry, chronic renal failure was diagnosed. Renal histopathology was consistent with juvenile nephropathy, revealing lesions similar to the juvenile renal disease of dobermann dogs. To the authors' knowledge, this is the first report of juvenile nephropathy in related Pembroke Welsh corgi dogs. Familial nephropathy should now be considered as a differential diagnosis in cases of young Pembroke Welsh corgi dogs presenting with clinical signs indicating renal failure. PMID:15553196

  17. Karyomegalic interstitial nephropathy following ifosfamide therapy

    PubMed Central

    Jayasurya, R.; Srinivas, B. H.; Ponraj, M.; Haridasan, S.; Parameswaran, S.; Priyamvada, P. S.

    2016-01-01

    Ifosfamide (IFO), an alkylating agent used for the management of solid organ tumors, can cause reversible Fanconi's syndrome and acute kidney injury. Karyomegalic interstitial nephropathy (KIN) is a rare form of chronic tubulointerstitial nephritis, initially described as a familial nephropathy in adults. So far, four cases of KIN have been reported in pediatric and adolescent population following treatment with IFO. We report a 22-year-old man who developed renal dysfunction following IFO therapy for relapsed Hodgkin's lymphoma. Renal biopsy revealed chronic tubulointerstitial nephritis with atypical tubular epithelial cells showing nuclear enlargement and hyperchromasia, consistent with a diagnosis of KIN. The renal function improved following a short course of corticosteroids. PMID:27512305

  18. Crystalglobulin-Induced Nephropathy

    PubMed Central

    Gupta, Vinay; El Ters, Mireille; Kashani, Kianoush; Leung, Nelson

    2015-01-01

    Crystalline nephropathy refers to renal parenchymal deposition of crystals leading to kidney damage. The most common forms of crystalline nephropathy encountered in renal pathology are nephrocalcinosis and oxalate nephropathy. Less frequent types include urate nephropathy, cystinosis, dihydroxyadeninuria, and drug-induced crystalline nephropathy (e.g., caused by indinavir or triamterene). Monoclonal proteins can also deposit in the kidney as crystals and cause tissue damage. This occurs in conditions such as light chain proximal tubulopathy, crystal-storing histiocytosis, and crystalglobulinemia. The latter is a rare complication of multiple myeloma that results from crystallization of monoclonal proteins in the systemic vasculature, leading to vascular injury, thrombosis, and occlusion. In this report, we describe a case of crystalglobulin-induced nephropathy and discuss its pathophysiology and the differential diagnosis of paraprotein-induced crystalline nephropathy. PMID:25190731

  19. [A case of nephrotic syndrome achieving remission with cyclosporine monotherapy].

    PubMed

    Nagatoya, Katsuyuki

    2010-01-01

    The case was a female in her early 80's. Due to abdominal bloating and lower limb edema, she visited a nearby doctor, was diagnosed to have nephrotic syndrome, and then was referred to our department. Upon initial consultation, TP of 4.1 g/dl, Alb of 1.7 g/dl, UN of 73 mg/dl, and Cr of 1.43 mg/dl, along with pleural effusion were observed by chest X-ray. A renal biopsy was not performed because permission could not be obtained. Despite the fact that management of the edema was performed using diuretic agents and albumin preparations, a reduced renal function and deterioration of the fluid retention were gradually observed. She originally displayed lower back pain and digestive symptoms and, therefore, cyclosporine monotherapy was initiated in order to address concerns of side effects such as osteoporosis and peptic ulcer due to adrenocortical steroid drugs (hereinafter abbreviated as steroid). Subsequently, hemodialysis was temporarily required but reduced urine protein and an improved renal function were gradually observed and she eventually achieved a complete remission. The possibility of a spontaneous remission of membranous nephropathy, etc. was considered, but a relapse occurred when the amount of cyclosporine was reduced. Thereafter, a complete remission was obtained with an increased dosage. As a result, the effectiveness of cyclosporine was thus confirmed. In treating nephrotic syndrome, steroid therapy is commonly performed and it is common for cyclosporine to be limited to steroid-resistant cases and/or steroid-dependent cases. However, it is believed that monotherapy could also be an option in cases in which the use of steroids is difficult, such as in cases of elderly patients. PMID:21116092

  20. Clinical and pathological aspects of analgesic nephropathy

    PubMed Central

    Nanra, R. S.

    1980-01-01

    1 Analgesic nephropathy is part of the analgesic syndrome which has gastrointestinal, haematological, cardiovascular, psychological and psychiatric, and pregnancy and gonadal manifestations; premature ageing may also be a feature. 2 Analgesic nephropathy is a form of renal disease characterized by renal papillary necrosis, secondary chronic interstitial nephritis and renal failure with features of predominant tubulointerstitial dysfunction. 3 The percentage of patients with analgesic nephropathy who present with terminal renal failure is 12%. With appropriate management, 17% of analgesic nephropathy patients improve, 50% remain stable and 23% deteriorate. The 6 year cumulative survival is 70%. The major factors influencing deterioration are malignant hypertension, persistent proteinuria and small initial renal size. 4 The risk of renal papillary carcinoma in patients who regularly take analgesics is 8 per 100,000 patients per year. 5 Renal papillary necrosis is a consequence of the chronic toxicity of all non-steroidal anti-inflammatory drugs and results from medullary ischaemia secondary to suppression of prostaglandin E2 synthesis and from direct cellular toxicity. 6 Analgesic nephropathy is a preventable form of renal disease and renal failure. It can be prevented by limiting the abuse potential of analgesics rather than by making minor modifications in the composition of analgesic mixtures. ImagesFigure 1Figure 3Figure 4 PMID:7002190

  1. Long-Term and Interactive Effects of Pay-For-Performance Interventions among Diabetic Nephropathy Patients at the Early Chronic Kidney Disease Stage.

    PubMed

    Liao, Pei-Ju; Lin, Tzu-Yu; Wang, Tzu-Ching; Ting, Ming-Kuo; Wu, I-Wen; Huang, Hsin-Tsung; Wang, Fu-Chung; Chang, Huan-Cheng; Hsu, Kuang-Hung

    2016-04-01

    Chronic kidney disease (CKD) is a major health problem worldwide because of the aging population and lifestyle changes. One of the important etiologies of CKD is diabetes mellitus (DM). The long-term effects of pay-for-performance (P4P) on disease progression have not been thoroughly examined.This study is a retrospective population-based patient cohort design to examine the continuous effects of diabetes and CKD P4P interventions. This study used the health insurance claims database to conduct a longitudinal analysis. A total of 32,084 early CKD patients with diabetes were extracted from the outpatient claims database from January 2011 to December 2012, and the follow-up period was extended to August 2014. A 4-group matching design, including both diabetes and early CKD P4P interventions, with only diabetes P4P intervention, with only early CKD P4P intervention, and without any P4P interventions, was performed according to their descending intensity. The primary outcome of this study was all-cause mortality and the causes of death. The statistical methods included a Chi-squared test, ANOVA, and multi-variable Cox regression models.A dose-response relationship between the intervention groups and all-cause mortality was observed as follows: comparing to both diabetes and early CKD P4P interventions (reference), hazard ratio (HR) was 1.22 (95% confidence interval [CI], 1.00-1.50) for patients with only a diabetes P4P intervention; HR was 2.00 (95% CI, 1.66-2.42) for patients with only an early CKD P4P intervention; and HR was 2.42 (95% CI, 2.02-2.91) for patients without any P4P interventions. The leading cause of death of the total diabetic nephropathy patient cohort was infectious diseases (34.32%) followed by cardiovascular diseases (17.12%), acute renal failure (1.50%), and malignant neoplasm of liver (1.40%).Because the earlier interventions have lasting long-term effects on the patient's prognosis regardless of disease course, an integrated early intervention

  2. Beneficial effects of nilotinib, tyrosine kinase inhibitor on cyclosporine-A induced renal damage in rats.

    PubMed

    Nader, Manar A; Attia, Ghalia M

    2016-04-01

    Nilotinib is a known tyrosine kinase inhibitor that has been approved for treatment of leukemia. The possible protective effect of nilotinib on cyclosporine A-induced nephropathy was investigated in this study and the possible underlying mechanism was explored. Nilotinib (25mg/kg, orally) and cyclosporine A (15 mg/kg/day, subcutaneous) were given to male SD rats for 28 days. Cyclosporine A alone was found to significantly increase serum creatinine, blood urea nitrogen, lactate dehydrogenase, urinary micrototal protein, renal thiobarbituric acid reactive substance, Bax, cytosol cytochrome c release and nuclear factor kappa B activation. Moreover, cyclosporine A significantly reduced serum albumin, creatinine clearance, urinary total antioxidant, superoxide dismutase, glutathione and Bcl2 protein levels. Pathological results showed that in the model group; there was an obvious shrinkage and congestion of the glomeruli and widening of urinary spaces of renal corpuscles, in addition to marked renal tubular injury and fibrosis, while in the group pretreated with nilotinib all measured serum, renal and pathological changes were significantly reduced. This protective effect of nilotinib is linked to the enhanced antioxidant status and reduced inflammation and apoptosis induced by cyclosporine A. PMID:26844915

  3. Renal function in diabetic nephropathy.

    PubMed

    Dabla, Pradeep Kumar

    2010-05-15

    Diabetic nephropathy is the kidney disease that occurs as a result of diabetes. Cardiovascular and renal complications share common risk factors such as blood pressure, blood lipids, and glycemic control. Thus, chronic kidney disease may predict cardiovascular disease in the general population. The impact of diabetes on renal impairment changes with increasing age. Serum markers of glomerular filtration rate and microalbuminuria identify renal impairment in different segments of the diabetic population, indicating that serum markers as well as microalbuminuria tests should be used in screening for nephropathy in diabetic older people. The American Diabetes Association and the National Institutes of Health recommend Estimated glomerular filtration rate (eGFR) calculated from serum creatinine at least once a year in all people with diabetes for detection of kidney dysfunction. eGFR remains an independent and significant predictor after adjustment for conventional risk factors including age, sex, duration of diabetes, smoking, obesity, blood pressure, and glycemic and lipid control, as well as presence of diabetic retinopathy. Cystatin-C (Cys C) may in future be the preferred marker of diabetic nephropathy due differences in measurements of serum creatinine by various methods. The appropriate reference limit for Cys C in geriatric clinical practice must be defined by further research. Various studies have shown the importance of measurement of albuminuria, eGFR, serum creatinine and hemoglobin level to further enhance the prediction of end stage renal disease. PMID:21537427

  4. Gene 33/Mig-6, a transcriptionally inducible adapter protein that binds GTP-Cdc42 and activates SAPK/JNK. A potential marker transcript for chronic pathologic conditions, such as diabetic nephropathy. Possible role in the response to persistent stress.

    PubMed

    Makkinje, A; Quinn, D A; Chen, A; Cadilla, C L; Force, T; Bonventre, J V; Kyriakis, J M

    2000-06-01

    Chronic stresses, including the mechanical strain caused by hypertension or excess pulmonary ventilation pressure, lead to important clinical consequences, including hypertrophy and acute respiratory distress syndrome. Pathologic hypertrophy contributes to decreased organ function and, ultimately, organ failure; and cardiac and diabetic renal hypertrophy are major causes of morbidity and morality in the developed world. Likewise, acute respiratory distress syndrome is a serious potential side effect of mechanical pulmonary ventilation. Whereas the deleterious effects of chronic stress are well established, the molecular mechanisms by which these stresses affect cell function are still poorly characterized. gene 33 (also called mitogen-inducible gene-6, mig-6) is an immediate early gene that is transcriptionally induced by a divergent array of extracellular stimuli. The physiologic function of Gene 33 is unknown. Here we show that gene 33 mRNA levels increase sharply in response to a set of commonly occurring chronic stress stimuli: mechanical strain, vasoactive peptides, and diabetic nephropathy. Induction of gene 33 requires the stress-activated protein kinases (SAPKs)/c-Jun NH(2)-terminal kinases. This expression pattern suggests that gene 33 is a potential marker for diabetic nephropathy and other pathologic responses to persistent sublethal stress. The structure of Gene 33 indicates an adapter protein capable of binding monomeric GTPases of the Rho subfamily. Consistent with this, Gene 33 interacts in vivo and, in a GTP-dependent manner, in vitro with Cdc42Hs; and transient expression of Gene 33 results in the selective activation of the SAPKs. These results imply a reciprocal, positive feedback relationship between Gene 33 expression and SAPK activation. Expression of Gene 33 at sufficient levels may enable a compensatory reprogramming of cellular function in response to chronic stress, which may have pathophysiological consequences. PMID:10749885

  5. The role of peroxisome-proliferator-activating receptor gamma agonists: rosiglitazone and 15-deoxy-delta12,14-prostaglandin J2 in chronic experimental cyclosporine A-induced nephrotoxicity.

    PubMed

    Korolczuk, A; Maciejewski, M; Smolen, A; Dudka, J; Czechowska, G; Widelska, I

    2014-12-01

    Cyclosporine A(CsA) is an immunosuppressor frequently used in the transplant surgery and in the treatment of autoimmune diseases. The therapeutic benefits of CsA are often limited by it's main side effect-nephrotoxicity. Mechanisms of chronic CsA- induced renal damage include: activation of renin-angiotensin-aldosterone system, upregulation of transforming growth factor beta (TGF-β), oxidative stress. This study was undertaken to investigate the protective effect of the peroxisome-proliferator-activated receptors gamma (PPARs-γ) agonists: rosiglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (PGDJ2), against CsA-induced kidney injury in male Wistar rats. CsA was administered subcutaneously at a dose of 15 mg/kg/day for 28 days. Both PPAR-γ agonists were given for 28 days 0.5 hour before the administration of CsA. Rosiglitazone was administered orally at a dose of 8 mg/kg/day and PGDJ2 was given intraperitoneally at a dose of 30 μg/kg/day. CsA induced renal failure was evidenced by increased serum levels of urea, uric acid and creatinine. Serum concentrations of GSH and GSSG, lipid peroxidation products as well as NAD+/NADH, NADP+/NADPH and ADP/ATP ratios showed, that CsA induced oxidative stress and evoked an imbalanced red-ox state in the kidney. Light and electron microscope studies showed degenerative changes within renal tubules with damage to their mitochondria, interstitial fibrosis and arteriolopathy. Immunohistochemical expression of profibrotic TGF-β was assessed. The biochemical and morphological changes induced by CsA were limited by administration of both rosiglitazone and PGDJ2. Ultrastructural examination of renal tubular epithelial cells showed marked improvement within mitochondria. Our results indicate that both PPAR-γ agonists used in the experiment may play an important role in protecting against CsA-induced damage in the kidney. PMID:25554991

  6. IgA nephropathy and infections.

    PubMed

    Rollino, Cristiana; Vischini, Gisella; Coppo, Rosanna

    2016-08-01

    In this paper we concentrate on the role of infections in IgA nephropathy both from a pathogenetic and clinic point of view. The current hypotheses as regards the role of infections in the pathogenesis of IgA nephropathy are: (a) role of particular pathogens, (b) chronic exposure to mucosal infections, (c) abnormal handling of commensal microbes (gut microbiota). We also focus on particular infections reported in association with classic IgA nephropathy (HIV, malaria, Chlamydia, Lyme disease), as well as on IgA dominant-infection-associated glomerulonephritis. This is a unique form of glomerulonephritis, where IgA deposition is dominant. It is mostly recognized in old, diabetic patients and in association with staphylococcal infection. PMID:26800970

  7. IgA Nephropathy

    MedlinePlus

    ... Kidney Disease and Kidney Failure . [ Top ] How is kidney disease diagnosed? A health care provider diagnoses kidney disease ... levels Control Blood Pressure and Slow Progression of Kidney Disease People with IgA nephropathy that is causing high ...

  8. IgA nephropathy

    MedlinePlus

    ... family history of IgA nephropathy or Henoch Schonlein purpura , a form of vasculitis that affects many parts ... End-stage kidney disease Hypersensitivity vasculitis Nephrotic syndrome Purpura Urine - bloody Update Date 9/22/2015 Updated ...

  9. Triamterene crystalline nephropathy.

    PubMed

    Nasr, Samih H; Milliner, Dawn S; Wooldridge, Thomas D; Sethi, Sanjeev

    2014-01-01

    Medications can cause a tubulointerstitial insult leading to acute kidney injury through multiple mechanisms. Acute tubular injury, a dose-dependent process, occurs due to direct toxicity on tubular cells. Acute interstitial nephritis characterized by interstitial inflammation and tubulitis develops from drugs that incite an allergic reaction. Other less common mechanisms include osmotic nephrosis and crystalline nephropathy. The latter complication is rare but has been associated with several drugs, such as sulfadiazine, indinavir, methotrexate, and ciprofloxacin. Triamterene crystalline nephropathy has been reported only rarely, and its histologic characteristics are not well characterized. We report 2 cases of triamterene crystalline nephropathy, one of which initially was misdiagnosed as 2,8-dihydroxyadenine crystalline nephropathy. PMID:23958399

  10. Lipid mediators in diabetic nephropathy

    PubMed Central

    2014-01-01

    The implications of lipid lowering drugs in the treatment of diabetic nephropathy have been considered. At the same time, the clinical efficacy of lipid lowering drugs has resulted in improvement in the cardiovascular functions of chronic kidney disease (CKD) patients with or without diabetes, but no remarkable improvement has been observed in the kidney outcome. Earlier lipid mediators have been shown to cause accumulative effects in diabetic nephropathy (DN). Here, we attempt to analyze the involvement of lipid mediators in DN. The hyperglycemia-induced overproduction of diacyglycerol (DAG) is one of the causes for the activation of protein kinase C (PKCs), which is responsible for the activation of pathways, including the production of VEGF, TGFβ1, PAI-1, NADPH oxidases, and NFҟB signaling, accelerating the development of DN. Additionally, current studies on the role of ceramide are one of the major fields of study in DN. Researchers have reported excessive ceramide formation in the pathobiological conditions of DN. There is less report on the effect of lipid lowering drugs on the reduction of PKC activation and ceramide synthesis. Regulating PKC activation and ceramide biosynthesis could be a protective measure in the therapeutic potential of DN. Lipid lowering drugs also upregulate anti-fibrotic microRNAs, which could hint at the effects of lipid lowering drugs in DN. PMID:25206927

  11. Post-Transplant Membranous Nephropathy Associated with Chronic Active Antibody-Mediated Rejection and Hepatitis C Infection after Deceased Donor Renal Transplantation.

    PubMed

    Doke, Tomohito; Sato, Waichi; Takahashi, Kazuo; Hayashi, Hiroki; Koide, Sigehisa; Sasaki, Hitomi; Kusaka, Mamoru; Shiroki, Ryoichi; Hoshinaga, Kiyotaka; Takeda, Asami; Yuzawa, Yukio; Hasegawa, Midori

    2016-01-01

    A 53-year-old woman who had undergone deceased donor kidney transplantation twice, at 35 and 43 years of age, presented with renal impairment. She was infected with hepatitis C virus (HCV). The histology of the graft kidney revealed post-transplant membranous nephropathy (MN) with podocytic infolding and antibody-mediated rejection (AMR). IgG subclass staining showed fine granular deposits of IgG1 and IgG3, but not IgG4, in the glomerular capillary walls. Panel reactive antibody scores for human leukocyte antigen class I and class II were 92.67% and 66.68%, respectively. Thus, this case of post-transplanted MN was considered to be associated with AMR and HCV infection. PMID:26875963

  12. Cyclosporine A-Induced Renal Fibrosis

    PubMed Central

    Slattery, Craig; Campbell, Eric; McMorrow, Tara; Ryan, Michael P.

    2005-01-01

    Cyclosporine A, which has been the foremost immunosuppressive agent since the early 1980’s, significantly improves the success of organ transplantation. However, common complications of cyclosporine A therapy, such as severe renal tubulointerstitial fibrosis, limit the drug’s clinical use. Although the exact mechanisms driving cyclosporine A-induced tubulointerstitial fibrosis remain elusive, we hypothesized that epithelial-mesenchymal transition (EMT) may play a major role. We investigated this in vitro by treating human proximal tubular cells with cyclosporine A. Morphological changes were observed after cyclosporine A treatment, including cell elongation (with a large degree of detachment), cytoskeletal rearrangement, and junctional disruption. In addition, expression of the myofibroblast-specific marker α-smooth muscle actin was detected in treated cells. These observations are consistent with events described during EMT. Using Affymetrix gene microarrays, we identified 128 genes that were differentially regulated in renal tubular cells after cyclosporine A treatment, including known profibrotic factors, oncogenes, and transcriptional regulators. Cyclosporine A induced a dose-dependent increase in transforming growth factor-β secretion from proximal tubular cells. Subsequent functional studies revealed that protein kinase C-β isoforms play a key role in cyclosporine A-induced effects. These findings provide novel insights into cyclosporine A-induced renal fibrosis and the molecular mechanisms underlying EMT, events that may be relevant in other disease states. PMID:16049326

  13. [Diabetic nephropathy: emerging treatments].

    PubMed

    Gueutin, Victor; Gauthier, Marion; Cazenave, Maud; Izzedine, Hassane

    2014-07-01

    Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been management of hyperglycaemia, blood pressure and proteinuria using hypoglycemic agents, ACE inhibitors, and angiotensin receptor blockers. Since 2000, new therapeutic strategies began to emerge targeting the biochemical activity of glucose molecules on the renal tissue. Various substances have been studied with varying degrees of success, ranging from vitamin B to camel's milk. Silymarin reduces urinary excretion of albumin, tumor necrosis factor (TNF)-α, and malondialdehyde in patients with diabetic nephropathy and may be considered as a novel addition to the anti-diabetic nephropathy armamentarium. Although some results are promising, studies on a larger scale are needed to validate the utility of these molecules in the treatment of the DN. PMID:24938412

  14. MYH9 nephropathy

    PubMed Central

    Oh, Taehoon; Jung Seo, Hyun; Taek Lee, Kyu; Jo Kim, Han; Jun Kim, Hwi; Lee, Ji-Hye; Il Cheong, Hae; Young Lee, Eun

    2014-01-01

    MYH9-related disorder is an autosomal dominant disease caused by a mutation in the MYH9 gene, which encodes nonmuscle myosin heavy chain IIA (NMMHC-IIA). This disease is characterized by giant platelets, thrombocytopenia, granulocyte inclusion bodies, proteinuria, and high-pitch sensorineural deafness. Nephropathy has been observed in 30% of patients with MYH9-related disorder. The characteristic features are early onset proteinuria and rapidly progressing renal disorder. However, the prognosis of MYH9 nephropathy remains unclear. Herein, we describe a 36-year-old woman who presented with proteinuria and was diagnosed with MYH9 nephropathy via renal biopsy and gene analysis. Her proteinuria improved after administration of an angiotensin II receptor blocker, but was aggravated after changing to a calcium channel blocker. PMID:26484020

  15. Prognosis in diabetic nephropathy.

    PubMed Central

    Parving, H. H.; Hommel, E.

    1989-01-01

    OBJECTIVE--To assess the effect of long term antihypertensive treatment on prognosis in diabetic nephropathy. DESIGN--Prospective study of all insulin dependent diabetic patients aged under 50 with onset of diabetes before the age of 31 who developed diabetic nephropathy between 1974 and 1978 at Steno Memorial Hospital. SETTING--Outpatient diabetic clinic in tertiary referral centre. PATIENTS--Forty five patients (20 women) with a mean age of 30 (SD 7) years and a mean duration of diabetes of 18 (7) years at onset of persistent proteinuria were followed until death or for at least 10 years. INTERVENTIONS--Antihypertensive treatment was started a median of three (0-13) years after onset of nephropathy. Four patients (9%) received no treatment, and 9 (20%), 13 (29%), and 19 (42%) were treated with one, two, or three drugs, respectively. The median follow up was 12 (4-15) years. MAIN OUTCOME MEASURES--Arterial blood pressure and death. RESULTS--Mean blood pressure at start of antihypertensive treatment was 148/95 (15/50) mm Hg. Systolic blood pressure remained almost unchanged (slope -0.01 (95% confidence interval -0.39 to 0.37) mm Hg a year) while diastolic blood pressure decreased significantly (0.87 (0.65 to 1.10) mm Hg a year) during antihypertensive treatment. The cumulative death rate was 18% (8 to 32%) 10 years after onset of nephropathy, in contrast to previous reports of 50% to 77% 10 years after onset of nephropathy. As in previous studies, uraemia was the main cause of death (9 patients; 64%). CONCLUSIONS--The prognosis of diabetic nephropathy has improved during the past decade largely because of effective antihypertensive treatment. PMID:2504376

  16. Early Diabetic Nephropathy

    PubMed Central

    Bjornstad, Petter; Snell-Bergeon, Janet K.; Rewers, Marian; Jalal, Diana; Chonchol, Michel B.; Johnson, Richard J.; Maahs, David M.

    2013-01-01

    OBJECTIVE Diabetic nephropathy (DN) is a major cause of mortality in type 1 diabetes. Reduced insulin sensitivity is a well-documented component of type 1 diabetes. We hypothesized that baseline insulin sensitivity would predict development of DN over 6 years. RESEARCH DESIGN AND METHODS We assessed the relationship between insulin sensitivity at baseline and development of early phenotypes of DN—microalbuminuria (albumin-creatinine ratio [ACR] ≥30 mg/g) and rapid renal function decline (glomerular filtration rate [GFR] loss >3 mL/min/1.73 m2 per year)—with three Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations over 6 years. Subjects with diabetes (n = 449) and without diabetes (n = 565) in the Coronary Artery Calcification in Type 1 Diabetes study had an estimated insulin sensitivity index (ISI) at baseline and 6-year follow-up. RESULTS The ISI was lower in subjects with diabetes than in those without diabetes (P < 0.0001). A higher ISI at baseline predicted a lower odds of developing an ACR ≥30 mg/g (odds ratio 0.65 [95% CI 0.49–0.85], P = 0.003) univariately and after adjusting for HbA1c (0.69 [0.51–0.93], P = 0.01). A higher ISI at baseline conferred protection from a rapid decline of GFR as assessed by CKD-EPI cystatin C (0.77 [0.64–0.92], P = 0.004) and remained significant after adjusting for HbA1c and age (0.80 [0.67–0.97], P = 0.02). We found no relation between ISI and rapid GFR decline estimated by CKD-EPI creatinine (P = 0.38) or CKD-EPI combined cystatin C and creatinine (P = 0.50). CONCLUSIONS Over 6 years, a higher ISI independently predicts a lower odds of developing microalbuminuria and rapid GFR decline as estimated with cystatin C, suggesting a relationship between insulin sensitivity and early phenotypes of DN. PMID:24026551

  17. Production of cyclosporins by Tolypocladium niveum strains.

    PubMed Central

    Isaac, C E; Jones, A; Pickard, M A

    1990-01-01

    Nine strains of Tolypocladium niveum (= inflatum) were compared for their production of cyclosporins. Two of the strains, which were originally from the parental NRRL 8044 strain, were among the lower producers, while seventeen Tolypocladium strains belonging to seven other species produced no detectable cyclosporins. Variable cyclosporin production was observed initially. Once extraction and quantitation methods had been established, spore inoculum density and cultural morphology and carbon and nitrogen sources were found to be among the variables affecting cyclosporin production. Cyclosporin A was identified by cochromatography by using high-performance liquid chromatography, and cyclosporins A, B, and C were identified by gas chromatography-mass spectroscopy; all three compounds exhibited biological activity. They were routinely produced as a mixture in the ratio 7:1:2 in T. niveum UAMH 2472, which was selected on the basis of single-spore isolate total cyclosporin production and was used for most studies. This strain routinely produced total cyclosporin levels of 150 to 200 mg.liter-1 after 12 days of growth on a 2% sorbose-1% vitamin assay Casamino Acids medium. PMID:2327746

  18. Recombinant Brain Natriuretic Peptide for the Prevention of Contrast-Induced Nephropathy in Patients with Chronic Kidney Disease Undergoing Nonemergent Percutaneous Coronary Intervention or Coronary Angiography: A Randomized Controlled Trial

    PubMed Central

    Liu, Jinming; Xie, Yanan; He, Fang; Gao, Zihan; Hao, Yuming; Zu, Xiuguang; Chang, Liang; Li, Yongjun

    2016-01-01

    The role of brain natriuretic peptide (BNP) in the prevention of contrast-induced nephropathy (CIN) is unknown. This study aimed to investigate BNP's effect on CIN in chronic kidney disease (CKD) patients undergoing elective percutaneous coronary intervention (PCI) or coronary angiography (CAG). The patients were randomized to BNP (0.005 μg/kg/min before contrast media (CM) exposure and saline hydration, n = 106) or saline hydration alone (n = 103). Cystatin C, serum creatinine (SCr) levels, and estimated glomerular filtration rates (eGFR) were assessed at several time points. The primary endpoint was CIN incidence; secondary endpoint included changes in cystatin C, SCr, and eGFR. CIN incidence was significantly lower in the BNP group compared to controls (6.6% versus 16.5%, P = 0.025). In addition, a more significant deterioration of eGFR, cystatin C, and SCr from 48 h to 1 week (P < 0.05) was observed in controls compared to the BNP group. Although eGFR gradually deteriorated in both groups, a faster recovery was achieved in the BNP group. Multivariate logistic regression revealed that using >100 mL of CM (odds ratio: 4.36, P = 0.004) and BNP administration (odds ratio: 0.21, P = 0.006) were independently associated with CIN. Combined with hydration, exogenous BNP administration before CM effectively decreases CIN incidence in CKD patients. PMID:26949703

  19. Cyclosporine inhibits macrophage-mediated antigen presentation

    SciTech Connect

    Ziegler, H.K.; Palay, D.; Wentworth, P.; Cluff, C.

    1986-03-01

    The influence of cyclosporine on antigen-specific, macrophage-dependent T cell activation was analyzed in vitro. Murine T cell activation by antigens derived from Listeria monocytogenes was monitored by the production of interleukin-2. Pretreatment (2 hrs., 37/sup 0/C) of macrophages with cyclosporine resulted in a population of macrophages with a markedly diminished capacity to support the activation of T lymphocytes. When cyclosporine-pretreated macrophages were added to cultures of antigen and untreated T cells, the dose of cyclosporine which produced 50% inhibition was 1.5 ..mu..g/ml. Appropriate control experiments indicated that cyclosporine was indeed inhibiting at the macrophage level. The addition of interleukin-1 or indomethacin to the cultures did not alter the inhibitory effect of cyclosporine. Under conditions which produced >90% inhibition of antigen presentation, macrophage surface Ia expression was not altered, and the uptake and catabolism of radiolabelled antigen was normal. Thus, cyclosporine inhibits antigen presentation by a mechanism which appears unrelated to changes in Il-1 elaboration, prostaglandin production, Ia expression, or antigen uptake and catabolism.

  20. An Interleukin-6 Neutralizing Antibody Prevents Cyclosporine Induced Nephrotoxicity in Mice

    PubMed Central

    LaSpina, Mark; Tripathi, Sudipta; Gatto, Louis A.; Bruch, David; Maier, Kristopher G.; Kittur, Dilip S.

    2008-01-01

    Introduction Chronic use of cyclosporine A (CyA) induces nephrotoxicity primarily due to endothelial dysfunction. In our previous studies, potential mechanisms were identified in vitro and implicated NADPH oxidase and Interleukin-6 (IL-6) as key components in causing endothelial dysfunction. In this study, we tested the hypothesis that NADPH oxidase activity and IL-6 are key components in renal damage in an in vivo model. Methods Male mice C57B/6 mice from JAX Laboratories at 6–8 weeks were subjected to a low salt diet throughout the trial. After one week on a low salt diet, the mice were injected daily with treatments in 50µL vehicle composed of 75% cremaphor and Ethanol for five weeks. A vehicle alone group was also set aside. Mice were weighed and 25mg/kg/day cyclosporine was injected daily. Apocynin 20mg/kg were injected either alone or concomitantly with CyA. Another group of mice were administered IL-6 Antibody at 2µg/day along with CyA. The kidneys were removed en bloc immediately and submitted in formalin for paraffin sections. Trichrome stains were performed. Slides were blinded and ten photographs of cortical areas per treatment group were taken, which covered an estimate of 10% surface area in random fashion. Areas of renal damage, which were determined by tubular necrosis, were identified and quantified by amount of necrosis per photograph. Each photograph was divided into ten blocks, and the number of blocks that contained necrotic tubules per photo was recorded. Results The two control mice (low salt only) had no damage. The four vehicle mice had trace amounts of tubular necrosis. CyA treatment group demonstrated the highest amount of damage (29/70; 41%). CyA with apocynin, a specific NADPH oxidase inhibitor, was found to have 36% (22/60) damage, whereas the CyA with IL-6 antibody only was observed to have 15% (6/40) damage. Comparing imaging analysis, there was no difference between mice treated with CyA alone and with CyA with apocynin. However

  1. Cyclosporine

    MedlinePlus

    ... modified) is also used to treat psoriasis (a skin disease in which red, scaly patches form on some ... as well as any products such as vitamins, minerals, or other dietary supplements. You should bring this ...

  2. Cyclosporine

    MedlinePlus

    ... oral solution may be mixed with milk, chocolate milk, or orange juice. You should choose one drink from the appropriate list and always mix your medication with that drink.To take either type of oral solution, follow these steps: Fill a glass (not plastic) cup with the drink you have chosen. Remove ...

  3. Derivatives of cyclosporin compatible with antibody-based assays. I. The generation of (/sup 125/I)-labeled cyclosporin

    SciTech Connect

    Mahoney, W.C.; Orf, J.W.

    1985-03-01

    The immunosuppressive drug cyclosporin A, has been successfully iodinated to a specific activity of 300 Ci per gram. /sup 125/I-labeled cyclosporin and (/sup 3/H)cyclosporin are nearly equivalent as tracers in a radioimmunoassay in producing standard lines (suppression by unlabeled cyclosporin) and in assigning values to clinical samples. In addition, the (/sup 125/I)-labeled cyclosporin has greater than twice the sensitivity, and it is stable to long-term storage. Use of a (/sup 125/I)-labeled cyclosporin tracer is more convenient, more reproducible, more precise, and easier than the tritiated-cyclosporin alternative in radioimmunoassay of this compound.

  4. Potential interest of anti-ischemic agents for limiting cyclosporin A nephrotoxicity.

    PubMed

    Simon, N; Tillement, J P; Albengres, E; Jaber, K; Hestin, D; Roux, F; Olivier, P; d'Athis, P; Kessler, M; Berland, Y; Crevat, A

    1997-01-01

    Chronic administration of cyclosporin A induces nephrotoxicity in humans. This is related to a cyclosporin A-induced constriction of afferent glomerular arterioles and mesangial cells, which leads to a decrease in filtration pressure and creatinine clearance. Afterwards, cellular lesions are observed involving mainly tubular atrophy and interstitial fibrosis, both of which are nonspecific. The initial mechanism of its toxicity is not clearly explained. The current pharmacological approach is symptomatic in order to counteract or minimize the consequences of a prime cause, which still remains to be defined. However, cyclosporin A has a deletereous effect on mitochondrial functions and mainly on ATP synthesis, which occurs when Ca2+ accumulates in matrix mitochondria. The effects of trimetazidine, an antischemic drug used in the treatment of angina pectoris, have been assessed. This drug is effective in experimental models of hypoxia induced by cyclosporin A: it restores ATP synthesis previously decreased by Ca2+ and cyclosporin A, and releases a part of Ca2+ excess accumulated by mitochondria at concentrations reached in humans at usual dosage regimens. At higher concentrations, it reverses the mitochondrial permeability transition previously generated (opened) by Ca2+ and a pro-oxidant such as terbutylperoxide (t-BH). It was also observed that trimetazidine does not modify the immunosuppressive effects of cyclosporin A in various models. These data suggest that nephrotoxicity of cyclosporin A is not irrevocably linked to its immunosuppressive effect but that it may be possible to counteract at least partly its nephrotoxic effects without altering its effectiveness in preventing graft rejection. PMID:9526174

  5. Exposure to Nerve Growth Factor Worsens Nephrotoxic Effect Induced by Cyclosporine A in HK-2 Cells

    PubMed Central

    Lofaro, Danilo; Toteda, Giuseppina; Lupinacci, Simona; Leone, Francesca; Gigliotti, Paolo; Papalia, Teresa; Bonofiglio, Renzo

    2013-01-01

    Nerve growth factor is a neurotrophin that promotes cell growth, differentiation, survival and death through two different receptors: TrkANTR and p75NTR. Nerve growth factor serum concentrations increase during many inflammatory and autoimmune diseases, glomerulonephritis, chronic kidney disease, end-stage renal disease and, particularly, in renal transplant. Considering that nerve growth factor exerts beneficial effects in the treatment of major central and peripheral neurodegenerative diseases, skin and corneal ulcers, we asked whether nerve growth factor could also exert a role in Cyclosporine A-induced graft nephrotoxicity. Our hypothesis was raised from basic evidence indicating that Cyclosporine A-inhibition of calcineurin-NFAT pathway increases nerve growth factor expression levels. Therefore, we investigated the involvement of nerve growth factor and its receptors in the damage exerted by Cyclosporine A in tubular renal cells, HK-2. Our results showed that in HK-2 cells combined treatment with Cyclosporine A + nerve growth factor induced a significant reduction in cell vitality concomitant with a down-regulation of Cyclin D1 and up-regulation of p21 levels respect to cells treated with Cyclosporine A alone. Moreover functional experiments showed that the co-treatment significantly up-regulated human p21promoter activity by involvement of the Sp1 transcription factor, whose nuclear content was negatively regulated by activated NFATc1. In addition we observed that the combined exposure to Cyclosporine A + nerve growth factor promoted an up-regulation of p75 NTR and its target genes, p53 and BAD leading to the activation of intrinsic apoptosis. Finally, the chemical inhibition of p75NTR down-regulated the intrinsic apoptotic signal. We describe two new mechanisms by which nerve growth factor promotes growth arrest and apoptosis in tubular renal cells exposed to Cyclosporine A. PMID:24244623

  6. Perinatal obstructive nephropathy.

    PubMed

    Chevalier, Robert L

    2004-04-01

    Significant advances have been made recently in elucidating the cellular consequences of urinary tract obstruction during renal development. Urinary tract obstruction impairs growth and maturation of the kidney, and can also cause renal maldevelopment. This includes a reduction in the number of nephrons, tubular atrophy, and progressive interstitial fibrosis. Apoptosis (programmed cell death) accounts for much of the loss of tubular epithelial cells. Factors contributing to apoptosis include stretching of cells in dilated tubules, altered renal production of growth factors, and infiltration of the renal interstitium by macrophages. Two major controversies remain regarding the surgical management of congenital obstructive nephropathy: first, which fetuses with bladder outlet obstruction should undergo prenatal intervention, and second, which infants should undergo early pyeloplasty for ureteropelvic junction obstruction? Even after successful surgery for congential obstructive nephropathy, all patients should be followed for hypertension, proteinuria, or renal deterioration. PMID:15200251

  7. Histological changes of kidney in diabetic nephropathy

    PubMed Central

    Pourghasem, Mohsen; Shafi, Hamid; Babazadeh, Zahra

    2015-01-01

    Diabetes mellitus is the most common cause of chronic renal disorders and end-stage kidney disease in developed countries. It is the major cause of dialysis and transplantation. Failure in renal function causes wide disorders in the body. Diabetes results in wide range of alterations in the renal tissue. It is believed that early histological changes in diabetic nephropathy are detectable 2 years after diabetes is diagnosed. The glomerular alterations are the most important lesions in the diabetic nephropathy (DN). The Renal Pathology Society provides a new pathological classification for the detection of histopathology of DN. It divides diabetic nephropathy into four hierarchical glomerular lesions. Alloxan or streptozotocin induced diabetic rat is the one most widely used specie to study DN. Histological changes in the rat DN closely resemble the human disease and the most information of this review was obtained through the study of rat DN. All cell types of the kidney such as mesangial cells, podocytes and tubulointerstitial cells are liable to be affected in the event of DN. Severity of renal lesions is associated to the clinical aspect of renal outcome, but the aim of this article was only to review the histological changes of kidney in diabetes mellitus. PMID:26644877

  8. Light chain nephropathy.

    PubMed

    Darouich, Sihem; Bettaieb, Ilhem; Aouadia, Raja; Hedri, Hafedh; Abderrahim, Ezzeddine; Goucha, Rym; Khedher, Adel

    2015-01-01

    Light chain deposition disease (LCDD) is characterized by the tissue deposition of monotypic immunoglobulin light chains of either kappa or lambda isotype. It is the archetypal systemic disease that is most frequently diagnosed on a kidney biopsy, although the deposits may involve several other organs. This brief review focuses on the clinicopathological features of LCDD-associated nephropathy with an emphasis on the diagnostic and therapeutic difficulties related to this elusive condition. PMID:26022011

  9. Kimura's disease with eosinophilic panniculitis - treated with cyclosporine: a case report

    PubMed Central

    2010-01-01

    Kimura's disease is a rare, benign, slow growing chronic inflammatory swelling with a predilection for the head and neck region and almost always with peripheral blood eosinophilia and elevated serum IgE levels. Here, we report a 25-year-old male patient with asthma, Reynaud phenomenon, eosinophilic panniculitis, bilateral inguinal lymphadenopathy and peripheral blood eosinophilia. He responded initially to oral prednisolone with the subsidence of peripheral blood eosinophilia, asthma and the Reynaud phenomenon. But with tapering of prednisolone symptoms reappeared and hereby he was treated with cyclosporine. He has been symptom free for 6 months of follow up while taking cyclosporine 25 mg orally per day. Eosinophilia has resolved. This case shows that in addition to previously reported associations, Kimura disease may be associated with eosinophilic panniculitis and that cyclosporine could be effective in its treatment. PMID:20236545

  10. Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog.

    PubMed Central

    Rosenwirth, B; Billich, A; Datema, R; Donatsch, P; Hammerschmid, F; Harrison, R; Hiestand, P; Jaksche, H; Mayer, P; Peichl, P

    1994-01-01

    (Me-Ile-4)cyclosporin (SDZ NIM 811) is a 4-substituted cyclosporin which is devoid of immunosuppressive activity but retains full capacity for binding to cyclophilin and exhibits potent anti-human immunodeficiency virus type 1 (HIV-1) activity. SDZ NIM 811 selectively inhibits HIV-1 replication in T4 lymphocyte cell lines, in a monocytic cell line, and in HeLa T4 cells. Furthermore, its antiviral activity against laboratory strains and against clinical isolates from geographically distinct regions in primary T4 lymphocytes and in primary monocytes (50% inhibitory concentration = 0.011 to 0.057 micrograms/ml) was demonstrated. SDZ NIM 811 does not inhibit proviral gene expression or virus-specific enzyme functions, either free or bound to cyclophilin. The compound does not influence CD4 expression or inhibit fusion between virus-infected and uninfected cells. SDZ NIM 811 was, however, found to block formation of infectious particles from chronically infected cells. Oral administration to mice, rats, dogs, and monkeys resulted in levels in blood considerably exceeding the drug concentration, which completely blocked virus replication in primary cells. SDZ NIM 811 caused changes of toxicity parameters in rats to a smaller degree than cyclosporine (formerly cyclosporin A). Thus, the potent and selective anti-HIV-1 activity of SDZ NIM 811 and its favorable pharmacokinetic behavior together with its lower nephrotoxicity than that of cyclosporine make this compound a promising candidate for development as an anti-HIV drug. PMID:7527198

  11. Identification of novel indicators of cyclosporine A nephrotoxicity in a CD-1 mouse model

    SciTech Connect

    O'Connell, Sein; Slattery, Craig; Ryan, Michael P.; McMorrow, Tara

    2011-04-15

    The calcineurin inhibitor cyclosporine A (CsA) is a widely used immunosuppressive agent. However, nephrotoxicity is a serious side effect observed in patients which limits clinical use of CsA. CsA nephrotoxicity is associated with tubulointerstitial injury progressing to nephropathy. This is typically diagnosed by invasive renal biopsy and is often only detected when the disease process is well advanced. Therefore identification of novel, early indicators of CsA nephrotoxicity could be clinically advantageous. This study aimed to establish a murine model of CsA nephrotoxicity and to identify urinary proteins that may indicate the onset of CsA-induced nephropathy using 2-D gel electrophoresis. CsA nephrotoxicity was induced in CD-1 mice by daily CsA administration for 4 weeks. By week 4, elevated serum creatinine and proteinuria were observed after CsA treatment indicating significant renal dysfunction. Decreased cadherin-1, increased {alpha}-smooth muscle actin and fibroblast specific protein 1 in kidney tissue indicated disruption of normal tubular architecture. Alterations in podocin and uromodulin were also observed which may indicate damage to other segments of the nephron. Proteomic analysis of urine identified a number of differentially regulated proteins that may be involved in early CsA nephropathy including cadherin 1, superoxide dismutase and vinculin. These findings suggest novel mechanisms of CsA nephrotoxicity and identify novel potential markers of the disease.

  12. The effect of systemic cyclosporin A on a hairless mouse model of photoaging.

    PubMed

    Moloney, S J; Learn, D B

    1992-10-01

    The mechanisms that cause skin wrinkling in response to chronic exposure to sunlight are unknown. We investigated the possibility that wrinkling of Skh-1 hairless mice is associated with an ultraviolet (UV) radiation-induced immunologic alteration. Exposing Skh-1 hairless mice to a regimen of nonerythemal UV-B (290-320 nm) radiation induced skin wrinkles after 6-7 weeks. Concomitant treatment with cyclosporin A decreased the time to the onset of wrinkles to approximately 4 weeks. Exposing HRS/J hairless mice or athymic nude mice to a similar nonerythemal UV-B radiation regimen for 10 weeks failed to induce skin wrinkles. Concomitant administration of cyclosporin A and UV-B radiation for 7 weeks to HRS/J hairless mice induced no skin wrinkles. Ultraviolet-B or UV-B plus cyclosporin A exposure caused increased immunohistochemical staining for Ia and F4/80 antigens in the upper dermis of tissue from Skh-1 mice, as compared to controls. Treating Skh-1 mice with UV-B radiation plus cyclosporin A was also associated with a large increase in the number of CD3+ cells in the dermis. These staining patterns were absent in similarly treated HRS/J hairless mice. Dermal mast cell numbers in Skh-1 mice were 2-3-fold higher than in HRS/J, athymic nude or NSA mice. Treatment with cyclosporin A increased Skh-1 dermal mast cell numbers approximately 2-fold but had no effect on the dermal mast cell numbers in HRS/J or NSA mice. Based on these findings we postulate that UV-B light and cyclosporin A exacerbate an immunological condition in Skh-1 mice, one consequence of which is manifested as skin wrinkles. Thus, the induction of skin wrinkles in this mouse strain may have no relevance to the wrinkles observed in human skin after chronic exposure to sunlight. PMID:1454879

  13. Beethoven's nephropathy and death: discussion paper.

    PubMed Central

    Davies, P J

    1993-01-01

    The autopsy description of Beethoven's nephropathy is so typical of renal papillary necrosis, that the diagnosis is as near to certain as is possible, in the absence of a histological examination. A review of the symptoms and clinical course of Beethoven's final illness is consistent with this diagnosis. It is proposed that the cause was an acute onset diabetes mellitus, complicating chronic pancreatitis. Beethoven's case appears to be the first report in the literature of an autopsy proven case of renal papillary necrosis. PMID:8459382

  14. Analyzing antibody activity in IgA nephropathy

    PubMed Central

    Glassock, Richard J.

    2009-01-01

    IgA nephropathy is a chronic kidney disease defined by deposition of IgA in the glomeruli. An abnormality in the glycosylation of the hinge region of the IgA1 isotype of IgA is fundamental to the origins of this very common form of glomerulonephritis. In this issue of the JCI, Suzuki and coworkers describe the characteristics of IgG autoantibodies to the abnormally glycosylated IgA1 secreted by immortalized B cells derived from patients with sporadic forms of IgA nephropathy (see the related article beginning on page 1668). These IgG autoantibodies displayed remarkably restricted heterogeneity. These observations offer new insights into disease pathogenesis and may lead to new methods of diagnosis, monitoring, and therapy for patients with IgA nephropathy. PMID:19504718

  15. Novel Oxidation of Cyclosporin A: Preparation of Cyclosporin Methyl Vinyl Ketone (Cs-MVK)

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Cyclosporin A (CsA) was converted into cyclosporin methyl vinyl ketone (Cs-MVK) by either a biocatalytic method utilizing 1-hydroxybenzotriazole-mediated laccase oxidation or by a chemical oxidation using t-butyl hydroperoxide and potassium ­periodate as co-oxidants. Cs-MVK is a novel, versatile sy...

  16. Partial response to cyclosporine in a patient with Schnitzler's syndrome.

    PubMed

    Carbone, J; Paravisini, A; Sarmiento, E; Rodríguez-Molina, J; Fernández-Cruz, E

    2007-01-01

    Schnitzler's syndrome is an unusual clinical association of chronic urticaria, intermittent fever and monoclonal immunoglobulin M (IgM) gammopathy. The pathogenesis of the urticaria is unclear and treatment is problematic. We describe the case of a 61-year-old woman with a long history of chronic urticaria with severe pruritus, spiking fever and malaise. The IgM-kappa monoclonal component was detected in the patient's serum 4 years after symptom onset. After ineffective treatment with antihistamines and systemic corticosteroids, oral cyclosporine resulted in complete remission of the fever and malaise, which has persisted after an 18-month follow-up. Partial but maintained remission of the urticaria was also observed, allowing corticosteroid doses to be decreased. PMID:17428403

  17. Heroin crystal nephropathy

    PubMed Central

    Bautista, Josef Edrik Keith; Merhi, Basma; Gregory, Oliver; Hu, Susie; Henriksen, Kammi; Gohh, Reginald

    2015-01-01

    In this paper we present an interesting case of acute kidney injury and severe metabolic alkalosis in a patient with a history of heavy heroin abuse. Urine microscopy showed numerous broomstick-like crystals. These crystals are also identified in light and electron microscopy. We hypothesize that heroin crystalizes in an alkaline pH, resulting in tubular obstruction and acute kidney injury. Management is mainly supportive as there is no known specific therapy for this condition. This paper highlights the utility of urine microscopy in diagnosing the etiology of acute kidney injury and proposes a novel disease called heroin crystal nephropathy. PMID:26034599

  18. Scorpion sting nephropathy

    PubMed Central

    Prabhu, Chaitanya

    2011-01-01

    Scorpion envenomations are ubiquitous, but nephropathy is a rare manifestation, reported mainly from the Middle East and North Africa. Rapid venom redistribution from blood, delayed excretion from the kidneys, direct toxicity of venom enzymes, cytokine release and afferent arteriolar constriction have been seen in experimental animals. Haemoglobinuria, acute tubular necrosis, interstitial nephritis and haemolytic–uraemic syndrome have been documented in human victims of scorpion envenomation. Epidemiology, venom components and toxins, effects on the laboratory mammals especially the kidneys and reports of renal failure in humans are reviewed in this article. PMID:25984198

  19. Cyclosporine and Herbal Supplement Interactions

    PubMed Central

    Colombo, D.; Lunardon, L.; Bellia, G.

    2014-01-01

    Cyclosporine (CyA) is a well-known immunosuppressant with a narrow therapeutic window. Its bioavailability is affected by many other traditional drugs and herbal extracts. Cytochrome P-450 isoenzymes CYP3A4 and CYP3A5 and protein P-glycoprotein (P-gp) are involved in CyA bioavailability. Interactions of CyA with herbal extracts are not well known, but, given their increased concomitant use, it is important to know which extracts, many of which are commonly self-prescribed, can affect CyA blood concentrations. Decreased CyA blood concentration has been shown with St John's wort in case reports and, in vivo animal studies, with ginger, liquorice, scutellariae radix, and quercetin. Increased CyA concentration has been reported in patients with grapefruit juice, chamomile, or berberine, and with cannabidiol or resveratrol in animal studies. Effects of Echinacea and Serenoa repens on CyA levels have not been shown consistently, but concomitant use should be avoided. Although findings from animal studies cannot be directly translated into humans, avoiding concomitant use of herbal extracts is prudent until human clinical studies have ruled out any possible interaction. Clinicians should interview their patients carefully about their use of herbal supplements before CyA administration, and those receiving CyA should be warned about possible interactions between herbal preparations and CyA. PMID:24527031

  20. Morphometric and ultrastructural analysis of the effect of bromocriptine and cyclosporine on the vasospastic femoral artery of rats

    PubMed Central

    Tokmak, Mehmet; Başocak, Kahan; Canaz, Hüseyin; Canaz, Gökhan; İplikçioğlu, Celal

    2015-01-01

    Vasospasm is the main causes of mortality and morbidity in patiens with subarachnoid hemorrhage (SAH). The arterial narrowing mechanism that develops after SAH is not yet fully understood but many studies showed that hypotension, neurogenic reflexes, clots in the subarachnoidal space, spasmogenic agents, humoral and celluler immunity play a role in the etiology. In this study we investigate the effects of Bromocriptine and Cyclosporine A in vasospasm secondary to SAH on rat femoral artery from ultrastructural and morphometric perspectives. 120 male Sprague-Dawley rats divided into 12 groups: Vasospasm (V), control (K), surgical control (CK) groups, vasospasm+Bromocriptine and/or Cyclosporine-A groups (VCyA, VBr, VBr+CyA), Bromocriptine and/or Cyclosporine-A control groups (CK, BK, Br+CyAK), Bromocriptine and/or Cyclosporine-A surgical control groups (BCK, CyCK, Br+CyACK). In order to create SAH model, 0, 1 cm3 blood injected into silastic sheath wrapped rat femoral artery. Bromocriptine (2 mg/kg/d) and Cyclosporine A (10 mg/kg/d) combinations applied to control, surgical control and vasospastic models. Light microscopy, transmission electron microscopy and scanning electron microscopy used during this study. Statistical evaluation of the morphometric measurement data concerning vascular wall thickness and luminal cross-sectional areas of all groups were performed using Mann-Whitney U, Wilcoxon-signed rank, and Student-t tests. Cyclosporine A, whose effects in the prevention of vasospasm have been demonstrated in previous studies. In this study we discovered that Bromocriptine demonstrated strong effects similar to Cyclosporine-A. Bromocriptine and Cyclosporine A markedly prevent the development of chronic morphologic vasospasm following SAH. The combined use of both drugs does not change this preventive effect. PMID:26770311

  1. Immunopathology of nephropathies associated with malaria*

    PubMed Central

    Houba, V.

    1975-01-01

    Immune complexes play an important role in the pathogenesis of malaria-associated nephropathies. Two main types of lesion are demonstrable: (a) acute (transient—reversible) lesions typical of falciparum infections in man, with mild clinical symptoms developing a week or two after infection. Renal biopsies at that time show deposits of immunoglobulins, complement, and sometimes antigen. The lesions respond to antimalarials. (b) Chronic (progressive) lesions characteristic of quartan infections in man, developing slowly into a chronic stage with persistent proteinuria and gradually deteriorating renal function and hypertension. Renal biopsies at the onset of the disease show deposits of immunoglobulins, complement, and P. malariae antigens in glomerular capillary walls. Antimalarial therapy has no effect. Recent immunochemical findings confirm that these lesions are of the immune-complex type and are associated with malaria infection. However, several questions remain to be solved. PMID:1083308

  2. Adaptive changes in renal mitochondrial redox status in diabetic nephropathy

    SciTech Connect

    Putt, David A.; Zhong, Qing; Lash, Lawrence H.

    2012-01-15

    Nephropathy is a serious and common complication of diabetes. In the streptozotocin (STZ)-treated rat model of diabetes, nephropathy does not typically develop until 30 to 45 days post-injection, although hyperglycemia occurs within 24 h. We tested the hypothesis that chronic hyperglycemia results in a modest degree of oxidative stress that is accompanied by compensatory changes in certain antioxidants and mitochondrial redox status. We propose that as kidneys progress to a state of diabetic nephropathy, further adaptations occur in mitochondrial redox status. Basic parameters of renal function in vivo and several parameters of mitochondrial function and glutathione (GSH) and redox status in isolated renal cortical mitochondria from STZ-treated and age-matched control rats were examined at 30 days and 90 days post-injection. While there was no effect of diabetes on blood urea nitrogen, measurement of other, more sensitive parameters, such as urinary albumin and protein, and histopathology showed significant and progressive worsening in diabetic rats. Thus, renal function is compromised even prior to the onset of frank nephropathy. Changes in mitochondrial respiration and enzyme activities indicated existence of a hypermetabolic state. Higher mitochondrial GSH content and rates of GSH transport into mitochondria in kidneys from diabetic rats were only partially due to changes in expression of mitochondrial GSH carriers and were mostly due to higher substrate supply. Although there are few clear indicators of oxidative stress, there are several redox changes that occur early and change further as nephropathy progresses, highlighting the complexity of the disease. Highlights: ►Adaptive changes in renal mitochondrial and redox status in diabetic rats. ►Modest renal dysfunction even prior to onset of nephropathy. ►Elevated concentrations of mitochondrial GSH in diabetic kidneys. ►Change in GSH due partly to increased protein expression of transporter.

  3. Treatment of Idiopathic Membranous Nephropathy

    PubMed Central

    Austin, Howard A.

    2012-01-01

    Exciting progress recently has been made in our understanding of idiopathic membranous nephropathy, as well as treatment of this disease. Here, we review important advances regarding the pathogenesis of membranous nephropathy. We will also review the current approach to treatment and its limitations and will highlight new therapies that are currently being explored for this disease including Rituximab, mycophenolate mofetil, and adrenocorticotropic hormone, with an emphasis on results of the most recent clinical trials. PMID:22859855

  4. Diabetic Nephropathy without Diabetes

    PubMed Central

    López-Revuelta, Katia; Méndez Abreu, Angel A.; Gerrero-Márquez, Carmen; Stanescu, Ramona-Ionela; Martínez Marín, Maria Isabel; Pérez Fernández, Elia

    2015-01-01

    Diabetic nephropathy without diabetes (DNND), previously known as idiopathic nodular glomerulosclerosis, is an uncommon entity and thus rarely suspected; diagnosis is histological once diabetes is discarded. In this study we describe two new cases of DNND and review the literature. We analyzed all the individualized data of previous publications except one series of attached data. DNND appears to be favored by recognized cardiovascular risk factors. However, in contrast with diabetes, apparently no factor alone has been demonstrated to be sufficient to develop DNND. Other factors not considered as genetic and environmental factors could play a role or interact. The most plausible hypothesis for the occurrence of DNND would be a special form of atherosclerotic or metabolic glomerulopathy than can occur with or without diabetes. The clinical spectrum of cardiovascular risk factors and histological findings support this theory, with hypertension as one of the characteristic clinical features. PMID:26239683

  5. Angiopoietins and diabetic nephropathy.

    PubMed

    Gnudi, Luigi

    2016-08-01

    Diabetic nephropathy is the main cause of end-stage renal failure in the Western world. In diabetes, metabolic and haemodynamic perturbations disrupt the integrity of the glomerular filtration barrier, leading to ultrastructural alterations of the glomeruli, including podocyte foot process fusion and detachment, glomerular basement membrane thickening, reduced endothelial cell glycocalyx, and mesangial extracellular matrix accumulation and glomerulosclerosis, ultimately leading to albuminuria and end-stage renal disease. Many vascular growth factors, such as angiopoietins, are implicated in glomerular biology. In normal physiology angiopoietins regulate the function of the glomerular filtration barrier. When they are dysregulated, however, as they are in diabetes, they drive the cellular mechanisms that mediate diabetic glomerular pathology. Modulation of angiopoietins expression and signalling has been proposed as a tool to correct the cellular mechanisms involved in the pathophysiology of diabetic microvascular disease, such as retinopathy in humans. Future work might evaluate whether this novel therapeutic approach should be extended to diabetic kidney disease. PMID:27207083

  6. Diabetic nephropathy in Africa: A systematic review

    PubMed Central

    Noubiap, Jean Jacques N; Naidoo, Jashira; Kengne, Andre P

    2015-01-01

    AIM: To determine the prevalence and incidence of diabetic nephropathy in Africa. METHODS: We performed a systematic narrative review of published literature following the MOOSE Guidelines for Meta-Analysis and Systematic Reviews of Observational Studies. We searched PubMed-MEDLINE for all articles published in English and French languages between January 1994 and July 2014 using a predefined strategy based on the combination of relevant terms and the names of each of the 54 African countries and African sub-regions to capture the largest number of studies, and hand-searched the reference lists of retrieved articles. Included studies reported on the prevalence, incidence or determinants of chronic kidney disease (CKD) in people with diabetes within African countries. RESULTS: Overall, we included 32 studies from 16 countries; two being population-based studies and the remaining being clinic-based surveys. Most of the studies (90.6%) were conducted in urban settings. Methods for assessing and classifying CKD varied widely. Measurement of urine protein was the most common method of assessing kidney damage (62.5% of studies). The overall prevalence of CKD varied from 11% to 83.7%. Incident event rates were 94.9% for proteinuria at 10 years of follow-up, 34.7% for end-stage renal disease at 5 years of follow-up and 18.4% for mortality from nephropathy at 20 years of follow-up. Duration of diabetes, blood pressure, advancing age, obesity and glucose control were the common determinants of kidney disease. CONCLUSION: The burden of CKD is important among people with diabetes in Africa. High quality data from large population-based studies with validated measures of kidney function are still needed to better capture the magnitude and characteristics of diabetic nephropathy in Africa. PMID:26069725

  7. What's New in Chronic Myeloid Leukemia Research and Treatment?

    MedlinePlus

    ... Topic Additional resources for chronic myeloid leukemia What`s new in chronic myeloid leukemia research and treatment? Studies ... such as cyclosporine or hydroxychloroquine, with a TKI. New drugs for CML Because researchers now know the ...

  8. Concomitant administration of cyclosporin and ketoconazole in renal transplant recipients.

    PubMed

    First, M R; Schroeder, T J; Weiskittel, P; Myre, S A; Alexander, J W; Pesce, A J

    1989-11-18

    18 renal transplant recipients receiving cyclosporin, prednisone, and azathioprine were given ketoconazole, a potent inhibitor of the cytochrome P-450 enzyme system. Within a month ketoconazole-induced blockade of cyclosporin metabolism allowed a significant reduction (451 vs 106 mg/day; 77%) of the mean dose of cyclosporin without altering cyclosporin whole blood trough levels, although maximum blood levels were almost halved. This dose reduction was maintained in patients followed up for up to 13 months. Renal and hepatic function were unchanged after the addition of ketoconazole. This drug interaction has the potential to reduce dramatically expenditure on cyclosporin in transplant recipients. PMID:2572912

  9. Cyclosporine versus tacrolimus: cost-effectiveness analysis for renal transplantation in Brazil

    PubMed Central

    Guerra, Augusto Afonso; Silva, Grazielle Dias; Andrade, Eli Iola Gurgel; Cherchiglia, Mariângela Leal; Costa, Juliana de Oliveira; Almeida, Alessandra Maciel; Acurcio, Francisco de Assis

    2015-01-01

    OBJECTIVE To analyze the cost-effectiveness of treatment regimens with cyclosporine or tacrolimus, five years after renal transplantation. METHODS This cost-effectiveness analysis was based on historical cohort data obtained between 2000 and 2004 and involved 2,022 patients treated with cyclosporine or tacrolimus, matched 1:1 for gender, age, and type and year of transplantation. Graft survival and the direct costs of medical care obtained from the National Health System (SUS) databases were used as outcome results. RESULTS Most of the patients were women, with a mean age of 36.6 years. The most frequent diagnosis of chronic renal failure was glomerulonephritis/nephritis (27.7%). In five years, the tacrolimus group had an average life expectancy gain of 3.96 years at an annual cost of R$78,360.57 compared with the cyclosporine group with a gain of 4.05 years and an annual cost of R$61,350.44. CONCLUSIONS After matching, the study indicated better survival of patients treated with regimens using tacrolimus. However, regimens containing cyclosporine were more cost-effective. PMID:25741648

  10. Correlation of secreted protein acidic and rich in cysteine with diabetic nephropathy

    PubMed Central

    Li, Lei; Song, Hai-Yan; Liu, Kai; An, Meng-Meng

    2015-01-01

    To detect the serum concentrations of secreted protein acidic and rich in cysteine (SPARC) in patients with diabetic nephropathy and SPARC mRNA and protein expressions in renal tissue of db/db mice (C57BL/KsJ, diabetic nephropathy mice), thus preliminary exploration on the role of secreted protein acidic riches in cysteine in the development of diabetic nephropathy were carried out. Serum SPARC levels in normal subjects, patients with type 2 diabetes mellitus (without diabetic nephropathy), chronic renal failure (without diabetes mellitus), and diabetic nephropathy were determined with enzyme-linked immunosorbent assay. 12-week-old db/db mice (db/db group) and its littermate wild-type control mice (NC group) were selected with 6 from each group, and the kidney tissue were taken. RT-PCR, Western blot, and immunofluorescence were used to detect the mRNA, targeted protein expressions of SPARC and the staining of renal tissue. The serum level of SPARC in diabetic nephropathy group was significantly higher than those in normal group, type 2 diabetes mellitus, and chronic renal failure group (P < 0.05 or P < 0.01). The SPARC level in the type 2 diabetes mellitus group was higher than that in normal group (P < 0.05), but there was no difference between normal group and chronic renal failure. SPARC mRNA and protein levels in renal tissue of db/db mice were higher compared with the normal control group (P < 0.05). The long term hyperglycemic state in patients with diabetic nephropathy causes pathological change of renal tissue. Simultaneously, increased secretion of SPARC from renal tissue results in elevation of serum SPARC level. SPARC correlates with the occurrence and progression of diabetes, and it may play a role in pathological change of diabetic nephropathy. PMID:26550188

  11. Association of Haemostatic and Inflammatory Biomarkers with Nephropathy in Type 1 Diabetes Mellitus

    PubMed Central

    Domingueti, Caroline Pereira; Fóscolo, Rodrigo Bastos; Reis, Janice Sepúlveda; Campos, Fernanda Magalhães Freire; Dusse, Luci Maria S.; Carvalho, Maria das Graças; Braga Gomes, Karina; Fernandes, Ana Paula

    2016-01-01

    This study aimed at investigating the association between haemostatic biomarkers, proinflammatory, and anti-inflammatory cytokines with chronic kidney disease in type 1 diabetic patients. Patients were divided into two groups: with nephropathy (albuminuria ≥ 30 mg/g and/or GFR < 60 mL/min/1.73 m2), n = 65; and without nephropathy (albuminuria < 30 mg/g and GFR ≥ 60 mL/min/1.73 m2), n = 60. INF-γ, IL-6, IL-10, and TNF-α plasma levels were determined by flow cytometry. VWF, ADAMTS13 antigen, and D-Dimer plasma levels were determined by enzyme-linked immunosorbent assay and ADAMTS13 activity was assessed by fluorescence resonance energy transfer assay. Elevated levels of INF-γ, VWF, ADAMTS13 antigen, D-Dimer, and reduced ADAMTS13 activity/antigen ratio were observed in patients with nephropathy as compared to those without nephropathy (P = 0.001, P < 0.001, P < 0.001, P < 0.001, and P < 0.001, resp.). Cytokines and haemostatic biomarkers remained associated with nephropathy after adjustments (use of statin, acetylsalicylic acid, angiotensin converting enzyme inhibitor, and angiotensin antagonist). INF-γ, TNF-α, and IL-10 significantly correlated with haemostatic biomarkers. Inflammatory and hypercoagulability status are associated with nephropathy in type 1 diabetes mellitus and an interrelationship between them may play an important role in pathogenesis of diabetic nephropathy. PMID:26770985

  12. Association of Haemostatic and Inflammatory Biomarkers with Nephropathy in Type 1 Diabetes Mellitus.

    PubMed

    Domingueti, Caroline Pereira; Fóscolo, Rodrigo Bastos; Reis, Janice Sepúlveda; Campos, Fernanda Magalhães Freire; Dusse, Luci Maria S; Carvalho, Maria das Graças; Braga Gomes, Karina; Fernandes, Ana Paula

    2016-01-01

    This study aimed at investigating the association between haemostatic biomarkers, proinflammatory, and anti-inflammatory cytokines with chronic kidney disease in type 1 diabetic patients. Patients were divided into two groups: with nephropathy (albuminuria ≥ 30 mg/g and/or GFR < 60 mL/min/1.73 m(2)), n = 65; and without nephropathy (albuminuria < 30 mg/g and GFR ≥ 60 mL/min/1.73 m(2)), n = 60. INF-γ, IL-6, IL-10, and TNF-α plasma levels were determined by flow cytometry. VWF, ADAMTS13 antigen, and D-Dimer plasma levels were determined by enzyme-linked immunosorbent assay and ADAMTS13 activity was assessed by fluorescence resonance energy transfer assay. Elevated levels of INF-γ, VWF, ADAMTS13 antigen, D-Dimer, and reduced ADAMTS13 activity/antigen ratio were observed in patients with nephropathy as compared to those without nephropathy (P = 0.001, P < 0.001, P < 0.001, P < 0.001, and P < 0.001, resp.). Cytokines and haemostatic biomarkers remained associated with nephropathy after adjustments (use of statin, acetylsalicylic acid, angiotensin converting enzyme inhibitor, and angiotensin antagonist). INF-γ, TNF-α, and IL-10 significantly correlated with haemostatic biomarkers. Inflammatory and hypercoagulability status are associated with nephropathy in type 1 diabetes mellitus and an interrelationship between them may play an important role in pathogenesis of diabetic nephropathy. PMID:26770985

  13. Posterior encephalopathy subsequent to cyclosporin A presenting as irreversible abulia.

    PubMed

    Nishie, Makoto; Kurahashi, Kozo; Ogawa, Masaya; Yoshida, Yasuji; Midorikawa, Hiroshi

    2003-08-01

    A case of cyclosporin A (Cys A)-induced posterior encephalopathy developed into persistent abulia despite rapid and marked improvement of abnormal T2- and FLAIR MRI hyperintense regions. Diffusion-weighted MRI signal intensity was also high at the onset. This change is atypical in Cys A-induced encephalopathy and was thought to predict poor recovery from the encephalopathy. Persistent abulia was probably due to marked hypoperfusion in the whole cortex including bilateral frontal lobes and basal ganglia as detected by SPECT. Apart from the breakdown of the blood-brain barrier, direct toxicity of Cys A to the brain may play a role in the pathogenesis of chronic, irreversible encephalopathy. PMID:12924507

  14. IgA Nephropathy in a Patient Presenting with Pseudotumor Cerebri

    PubMed Central

    Ahmed, Umair Syed; Bacaj, Patrick; Iqbal, Hafiz Imran; Onder, Songul

    2016-01-01

    IgA nephropathy is the most common glomerulonephritis worldwide and typically has minimal signs for chronicity in histopathology at the time of initial presentation. Pseudotumor cerebri (PTC) is characterized by increased intracranial pressure in the absence of any intracranial lesions, inflammation, or obstruction. PTC has been reported in renal transplant and dialysis patients, but we are unaware of any reports of pseudotumor cerebri in patients with IgA nephropathy. We report a case of a young female who presented with signs and symptoms of pseudotumor cerebri and was subsequently diagnosed with IgA nephropathy and end-stage renal disease. To our knowledge this is the first report of IgA nephropathy presenting as end-stage renal disease in a patient who presented with pseudotumor cerebri. PMID:26989531

  15. IgA Nephropathy in a Patient Presenting with Pseudotumor Cerebri.

    PubMed

    Ahmed, Umair Syed; Bacaj, Patrick; Iqbal, Hafiz Imran; Onder, Songul

    2016-01-01

    IgA nephropathy is the most common glomerulonephritis worldwide and typically has minimal signs for chronicity in histopathology at the time of initial presentation. Pseudotumor cerebri (PTC) is characterized by increased intracranial pressure in the absence of any intracranial lesions, inflammation, or obstruction. PTC has been reported in renal transplant and dialysis patients, but we are unaware of any reports of pseudotumor cerebri in patients with IgA nephropathy. We report a case of a young female who presented with signs and symptoms of pseudotumor cerebri and was subsequently diagnosed with IgA nephropathy and end-stage renal disease. To our knowledge this is the first report of IgA nephropathy presenting as end-stage renal disease in a patient who presented with pseudotumor cerebri. PMID:26989531

  16. Analgesic nephropathy as a cause of end-stage renal disease in a 55 year-old Nigerian.

    PubMed

    Okafor, U H; Unuigbe, E I; Onwuchekwa, A C; Emem-Chioma, P

    2012-01-01

    Analgesic nephropathy is a subtle but significant cause of chronic renal failure. There is paucity of data on analgesic nephropathy in Nigeria. This case presentation is to highlight the need to have high index of suspicion in patients at risk of developing analgesic nephropathy. In March 2009 a 55-year-old businessman was referred to the renal unit on account of azotemia by the hematologist who had hitherto managed the patient as a case of refractory anemia. The patient had osteoarthritis for over 10 years and was managed with several analgesic drugs over the same period. He was found to have features suggestive of analgesic nephropathy and had end-stage renal disease. He was commenced on appropriate therapy, and he had a live related kidney transplant six months later. Analgesic nephropathy is preventable and morbidity/mortality can be remarkably reduced with appropriate and prompt intervention. PMID:22718180

  17. Polyomavirus-associated nephropathy

    PubMed Central

    Costa, Cristina; Cavallo, Rossana

    2012-01-01

    Polyomaviruses BK and JC are ubiquitous viruses with high seroprevalence rates in general population. Following primary infection, polyomaviruses BK and JC persist latently in different sites, particularly in the reno-urinary tract. Reactivation from latency may occur in normal subjects with asymptomatic viruria, while it can be associated to nephropathy (PVAN) in kidney transplantat recipients. PVAN may occur in 1%-10% of renal transplant patients with loss of the transplanted organ in 30% up to 80% of the cases. Etiology of PVAN is mainly attributable to BK virus, although approximately 5% of the cases may be due to JC. Pathogenesis of PVAN is still unknown, although viral replication and the lack of immune control play a major role. Immunosuppression represents the condicio sine qua non for the development of PVAN and the modulation of anti-rejection treatment represents the first line of intervention, given the lack of specific antiviral agents. At moment, an appropriate immunemodulation can only be accomplished by early identification of viral reactivacation by evaluation of polyomavirus load on serum and/or urine specimens, particularly in the first year post-trasplantation. Viro-immunological monitoring of specific cellular immune response could be useful to identify patients unable to recover cellular immunity posttransplantation, that are at higher risk of viral reactivation with development of PVAN. Herein, the main features of polyomaviruses BK and JC, biological properties, clinical characteristics, etiopathogenesis, monitoring and diagnosing of PVAN will be described and discussed, with an extended citation of related relevant literature data. PMID:24175200

  18. IgA Nephropathy

    PubMed Central

    McCoy, Ralph C.; Abramowsky, Carlos R.; Tisher, C. Craig

    1974-01-01

    From a series of 470 specimens of renal tissue examined by immunofluorescence microscopy, 20 specimens were identified and studied in detail from patients without evidence of systemic disease in which IgA was the predominant localizing immunoglobulin. All patients presented with hematuria which was recurrent or persistent, often being exacerbated by upper respiratory infection. Most of the group pursued a benign clinical course with little evidence of decline in renal function. Histopathologic changes in renal biopsy specimens of most of the group consisted of a proliferative glomerulonephritis of variable intensity. Characteristic alterations were seen by electron microscopy which included the presence of electron-dense deposits within the mesangium, the hilar regions of the glomerulus and the basement membrane of Bowman's capsule. Evidence for activation of complement by the alternate pathway at C3 was found with properdin localization in 14 of 15 specimens and with the absence of detectable Clq and C4 in 15 specimens studied for these early acting components. It is concluded that the combined clinical, morphologic and immunologic findings warrant consideration of IgA nephropathy as a distinct clinicopathologic entity. ImagesFig 1Fig 2Fig 3Fig 4Fig 5Fig 6Fig 7Fig 8Fig 9Fig 10Fig 11 PMID:4601708

  19. Autophagy in diabetic nephropathy.

    PubMed

    Ding, Yan; Choi, Mary E

    2015-01-01

    Diabetic nephropathy (DN) is the most common cause of end-stage kidney disease worldwide, and is associated with increased morbidity and mortality in patients with both type 1 and type 2 diabetes. Increasing prevalence of diabetes has made the need for effective treatment of DN critical and thereby identifying new therapeutic targets to improve clinical management. Autophagy is a highly conserved 'self-eating' pathway by which cells degrade and recycle macromolecules and organelles. Autophagy serves as an essential mechanism to maintain homeostasis of glomeruli and tubules, and plays important roles in human health and diseases. Impairment of autophagy is implicated in the pathogenesis of DN. Emerging body of evidence suggests that targeting the autophagic pathway to activate and restore autophagy activity may be renoprotective. In this review, we examine current advances in our understanding of the roles of autophagy in diabetic kidney injury, focusing on studies in renal cells in culture, human kidney tissues, and experimental animal models of diabetes. We discuss the major nutrient-sensing signal pathways and diabetes-induced altered intracellular metabolism and cellular events, including accumulation of advanced glycation end-products, increased oxidative stress, endoplasmic reticulum stress, hypoxia, and activation of the renin-angiotensin system, which modulate autophagic activity and contribute to the development of DN. We also highlight recent studies of autophagy and transforming growth factor-β in renal fibrosis, the final common response to injury that ultimately leads to end-stage kidney failure in both type 1 and type 2 diabetes. These findings suggest the possibility that autophagy can be a therapeutic target against DN. PMID:25349246

  20. Cobrotoxin from Naja naja atra Venom Ameliorates Adriamycin Nephropathy in Rats

    PubMed Central

    Wang, Shu-Zhi; Xu, Yin-li; Zhu, Qi; Kou, Jian-qun; Qin, Zheng-Hong

    2015-01-01

    Chronic kidney disease (CKD) becomes a global health problem with high morbidity and mortality. Adriamycin- (ADR-) induced rodent chronic nephropathy is a classic experimental model of human minimal lesion nephrotic syndrome. The present study investigated the effect of cobrotoxin (CTX) on ADR-induced nephropathy. Rats were given 6 mg/kg ADR once through the tail vein to replicate ADR nephropathy model. CTX was administered to rats daily by placing a fast dissolving CTX membrane strip under the tongue starting from 5 days prior to ADR administration until the end of experiment. The results showed that CTX ameliorated the symptoms of ADR nephropathy syndrome with reduced body weight loss, proteinuria, hypoalbuminemia, dyslipidemia, serum electrolyte imbalance, oxidative stress, renal function abnormities, and kidney pathological lesions. Anti-inflammatory cytokine IL-10 expression was elevated after CTX administration in ADR nephropathy model. CTX inhibited the phosphorylation of IκB-α and NF-κB p65 nuclear translocation. Meanwhile, CTX upregulated the protein level of podocyte-specific nephrin and downregulated the level of fibrosis-related TGF-β. These findings suggest that CTX may be a potential drug for chronic kidney diseases. PMID:26640497

  1. Cyclosporine for the Treatment of HTLV-1-Induced HAM/TSP

    PubMed Central

    Sánchez-Montalvá, Adrián; Salvador, Fernando; Caballero, Estrella; Molina, Israel

    2015-01-01

    Abstract HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) remains a challenging disease. Treatment options are scarce, and their safety and efficacy are currently a matter of concern. We present a case report describing our experience using cyclosporine in a patient with early HAM/TSP who started with a gait disturbance at Vall d’Hebron University Hospital (Barcelona) from August 2012 to October 2013. After 62 weeks of treatment, clinical improvement was observed and proviral load diminished. No safety concerns were observed. Cyclosporine seems to be effective in new-onset HAM/TSP or in chronic HAM/TSP that develops a relapse. However, the duration and safety profile of this steroid-sparing therapy remain unknown and should be further investigated. PMID:25569667

  2. [Use of cyclosporine 0.05% in various ocular surface disorders].

    PubMed

    Maĭchuk, D Iu; Vasil'eva, O A; Shokirova, M M

    2014-01-01

    It is proved that chronic ocular surface inflammatory disease (including allergic blepharitis, recurrent chalyazia, punctuate keratitis, recurrent herpetic corneal erosions, late stages of adenoviral keratoconjunctivitis, etc.) takes part in the development of secondary dry eye syndrome (DES). However, therapies for inflammation-induced impairment of tear production do not provide long-term control of inflammatory process. Cyclosporine 0.05% eye drops are an option. Their effect is well-studied in foreign practice. Local application experience of cyclosporine 0.05% eye drops was summarized at a meeting of the Russian expert group on DES and conclusions were made on their effectiveness in treatment of dry eye syndrome associated with certain ocular surface inflammatory disorders, such as allergic blepharoconjunctivitis, late stages of adenoviral keratoconjunctivitis, and others. PMID:24864503

  3. Pathophysiological role and therapeutic implications of inflammation in diabetic nephropathy

    PubMed Central

    Luis-Rodríguez, Desirée; Martínez-Castelao, Alberto; Górriz, José Luis; De-Álvaro, Fernando; Navarro-González, Juan F

    2012-01-01

    Diabetes mellitus and its complications are becoming one of the most important health problems in the world. Diabetic nephropathy is now the main cause of end-stage renal disease. The mechanisms leading to the development and progression of renal injury are not well known. Therefore, it is very important to find new pathogenic pathways to provide opportunities for early diagnosis and targets for novel treatments. At the present time, we know that activation of innate immunity with development of a chronic low grade inflammatory response is a recognized factor in the pathogenesis of diabetic nephropathy. Numerous experimental and clinical studies have shown the participation of different inflammatory molecules and pathways in the pathophysiology of this complication. PMID:22253941

  4. [C1Q NEPHROPATHY: CASE REPORTS AND LITERATURE REVIEW].

    PubMed

    Galešić, Krešimir; Horvatić, Ivica; Batinić, Danica; Milošević, Danko; Saraga, Marijan; Durdov, Merica Glavina; Ljubanović, Danica Galešić

    2015-01-01

    C1q nephropathy is considered a form of glomerulonephritis, defined by histological findings of dominant Clq immune deposits in renal biopsy. It is a rare disease, most often manifested in children and young adults. The most common clinical manifestation of the disease is nephrotic syndrome, but other renal syndromes could also be found. The cause of the disease is not known, but the immune pathogenesis could be assumed. Often, resistance to glucocorticoid or other immunosuppressive therapy is present, potentially leading to chronic renal insufficiency. We present ten patients with renal biopsy and clinical findings of Clq nephropathy. None of the patients had clinical or serological manifestations of systemic lupus. All patients had normal findings of C3 and C4 components of complement, as well as normal ANF, anti-dsD-NA and ANCA antibodies. PMID:26749950

  5. Membranous nephropathy in sibling cats.

    PubMed

    Nash, A S; Wright, N G

    1983-08-20

    Membranous nephropathy was diagnosed in two sibling cats from the same household. Both cases presented with the nephrotic syndrome but 33 months elapsed before the second cat became ill, by which time the first cat had been in full clinical remission for over a year. PMID:6623883

  6. Current Challenges in Diabetic Nephropathy: Early Diagnosis and Ways to Improve Outcomes

    PubMed Central

    Kim, Jong Ho

    2016-01-01

    Diabetes is often associated with chronic kidney disease (CKD) and is the primary cause of kidney failure in half of patients who receive dialysis therapy. Given the increasing prevalence of diabetes and its high morbidity and mortality, diabetic nephropathy is a serious drawback in individual patients and a tremendous socioeconomic burden on society. Despite growing concern for the management of diabetic nephropathy, the prevalence of CKD with diabetes is the same today as it was 20 years ago. The current strategy to manage diabetic nephropathy, including the control of hyperglycemia, dyslipidemia, and blood pressure and the wide-spread use of renin-angiotensin-aldosterone system inhibitors, is well established to be beneficial in the early stages of diabetic nephropathy. However, the effects are uncertain in patients with relatively progressed CKD. Therefore, early diagnosis or risk verification is extremely important in order to reduce the individual and socioeconomic burdens associated with diabetic nephropathy by providing appropriate management to prevent the development and progression of this condition. This review focuses on recent research and guidelines regarding risk assessment, advances in medical treatment, and challenges of and future treatments for diabetic nephropathy. PMID:27246284

  7. Management of Membranous Nephropathy in Western Countries

    PubMed Central

    Alfaadhel, Talal; Cattran, Daniel

    2015-01-01

    Background Idiopathic membranous nephropathy (IMN) is a common cause of nephrotic syndrome (NS) in adults in Western countries. In 2012, the KDIGO (Kidney Disease: Improving Global Outcomes) working group published guidelines for the management of glomerulonephritis, thus providing a template for the treatment of this condition. While being aware of the impact of the clinicians' acumen and that patients may choose a different therapeutic option due to the risks of specific drugs and also of the evolving guidelines, this review details our approach to the management of patients with IMN in a Western center (Toronto). Summary Based on studies published in Europe and North America, we included recent advances in the diagnosis and management of patients with membranous nephropathy similar to our practice population. We highlight the importance of establishing the idiopathic nature of this condition before initiating immunosuppressive therapy, which should include the screening for secondary causes, especially malignancy in the elderly population. The expected outcomes with and without treatment for patients with different risks of progression will be discussed to help guide clinicians in choosing the appropriate course of treatment. The role of conservative therapy as well as of established immunosuppressive treatment, such as the combination of cyclophosphamide and prednisone, and calcineurin inhibitors (CNIs), as well as of newer agents such as rituximab will be reviewed. Key Messages Appropriate assessment is required to exclude secondary conditions causing membranous glomerulonephritis. The role of antibodies to phospholipase A2 receptor (anti-PLA2R) in establishing the primary disease is growing, though more data are required. The increase in therapeutic options supports treatment individualization, taking into account the availability, benefits and risks, as well as patient preference. Facts from East and West (1) The prevalence of IMN is increasing worldwide

  8. Effect of cyclosporin on immune complex deposition in murine glomerulonephritis.

    PubMed Central

    Quinn, D G; Fennell, J S; Sheils, O; Gaffney, E F; Feighery, C F

    1991-01-01

    Chronic glomerulonephritis (GN) was induced in N/M mice by daily injections of human serum albumin (HSA). The glomerular lesion was similar to that observed in human membranous GN and was characterized by intense mesangial and capillary loop immunofluorescent staining for HSA, IgG and C3. Electron microscopic examination revealed numerous electron-dense deposits in the mesangium and along the subepithelial side of the glomerular basement membrane, the latter deposits being associated with membranous spikes. Chronically injected mice that had been treated with cyclosporin (CsA) from Day 1 had different patterns of immune complex deposition. Mesangial deposition was apparently unaltered but no subepithelial deposits or spikes were evident. In addition, only two out of 21 HSA-injected mice which began CsA treatment on Day 21 had subepithelial deposits. There was no significant difference in serum levels of HSA-specific IgG between the three groups of mice. CsA treatment would therefore appear to ameliorate the immunopathology of antigen-induced glomerulonephritis in this model without affecting serum antibody levels, and may be of therapeutic value in the treatment of human membranous GN. Images Figure 1 Figure 2 Figure 3 PMID:1828056

  9. Exacerbation of allergic contact dermatitis during immunosuppression with cyclosporine A.

    PubMed

    Prignano, F; Bonciolini, V; Bonciani, D; Lotti, T

    2010-08-01

    Allergic contact dermatitis (ACD) is one of the commonest occupational diseases in industrialized countries, where it comprises 20-70% of all occupational diseases. Recent studies found out the top ten allergens, but there are some differences in their frequency in relation to gender and age of patients: Myroxylon pereirae and Carba mix resulted the most prevalent allergens in men, while in women the most common sensitizers were nickel sulfate, PPD, fragrance mix and cobalt chloride. ACD is an inflammatory skin disease caused by repeated skin exposure to contact allergens, in which the lesions are due to T CD8+ cells in a type IV, delayed or cell-mediated, immune reaction. The typical skin lesions of ACD in general outburst in contact areas with the specific allergens and they are erythematosus-squamous lesions with other little differences in relation to localization, for example edema, vesicular-exuding lesions or onychodystrophy. Different treatment options exist and are applied according to the severity of the lesions. Topical treatments consist of bland emollients, corticosteroids ointments, topical immunomodulators such as tacrolimus and pimecrolimus ointments, coal tar and derivatives and irradiation with ultraviolet lights or X-rays; while azathioprine, methotrexate, cyclosporine A, oral retinoids or oral corticosteroids represent systemic options of therapy. Nevertheless, the control of chronic ACD is often difficult, overall in patients with chronic ACD. PMID:20823796

  10. Three-year outcomes from BENEFIT-EXT: a phase III study of belatacept versus cyclosporine in recipients of extended criteria donor kidneys.

    PubMed

    Pestana, J O Medina; Grinyo, J M; Vanrenterghem, Y; Becker, T; Campistol, J M; Florman, S; Garcia, V D; Kamar, N; Lang, P; Manfro, R C; Massari, P; Rial, M D C; Schnitzler, M A; Vitko, S; Duan, T; Block, A; Harler, M B; Durrbach, A

    2012-03-01

    Recipients of extended-criteria donor (ECD) kidneys have poorer long-term outcomes compared to standard-criteria donor kidney recipients. We report 3-year outcomes from a randomized, phase III study in recipients of de novo ECD kidneys (n = 543) assigned (1:1:1) to either a more intensive (MI) or less intensive (LI) belatacept regimen, or cyclosporine. Three hundred twenty-three patients completed treatment by year 3. Patient survival with a functioning graft was comparable between groups (80% in MI, 82% in LI, 80% in cyclosporine). Mean calculated GFR (cGFR) was 11 mL/min higher in belatacept-treated versus cyclosporine-treated patients (42.7 in MI, 42.2 in LI, 31.5 mL/min in cyclosporine). More cyclosporine-treated patients (44%) progressed to GFR <30 mL/min (chronic kidney disease [CKD] stage 4/5) than belatacept-treated patients (27-30%). Acute rejection rates were similar between groups. Posttransplant lymphoproliferative disorder (PTLD) occurrence was higher in belatacept-treated patients (two in MI, three in LI), most of which occurred during the first 18 months; four additional cases (3 in LI, 1 in cyclosporine) occurred after 3 years. Tuberculosis was reported in two MI, four LI and no cyclosporine patients. In conclusion, at 3 years after transplantation, immunosuppression with belatacept resulted in similar patient survival, graft survival and acute rejection, with better renal function compared with cyclosporine. As previously reported, PTLD and tuberculosis were the principal safety findings associated with belatacept in this study population. PMID:22300431

  11. 21 CFR 524.575 - Cyclosporine ophthalmic ointment.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Cyclosporine ophthalmic ointment. 524.575 Section... (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS OPHTHALMIC AND TOPICAL DOSAGE FORM NEW ANIMAL DRUGS § 524.575 Cyclosporine ophthalmic ointment. (a) Specifications. Each gram of ointment contains...

  12. Use of Cyclosporine Therapy in Steroid Resistant Nephrotic Syndrome (SRNS): A Review

    PubMed Central

    Shah, Syed Raza; Altaf, Areeba; Arshad, Mohammad Hussham; Mari, Anum; Noorani, Sahir; Saeed, Eraj; Mevawalla, Areesh Amir; Haq, Zaiyn Ul; Faquih, Muhammad Ehsan

    2016-01-01

    A chronic, progressive disorder Steroid Resistant Nephrotic Syndrome (SRNS) accounts for 10-20% of all children with Nephrotic Syndrome. It is a heterogeneous disorder comprised of persistent edema, proteinuria, hypoalbuminemia and hyperlipidemia. Treatment for steroid-resistant nephrotic syndrome (SRNS) is challenging and children who suffer from SRNS require aggressive treatment to achieve remission. Calcineurin inhibitors have been used more in an empirical manner than on the basis of clear rationale. It was in 1984 when cyclosporine was first considered for the treatment of steroid resistant nephrotic syndrome. Cyclosporin is a calcineurin inhibitor that suppresses immune response by downregulating the transcription of various cytokine genes. Till now many studies have been conducted to determine dosages, duration of therapy, side effects and advantages of cyclosporine. Treatment of SRNS remains a difficult challenge in pediatric nephrology. Treatment should be individualized according to the underlying histopathology, and clinical and environmental conditions of the children. There is an urgent need to distinguish as soon as possible those patients who may benefit from prolonged immunosuppressive treatment from those who will not benefit from such treatment and who will just suffer from its major side effects. The emerging evidence that the majority of genetic forms of SRNS should receive symptomatic treatment only, should also be clinically tested and studies baring its significance should be evaluated in the future. PMID:26573045

  13. Possible Antipruritic Mechanism of Cyclosporine A in Atopic Dermatitis.

    PubMed

    Ko, Kyi Chan; Tominaga, Mitsutoshi; Kamata, Yayoi; Umehara, Yoshie; Matsuda, Hironori; Takahashi, Nobuaki; Kina, Katsunari; Ogawa, Mayuko; Ogawa, Hideoki; Takamori, Kenji

    2016-06-15

    Cyclosporine A is an immunosuppressive agent that suppresses pruritus and is currently used in the treatment of patients with severe atopic dermatitis. The aim of this study was to elucidate the antipruritic mechanism of cyclosporine A using a mouse model of atopic dermatitis. Intraperitoneal injection of cyclosporine A (5 mg/kg) significantly reduced epidermal nerve density, number of scratching bouts, dermatitis scores, and transepidermal water loss, as well as decreasing the numbers of inflammatory cells in the dermis and decreasing epidermal thickness. Intraperitoneal injection of cyclosporine A dose-dependently inhibited increased itch-related receptor gene expression, such as interleukin-31 receptor A and neurokinin-1 receptor, in the dorsal root ganglion of atopic dermatitis model mice. Thus, the antipruritic efficacy of cyclosporine A may involve reduced epidermal nerve density and expression levels of itch-related receptor genes in the dorsal root ganglion, as well as improvement in acanthosis and reduction in cutaneous inflammatory cell number. PMID:26671728

  14. Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients.

    PubMed

    First, M R; Schroeder, T J; Alexander, J W; Stephens, G W; Weiskittel, P; Myre, S A; Pesce, A J

    1991-02-01

    Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, has been shown to inhibit the cytochrome P-450 enzyme system. Thirty-six renal transplant recipients receiving cyclosporine as part of a triple immunosuppressive drug regimen were started on 200 mg/day of oral ketoconazole. The dose of cyclosporine was reduced by 70% at the start of ketoconazole; this dose reduction was based on our previous experience with concomitant cyclosporine-ketoconazole therapy. Ketoconazole was started in patients who had been on cyclosporine for between 10 days and 74 months. The mean cyclosporine dose was 420 mg/day (5.9 mg/kg/day) before starting ketoconazole and 66 mg/day (0.9 mg/kg/day) one year after the addition of ketoconazole; this represents a cyclosporine dose reduction of 84.7% (P less than 0.0001). The mean trough whole-blood cyclosporine concentrations measured by HPLC, were 130 ng/mL preketoconazole and 149 ng/mL after 1 year of combination therapy. Mean serum creatinine and BUN levels were unchanged before and during ketoconazole administration, and no changes in liver function tests were noted. Cyclosporine pharmacokinetics were performed before and after at least three weeks of ketoconazole. Hourly whole-blood samples were measured by HPLC (parent cyclosporine only) and TDX (parent + metabolites). Combination therapy resulted in decreases in the maximum blood concentration and the steady-state volume of distribution divided by the fractional absorption, and increases in mean residence time and the parent-to-parent plus metabolite ratio (calculated by dividing the HPLC by the TDX value). The addition of ketoconazole to cyclosporine-treated patients resulted in a significant inhibition of cyclosporine metabolism and decrease in the dosage. There was minimal nephrotoxicity, and only four rejection episodes occurred on combined therapy. The concomitant administration of the two drugs was well

  15. Emerging therapeutics for the treatment of diabetic nephropathy.

    PubMed

    Brenneman, Jehrod; Hill, Jon; Pullen, Steve

    2016-09-15

    Diabetic nephropathy (DN) is the most common pathology contributing to the development of chronic kidney disease (CKD). DN caused by hypertension and unmitigated inflammation in diabetics, renders the kidneys unable to perform normally, and leads to renal fibrosis and organ failure. The increasing global prevalence of DN has been directly attributed to rising incidences of Type II diabetes, and is now the largest non-communicable cause of death worldwide. Despite the high morbidity, successful new treatments for DN are lacking. This review seeks to provide new insight on emerging clinical candidates under investigation for the treatment of DN. PMID:27520943

  16. The effect of oral metoclopramide on the absorption of cyclosporine.

    PubMed

    Wadhwa, N K; Schroeder, T J; O'Flaherty, E; Pesce, A J; Myre, S A; First, M R

    1987-02-01

    This study was performed to determine the effect of coadministered oral metoclopramide on the absorption of oral cyclosporine in 14 kidney transplant patients with stable renal function. The study was conducted on two consecutive days. Ten patients were studied twice and four patients once, giving 24 studies. The total dosage of metoclopramide was 20 mg. The day on which metoclopramide was administered was chosen randomly. Whole blood cyclosporine levels were analyzed by high performance liquid chromatography. Coadministration of cyclosporine with metoclopramide resulted in a significant increase in mean maximum blood concentration (567 ng/mL nu 388 ng/mL) and mean area under the blood concentration nu time curve (4120 ng X h/mL nu 3370 ng X h/mL), and a significant decrease in mean time to reach maximum concentration: The mean increase in area under the blood concentration versus time curve was 29%. No significant changes were observed in the elimination of cyclosporine when it was coadministered with metoclopramide. These observations suggest that coadministered metoclopramide increased the total absorption of cyclosporine. Metoclopramide has been shown to hasten gastric emptying; since cyclosporine is absorbed predominantly in the small intestine, coadministration of metoclopramide resulted in increased bioavailability of cyclosporine. PMID:3547879

  17. The effect of oral metoclopramide on the absorption of cyclosporine.

    PubMed

    Wadhwa, N K; Schroeder, T J; O'Flaherty, E; Pesce, A J; Myre, S A; First, M R

    1987-02-01

    This study was performed to determine the effect of coadministered oral metoclopramide on the absorption of oral cyclosporine in 14 kidney transplant patients. The study was conducted on two consecutive days. Ten patients were studied twice, and 4 patients once, giving 24 studies. The total dosage of metoclopramide was 20 mg. The day on which metoclopramide was administered was chosen randomly. Whole-blood cyclosporine levels were analyzed by high-performance liquid chromatography. Coadministration of cyclosporine with metoclopramide resulted in a significant increase in mean maximum blood concentration (567 ng/ml versus 388 ng/ml) and mean area under the blood-concentration-versus-time curve (4120 ng X hr/ml versus 3370 ng X hr/ml); and a significant decrease in mean time to reach maximum concentration. The mean increase in area under the blood-concentration-versus-time curve was 29%. No significant changes were observed in the elimination of cyclosporine when it was coadministered with metoclopramide. These observations suggest that coadministered metoclopramide increased the total absorption of cyclosporine. Metoclopramide has been shown to hasten gastric emptying; since cyclosporine is absorbed predominantly in the small intestine, coadministration of metoclopramide resulted in increased bioavailability of cyclosporine. PMID:3544377

  18. Inhibition of Human Immunodeficiency Virus and Growth of Infected T Cells by the Immunosuppressive Drugs Cyclosporin A and FK 506

    NASA Astrophysics Data System (ADS)

    Karpas, Abraham; Lowdell, Mark; Jacobson, S. Kim; Hill, Fergal

    1992-09-01

    The effects of the immunosuppressive drugs cyclosporin A and FK 506 were studied on cells chronically infected with human immunodeficiency virus type 1 (HIV-1) as well as on uninfected and newly infected cells. When cells chronically infected with HIV-1 or with HIV-2 were cocultivated with uninfected cells in the presence of cyclosporin A or FK 506 there was a delay in the formation of syncytia and of cytopathic effects. This inhibitory effect was not due to decreased membrane expression of CD4. In addition, there was an ≈100-fold reduction in the yield of infectious HIV-1 when the infected cells were grown in the presence of these drugs, a finding consistent with other evidence of decreased HIV expression. Both drugs were found to inhibit the growth of chronically infected cells at concentrations that did not inhibit the growth of the uninfected cells. These results, demonstrating that cyclosporin A and FK 506 interfere with HIV production and selectively inhibit the growth of infected cells, suggest that they may be useful in the treatment of this infection and indicate further cellular targets for antiviral agents.

  19. Association of genetic variants with diabetic nephropathy

    PubMed Central

    Rizvi, Saliha; Raza, Syed Tasleem; Mahdi, Farzana

    2014-01-01

    Diabetic nephropathy accounts for the most serious microvascular complication of diabetes mellitus. It is suggested that the prevalence of diabetic nephropathy will continue to increase in future posing a major challenge to the healthcare system resulting in increased morbidity and mortality. It occurs as a result of interaction between both genetic and environmental factors in individuals with both type 1 and type 2 diabetes. Genetic susceptibility has been proposed as an important factor for the development and progression of diabetic nephropathy, and various research efforts are being executed worldwide to identify the susceptibility gene for diabetic nephropathy. Numerous single nucleotide polymorphisms have been found in various genes giving rise to various gene variants which have been found to play a major role in genetic susceptibility to diabetic nephropathy. The risk of developing diabetic nephropathy is increased several times by inheriting risk alleles at susceptibility loci of various genes like ACE, IL, TNF-α, COL4A1, eNOS, SOD2, APOE, GLUT, etc. The identification of these genetic variants at a biomarker level could thus, allow the detection of those individuals at high risk for diabetic nephropathy which could thus help in the treatment, diagnosis and early prevention of the disease. The present review discusses about the various gene variants found till date to be associated with diabetic nephropathy. PMID:25512783

  20. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy.

    PubMed

    Sato, Atsuhisa

    2015-06-01

    Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy is the most common primary disease necessitating dialysis treatment in the world including Japan. Major guidelines for treatment of hypertension in Japan, the United States and Europe recommend the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which suppress the renin-angiotensin system (RAS), as the antihypertensive drugs of first choice in patients with coexisting diabetes. However, even with the administration of RAS inhibitors, failure to achieve adequate anti-albuminuric, renoprotective effects and a reduction in cardiovascular events has also been reported. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with diabetic nephropathy. This review focuses on treatment in diabetic nephropathy and discusses the significance of aldosterone blockade. In pre-nephropathy without overt nephropathy, a mineralocorticoid receptor antagonist can be used to enhance the blood pressure-lowering effects of RAS inhibitors, improve insulin resistance and prevent clinical progression of nephropathy. In CKD categories A2 and A3, the addition of a mineralocorticoid receptor antagonist to an RAS inhibitor can help to maintain 'long-term' antiproteinuric and anti-albuminuric effects. However, in category G3a and higher, sufficient attention must be paid to hyperkalemia. Mineralocorticoid receptor antagonists are not currently recommended as standard treatment in diabetic nephropathy. However, many studies have shown promise of better renoprotective effects if mineralocorticoid receptor antagonists are appropriately used. PMID:25762415

  1. Optimized method for measuring cyclosporin A with /sup 125/I-labeled cyclosporin

    SciTech Connect

    Felder, R.A.; Mifflin, T.E.; Bastani, B.

    1986-07-01

    We evaluated the use of the new iodinated ligand for the in vitro measurement of cyclosporin A by radioimmunoassay (RIA). Substitution of the iodinated cyclosporin (/sup 125/I-CyA) for the corresponding tritium-labeled analog (/sup 3/H-CyA) considerably simplifies and accelerates the currently available RIA, and improves its precision. Analysis of the respective dose-response curves showed that the 50% B0 value was lower for the /sup 125/I-CyA assay than for the /sup 3/H-CyA assay (37 vs 77 micrograms/L). Use of whole-blood specimens minimized interferences from temperature and hematocrit. We conclude that the use of /sup 125/I-CyA in a commercially available RIA for whole-blood specimens is accessible to most laboratories and provides rapid, reproducible data for management of transplant patients.

  2. An unusual cause of acute kidney injury due to oxalate nephropathy in systemic scleroderma.

    PubMed

    Mascio, Heather M; Joya, Christie A; Plasse, Richard A; Baker, Thomas P; Flessner, Michael F; Nee, Robert

    2015-08-01

    Oxalate nephropathy is an uncommon cause of acute kidney injury. Far rarer is its association with scleroderma, with only one other published case report in the literature. We report a case of a 75-year-old African-American female with a history of systemic scleroderma manifested by chronic pseudo-obstruction and small intestinal bacterial overgrowth (SIBO) treated with rifaximin, who presented with acute kidney injury with normal blood pressure. A renal biopsy demonstrated extensive acute tubular injury with numerous intratubular birefringent crystals, consistent with oxalate nephropathy. We hypothesize that her recent treatment with rifaximin for SIBO and decreased intestinal transit time in pseudo-obstruction may have significantly increased intestinal oxalate absorption, leading to acute kidney injury. Oxalate nephropathy should be considered in the differential diagnosis of acute kidney injury in scleroderma with normotension, and subsequent evaluation should be focused on bowel function to include alterations in gut flora due to antibiotic administration. PMID:25500295

  3. Bile cast nephropathy: A case report and review of the literature

    PubMed Central

    Patel, Jaymon; Walayat, Saqib; Kalva, Nikhil; Palmer-Hill, Sidney; Dhillon, Sonu

    2016-01-01

    Bile cast nephropathy is a condition of renal dysfunction in the setting of hyperbilirubinemia. There are very few cases of this condition reported in the last decade and a lack of established treatment guidelines. While the exact etiology remains unknown, bile cast nephropathy is presumed to be secondary to multiple concurrent insults to the kidney including direct toxicity from bile acids, obstructive physiology from bile casts, and systemic hypoperfusion from vasodilation. Therapy directed at bilirubin reduction may improve renal function, but will likely need dialysis or plasmapheresis as well. We report our case of bile cast nephropathy and the therapeutic measures undertaken in a middle-aged male with chronic renal insufficiency that developed hyperbilirubinemia and drug-induced liver injury secondary to antibiotic use. He developed acute renal injury in the setting of rising bilirubin. He subsequently had a progressive decline in renal and hepatic function, requiring dialysis and plasmapheresis with some improvement, ultimately requiring transplantation. PMID:27468221

  4. Bile cast nephropathy: A case report and review of the literature.

    PubMed

    Patel, Jaymon; Walayat, Saqib; Kalva, Nikhil; Palmer-Hill, Sidney; Dhillon, Sonu

    2016-07-21

    Bile cast nephropathy is a condition of renal dysfunction in the setting of hyperbilirubinemia. There are very few cases of this condition reported in the last decade and a lack of established treatment guidelines. While the exact etiology remains unknown, bile cast nephropathy is presumed to be secondary to multiple concurrent insults to the kidney including direct toxicity from bile acids, obstructive physiology from bile casts, and systemic hypoperfusion from vasodilation. Therapy directed at bilirubin reduction may improve renal function, but will likely need dialysis or plasmapheresis as well. We report our case of bile cast nephropathy and the therapeutic measures undertaken in a middle-aged male with chronic renal insufficiency that developed hyperbilirubinemia and drug-induced liver injury secondary to antibiotic use. He developed acute renal injury in the setting of rising bilirubin. He subsequently had a progressive decline in renal and hepatic function, requiring dialysis and plasmapheresis with some improvement, ultimately requiring transplantation. PMID:27468221

  5. Radioimmunoassay of salivary cyclosporine with use of /sup 125/I-labeled cyclosporine

    SciTech Connect

    Coates, J.E.; Lam, S.F.; McGaw, W.T.

    1988-08-01

    We prepared /sup 125/I-labeled cyclosporine (/sup 125/I-CS) by modifying the procedure of Mahoney and Orf and characterized it with regards to maximal immunoreactivity (greater than 90%), trichloroacetic acid precipitability (greater than 90%), and stability (90% immunoreactive after five half-lives of /sup 125/I). For a particular preparation of /sup 125/I-CS, we estimated its immunoreaction concentration (50 pmol/L) and the equilibrium constant for its reaction with Sandoz polyclonal antiserum (K = 3.9 X 10(9) L/mol). By substituting /sup 125/I-CS as tracer in the Sandoz radioimmunoassay and by modifying other aspects of the assay, we developed a procedure that is sufficiently sensitive (0.34 micrograms/L) to allow measurement of trough (lowest inter-dose) cyclosporine concentrations in parotid saliva. Of 38 kidney-transplant patients, 35 had measurable concentrations in saliva (mean 8.3, SD 5.2 micrograms/L), and these correlated moderately with paired serum concentrations (r = 0.68, P less than 0.001). We believe that measurement of salivary cyclosporine may offer a simple way of estimating the free fraction of the drug in serum or plasma.

  6. HNF1 AND HYPERTENSIVE NEPHROPATHY

    PubMed Central

    Dmitrieva, Renata I.; Hinojos, Cruz A.; Boerwinkle, Eric; Braun, Michael C.; Fornage, Myriam; Doris, Peter A.

    2009-01-01

    Hypertension in SHR is associated with renal redox stress and we hypothesized that nephropathy arises in SHR-A3 from altered capacity to mitigate redox stress compared with nephropathy-resistant SHR lines. We measured renal expression of redox genes in distinct lines of the spontaneously hypertensive rat (SHR-A3, SHR-B2, SHR-C) and the normotensive WKY strain. The SHR lines differ in either resisting (SHR-B2, SHR-C) or experiencing hypertensive nephropathy (SHR-A3). Immediately prior to the emergence of hypertensive renal injury expression of redox genes in SHR-A3 was profoundly altered compared with the injury-resistant SHR lines and WKY. This change appeared to arise in anti-oxidant genes where 16 of 28 were expressed at 34.3% of the level in the reference strain (WKY). No such change was observed in the injury-resistant SHR lines. We analyzed occurrence of transcription factor matrices (TFM) in the promoters of the down-regulated antioxidant genes. In these genes, the HNF1 TFM was found to be nearly twice as likely to be present and the overall frequency of HNF1 sites was nearly 5 times higher, compared with HNF1 TFMs in anti-oxidant genes that were not down-regulated. We identified 35 other (non-redox) renal genes regulated by HNF1. These were also significantly down-regulated in SHR-A3, but not in SHR-B2 or SHR-C. Finally, expression of genes that comprise HNF1 (Tcf1, Tcf2 and Dcoh) was also down-regulated in SHR-A3. The present experiments uncover a major change in transcriptional control by HNF1 that affects redox and other genes and precedes emergence of hypertensive renal injury. PMID:18443232

  7. Cyclosporin metabolism by human gastrointestinal mucosal microsomes.

    PubMed Central

    Webber, I R; Peters, W H; Back, D J

    1992-01-01

    The in vitro metabolism of the immunosuppressant cyclosporin (CsA) by human gastrointestinal mucosal microsomes has been studied. Macroscopically normal intestinal (n = 4) and liver (n = 2) tissue was obtained from kidney transplant donors, and microsomes prepared. Intestinal metabolism was most extensive with duodenal protein (15% conversion to metabolites M1/M17 after 2 h incubation at 37 degrees C; metabolite measurement by h.p.l.c). Western blotting confirmed the presence of P-4503A (enzyme subfamily responsible for CsA metabolism) in duodenum and ileum tissue, but not in colon tissue. The results of this study indicate that the gut wall may play a role in the first-pass metabolism of CsA, and could therefore be a contributory factor to the highly variable oral bioavailability of CsA. PMID:1389941

  8. Cyclosporine alters opiate withdrawal in rodents.

    PubMed

    Dafny, N; Wagle, V G; Drath, D B

    1985-05-01

    Opiates exert numerous effects on all levels of the central nervous system with tolerance, physical dependence and withdrawal being characteristics of this drug class. The degree of dependence is directly correlated to the intensity of withdrawal. Therefore, success in modifying the withdrawal syndrome may shed light on the dynamics of opiate addiction. The present study demonstrates that cyclosporine, a widely used immunosuppressive drug, considerably modified the behavioral signs of a naloxone-induced abstinence syndrome in morphine-addicted rats. In previous experiments, alpha-interferon has shown similar results. The similarity in actions of these two immunomodulator drugs is discussed and we suggest that opiate addiction may involve the immune system. PMID:4039025

  9. Use of Cyclosporine in Uterine Transplantation

    PubMed Central

    Saso, Srdjan; Logan, Karl; Abdallah, Yazan; Louis, Louay S.; Ghaem-Maghami, Sadaf; Smith, J. Richard; Del Priore, Giuseppe

    2012-01-01

    Uterine transplantation has been proposed as a possible solution to absolute uterine factor infertility untreatable by any other option. Since the first human attempt in 2000, various teams have tried to clarify which immunosuppressant would be most suitable for protecting the allogeneic uterine graft while posing a minimal risk to the fetus. Cyclosporine A (CsA) is an immunosuppressant widely used by transplant recipients. It is currently being tested as a potential immunosuppressant to be used during UTn. Its effect on the mother and fetus and its influence upon the graft during pregnancy have been of major concern. We review the role of CsA in UTn and its effect on pregnant transplant recipients and their offspring. PMID:22132302

  10. Treatment of myelodysplasia with oral cyclosporin.

    PubMed

    Atoyebi, W; Bywater, L; Rawlings, L; Brunskill, S; Littlewood, T J

    2002-08-01

    Recent studies have shown a good response to immunosuppressive treatment with cyclosporin A (CSA) in patients with the myelodysplastic syndrome (MDS). We have treated six transfusion-dependent MDS patients with CSA for a minimum of 3 months. None of these patients showed a significant response, while the drug was withdrawn in 3/6 patients because of intolerable side-effects. Two reasons for the failure of this treatment in our patients can be advanced. Firstly, the hypoplastic variant of MDS predominated in previous studies in contrast to ours. Secondly, the concomitant use of other immunosuppressive agents in previous studies might have enhanced the effect of CSA. We suggest further therapeutic trials of CSA in MDS, selecting patients on the basis of in vitro studies that predict an immunological basis for their disease, to assess its efficacy in prolonging survival. PMID:12181023

  11. Balkan nephropathy: evolution of our knowledge.

    PubMed

    Bamias, Giorgos; Boletis, John

    2008-09-01

    Balkan endemic nephropathy (BEN), originally described in the late 1950s as a chronic tubulointerstitial kidney disease, is identified by its unique epidemiological features. The most remarkable characteristic of BEN is the focal topographical nature that characterizes its occurrence at the global, national, and even household level. BEN affects only certain endemic rural foci along tributaries of the Danube River in the Balkan countries of Bosnia, Bulgaria, Croatia, Romania, and Serbia. The spatial distribution has remained astonishingly unchanged with time because the disease affects the same endemic clusters as 50 years ago. The natural course of the disease is characterized by universal development of end-stage renal disease and the frequent development of upper urinary tract tumors, posing a substantial disease burden to the afflicted areas. The greatest challenge in the study of BEN has been the elucidation of its cause. The unique features of the disease, in particular its endemic nature and the long incubation period required for the disease to develop, have led to the proposal that BEN represents a unique environmental disease. The quest for the responsible environmental factor has been long and diverse, and although no definitive answer has been provided to date, converging lines of evidence support the theory that long-term consumption of food contaminated with aristolochic acid underlies the pathogenesis of BEN. The present review describes the evolution of our knowledge of BEN in relation to the development of the main theories for its pathogenesis. PMID:18725017

  12. Prevalence of acute and chronic viral seropositivity and characteristics of disease in patients with psoriatic arthritis treated with cyclosporine: a post hoc analysis from a sex point of view on the observational study of infectious events in psoriasis complicated by active psoriatic arthritis

    PubMed Central

    Colombo, Delia; Chimenti, Sergio; Grossi, Paolo Antonio; Marchesoni, Antonio; Bardazzi, Federico; Ayala, Fabio; Simoni, Lucia; Vassellatti, Donatella; Bellia, Gilberto

    2016-01-01

    Background Sex medicine studies have shown that there are sex differences with regard to disease characteristics in immune-mediated inflammatory diseases, including psoriasis, in immune response and susceptibility to viral infections. We performed a post hoc analysis of the Observational Study of infectious events in psoriasis complicated by active psoriatic arthritis (SYNERGY) study in patients with psoriatic arthritis (PsA) treated with immunosuppressive regimens including cyclosporine, in order to evaluate potential between-sex differences in severity of disease and prevalence of viral infections. Methods SYNERGY was an observational study conducted in 24 Italian dermatology clinics, which included 238 consecutively enrolled patients with PsA, under treatment with immunosuppressant regimens including cyclosporin A. In this post hoc analysis, patients’ demographical data and clinical characteristics of psoriasis, severity and activity of PsA, prevalence of seropositivity for at least one viral infection, and treatments administered for PsA and infections were compared between sexes. Results A total of 225 patients were evaluated in this post hoc analysis, and 121 (54%) were males. Demographic characteristics and concomitant diseases were comparable between sexes. Statistically significant sex differences were observed at baseline in Psoriasis Area and Severity Index score (higher in males), mean number of painful joints, Bath Ankylosing Spondylitis Disease Activity Index, and the global activity of disease assessed by patients (all higher in females). The percentage of patients with at least one seropositivity detected at baseline, indicative of concomitant or former viral infection, was significantly higher among women than among men. No between-sex differences were detected in other measures, at other time points, and in treatments. Patients developed no hepatitis B virus or hepatitis C virus reactivation during cyclosporine treatment. Conclusion Our post hoc

  13. Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?

    PubMed Central

    Kang, Sung-Yoon; Sohn, Kyoung-Hee; Lee, Jeong-Ok; Kim, Sae-Hoon; Cho, Sang-Heon

    2015-01-01

    Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80. PMID:26240796

  14. Intravenous tacrolimus and cyclosporine induced anaphylaxis: what is next?

    PubMed

    Kang, Sung-Yoon; Sohn, Kyoung-Hee; Lee, Jeong-Ok; Kim, Sae-Hoon; Cho, Sang-Heon; Chang, Yoon-Seok

    2015-07-01

    Tacrolimus and cyclosporine have been used in various formulations, but their hypersensitivity reactions are rare in practice. Castor oil derivatives are nonionic surfactants used in aqueous preparations of hydrophobic active pharmaceutical ingredients. Castor oil derivatives that can be used as additives to tacrolimus and cyclosporine may play a role in the development of hypersensitivity reactions, especially anaphylaxis. Various immunologic and nonimmunologic mechanisms have been implicated in hypersensitivity reactions induced by castor oil derivatives. Physicians should be aware that not only the drug itself, but also its additives or metabolites could induce hypersensitivity reactions. We report a case of anaphylaxis caused by vitamin K (phytonadine), serotonin antagonist (granisetron), intravenous tacrolimus, and cyclosporine. Interestingly, the patient tolerated oral cyclosporine, which did not contain Cremophor EL or polysorbate 80. PMID:26240796

  15. Childhood AIDS nephropathy: a 10-year experience.

    PubMed Central

    Rajpoot, D.; Kaupke, C. J.; Vaziri, N. D.; Rao, T. K.; Pomrantz, A.; Fikrig, S.

    1996-01-01

    The objective of this study was to define the demographic, immunologic, and clinical characteristics of children with acquired immunodeficiency syndrome (AIDS) and AIDS nephropathy, and contrast this with the existing adult data. Data from 62 pediatric patients with AIDS who were treated at SUNY Health Science Center, Brooklyn, New York, between 1983 and 1993 were analyzed. Human immunodeficiency virus (HIV) infection was acquired during the neonatal period by vertical transmission (n = 60) or blood transfusion (n = 2). All children with AIDS who exhibited clinical nephropathy died (n = 16), with mean survival of 55.3 months. In contrast, 32 of 56 AIDS patients (70%) who did not manifest nephropathy were alive at the end of the study period. Patients with nephropathy were noted to have significantly lower CD4+ lymphocyte counts than those without nephropathy. These observations suggest that the predominant renal lesion in pediatric patients who acquired HIV infection during the perinatal period is focal segmental glomerulosclerosis, although a variety of other histological lesions were present. As in adults, the survival in children is dismal following the onset of clinical renal disease. In contrast to the adult population in whom multiple risk factors can potentially contribute to AIDS-associated nephropathy, occurrence of nephropathy in children with vertical HIV transmission provides convincing evidence for the pathogenetic role of HIV infection. PMID:8803430

  16. Cyclosporin for treatment of life-threatening alloimmunization.

    PubMed

    Tilly, H; Azagury, M; Bastit, D; Lallemand, A; Piguet, H

    1990-05-01

    We describe a 16-year-old girl with aplastic anemia who, 1 year after initial diagnosis developed a refractory state to platelet transfusions due to alloimmunization and resulting in severe bleeding. Treatment with cyclosporin, initially prescribed as treatment of the bone marrow failure, resulted in prompt decrease in lymphocytotoxic antibodies, which paralleled a marked improvement in platelet recovery. To our knowledge, such a dramatic effect of cyclosporin on alloimmunization has not been previously reported and merits further attention. PMID:2327409

  17. Anorexia nervosa: from purgative behaviour to nephropathy. a case report

    PubMed Central

    2009-01-01

    Background Individuals who suffer from Anorexia Nervosa refuse to maintain a minimally normal body weight, are intensely afraid of gaining weight and exhibit a significant disturbance in the perception of the shape and size of their body. Postmenarchal females with this disorder are amenorrohic. In the Binge-Eating/Purging subtype individuals regularly engage in binge eating and purging behaviour (i.e self-induced vomiting or misuse of laxatives, diuretics, or enemas). Hypokalaemia is often seen in chronic Anorexia Nervosa, especially that of the purging type (ANp), and, as well as electrocardiographic anomalies, this can lead to tubulointerstitial nephritis (hypokalaemic nephropathy) with typical histological characteristics. The physiopathological mechanisms behind this damage are linked to altered stimulation of vasoactive mediators, and to the ammonium-mediated activation of the alternative complement pathway. However, it has not yet been ascertained whether a variant of the pathway specific for ANp [1], exists. Case presentation We describe herein a case of hypokalaemic nephropathy in a patient affected by chronic ANp who presented to our Centre for Eating Disorders. Conclusion Hypokalaemia can provoke cardiovascular alterations as well as muscular and renal complications, and thus potential renal damage needs to be investigated in patients suffering from long-term purgative anorexia. PMID:19144110

  18. The endothelium in diabetic nephropathy.

    PubMed

    Advani, Andrew; Gilbert, Richard E

    2012-03-01

    The long-term complications of diabetes are characterized by pathologic changes in both the microvasculature and conduit vessels. Although the fenestrated glomerular endothelium classically has been viewed as providing little in the way of an impediment to macromolecular flow, increasing evidence illustrates that this is not the case. Rather, hyperglycemia-mediated endothelial injury may predispose to albuminuria in diabetes both through direct effects and through bidirectional communication with neighboring podocytes. Although neo-angiogenesis of the glomerular capillaries may be a feature of early diabetes, particularly in the experimental setting, loss of capillaries in the glomerulus and in the interstitium are key events that each correlate closely with declining glomerular filtration rate in patients with diabetic nephropathy. The hypoxic milieu that follows the microvascular rarefaction provides a potent stimulus for fibrogenesis, leading to the glomerulosclerosis and tubulointerstitial fibrosis that characterize advanced diabetic kidney disease. Given the pivotal role the endothelium plays in both the development and the progression of diabetic nephropathy we need effective strategies that prevent its loss or accelerate its regeneration. Such advances likely will lead not only to improved tissue oxygenation and reduced fibrosis, but also to improved long-term renal function. PMID:22617769

  19. Comprehensive approach to diabetic nephropathy

    PubMed Central

    Satirapoj, Bancha; Adler, Sharon G.

    2014-01-01

    Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with diabetes. This complication reflects a complex pathophysiology, whereby various genetic and environmental factors determine susceptibility and progression to end-stage renal disease. DN should be considered in patients with type 1 diabetes for at least 10 years who have microalbuminuria and diabetic retinopathy, as well as in patients with type 1 or type 2 diabetes with macroalbuminuria in whom other causes for proteinuria are absent. DN may also present as a falling estimated glomerular filtration rate with albuminuria as a minor presenting feature, especially in patients taking renin–angiotensin–aldosterone system inhibitors (RAASi). The pathological characteristic features of disease are three major lesions: diffuse mesangial expansion, diffuse thickened glomerular basement membrane, and hyalinosis of arterioles. Functionally, however, the pathophysiology is reflected in dysfunction of the mesangium, the glomerular capillary wall, the tubulointerstitium, and the vasculature. For all diabetic patients, a comprehensive approach to management including glycemic and hypertensive control with RAASi combined with lipid control, dietary salt restriction, lowering of protein intake, increased physical activity, weight reduction, and smoking cessation can reduce the rate of progression of nephropathy and minimize the risk for cardiovascular events. This review focuses on the latest published data dealing with the mechanisms, diagnosis, and current treatment of DN. PMID:26894033

  20. Effects of Nigella sativa and Lepidium sativum on Cyclosporine Pharmacokinetics

    PubMed Central

    Al-Jenoobi, F. I.; Al-Suwayeh, S. A.; Muzaffar, Iqbal; Al-Kharfy, Khalid M.; Korashy, Hesham M.; Al-Mohizea, Abdullah M.; Raish, Mohd

    2013-01-01

    The present study was conducted to investigate the effects of Nigella sativa and Lepidium sativum on the pharmacokinetics of cyclosporine in rabbits. Two groups of animals were treated separately with Nigella sativa (200 mg/kg p.o.) or Lepidium sativum (150 mg/kg p.o.) for eight consecutive days. On the 8th day, cyclosporine (30 mg/kg p.o.) was administered to each group one hour after herbal treatment. Blood samples were withdrawn at different time intervals (0.0, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 6.0, 8.0, 12, and 24 hrs) from marginal ear vein. Cyclosporine was analyzed using UPLC/MS method. The coadministration of Nigella sativa significantly decreased the Cmax and AUC0−∞ of cyclosporine; the change was observed by 35.5% and 55.9%, respectively (P ≤ 0.05). Lepidium sativum did not produce any significant change in Cmax of cyclosporine, although its absorption was significantly delayed compared with control group. A remarkable change was observed in Tmax and AUC0−t of Lepidium sativum treated group. Our findings suggest that concurrent consumption of Nigella sativa and Lepidium sativum could alter the pharmacokinetics of cyclosporine at various levels. PMID:23957013

  1. Histopathological Study of Cyclosporine Pulmonary Toxicity in Rats.

    PubMed

    Elshama, Said Said; El-Kenawy, Ayman El-Meghawry; Osman, Hosam-Eldin Hussein

    2016-01-01

    Cyclosporine is considered one of the common worldwide immunosuppressive drugs that are used for allograft rejection prevention. However, articles that address adverse effects of cyclosporine use on the vital organs such as lung are still few. This study aims to investigate pulmonary toxic effect of cyclosporine in rats by assessment of pulmonary histopathological changes using light and electron microscope examination. Sixty male adult albino rats were divided into three groups; each group consists of twenty rats. The first received physiological saline while the second and third groups received 25 and 40 mg/kg/day of cyclosporine, respectively, by gastric gavage for forty-five days. Cyclosporine reduced the lung and body weight with shrinkage or pyknotic nucleus of pneumocyte type II, degeneration of alveoli and interalveolar septum beside microvilli on the alveolar surface, emphysema, inflammatory cellular infiltration, pulmonary blood vessels congestion, and increase of fibrous tissues in the interstitial tissues and around alveoli with negative Periodic Acid-Schiff staining. Prolonged use of cyclosporine induced pulmonary ultrastructural and histopathological changes with the lung and body weight reduction depending on its dose. PMID:26941796

  2. Histopathological Study of Cyclosporine Pulmonary Toxicity in Rats

    PubMed Central

    Elshama, Said Said; EL-Kenawy, Ayman El-Meghawry; Osman, Hosam-Eldin Hussein

    2016-01-01

    Cyclosporine is considered one of the common worldwide immunosuppressive drugs that are used for allograft rejection prevention. However, articles that address adverse effects of cyclosporine use on the vital organs such as lung are still few. This study aims to investigate pulmonary toxic effect of cyclosporine in rats by assessment of pulmonary histopathological changes using light and electron microscope examination. Sixty male adult albino rats were divided into three groups; each group consists of twenty rats. The first received physiological saline while the second and third groups received 25 and 40 mg/kg/day of cyclosporine, respectively, by gastric gavage for forty-five days. Cyclosporine reduced the lung and body weight with shrinkage or pyknotic nucleus of pneumocyte type II, degeneration of alveoli and interalveolar septum beside microvilli on the alveolar surface, emphysema, inflammatory cellular infiltration, pulmonary blood vessels congestion, and increase of fibrous tissues in the interstitial tissues and around alveoli with negative Periodic Acid-Schiff staining. Prolonged use of cyclosporine induced pulmonary ultrastructural and histopathological changes with the lung and body weight reduction depending on its dose. PMID:26941796

  3. IFI27 Is a Useful Genetic Marker for Diagnosis of Immunoglobulin A Nephropathy and Membranous Nephropathy Using Peripheral Blood

    PubMed Central

    Muso, Eri; Yamamoto, Ryohei; Shinzawa, Maki; Iwasaki, Yukako; Iwatani, Hirotsugu; Nakanishi, Takeshi; Isaka, Yoshitaka; Nojima, Hiroshi

    2016-01-01

    Diagnosis of chronic glomerulonephritis (CGN) depends primarily on renal biopsy, which is expensive and requires hospitalization, creating a demand for noninvasive diagnostic method for this disease. We used DNA microarray analysis to search for genes whose expression levels in peripheral blood mononuclear cells (PBMCs) could distinguish between patients with CGN and healthy volunteers (HVs). We selected immunoglobulin A nephropathy (IgAN) and membranous nephropathy (MN) as typical forms of CGN. The mRNA level of the gene encoding interferon (IFN)-alpha-inducible protein 27, IFI27, which is preferentially expressed in podocytes of glomeruli, was lower in PBMCs of IgAN and MN patients than in those of HVs. This result was confirmed by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). Moreover, qRT-PCR analysis revealed that the IFI27 mRNA level was reduced in PBMCs of patients with other types of chronic glomerulonephritis. IFI27 immunohistochemical staining of biopsied specimens also confirmed reduced expression of IFI27 protein in IgAN and MN patients. Based on these results, we propose that IFI27 could serve as a noninvasive diagnostic marker for CGNs using peripheral blood. PMID:27100186

  4. Analgesic Nephropathy (Painkillers and the Kidneys)

    MedlinePlus

    ... American Kidney Fund National Kidney Foundation, Inc. MedlinePlus Kidney and Urologic Disease Organizations Many organizations provide support ... Alternate Language URL Analgesic Nephropathy (Painkillers and the Kidneys) Page Content On this page: Acute Kidney Failure ...

  5. Low-Dose IL-17 Therapy Prevents and Reverses Diabetic Nephropathy, Metabolic Syndrome, and Associated Organ Fibrosis.

    PubMed

    Mohamed, Riyaz; Jayakumar, Calpurnia; Chen, Feng; Fulton, David; Stepp, David; Gansevoort, Ron T; Ramesh, Ganesan

    2016-03-01

    Diabetes is the leading cause of kidney failure, accounting for >45% of new cases of dialysis. Diabetic nephropathy is characterized by inflammation, fibrosis, and oxidant stress, pathologic features that are shared by many other chronic inflammatory diseases. The cytokine IL-17A was initially implicated as a mediator of chronic inflammatory diseases, but recent studies dispute these findings and suggest that IL-17A can favorably modulate inflammation. Here, we examined the role of IL-17A in diabetic nephropathy. We observed that IL-17A levels in plasma and urine were reduced in patients with advanced diabetic nephropathy. Type 1 diabetic mice that are genetically deficient in IL-17A developed more severe nephropathy, whereas administration of low-dose IL-17A prevented diabetic nephropathy in models of type 1 and type 2 diabetes. Moreover, IL-17A administration effectively treated, prevented, and reversed established nephropathy in genetic models of diabetes. Protective effects were also observed after administration of IL-17F but not IL-17C or IL-17E. Notably, tubular epithelial cell-specific overexpression of IL-17A was sufficient to suppress diabetic nephropathy. Mechanistically, IL-17A administration suppressed phosphorylation of signal transducer and activator of transcription 3, a central mediator of fibrosis, upregulated anti-inflammatory microglia/macrophage WAP domain protein in an AMP-activated protein kinase-dependent manner and favorably modulated renal oxidative stress and AMP-activated protein kinase activation. Administration of recombinant microglia/macrophage WAP domain protein suppressed diabetes-induced albuminuria and enhanced M2 marker expression. These observations suggest that the beneficial effects of IL-17 are isoform-specific and identify low-dose IL-17A administration as a promising therapeutic approach in diabetic kidney disease. PMID:26334030

  6. Tissue distribution, disposition, and metabolism of cyclosporine in rats

    SciTech Connect

    Wagner, O.; Schreier, E.; Heitz, F.; Maurer, G.

    1987-05-01

    Tissue distribution, disposition, and metabolism of /sup 3/H-cyclosporine were studied in rats after single and repeated oral doses of 10 and 30 mg/kg and after an iv dose of 3 mg/kg. The oral doses of 10 and 30 mg/kg were dissolved in polyethylene glycol 200/ethanol or in olive oil/Labrafil/ethanol. Absorption from both formulations was slow and incomplete, with peak /sup 3/H blood levels at 3-4 hr. Approximately 30% of the radioactive dose was absorbed, which is consistent with oral bioavailability data for cyclosporine. More than 70% of the radioactivity was excreted in feces and up to 15% in urine. Elimination via the bile accounted for 10 and 60% of the oral and iv doses, respectively. Since unchanged cyclosporine predominated in both blood and tissues at early time points, the half-lives of the distribution phases (t 1/2 alpha) of parent drug and of total radioactivity were similar. In blood, kidney, liver, and lymph nodes, t 1/2 alpha of cyclosporine ranged from 6-10 hr. Elimination of radioactivity from the systemic circulation was multiphasic, with a terminal half-life of 20-30 hr. /sup 3/H-Cyclosporine was extensively distributed throughout the body, with highest concentrations in liver, kidney, endocrine glands, and adipose tissue. The concentrations of both total radioactivity and parent drug were greater in tissues than in blood, which is consistent with the high lipid solubility of cyclosporine and some of its metabolites. Skin and adipose tissue were the main storage sites for unchanged cyclosporine. Elimination half-lives were slower for most tissues than for blood and increased with multiple dosing. The amount of unchanged drug was negligible in urine and bile.

  7. Amadori albumin in diabetic nephropathy.

    PubMed

    Neelofar, Km; Ahmad, Jamal

    2015-01-01

    Nonenzymatic glycation of macromolecules in diabetes mellitus (DM) is accelerated due to persistent hyperglycemia. Reducing sugar such as glucose reacts non enzymatically with free €-amino groups of proteins through series of reactions forming Schiff bases. These bases are converted into Amadori product and further into AGEs. Non enzymatic glycation has the potential to alter the biological, structural and functional properties of macromolecules both in vitro and in vivo. Studies have suggested that amadori as well as AGEs are involved in the micro-macro vascular complications in DM, but most studies have focused on the role of AGEs in vascular complications of diabetes. Recently putative AGE-induced patho-physiology has shifted attention from the possible role of amadori-modified proteins, the predominant form of the glycated proteins in the development of the diabetic complications. Human serum albumin (HSA), the most abundant protein in circulation contains 59 lysine and 23 arginine residues that could, in theory be involved in glycation. Albumin has dual nature, first as a marker of intermediate glycation and second as a causative agent of the damage of tissues. Among the blood proteins, hemoglobin and albumin are the most common proteins that are glycated. HSA with a shorter half life than RBC, appears to be an alternative marker of glycemic control as it can indicate blood glucose status over a short period (2-3 weeks) and being unaffected by RBCs life span and variant haemoglobin, anemia etc which however, affect HbA1c. On the other hand, Amadori albumin may accumulate in the body tissues of the diabetic patients and participate in secondary complications. Amadori-albumin has potential role in diabetic glomerulosclerosis due to long term hyperglycaemia and plays an important role in the pathogenesis of diabetic nephropathy. This review is an approach to compile both the nature of glycated albumin as a damaging agent of tissues and as an intermediate

  8. Cyclosporin in cell therapy for cardiac regeneration.

    PubMed

    Jansen Of Lorkeers, S J; Hart, E; Tang, X L; Chamuleau, M E D; Doevendans, P A; Bolli, R; Chamuleau, S A J

    2014-07-01

    Stem cell therapy is a promising strategy in promoting cardiac repair in the setting of ischemic heart disease. Clinical and preclinical studies have shown that cell therapy improves cardiac function. Whether autologous or allogeneic cells should be used, and the need for immunosuppression in non-autologous settings, is a matter of debate. Cyclosporin A (CsA) is frequently used in preclinical trials to reduce cell rejection after non-autologous cell therapy. The direct effect of CsA on the function and survival of stem cells is unclear. Furthermore, the appropriate daily dosage of CsA in animal models has not been established. In this review, we discuss the pros and cons of the use of CsA on an array of stem cells both in vitro and in vivo. Furthermore, we present a small collection of data put forth by our group supporting the efficacy and safety of a specific daily CsA dosage in a pig model. PMID:24831573

  9. Lack of effect of spiramycin on cyclosporin pharmacokinetics.

    PubMed Central

    Vernillet, L; Bertault-Peres, P; Berland, Y; Barradas, J; Durand, A; Olmer, M

    1989-01-01

    1. The influence of spiramycin coadministration on cyclosporin pharmacokinetics was studied in five renal transplant patients. The plasma concentrations of cyclosporin were measured both by non-specific radioimmunoassay (RIA) and high-performance liquid chromatography (h.p.l.c.). 2. The kinetics of cyclosporin were followed before treatment, and after 1 day and then 2 weeks of oral treatment with spiramycin (3 X 10(6) iu, twice daily). The main pharmacokinetic parameters (the area under the plasma drug concentration-time curve, the maximum plasma drug concentration and the time to reach it) obtained both by RIA and h.p.l.c. were not modified by spiramycin cotreatment after 1 day, nor after 2 weeks of spiramycin administration. Therefore, the pharmacokinetics of cyclosporin (parent drug and parent drug plus metabolites) are not influenced by the coadministration of spiramycin macrolide at therapeutic dosage. 3. Spiramycin may be preferable to other macrolide antibiotics known to interact with cyclosporin such as erythromycin or josamycin. PMID:2667601

  10. Diabetic Nephropathy for the Primary Care Provider: New Understandings on Early Detection and Treatment

    PubMed Central

    Kowalski, Andrew; Krikorian, Armand; Lerma, Edgar V.

    2014-01-01

    Background Diabetic nephropathy is the leading cause of renal disease in the United States, occurring in 20%-40% of patients with diabetes. This condition is a distinct manifestation of diabetic renal disease seen in patients with type 1 and type 2 diabetes. Despite clear screening and management recommendations, diabetic nephropathy remains substantially underdiagnosed. Methods This review presents recent guidelines and recommendations from varied work groups to identify, monitor, and halt the progression of diabetic nephropathy. Our search of the recent literature focused on diagnostic criteria, the latest screening recommendations, novel screening methods, current research, new treatment recommendations, and goals for early intervention. Results Current recommendations for early detection and treatment of diabetic nephropathy include yearly albumin to creatinine ratio checks and more frequent tests if indicated based on glomerular filtration rate and albuminuria; optimizing glucose control with a target hemoglobin A1c goal of <7%; initiating angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) as the first line in disease management with dual therapy of ACE inhibitors and ARBs no longer recommended; managing blood pressure with a goal of <140/90 mmHg as the target for all patients with diabetes; and initiating statin therapy for patients <50 years old and with concomitant chronic kidney disease and diabetes and in all patients with chronic kidney disease >50 years of age regardless of the coexistence of diabetes. Conclusion With early detection, proper screening, and management, the impact of diabetic nephropathy may be better mitigated to lessen its impact on society and healthcare. PMID:25249803

  11. Early Differential Expression of Oncostatin M in Obstructive Nephropathy

    PubMed Central

    Truong, Luan D.; Tawil, Ahmad; Wang, Wansheng; Dawson, Sara; Lan, Hui Y.; Zhang, Ping; Garcia, Gabriela E.; Smith, C. Wayne

    2010-01-01

    Interstitial fibrosis plays a major role in progression of renal diseases. Oncostatin M (OSM) is a cytokine that regulates cell survival, differentiation, and proliferation. Renal tissue from patients with chronic obstructive nephropathy was examined for OSM expression. The elevated levels in diseased human kidneys suggested possible correlation between OSM level and kidney tissue fibrosis. Indeed, unilateral ureteral obstruction (UUO), a model of renal fibrosis, increased OSM and OSM receptor (OSM-R) expression in a time-dependent manner within hours following UUO. In vitro, OSM overexpression in tubular epithelial cells (TECs) resulted in epithelial-myofibroblast transdifferentiation. cDNA microarray technology identified up-regulated expression of immune modulators in obstructed compared with sham-operated kidneys. In vitro, OSM treatment up-regulated CC chemokine ligand CCL7, and CXC chemokine ligand (CXCL)-14 mRNA in kidney fibroblasts. In vivo, treatment of UUO mice with neutralizing anti-OSM antibody decreased renal chemokines expression. In conclusion, OSM is up-regulated in kidney tissue early after urinary obstruction. Therefore, OSM might play an important role in initiation of renal fibrogenesis, possibly by inducing myofibroblast transdifferentiation of TECs as well as leukocyte infiltration. This process may, in turn, contribute in part to progression of obstructive nephropathy and makes OSM a promising therapeutic target in renal fibrosis. PMID:20626292

  12. APOL1 nephropathy: from gene to mechanisms of kidney injury.

    PubMed

    Kruzel-Davila, Etty; Wasser, Walter G; Aviram, Sharon; Skorecki, Karl

    2016-03-01

    The contribution of African ancestry to the risk of focal segmental glomerulosclerosis and chronic kidney disease has been partially explained by the recently described chromosome 22q variants in the gene apolipoprotein L1 (APOL1). The APOL1 variants appear at a high allele frequency in populations of West African ancestry as a result of apparent adaptive selection of the heterozygous state. Heterozygosity protects from infection with Trypanosoma brucei rhodesiense. This review will describe the role of the approaches in population genetics for the description of APOL1-associated nephropathies and draw inferences as to the biologic mechanisms from genetic epidemiology findings to date. Modifier loci can influence APOL1 risk for the development of kidney disease. 'Second hits', both viral and non-viral, may explain the discrepancy between the remarkably high odds ratios and the low lifetime risks of kidney disease in two allele carriers of APOL1 risk variants. Therapeutic strategies for APOL1-associated nephropathies will require the prevention and treatment of these 'second hits' and the development of drugs to protect the APOL1 downstream renal injury pathways. PMID:25561578

  13. Extracorporeal shock wave therapy does not improve hypertensive nephropathy.

    PubMed

    Caron, Jonathan; Michel, Pierre-Antoine; Dussaule, Jean-Claude; Chatziantoniou, Christos; Ronco, Pierre; Boffa, Jean-Jacques

    2016-06-01

    Low-energy extracorporeal shock wave therapy (SWT) has been shown to improve myocardial dysfunction, hind limb ischemia, erectile function, and to facilitate cell therapy and healing process. These therapeutic effects were mainly due to promoting angiogenesis. Since chronic kidney diseases are characterized by renal fibrosis and capillaries rarefaction, they may benefit from a proangiogenic treatment. The objective of our study was to determine whether SWT could ameliorate renal repair and favor angiogenesis in L-NAME-induced hypertensive nephropathy in rats. SWT was started when proteinuria exceeded 1 g/mmol of creatinine and 1 week after L-NAME removal. SWT consisted of implying 0.09 mJ/mm(2) (400 shots), 3 times per week. After 4 weeks of SWT, blood pressure, renal function and urinary protein excretion did not differ between treated (LN + SWT) and untreated rats (LN). Histological lesions including glomerulosclerosis and arteriolosclerosis scores, tubular dilatation and interstitial fibrosis were similar in both groups. In addition, peritubular capillaries and eNOS, VEGF, VEGF-R, SDF-1 gene expressions did not increase in SWT-treated compared to untreated animals. No procedural complications or adverse effects were observed in control (C + SWT) and hypertensive rats (LN + SWT). These results suggest that extracorporeal kidney shock wave therapy does not induce angiogenesis and does not improve renal function and structure, at least in the model of hypertensive nephropathy although the treatment is well tolerated. PMID:27255359

  14. Tempol effects on diabetic nephropathy in male rats

    PubMed Central

    Ranjbar, Akram; Ghasemi, Hassan; Hatami, Mahdi; Dadras, Farahanaz; Heidary Shayesteh, Tavakol; Khoshjou, Farhad

    2016-01-01

    Introduction: Diabetic nephropathy (DN) is the most common cause of the chronic kidney disease in the world. Oxidative stress on the other hand has a major and well known role in its pathophysiology. Objectives: The aim of the study is to figure out if tempol, a synthetic antioxidant agent, modifies DN and to determine its relevance to changes of serum oxidative biomarkers. Materials and Methods: Twenty-seven male rats were equally divided in to 4 groups (7 rats for each group). Group I (control or C), group II (diabetic or D), groups III (Tempol) which were given tempol (100 mg/kg/day) by gavages for 28 days and group IV (D&T) which includes diabetic rats that also received same dose of tempol. After treatment, blood samples were isolated. Enzymatic scavengers including catalase (CAT), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activities, lipid peroxidation (LPO), total antioxidant capacity (TAC) and total thiol molecules (TTM) were measured. Blood urea nitrogen (BUN), creatinine (Cr) an albumin/Cr ratio were evaluated as well. Statistical differences were assessed with one-way analysis of variance (ANOVA) by SPSS followed by Tukey t test. Results: Oxidative stress biomarkers modified and Alb/Cr ratio increased in diabetic group (II), however, they were altered to normal in group IV (D&T) compared with diabetic group (D). Conclusion: Tempol can modify oxidative stress biomarkers and presumably nephropathy in diabetic rats. PMID:27471738

  15. Conversion from Tacrolimus to Cyclosporine A Improves Glucose Tolerance in HCV-Positive Renal Transplant Recipients

    PubMed Central

    Handisurya, Ammon; Kerscher, Corinna; Tura, Andrea; Herkner, Harald; Payer, Berit Anna; Mandorfer, Mattias; Werzowa, Johannes; Winnicki, Wolfgang; Reiberger, Thomas; Kautzky-Willer, Alexandra; Pacini, Giovanni; Säemann, Marcus; Schmidt, Alice

    2016-01-01

    Background Calcineurin-inhibitors and hepatitis C virus (HCV) infection increase the risk of post-transplant diabetes mellitus. Chronic HCV infection promotes insulin resistance rather than beta-cell dysfunction. The objective was to elucidate whether a conversion from tacrolimus to cyclosporine A affects fasting and/or dynamic insulin sensitivity, insulin secretion or all in HCV-positive renal transplant recipients. Methods In this prospective, single-center study 10 HCV-positive renal transplant recipients underwent 2h-75g-oral glucose tolerance tests before and three months after the conversion of immunosuppression from tacrolimus to cyclosporine A. Established oral glucose tolerance test-based parameters of fasting and dynamic insulin sensitivity and insulin secretion were calculated. Data are expressed as median (IQR). Results After conversion, both fasting and challenged glucose levels decreased significantly. This was mainly attributable to a significant amelioration of post-prandial dynamic glucose sensitivity as measured by the oral glucose sensitivity-index OGIS [422.17 (370.82–441.92) vs. 468.80 (414.27–488.57) mL/min/m2, p = 0.005), which also resulted in significant improvements of the disposition index (p = 0.017) and adaptation index (p = 0.017) as markers of overall glucose tolerance and beta-cell function. Fasting insulin sensitivity (p = 0.721), insulinogenic index as marker of first-phase insulin secretion [0.064 (0.032–0.106) vs. 0.083 (0.054–0.144) nmol/mmol, p = 0.093) and hepatic insulin extraction (p = 0.646) remained unaltered. No changes of plasma HCV-RNA levels (p = 0.285) or liver stiffness (hepatic fibrosis and necroinflammation, p = 0.463) were observed after the conversion of immunosuppression. Conclusions HCV-positive renal transplant recipients show significantly improved glucose-stimulated insulin sensitivity and overall glucose tolerance after conversion from tacrolimus to cyclosporine A. Considering the HCV

  16. Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling.

    PubMed

    Rodrigues-Diez, Raquel; González-Guerrero, Cristian; Ocaña-Salceda, Carlos; Rodrigues-Diez, Raúl R; Egido, Jesús; Ortiz, Alberto; Ruiz-Ortega, Marta; Ramos, Adrián M

    2016-01-01

    The introduction of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus greatly reduced the rate of allograft rejection, although their chronic use is marred by a range of side effects, among them vascular toxicity. In transplant patients, it is proved that innate immunity promotes vascular injury triggered by ischemia-reperfusion damage, atherosclerosis and hypertension. We hypothesized that activation of the innate immunity and inflammation may contribute to CNI toxicity, therefore we investigated whether TLR4 mediates toxic responses of CNIs in the vasculature. Cyclosporine and tacrolimus increased the production of proinflammatory cytokines and endothelial activation markers in cultured murine endothelial and vascular smooth muscle cells as well as in ex vivo cultures of murine aortas. CNI-induced proinflammatory events were prevented by pharmacological inhibition of TLR4. Moreover, CNIs were unable to induce inflammation and endothelial activation in aortas from TLR4(-/-) mice. CNI-induced cytokine and adhesion molecules synthesis in endothelial cells occurred even in the absence of calcineurin, although its expression was required for maximal effect through upregulation of TLR4 signaling. CNI-induced TLR4 activity increased O2(-)/ROS production and NF-κB-regulated synthesis of proinflammatory factors in cultured as well as aortic endothelial and VSMCs. These data provide new insight into the mechanisms associated with CNI vascular inflammation. PMID:27295076

  17. Calcineurin inhibitors cyclosporine A and tacrolimus induce vascular inflammation and endothelial activation through TLR4 signaling

    PubMed Central

    Rodrigues-Diez, Raquel; González-Guerrero, Cristian; Ocaña-Salceda, Carlos; Rodrigues-Diez, Raúl R.; Egido, Jesús; Ortiz, Alberto; Ruiz-Ortega, Marta; Ramos, Adrián M.

    2016-01-01

    The introduction of the calcineurin inhibitors (CNIs) cyclosporine and tacrolimus greatly reduced the rate of allograft rejection, although their chronic use is marred by a range of side effects, among them vascular toxicity. In transplant patients, it is proved that innate immunity promotes vascular injury triggered by ischemia-reperfusion damage, atherosclerosis and hypertension. We hypothesized that activation of the innate immunity and inflammation may contribute to CNI toxicity, therefore we investigated whether TLR4 mediates toxic responses of CNIs in the vasculature. Cyclosporine and tacrolimus increased the production of proinflammatory cytokines and endothelial activation markers in cultured murine endothelial and vascular smooth muscle cells as well as in ex vivo cultures of murine aortas. CNI-induced proinflammatory events were prevented by pharmacological inhibition of TLR4. Moreover, CNIs were unable to induce inflammation and endothelial activation in aortas from TLR4−/− mice. CNI-induced cytokine and adhesion molecules synthesis in endothelial cells occurred even in the absence of calcineurin, although its expression was required for maximal effect through upregulation of TLR4 signaling. CNI-induced TLR4 activity increased O2−/ROS production and NF-κB-regulated synthesis of proinflammatory factors in cultured as well as aortic endothelial and VSMCs. These data provide new insight into the mechanisms associated with CNI vascular inflammation. PMID:27295076

  18. Cyclosporine Amicellar delivery system for dry eyes

    PubMed Central

    Kang, Han; Cha, Kwang-Ho; Cho, Wonkyung; Park, Junsung; Park, Hee Jun; Sun, Bo Kyung; Hyun, Sang-Min; Hwang, Sung-Joo

    2016-01-01

    Background The objectives of this study were to develop stable cyclosporine A (CsA) ophthalmic micelle solutions for dry-eye syndrome and evaluate their physicochemical properties and therapeutic efficacy. Materials and methods CsA-micelle solutions (MS-CsA) were created by a simple method with Cremophor EL, ethanol, and phosphate buffer. We investigated the particle size, pH, and osmolarity. In addition, long-term physical and chemical stability for MS-CsA was observed. To confirm the therapeutic efficacy, tear production in dry eye-induced rabbits was evaluated using the Schirmer tear test (STT). When compared to a commercial product, Restasis, MS-CsA demonstrated improvement in goblet-cell density and conjunctival epithelial morphology, as demonstrated in histological hematoxylin and eosin staining. Results MS-CsA had a smaller particle size (average diameter 14–18 nm) and a narrow size distribution. Physicochemical parameters, such as particle size, pH, osmolarity, and remaining CsA concentration were all within the expected range of 60 days. STT scores significantly improved in MS-CsA treated groups (P<0.05) in comparison to those of the Restasis-treated group. The number of goblet cells for rabbit conjunctivas after the administration of MS-CsA was 94.83±8.38, a significantly higher result than the 65.17±11.51 seen with Restasis. The conjunctival epithelial morphology of dry eye-induced rabbits thinned with loss of goblet cells. However, after 5 days of treatment with drug formulations, rabbit conjunctivas recovered epithelia and showed a relative increase in the number of goblet cells. Conclusion The results of this study indicate the potential use of a novel MS for the ophthalmic delivery of CsA in treating dry eyes. PMID:27382280

  19. Cyclosporine A and tacrolimus inhibit urothelial tumorigenesis.

    PubMed

    Kawahara, Takashi; Kashiwagi, Eiji; Li, Yi; Zheng, Yichun; Miyamoto, Yurina; Netto, George J; Ishiguro, Hitoshi; Miyamoto, Hiroshi

    2016-02-01

    The functional role of nuclear factor of activated T-cells (NFAT), while it has been extensively investigated in the immune system, remains uncertain in bladder cancer development. We here aim to assess the effects of cyclosporine A (CsA) and tacrolimus (FK506), immunosuppressants known to specifically inactivate the NFAT pathway in immune cells, on neoplastic transformation of urothelial cells. Immunohistochemistry revealed that the expression levels of NFATc1, a NFAT isoform shown to function as an oncogene in a sarcoma model, were elevated in urothelial neoplasms, compared with non-neoplastic urothelial tissues, and in low-grade and high-grade papillary urothelial carcinomas, compared with papillary urothelial neoplasms of low malignant potential. In an immortalized normal urothelial cell line SVHUC, CsA and FK506 reduced NFATc1 expression, NFAT transcriptional activity, and the expression of c-myc, a downstream target of NFATc1 signals. Treatment with CsA or FK506 in the SVHUC cells undergoing neoplastic transformation induced by exposure to a chemical carcinogen 3-methylcholanthrene resulted in strong inhibition in colony formation in vitro as well as tumor formation in NOD-SCID mice. CsA and FK506 were additionally found to up-regulate the expression of several molecules that play a protective role in bladder tumorigenesis, including p53, p21, and p27, and down-regulate that of oncogenic genes, such as cyclin D1, cyclin D3, and cyclin E, in SVHUC cells with the carcinogen challenge. Thus, CsA and FK506 likely inhibit urothelial tumorigenesis. These findings offer a potential chemopreventive approach for urothelial tumors using NFAT inhibitors. PMID:25594762

  20. Heat Stress Nephropathy From Exercise-Induced Uric Acid Crystalluria: A Perspective on Mesoamerican Nephropathy.

    PubMed

    Roncal-Jimenez, Carlos; García-Trabanino, Ramón; Barregard, Lars; Lanaspa, Miguel A; Wesseling, Catharina; Harra, Tamara; Aragón, Aurora; Grases, Felix; Jarquin, Emmanuel R; González, Marvin A; Weiss, Ilana; Glaser, Jason; Sánchez-Lozada, Laura G; Johnson, Richard J

    2016-01-01

    Mesoamerican nephropathy (MeN), an epidemic in Central America, is a chronic kidney disease of unknown cause. In this article, we argue that MeN may be a uric acid disorder. Individuals at risk for developing the disease are primarily male workers exposed to heat stress and physical exertion that predisposes to recurrent water and volume depletion, often accompanied by urinary concentration and acidification. Uric acid is generated during heat stress, in part consequent to nucleotide release from muscles. We hypothesize that working in the sugarcane fields may result in cyclic uricosuria in which uric acid concentrations exceed solubility, leading to the formation of dihydrate urate crystals and local injury. Consistent with this hypothesis, we present pilot data documenting the common presence of urate crystals in the urine of sugarcane workers from El Salvador. High end-of-workday urinary uric acid concentrations were common in a pilot study, particularly if urine pH was corrected to 7. Hyperuricemia may induce glomerular hypertension, whereas the increased urinary uric acid may directly injure renal tubules. Thus, MeN may result from exercise and heat stress associated with dehydration-induced hyperuricemia and uricosuria. Increased hydration with water and salt, urinary alkalinization, reduction in sugary beverage intake, and inhibitors of uric acid synthesis should be tested for disease prevention. PMID:26455995

  1. [Pregnancy following liver transplantation and during immunosuppression with cyclosporine].

    PubMed

    Günter, H H; Mauz, S; Ringe, B; Niesert, S

    1990-05-11

    Orthotopic liver transplantation had been performed in 1983 in a now 40-year-old woman in the terminal stage of posthepatitis liver cirrhosis with recurrent oesophageal bleedings and precoma from complete liver-cell failure. She became pregnant in 1988 while under immunosuppression with cyclosporin (2.1-2.7 mg/kg body-weight) and prednisolone (5 or 7.5 mg daily in rotation). Pregnancy proceeded without complication and there were no side effects from cyclosporin. After premature membrane rupture in the 39th week of pregnancy uterine inertia developed during oxytocin stimulation of contractions, and caesarean section was performed. The female infant was normally developed without any malformations. Liver, kidney and adrenal functions were normal, as was haemopoiesis. But possible late sequelae of cyclosporin treatment in the child cannot as yet be assessed because of the short follow-up. PMID:2338057

  2. [Cyclosporine-induced gingival hyperplasia: report of one case].

    PubMed

    Bahamondes, Carlos; Godoy, Jorge

    2007-03-01

    Gingival enlargement can be an adverse effect of cyclosporine A and nifedipine use. It has a high relapse rate if the drugs are not discontinued. There is a genetic predisposition to the development of this condition and dental biofilm can also play a role. We report a 64 years old male who received a renal allograft and was treated with cyclosporine and nifedipine. He required six surgical interventions for generalized gingival enlargement. After the sixth relapse, the patient was subjected to a periodontal treatment to eliminate the dental biofilm, which decreased the rate of recurrence of gingival enlargement. PMID:17505584

  3. Successful treatment of postoperative pyoderma gangrenosum with cyclosporin.

    PubMed

    Schöfer, H; Baur, S

    2002-03-01

    Postoperative pyoderma gangrenosum (PPG), also known as postoperative progressive gangrene of Cullen, is a rare and rapidly evolving complication of surgical procedures. Since the first description by Cullen in 1924 (Surg Gynecol Obstet 1924; 38: 579-582) various case reports have been published. Even in typical cases PPG is often misdiagnosed and therefore wrongly treated; the unknown aetiology makes treatment difficult. The therapies used for pyoderma gangrenosum include systemic corticosteroids, azathioprine, dapsone, mercaptopurine, sulphasalazine, sulphapyridine, thalidomide, cyclophosphamide, clofazimine, isotretinoin, immunoglobulins and cyclosporin. We report on two patients with PPG following breast surgery who were successfully treated with low-dose cyclosporin (2.5-5 mg/kg per day). PMID:12046819

  4. Nephrotic syndrome is a rare manifestation of IGA nephropathy

    PubMed Central

    Alshomar, Ahmad A

    2016-01-01

    Nephrotic syndrome is a rare presentation of IgA nephropathy. The degree of proteinuria in IgA nephropathy predicts poor prognosis. We herein report a teenager with IGA nephropathy, the nephrotic syndrome and segmental glomerular scars who after developing complications from high dose corticosteroid therapy was successfully treated with tacrolimus and low dose prednisone. PMID:27610069

  5. Signaling pathways in diabetic nephropathy.

    PubMed

    Kawanami, Daiji; Matoba, Keiichiro; Utsunomiya, Kazunori

    2016-10-01

    Diabetic nephropathy (DN) is a major cause of end-stage renal disease (ESRD), however, specific treatment for DN has not yet been elucidated. Therefore, it is critically important to understand the molecular mechanism underlying DN to develop cause-related therapeutic strategy. To date, various factors such as hemodynamic changes and metabolic pathways have been shown to be involved in the pathogenesis of DN. Excessive glucose influx activates cellular signaling pathways, including the diacylglycerol (DAG)-protein kinase C (PKC) pathway, advanced glycation end-products (AGE), polyol pathway, hexosamine pathway and oxidative stress. These factors interact with one another, thereby facilitating inflammatory processes, leading to the development of glomerulosclerosis under diabetic conditions. In addition to metabolic pathways, Rho-kinase, an effector of small-GTPase binding protein Rho, has been implicated as an important factor in the pathogenesis of DN. A number of studies have demonstrated that Rho-kinase plays key roles in the development of DN by inducing endothelial dysfunction, mesangial excessive extracellular matrix (ECM) production, podocyte abnormality, and tubulointerstitial fibrosis. In this review article, we describe our current understanding of the signaling pathways in DN. PMID:27094540

  6. Diabetic nephropathy among Mexican Americans

    PubMed Central

    Debnath, Subrata; Thameem, Farook; Alves, Tahira; Nolen, Jacqueline; Al-Shahrouri, Hania; Bansal, Shweta; Abboud, Hanna E.; Fanti, Paolo

    2012-01-01

    The incidence of diabetic nephropathy (DN) is growing rapidly worldwide as a consequence of the rising prevalence of Type 2 diabetes mellitus (T2DM). Among U.S. ethnic groups, Mexican Americans have a disproportionately high incidence and prevalence of DN and associated end-stage renal disease (ESRD). In communities bordering Mexico, as many as 90% of Mexican American patients with ESRD also suffer from T2DM compared to only 50% of non-Hispanic Whites (NHW). Both socio-economic factors and genetic predisposition appear to have a strong influence on this association. In addition, certain pathogenetic and clinical features of T2DM and DN are different in Mexican Americans compared to NHW, raising questions as to whether the diagnostic and treatment strategies that are standard practice in the NHW patient population may not be applicable in Mexican Americans. This article reviews the epidemiology of DN in Mexican Americans, describes the pathophysiology and associated risk factors, and identifies gaps in our knowledge and understanding that needs to be addressed by future investigations. PMID:22445478

  7. The role of ultrasonography in the study of medical nephropathy

    PubMed Central

    Fiorini, F.; Barozzi, L.

    2007-01-01

    Diagnostic techniques in nephrology include clinical history, physical examination, laboratory tests, scintigraphy, diagnostic imaging techniques as well as renal biopsy. In kidney diseases, ultrasonography is used as a first-line imaging technique, and its role in medical nephropathy is to exclude urological pathologies, to differentiate between acute and chronic renal failure, to follow-up on the course of a disease, to guide needle biopsy, etc. Ultrasound images are useful at characterizing the pelvis, assessing renal dimensions and parenchymal echogenicity, sampling color–power Doppler signals and evaluating their characteristics and distribution as well as measuring parenchymal resistive index. Taken together, these data can provide useful clues to the diagnosis and help to reduce the number of possible differential diagnoses. PMID:23396246

  8. Dabigatran-Related Nephropathy in a Patient with Undiagnosed IgA Nephropathy.

    PubMed

    Escoli, Rachele; Santos, Paulo; Andrade, Sequeira; Carvalho, Fernanda

    2015-01-01

    Dabigatran is a direct thrombin inhibitor used as an alternative to warfarin for long term anticoagulation. Warfarin-related nephropathy is an increasingly recognized entity, but recent evidence suggests that dabigatran can cause a WRN-like syndrome. We describe a case of a biopsy-proven anticoagulant nephropathy related to dabigatran in a patient with IgA nephropathy and propose that, despite the base glomerular disease, acute kidney injury was due to tubular obstruction by red blood cells and heme-associated tubular injury, and through a mechanism involving inhibition of anticoagulation cascade and barrier abnormalities caused by molecular mechanisms. PMID:26347498

  9. Dabigatran-Related Nephropathy in a Patient with Undiagnosed IgA Nephropathy

    PubMed Central

    Escoli, Rachele; Santos, Paulo; Andrade, Sequeira; Carvalho, Fernanda

    2015-01-01

    Dabigatran is a direct thrombin inhibitor used as an alternative to warfarin for long term anticoagulation. Warfarin-related nephropathy is an increasingly recognized entity, but recent evidence suggests that dabigatran can cause a WRN-like syndrome. We describe a case of a biopsy-proven anticoagulant nephropathy related to dabigatran in a patient with IgA nephropathy and propose that, despite the base glomerular disease, acute kidney injury was due to tubular obstruction by red blood cells and heme-associated tubular injury, and through a mechanism involving inhibition of anticoagulation cascade and barrier abnormalities caused by molecular mechanisms. PMID:26347498

  10. Schnitzler's syndrome with monoclonal IgG kappa gammopathy: good response to cyclosporin.

    PubMed

    Pascual-López, M; Hernández-Núñez, A; Sánchez-Pérez, J; Fernández-Herrera, J; García-Díez, A

    2002-05-01

    Schnitzler's syndrome (SS) is a rare entity characterized by the association of chronic urticaria and monoclonal IgM gammopathy. Usually, intermittent fever, arthralgia and elevation of erythrocyte sedimentation rate also occur. We report a patient with the same symptoms, but with monoclonal IgG instead of IgM paraproteinaemia. Histological examination of the urticarial lesions showed signs of leucocytoclastic vasculitis. After 20 years of therapeutic failure, cyclosporin has achieved a total clearance of urticarial lesions in our patient. Two previous similar cases with clinical features of SS and monoclonal IgG immunoglobulin have been described. We suggest our case also represents a variant of SS with IgG gammopathy. PMID:12195569

  11. Marked decrease of cyclosporin bioavailability caused by coadministration of ginkgo and onion in rats.

    PubMed

    Yang, C Y; Chao, P D L; Hou, Y C; Tsai, S Y; Wen, K C; Hsiu, S L

    2006-09-01

    Quercetin was reported to modulate CYP isoenzymes and P-glycoprotein (Pgp), a drug efflux transporter. Our previous study reported that quercetin significantly decreased the bioavailability of cyclosporin, a substrate for CYP3A4 and Pgp, in rats and pigs. Ginkgo and onion contain quercetin and its glycosides as St. John's Wort. The coadministration of cyclosporin with ginkgo or onion may be subject to clinically relevant interactions as St. John's Wort. Therefore, this study aimed to investigate the influences of ginkgo and onion on the absorption and disposition of cyclosporin in rats. Cyclosporin was administered orally and intravenously to rats with and without an oral dose of ginkgo or onion in crossover designs. Blood samples were collected via cardiopuncture and blood cyclosporin concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. Everted gut sac was used to investigate the effects of ginkgo and onion on the function of intestinal Pgp. Oral coadministration of ginkgo and onion significantly decreased the Cmax of cyclosporin by 62% and 60%, and reduced the AUC0-t by 51% and 68%, respectively, whereas no influence was observed when cyclosporin was given intravenously. This indicates that the interactions between cyclosporin and ginkgo or onion occurred mainly at the absorption site. In conclusion, ginkgo and onion markedly decreased the oral bioavailability of cyclosporin. We suggest that concurrent intake of quercetin-rich herbs or foods with cyclosporin are better avoided in order to ensure the efficacy of cyclosporin. PMID:16762474

  12. Pomelo enhances cyclosporine bioavailability in healthy male Thai volunteers.

    PubMed

    Anlamlert, Wirin; Sermsappasuk, Pakawadee; Yokubol, Dhirayudh; Jones, Sirada

    2015-04-01

    The aim of this study was to investigate the effect of pomelo pulp on the pharmacokinetics of cyclosporine in healthy male Thai volunteers. The study design was an open-label, randomized, single dose, crossover study with a 2-week washout period. A single oral dose of 2 × 100 mg cyclosporine was administered with 200 mL of water. Each subject received 250 g of pomelo pulp or 250 mL of water 1 hour before drug administration and once again 10 minutes following drug administration. Blood samples were collected over a 24 hour period. The point estimates (90% confidence intervals) of the test/control ratio using logarithmic transformed data for the area under the curve (AUC) for blood concentration from time 0 to infinity (AUC(0- ∞)) and the observed maximum concentration (C(max)) were 128.8% (120.6-137.6) and 136.1% (126.0-146.8), respectively. These 90% confidence intervals were higher than the accepted bioequivalence range defined by the European Medicines Agency guidelines for narrow therapeutic index drugs (90%-111% for AUC and 80%-125% for C(max)). However, the apparent terminal half-life (t(1/2)) was not significantly different. In conclusion, co-administration of cyclosporine and pomelo pulp increased the relative bioavailability of cyclosporine. PMID:25408261

  13. Effects of embryonic cyclosporine exposures on brain development and behavior

    PubMed Central

    Clift, Danielle E.; Thorn, Robert J.; Passarelli, Emily A.; Kapoor, Mrinal; LoPiccolo, Mary K.; Richendrfer, Holly A.; Colwill, Ruth M.; Creton, Robbert

    2015-01-01

    Cyclosporine, a calcineurin inhibitor, is successfully used as an immunosuppressant in transplant medicine. However, the use of this pharmaceutical during pregnancy is concerning, since calcineurin is thought to play a role in neural development. The risk for human brain development is difficult to evaluate, because of a lack of basic information on the sensitive developmental times and the potentially pleiotropic effects on brain development and behavior. In the present study, we use zebrafish as a model system to examine the effects of embryonic cyclosporine exposures. Early embryonic exposures reduced the size of the eyes and brain. Late embryonic exposures did not affect the size of the eyes or brain, but did lead to substantial behavioral defects at the larval stages. The cyclosporine-exposed larvae displayed a reduced avoidance response to visual stimuli, low swim speeds, increased resting, an increase in thigmotaxis, and changes in the average distance between larvae. Similar results were obtained with the calcineurin inhibitor FK506, suggesting that most, but not all, effects on brain development and behavior are mediated by calcineurin inhibition. Overall, the results show that cyclosporine can induce either structural or functional brain defects, depending on the exposure window. The observed functional brain defects highlight the importance of quantitative behavioral assays when evaluating the risk of developmental exposures. PMID:25591474

  14. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 8 2013-04-01 2013-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  15. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 8 2012-04-01 2012-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  16. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 8 2014-04-01 2014-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  17. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 8 2011-04-01 2011-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  18. 21 CFR 862.1235 - Cyclosporine test system.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Cyclosporine test system. 862.1235 Section 862.1235 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) MEDICAL DEVICES CLINICAL CHEMISTRY AND CLINICAL TOXICOLOGY DEVICES Clinical Chemistry Test Systems §...

  19. Effects of embryonic cyclosporine exposures on brain development and behavior.

    PubMed

    Clift, Danielle E; Thorn, Robert J; Passarelli, Emily A; Kapoor, Mrinal; LoPiccolo, Mary K; Richendrfer, Holly A; Colwill, Ruth M; Creton, Robbert

    2015-04-01

    Cyclosporine, a calcineurin inhibitor, is successfully used as an immunosuppressant in transplant medicine. However, the use of this pharmaceutical during pregnancy is concerning since calcineurin is thought to play a role in neural development. The risk for human brain development is difficult to evaluate because of a lack of basic information on the sensitive developmental times and the potentially pleiotropic effects on brain development and behavior. In the present study, we use zebrafish as a model system to examine the effects of embryonic cyclosporine exposures. Early embryonic exposures reduced the size of the eyes and brain. Late embryonic exposures did not affect the size of the eyes or brain, but did lead to substantial behavioral defects at the larval stages. The cyclosporine-exposed larvae displayed a reduced avoidance response to visual stimuli, low swim speeds, increased resting, an increase in thigmotaxis, and changes in the average distance between larvae. Similar results were obtained with the calcineurin inhibitor FK506, suggesting that most, but not all, effects on brain development and behavior are mediated by calcineurin inhibition. Overall, the results show that cyclosporine can induce either structural or functional brain defects, depending on the exposure window. The observed functional brain defects highlight the importance of quantitative behavioral assays when evaluating the risk of developmental exposures. PMID:25591474

  20. [Value of protecting mitochondrial functions during treatment with cyclosporin A].

    PubMed

    Simon, N; Albengres, E; Barré, J; Jolliet, P; Urien, S; Settaf, A; Tillement, J P

    1997-01-01

    The use of cyclosporin A is often limited by its nephrotoxicity. This dose-dependent toxicity can occur in all kinds of transplantation and is reversed with drug withdrawal. Cyclosporin A induces a vasoconstriction leading to an increase of renal vascular resistance and a reduction of glomerular filtration. Histochemical studies show mitochondrial alterations and an excess of cytosolic and mitochondrial calcium leading to a decrease of ATP synthesis. Two strategies can be evoked for limiting cyclosporin-A-induced nephrotoxicity. First, the use of drugs counteracting the vasoconstriction has been proposed. Second, drugs acting by restoration of ATP synthesis could also be of interest. For example, calcium channel blockers may be used for limiting the Ca2+ fluxes into cells. Another way to protect ATP synthesis is to inhibit the cyclosporin-A-induced increase of mitochondrial Ca2+ concentrations; Trimetazidine has shown its efficiency in vitro for protecting mitochondria against these modifications of Ca2+ homeostasis and is under clinical evaluation. PMID:9231511

  1. An underlying role for hepatobiliary dysfunction in cyclosporine A nephrotoxicity

    SciTech Connect

    Aleo, Michael D.

    2008-07-01

    Renal-derived cysteinyl leukotrienes (cysLT), such as leukotrienes C{sub 4} (LTC{sub 4}) and D{sub 4} (LTD{sub 4}) are thought to mediate acute and chronic cyclosporine A (CSA) nephrotoxicity. However, whole-body cysLT elimination is regulated primarily by hepatobiliary excretion. Since CSA is known to alter hepatobiliary function, the effects of CSA on whole-body cysLT elimination were investigated in vivo, with respect to hepatobiliary and renal function. Male rats were anesthetized and cannulated (jugular vein, bile duct, and urinary bladder). A tracer dose of tritiated LTC{sub 4} ({sup 3}H-LTC{sub 4}) was administered systemically (i.v.) immediately following vehicle and then 90 min later after vehicle or CSA. In vehicle/vehicle controls, hepatobiliary {sup 3}H-cysLT elimination predominated over renal elimination without altering glomerular filtration rate (GFR), bile flow, and urine production. {sup 3}H-cysLT elimination kinetics were comparable between each 90 min collection period. In vehicle/CSA-treated rats, an acutely nephrotoxic dose of CSA (20 mg/kg, i.v.) reduced urine flow 74 {+-} 9% and caused a transient reduction in GFR, while total bile flow decreased 40 {+-} 13%. Hepatobiliary and renal {sup 3}H-cysLT elimination was also impaired 59 {+-} 5 and 61 {+-} 18%, respectively. In contrast, a non-nephrotoxic dose (2 mg/kg i.v.) increased renal {sup 3}H-cysLT elimination due to impaired hepatobiliary elimination without affecting GFR, bile flow or urine production. Both doses caused {sup 3}H-cysLT retention in hepatic and renal tissue. These findings demonstrate that CSA alters whole-body handling of cysLT by disrupting hepatobiliary cysLT elimination. This disruption leads to increased renal exposure to systemically derived cysLT and renal cysLT tissue retention. Renal exposure to and accumulation of systemically derived cysLT products may be underlying factors in CSA nephrotoxicity.

  2. Study of Aplastic Anaemia with Cyclosporine in Resource Poor Setting

    PubMed Central

    Narendra, Anukonda Moti Venkata Raja; Adiraju, Krishna Prasad; Modugu, Nageshwar Rao

    2016-01-01

    Introduction Aplastic Anaemia (AA) is a syndrome characterized by peripheral pancytopenia with hypo-cellular marrow. Acquired idiopathic AA is the most common variety, probably of an autoimmune aetiology. Bone Marrow Transplantation (BMT) is the treatment of choice but cost is the limiting factor. Antithymocyte Globulin and Cyclosporine-A is an alternative to BMT. Cyclosporine alone has been tried as a single agent in resource poor setting. Aim The study was conducted with the aim to observe the treatment response in aplastic anaemia to Cycloserine-A. Materials and Methods Patients who were diagnosed as AA and opted for Cyclosporine with informed consent were included in the study. All the subjects were started on 5mg/kg of Cyclosporine and were followed up for three months to see the treatment response. This study had the approval from IEC. Results Twenty patients were enrolled in the study. Age of the patients ranged from 10 to 65 years. Maximum number (10/20) of patients was in the 2nd decade. Most of the patients presented with mucosal bleeds and breathlessness on exertion; the predominant sign was pallor. Eleven patients had severe AA, eight had non severe and one had very severe anaemia. Out of 20, three patients were lost to follow-up and one patient discontinued therapy due to renal dysfunction; finally sixteen patients’ data was analysed. Out of 16 patients, 9 responded was and 7 did not respond. Complete response was observed in three patients, partial response in six patients. Seven patients had drug toxicity in the form of acute renal failure and gum hypertrophy. Conclusion Cyclosporine seems to be a reasonable therapeutic option with good response rate and minimal side effects. PMID:27504327

  3. Effect of cyclosporine in a murine model of experimental colitis.

    PubMed

    Banić, Marko; Anić, Branimir; Brkić, Tomislav; Ljubicić, Neven; Plesko, Sanja; Dohoczky, Csaba; Erceg, Damir; Petrovecki, Mladen; Stipancić, Igor; Rotkvić, Ivo

    2002-06-01

    The use of immunosuppressive therapy may be associated with significant toxicity. The aim of this study was to investigate the effect of cyclosporine A (CsA) in murine model of experimental colitis. Experimental colitis was induced in NMRI mice using an enema of 0.2% solution of dinitrofluorobenzene, combined with skin sensitization. After inducing colitis, experimental groups of animals were treated with CsA (1, 3, 5, 10, 25, 50 mg/kg/day) intraperitoneally (i.p.) or intracolonically (i.c.), and control groups were treated with phosphate-buffered saline intraperitoneally or intracolonically, respectively. Colonic inflammatory changes were assessed using a histopathologic score of 0-30, and pooled whole blood samples were processed with monoclonal antibodies for cyclosporine concentration. In addition, two groups of animals with experimental colitis were treated intraperitoneally or intracolonically with 3 mg/kg/day of CsA, and the colons were also taken for immunohistochemistry for CD25. CsA diminished the extent of colitis in groups treated with 3, 5, 10, or 25 mg/kg intraperitoneally or intracolonically, and in groups treated with 1 and 50 mg/kg intracolonically (P < 0.05). The effect of intracolonic application of CsA was not related to whole blood cyclosporine concentrations. In addition, the effect of CsA at 3 mg/kg, applied intraperitoneally or intracolonically was, in part, expressed in decreasing the numbers of CD25+ cells within colonic mucosa/submucosa (P < 0.05). In conclusions, the results of this study indicate the possibility of intracolonic application of cyclosporine in order to widen the therapeutic window for effective, but possibly toxic drug, such as cyclosporine. PMID:12064814

  4. Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial

    PubMed Central

    Winkler, Cheryl A.; Zhao, Xiongce; Radeva, Milena K.; Gassman, Jennifer J.; D’Agati, Vivette D.; Nast, Cynthia C.; Wei, Changli; Reiser, Jochen; Guay-Woodford, Lisa M.; Pollak, Martin R.; Hildebrandt, Friedhelm; Moxey-Mims, Marva; Gipson, Debbie S.; Trachtman, Howard; Friedman, Aaron L.; Kaskel, Frederick J.

    2015-01-01

    Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone. PMID:25573908

  5. Clinical Features and Histology of Apolipoprotein L1-Associated Nephropathy in the FSGS Clinical Trial.

    PubMed

    Kopp, Jeffrey B; Winkler, Cheryl A; Zhao, Xiongce; Radeva, Milena K; Gassman, Jennifer J; D'Agati, Vivette D; Nast, Cynthia C; Wei, Changli; Reiser, Jochen; Guay-Woodford, Lisa M; Pollak, Martin R; Hildebrandt, Friedhelm; Moxey-Mims, Marva; Gipson, Debbie S; Trachtman, Howard; Friedman, Aaron L; Kaskel, Frederick J

    2015-06-01

    Genetic variants in apolipoprotein L1 (APOL1) confer risk for kidney disease. We sought to better define the phenotype of APOL1-associated nephropathy. The FSGS Clinical Trial involved 138 children and young adults who were randomized to cyclosporin or mycophenolate mofetil plus pulse oral dexamethasone with a primary outcome of proteinuria remission. DNA was available from 94 subjects who were genotyped for APOL1 renal risk variants, with two risk alleles comprising the risk genotype. Two APOL1 risk alleles were present in 27 subjects, of whom four subjects did not self-identify as African American, and 23 of 32 (72%) self-identified African Americans. Individuals with the APOL1 risk genotype tended to present at an older age and had significantly lower baseline eGFR, more segmental glomerulosclerosis and total glomerulosclerosis, and more tubular atrophy/interstitial fibrosis. There were differences in renal histology, particularly more collapsing variants in those with the risk genotype (P=0.02), although this association was confounded by age. APOL1 risk genotype did not affect response to either treatment regimen. Individuals with the risk genotype were more likely to progress to ESRD (P<0.01). In conclusion, APOL1 risk genotypes are common in African-American subjects with primary FSGS and may also be present in individuals who do not self-identify as African American. APOL1 risk status is associated with lower kidney function, more glomerulosclerosis and interstitial fibrosis, and greater propensity to progress to ESRD. The APOL1 risk genotype did not influence proteinuria responses to cyclosporin or mycophenolate mofetil/dexamethasone. PMID:25573908

  6. Acute oxalate nephropathy due to pancreatic atrophy in newly diagnosed pancreatic carcinoma.

    PubMed

    Moinuddin, Irfan; Bala, Asif; Ali, Butool; Khan, Husna; Bracamonte, Erika; Sussman, Amy

    2016-02-01

    Acute oxalate nephropathy can occur due to primary hyperoxaluria and secondary hyperoxaluria. The primary hyperoxalurias are a group of autosomal recessive disorders of endogenous oxalate overproduction. Secondary hyperoxaluria may occur as a result of excess dietary intake, poisoning with oxalate precursors (ethylene glycol), or enteric hyperoxaluria. The differential diagnosis of enteric hyperoxaluria includes inflammatory bowel disease, short bowel syndrome, bariatric surgery (with jejunoileal bypass or Roux-en-Y gastric bypass), celiac disease, partial colectomy, and chronic pancreatitis. The common etiology in all these processes is fat malabsorption, steatorrhea, saponification of calcium, and absorption of free oxalate. Hyperoxaluria causes increased urinary oxalate excretion, urolithiasis (promoted by hypovolemia, decreased urinary pH caused by metabolic acidosis, and decreased citrate and magnesium concentrations in urine), tubulointerstitial oxalate deposits, and tubulointerstitial nephritis. We report a rare case of acute oxalate nephropathy due to pancreatic atrophy and exocrine insufficiency caused by newly diagnosed pancreatic cancer. PMID:26614399

  7. Monitoring Diabetic Nephropathy by Circulating Gangliosides.

    PubMed

    Ene, Corina Daniela; Penescu, Mircea; Anghel, Amalia; Neagu, Monica; Budu, Vlad; Nicolae, Ilinca

    2016-01-01

    Gangliosides are multifunctional molecules, abundantly expressed in renal cell membrane but also in sera of patients with renal disease. The aim of this study was to quantify the serum levels of sialic acid-ganglioside in patients diagnosed with diabetes for an eventual biomarker stratification of patients with renal complications. We included 35 diabetic patients without metabolic complications, 35 patients with diabetic nephropathy, 35 non-diabetic individuals. We found that sialic acid ganglioside serum level was significantly increased in patients with diabetic nephropathy compared to the level obtained in patients with uncomplicated diabetes and to non-diabetic controls. A statistically significant positive correlation was obtained between serum levels of sialic acid gangliosides, HbA1c, and serum creatinine in patients with diabetes without complications. Moreover positive correlation was found between sialic acid ganglioside and blood glucose, HbA1c, urea, creatinine, microalbuminuria in patients with diabetic nephropathy. We can conclude that serum sialic acid-gangliosides are statistically increased in diabetic nephropathy positively correlated with microalbuminuria. PMID:26359623

  8. Diabetic Nephropathy and Its Risk Factors in a Society with a Type 2 Diabetes Epidemic: A Saudi National Diabetes Registry-Based Study

    PubMed Central

    Al-Rubeaan, Khalid; Youssef, Amira M.; Subhani, Shazia N.; Ahmad, Najlaa A.; Al-Sharqawi, Ahmad H.; Al-Mutlaq, Hind M.; David, Satish K.; AlNaqeb, Dhekra

    2014-01-01

    Aims The prevalence of diabetic nephropathy and its risk factors have not been studied in a society known to have diabetes epidemic like Saudi Arabia. Using a large data base registry will provide a better understanding and accurate assessment of this chronic complication and its related risk factors. Methodology A total of 54,670 patients with type 2 diabetes aged ≥25 years were selected from the Saudi National Diabetes Registry (SNDR) and analyzed for the presence of diabetic nephropathy. The American Diabetes Association (ADA) criterion was used to identify cases with microalbuminuria, macroalbuminuria and end stage renal disease (ESRD) for prevalence estimation and risk factor assessment. Results The overall prevalence of diabetic nephropathy was 10.8%, divided into 1.2% microalbuminuria, 8.1%macroalbuninuria and 1.5% ESRD. Age and diabetes duration as important risk factors have a strong impact on the prevalence of diabetic nephropathy, ranging from 3.7% in patients aged 25–44 years and a duration of >5 years, to 21.8% in patients ≥65 years with a diabetes duration of ≥15 years. Diabetes duration, retinopathy, neuropathy, hypertension, age >45 years, hyperlipidemia, male gender, smoking, and chronologically, poor glycemic control has a significantly high risk for diabetic nephropathy. Conclusion The prevalence of diabetic nephropathy is underestimated as a result of a shortage of screening programs. Risk factors related to diabetic nephropathy in this society are similar to other societies. There is thus an urgent need for screening and prevention programs for diabetic nephropathy among the Saudi population. PMID:24586457

  9. Cyclosporin in subcutaneous panniculitis-like T-cell lymphoma.

    PubMed

    Rojnuckarin, Ponlapat; Nakorn, Thanyaphong Na; Assanasen, Thamathorn; Wannakrairot, Pongsak; Intragumtornchai, Tanin

    2007-03-01

    Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of hematologic malignancy characterized by lesions in subcutaneous fat associated with systemic symptoms. The standard treatment of the disease, currently, is not established, but CHOP or CHOP-like regimens are usually given. We report, herein, 4 cases of SPTCL diagnosed by histopathology and immunohistochemistry who were refractory to CHOP and/or ESHAP and/or fludarabine-based regimen, but showed rapid improvement within weeks after oral cyclosporin 4 mg/kg/day. Three sustained complete remission for the durations of 8 - 9 months off-treatments. T-cell receptor gene rearrangement revealed polyclonality in 3 cases and monoclonality in 1 case. Our data suggest the benefit of incorporating cyclosporin into the treatment regimen for SPTCL. PMID:17454599

  10. Management of Cyclosporine and Nifedipine-Induced Gingival Hyperplasia

    PubMed Central

    Dilber, Erhan; Aral, Kübra; Sarica, Yagmur; Sivrikoz, Oya Nermin

    2015-01-01

    Gingival enlargements modified by medications are becoming more common because of the increased use of inducing drugs, and may create speech, mastication, tooth eruption, periodontal, and aesthetic problems. We hereby present a case of a 54-year-old man with 12-month history of generalized gingival enlargement in the keratinized gingiva was referred to our clinic. The patient had a history of kidney transplant and was under medication of cyclosporine and nifedipine. After medical consultation, cyclosporine was changed to tacrolimus and nifedipine was changed to captopril. Gingivectomy was performed using a diode laser, and scaling and root planning were performed. At five months postoperative, the gingival enlargements relapsed and diode laser-assisted surgery was repeated. The patient was followed-up on second postoperatively at 18 months and no relapse was seen. Diode laser-assisted gingivectomy was found to be useful for coagulation during surgery and decreased postoperative bleeding. Recurrence risk of cyclosporine and nifedipine-induced gingival overgrowth is high, thus, there is a great need for prolonged care of patients following treatment and prosthetic restoration. PMID:26812935

  11. The Genome of Tolypocladium inflatum: Evolution, Organization, and Expression of the Cyclosporin Biosynthetic Gene Cluster

    PubMed Central

    Bushley, Kathryn E.; Raja, Rajani; Jaiswal, Pankaj; Cumbie, Jason S.; Nonogaki, Mariko; Boyd, Alexander E.; Owensby, C. Alisha; Knaus, Brian J.; Elser, Justin; Miller, Daniel; Di, Yanming; McPhail, Kerry L.; Spatafora, Joseph W.

    2013-01-01

    The ascomycete fungus Tolypocladium inflatum, a pathogen of beetle larvae, is best known as the producer of the immunosuppressant drug cyclosporin. The draft genome of T. inflatum strain NRRL 8044 (ATCC 34921), the isolate from which cyclosporin was first isolated, is presented along with comparative analyses of the biosynthesis of cyclosporin and other secondary metabolites in T. inflatum and related taxa. Phylogenomic analyses reveal previously undetected and complex patterns of homology between the nonribosomal peptide synthetase (NRPS) that encodes for cyclosporin synthetase (simA) and those of other secondary metabolites with activities against insects (e.g., beauvericin, destruxins, etc.), and demonstrate the roles of module duplication and gene fusion in diversification of NRPSs. The secondary metabolite gene cluster responsible for cyclosporin biosynthesis is described. In addition to genes necessary for cyclosporin biosynthesis, it harbors a gene for a cyclophilin, which is a member of a family of immunophilins known to bind cyclosporin. Comparative analyses support a lineage specific origin of the cyclosporin gene cluster rather than horizontal gene transfer from bacteria or other fungi. RNA-Seq transcriptome analyses in a cyclosporin-inducing medium delineate the boundaries of the cyclosporin cluster and reveal high levels of expression of the gene cluster cyclophilin. In medium containing insect hemolymph, weaker but significant upregulation of several genes within the cyclosporin cluster, including the highly expressed cyclophilin gene, was observed. T. inflatum also represents the first reference draft genome of Ophiocordycipitaceae, a third family of insect pathogenic fungi within the fungal order Hypocreales, and supports parallel and qualitatively distinct radiations of insect pathogens. The T. inflatum genome provides additional insight into the evolution and biosynthesis of cyclosporin and lays a foundation for further investigations of the role

  12. Potential clinical implications of substitution of generic cyclosporine formulations for cyclosporine microemulsion (Neoral) in transplant recipients.

    PubMed

    Johnston, Atholl; Belitsky, Philip; Frei, Ulrich; Horvath, John; Hoyer, Peter; Helderman, J Harold; Oellerich, Michael; Pollard, Stephen; Riad, Hany; Rigotti, Paolo; Keown, Paul; Nashan, Björn

    2004-08-01

    Cyclosporine (CsA) is a critical-dose drug for which a minor change in absorption can have important clinical implications. Generic formulations of CsA are becoming more widely available, but standard criteria for bioequivalence require only that a single study in healthy volunteers demonstrate that mean pharmacokinetic parameters fall within 80-125% of the mean values for Neoral, the reference formulation of CsA. However, CsA absorption is known to differ between healthy volunteers and transplant patients and between different types of transplant patients, such that standard bioequivalence testing may be inadequate to ensure interchangeability of CsA formulations in all patients. The limited available clinical evidence has shown that stable renal transplant patients receiving Neoral have a significant reduction in mean CsA trough level after transfer to the Cicloral formulation. Mean pharmacokinetic values have been reported as equivalent following transfer to Gengraft in one study, but mean CsA trough fell and mean serum creatinine rose significantly in a separate trial. The only clinical outcomes data available are from a retrospective study of de novo renal transplant patients, which reported a significantly higher incidence of biopsy-proven acute rejection in patents receiving Gengraf versus Neoral (39% versus 25%, P<0.05). Until robust clinical data demonstrate that different formulations of CsA are interchangeable, it is advisable to prescribe CsA by brand, and any transfer to a different CsA formulation should be undertaken with close supervision and only at the direction of the transplant physician. PMID:15205865

  13. Recent advances in managing and understanding diabetic nephropathy

    PubMed Central

    Tang, Sydney C.W.; Chan, Gary C.W.; Lai, Kar Neng

    2016-01-01

    Diabetic nephropathy is the commonest cause of end-stage renal disease in most developed economies. Current standard of care for diabetic nephropathy embraces stringent blood pressure control via blockade of the renin-angiotensin-aldosterone system and glycemia control. Recent understanding of the pathophysiology of diabetic nephropathy has led to the development of novel therapeutic options. This review article focuses on available data from landmark studies on the main therapeutic approaches and highlights some novel management strategies. PMID:27303648

  14. Tubular biomarkers to assess progression of diabetic nephropathy.

    PubMed

    Tramonti, Gianfranco; Kanwar, Yashpal S

    2011-05-01

    Despite aggressive management, many patients with diabetic nephropathy still develop end-stage renal disease. Accompanying tubulointerstitial damage is important in the progression of diabetic nephropathy. Markers of tubular damage, such as NGAL, KIM-1, and LFABP, have been proposed for monitoring the effectiveness of therapy. However, Nielsen et al. report a lack of an independent correlation between these biomarkers and glomerular filtration rate. Therefore, these markers seem to offer no improvement in the management of diabetic nephropathy. PMID:21527942

  15. Use of cyclosporine and ketoconazole without nephrotoxicity in two heart transplant recipients.

    PubMed

    Schroeder, T J; Melvin, D B; Clardy, C W; Wadhwa, N K; Myre, S A; Reising, J M; Wolf, R K; Collins, J A; Pesce, A J; First, M R

    1987-01-01

    A cyclosporine-ketoconazole drug interaction was first described in 1981. It has been suggested that the two drugs should not be used concomitantly because of the danger of severe nephrotoxicity. Two reported cases indicate that cyclosporine and ketoconazole can be safely coadministered, provided that the dosage of cyclosporine is reduced appropriately. Two patients were initially given 8 mg/kg/day of cyclosporine at the time of heart transplantation, and the dosage was tapered to meet appropriate blood levels (250 to 350 ng/ml by whole blood high-performance liquid chromatography). During ketoconazole therapy (400 mg daily for 4 weeks), patient 1 received 80 to 100 mg/day of cyclosporine, which is equal to approximately 1 mg/kg/day, and patient 2 received between 40 and 80 mg/day of cyclosporine, which is equivalent to 0.4 to 0.8 mg/kg/day. Neither patient exhibited a creatinine value above 1.4 mg/dl while on combined therapy, and there were no problems with allograft rejection. Both patients had inappropriately high cyclosporine blood levels even with this marked reduction in dosage (patient 1, 520 to 1310 ng/ml and patient 2, 320 to 600 ng/ml). Thus it appears that cyclosporine and ketoconazole can be administered together safely, provided that there is an appropriate reduction in the dosage of cyclosporine; this results in the maintenance of adequate immunosuppression without development of nephrotoxicity. PMID:3305834

  16. Endothelial dysfunction as a potential contributor in diabetic nephropathy

    PubMed Central

    Nakagawa, Takahiko; Tanabe, Katsuyuki; Croker, Byron P.; Johnson, Richard J.; Grant, Maria B.; Kosugi, Tomoki; Li, Qiuhong

    2013-01-01

    The mechanisms that drive the development of diabetic nephropathy remain undetermined. Only 30–40% of patients with diabetes mellitus develop overt nephropathy, which suggests that other contributing factors besides the diabetic state are required for the progression of diabetic nephropathy. Endothelial dysfunction is associated with human diabetic nephropathy and retinopathy, and advanced diabetic glomerulopathy often exhibits thrombotic microangiopathy, including glomerular capillary microaneurysms and mesangiolysis, which are typical manifestations of endothelial dysfunction in the glomerulus. Likewise, diabetic mice with severe endothelial dysfunction owing to deficiency of endothelial nitric oxide synthase develop progressive nephropathy and retinopathy similar to the advanced lesions observed in humans with diabetes mellitus. Additionally, inhibitors of the renin–angiotensin system fail to be renoprotective in some individuals with diabetic nephropathy (due in part to aldosterone breakthrough) and in some mouse models of the disease. In this Review, we discuss the clinical and experimental evidence that supports a role for endothelial nitric oxide deficiency and subsequent endothelial dysfunction in the progression of diabetic nephropathy and retinopathy. If endothelial dysfunction is the key factor required for diabetic nephropathy, then agents that improve endothelial function or raise intraglomerular nitric oxide level could be beneficial in the treatment of diabetic nephropathy. PMID:21045790

  17. Chaga mushroom-induced oxalate nephropathy.

    PubMed

    Kikuchi, Yuko; Seta, Koichi; Ogawa, Yayoi; Takayama, Tatsuya; Nagata, Masao; Taguchi, Takashi; Yahata, Kensei

    2014-06-01

    Chaga mushrooms have been used in folk and botanical medicine as a remedy for cancer, gastritis, ulcers, and tuberculosis of the bones. A 72-year-old Japanese female had been diagnosed with liver cancer 1 year prior to presenting at our department. She underwent hepatectomy of the left lobe 3 months later. Chaga mushroom powder (4 - 5 teaspoons per day) had been ingested for the past 6 months for liver cancer. Renal function decreased and hemodialysis was initiated. Renal biopsy specimens showed diffuse tubular atrophy and interstitial fibrosis. Oxalate crystals were detected in the tubular lumina and urinary sediment and oxalate nephropathy was diagnosed. Chaga mushrooms contain extremely high oxalate concentrations. This is the first report of a case of oxalate nephropathy associated with ingestion of Chaga mushrooms. PMID:23149251

  18. [Nephropathy associated with electrolyte disorders].

    PubMed

    Tsuchiya, K; Nakauchi, M; Hondo, I; Nihei, H

    1995-08-01

    It is well known that renal dysfunction is associated with several types of electrolyte disorders. On the other hand, renal manifestations have been attributed to electrolyte disorders. Hypokalemia is the most frequent electrolyte abnormality encountered in clinical practice. The main cause of hypokalemia is due to abuse of laxatives and diuretics or to anorexia nervosa. Hypercalcemia is another major electrolyte abnormality, associated with numerous renal manifestations. Renal tubules damages and chronic interstitial nephritis are characteristic pathological findings in prolonged electrolyte disorders. The mechanism of renal involvement and characteristic clinical manifestations of the electrolyte disorders are reviewed. PMID:7563640

  19. Corticosteroid therapy in IgA nephropathy.

    PubMed

    Lv, Jicheng; Xu, Damin; Perkovic, Vlado; Ma, Xinxin; Johnson, David W; Woodward, Mark; Levin, Adeera; Zhang, Hong; Wang, Haiyan

    2012-06-01

    The benefits and risks of steroids for the treatment of IgA nephropathy remain uncertain. We systematically searched MEDLINE, EMBASE, and the Cochrane Library for randomized, controlled trials of corticosteroid therapy for IgA nephropathy published between 1966 and March 2011. We identified nine relevant trials that included 536 patients who had urinary protein excretion >1 g/d and normal renal function. Forty-six (8.6%) of these patients developed a kidney failure event, defined as doubling of the serum creatinine/halving of the GFR or ESRD. Overall, steroid therapy was associated with a lower risk for kidney failure (relative risk, 0.32 [95% confidence interval [CI], 0.15-0.67]; P=0.002) and a reduction in proteinuria (weighted mean difference, -0.46 g/d [95% CI, -0.63 to -0.29 g/d]), with no evidence of heterogeneity in these outcomes. Subgroup analysis suggested that the dose modifies the effect of steroids for renal protection (P for heterogeneity=0.030): Relatively high-dose and short-term therapy (prednisone >30 mg/d or high-dose pulse intravenous methylprednisolone with duration ≤1 year) produced significant renal protection, whereas low-dose, long-term steroid use did not. Steroid therapy was associated with a 55% higher risk for adverse events. The quality of included studies was low, however, limiting the generalizability of the results. In conclusion, steroids appear to provide renal protection in patients with IgA nephropathy but increase the risk for adverse events. Reliably defining the efficacy and safety of steroids in IgA nephropathy requires a high-quality trial with a large sample size. PMID:22539830

  20. Importance of endogenous prostaglandins for the toxicity of cyclosporin A to rat endocrine and exocrine pancreas?

    PubMed Central

    Rünzi, M; Peskar, B M; von Schönfeld, J; Müller, M K

    1992-01-01

    Previous work has shown that cyclosporin A is toxic to the endocrine and exocrine pancreas. The aim of this study was to examine whether endogenous eicosanoids play a role in controlling cyclosporin A induced toxicity. Rats were treated for eight days with indomethacin (2 mg/kg, twice daily) in addition to cyclosporin A (5 or 10 mg/kg daily). Effects of drug treatments on exocrine (as assessed by amylase and protein secretion into the pancreatic juice) and endocrine (as assessed by the glucose dependent insulin release) pancreatic functions, and pancreatic formation of prostaglandins and thromboxane were evaluated. Treatment with cyclosporin A in the doses used did not inhibit eicosanoid formation by the pancreatic tissue ex vivo. Indomethacin caused significant inhibition of pancreatic formation of prostaglandin E2, 6k prostaglandin F1 alpha and thromboxane B2. Combined treatment with indomethacin and cyclosporin A (5 or 10 mg/kg) augmented cyclosporin A induced pancreatic toxicity with further impairment of insulin release, amylase secretion, and pancreatic juice protein content, but did not result in more pronounced inhibition of pancreatic eicosanoid formation. The increased toxicity of the combined treatment was, however, associated with raised cyclosporin A whole blood concentrations. The data suggest that the potentiation of pancreatic toxicity of cyclosporin A observed during coadministration of indomethacin is not the result of suppression of endogenous pancreatic eicosanoid biosynthesis, but more likely results from altered cyclosporin A pharmacokinetic which may be caused by an interference of indomethacin with the hepatic cytochrome P-450 dependent monooxygenase involved in cyclosporin A metabolism. The possibility that coadministration of non-steroidal antiinflammatory drugs aggravates toxic effects in cyclosporin A treated patients should be considered. PMID:1280611

  1. Recent advances in the understanding and management of IgA nephropathy

    PubMed Central

    Lai, Kar Neng; Leung, Joseph C.K.; Tang, Sydney C.W.

    2016-01-01

    Since its first description in 1968, IgA nephropathy has remained the most common form of primary glomerulonephritis leading to chronic kidney disease in developed countries. The clinical progression varies, and consequent end-stage renal disease occurs in 30% to 40% of patients 20 to 30 years after the first clinical presentation. Current data implicate overproduction of aberrantly glycosylated IgA1 as being pivotal in the induction of renal injury. Effective and specific treatment is still lacking, and new therapeutic approaches will be developed after better understanding the disease pathogenesis.

  2. Necrotizing and crescentic glomerulonephritis with membranous nephropathy in a patient exposed to levamisole-adulterated cocaine

    PubMed Central

    Carrara, Camillo; Emili, Stefano; Lin, Mercury; Alpers, Charles E.

    2016-01-01

    Levamisole is an antihelminthic agent widely used as an adulterant of illicit cocaine recently implicated as a cause of antineutrophil cytoplasmic antibody (ANCA)–associated microscopic polyangiitis in cocaine abusers. An isolated case of membranous nephropathy (MN) associated with levamisole exposure has also been reported. We report the first case, to our knowledge, of a patient with both microscopic polyangiitis manifest as a pauci-immune necrotizing and crescentic glomerulonephritis and concurrent MN in the setting of chronic cocaine abuse and presumed levamisole exposure, raising the hypothesis that levamisole was the causative agent in the development of this rare dual glomerulopathy. PMID:26985374

  3. Treatment of chronic urticaria.

    PubMed

    Jurakić Toncić, Ruzica; Lipozencić, Jasna; Marinović, Branka

    2009-01-01

    Urticaria is a disorder characterized by rapid onset of localized swelling of the skin or mucosa, called wheals or urtica. According to frequency and duration, urticaria can be divided into acute and chronic type. Chronic urticaria is any type of urticaria occurring every day or twice per week, lasting longer than 6 weeks. Chronic urticaria is a common disorder and estimated prevalence is 1% of the population. Also, it is not rare in childhood. The pathogenesis of chronic urticaria has not yet been completely understood. Chronic urticaria is a heterogeneous group of disorders, and according to the etiology and cause, several groups of chronic urticaria are distinguished, i.e. autoimmune, pseudoallergic, infection-related, physical urticaria, vasculitis urticaria and idiopathic urticaria. Treatment and management of chronic urticaria can be non-pharmacological and pharmacological, and sometimes it is not possible to control the disease with antihistamines only, which are considered to be the mainstay of treatment. In severe cases of chronic urticaria, especially if autoimmunity has been proven, several authors describe different modules of immunomodulation: cyclosporine, cyclophosphamide, mycophenolate-mofetil, omalizumab, plasmapheresis, systemic corticosteroids, and immunoglobulin therapy. This article primarily addresses the treatment of chronic idiopathic and autoimmune urticaria. PMID:20021986

  4. Effect of Posaconazole on Cyclosporine Blood Levels and Dose Adjustment in Allogeneic Blood and Marrow Transplant Recipients

    PubMed Central

    Sánchez-Ortega, Isabel; Vázquez, Lourdes; Montes, Carmen; Patiño, Beatriz; Arnan, Montserrat; Bermúdez, Arancha; Yáñez, Lucrecia; Caballero, Teresa

    2012-01-01

    The posaconazole prescribing information recommends an upfront cyclosporine dose reduction upon initiation of posaconazole prophylaxis. We examined this recommendation in the early phase of allogeneic transplantation, where cyclosporine levels potentially becoming subtherapeutic following upfront dose reduction would be deleterious to transplant outcome. Our data show that while posaconazole leads to an increase in cyclosporine levels, subsequent cyclosporine dose reduction can be safely guided by therapeutic drug monitoring and is not required upfront. Therefore, the current recommendation may be modified. PMID:23027192

  5. Clinical Scenarios in Chronic Kidney Disease: Chronic Tubulointerstitial Diseases.

    PubMed

    Meola, Mario; Samoni, Sara; Petrucci, Ilaria

    2016-01-01

    Chronic tubulointerstitial diseases are a common final pathway toward chronic renal failure regardless the primary damage (glomerular, vascular or directly the tubulointerstitium). Chronic tubulointerstitial nephritis (CTN) is characterized by interstitial scarring, fibrosis and tubule atrophy, resulting in progressive chronic kidney disease. Most frequent causes of CTN are drugs, heavy metals, obstructive uropathy, nephrolithiasis, reflux disease, immunologic diseases, neoplasia, ischemia, metabolic diseases, genetics and miscellaneous. At ultrasound (US), kidneys' morphological aspect is similar in all forms of chronic interstitial nephropathy and only chronic pyelonephritis with or without reflux shows distinguishing characteristics. In interstitial nephropathy, kidneys' profiles are finely irregular and corticomedullary differentiation is altered because of a diffused hyperechogenicity. The only indirect sign of chronic interstitial damage can be derived from the value of intrarenal resistive indexes that hardly overcome 0.75. US is mandatory in clinical chronic pyelonephritis work-up because it provides information on kidney's diameter and on growth nomogram in children. Renal profiles can be more or less altered depending on the number of cortical scars and the presence of pseudonodular areas of segmental compensatory hypertrophy. In the early stages, US diagnosis of renal tuberculosis is difficult because parenchymal lesions are non-specific. US sensitivity in the diagnosis of hydronephrosis is very high, close to 100% and, finally, US is the first choice imaging technique in the diagnosis of urinary lithiasis. PMID:27169608

  6. Cyclosporin-erythromycin interaction in renal transplant patients.

    PubMed Central

    Gupta, S K; Bakran, A; Johnson, R W; Rowland, M

    1989-01-01

    1. The interaction between cyclosporin (CyA) and erythromycin was studied in renal transplant patients following oral and intravenous administration of CyA. 2. Blood and plasma CyA concentrations and blood concentrations of metabolite 17 were measured by h.p.l.c. 3. Erythromycin produced almost a two-fold increase in bioavailability, from 36% to 60%; with a small (13%) decrease in clearance of CyA. 4. The metabolite 17 data further support the postulate that erythromycin increases the absorption of CyA rather than inhibits its metabolism, as generally believed. PMID:2655690

  7. Decreased cyclosporin A absorption after treatment with GoLytely lavage solution in rats.

    PubMed

    Santa, T; Nishihara, K; Horie, S; Kotaki, H; Sawada, Y; Kawabe, K; Iga, T

    1994-07-01

    Recently we observed a case in which the cyclosporin A absorption decreased after treatment with GoLytely lavage solution in a kidney transplant patient. In this study, we confirmed the decrease of the blood concentration of cyclosporin A after oral administration by GoLytely (Macrogol 3350) based on experiments with rats. The peak blood cyclosporin A concentration, and the area under the blood drug concentration-time curve from 0 to 24 h in the GoLytely-administered group were significantly lower than the control group. In the case of gastrointestinal dysfunction such as diarrhoea, or in treatment with laxatives such as GoLytely lavage solution, whole blood cyclosporin levels must be carefully monitored, and intravenous cyclosporin A may be more suitable for providing adequate immunosuppression. PMID:7996392

  8. Effect of cyclosporin on hair-existing area of nude mice.

    PubMed

    Hozumi, Y; Imaizumi, T; Kondo, S

    1994-07-01

    We investigated the effect of cyclosporin, as well as minoxidil, testosterone, estradiol and corticosteroid on the hair growth on the hairy part of nude mice. Aliquots of solutions of cyclosporin and other agents were applied once per every day topically on the tails and the lower backs of 5 week-old BALB/c nude mice, for as long as 6 weeks. Cyclosporin prolonged the hair-existing phase of the hair cycle, but did not change the term of the hair cycle, i.e., the resting phase was not affected. Minoxidil, testosterone and estradiol did not influence the hair growth cycle. Combination of cyclosporin and other agents demonstrated that there was neither additive nor synergistic effect, but a high dose of corticosteroid inhibit the cyclosporin effect, as well as suppressing completely the reappearance of the growing phase. PMID:7999675

  9. L-arginine prevents bone loss and bone collagen breakdown in cyclosporin A-treated rats.

    PubMed

    Fiore, C E; Pennisi, P; Cutuli, V M; Prato, A; Messina, R; Clementi, G

    2000-11-24

    Cyclosporin A is implicated in the pathogenesis of post-transplantation bone disease. Because of recent evidence that cyclosporin A may cause renal and cardiovascular toxicity by inhibiting nitric oxide (NO) activity, and that NO slows bone remodeling and bone loss in animal and human studies, we investigated a possible link between NO production and beneficial effects on bone health in cyclosporin A-treated rats. Thirty-six 10-week-old male rats were assigned to six groups of six animals each, and treated for 4 weeks with: vehicle; cyclosporin A; L-arginine; N(G)-nitro-L-arginine methylester (L-NAME, a general inhibitor of NO synthase activity); a combination of cyclosporin A+L-arginine; and a combination of cyclosporin A+L-NAME. Whole body and regional (spine and pelvis) bone mineral content of rats were measured under basal conditions and at the end of the treatment period by dual-energy X-ray absorptiometry (DXA) scanning. Femur weights and serum concentrations of pyridinoline, a reliable marker of bone resorption, were measured at the end of the study period. Cyclosporin A-, L-NAME-, and cyclosporin A+L-NAME-treated rats had significantly lower bone mineral content and femur weights, and significantly higher pyridinoline levels than did control animals. The administration of L-arginine appeared to prevent bone loss caused by cyclosporin A, suggesting that this amino acid, which can be converted to produce NO, might prove useful in preventing disturbed bone modeling and inhibition of bone growth associated with cyclosporin A therapy. PMID:11090650

  10. Oral Administration of Ginseng Ameliorates Cyclosporine-Induced Pancreatic Injury in an Experimental Mouse Model

    PubMed Central

    Lim, Sun Woo; Doh, Kyoung Chan; Jin, Long; Piao, Shang Guo; Heo, Seong Beom; Zheng, Yu Fen; Bae, Soo Kyung; Chung, Byung Ha; Yang, Chul Woo

    2013-01-01

    Background This study was performed to investigate whether ginseng has a protective effect in an experimental mouse model of cyclosporine-induced pancreatic injury. Methods Mice were treated with cyclosporine (30 mg/kg/day, subcutaneously) and Korean red ginseng extract (0.2 or 0.4 g/kg/day, oral gavage) for 4 weeks while on a 0.01% salt diet. The effect of ginseng on cyclosporine-induced pancreatic islet dysfunction was investigated by an intraperitoneal glucose tolerance test and measurements of serum insulin level, β cell area, macrophage infiltration, and apoptosis. Using an in vitro model, we further examined the effect of ginseng on a cyclosporine-treated insulin-secreting cell line. Oxidative stress was measured by the concentration of 8-hydroxy-2′-deoxyguanosine in serum, tissue sections, and culture media. Results Four weeks of cyclosporine treatment increased blood glucose levels and decreased insulin levels, but cotreatment with ginseng ameliorated the cyclosporine-induced glucose intolerance and hyperglycemia. Pancreatic β cell area was also greater with ginseng cotreatment compared with cyclosporine monotherapy. The production of proinflammatory molecules, such as induced nitric oxide synthase and cytokines, and the level of apoptotic cell death also decreased in pancreatic β cell with ginseng treatment. Consistent with the in vivo results, the in vitro study showed that the addition of ginseng protected against cyclosporine-induced cytotoxicity, inflammation, and apoptotic cell death. These in vivo and in vitro changes were accompanied by decreases in the levels of 8-hydroxy-2′-deoxyguanosine in pancreatic β cell in tissue section, serum, and culture media during cotreatment of ginseng with cyclosporine. Conclusions The results of our in vivo and in vitro studies demonstrate that ginseng has a protective effect against cyclosporine-induced pancreatic β cell injury via reducing oxidative stress. PMID:24009697

  11. Hypertension-attributed nephropathy: what's in a name?

    PubMed

    Freedman, Barry I; Cohen, Arthur H

    2016-01-01

    Unrelated disease processes commonly occur in non-diabetic individuals with mild-to-moderate hypertension and low level or absent proteinuria who present with chronic kidney disease: primary glomerulosclerosis in those with recent African ancestry, and arteriolar nephrosclerosis with resultant glomerular ischaemia potentially related to hypertension and vascular disease risk factors in other cases. Unfortunately, nephrologists often indiscriminately apply a diagnosis of 'hypertensive nephrosclerosis' to patients in either scenario, which implies that the hypertension is causative of their renal disease. Although nephropathies that are associated with variants in the apolipoprotein L1 gene (APOL1) often cause secondarily elevated blood pressure, they belong to the spectrum of focal segmental glomerulosclerosis and are not initiated by systemic hypertension. Because genetic testing for APOL1 variants and other glomerulosclerosis-associated gene variants is available and can provide a precise definition of disease pathogenesis, we believe that the term 'hypertensive nephrosclerosis' should now be abandoned and replaced with either gene-based (for example, APOL1-associated) glomerulosclerosis or arteriolar nephrosclerosis. Precision medicine will be key to improving diagnostic accuracy in this field. Discrimination of these disparate disorders has the potential to eradicate primary forms of glomerulosclerosis that are associated with APOL1 renal-risk variants. PMID:26553514

  12. Aristolochic acid nephropathy: epidemiology, clinical presentation, and treatment.

    PubMed

    Luciano, Randy L; Perazella, Mark A

    2015-01-01

    Aristolochic acid (AA) is a compound extracted from the Aristolochia species of herbs. It has been used for centuries as a remedy for various illnesses and diseases. However, in the early 1990s in the setting of a weight loss herbal remedy, AA exposure was associated with a syndrome of kidney injury, termed aristolochic acid nephropathy (AAN). This entity is marked by elevated serum creatinine, significant anemia, and histopathologic changes demonstrating a hypocellular interstitial infiltrate with severe fibrosis. Progression towards end-stage renal disease (ESRD) is rapid, with most patients having chronic kidney disease for less than 2 years. In addition, AAN is associated with a 40-45 % prevalence of urothelial carcinomas. Treatment of AAN is limited to glucocorticoids that have been shown to delay progression in non-randomized trials. As most patients progress to ESRD, need for renal replacement therapy, as either dialysis or kidney transplant, usually ensues. However, given the high malignant potential, care must be taken to minimize future development of upper urinary tract cancers by performing prophylactic bilateral nephroureterectomies and aggressive cancer surveillance. PMID:25446374

  13. Maternal Obesity Promotes Diabetic Nephropathy in Rodent Offspring.

    PubMed

    Glastras, Sarah J; Tsang, Michael; Teh, Rachel; Chen, Hui; McGrath, Rachel T; Zaky, Amgad A; Pollock, Carol A; Saad, Sonia

    2016-01-01

    Maternal obesity is known to increase the risk of obesity and diabetes in offspring. Though diabetes is a key risk factor for the development of chronic kidney disease (CKD), the relationship between maternal obesity and CKD has not been clearly defined. In this study, a mouse model of maternal obesity was employed to determine the impact of maternal obesity on development of diabetic nephropathy in offspring. Female C57BL/6 mice were fed high-fat diet (HFD) for six weeks prior to mating, during gestation and lactation. Male offspring were weaned to normal chow diet. At postnatal Week 8, offspring were randomly administered low dose streptozotocin (STZ, 55 mg/kg/day for five days) to induce diabetes. Assessment of renal damage took place at postnatal Week 32. We found that offspring of obese mothers had increased renal fibrosis, inflammation and oxidative stress. Importantly, offspring exposed to maternal obesity had increased susceptibility to renal damage when an additional insult, such as STZ-induced diabetes, was imposed. Specifically, renal inflammation and oxidative stress induced by diabetes was augmented by maternal obesity. Our findings suggest that developmental programming induced by maternal obesity has implications for renal health in offspring. Maternal obesity should be considered a risk factor for CKD. PMID:27277011

  14. Maternal Obesity Promotes Diabetic Nephropathy in Rodent Offspring

    PubMed Central

    Glastras, Sarah J.; Tsang, Michael; Teh, Rachel; Chen, Hui; McGrath, Rachel T.; Zaky, Amgad A.; Pollock, Carol A.; Saad, Sonia

    2016-01-01

    Maternal obesity is known to increase the risk of obesity and diabetes in offspring. Though diabetes is a key risk factor for the development of chronic kidney disease (CKD), the relationship between maternal obesity and CKD has not been clearly defined. In this study, a mouse model of maternal obesity was employed to determine the impact of maternal obesity on development of diabetic nephropathy in offspring. Female C57BL/6 mice were fed high-fat diet (HFD) for six weeks prior to mating, during gestation and lactation. Male offspring were weaned to normal chow diet. At postnatal Week 8, offspring were randomly administered low dose streptozotocin (STZ, 55 mg/kg/day for five days) to induce diabetes. Assessment of renal damage took place at postnatal Week 32. We found that offspring of obese mothers had increased renal fibrosis, inflammation and oxidative stress. Importantly, offspring exposed to maternal obesity had increased susceptibility to renal damage when an additional insult, such as STZ-induced diabetes, was imposed. Specifically, renal inflammation and oxidative stress induced by diabetes was augmented by maternal obesity. Our findings suggest that developmental programming induced by maternal obesity has implications for renal health in offspring. Maternal obesity should be considered a risk factor for CKD. PMID:27277011

  15. MicroRNAs in Diabetic Nephropathy: From Biomarkers to Therapy.

    PubMed

    Simpson, Kate; Wonnacott, Alexa; Fraser, Donald J; Bowen, Timothy

    2016-03-01

    Recent estimates suggest that 1 in 12 of the global population suffers from diabetes mellitus. Approximately 40 % of those affected will go on to develop diabetes-related chronic kidney disease or diabetic nephropathy (DN). DN is a major cause of disability and premature death. Existing tests for prognostic purposes are limited and can be invasive, and interventions to delay progression are challenging. MicroRNAs (miRNAs) are a recently described class of molecular regulators found ubiquitously in human tissues and bodily fluids, where they are highly stable. Alterations in miRNA expression profiles have been observed in numerous diseases. Blood and tissue miRNAs are already established cancer biomarkers, and cardiovascular, metabolic and immune disease miRNA biomarkers are under development. Urinary miRNAs represent a potential novel source of non-invasive biomarkers for kidney diseases, including DN. In addition, recent data suggest that miRNAs may have therapeutic applications. Here, we review the utility of miRNAs as biomarkers for the early detection and progression of DN, assess emerging data on miRNAs implicated in DN pathology and discuss how the data from both fields may contribute to the development of novel therapeutic agents. PMID:26973290

  16. Prognostic factors and biomarkers of congenital obstructive nephropathy.

    PubMed

    Chevalier, Robert L

    2016-09-01

    Congenital obstructive nephropathy (CON) is the leading cause of chronic kidney disease (CKD) in children. Anomalies of the urinary tract are often associated with abnormal nephrogenesis, which is compounded by obstructive injury and by maternal risk factors associated with low birth weight. Currently available fetal and postnatal imaging and analytes of amniotic fluid, urine, or blood lack predictive value. For ureteropelvic junction obstruction, biomarkers are needed for optimal timing of pyeloplasty; for posterior urethral valves, biomarkers of long-term prognosis and CKD are needed. The initial nephron number may be a major determinant of progression of CKD, and most patients with CON who progress to renal failure reach this point in adulthood, presumably compounded by episodes of acute kidney injury. Biomarkers of tubular injury may be of particular value in predicting the need for surgical intervention or in tracking progression of CKD, and must be adjusted for patient age. Discovery of new biomarkers may depend on "unbiased" proteomics, whereby patterns of urinary peptide fragments from patients with CON are analyzed in comparison to controls. Most promising are the analysis of urinary exosomes (restricting biomarkers to relevant tubular cells) and quantitative magnetic resonance imaging techniques allowing precise determination of nephron number and tubular mass. The greatest need is for large prospective multicenter studies with centralized biomarker sample repositories to follow patients with CON from fetal life through adulthood. PMID:26667236

  17. Protein-losing nephropathy in small animals.

    PubMed

    Littman, Meryl P

    2011-01-01

    Genetic and acquired defects of glomerular permselectivity may lead to proteinuria and protein-losing nephropathy (PLN). Morbidity and mortality from complications of PLN may be severe even before progression to azotemia and renal failure. Leakage of plasma proteins into the glomerular filtrate can damage tubular cells and the function of the entire nephron. Detection, localization, and treatment of proteinuria are important to decrease the clinical signs and complications of PLN and the likelihood of progression to renal failure. Thorough diagnostic work-ups help to identify subsets of glomerular disease and their response to specific treatment protocols. PMID:21251510

  18. Chronic kidney disease in human immunodeficiency virus infection.

    PubMed

    Fabian, J; Katz, I; Gerntholtz, T; Goetsch, S; Naicker, S

    2007-06-01

    The number of people living with human immunodeficiency virus (HIV) worldwide was estimated to be 39.5 million in 2006, 2.6 million more than in 2004. The manifestations of HIV infection in the kidney are multiple and varied, highlighting the complexity of the disease process. There is a wide spectrum of renal disease that occurs in the course of HIV infection. Biopsy studies reveal varying frequencies of histological patterns. HIV-associated nephropathy (HIVAN) is most common. A biopsy study at Chris Baragwanath Hospital in Soweto, South Africa showed that HIVAN was present in 27% and immune complex disease in 21%. Han et al. studied HIV-positive patients in Durban, South Africa and screened for proteinuria, including microalbuminuria. They found persistent proteinuria in 6%; HIVAN in 21/30 (72.4%) and the prevalence of HIVAN in patients with persistent microalbuminuria was 85.7%. Studies in black patients have shown a higher prevalence of both severe glomerular lesions (focal glomerulosclerosis) and nephrotic range proteinuria with renal dysfunction in the presence of normo-hypotension. There have been no prospective randomised controlled studies with any form of therapy for HIVAN to date. Therapy of HIVAN has included corticosteroids, cyclosporine and antiretroviral therapy (ART). ART appears to be a logical choice in the management of HIV-associated renal disease. Regimens containing protease inhibitors have been shown to be associated with significant slowing of the decline in creatinine clearance. Both peritoneal dialysis and haemodialysis are appropriate treatment modalities for HIV-infected patients with end stage renal disease. The choice of dialysis modality between haemodialysis and peritoneal dialysis is not a factor in predicting survival, if patients are stable on ART. Preliminary short-term data in case reports and small cohorts of liver, kidney, and heart transplant recipients suggest that patient survival rates may be similar to those in HIV

  19. Anti-microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways.

    PubMed

    Gomez, Ivan G; MacKenna, Deidre A; Johnson, Bryce G; Kaimal, Vivek; Roach, Allie M; Ren, Shuyu; Nakagawa, Naoki; Xin, Cuiyan; Newitt, Rick; Pandya, Shweta; Xia, Tai-He; Liu, Xueqing; Borza, Dorin-Bogdan; Grafals, Monica; Shankland, Stuart J; Himmelfarb, Jonathan; Portilla, Didier; Liu, Shiguang; Chau, B Nelson; Duffield, Jeremy S

    2015-01-01

    MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously and evaluated the therapeutic potential of these anti-miR-21 oligonucleotides in chronic kidney disease. In a murine model of Alport nephropathy, miR-21 silencing did not produce any adverse effects and resulted in substantially milder kidney disease, with minimal albuminuria and dysfunction, compared with vehicle-treated mice. miR-21 silencing dramatically improved survival of Alport mice and reduced histological end points, including glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Anti-miR-21 enhanced PPARα/retinoid X receptor (PPARα/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Moreover, miR-21 silencing enhanced mitochondrial function, which reduced mitochondrial ROS production and thus preserved tubular functions. Inhibition of miR-21 was protective against TGF-β-induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPARα/RXR activity and improved mitochondrial function. Together, these results demonstrate that inhibition of miR-21 represents a potential therapeutic strategy for chronic kidney diseases including Alport nephropathy. PMID:25415439

  20. Wt-1 Expression Linked to Nitric Oxide Availability during Neonatal Obstructive Nephropathy

    PubMed Central

    Mazzei, Luciana; Manucha, Walter

    2013-01-01

    The wt-1 gene encodes a zinc finger DNA-binding protein that acts as a transcriptional activator or repressor depending on the cellular or chromosomal context. The wt-1 regulates the expression of a large number of genes that have a critical role in kidney development. Congenital obstructive nephropathy disrupts normal renal development and causes chronic progressive interstitial fibrosis, which contributes to renal growth arrest, ultimately leading to chronic renal failure. Wt-1 is downregulated during congenital obstructive nephropathy, leading to apoptosis. Of great interest, nitric oxide bioavailability associated with heat shock protein 70 (Hsp70) interaction may modulate wt-1 mRNA expression, preventing obstruction-induced cell death during neonatal unilateral ureteral obstruction. Moreover, recent genetic researches have allowed characterization of many of the complex interactions among the individual components cited, but the realization of new biochemical, molecular, and functional experiments as proposed in our and other research labs allows us to establish a deeper level of commitment among proteins involved and the potential pathogenic consequences of their imbalance. PMID:24288526

  1. Anti–microRNA-21 oligonucleotides prevent Alport nephropathy progression by stimulating metabolic pathways

    PubMed Central

    Gomez, Ivan G.; MacKenna, Deidre A.; Johnson, Bryce G.; Kaimal, Vivek; Roach, Allie M.; Ren, Shuyu; Nakagawa, Naoki; Xin, Cuiyan; Newitt, Rick; Pandya, Shweta; Xia, Tai-He; Liu, Xueqing; Borza, Dorin-Bogdan; Grafals, Monica; Shankland, Stuart J.; Himmelfarb, Jonathan; Portilla, Didier; Liu, Shiguang; Chau, B. Nelson; Duffield, Jeremy S.

    2014-01-01

    MicroRNA-21 (miR-21) contributes to the pathogenesis of fibrogenic diseases in multiple organs, including the kidneys, potentially by silencing metabolic pathways that are critical for cellular ATP generation, ROS production, and inflammatory signaling. Here, we developed highly specific oligonucleotides that distribute to the kidney and inhibit miR-21 function when administered subcutaneously and evaluated the therapeutic potential of these anti–miR-21 oligonucleotides in chronic kidney disease. In a murine model of Alport nephropathy, miR-21 silencing did not produce any adverse effects and resulted in substantially milder kidney disease, with minimal albuminuria and dysfunction, compared with vehicle-treated mice. miR-21 silencing dramatically improved survival of Alport mice and reduced histological end points, including glomerulosclerosis, interstitial fibrosis, tubular injury, and inflammation. Anti–miR-21 enhanced PPARα/retinoid X receptor (PPARα/RXR) activity and downstream signaling pathways in glomerular, tubular, and interstitial cells. Moreover, miR-21 silencing enhanced mitochondrial function, which reduced mitochondrial ROS production and thus preserved tubular functions. Inhibition of miR-21 was protective against TGF-β–induced fibrogenesis and inflammation in glomerular and interstitial cells, likely as the result of enhanced PPARα/RXR activity and improved mitochondrial function. Together, these results demonstrate that inhibition of miR-21 represents a potential therapeutic strategy for chronic kidney diseases including Alport nephropathy. PMID:25415439

  2. The Treatment of IgA Nephropathy

    PubMed Central

    Lai, Kar Neng; Leung, Joseph C.K.; Tang, Sydney C.W.

    2015-01-01

    Background IgA nephropathy (IgAN) is a very common glomerulonephritis worldwide. Nevertheless, treatment options for primary IgAN are still largely based on opinion or weak evidence. There is a lack of large randomized controlled trials (RCT) that provide a definitive immunosuppressive protocol for IgAN. The recent KDIGO Clinical Practice Guidelines for Glomerulonephritis have assigned low levels of evidence for almost all recommendations and suggestions related to this nephropathy. Summary In this article, we review different treatment options and emphasize that the key to therapeutic decision-making is the assessment of an individual's prognosis. The risk of disease progression is closely related to clinical parameters such as proteinuria, hypertension, and impaired glomerular filtration rate. For patients with minor urinary abnormalities, the mainstay of treatment is long-term regular follow-up to detect renal progression and hypertension. Optimized supportive care aiming to maintain proteinuria <1 g/day is preferred in the typical patient presenting with microhematuria, significant but nonnephrotic proteinuria, hypertension, and variable degrees of renal failure. The atypical patient with overt nephritic syndrome or rapidly progressive kidney injury that represents a vasculitic form of IgAN should be treated with immunosuppression. Finally, the variant of overlapping syndrome of IgAN and lipoid nephrosis that runs a good prognosis should be treated as lipoid nephrosis. Key Message The treatment of IgAN should be structured according to the clinical scenario.

  3. Biomarkers in diabetic nephropathy: Present and future

    PubMed Central

    Currie, Gemma; McKay, Gerard; Delles, Christian

    2014-01-01

    Diabetic nephropathy (DN) is the leading cause of end stage renal disease in the Western world. Microalbuminuria (MA) is the earliest and most commonly used clinical index of DN and is independently associated with cardiovascular risk in diabetic patients. Although MA remains an essential tool for risk stratification and monitoring disease progression in DN, a number of factors have called into question its predictive power. Originally thought to be predictive of future overt DN in 80% of patients, we now know that only around 30% of microalbuminuric patients progress to overt nephropathy after 10 years of follow up. In addition, advanced structural alterations in the glomerular basement membrane may already have occurred by the time MA is clinically detectable.Evidence in recent years suggests that a significant proportion of patients with MA can revert to normoalbuminuria and the concept of nonalbuminuric DN is well-documented, reflecting the fact that patients with diabetes can demonstrate a reduction in glomerular filtration rate without progressing from normo-to MA. There is an unmet clinical need to identify biomarkers with potential for earlier diagnosis and risk stratification in DN and recent developments in this field will be the focus of this review article. PMID:25512779

  4. Diabetic nephropathy: What does the future hold?

    PubMed

    Montero, R M; Covic, A; Gnudi, L; Goldsmith, D

    2016-01-01

    The consensus management of diabetic nephropathy (DN) in 2015 involves good control of glycaemia, dyslipidaemia and blood pressure (BP). Blockade of the renin-angiotensin-aldosterone system using angiotensin-converting enzyme inhibitors, angiotensin-2 receptor blockers or mineralocorticoid inhibitors are key therapeutic approaches, shown to be beneficial once overt nephropathy is manifest, as either, or both, of albuminuria and loss of glomerular filtration rate. Some significant additional clinical benefits in slowing the progression of DN was reported from the Remission clinic experience, where simultaneous intensive control of BP, tight glycaemic control, weight loss, exercise and smoking cessation were prioritised in the management of DN. This has not proved possible to translate to more conventional clinical settings. This review briefly looks over the history and limitations of current therapy from landmark papers and expert reviews, and following an extensive PubMed search identifies the most promising clinical biomarkers (both established and proposed). Many challenges need to be addressed urgently as in order to obtain novel therapies in the clinic; we also need to examine what we mean by remission, stability and progression of DN in the modern era. PMID:26438328

  5. Management of cyclosporine-induced gingival hyperplasia by use of an argon laser

    NASA Astrophysics Data System (ADS)

    Blankenau, Richard J.; Triolo, P.; Powell, G. L.

    1994-09-01

    This is a report of a case study with interesting laser applications. A 7 year old female was referred to us for treatment of hyperplastic tissue. At age two the patient had successfully undergone a liver transplant. She had undergone two periodontal surgeries under general anesthetic for the same soft tissue problem. Other possible complications were chronic sinusitis and frequent headaches. She has allergies to penicillin and sulfa. Her daily medications are Predisone and Cyclosporin. We consulted with her transplant team and they had no contraindication for the proposed dental surgery. The doctor placed her on prophylactic erythromycin for the procedure, as a preventive measure. The patient desired not to have any more general anesthetics administered. Clinical examination revealed electric pulp tests were normal for all teeth tested. No visible carious lesions were observed and there was no need for radiographs at this time. Soft tissue revealed red inflamed fibrous tissue consistent with gingival hyperplasia. Probing demonstrated 4 - 6 mm pockets around the anterior teeth.

  6. Successful treatment of acute kidney injury secondary to haeme nephropathy in paroxysmal nocturnal haemoglobinuria with alkaline diuresis

    PubMed Central

    Sakthiswary, R.; Das, S.; Fadilah, S.A.W.

    2012-01-01

    Paroxysmal nocturnal haemoglobinuria (PNH) also known as 'Marchiafava Micheli syndrome' is a rare condition which can lead to both acute and chronic forms of renal failure through renal tubular haemosiderin deposition. A 45-year-old lady with underlying PNH, presented with complaints of fever, productive cough followed by dark coloured urine. Investigations revealed pancytopenia with a markedly raised creatinine from her baseline (from 65 mmol/L to 385 mmol/L) consistent with acute kidney injury (AKI). Renal biopsy confirmed the diagnosis of haeme nephropathy. The renal impairment improved rapidly and normalised over a period of 5 days with alkaline diuresis (AD). The patient did not require haemodialysis unlike most other reported cases of AKI secondary to haeme nephropathy in PNH. This is the second reported case of AKI in PNH which was successfully treated with AD alone emphasizing the role of AD as a promising therapeutic strategy in this condition.

  7. Investigation of developmental toxicity and teratogenicity of cyclosporine A, tacrolimus and their combinations with prednisolone.

    PubMed

    Unver Dogan, Nadire; Uysal, Ismihan Ilknur; Fazliogullari, Zeliha; Karabulut, Ahmet Kagan; Acar, Hasan

    2016-06-01

    In this study, it was aimed to investigate the toxic and teratogenic effects of cyclosporine A and tacrolimus and their combinations with prednisolone using an in vitro rat embryo culture technique. Cyclosporine A (4-40 μg/ml), tacrolimus (1-20 μg/ml) and combinations of these drugs with prednisolone (20 μg/ml) at different concentrations were tested. Cyclosporine A and its combination with prednisolone were determined to have toxic effects on embryonic growth after 10 μg/ml. When used alone, the lowest dose of tacrolimus had embryotoxic effects on the total morphological score and number of somites. It was determined that cyclosporine A caused hematoma at 4 μg/ml and higher doses, and tacrolimus especially at 20 μg/ml caused an open neural tube beside hematoma. It was observed that cyclosporine A at 40 μg/ml dose initiated apoptotic effects at a very low rate, prednisolone increased this effect, tacrolimus led to excessive apoptosis after 15 μg/ml, and this effect did not change with prednisolone supplement. We are of the opinion that the doses should be determined carefully when cyclosporine A and tacrolimus are required to be administered to pregnant women with prednisolone combination, as prednisolone increases the toxic effects of cyclosporine A, and increases teratogenic effects of tacrolimus. PMID:26993750

  8. Efficacy of topical cyclosporin 0.05% in the treatment of posterior blepharitis.

    PubMed

    Rubin, Michael; Rao, Sanjay N

    2006-02-01

    We assessed the efficacy of topical cyclosporin 0.05% ophthalmic emulsion versus tobramycin 0.3%/dexamethasone 0.1% in patients with posterior blepharitis. Posterior blepharitis improved significantly from the initial study visit with both cyclosporin treatment and tobramycin/dexamethasone. Cyclosporin provided greater improvements in Schirmer's scores (P < 0.001) and tear break-up time (P = 0.018) than tobramycin/dexamethasone after 12 weeks of treatment. Eyelid health also improved in both groups, but the mean improvement in meibomian gland secretion quality was significantly greater with cyclosporin than with tobramycin/dexamethasone (P = 0.015). Moreover, a higher percentage of patients in the cyclosporin treatment group had improvements in symptoms of blurred vision, burning, and itching and more cyclosporin-treated patients experienced resolution of lid telangiectasia. The findings in this prospective study suggest that posterior blepharitis can be more effectively treated with cyclosporin than with tobramycin/dexamethasone. These findings should be further evaluated in large-scale, controlled, clinical trials. PMID:16503775

  9. Prolonged heart xenograft survival using combined total lymphoid irradiation and cyclosporine

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Saad, T.; Bollinger, R.R.

    1986-05-01

    Total lymphoid irradiation and cyclosporine have profound immunosuppressive properties and permit successful heart allotransplantation. Cyclosporine used alone has not permitted consistently successful transplantation between species in all cases. Total lymphoid irradiation has not been applied to xenotransplantation. The efficacy of total lymphoid irradiation alone and in combination with cyclosporine was examined using an animal model of heart xenotransplantation. Heterotopic heart transplants were performed using inbred Syrian hamsters as donors and Lewis rats as recipients. Total lymphoid irradiation was administered preoperatively over 3 weeks for a total dose of 15 gray. Cyclosporine was started on the day of surgery and was given as a daily intramuscular injection of 2.5, 5, or 10 mg/kg/day until rejection was complete. Neither total lymphoid irradiation nor cyclosporine alone markedly prolonged graft survival. However, combined total lymphoid irradiation and cyclosporine, 5 or 10 mg/kg/day, dramatically prolonged graft survival to greater than 100 days in most recipients. There were no treatment-related deaths. In conclusion, combined total lymphoid irradiation and cyclosporine permit successful long-term survival of heart xenotransplants in this hamster-to-rat model.

  10. Cyclosporine A stimulated hair growth from mouse vibrissae follicles in an organ culture model

    PubMed Central

    Xu, Wenrong; Fan, Weixin; Yao, Kun

    2012-01-01

    Hypertrichosis is one of the most common side effects of systemic cyclosporine A therapy. It has been previously shown that cyclosporine A induces anagen and inhibits catagen development in mice. In the present study, to explore the mechanisms of cyclosporine A, we investigated the effects of cyclosporine A on hair shaft elongation, hair follicle cell proliferation, apoptosis, and mRNA expression of selected growth factors using an organ culture model of mouse vibrissae. In this model, cyclosporine A stimulated hair growth of normal mouse vibrissae follicles by inhibiting catagen-like development and promoting matrix cell proliferation. In addition, cyclosporine A caused an increase in the expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and nerve growth factor (NGF), and inhibited follistatin expression. Our findings provide an explanation for the clinically observed effects of cyclosporine A on hair growth. The mouse vibrissae organ culture offers an attractive model for identifying factors involved in the modulation of hair growth. PMID:23554774

  11. Pharmacokinetic interaction studies of fenugreek with CYP3A substrates cyclosporine and carbamazepine.

    PubMed

    Al-Jenoobi, Fahad I; Alam, Mohd Aftab; Alkharfy, Khalid M; Al-Suwayeh, Saleh A; Korashy, Hesham M; Al-Mohizea, Abdullah M; Iqbal, Muzaffar; Ahad, Abdul; Raish, Mohammad

    2014-06-01

    The present study investigated the effect of fenugreek seed powder on disposition of CYP3A substrates, cyclosporine and carbamazepine. Rabbits were treated with fenugreek seed powder (300 mg/kg p.o.) for 8 days and on 8th day the single dose of cyclosporine (30 mg/kg, p.o.) and carbamazepine (40 mg/kg, p.o.) were administered to the corresponding group after 1 h of fenugreek administration. Blood samples were drawn at several time points and analyzed by using UPLC-MS (cyclosporine) and HPLC (carbamazepine). Pharmacokinetic parameters were calculated by using PK Solver. The present investigation reveals that there was no statistically significant difference between pre- and post-treated pharmacokinetic parameters such as AUC(o-t), AUC(o-∞), C(max), T(max), T(1/2), K(el), MRT(o-∞) , V(z/F), and Cl/F for cyclosporine and carbamazepine. Two tailed "P" values for all these pharmacokinetic parameters were more than 0.05, indicating insignificant impact of fenugreek treatment on the disposition of cyclosporine and carbamazepine. Further, fenugreek may also not have any significant effect on the functionality of P-glycoprotein as cyclosporine is a substrate to P-glycoprotein. The outcomes of present study suggested that fenugreek may not likely to interfere cyclosporine and carbamazepine pharmacokinetics, when co-administered with these drugs. PMID:24022709

  12. Immunotoxic effects of cyclophosphamide and cyclosporine in the dog.

    PubMed

    Legrand, Jean-Jacques; Bouchez, Caroline; Mimouni, Cécile; N'Guyen, Armelle; Bouchard, Johanne; Ameller, Thibault; Descotes, Jacques

    2013-01-01

    Limited non-clinical immunotoxicity data are available in the dog, although this is a major non-rodent species in regulatory safety studies. The present study aimed to test whether widely accepted immunotoxicity endpoints including lymphocyte subset immunophenotyping, the anti-KLH TDAR assay, and histological examination of the main lymphoid organs were reliable to detect immunosuppression induced by cyclosporine and cyclophosphamide in dogs and could, therefore, be used for non-clinical immunotoxicity evaluation in this species. Male and female Beagle dogs were treated orally from Day 1 for 4 weeks with 25 mg/kg cyclosporine daily, or with 2 mg/kg cyclophosphamide on 4 consecutive days each week, or the same volume of drinking water daily. Blood samples were withdrawn pre-test and on Days 11, 18, and 23 to measure standard hematology parameters and analyze lymphocyte subsets. All animals received an intramuscular injection of 5 mg KLH on Day 11. Sandwich ELISA assays were used to quantify anti-KLH IgM and anti-KLH IgG levels in blood samples taken pre-test, on Days 18 and 23, and pre-test, on Days 23 and 28, respectively. At the end of the treatment period, all animals were submitted to histological examination of lymphoid organs, liver, and kidneys. No signs of marked toxicity were observed. No changes in lymphocyte subsets, but markedly decreased primary anti-KLH IgM and IgG responses, and a slightly-to-markedly increased cortex/medulla ratio in the thymus were observed in cyclosporine-treated dogs. Lower total WBC counts correlating with lower total and B-lymphocyte subset and decreased germinal center development in mesenteric lymph nodes, but no changes in primary anti-KLH IgM and IgG responses were observed in cyclophosphamide-treated dogs. These results demonstrate that widely accepted immunotoxicity endpoints can adequately detect the effects of known immunosuppressive drugs in the dog and support the conclusion that it is a relevant animal species

  13. Investigation of potential interaction of ciprofloxacin with cyclosporine in bone marrow transplant recipients.

    PubMed Central

    Krüger, H U; Schuler, U; Proksch, B; Göbel, M; Ehninger, G

    1990-01-01

    The effect of the 4-quinolone antimicrobial agent ciprofloxacin on the concentration in plasma and the pharmacokinetics of the immunosuppressive agent cyclosporine was studied in 10 bone marrow transplant recipients. There were no statistically or clinically significant changes in cyclosporine trough concentrations or areas under the concentration-time curve following oral doses of 500 mg of ciprofloxacin every 12 h for 4 days. The data suggest a lack of relevant pharmacokinetic interaction of ciprofloxacin with cyclosporine. There was no indication of an enhanced nephrotoxicity for this drug combination. PMID:2203301

  14. S15176 and S16950 interaction with Cyclosporin A antiproliferative effect on cultured human lymphocytes.

    PubMed

    Albengres, E; Le Louët, H; d'Athis, P; Tillement, J P

    2001-02-01

    S15176 and S16950 are trimetazidine derivatives that antagonize more strongly than the parent drug mitochondrial toxicity, which leads to cellular hypoxia and nephrotoxicity in kidneys experimentally exposed to cyclosporin A. We have investigated whether every derivative might interact or not with the inhibitory effect of Cyclosporin A on the proliferation of cultured human lymphocytes. S15176 significantly increased the antilymphoproliferative effect of Cyclosporin A, whereas S15176 by itself neither displayed any antilymphoproliferative effect, nor did it induce any apoptotic process in cultured human lymphocytes. The effect of S16950 was not significant. PMID:11468012

  15. Modern approaches to the ocular delivery of cyclosporine A.

    PubMed

    Agarwal, Priyanka; Rupenthal, Ilva D

    2016-06-01

    Cyclosporine A (CsA) has long been the mainstay treatment for dry eye syndrome (DES), one of the most common disorders of the eye. However, the poor water solubility of CsA renders it difficult to formulate it into topical ocular dosage forms. Restasis® is currently the only US Food and Drug Administration (FDA)-approved CsA formulation, while Ikervis® has recently been launched in Europe, with both commonly associated with severe ocular discomfort. Therefore, several CsA formulations have been investigated with the aim to improve bioavailability while reducing adverse effects associated with the marketed formulations. In this review, we summarize recent advances in ocular CsA delivery that provide safer and more effective alternatives for the management of DES and other ocular inflammatory conditions. PMID:27080149

  16. Conformational Heterogeneity of Cyclosporin A in Cyclophilin 18 Binding

    PubMed Central

    Lin, Weilin; Quintero, Andres; Zhang, Yixin

    2016-01-01

    The immunosuppressive drug cyclosporin A (CsA) binds to its receptor protein cyclophilin 18 (Cyp18) in two distinct kinetic phases, while the mechanism remains elusive. Stopped-flow measurements coupled with titration and competition experiments were used to investigate the puzzling two-phase process of CsA and Cyp18 interaction. This study leads to the dissection of different conformational fractions of either direct fast binding or slow binding with rate-limiting conformational inter-conversion and the real-time measurement of kon value (8.34 ± 0.22 x106 M-1s-1) in solution. Furthermore, our study indicates that the structure of CsA during dissociation from the protein possesses a distribution of conformations different from those in solution under equilibrium condition. PMID:27082870

  17. Acute bile nephropathy secondary to anabolic steroids.

    PubMed

    Alkhunaizi, Ahmed M; ElTigani, Mohamed A; Rabah, Rola S; Nasr, Samih H

    2016-02-01

    Renal dysfunction in cholestatic liver disease is multifactorial. Acute kidney injury may develop secondary to renal vasoconstriction in the setting of peripheral vasodilation and relative hypovolemia, tubular obstruction by bile casts, and direct tubular toxicity from bile. Anabolic steroids are frequently used by athletes to boost endurance and increase muscle mass. These agents are a recently recognized cause of hepatotoxicity and jaundice and may lead to acute kidney injury. To increase awareness about this growing problem and to characterize the pathology of acute kidney injury in this setting, we report on a young male who developed acute kidney injury in the setting of severe cholestatic jaundice related to ingestion of anabolic steroids used for bodybuilding. Kidney biopsy showed bile casts within distal tubular lumina, filamentous bile inclusions within tubular cells, and signs of acute tubular injury. This report supports the recently re-emerged concept of bile nephropathy cholemic nephrosis. PMID:26587777

  18. Fructose and uric acid in diabetic nephropathy

    PubMed Central

    Bjornstad, Petter; Lanaspa, Miguel A.; Ishimoto, Takuji; Kosugi, Tomoki; Kume, Shinji; Jalal, Diana; Maahs, David M.; Snell-Bergeon, Janet K.; Johnson, Richard J.

    2016-01-01

    Clinical studies have reported associations between serum uric acid levels and the development of diabetic nephropathy, but the underlying mechanisms remain elusive. There is evidence from animal studies that blocking uric acid production protects the kidney from tubulointerstitial injury, which may suggest a causal role for uric acid in the development of diabetic tubular injury. In turn, when fructose, which is endogenously produced in diabetes via the polyol pathway, is metabolised, uric acid is generated from a side-chain reaction driven by ATP depletion and purine nucleotide turnover. For this reason, uric acid derived from endogenous fructose could cause tubulointerstitial injury in diabetes. Accordingly, our research group recently demonstrated that blocking fructose metabolism in a diabetic mouse model mitigated the development of tubulointerstitial injury by lowering tubular uric acid production. In this review we discuss the relationship between uric acid and fructose as a novel mechanism for the development of diabetic tubular injury. PMID:26049401

  19. Fructose and uric acid in diabetic nephropathy.

    PubMed

    Bjornstad, Petter; Lanaspa, Miguel A; Ishimoto, Takuji; Kosugi, Tomoki; Kume, Shinji; Jalal, Diana; Maahs, David M; Snell-Bergeon, Janet K; Johnson, Richard J; Nakagawa, Takahiko

    2015-09-01

    Clinical studies have reported associations between serum uric acid levels and the development of diabetic nephropathy, but the underlying mechanisms remain elusive. There is evidence from animal studies that blocking uric acid production protects the kidney from tubulointerstitial injury, which may suggest a causal role for uric acid in the development of diabetic tubular injury. In turn, when fructose, which is endogenously produced in diabetes via the polyol pathway, is metabolised, uric acid is generated from a side-chain reaction driven by ATP depletion and purine nucleotide turnover. For this reason, uric acid derived from endogenous fructose could cause tubulointerstitial injury in diabetes. Accordingly, our research group recently demonstrated that blocking fructose metabolism in a diabetic mouse model mitigated the development of tubulointerstitial injury by lowering tubular uric acid production. In this review we discuss the relationship between uric acid and fructose as a novel mechanism for the development of diabetic tubular injury. PMID:26049401

  20. Contrast induced nephropathy in vascular surgery.

    PubMed

    Wong, G T C; Lee, E Y P; Irwin, M G

    2016-09-01

    Contrast induced nephropathy (CIN) is traditionally associated with outpatient imaging studies. More recently, patients afflicted with vascular pathologies are increasingly undergoing endovascular treatments that require the use of iodinated contrast media (CM) agents, thus placing them as risk of developing CIN. As perioperative physicians, anaesthetists should be aware of the risk factors and measures that might minimize acute kidney injury caused by CM. This review evaluates recent data regarding preventive measures against CIN and where possible, places the evidence in the context of the patient receiving endovascular surgical treatment. Measures including the use of peri-procedural hydration, N-acetylcysteine, statins, remote ischaemic preconditioning, renal vasodilators and renal replacement therapy and the use of alternatives to iodinated contrast agents are discussed. It should be noted that most of the available data regarding CIN are from non-surgical patients. PMID:27566809

  1. The Treatment of HIV-Associated Nephropathy

    PubMed Central

    Kalayjian, Robert C.

    2010-01-01

    Antiretroviral therapy (ART) preserves kidney function in patients with human immunodeficiency virus (HIV)-associated nephropathy (HIVAN). Emerging data also document substantial renal benefits of ART in the general HIV-infected population, which is associated in part with suppression of HIV-1 viral replication. The extent to which the response to ART differs in persons with HIVAN, compared to those with other HIV-associated kidney disorders, is unknown. Beneficial effects of corticosteroids and angiotensin-converting enzyme (ACE) inhibitors on kidney function also are suggested by retrospective cohort studies and uncontrolled trials of patients with HIVAN. Underexposure to ART, or inadequate ART dosing in HIV-infected patients with CKD, may curtail the optimal benefits that may be derived from this therapy. PMID:20005490

  2. Complex networks analysis of obstructive nephropathy data

    NASA Astrophysics Data System (ADS)

    Zanin, M.; Boccaletti, S.

    2011-09-01

    Congenital obstructive nephropathy (ON) is one of the most frequent and complex diseases affecting children, characterized by an abnormal flux of the urine, due to a partial or complete obstruction of the urinary tract; as a consequence, urine may accumulate in the kidney and disturb the normal operation of the organ. Despite important advances, pathological mechanisms are not yet fully understood. In this contribution, the topology of complex networks, based on vectors of features of control and ON subjects, is related with the severity of the pathology. Nodes in these networks represent genetic and metabolic profiles, while connections between them indicate an abnormal relation between their expressions. Resulting topologies allow discriminating ON subjects and detecting which genetic or metabolic elements are responsible for the malfunction.

  3. Cyclosporine Plus Methotrexate or Cyclosporine Plus Mycophenolate Mofetil as Graft Versus Host Disease Prophylaxis in Acute Leukemia Transplant: Comparison of Toxicity, Engraftment Kinetics and Transplant Outcome.

    PubMed

    Gupta, Alok; Punatar, Sachin; Mathew, Libin; Kannan, Sadhana; Khattry, Navin

    2016-09-01

    We sought to compare two graft-versus-host disease (GVHD) prophylaxis regimen, cyclosporine and methotrexate (CsA+MTX) with CsA+mycophenolate mofetil (MMF) in 77 acute leukemia patients who underwent hematopoietic stem cell transplant (HSCT) between January 2008 and March 2013. Fifty-three patients received CsA+MTX while 24 received CsA+MMF. The incidence of grade 3-4 mucositis and grade 3-4 diarrhea was 74 and 6 % with CsA+MTX compared to 33 % and 21 % with CsA+MMF (P = 0.001 and 0.09 respectively). Forty-two (79 %) patients in CsA+MTX group required total parenteral nutrition compared to 14 (58 %) in CsA+MMF group (P = 0.09). The incidence of engraftment fever was 17 % with CsA+MTX and 41 % with CsA+MMF (P = 0.02). The median time to neutrophil and platelet engraftment was 14 days and 13 days with CsA+MTX compared to 12 days and 10 days with CsA+MMF (P = 0.003 and 0.08 respectively). The incidence of any grade and grade II-IV acute GVHD was 45 and 13 % with CsA+MTX compared to 42 and 29 % with CsA+MMF (P = NS). Incidence of overall and extensive chronic GVHD was 57 and 38 % with CsA+MTX compared to 42 and 17 % with CsA+MMF (P = NS). Incidence of relapse was 38 % with CsA+MTX compared to 33 % with CsA+MMF (P = NS). TRM was 6 % with CsA+MTX and 21 % with CsA+MMF (P = NS). At 2 years, overall survival (OS) was 64 % in CsA+MTX group compared to 46 % in CsA+MMF group (P = NS). We conclude that CsA+MMF is associated with lesser toxicity, faster myeloid engraftment and similar rates of acute and chronic GVHD, TRM, relapse and OS compared to CsA+MTX in acute leukemia transplant. PMID:27429515

  4. Prolactin as a modulator of lymphocyte responsiveness provides a possible mechanism of action for cyclosporine.

    PubMed Central

    Hiestand, P C; Mekler, P; Nordmann, R; Grieder, A; Permmongkol, C

    1986-01-01

    Lymphocyte responsiveness in rats was found to depend on serum prolactin levels. Blocking pituitary prolactin release with bromocriptine severely reduces lymphocyte reactivity in vitro (mixed lymphocyte reaction) as well as in vivo (graft-versus-host reaction). In addition, evidence for a prolactin/growth hormone-related mRNA species produced in mitogen- and antigen-stimulated lymphocytes has been obtained. Prolactin was shown to compete in a dose-dependent fashion with the immunosuppressant cyclosporine (cyclosporin A) for a common binding site on the surface of T lymphocytes. Further, stimulation of prolactin secretion reversed the immunosuppression induced by cyclosporine. We conclude that prolactin is involved in the maintenance of T-cell immunocompetence and that the immunosuppressive effects of cyclosporine may be mediated by the displacement of prolactin from binding sites on lymphocytes. Images PMID:2939454

  5. [Pharmacological modulation of mitochondrial oxidative phosphorylation: inhibition by cyclosporine A, restoration by trimetazidine].

    PubMed

    Tillement, J P; Crevat, A; Testa, B; Le Ridant, A

    1996-01-01

    When applied to a suspension of isolated mitochondria extracted from rat hepatocytes, cyclosporine A decreases ATP synthesis and induces Ca2+ accumulation. Both effects are considered as possible determinants, even partly, of renal toxicity observed with this drug. Trimetazidine antagonizes both effects at concentrations easily reached in man with therapeutic dosages. It is concluded that the association of both drugs may improve the renal tolerance of Cyclosporine A. PMID:9008901

  6. The NMR structure of cyclosporin A bound to cyclophilin in aqueous solution

    SciTech Connect

    Weber, C.; Wilder, G.; von Freyberg, B.; Braun, W.; Wuethrich, K. ); Traber, R.; Widmer, H. )

    1991-07-02

    Cyclosporin A bound to the presumed receptor protein cyclophilin was studied in aqueous solution at pH 6.0 by nuclear magnetic resonance spectroscopy using uniform {sup 15}N- or {sup 13}C-labeling of cyclosporin A and heteronuclear spectral editing techniques. With an input of 108 intramolecular NOEs and four vicinal {sup 3}J{sub HN{alpha}} coupling constants, the three-dimensional structure of cyclosporin A bound to cyclophilin was calculated with the distance geometry program DISMAN, and the structures resulting from 181 converged calculations were energy refined with the program FANTOM. A group of 120 conformers was selected on the basis of the residual constraint violations and energy criteria to represent the solution structure. The average of the pairwise root-mean-square distances calculated for the backbone atoms of the 120 structures was 0.58 {angstrom}. The structure represents a novel conformation of cyclosporin A, for which the backbone conformation is significantly different from the previously reported structures in single crystals and in chloroform solution. The structure has all peptide bonds in the trans form, contains no elements of regular secondary structure and no intramolecular hydrogen bonds, and exposes nearly all polar groups to its environment. The root-mean-square distance between the backbone atoms of the crystal structure of cyclosporin A and the mean of the 120 conformers representing the NMR structure of cyclosporin A bound to cyclophilin is 2.5 {angstrom}.

  7. Risks and benefits of low-dosage cyclosporin in rheumatoid arthritis.

    PubMed

    Pasero, G; Ferraccioli, G F; Portioli, I

    1997-05-01

    The effects of cyclosporin on the activity of rheumatoid arthritis have mainly been investigated in patients with active, refractory, long-standing disease. The data obtained in these trials suggest that cyclosporin is not only a symptomatic treatment for rheumatoid arthritis but can also be considered a disease-modifying antirheumatic drug (DMARD), since it seems to be capable of slowing the progression of cartilage and bone damage due to rheumatoid arthritis. The trials conducted so far have led to a better understanding of cyclosporin toxicity and, therefore, to better monitoring of patients in order to avoid it. The reasons for studying the role of cyclosporin in patients with early, active and potentially severe rheumatoid arthritis are the poor prognosis of the disease despite the use of the presently available DMARDs, and the hypothesis that the drug is more efficacious and better tolerated in early rheumatoid arthritis. A new classification of antirheumatic drugs proposes that disease-controlling antirheumatic therapies decrease inflammatory synovitis and prevent structural joint damage or significantly reduce its rate of progression. However, few existing drugs meet these criteria. The 12-month results of a disease-controlling antirheumatic therapy clinical trial with a blinded radiological end-point, named GRISAR (Gruppo Reumatologi Italiani Studio Artrite Reumatoide) comparing cyclosporin with conventional DMARDs in patients with early rheumatoid arthritis provide strong evidence that cyclosporin offers better control of ongoing joint damage than do conventional DMARDs. PMID:18031101

  8. Atorvastatin and prevention of contrast induced nephropathy following coronary angiography

    PubMed Central

    Bidram, Peyman; Roghani, Farshad; Sanei, Hamid; Hedayati, Zahraparin; Golabchi, Allahyar; Mousavi, Mehdi; Hajiannejad, Alireza; Pourheidar, Behrouz; Badalabadi, Mehdi Mohseni; Gharaati, Maryam; Akhbari, Mohammadreza; Salesi, Asieh

    2015-01-01

    Background: Contrast induced nephropathy (CIN) is one of the most common complications after radiographic procedures using intravascular radiocontrast media. The aim of the current study was to assess the effect of atorvastatin on prevention of CIN in patients undergoing coronary angiography. Materials and Methods: In a clinical trial study, 200 patients referred for angiography were randomly divided into two groups of using 80 mg atorvastatin and placebo before the procedure. Furthermore, 100 patients who were under chronic treatment of statins were included as the third group. Serum creatinine (Scr) levels before and after the procedure were evaluated and incidence of CIN (post-procedural Scr of >0.5 mg/dl or >25% from baseline) was assessed. Results: Mean age of the participants was 60.06 ± 0.69 years and 276 (92%) were male. There were no significant differences between group with respect to age and gender. In pre-operation atorvastatin, placebo and long term statin groups, the incidence of CIN was 1%, 2% and 1%, and mean changes of Glomerular filtration rate (GFR) was 3.68 ± 1.32, −0.77 ± 1.21 and 1.37 ± 0.86; and mean changes of creatinine (Cr) was −0.05 ± 0.02, 0.02 ± 0.02 and −0.01 ± 0.01 respectively. (P = 0.776, 0.026 and 0.041 respectively). In pre-operation atorvastatin group, Cr decreased, and GFR increased significantly (P = 0.019 and 0.007 respectively). Conclusion: pre-operation short term high dose atorvastatin use was associated with a significant decrease in serum Cr level and increase in GFR after angiography. PMID:25767514

  9. Spectrum of IgA nephropathy in a single center.

    PubMed

    Das, Uttara; Dakshinamurty, Kaligotla Venkata; Prayaga, Aruna; Uppin, Megha

    2015-09-01

    Immunoglobulin A (IgA) nephropathy (IgAN) is the most common biopsy-proven primary glomerular disease in the world and a major contributor to the worldwide burden of endstage renal failure, with a wide geographical variation. To determine the incidence, clinical profile and histological pattern of IgAN in our institute, we reviewed all the patients who had native kidney biopsies with the diagnosis of primary IgAN during the period from 1998 to 2009 in the context of the clinical features. A total of 116 patients with IgAN were finally analyzed; 85 (73%) of the patients were male, the mean age of the patients was 29.2 ± 12.2 (range 10-70) years and the mean duration of disease was 10.4 ± 18.7 months (median: 2 months). Hypertension was present in 74 (63.2%) cases. Gross hematuria was rare. The most common clinical presentation was nephrotic syndrome, followed by chronic renal failure. The mean proteinuria level was 2.5 ± 2.3 g/day (median: 1.7 g/day) and the mean serum creatinine level was 3.04 ± 3.3 mg/dL (median:1.7 mg/dL). The morphological sub-classification (Haas): Class I was the most common (44.4%), followed by class V (23%). IgA co-deposition with C3 and lambda was the most common finding in the immunofluorescence study. The glomerular filtration rate decreased with advanced histological damage. The incidence of IgAN was 7.5%, which is lower as compared with studies from elsewhere. IgAN in our population had a more severe clinical presentation. PMID:26354591

  10. Ibuprofen attenuates nephropathy in streptozotocin‑induced diabetic rats.

    PubMed

    Liu, Yao-Wu; Zhu, Xia; Cheng, Ya-Qin; Lu, Qian; Zhang, Fan; Guo, Hao; Yin, Xiao-Xing

    2016-06-01

    Ibuprofen, a commonly administered nonsteroidal anti‑inflammatory therapeutic agent, is also a partial agonist of peroxisome proliferator‑activated receptor γ (PPARγ). The present study investigated the effects of ibuprofen on type 1 diabetic nephropathy (DN) in rats, and the potential mechanisms associated with the activation of PPARγ. Diabetic rats were induced through a single intraperitoneal injection of streptozotocin before oral treatment with ibuprofen or pioglitazone for 8 weeks. The 24‑h urine collection was performed for measurement of total protein content. The kidney was fixed in 10% formalin for periodic acid‑Schiff and Masson's trichrome staining. Blood and residual kidney tissue samples were collected to measure the associated biochemical parameters. Chronic ibuprofen treatment decreased urinary protein excretion, blood urea nitrogen, glomerular basement membrane thickening and renal fibrosis, which were accompanied by increases in PPARγ protein expression, glutathione (GSH) level, and superoxide dismutase (SOD) activity, decreases in cyclooxygenase 2 and inducible nitric oxide synthase protein expressions, as well as a decreased interleukin 1β (IL‑1β) level in the renal cortex of DN rats. Furthermore, the reduced IL‑1β level, increased GSH quantities and stronger SOD activity in the rat serum were evaluated in ibuprofen‑treated diabetic rats and were compared with untreated diabetic rats. Regarding GSH and IL‑1β levels, ibuprofen was identified to be superior to the positive control, pioglitazone, while levels of the other indices were identified to be similar. Thus, ibuprofen was observed to prevent the development of DN, caused by type 1 diabetes, by anti‑inflammatory and anti‑oxidative action, potentially via PPARγ activation. PMID:27109015

  11. Drug Targets for Oxidative Podocyte Injury in Diabetic Nephropathy

    PubMed Central

    Usman, Muhammad

    2015-01-01

    Diabetic nephropathy (DN) is one the most prevalent chronic complications of diabetes mellitus that affects as much as one-third of diabetic patients irrespective of the type of diabetes. Hyperglycemia is the key trigger for DN that initiates a number of microscopic and ultramicroscopic changes in kidney architecture. Microscopic changes include thickening of the glomerular basement membrane (GBM), tubular basement membrane (TBM), mesangial proliferation, arteriosclerosis, and glomerulotubular junction abnormalities (GTJA). Among the ultramicroscopic changes, effacement of podocytes and decrease in their density seem to be the centerpiece of DN pathogenesis. These changes in kidney architecture then produce functional deficits, such as microalbuminuria and decreased glomerular filtration rate (GFR). Among several mechanisms involved in inflicting damage to podocytes, injuries sustained by increased oxidative stress turns out to be the most important mechanism. Different variables that are included in increased production of reactive oxygen species (ROS) include a hyperglycemia-induced reduction in glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation via hyperglycemia, advanced glycation end products (AGEs), protein kinase C (PKC), and renin-angiotensin-aldosterone system (RAAS). Unfortunately, control of podocyte injury hasn’t received much attention as a treatment approach for DN. Therefore, this review article is mainly concerned with the exploration of various treatment options that might help in decreasing the podocyte injury, mainly by reducing the level of NADPH oxidase-mediated generation of ROS. This article concludes with a view that certain NADPH oxidase inhibitors, RAAS inhibitors, statins, antidiabetic drugs, and antioxidant vitamins might be useful in decreasing podocyte injury and resultant structural and functional kidney impairments in DN. PMID:26798569

  12. Drug Targets for Oxidative Podocyte Injury in Diabetic Nephropathy.

    PubMed

    Bhatti, Adnan Bashir; Usman, Muhammad

    2015-01-01

    Diabetic nephropathy (DN) is one the most prevalent chronic complications of diabetes mellitus that affects as much as one-third of diabetic patients irrespective of the type of diabetes. Hyperglycemia is the key trigger for DN that initiates a number of microscopic and ultramicroscopic changes in kidney architecture. Microscopic changes include thickening of the glomerular basement membrane (GBM), tubular basement membrane (TBM), mesangial proliferation, arteriosclerosis, and glomerulotubular junction abnormalities (GTJA). Among the ultramicroscopic changes, effacement of podocytes and decrease in their density seem to be the centerpiece of DN pathogenesis. These changes in kidney architecture then produce functional deficits, such as microalbuminuria and decreased glomerular filtration rate (GFR). Among several mechanisms involved in inflicting damage to podocytes, injuries sustained by increased oxidative stress turns out to be the most important mechanism. Different variables that are included in increased production of reactive oxygen species (ROS) include a hyperglycemia-induced reduction in glutathione (GSH), nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation via hyperglycemia, advanced glycation end products (AGEs), protein kinase C (PKC), and renin-angiotensin-aldosterone system (RAAS). Unfortunately, control of podocyte injury hasn't received much attention as a treatment approach for DN. Therefore, this review article is mainly concerned with the exploration of various treatment options that might help in decreasing the podocyte injury, mainly by reducing the level of NADPH oxidase-mediated generation of ROS. This article concludes with a view that certain NADPH oxidase inhibitors, RAAS inhibitors, statins, antidiabetic drugs, and antioxidant vitamins might be useful in decreasing podocyte injury and resultant structural and functional kidney impairments in DN. PMID:26798569

  13. Protective effect of thymol on high fat diet induced diabetic nephropathy in C57BL/6J mice.

    PubMed

    Saravanan, Settu; Pari, Leelevinothan

    2016-02-01

    Obesity is one of several factors implicated in chronic kidney disease (CKD). Thymol, a monoterpene phenolic compound found in the oils of thyme with multiple biological properties especially antidiabetic activity. The present study was undertaken to evaluate the thymol against diabetic nephropathy by high fat diet (HFD)-induced diabetic C57BL/6J mice. After 10 weeks of continuous dietary intervention, HFD (fat- 35.2%) to mice presented characteristic features of progressive nephropathy by significant increased in kidney weight, blood, and urinary parameters, glomerulosclerosis, oxidative stress, hyperlipidemia and subsequent renal injuries. After intragastric administration of thymol (40 mg/kg BW) daily for the subsequent 5 weeks significantly decreased the blood, urinary parameters and kidney weight. Thymol inhibited the activation of transforming growth factor-β1 (TGF-β1) and vascular endothelial growth factor (VEGF). Also, significantly increased the antioxidants and suppresses the lipid peroxidation markers in erythrocytes and kidney tissue compared to the diabetic mice. Thymol downregulated the expression level of sterol regulatory element binding protein-1c (SREBP-1c) and reduced the lipid accumulation in renal. Histopathological study of kidney tissues showed that extracellular mesangial matrix expansion, glomerulosclerosis in diabetic mice were suppressed by thymol. Further, our results indicate that administration of thymol afforded remarkable protection against HFD-induced diabetic nephropathy. PMID:26680107

  14. Nodes with high centrality in protein interaction networks are responsible for driving signaling pathways in diabetic nephropathy

    PubMed Central

    Abedi, Maryam

    2015-01-01

    In spite of huge efforts, chronic diseases remain an unresolved problem in medicine. Systems biology could assist to develop more efficient therapies through providing quantitative holistic sights to these complex disorders. In this study, we have re-analyzed a microarray dataset to identify critical signaling pathways related to diabetic nephropathy. GSE1009 dataset was downloaded from Gene Expression Omnibus database and the gene expression profile of glomeruli from diabetic nephropathy patients and those from healthy individuals were compared. The protein-protein interaction network for differentially expressed genes was constructed and enriched. In addition, topology of the network was analyzed to identify the genes with high centrality parameters and then pathway enrichment analysis was performed. We found 49 genes to be variably expressed between the two groups. The network of these genes had few interactions so it was enriched and a network with 137 nodes was constructed. Based on different parameters, 34 nodes were considered to have high centrality in this network. Pathway enrichment analysis with these central genes identified 62 inter-connected signaling pathways related to diabetic nephropathy. Interestingly, the central nodes were more informative for pathway enrichment analysis compared to all network nodes and also 49 differentially expressed genes. In conclusion, we here show that central nodes in protein interaction networks tend to be present in pathways that co-occur in a biological state. Also, this study suggests a computational method for inferring underlying mechanisms of complex disorders from raw high-throughput data. PMID:26557424

  15. Mining the genome for susceptibility to diabetic nephropathy: the role of large-scale studies and consortia.

    PubMed

    Iyengar, Sudha K; Freedman, Barry I; Sedor, John R

    2007-03-01

    Approximately 30% of individuals with type 1 and type 2 diabetes develop persistent albuminuria, lose renal function, and are at increased risk for cardiovascular and other microvascular complications. Diabetes and kidney diseases rank within the top 10 causes of death in Westernized countries and cause significant morbidity. Given these observations, genetic, genomic, and proteomic investigations have been initiated to better define basic mechanisms for disease initiation and progression, to identify individuals at risk for diabetic complications, and to develop more efficacious therapies. In this review we have focused on linkage analyses of candidate genes or chromosomal regions, or coarse genome-wide scans, which have mapped either categorical (chronic kidney disease or end-stage renal disease) or quantitative kidney traits (albuminuria/proteinuria or glomerular filtration rate). Most loci identified to date have not been replicated, however, several linked chromosomal regions are concordant between independent samples, suggesting the presence of a diabetic nephropathy gene. Two genes, carnosinase (CNDP1) on 18q, and engulfment and cell motility 1 (ELMO1) on 7p14, have been identified as diabetic nephropathy susceptibility genes, but these results require authentication. The availability of patient data sets with large sample sizes, improvements in informatics, genotyping technology, and statistical methodologies should accelerate the discovery of valid diabetic nephropathy susceptibility genes. PMID:17418689

  16. The incidence of biopsy-proven IgA nephropathy is associated with multiple socioeconomic deprivation.

    PubMed

    McQuarrie, Emily P; Mackinnon, Bruce; McNeice, Valerie; Fox, Jonathan G; Geddes, Colin C

    2014-01-01

    Chronic kidney disease is more common in areas of socioeconomic deprivation, but the relationship with the incidence and diagnosis of biopsy-proven renal disease is unknown. In order to study this, all consecutive adult patients undergoing renal biopsy in West and Central Scotland over an 11-year period were prospectively analyzed for demographics, indication, and histologic diagnosis. Using the Scottish Index of Multiple Deprivation, 1555 eligible patients were separated into quintiles of socioeconomic deprivation according to postcode. Patients in the most deprived quintile were significantly more likely to undergo biopsy compared with patients from less deprived areas (109.5 compared to 95.9 per million population/year). Biopsy indications were significantly more likely to be nephrotic syndrome, or significant proteinuria without renal impairment. Patients in the most deprived quintile were significantly more likely to have glomerulonephritis. There was a significant twofold increase in the diagnosis of IgA nephropathy in the patients residing in the most compared with the least deprived postcodes not explained by the demographics of the underlying population. Thus, patients from areas of socioeconomic deprivation in West and Central Scotland are significantly more likely to undergo native renal biopsy and have a higher prevalence of IgA nephropathy. PMID:24025641

  17. CD36 mediates proximal tubular binding and uptake of albumin and is upregulated in proteinuric nephropathies.

    PubMed

    Baines, Richard J; Chana, Ravinder S; Hall, Matthew; Febbraio, Maria; Kennedy, David; Brunskill, Nigel J

    2012-10-01

    Dysregulation of renal tubular protein handling in proteinuria contributes to the development of chronic kidney disease. We investigated the role of CD36 as a novel candidate mediator of albumin binding and endocytosis in the kidney proximal tubule using both in vitro and in vivo approaches, and in nephrotic patient renal biopsy samples. In CD36-transfected opossum kidney proximal tubular cells, both binding and uptake of albumin were substantially enhanced. A specific CD36 inhibitor abrogated this effect, but receptor-associated protein, which blocks megalin-mediated endocytosis of albumin, did not. Mouse proximal tubular cells expressed CD36 and this was absent in CD36 null animals, whereas expression of megalin was equal in these animals. Compared with wild-type mice, CD36 null mice demonstrated a significantly increased urinary protein-to-creatinine ratio and albumin-to-creatinine ratio. Proximal tubular cells expressed increased CD36 when exposed to elevated albumin concentrations in culture medium. Expression of CD36 was studied in renal biopsy tissue obtained from adult patients with heavy proteinuria due to minimal change disease, membranous nephropathy, or focal segmental glomerulosclerosis. Proximal tubular CD36 expression was markedly increased in proteinuric individuals. We conclude that CD36 is a novel mediator influencing binding and uptake of albumin in the proximal tubule that is upregulated in proteinuric renal diseases. CD36 may represent a potential therapeutic target in proteinuric nephropathy. PMID:22791331

  18. The Impact of Hypoxemia on Nephropathy in Extremely Obese Patients with Type 2 Diabetes Mellitus

    PubMed Central

    Leong, Wen Bun; Nolen, Melissa; Thomas, G. Neil; Adab, Paymanè; Banerjee, Dev; Taheri, Shahrad

    2014-01-01

    Study Objectives: Diabetes mellitus (DM) is associated with obstructive sleep apnea (OSA) and nephropathy. The hypoxemia associated with OSA may exacerbate renal deterioration in DM nephropathy. We examined the role of hypoxemia in the development of DM nephropathy in severely obese patients. Methods: This cross-sectional study examined anonymized data from 90 DM patients with extreme obesity attending a weight management service. All patients underwent a routine overnight sleep study. Respiratory parameters measured included apnea-hypopnea index (AHI), mean and minimum oxygen (O2) saturations, and time spent under 90% O2 saturation (%TST < 90%). Chronic kidney disease (CKD+) was defined as estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/1.73 m2. Results: Twenty (22%) patients were CKD+. These patients were 7 years older (mean age ± SD 57 ± 11 years, p = 0.003) and had greater adiposity (mean body mass index [BMI] ± SD 50.6 ± 8.7 kg/m2, p = 0.012). No significant differences were found for median AHI and minimum O2 saturation. %TST < 90% was 4 times greater in CKD+ group (p = 0.046). Multivariate regression analysis showed that AHI (β = −0.17, 95% CI: −0.316 to −0.024) and %TST < 90% (β = −0.215, 95% CI: −0.406 to −0.023) were negatively correlated with eGFR after adjustment for age, gender, BMI, comorbidities, insulin treatment, and drugs affecting the renin-angiotensin system. No associations were found between mean and minimum O2 saturations, and eGFR. Conclusion: Apnea and hypopnea events as well as duration of nocturnal hypoxemia were inversely associated with renal function after adjusting for potential confounders. Given the significant burden of renal disease in diabetes, greater vigilance is required in identifying OSA in DM patients with extreme obesity. Citation: Leong WB, Nolen M, Thomas GN, Adab P, Banerjee D, Taheri S. The impact of hypoxemia on nephropathy in extremely obese patients with type 2 diabetes mellitus. J Clin

  19. Genetics Home Reference: hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome

    MedlinePlus

    ... Health Conditions HANAC syndrome hereditary angiopathy with nephropathy, aneurysms, and muscle cramps syndrome Enable Javascript to view ... All Close All Description Hereditary angiopathy with nephropathy, aneurysms, and muscle cramps (HANAC) syndrome is part of ...

  20. Treatment of Refractory Chronic Urticaria

    PubMed Central

    Mehta, Aayushi; Godse, Kiran; Patil, Sharmila; Nadkarni, Nitin; Gautam, Manjyot

    2015-01-01

    Chronic spontaneous urticaria is a distressing disease encountered frequently in clinical practice. The current mainstay of therapy is the use of second-generation, non-sedating antihistamines. However, in patients who do not respond satisfactorily to these agents, a variety of other drugs are used. This article examines the available literature for frequently used agents including systemic corticosteroids, leukotriene receptor antagonists, dapsone, sulfasalazine, hydroxychloroquine, H2 antagonists, methotrexate, cyclosporine A, omalizumab, autologous serum therapy, and mycophenolate mofetil, with an additional focus on publications in Indian literature. PMID:26120147

  1. The in vivo effect of cyclosporine A on macrophages.

    PubMed

    Matsushima, Y; Baba, T

    1990-01-01

    The macrophage disappearance reaction (MDR) was induced when muramyl dipeptide (MDP) was injected intraperitoneally into guinea pigs bearing macrophage-rich peritoneal exudate cells. Heparin could inhibit the MDR induced by MDP. In the present study, we tested the effect of the immunosuppressive agent cyclosporine A (CsA) on MDR. The MDR was significantly suppressed in guinea pigs given 20 or 100 mg/kg of CsA, although 5 mg/kg of CsA had no effect. The number of macrophages elicited by liquid paraffin was significantly reduced in guinea pigs given with 20 or 100 mg/kg of CsA, but not in those given 5 mg/kg of CsA. These results indicate that CsA could directly affect macrophages in vivo, through a relatively high dose was required. Cyclosporine A (CsA), a cyclic peptide of 11 amino acids, is a fungal metabolite with potent immunosuppressive properties. Numerous experimental and clinical trials have demonstrated its effectiveness in organ transplantation. It has been suggested that primary target cells of CsA were T-lymphocytes, and macrophages were not directly affected. However, recent studies in an in vitro system have shown that some functions of macrophage are affected by CsA. These include chemotaxis (Drath & Kahan, 1983), interleukin-1 generation (Bunjes et al., 1981), prostaglandin E production (Whisler et al., 1984) and procoagulant activity (Carlsen et al., 1985). However, the effect of CsA on macrophages has not been elucidated in vivo. The macrophage disappearance reaction (MDR) is an in vivo manifestation of cell-mediated immunity and/or delayed type hypersensitivity (Sonozaki et al., 1975). Furthermore, our previous study demonstrated a possibility that MDR was an in vivo manifestation of macrophage activation (Ochiya et al., 1982). Muramyl dipeptide (MDP; N-acetyl-muramyl-L-alanyl-D-isoglutamine), a synthetic analogue of water soluble components of bacterial cell wall peptidoglycans, is known to have the ability to activate macrophages (Nagao et al

  2. Cyclosporin A renders target cells resistant to immune cytolysis.

    PubMed

    Hudnall, S D

    1991-01-01

    Exposure of cytolytically susceptible human target cells with therapeutic concentrations of the immunosuppressive drug cyclosporin A renders these cells highly resistant to T cell-mediated, natural killer (NK) cell-mediated, and complement-mediated cytolysis. The resistance is dose dependent, time dependent and reversible. The resistance is accompanied by target cell growth inhibition as measured by thymidine uptake. Surprisingly, target cell growth inhibition induced by serum depletion is associated with cell-mediated cytolytic resistance. These data suggest that cyclosporin A (CsA) may block some target cell biochemical pathway(s) important in the suicidal cytolytic process which is (are) linked to some G0/G1 cell cycle events. In addition, these results suggest that the increased risk of Epstein-Barr virus (EBV)-associated lymphoproliferative disease in human organ transplant recipients may be contributed to by CsA-induced resistance of EBV-transformed B lymphocytes to immune cytolysis. In the post-transplant setting, CsA probably blocks T cell-dependent responses to EBV-transformed B lymphocytes (Bird, A.G., McLachlan, S.M. and Britton, S., Nature 1981, 289: 300) yet leaving the NK cell and antibody-dependent responses intact (Shao-Hsien, C. et al. Transplantation 1983. 35: 127). However, given the direct effect of CsA upon EBV-transformed B lymphocytes, these cells would be rendered resistant to nearly all forms of cytolytic immune control (cytotoxic T lymphocyte, natural killer, antibody-dependent cell-mediated cytotoxicity, complement). Unregulated EBV-transformed B lymphocytes may then proliferate in the CsA-treated host thus leading to a polyclonal B cell hyperplasia. Our data would suggest that this early pre-malignant process is likely to be reversible following CsA dose reduction. Indeed, EBV-dependent polyclonal B cell hyperplasia is seen in early post-transplant lymphoproliferative disorders (Hanto, D.W., et al., Transplantation 1989, 47: 458

  3. Cyclosporine Treatment in Traumatic Brain Injury: Operation Brain Trauma Therapy.

    PubMed

    Dixon, C Edward; Bramlett, Helen M; Dietrich, W Dalton; Shear, Deborah A; Yan, Hong Q; Deng-Bryant, Ying; Mondello, Stefania; Wang, Kevin K W; Hayes, Ronald L; Empey, Philip E; Povlishock, John T; Tortella, Frank C; Kochanek, Patrick M

    2016-03-15

    Operation Brain Trauma Therapy (OBTT) is a consortium of investigators using multiple pre-clinical models of traumatic brain injury (TBI) to bring acute therapies to clinical trials. To screen therapies, we used three rat models (parasagittal fluid percussion injury [FPI], controlled cortical impact [CCI], and penetrating ballistic-like brain injury [PBBI]). We report results of the third therapy (cyclosporin-A; cyclosporine; [CsA]) tested by OBTT. At each site, rats were randomized to treatment with an identical regimen (TBI + vehicle, TBI + CsA [10 mg/kg], or TBI + CsA [20 mg/kg] given intravenously at 15 min and 24 h after injury, and sham). We assessed motor and Morris water maze (MWM) tasks over 3 weeks after TBI and lesion volume and hemispheric tissue loss at 21 days. In FPI, CsA (10 mg/kg) produced histological protection, but 20 mg/kg worsened working memory. In CCI, CsA (20 mg/kg) impaired MWM performance; surprisingly, neither dose showed benefit on any outcome. After PBBI, neither dose produced benefit on any outcome, and mortality was increased (20 mg/kg) partly caused by the solvent vehicle. In OBTT, CsA produced complex effects with histological protection at the lowest dose in the least severe model (FPI), but only deleterious effects as model severity increased (CCI and PBBI). Biomarker assessments included measurements of glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in blood at 4 or 24 h after injury. No positive treatment effects were seen on biomarker levels in any of the models, whereas significant increases in 24 h UCH-L1 levels were seen with CsA (20 mg/kg) after CCI and 24 h GFAP levels in both CsA treated groups in the PBBI model. Lack of behavioral protection in any model, indicators of toxicity, and a narrow therapeutic index reduce enthusiasm for clinical translation. PMID:26671075

  4. Infliximab versus Cyclosporine Treatment for Severe Corticosteroid-Refractory Ulcerative Colitis: A Korean, Retrospective, Single Center Study

    PubMed Central

    Kim, Eun Hye; Kim, Duk Hwan; Park, Soo Jung; Hong, Sung Pil; Kim, Tae Il; Kim, Won Ho; Cheon, Jae Hee

    2015-01-01

    Background/Aims In patients with corticosteroid-refractory ulcerative colitis (UC), cyclosporine or infliximab may be added to the treatment regimen to induce remission. Here, we aimed to compare the efficacy of cyclosporine and infliximab. Methods Between January 1995 and May 2012, the medical records of 43 patients with corticosteroid-refractory UC who received either infliximab or cyclosporine as a rescue therapy at a tertiary care hospital in Korea were reviewed. Results Among the 43 patients, 10 underwent rescue therapy with cyclosporine and the remaining 33 patients received infliximab. A follow-up of 12 months was completed for all patients. The colectomy rate at 12 months was 30% and 3% in the cyclosporine and the infliximab groups, respectively (p=0.034). However, the Cox proportional hazard model indicated that the treatment of rescue therapy was not an independent associate factor for preventing colectomy (p=0.164). In the subgroup analysis, infliximab with azathioprine was superior to cyclosporine for preventing colectomy (hazard ratio of infliximab with azathioprine compared with cyclosporine only, 0.073; 95% confidence interval, 0.008 to 0.629). Conclusions No difference between infliximab and cyclosporine with respect to preventing colectomy was noted. However, infliximab with azathioprine may be more effective than cyclosporine alone for preventing colectomy. PMID:25473080

  5. Membranous nephropathy in the cat and dog: a renal biopsy and follow-up study of sixteen cases.

    PubMed

    Wright, N G; Nash, A S; Thompson, H; Fisher, E W

    1981-09-01

    A morphologic study of biopsy specimens from 16 cases of membranous nephropathy in the cat (11 cases) and dog (five cases) was carried out using conventional light microscopy, immunofluorescence, transmission electron microscopy, and scanning electron microscopy. Depending on the degree of membranous change of the capillary loops and glomerular scarring, each case was graded "mild," "moderately severe," or "advanced." Clinically, most cases were presented showing the nephrotic syndrome, although two cases were presented in chronic renal failure. Most cases were followed through to necropsy after an interval ranging between 2 days and 3 years. In some cases, repeated biopsies were taken during this period. PMID:7024632

  6. A Multidisciplinary Evaluation of the Effectiveness of Cyclosporine A in Dystrophic Mdx Mice

    PubMed Central

    De Luca, Annamaria; Nico, Beatrice; Liantonio, Antonella; Paola Didonna, Maria; Fraysse, Bodvael; Pierno, Sabata; Burdi, Rosa; Mangieri, Domenica; Rolland, Jean-François; Camerino, Claudia; Zallone, Alberta; Confalonieri, Paolo; Andreetta, Francesca; Arnoldi, Elisa; Courdier-Fruh, Isabelle; Magyar, Josef P.; Frigeri, Antonio; Pisoni, Michela; Svelto, Maria; Conte-Camerino, Diana

    2005-01-01

    Chronic inflammation is a secondary reaction of Duchenne muscular dystrophy and may contribute to disease progression. To examine whether immunosuppressant therapies could benefit dystrophic patients, we analyzed the effects of cyclosporine A (CsA) on a dystrophic mouse model. Mdx mice were treated with 10 mg/kg of CsA for 4 to 8 weeks throughout a period of exercise on treadmill, a protocol that worsens the dystrophic condition. The CsA treatment fully prevented the 60% drop of forelimb strength induced by exercise. A significant amelioration (P < 0.05) was observed in histological profile of CsA-treated gastrocnemius muscle with reductions of nonmuscle area (20%), centronucleated fibers (12%), and degenerating area (50%) compared to untreated exercised mdx mice. Consequently, the percentage of normal fibers increased from 26 to 35% in CsA-treated mice. Decreases in creatine kinase and markers of fibrosis were also observed. By electrophysiological recordings ex vivo, we found that CsA counteracted the decrease in chloride conductance (gCl), a functional index of degeneration in diaphragm and extensor digitorum longus muscle fibers. However, electrophysiology and fura-2 calcium imaging did not show any amelioration of calcium homeostasis in extensor digitorum longus muscle fibers. No significant effect was observed on utrophin levels in diaphragm muscle. Our data show that the CsA treatment significantly normalized many functional, histological, and biochemical endpoints by acting on events that are independent or downstream of calcium homeostasis. The beneficial effect of CsA may involve different targets, reinforcing the usefulness of immunosuppressant drugs in muscular dystrophy. PMID:15681831

  7. Hypertension in Chronic Glomerulonephritis.

    PubMed

    Ihm, Chun-Gyoo

    2015-12-01

    Chronic glomerulonephritis (GN), which includes focal segmental glomerulosclerosis and proliferative forms of GN such as IgA nephropathy, increases the risk of hypertension. Hypertension in chronic GN is primarily volume dependent, and this increase in blood volume is not related to the deterioration of renal function. Patients with chronic GN become salt sensitive as renal damage including arteriolosclerosis progresses and the consequent renal ischemia causes the stimulation of the intrarenal renin-angiotensin-aldosterone system(RAAS). Overactivity of the sympathetic nervous system also contributes to hypertension in chronic GN. According to the KDIGO guideline, the available evidence indicates that the target BP should be ≤140mmHg systolic and ≤90mmHg diastolic in chronic kidney disease patients without albuminuria. In most patients with an albumin excretion rate of ≥30mg/24 h (i.e., those with both micro-and macroalbuminuria), a lower target of ≤130mmHg systolic and ≤80mmHg diastolic is suggested. The use of agents that block the RAAS system is recommended or suggested in all patients with an albumin excretion rate of ≥30mg/ 24 h. The combination of a RAAS blockade with a calcium channel blocker and a diuretic may be effective in attaining the target BP, and in reducing the amount of urinary protein excretion in patients with chronic GN. PMID:26848302

  8. Alterations in rat pulmonary macrophage function by the immunosuppressive agents cyclosporine, azathioprine, and prednisolone.

    PubMed

    Drath, D B; Kahan, B D

    1983-06-01

    Disturbances of the immune response of the lung induced by the action of immunosuppressive agents on the functional abilities of rat pulmonary alveolar macrophages (PAM) were analyzed following in vitro incubation or in vivo administration (for 30 days) of cyclosporinea, (CsA) azathioprine (Az) or prednisolone (Pr). Two major parameters were analyzed: oxygen consumption and superoxide release as indices of the overall state of oxygen metabolism of these cells reflecting the integrity of PAM oxidative mechanisms of microbicidal activity, and chemotaxis, an event clinically important for normal defense to infection. In vitro incubation with cyclosporine at concentrations as low as 10(-9) M caused a 52% inhibition of PAM superoxide release, but Az had no effect at concentrations up to 10(-6) M. Prednisolone caused a 38% inhibition of superoxide release; comparable levels of inhibition with Pr required concentrations at least 10-fold greater than with cyclosporine. Further experiments indicated that cyclosporine induced a 40% inhibition after contact with PAM for only 30 min. In vivo experiments indicated that cyclosporine (5 mg/kg), Az (20 mg/kg), or Pr (2 or 0.5 mg/kg) administered intraperitoneally had no effect on the number of PAM available for host defense, PAM oxygen consumption, or PAM superoxide release. However, PAM from cyclosporine-treated animals demonstrated complete inhibition of active migration or chemotaxis in modified Boyden chambers upon incubation with formylmethionyl-leucyl-phenylalanine (FMLP). The effect was apparently dampened by simultaneous administration of Pr with cyclosporine. These experiments suggest that with the exception of a marked effect on chemotaxis the in vivo effects of physiologic amounts of cyclosporine on PAM function are modest compared with the marked depression after in vitro addition. PMID:6306880

  9. Cyclosporine A and PSC833 inhibit ABCA1 function via direct binding.

    PubMed

    Nagao, Kohjiro; Maeda, Minami; Mañucat, Noralyn B; Ueda, Kazumitsu

    2013-02-01

    ATP-binding cassette protein A1 (ABCA1) plays a key role in generating high-density lipoprotein (HDL). However, the detailed mechanism of HDL formation remains unclear; in order to reveal it, chemicals that specifically block each step of HDL formation would be useful. Cyclosporine A inhibits ABCA1-mediated cholesterol efflux, but it is not clear whether this is mediated via inhibition of calcineurin. We analyzed the effects of cyclosporine A and related compounds on ABCA1 function in BHK/ABCA1 cells. Cyclosporine A, FK506, and pimecrolimus inhibited ABCA1-mediated cholesterol efflux in a concentration-dependent manner, with IC(50) of 7.6, 13.6, and 7.0μM, respectively. An mTOR inhibitor, rapamycin also inhibited ABCA1, with IC(50) of 18.8μM. The primary targets for these drugs were inhibited at much lower concentrations in BHK/ABCA1 cells, suggesting that they were not involved. Binding of [(3)H] cyclosporine A to purified ABCA1 could be clearly detected. Furthermore, a non-immunosuppressive cyclosporine, PSC833, inhibited ABCA1-mediated cholesterol efflux with IC(50) of 1.9μM, and efficiently competed with [(3)H] cyclosporine A binding to ABCA1. These results indicate that cyclosporine A and PSC833 inhibit ABCA1 via direct binding, and that the ABCA1 inhibitor PSC833 is an excellent candidate for further investigations of the detailed mechanisms underlying formation of HDL. PMID:23153588

  10. Autophagy: A Novel Therapeutic Target for Diabetic Nephropathy

    PubMed Central

    Kume, Shinji

    2015-01-01

    Diabetic nephropathy is a leading cause of end stage renal disease and its occurance is increasing worldwide. The most effective treatment strategy for the condition is intensive treatment to strictly control glycemia and blood pressure using renin-angiotensin system inhibitors. However, a fraction of patients still go on to reach end stage renal disease even under such intensive care. New therapeutic targets for diabetic nephropathy are, therefore, urgently needed. Autophagy is a major catabolic pathway by which mammalian cells degrade macromolecules and organelles to maintain intracellular homeostasis. The accumulation of damaged proteins and organelles is associated with the pathogenesis of diabetic nephropathy. Autophagy in the kidney is activated under some stress conditions, such as oxidative stress and hypoxia in proximal tubular cells, and occurs even under normal conditions in podocytes. These and other accumulating findings have led to a hypothesis that autophagy is involved in the pathogenesis of diabetic nephropathy. Here, we review recent findings underpinning this hypothesis and discuss the advantages of targeting autophagy for the treatment of diabetic nephropathy. PMID:26706914

  11. Cyclosporine A protects podocytes by regulating WAVE1 phosphorylation

    PubMed Central

    Li, Xuejuan; Ding, Fangrui; Wang, Suxia; Li, Baihong; Ding, Jie

    2015-01-01

    Accumulating evidence suggests that podocytes are direct targets of many classic antiproteinuric drugs. The immunosuppressive drug cyclosporine A (CsA), which is a calcineurin inhibitor, is used to treat proteinuric kidney diseases. One novel mechanism by which CsA reduces proteinuria is by directly stabilizing the podocyte cytoskeleton. Previous studies showed that calcineurin can directly regulate WAVE1 within mouse striatal slices. In this study, WAVE1 was expressed in podocytes and was localized in the podocyte cell bodies and foot processes (FPs). WAVE1 expression increased in both in vivo and in vitro models of puromycin aminonucleoside (PAN)-induced podocyte injury. CsA restored WAVE1 expression and also partially rescued the disordered F-actin arrangement after PAN injury. Co-immunoprecipitation assays showed that calcineurin directly interacted with WAVE1 and regulated WAVE1 phosphorylation in podocytes. Synaptopodin is a well-characterized target of CsA. WAVE1 overexpression and synaptopodin knockdown experiments directly demonstrated that WAVE1 expression is not dependent on synaptopodin expression, and vice versa. Overexpression of WAVE1 using a WAVE1 plasmid disrupted F-actin structure and promoted podocyte migration compared with the empty vector group. Therefore, WAVE1 may be a novel molecular target for the maintenance of podocyte FPs and for antiproteinuric treatment in the future. PMID:26634693

  12. Cyclosporin A and intravenous immunoglobulin treatment in polymyositis/dermatomyositis

    PubMed Central

    Danieli, M; Malcangi, G; Palmieri, C; Logullo, F; Salvi, A; Piani, M; Danieli, G

    2002-01-01

    Objective: To describe the treatment of polymyositis (PM) and dermatomyositis (DM) with prednisone (PRED) and cyclosporin A (CSA) alone or associated with intravenous immunoglobulin (IVIg) and plasmapheresis (PEX). Methods: Between 1992 and 1999 CSA and PRED were used to treat 20 patients with idiopathic myositis (12 with DM, eight with PM), diagnosed according to the Bohan and Peter criteria. In patients with refractory or relapsed disease, IVIg was added alone (seven cases) or synchronised with PEX (six cases). A standardised protocol was used to evaluate the patients, and assess disease activity and treatment response. Results: Despite a transient response to PRED and CSA in 16/20 cases, this combination did not induce full remission in 13/20 cases, which led to the IVIg trial with or without PEX. Patients receiving PRED and CSA plus IVIg had a significantly higher probability of maintaining complete remission at the end of the four year follow up period than those treated with PRED and CSA alone (p<0.001). No further benefit was added by the PEX. The presence of arthritis significantly correlated with a poorer response to treatment (p<0.05). Adverse effects were gingival hyperplasia (one patient) and transient renal dysfunction (one). Conclusions: This open study suggests that combined treatment with PRED, CSA, and IVIg is useful in patients with myositis, even those with refractory or relapsed disease; no increase in the number or type of side effects is seen. PMID:11779756

  13. Supersaturated polymeric micelles for oral cyclosporine A delivery.

    PubMed

    Yu, Hongzhen; Xia, Dengning; Zhu, Quanlei; Zhu, Chunliu; Chen, Dan; Gan, Yong

    2013-11-01

    Polymeric micelles provide a promising platform for improving oral absorption of poorly soluble drugs. However, improved understanding of how drug retention within the hydrophobic micelle core can reduce drug absorption is required. We designed supersaturated polymeric micelles (Super-PMs) to increase molecularly dissolved drug concentration and gain an insight into the effect of the degree of supersaturation on oral absorption of cyclosporine A (CsA) in rats. The drug release from Super-PMs increased with an increase in initial supersaturation degrees in micelles. The cellular uptake of coumarin-6 was reduced by the retention of drug in polymer micelles. The transport flux of CsA across Caco-2 monolayer was increased with initial supersaturation degrees of 0.81-3.53 (p < 0.05). However, increase in supersaturation to 5.64 actually resulted in decreased CsA transport. The same trend was observed in a rat in vivo absorption study, in which the highest bioavailability of 134.6 ± 24.7% (relative to a commercial product, Sandimmun Neoral®, p<0.01) was achieved when the supersaturation degree was 3.53. These results demonstrated that Super-PMs were a promising drug delivery system for compounds with low aqueous solubility. This study also provided an experimental proof for the hypothesis that moderately supersaturated formulations are valuable alternative to high supersaturation formulations, resulting in optimal in vivo performance, and the degree of supersaturation should be carefully controlled to optimize drug absorption. PMID:23954511

  14. Amelioration of cyclosporine induced nephrotoxicity by dipeptidyl peptidase inhibitor vildagliptin.

    PubMed

    Ateyya, Hayam

    2015-09-01

    Cyclosporine A (CsA) is an immunosuppressive drug used in organ transplantation and autoimmune diseases but its clinical uses may be limited due to its dose-related nephrotoxicity. This study was carried out to evaluate the possible protective effects of vildagliptin (VLD) against CsA-induced nephrotoxicity in rats. Animals were divided into four groups treated as follows: control group (CsA & VLD vehicle); VLD group (10mg/kg/day, orally); CsA group (20mg/kg in sunflower oil, S.C.); and CsA-VLD group (CsA &VLD). Induced nephrotoxicity was evidenced by a significant elevation of serum creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH) and urinary micro total proteins (MTP), while serum albumin and urinary creatinine clearance were significantly decreased compared to the control group. Moreover, renal dysfunction was further confirmed by a significant increase in renal lipid peroxide that was measured as renal malondialdehyde (MDA). Renal reduced glutathione (GSH) and superoxide dismutase (SOD) were significantly decreased. Nephrotoxicity was further confirmed by renal tissue histopathology. Also, a high protein expression of Bax with decreased Bcl-2 was revealed in the renal tissue of the CsA treated group. Administration of VLD significantly ameliorated the nephrotoxic effects of CsA suggesting antioxidant, anti-inflammatory and anti-apoptotic benefits of VLD in CsA-induced nephrotoxicity. PMID:26225924

  15. [Topical cyclosporine in ophthalmology: Pharmacology and clinical indications].

    PubMed

    Levy, O; Labbé, A; Borderie, V; Laroche, L; Bouheraoua, N

    2016-03-01

    Cyclosporine A (CsA) is a cyclic undecapeptide, which is an immunosuppressive drug in the calcineurin inhibitor class. CsA was initially used as a systemic immunosuppressant to minimize rejection of solid organ transplants. In ophthalmology, topically applied CsA was first used to inhibit corneal allograft rejection in the 1980s and later in various inflammatory ocular surface disorders (OSD). Currently, topical ophthalmic CsA is available as a licensed commercial emulsion or is prepared by hospital pharmacies with concentration ranging from 0.05 to 2%. Many of its pharmacological effects on the ocular surface are direct consequences of its ability to inhibit T ciclosporine activation and apoptosis. Topical CsA differs from topical steroids in its favourable local and systemic tolerability at the concentrations used. Most clinical studies have evaluated topical CsA in moderate to severe dry eye disease (DED) and demonstrated its efficacy for improvement of signs and symptoms, thus providing the sole indication for market approval and treatment protocols. For the other indications - corneal graft rejection, blepharitis, allergic or viral keratitis, and ocular surface disease due to graft versus host disease or post-operative DED - evidence-based medicine remains unclear due to the lack of major randomized controlled trials. Despite the lack of standardized protocols or market approval for these conditions, numerous studies suggest clinical efficacy. PMID:26997607

  16. Pharmacokinetic and pharmacodynamic interactions of morin and cyclosporin

    SciTech Connect

    Fang, S.-H. . E-mail: shfang@mail.cmu.edu.tw; Hou, Y.-C.; Chao, P.-D.L.

    2005-05-15

    Morin is a flavonoid present in mulberry and herbs. We have reported that morin exerted anti-inflammatory activity on the activated macrophages. Cyclosporin (CsA) is a potent immunosuppressive agent with narrow therapeutic range, which is widely used for the treatments of autoimmune diseases and transplantation rejection. This study aimed to measure the effects of morin on the disposition of CsA in lymphoid and non-lymphoid tissues, and on the functions of immune cells in mice. CsA (Neoral, 10 mg/kg) was orally administered with and without a concomitant dose of morin (0, 50, 100, 200 mg/kg) to mice once daily for 2 weeks. CsA concentrations in blood, liver, kidney, and spleen were determined by a specific monoclonal fluorescence polarization immunoassay. The decreased levels of CsA in tissues were found well correlated to increased doses of morin. The coadministration of 200 mg/kg morin significantly decreased CsA in blood, liver, kidney, and spleen by 33%, 17%, 38%, and 45%, respectively. On the other hand, coadministration of morin decreased dramatically the nitric oxide production by the activated macrophages when compared to CsA treatment alone. Moreover, morin maintained the level of CsA-suppressed T helper 1 (Th1) type cytokine, although the CsA concentration in spleen was markedly reduced. In conclusion, morin coadministration profoundly reduced CsA concentration but did not significantly alter the CsA-suppressed Th1 immune response in mice.

  17. The Death Ligand TRAIL in Diabetic Nephropathy

    PubMed Central

    Lorz, Corina; Benito-Martín, Alberto; Boucherot, Anissa; Ucero, Alvaro C.; Rastaldi, Maria Pia; Henger, Anna; Armelloni, Silvia; Santamaría, Beatriz; Berthier, Celine C.; Kretzler, Matthias; Egido, Jesus; Ortiz, Alberto

    2008-01-01

    Apoptotic cell death contributes to diabetic nephropathy (DN), but its role is not well understood. The tubulointerstitium from DN biopsy specimens was microdissected, and expression profiles of genes related to apoptosis were analyzed. A total of 112 (25%) of 455 cell death–related genes were found to be significantly differentially regulated. Among those that showed the greatest changes in regulation were two death receptors, OPG (the gene encoding osteoprotegerin) and Fas, and the death ligand TRAIL. Glomerular and proximal tubular TRAIL expression, assessed by immunohistochemistry, was higher in DN kidneys than controls and was associated with clinical and histologic severity of disease. In vitro, proinflammatory cytokines but not glucose alone regulated TRAIL expression in the human proximal tubular cell line HK-2. TRAIL induced tubular cell apoptosis in a dosage-dependant manner, an effect that was more marked in the presence of high levels of glucose and proinflammatory cytokines. TRAIL also activated NF-κB, and inhibition of NF-κB sensitized cells to TRAIL-induced apoptosis. It is proposed that TRAIL-induced cell death could play an important role in the progression of human DN. PMID:18287563

  18. Immune Cells and Inflammation in Diabetic Nephropathy

    PubMed Central

    Zheng, Zihan; Zheng, Feng

    2016-01-01

    Diabetic nephropathy (DN) is a serious complication of diabetes. At its core, DN is a metabolic disorder which can also manifest itself in terms of local inflammation in the kidneys. Such inflammation can then drive the classical markers of fibrosis and structural remodeling. As a result, resolution of immune-mediated inflammation is critical towards achieving a cure for DN. Many immune cells play a part in DN, including key members of both the innate and adaptive immune systems. While these cells were classically understood to primarily function against pathogen insult, it has also become increasingly clear that they also serve a major role as internal sensors of damage. In fact, damage sensing may serve as the impetus for much of the inflammation that occurs in DN, in a vicious positive feedback cycle. Although direct targeting of these proinflammatory cells may be difficult, new approaches that focus on their metabolic profiles may be able to alleviate DN significantly, especially since dysregulation of the local metabolic environment may well be responsible for triggering inflammation to begin with. In this review, the authors consider the metabolic profile of several relevant immune types and discuss their respective roles. PMID:26824038

  19. Role of Neuropilin-1 in Diabetic Nephropathy.

    PubMed

    Bondeva, Tzvetanka; Wolf, Gunter

    2015-01-01

    Diabetic nephropathy (DN) often develops in patients suffering from type 1 or type 2 diabetes mellitus. DN is characterized by renal injury resulting in proteinuria. Neuropilin-1 (NRP-1) is a single-pass transmembrane receptor protein devoid of enzymatic activity. Its large extracellular tail is structured in several domains, thereby allowing the molecule to interact with multiple ligands linking NRP-1 to different pathways through its signaling co-receptors. NRP-1's role in nervous system development, immunity, and more recently in cancer, has been extensively investigated. Although its relation to regulation of apoptosis and cytoskeleton organization of glomerular vascular endothelial cells was reported, its function in diabetes mellitus and the development of DN is less clear. Several lines of evidence demonstrate a reduced NRP-1 expression in glycated-BSA cultured differentiated podocytes as well as in glomeruli from db/db mice (a model of type 2 Diabetes) and in diabetic patients diagnosed with DN. In vitro studies of podocytes implicated NRP-1 in the regulation of podocytes' adhesion to extracellular matrix proteins, cytoskeleton reorganization, and apoptosis via not completely understood mechanisms. However, the exact role of NRP-1 during the onset of DN is not yet understood. This review intends to shed more light on NRP-1 and to present a link between NRP-1 and its signaling complexes in the development of DN. PMID:26239560

  20. Diabetic nephropathy: mechanisms of renal disease progression.

    PubMed

    Kanwar, Yashpal S; Wada, Jun; Sun, Lin; Xie, Ping; Wallner, Elisabeth I; Chen, Sheldon; Chugh, Sumant; Danesh, Farhad R

    2008-01-01

    Diabetic nephropathy is characterized by excessive amassing of extracellular matrix (ECM) with thickening of glomerular and tubular basement membranes and increased amount of mesangial matrix, which ultimately progress to glomerulosclerosis and tubulo-interstitial fibrosis. In view of this outcome, it would mean that all the kidney cellular elements, i.e., glomerular endothelia, mesangial cells, podocytes, and tubular epithelia, are targets of hyperglycemic injury. Conceivably, high glucose activates various pathways via similar mechanisms in different cell types of the kidney except for minor exceptions that are related to the selective expression of a given molecule in a particular renal compartment. To begin with, there is an obligatory excessive channeling of glucose intermediaries into various metabolic pathways with generation of advanced glycation products (AGEs), activation of protein kinase C (PKC), increased expression of transforming growth factor-beta (TGF-beta), GTP-binding proteins, and generation of reactive oxygen species (ROS). The ROS seem to be the common denominator in various pathways and are central to the pathogenesis of hyperglycemic injury. In addition, there are marked alterations in intraglomerular hemodynamics, i.e., hyperfiltration, and this along with metabolic derangements adversely compounds the hyperglycemia-induced injury. Here, the information compiled under various subtitles of this article is derived from an enormous amount of data summarized in several excellent literature reviews, and thus their further reading is suggested to gain in-depth knowledge of each of the subject matter. PMID:18156300

  1. Salivary Microbiota Associated with Immunoglobulin A Nephropathy.

    PubMed

    Piccolo, Maria; De Angelis, Maria; Lauriero, Gabriella; Montemurno, Eustacchio; Di Cagno, Raffaella; Gesualdo, Loreto; Gobbetti, Marco

    2015-08-01

    This study aimed at investigating the salivary microbiota of 28 patients affected by immunoglobulin A nephropathy (IgAN). Fourteen healthy volunteers (HC) were used as control. Compared to HC, the number of some cultivable bacteria groups (e.g., total anaerobes) significantly (P < 0.05) decreased in the salivary samples of IgAN patients. Total bacteria from salivary samples of IgAN patients and HC subjects were analyzed by pyrosequencing of 16S rRNA gene. Paired t test showed no significant (P > 0.05) differences of alpha-diversity parameters (OTU, ACE, Chao1, and Shannon index) between the salivary samples of HC and IgAN patients. The difference for the community structure was further analyzed using three phylogeny-based beta-diversity measures. Compared to HC, the ratio between Firmicutes/Proteobacteria markedly decreased in IgAN patients. Gemella haemolysins, Granulicatella adiacens, and Veillonella parvula were positively associated (P < 0.05) with HC. Within the phylum Bacteroidetes, Prevotella species (Prevotella nigrescens, Prevotella intermedia, Prevotella pallens, and Prevotella salivae) were the highest in HC. The only exception was for Prevotella aurantiaca. Compared to HC, the percentage of abundance of some species, belonging to Pasteurellaceae family (e.g., Haemophylus parainfluenzae), increased in IgAN patients. Fusobacteriaceae (Fusobacterium) and Corynebacterium sp. also differed between the salivary samples of HC and IgAN patients. PMID:25763757

  2. Ischemic nephropathy: detection and therapeutic intervention.

    PubMed

    García-Donaire, José A; Alcázar, José M

    2005-12-01

    Although the real prevalence of ischemic nephropathy as a cause of end-stage renal disease is unknown, its incidence has increased in past years. The diagnosis of this pathology requires that a number of functional and anatomic tests be carried out. The initial approach should be to perform duplex Doppler ultrasonography which, besides providing data on the size and extent of the stenosis, enables the intrarenal resistive index to be estimated to determine the pattern of renal parenchyma injury and the expected progression if revascularized. The most frequently used morphologic techniques are magnetic resonance angiography and computer tomography angiography. In the event of ischemic neuropathy, it is necessary to perform a renal arteriography regardless of the inherent risks of contrast toxicity or atheroembolism. Various therapeutic options are reviewed, with emphasis on percutaneous transluminal renal angiography plus stent as the first indication. Even though initial reports were contradictory, several meta-analyses have concluded that better blood pressure control and renal function improvement are achieved with percutaneous transluminal renal angiography plus stent than with conventional medical therapy. Surgical revascularization is preferable in patients with severe aorto-iliac pathology and renal artery ostium complete thrombosis. The risks and benefits of these procedures must be evaluated on an individual basis. PMID:16336566

  3. [Chronic complications in cardiac transplantation. Clinical implications and future strategies].

    PubMed

    Magaña-Serrano, José Antonio; Argüero-Sánchez, Rubén

    2005-01-01

    Chronic complications are situations which limit the long-term utility of cardiac transplantation. The allograft vasculopathy is the most important cause of death at 5 years alter transplantation. Another conditions are systemic arterial hypertension, nephropathies, diabetes mellitus, dyslipidemies and malignant neoplasies. The present manuscript summarizes the characteristics, clinical presentation and therapeutic strategies for this conditions. PMID:16524076

  4. Low molecular weight fucoidan modulates P-selectin and alleviates diabetic nephropathy.

    PubMed

    Xu, Yingjie; Zhang, Quanbin; Luo, Dali; Wang, Jing; Duan, Delin

    2016-10-01

    Diabetic nephropathy (DN) is a serious microvascular complication that can lead to chronic and end-stage renal failure. It is understood that inflammation is associated with the onset and process of DN. Low molecular weight fucoidan (LMWF) isolated from Saccharina japonica has anti-inflammatory properties. Therefore, this study aimed to explore the mechanism of LMWF in DN model induced by streptozotocin. The biochemical indices levels showed LMWF reduced the DN diagnostic indices to protect renal function. The HE stained sections exhibited LMWF protected normal morphological structures and reduced inflammatory cell infiltration in the kidneys of DN rats. Furthermore, the levels of P-selectin and selectin-dependent inflammatory cytokines resulting from LMWF were obviously decreased at both the transcriptional and protein levels. Thus, our results found that LMWF protected the renal function in DN rats and alleviated inflammation through the modulation of P-selectin and inflammatory cytokines. LMWF may have therapeutic potential against DN. PMID:27234491

  5. Idiopathic membranous nephropathy and IgG4: an interesting relationship

    PubMed Central

    Filippone, Edward J.

    2014-01-01

    Idiopathic membranous nephropathy (iMN) is a single-organ autoimmune disease characterized by subepithelial deposition of immune complexes containing IgG4 resulting in proteinuria, nephrotic syndrome, and, in some, end-stage renal disease. The pathogenesis involves a chronic IgG4 response against specific podocyte antigens which have now been at least partially defined in the neonatal, early childhood, and adult varieties. More has recently been learned about the genetic predisposition as well. This review discusses the pathophysiology of iMN in light of these discoveries and what is known about the genesis and potential clinical ramifications of an antigen-specific IgG4 response. PMID:23380389

  6. Acute tubular nephropathy in a patient with acute HIV infection: review of the literature.

    PubMed

    Ananworanich, Jintanat; Datta, Anandita A; Fletcher, James Lk; Townamchai, Natavudh; Chomchey, Nitiya; Kroon, Eugene; Sereti, Irini; Valcour, Victor; Kim, Jerome H

    2014-01-01

    We report a 57-year old man with diabetes mellitus and hypertension who presented with acute HIV infection. Routine blood tests showed an elevated blood urea nitrogen and creatinine. Renal biopsy showed acute tubular nephropathy, which has not been reported to occur during acute HIV infection, in the absence of rhabdomyolysis or multiple organ system failure. Antiretroviral therapy was initiated. His renal failure gradually resolved without further intervention. At one year of follow-up his HIV RNA was undetectable, and his renal function was normal. The case illustrates a rare manifestation of acute HIV infection - acute renal failure - in an older man with diabetes and hypertension. In this setting acute kidney injury might mistakenly have been attributed to his chronic comorbidities, and this case supports early HIV-1 testing in the setting of a high index of suspicion. PMID:25745498

  7. Renal deposition of cytomegalovirus antigen in immunoglobulin-A nephropathy.

    PubMed

    Gregory, M C; Hammond, M E; Brewer, E D

    Renal biopsy specimens from patients with various glomerular disorders were examined by indirect immunofluorescence microscopy with three different heterologous antibodies directed against cytomegalovirus and two heterologous antibodies against herpes simplex virus (HSV) type 1. All 31 samples from patients with immunoglobulin-A (IgA) nephropathy, 1 of 12 with systemic lupus erythematosus (SLE), and 1 of 5 with Henoch-Schönlein purpura (HSP) showed mesangial staining with cytomegalovirus antiserum, whereas no sample from 37 patients with other forms of glomerulonephritis was positive. Antigens of herpes simplex virus I were demonstrated in samples from 4 of 31 patients with IgA nephropathy, 1 of 12 patients with SLE, 1 of 5 patients with HSP, and 1 of 37 patients with other glomerular diseases. The consistent finding of glomerular cytomegalovirus antigen in IgA nephropathy suggests but does not prove that the virus has a role in the aetiology of this disorder. PMID:2891887

  8. Preventive effect of taurine on experimental type II diabetic nephropathy

    PubMed Central

    2010-01-01

    Background It has been verified that taurine has some preventive effects on diabetes and its complications when used alone or together with other drugs, but there are few reports about taurine on the prevention of diabetic nephropathy, the mechanisms of which are still unknown. Methods Taurine was administered to type Ⅱ diabetic rats induced by high fat high sugar diet combined with STZ injection. The preventive effect of taurine on diabetic nephropathy was investigated by detecting blood glucose, lipid metabolism, kidney function and glomerular basement membrane metabolism. Results Taurine could lower blood glucose, TG, TC, BUN, Scr, NAG, U-PRO, the expression of laminin B1( LBN1) mRNA, and increase HDL-C of diabetic rats. Conclusions The results indicated that taurine could prevent the occurrence and development of diabetic nephropathy by decreasing blood glucose, improving lipid metabolism, glomerular basement membrane metabolism, and kidney function. PMID:20804623

  9. Cyclosporine therapy of aplastic anaemia, congenital and acquired red cell aplasia.

    PubMed

    Leonard, E M; Raefsky, E; Griffith, P; Kimball, J; Nienhuis, A W; Young, N S

    1989-06-01

    We treated 22 patients with severe aplastic anaemia refractory to antithymocyte globulin (ATG) with cyclosporine, alone or in combination with prednisone. Eight patients showed significant clinical improvement, all but one to transfusion-independence. Although cyclosporine alone was effective, the addition of prednisone resulted in prompter and fuller haematologic improvement. No patient with an absolute granulocyte count less than 0.2 x 10(9)/l responded to treatment. Haematologic remissions were sustained beyond the treatment period. Of nine patients with Diamond-Blackfan syndrome, one showed a complete response to two separate courses of cyclosporine and relapse with withdrawal of therapy, and a second achieved significant reduction in corticosteroid dose without relapse; however, seven cases failed to respond. Two of three adults with acquired pure red cell aplasia recovered. A combination of cyclosporine and corticosteroids may be effective therapy in patients with aplastic anaemia who have failed ATG treatment. Occasional cases of congenital and acquired pure red cell aplasia may also respond to cyclosporine. PMID:2503027

  10. Effect of cyclosporine, total lymphoid irradiation, and cobra venom factor on hyperacute rejection

    SciTech Connect

    Knechtle, S.J.; Halperin, E.C.; Murphy, C.E.; Saad, T.; Abernethy, K.; Miller, D.; Bollinger, R.R.

    1985-09-01

    Transplantation into sensitized recipients is contraindicated due to the potential for hyperacute rejection. In order to study the mechanism of hyperacute rejection and the role of immunosuppression in the face of presensitization, we evaluated the effect of total lymphoid irradiation, cyclosporine, and cobra venom factor, alone and in combination, on hyperacute rejection of heterotopic rat heart allografts. Lewis rats were sensitized to strongly RT-1-incompatible ACI rats by three successive skin grafts. Heart allografts were then performed, and survived for a mean period of 15.7 +/- 7.4 hours. Neither preoperative treatment of hypersensitized rats with total lymphoid irradiation alone nor with cyclosporine (5 mg/kg/day) resulted in a prolongation of survival (20.4 +/- 16.6 hours and 35.6 +/- 6.2 hours, respectively). However, complement depletion using cobra venom factor significantly prolonged mean graft survival time to 114.4 +/- 31.0 hours (p less than 0.05). Cyclosporine (10 mg/kg/day) also significantly prolonged survival to 149 +/- 29 hours (p less than 0.01), but did not lower the antibody or complement levels. The addition of total lymphoid irradiation or cyclosporine to treatment with cobra venom factor did not result in longer survival than cobra venom factor alone. In conclusion, cobra venom factor and cyclosporine delay but do not prevent hyperacute rejection, while total lymphoid irradiation has no observable effect on hyperacute rejection.

  11. A 16 Month Survey of Cyclosporine Utilization Evaluation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

    PubMed Central

    Tavakoli Ardakani, Maria; Tafazoli, Ali; Mehdizadeh, Mahshid; Hajifathali, Abbas; Dadashzadeh, Simin

    2016-01-01

    Objectives: Graft versus host disease (GVHD) is a life threatening reaction in the stem cell transplantation process. Nowadays Cyclosporine is the most commonly utilized agent for GVHD prophylaxis and it has a major role in successful transplantation. Cyclosporine has been applied for many years in this field but it could be stated that currently no general consensus is available for its optimal method of administration. Conditions related to cyclosporine administration and possible related adverse reactions observed closely in our patients with the aim of constructing a comprehensive practice guideline in the future. Patients and Methods: Allogeneic stem cell transplant recipients who have been taking cyclosporine were monitored during and after their hospitalization while recording all observations on predefined questionnaires on the basis of periodic clinical and laboratory examinations for a 16 month period. Results: Mean recorded duration of infusions was 1.44 ± 0.68 h and by twice daily administration, means intravenous and oral dose was 101.85 ± 22.03 mg and 219.28 ± 63.9 mg, respectively. A mean CsA trough level after about 12 h of specified unique doses was 223 ± 65 ng/mL. We found hypertension, nephrotoxicity, neurotoxicity, hypertension, and dyslipidemia in about 14, 20, 48, and 94 percent of patients. Conclusions: This study proposed that permanent guidance of healthcare team according to a fixed and standard method of cyclosporine administration routine with using efficient facilities and protocols would be helpful considerably for an optimal pharmacotherapy. PMID:27610174

  12. Comparative neuroprotective effects of cyclosporin A and NIM811, a nonimmunosuppressive cyclosporin A analog, following traumatic brain injury

    PubMed Central

    Mbye, Lamin HAN; Singh, Indrapal N; Carrico, Kimberly M; Saatman, Kathryn E; Hall, Edward D

    2009-01-01

    Earlier experiments have shown that cyclosporin A (CsA) and its non-calcineurin inhibitory analog NIM811 attenuate mitochondrial dysfunction after experimental traumatic brain injury (TBI). Presently, we compared the neuroprotective effects of previously determined mitochondrial protective doses of CsA (20 mg/kg intraperitoneally) and NIM811 (10 mg/kg intraperitoneally) when administered at 15 mins postinjury in preventing cytoskeletal (α-spectrin) degradation, neurodegeneration, and neurological dysfunction after severe (1.0 mm) controlled cortical impact (CCI) TBI in mice. In a first set of experiments, we analyzed calpain-mediated α-spectrin proteolysis at 24 h postinjury. Both NIM811 and CsA significantly attenuated the increased α-spectrin breakdown products observed in vehicle-treated animals (P < 0.005). In a second set of experiments, treatment of animals with either NIM811 or CsA at 15 mins and again at 24 h postinjury attenuated motor function impairment at 48 h and 7 days (P < 0.005) and neurodegeneration at 7 days postinjury (P < 0.0001). Delayed administration of NIM811 out to 12 h was still able to significantly reduce α-spectrin degradation. These results show that the neuroprotective mechanism of CsA involves maintenance of mitochondrial integrity and that calcineurin inhibition plays little or no role because the non-calcineurin inhibitory analog, NIM811, is as effective as CsA. PMID:18714331

  13. Methylprednisolone in patients with membranous nephropathy and declining renal function.

    PubMed

    Short, C D; Solomon, L R; Gokal, R; Mallick, N P

    1987-11-01

    Fifteen consecutive patients aged 24 to 70 years, with membranous nephropathy and a progressive decline in renal function, were treated with methylprednisolone, 1 g intravenously daily for five days, followed immediately by a tapering dose of oral prednisolone. Plasma creatinine levels fell by a mean of 46 per cent (range 21-65). In 10 patients the beneficial effect was sustained, but in three it had reversed by six months. In the other two patients the progressive decline of renal function was not influenced. These observations suggest that many patients with membranous nephropathy and declining renal function could benefit from intervention with high dose steroids. PMID:3455548

  14. Specific Blood Pressure Targets for Patients With Diabetic Nephropathy?

    PubMed

    Grassi, Guido; Mancia, Giuseppe; Nilsson, Peter M

    2016-08-01

    Diabetic nephropathy represents a condition frequently detected in current clinical practice characterized by a very high cardiovascular risk profile. Blood pressure reduction via antihypertension drug treatment represents a therapeutic approach capable of exerting favorable effects on renal and cardiovascular outcomes. The purpose of this article is to review the current literature and results of key clinical trials pertaining to blood pressure goals of antihypertension treatment in these patients. The pros and cons of a less or a more intensive blood pressure goal in diabetic nephropathy will be discussed, with particular emphasis on the cardiovascular and renal effects of each therapeutic strategy. PMID:27440837

  15. Pregnancy in chronic kidney disease.

    PubMed

    Vellanki, Kavitha

    2013-05-01

    Despite vast improvements in fetal outcomes, pregnancy in women with CKD is fraught with hazards; worsening of renal function and complications like preeclampsia and premature delivery are common. To date, there is no accurate formula to calculate glomerular filtration rate (GFR). Also, whether the current CKD classification is better than the older classification at predicting outcomes in pregnant women with CKD is unknown. Women with an estimated GFR ≥1.4 mg/dL are at increased risk of progressive worsening of renal function regardless of the cause of the underlying kidney disease. Preeclampsia is difficult to diagnose in pregnant women with underlying CKD, and serum markers such as soluble fms-like tyrosine kinase 1 (sFlt1) and placental growth factor (PIGF) may lead the way for definitive diagnosis. New-onset lupus or lupus flare is an indication for kidney biopsy during pregnancy; cyclosporine is safe and is the most effective agent that can be used during pregnancy. Women with adult polycystic kidney disease are at increased risk of hypertension and preeclampsia during pregnancy, as well as hepatic cysts later in life, the latter occurring with multiple pregnancies. Strict blood pressure control is important in pregnant women with diabetic nephropathy. A multidisciplinary team that includes nephrologists and obstetricians who deal with high-risk pregnancies should be involved in the care of pregnant women with CKD for successful pregnancy outcomes. PMID:23928386

  16. Genetics and Epigenetics of Diabetic Nephropathy

    PubMed Central

    Liu, Ruijie; Lee, Kyung; He, John Cijiang

    2015-01-01

    Background Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD) in the USA and worldwide, contributing to significant morbidity and mortality in diabetic patients. A genetic factor for the development of DN is strongly implicated, as only one third of diabetic patients eventually develop kidney disease. Growing evidence also supports an important role of epigenetic modifications in DN. Summary Multiple studies have been performed to identify risk genes and loci associated with DN. So far, only several genes and loci have been identified, none of which showed a strong association with DN. Therefore, a better study design with a larger sample size to identify rare variants and a clinically defined patient population to identify genes and loci associated with progressive DN are still needed. In addition to genetic factors, epigenetic modifications, such as DNA methylation, histone modifications and microRNAs, also play a major role in the pathogenesis of DN through a second layer of gene regulation. Although a major progress has been made in this field, epigenetic studies in DN are still in the early phase and have been limited mostly due to the heterogeneity of kidney tissue samples with multiple cells. However, rapid development of high-throughput genome-wide techniques will help us to better identify genetic variants and epigenetic changes in DN. Key Message Understanding of genetic and epigenetic changes in DN is needed for the development of new biomarkers and better drug targets against DN. Summarized in this review are important recent findings on genetic and epigenetic studies in the field of DN.

  17. Cyclosporine Does Not Prevent Microvascular Loss in Transplantation but Can Synergize With a Neutrophil Elastase Inhibitor, Elafin, to Maintain Graft Perfusion During Acute Rejection.

    PubMed

    Jiang, X; Nguyen, T T; Tian, W; Sung, Y K; Yuan, K; Qian, J; Rajadas, J; Sallenave, J-M; Nickel, N P; de Jesus Perez, V; Rabinovitch, M; Nicolls, M R

    2015-07-01

    The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling. PMID:25727073

  18. Cyclosporine does not prevent microvascular loss in transplantation but can synergize with a neutrophil elastase inhibitor, elafin, to maintain graft perfusion during acute rejection

    PubMed Central

    Jiang, Xinguo; Nguyen, Tom T.; Tian, Wen; Sung, Yon K.; Yuan, Ke; Qian, Jin; Rajadas, Jayakumar; Sallenave, Jean-Michel; Nickel, Nils P.; de Jesus Perez, Vinicio; Rabinovitch, Marlene; Nicolls, Mark R.

    2015-01-01

    The loss of a functional microvascular bed in rejecting solid organ transplants is correlated with fibrotic remodeling and chronic rejection; in lung allografts, this pathology is predicted by bronchoalveolar fluid neutrophilia which suggests a role for polymorphonuclear cells in microcirculatory injury. In a mouse orthotopic tracheal transplant model, cyclosporine, which primarily inhibits T cells, failed as a monotherapy for preventing microvessel rejection and graft ischemia. To target neutrophil action that may be contributing to vascular injury, we examined the effect of a neutrophil elastase inhibitor, elafin, on the microvascular health of transplant tissue. We showed that elafin monotherapy prolonged microvascular perfusion and enhanced tissue oxygenation while diminishing the infiltration of neutrophils and macrophages and decreasing tissue deposition of complement C3 and the membrane attack complex, C5b-9. Elafin was also found to promote angiogenesis through activation of the extracellular signal-regulated kinase (ERK) signaling pathway but was insufficient as a single agent to completely prevent tissue ischemia during acute rejection episodes. However, when combined with cyclosporine, elafin effectively preserved airway microvascular perfusion and oxygenation. The therapeutic strategy of targeting neutrophil elastase activity alongside standard immunosuppression during acute rejection episodes may be an effective approach for preventing the development of irreversible fibrotic remodeling. PMID:25727073

  19. SCY-635, a Novel Nonimmunosuppressive Analog of Cyclosporine That Exhibits Potent Inhibition of Hepatitis C Virus RNA Replication In Vitro ▿ †

    PubMed Central

    Hopkins, Sam; Scorneaux, Bernard; Huang, Zhuhui; Murray, Michael G.; Wring, Stephen; Smitley, Craig; Harris, Richard; Erdmann, Frank; Fischer, Gunter; Ribeill, Yves

    2010-01-01

    SCY-635 is a novel nonimmunosuppressive cyclosporine-based analog that exhibits potent suppression of hepatitis C virus (HCV) replication in vitro. SCY-635 inhibited the peptidyl prolyl isomerase activity of cyclophilin A at nanomolar concentrations but showed no detectable inhibition of calcineurin phosphatase activity at concentrations up to 2 μM. Metabolic studies indicated that SCY-635 did not induce the major cytochrome P450 enzymes 1A2, 2B6, and 3A4. SCY-635 was a weak inhibitor and a poor substrate for P-glycoprotein. Functional assays with stimulated Jurkat cells and stimulated human peripheral blood mononuclear cells indicated that SCY-635 is a weaker inhibitor of interleukin-2 secretion than cyclosporine. A series of two-drug combination studies was performed in vitro. SCY-635 exhibited synergistic antiviral activity with alpha interferon 2b and additive antiviral activity with ribavirin. SCY-635 was shown to be orally bioavailable in multiple animal species and produced blood and liver concentrations of parent drug that exceeded the 50% effective dose determined in the bicistronic con1b-derived replicon assay. These results suggest that SCY-635 warrants further investigation as a novel therapeutic agent for the treatment of individuals who are chronically infected with HCV. PMID:19933795

  20. Cyclosporine A attenuates 3-nitropropionic acid-induced Huntington-like symptoms in rats: possible nitric oxide mechanism.

    PubMed

    Kumar, Puneet; Kalonia, Harikesh; Kumar, Anil

    2010-01-01

    Cyclosporine A is a well-known immunosuppressant drug that is currently used for prevention of allograft rejection. The current study was conducted to explore the therapeutic potential of cyclosporine A against 3-nitropropionic acid (3-NP)-induced neurotoxicity, an animal model of Huntington disease (HD). Systemic administration of 3-NP (10 mg/kg) for 14 days significantly impaired body weight, motor activity, biochemical parameters (raised lipid peroxidation, nitrite concentration, depletion of superoxide dismutase [SOD] and catalase), and mitochondrial enzymes. Cyclosporine A (2.5, 5, and 10 mg/kg) treatment significantly attenuated behavioral, biochemical, and cellular alterations. Furthermore, L-arginine pretreatment with cyclosporine A (5 mg/kg) significantly reversed the protective effect of cyclosporine A. However, L-nitro-arginine methyl ester (L-NAME; 10 mg/kg) pretreatment potentiated the protective effect of cyclosporine A (5 mg/kg). Study highlights the therapeutic potential of cyclosporine A in the treatment of HP. Study suggests that nitric oxide (NO) modulation is involved in the neuroprotective effect of cyclosporine A against 3-NP neurotoxicity. PMID:20448265

  1. Fibroadenomatosis involving bilateral breasts and axillary accessory breast tissues in a renal transplant recipient given cyclosporin A.

    PubMed

    Bulakci, Mesut; Gocmez, Ahmet; Demir, Ali Aslan; Salmaslioglu, Artur; Tukenmez, Mustafa; Yavuz, Ekrem; Acunas, Gulden

    2014-10-01

    We present the mammographic and sonographic findings in a case of fibroadenomatosis involving both breasts and axillae in a renal transplant patient after 16 years of treatment with cyclosporin A. Awareness of the fact that cyclosporin A may induce the formation of fibroadenomas, including in accessory breast tissue, is important for correct diagnosis and preventing unnecessary intervention. PMID:25131521

  2. The role of cyclosporine A on the periodontal tissues

    PubMed Central

    Jayasheela, Mallappa; Mehta, Dhoom Singh

    2013-01-01

    Background: Cyclosporin A (CsA) is a known immunosuppressive agent and can be considered as a lifesaving drug in the organ transplantation cases. However, it is associated with many side-effects on different tissues and body organs including the periodontal tissues. The present animal study was undertaken to evaluate the effects of CsA targeting the tissue triad of periodontal tissues, i.e., gingiva, alveolar bone and cementum in rats. Materials and Methods: Twelve 6-week-old male Wistar rats weighing 150-200 g were considered for the case-control study in rats. The rats were divided into 2 groups: (1) CsA (test) group (2) Saline (control) group and were administered the same subcutaneously daily once for 45 days. Impressions were taken and study casts were prepared on weekly basis for the morphometric analysis. At the end of 45 days, rats were sacrificed and specimens were analyzed for histomorphometric analysis. CsA and saline groups were analyzed to test of association using the Student t-test at 99% confidence interval. Results: The morphometric examination showed significant gingival overgrowth in the CsA group, whereas no such growth in the saline group. Similarly, on histomorphometric analysis, there was a significant loss of alveolar bone in CsA group as compared with control. Furthermore, there was large amount of cementum formation accompanied by insertion of new connective tissue fibers especially in the cervical region of the tooth in CsA group rats. Conclusion: CsA targets the periodontal tissues (gingiva, alveolar bone and cementum) in different pattern. Its role in cementogenesis can be utilized for periodontal regeneration, if its local application is testified and verified in the future animal studies. PMID:24379871

  3. Cyclosporin A Disrupts Notch Signaling and Vascular Lumen Maintenance

    PubMed Central

    Pandey, Raghav; Botros, Mark A.; Nacev, Benjamin A.; Albig, Allan R.

    2015-01-01

    Cyclosporin A (CSA) suppresses immune function by blocking the cyclophilin A and calcineurin/NFAT signaling pathways. In addition to immunosuppression, CSA has also been shown to have a wide range of effects in the cardiovascular system including disruption of heart valve development, smooth muscle cell proliferation, and angiogenesis inhibition. Circumstantial evidence has suggested that CSA might control Notch signaling which is also a potent regulator of cardiovascular function. Therefore, the goal of this project was to determine if CSA controls Notch and to dissect the molecular mechanism(s) by which CSA impacts cardiovascular homeostasis. We found that CSA blocked JAG1, but not Dll4 mediated Notch1 NICD cleavage in transfected 293T cells and decreased Notch signaling in zebrafish embryos. CSA suppression of Notch was linked to cyclophilin A but not calcineurin/NFAT inhibition since N-MeVal-4-CsA but not FK506 decreased Notch1 NICD cleavage. To examine the effect of CSA on vascular development and function, double transgenic Fli1-GFP/Gata1-RFP zebrafish embryos were treated with CSA and monitored for vasculogenesis, angiogenesis, and overall cardiovascular function. Vascular patterning was not obviously impacted by CSA treatment and contrary to the anti-angiogenic activity ascribed to CSA, angiogenic sprouting of ISV vessels was normal in CSA treated embryos. Most strikingly, CSA treated embryos exhibited a progressive decline in blood flow that was associated with eventual collapse of vascular luminal structures. Vascular collapse in zebrafish embryos was partially rescued by global Notch inhibition with DAPT suggesting that disruption of normal Notch signaling by CSA may be linked to vascular collapse. However, multiple signaling pathways likely cause the vascular collapse phenotype since both cyclophilin A and calcineurin/NFAT were required for normal vascular function. Collectively, these results show that CSA is a novel inhibitor of Notch signaling and

  4. Angiogenesis and chronic kidney disease

    PubMed Central

    2010-01-01

    The number of patients requiring renal replacement therapy due to end-stage renal disease (ESRD) is increasing worldwide. The prevalence of chronic kidney disease (CKD), and the importance of CKD as a risk factor in development of ESRD and in complicating cardiovascular disease (CVD) have been confirmed. In recent years, the involvement of angiogenesis-related factors in the progression of CKD has been studied, and the potential therapeutic effects on CKD of modulating these factors have been identified. Vascular endothelial growth factor (VEGF)-A, a potent pro-angiogenic factor, is involved in the development of the kidney, in maintenance of the glomerular capillary structure and filtration barrier, and in the renal repair process after injury. VEGF-A is also involved in the development of early diabetic nephropathy, demonstrated by the therapeutic effects of anti-VEGF-A antibody. Angiopoietin (Ang)-1 induces the maturation of newly formed blood vessels, and the therapeutic effects of Ang-1 in diabetic nephropathy have been described. In experimental models of diabetic nephropathy, the therapeutic effects of angiogenesis inhibitors, including angiostatin, endostatin and tumstatin peptides, the isocoumarin NM-3, and vasohibin-1, have been reported. Further analysis of the involvement of angiogenesis-related factors in the development of CKD is required. Determining the disease stage at which therapy is most effective and developing an effective drug delivery system targeting the kidney will be essential for pro-or anti-angiogenic strategies for patients with CKD. PMID:20687922

  5. Accurate diagnosis of renal transplant rejection by indium-111 platelet imaging despite postoperative cyclosporin therapy

    SciTech Connect

    Collier, B.D.; Adams, M.B.; Kauffman, H.M.; Trembath, L.; Hoffmann, R.G.; Tisdale, P.L.; Rao, S.A.; Hellman, R.S.; Isitman, A.T.

    1988-08-01

    Previous reports indicate that In-111 platelet scintigraphy (IPS) is a reliable test for the early diagnosis of acute post-operative renal transplant rejection (TR). However, the recent introduction of cyclosporin for post-transplantation immunosuppression requires that the diagnostic efficacy of IPS once again be established. Therefore, a prospective IPS study of 73 post-operative renal transplant recipients was conducted. Fourty-nine patients received cyclosporin and 24 patients did not receive this drug. Between these two patient groups, there were no significant differences in the diagnostic sensitivities (0.86 vs 0.80) and specificities (0.93 vs 0.84) with which TR was identified. We conclude that during the first two weeks following renal transplantation the cyclosporin treatment regimen used at our institution does not limit the reliability of IPS as a test for TR.

  6. Cyclosporin A for the treatment of graft-versus-host disease in man.

    PubMed

    Powles, R L; Barrett, A J; Clink, H; Kay, H E; Sloane, J; McElwain, T J

    Cyclosporin A was given to five patients with acute leukaemia in whom graft-versus-host disease (G.V.H.D.) had developed after bone-marrow transplantation from sibling donors. In all instances the acute erythematous skin reaction of G.V.H.D. resolved within two days, but four of the five patients died. Cyclosporin A in high doses produced anorexia, nausea, and a reversible rise in blood-urea. The four patients who died all had liver damage, but the histological changes varied. Cyclosporin A modifies the acute skin reaction of G.V.H.D. In the management of liver and gut G.V.H.D., and in prophylaxis of G.V.H.D., its role needs to be determined. PMID:82837

  7. Efficacy and safety of constant-rate intravenous cyclosporine infusion immediately after heart transplantation.

    PubMed

    Schroeder, T J; Myre, S A; Melvin, D B; Van der Bel-Kahn, J; Stephens, G W; Collins, J A; Wolf, R K; Brown, L L; Pesce, A J; First, M R

    1989-01-01

    Oral cyclosporine therapy immediately after heart transplantation is erratic and difficult to predict. The purpose of this study was to evaluate the relative efficacy and safety of cyclosporine when administered by constant-rate infusion immediately after transplantation. Nineteen patients (17 men and two women) aged 50 years (range 25 to 61 years) who weighed 71 +/- 9 kg, participated in the study and received cyclosporine, 7 to 10 mg/hr (117 +/- 15 micrograms/kg/hr). The infusions were initially maintained for 26 +/- 5 hours (range 18 to 42 hours) without adjustments in dosage. Whole blood samples were obtained at hourly intervals for the first 8 to 12 hours and then daily throughout the 7-day study period and were analyzed by high-performance liquid chromatography. Constant-rate cyclosporine infusion resulted in therapeutic blood levels (350 to 450 ng/ml) at 6 hours. These levels remained relatively steady throughout the 7-day infusion, requiring only minimal dosage adjustments. Kidney function was not altered significantly after 7 days of intravenous cyclosporine therapy as evidenced by a mean serum creatinine level of 1.3 mg/dl before therapy and 1.4 mg/dl after therapy. There, however, was a transient rise in serum creatinine level in most patients on the second or third day after transplantation that resolved without a reduction in cyclosporine dosage. The mean endomyocardial biopsy score at 1 week after transplantation was 0.1, and only four of the patients required additional immunosuppressive therapy to treat rejection during the first 6 weeks after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2647932

  8. Cyclosporine A or intravenous cyclophosphamide for lupus nephritis: the Cyclofa-Lune study.

    PubMed

    Zavada, J; Pesickova, Ss; Rysava, R; Olejarova, M; Horák, P; Hrncír, Z; Rychlík, I; Havrda, M; Vítova, J; Lukác, J; Rovensky, J; Tegzova, D; Böhmova, J; Zadrazil, J; Hána, J; Dostál, C; Tesar, V

    2010-10-01

    Intravenous cyclophosphamide is considered to be the standard of care for the treatment of proliferative lupus nephritis. However, its use is limited by potentially severe toxic effects. Cyclosporine A has been suggested to be an efficient and safe treatment alternative to cyclophosphamide. Forty patients with clinically active proliferative lupus nephritis were randomly assigned to one of two sequential induction and maintenance treatment regimens based either on cyclophosphamide or Cyclosporine A. The primary outcomes were remission (defined as normal urinary sediment, proteinuria <0.3 g/24 h, and stable s-creatinine) and response to therapy (defined as stable s-creatinine, 50% reduction in proteinuria, and either normalization of urinary sediment or significant improvement in C3) at the end of induction and maintenance phase. Secondary outcomes were incidence of adverse events, and relapse-free survival. At the end of the induction phase, 24% of the 21 patients treated by cyclophosphamide achieved remission, and 52% achieved response, as compared with 26% and 43%, respectively of the 19 patients treated by the Cyclosporine A. At the end of the maintenance phase, 14% of patients in cyclophosphamide group, and 37% in Cyclosporine A group had remission, and 38% and 58% respectively response. Treatment with Cyclosporine A was associated with transient increase in blood pressure and reversible decrease in glomerular filtration rate. There was no significant difference in median relapse-free survival. In conclusion, Cyclosporine A was as effective as cyclophosphamide in the trial of sequential induction and maintenance treatment in patients with proliferative lupus nephritis and preserved renal function.(ClinicalTrials.gov identifier: NCT00976300) PMID:20605876

  9. Treatment of IgA nephropathy with renal insufficiency.

    PubMed

    Pozzi, Claudio; Sarcina, Cristina; Ferrario, Francesca

    2016-08-01

    IgA Nephropathy leads young people to dialysis more often than other glomerular diseases, because often diagnosis and therapy are made late. Nephrologists waive to treat IgAN pts with chronic renal insufficiency, believing that treatment may not be effective and safe. Moreover, studies in IgAN pts with reduced renal function are lacking. Small studies seem to indicate a possible utility of RAS blockers and corticosteroids in these patients. Recently, VALIGA study showed that corticosteroids and immunosuppressants were more frequently used in pts with eGFR <30 ml/min than in those with eGFR >30 ml/min (60 vs. 44 %, respectively; p = 0.004). The goal of treating IgAN pts is to obtain a time-average proteinuria <1 g/day, regardless of the degree of renal function and histological damage. RASB and corticosteroids seem to be able to obtain this result. However, it's important to pay attention to the appearance of adverse events of CS. In the literature, major side effects occurred in 29 of 463 (6.2 %) patients enrolled in RCTs. However, scarce informations are obtained about the safety of CS in patients with reduced renal function. To better evaluate this aspect, we considered three studies, that used similar schemes of therapy and included patients with different degrees of renal function (1: GFR 90 ml/min/1.73 m(2), 2: 81 ml/min/1.73 m(2), 3: 34 ml/min/1.73 m(2)). The occurrence of adverse events increased with the worsening of renal function (2.3, 5.7 and 15.4 % in studies 1, 2 and 3 respectively). The aim of the treatment for a patient with an eGFR <30 is to slow the progression and to delay the need for dialysis. Therefore, in stage CKD 2, 3 and 4 with a proteinuria >1 g/day a 6-month course of corticosteroids could be useful and safe. PMID:26743078

  10. IgA nephropathy in Brazil: apropos of 600 cases.

    PubMed

    Soares, Maria Fernanda; Caldas, M L R; Dos-Santos, W L C; Sementilli, A; Furtado, P; Araújo, S; Pegas, K L; Petterle, R R; Franco, M F

    2015-01-01

    IgA nephropathy (IgAN) is th e commonest primary glomerular disease worldwide. Studies on its prevalence in Brazil are however scarce. Databases and clinical records from 10 reference centres were retrospectively reviewed. Clinical and laboratory features at the moment of the biopsy were retrieved (age, gender, presence of hematuria, serum creatinine [mg/dL], proteinuria [g/24 h]). Renal biopsy findings were classified according to Haas single grade classification scheme and the Oxford Classification of IgAN. 600 cases of IgAN were identified, of which 568 (94.7 %) were on native kidneys. Male to female ratio was 1.24:1. Patients averaged 32.76 ± 15.12 years old (range 4-89, median 32). Proteinuria and hematuria were observed, respectively in 56.63 and 72.29 % of patients. The association of both these findings occurred in 37.95 % of the cases. Serum creatinine averaged 1.65 ± 0.67 mg/dL (median 1.5 mg/dL) at diagnosis. Segmental sclerosis and mesangial hypercellularity were the main glomerular findings (47.6 and 46.2 %) The commonest combination by Oxford Classification of IgAN, was M0 E0 S0 T0 (22.4 %). Chronic tubulo-interstitial lesions with an extension wider than 25 % of the renal cortex could be identified in 32.2 % of the cases. Tubular atrophy and interstitial fibrosis were more strongly associated with higher 24-h proteinuria and serum creatinine levels. Segmental sclerosis (S1) showed a stronger tendency of association with the presence of tubulo-interstitial lesions (T1 and T2) than other glomerular variables. To the best of our knowledge this is the largest series of IgAN in Brazil. It depicts the main biopsy findings and their possible clinical correlates. Our set of data is comparable to previous reports. PMID:26435893

  11. Preferential effectiveness of cyclosporin in patients receiving kidney transplants after glomerulonephritis.

    PubMed

    Cats, S; Terasaki, P I; Perdue, S; Mickey, M R

    1985-03-01

    Glomerulonephritis patients transplanted with cadaver kidneys had a significantly higher one-year graft survival when immunosuppressed with cyclosporin rather than standard therapy (80% versus 59%, p less than 10(-5]. For nephrosclerosis patients the corresponding rates were 70% and 59% (p greater than 0.05); and in those with antecedent diabetes mellitus, polycystic kidney, and pyelonephritis the differences were negligible. In glomerulonephritis patients, but not in the other groups, cyclosporin was additive to the effect of transfusions and of HLA-A, B and HLA-Dr matching. PMID:2857855

  12. Low-dose allopurinol plus azathioprine/cyclosporin/prednisolone, a novel immunosuppressive regimen.

    PubMed

    Chocair, P; Duley, J; Simmonds, H A; Cameron, J S; Ianhez, L; Arap, S; Sabbaga, E

    1993-07-10

    Early rejection can still complicate renal transplantation even with cyclosporin. We added low-dose allopurinol (25 mg on alternative days) to "triple" immunosuppression with cyclosporin, prednisolone, and azathioprine for twelve recipients of cadaver renal grafts. The controls were fifteen patients on triple therapy alone. Only one rejection episode occurred among the allopurinol-treated patients, whereas eleven controls had rejections (seven with more than one episode). Allopurinol may be toxic when combined with azathioprine, yet the bone marrow tolerated the new regimen well. As expected, reduction of the azathioprine dose was necessary in the treated group. PMID:8100914

  13. Current update in the management of diabetic nephropathy.

    PubMed

    Van Buren, Peter Noel; Toto, Robert

    2013-01-01

    Diabetic nephropathy is the leading cause of end-stage renal disease in the United States. The progression of kidney disease in patients with diabetes can take many years, and interventions such as glycemic control, blood pressure control, and inhibition of the renin-angiotensin-aldosterone system have been shown to slow this progression. Despite the implementation of these strategies, the number of patients with diabetes that ultimately develop end-stage renal disease remains high. Recent investigation has focused on the optimization of renin-angiotensin-aldosterone system blockade in patients with diabetic nephropathy using combinations of drugs that target this pathway. Additional investigation has focused on the potential of novel therapies that either target various pathways upregulated by hyperglycemia or other targets believed to promote progression of diabetic nephropathy such as the endothelin system, inflammation and vitamin D receptors. This review article addresses some of the well-established principles regarding the progression and accepted management of diabetic nephropathy and includes current updates on the most recent clinical research trials exploring novel therapeutics in this field. PMID:23167665

  14. Overexpression of Mafb in Podocytes Protects against Diabetic Nephropathy

    PubMed Central

    Yoh, Keigyou; Ojima, Masami; Okamura, Midori; Nakamura, Megumi; Hamada, Michito; Shimohata, Homare; Moriguchi, Takashi; Yamagata, Kunihiro; Takahashi, Satoru

    2014-01-01

    We previously showed that the transcription factor Mafb is essential for podocyte differentiation and foot process formation. Podocytes are susceptible to injury in diabetes, and this injury leads to progression of diabetic nephropathy. In this study, we generated transgenic mice that overexpress Mafb in podocytes using the nephrin promoter/enhancer. To examine a potential pathogenetic role for Mafb in diabetic nephropathy, Mafb transgenic mice were treated with either streptozotocin or saline solution. Diabetic nephropathy was assessed by renal histology and biochemical analyses of urine and serum. Podocyte-specific overexpression of Mafb had no effect on body weight or blood glucose levels in either diabetic or control mice. Notably, albuminuria and changes in BUN levels and renal histology observed in diabetic wild-type animals were ameliorated in diabetic Mafb transgenic mice. Moreover, hyperglycemia-induced downregulation of Nephrin was mitigated in diabetic Mafb transgenic mice, and reporter assay results suggested that Mafb regulates Nephrin directly. Mafb transgenic glomeruli also overexpressed glutathione peroxidase, an antioxidative stress enzyme, and levels of the oxidative stress marker 8-hydroxydeoxyguanosine decreased in the urine of diabetic Mafb transgenic mice. Finally, Notch2 expression increased in diabetic glomeruli, and this effect was enhanced in diabetic Mafb transgenic glomeruli. These data indicate Mafb has a protective role in diabetic nephropathy through regulation of slit diaphragm proteins, antioxidative enzymes, and Notch pathways in podocytes and suggest that Mafb could be a therapeutic target. PMID:24722438

  15. Lumbar Tuberculosis Associated with Membranous Nephropathy and Interstitial Nephritis▿

    PubMed Central

    Yuan, Quan; Sun, Li; Feng, Jiangmin; Liu, Nan; Jiang, Yi; Ma, Jianfei; Wang, Lining

    2010-01-01

    Tuberculosis is a common disease worldwide. However, it now is clear that tuberculosis can affect the kidney more insidiously. We describe a case of lumbar tuberculosis associated with simultaneous membranous nephropathy and interstitial nephritis, in which recovery of renal function occurred after treatment with steroids in addition to antituberculosis agents. PMID:20375238

  16. Paracetamol and analgesic nephropathy: Are you kidneying me?

    PubMed Central

    Waddington, Freya; Naunton, Mark; Thomas, Jackson

    2015-01-01

    Introduction Analgesic nephropathy is a disease resulting from the frequent use of combinations of analgesic medications over many years, leading to significant impairment of renal function. The observation of a large number of cases of renal failure in patients abusing analgesic mixtures containing phenacetin led to the initial recognition of the nephrotoxicity from the use of analgesics. Phenacetin was subsequently exclusively blamed for this disease. However, the role of a single analgesic as a sole cause of analgesic nephropathy was challenged, and a number of researchers have since attempted to determine the extent of involvement of other analgesics including nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and paracetamol. Case presentation We present the case of an 83-year-old woman with a history of NSAID-induced nephropathy with poor pain control and reluctance to use paracetamol. We attempt to briefly review the evidence of paracetamol being implicated in the development of analgesic-induced nephropathy. Conclusion There is a lack of concrete data regarding causative analgesics, including paracetamol. Patients should therefore not be withheld paracetamol, an effective and commonly recommended agent, for fear of worsening renal function. PMID:25548527

  17. BK nephropathy in pediatric hematopoeitic stem cell transplant recipients

    PubMed Central

    Verghese, Priya S; Finn, Laura S; Englund, Janet A; Sanders, Jean E; Hingorani, Sangeeta

    2009-01-01

    BK nephropathy is a known cause of renal insufficiency in kidney transplant recipients. Activation of the polyoma virus may also occur in the native kidneys of non-renal allograft recipients. BK nephropathy has only been reported in a few patients after hematopoetic stem cell transplantation (HCT), most being adult patients, and the single reported pediatric case had evidence of hemorrhagic cystitis. The response to anti-viral therapy also seems to differ widely. Here, we describe two cases of BK nephropathy in the native kidneys of HCT recipients exposed to high levels of immunosuppression due to graft-versus-host-disease. Neither of our patients had any evidence of hemorrhagic cystitis. We present definitive renal pathology and detailed chronological evidence of the rising serum creatinine with simultaneous serum and urine BK PCR titers. In one of our cases, anti-viral therapy did not seem beneficial as documented by continued renal dysfunction and serum/urine BK PCR titers. Based on our report, intense immunosuppression in pediatric HCT recipients seems to be involved in the activation of BK virus and BK nephropathy should be suspected even in the absence of hematuria in HCT recipients with unexplained renal dysfunction. PMID:19067914

  18. Treatment of chronic kidney diseases with histone deacetylase inhibitors

    PubMed Central

    Liu, Na; Zhuang, Shougang

    2015-01-01

    Histone deacetylases (HDACs) induce deacetylation of both histone and non-histone proteins and play a critical role in the modulation of physiological and pathological gene expression. Pharmacological inhibition of HDAC has been reported to attenuate progression of renal fibrogenesis in obstructed kidney and reduce cyst formation in polycystic kidney disease. HDAC inhibitors (HDACis) are also able to ameliorate renal lesions in diabetes nephropathy, lupus nephritis, aristolochic acid nephropathy, and transplant nephropathy. The beneficial effects of HDACis are associated with their anti-fibrosis, anti-inflammation, and immunosuppressant effects. In this review, we summarize recent advances on the treatment of various chronic kidney diseases with HDACis in pre-clinical models. PMID:25972812

  19. Treatment of autoimmune urticaria with low-dose cyclosporin A: A one-year follow-up.

    PubMed

    Boubouka, Christine D; Charissi, Christina; Kouimintzis, Dimitris; Kalogeromitros, Dimitris; Stavropoulos, Panagiotis G; Katsarou, Alexandra

    2011-01-01

    Patients with autoimmune urticaria (AIU) and positive autologous serum skin test (ASST) represent a more serious type of chronic urticaria that does not respond to treatment with antihistamines, but responds completely to systemic corticosteroids. Because of the chronic course of the disease, there is a risk of side-effects. Cyclosporin A (CsA) is an alternative treatment for patients with AIU. In order to determine the efficacy of CsA at the lowest possible dose in patients with chronic idiopathic urticaria and positive ASST, 30 patients were included in a 5-month study with a follow-up one year after the end of treatment. All patients had positive ASST before treatment and autoantibodies were present in 73%. Twenty- three patients completed the study and responded to low-dose CsA treatment. Three patients did not respond to a dose of 2.5 mg/kg CsA, and 4 patients dropped-out due to side-effects. After the first month of treatment, an improvement of 31% was noted, reaching 88% after the fifth month of treatment. The mean dose of CsA was 2.16 mg/kg for the first month and 0.55 mg/kg for the fifth month. Three to 6 months after the end of the study, the ASST was repeated and was negative in 78.3% of patients. At the one-year follow-up, 20 patients were symptom-free (87%) and 3 had relapsed (13%). CsA, even in low-doses, can be an effective and short-term treat- ment with minimum side-effects in patients with AIU. PMID:21264453

  20. Obstructive Sleep Apnea and Diabetic Nephropathy

    PubMed Central

    Tahrani, Abd A.; Ali, Asad; Raymond, Neil T.; Begum, Safia; Dubb, Kiran; Altaf, Quratul-ain; Piya, Milan K.; Barnett, Anthony H.; Stevens, Martin J.

    2013-01-01

    OBJECTIVE Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Obstructive sleep apnea (OSA) is common in type 2 diabetes and increases oxidative stress. Hence, OSA could promote the development and progression of DN. RESEARCH DESIGN AND METHODS This was a cohort study in adults with type 2 diabetes. Patients with known OSA or ESRD were excluded. DN was defined as the presence of albuminuria or an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2. DN progression was based on eGFR measurements. OSA was defined as apnea hypopnea index (AHI) ≥5 events/h. Serum nitrotyrosine abundance (a marker of nitrosative stress) was measured by ELISA. RESULTS A total of 224 patients were included. OSA and DN prevalence was 64.3 and 40.2, respectively. DN prevalence was higher in patients with OSA (OSA+) compared with those without OSA (OSA−) (49.3% vs. 23.8%, P < 0.001). After adjustment, OSA (odds ratio 2.64 [95% CI 1.13–6.16], P = 0.02) remained independently associated with DN. After an average follow-up of 2.5 (0.7) years, eGFR decline was greater in OSA+ compared with OSA− patients (median −6.8% [interquartile range −16.1 to 2.2] vs. −1.6% [−7.7 to 5.3%], P = 0.002). After adjusting, both baseline OSA (B = −3.8, P = 0.044) and AHI (B = −4.6, P = 0.02) remained independent predictors of study-end eGFR. Baseline serum nitrotyrosine abundance (B = −0.24, P = 0.015) was an independent predictor of study-end eGFR after adjustment. CONCLUSIONS OSA is independently associated with DN in type 2 diabetes. eGFR declined faster in patients with OSA. Nitrosative stress may provide a pathogenetic link between OSA and DN. Interventional studies assessing the impact of OSA treatment on DN are needed. PMID:24062320

  1. Chronic urticaria: recent advances.

    PubMed

    Greaves, Malcolm W; Tan, Kian Teo

    2007-10-01

    Chronic urticaria is an umbrella term, which encompasses physical urticarias, chronic "idiopathic" urticaria and urticarial vasculitis. It is important to recognize patients with physical urticarias as the investigation and treatment differs in important ways from patients with idiopathic chronic urticaria or urticarial vasculitis. Although relatively uncommon, urticarial vasculitis is an important diagnosis to make and requires histological confirmation by biopsy. Underlying systemic disease and systemic involvement, especially of the kidneys, should be sought. It is now recognized that chronic "idiopathic" urticaria includes a subset with an autoimmune basis caused by circulating autoantibodies against the high affinity IgE receptor (FceR1) and less commonly against IgE. Although the autologous serum skin test has been proven useful in prompting search for and characterization of circulating wheal-producing factors in chronic urticaria, its specificity as a screening test for presence of functional anti-FceR1 is low, and confirmation by demonstration of histamine-releasing activity in the patient's serum must be the benchmark test in establishing this diagnosis. Improved screening tests are being sought; for example, ability of the chronic urticaria patient's serum to evoke expression of CD 203c on donor human basophils is showing some promise. The strong association between autoimmune thyroid disease and autoimmune urticaria is also an area of ongoing research. Drug treatment continues to be centered on the H1 antihistamines, and the newer second-generation compounds appear to be safe and effective even in off-label dosage. Use of systemic steroids should be confined to special circumstances such as tapering regimens for acute flare-ups. Use of leukotriene antagonists is becoming popular, but the evidence for efficacy is conflicting. Cyclosporin is also effective and can be used in selected cases of autoimmune urticaria, and it is also effective in non

  2. Randomized trial of tacrolimus versus cyclosporin microemulsion in renal transplantation.

    PubMed

    Trompeter, Richard; Filler, Guido; Webb, Nicholas J A; Watson, Alan R; Milford, David V; Tyden, Gunnar; Grenda, Ryszard; Janda, Jan; Hughes, David; Ehrich, Jochen H H; Klare, Bernd; Zacchello, Graziella; Bjorn Brekke, Inge; McGraw, Mary; Perner, Ferenc; Ghio, Lucian; Balzar, Egon; Friman, Styrbjörn; Gusmano, Rosanna; Stolpe, Jochen

    2002-03-01

    This study was undertaken to compare the efficacy and safety of tacrolimus (Tac) with the microemulsion formulation of cyclosporin (CyA) in children undergoing renal transplantation. A 6-month, randomized, prospective, open, parallel group study with an open extension phase was conducted in 18 centers from nine European countries. In total, 196 pediatric patients (<18 years) were randomly assigned (1:1) to receive either Tac ( n=103) or CyA microemulsion ( n=93) administered concomitantly with azathioprine and corticosteroids. The primary endpoint was incidence and time to first acute rejection. Baseline characteristics were comparable between treatment groups. Tac therapy resulted in a significantly lower incidence of acute rejection (36.9%) compared with CyA therapy (59.1%) ( P=0.003). The incidence of corticosteroid-resistant rejection was also significantly lower in the Tac group compared with the CyA group (7.8% vs. 25.8%, P=0.001). The differences were also significant for biopsy-confirmed acute rejection (16.5% vs. 39.8%, P<0.001). At 1 year, patient survival was similar (96.1% vs. 96.6%), while 10 grafts were lost in the Tac group compared with 17 graft losses in the CyA group ( P=0.06). At 1 year, mean glomerular filtration rate (Schwartz estimate) was significantly higher in the Tac group (62+/-20 ml/min per 1.73 m(2), n=84) than in the CyA group (56+/-21 ml/min per 1.73 m(2), n=74, P=0.03). The most frequent adverse events during the first 6 months were hypertension (68.9% vs. 61.3%), hypomagnesemia (34.0% vs. 12.9%, P=0.001), and urinary tract infection (29.1% vs. 33.3%). Statistically significant differences ( P<0.05) were observed for diarrhea (13.6% vs. 3.2%), hypertrichosis (0.0% vs. 7.5%), flu syndrome (0.0% vs. 5.4%), and gum hyperplasia (0.0% vs. 5.4%). In previously non-diabetic children, the incidence of long-term (>30 days) insulin use was 3.0% (Tac) and 2.2% (CyA). Post-transplant lymphoproliferative disease was observed in 1 patient in the

  3. Cyclosporin A and methotrexate in canine marrow transplantation: engraftment, graft-versus-host disease, and induction of intolerance

    SciTech Connect

    Deeg, H.J.; Storb, R.; Weiden, P.L.; Raff, R.F.; Sale, G.E.; Atkinson, K.; Graham, T.C.; Thomas, E.D.

    1982-07-01

    We examined the effect of methotrexate (MTX) and cyclosporin A (Cy A) on engraftment, graft-versus-host disease (GVHD), and the induction of tolerance in dogs prepared for marrow transplantation by 9 Gy of total body irradiation and grafted with bone marrow and buffy coat cells. Nineteen dogs were given grafts from DLA-identical littermates followed by immunosuppression with Cy A for 25 or 100 days. All had sustained engraftment, and 12 became healthy long-term chimeras. Sixty dogs were given grafts from DLA-nonidentical unrelated donors. Among nine given MTX only postgrafting, one rejected the graft nd eight died with GVHD. Among 18 dogs given Cy A only postgrafting, eight failed to achieve engraftment, seven died of various causes, and three died with GVHD. Thirty-four dogs were given both MTX and Cy A in various regimens postgrafting. The only long-term survivors were 4 of 10 dogs given MTX on days 1, 3, 6, and 11 and Cy A from days 0 through 100. Two have chronic GVHD. We conclude that Cy A can induce graft-host tolerance across minor, but not major, histocompatibility differences. The combination of MTX early after transplantation with Cy A prevents failure of engraftment of histoincompatible marrow and some recipients become long-term survivors.

  4. Capsaicin pretreatment increased the bioavailability of cyclosporin in rats: involvement of P-glycoprotein and CYP 3A inhibition.

    PubMed

    Zhai, Xue-jia; Shi, Fang; Chen, Fen; Lu, Yong-ning

    2013-12-01

    Capsaicin (CAP), the main ingredient responsible for the hot pungent taste of chilli peppers. This study investigated the effect of CAP on the pharmacokinetics of Cyclosporin A (CyA) in rats and the mechanism of this food-drug interaction. The results indicated that after 7 days of low or middle dose of CAP (0.3 or 1.0 mg/kg), the blood concentration of CyA was not significantly changed compared with that of vehicle-treated rats, whereas the blood concentration of CyA in high dose group (3.0 mg/kg) was significantly increased. The total clearance (CL/F) of CyA was decreased, and the bioavailability was significantly increased to about 1.44-fold of that in vehicle-treated rats after 7 days of high dose CAP treatment. At this time, the P-gp and CYP3A1/2 in the liver and intestine were decreased at both the mRNA and protein levels. These results demonstrated that chronic ingestion of high doses of CAP will increase the bioavailability of CyA to a significant extent in rats and the food-drug interaction between CAP and CyA appears to be due to modulation of P-gp and CYP3A gene expression by CAP, with differential dose-dependence. PMID:24013073

  5. [Polyneuropathy and central nervous system diseases before and after heart transplantation. Is cyclosporin neurotoxic?].

    PubMed

    Porschke, H; Strenge, H; Stauch, C

    1991-10-18

    In a cross-sectional study, 52 patients (44 men, 8 women, mean age 50.6 [19-68] years) were investigated clinically and electrophysiologically for evidence of peripheral and central nervous system damage before and after heart transplantation. 20 patients were investigated before heart transplantation (group 1), 16 at 7 days to 5 months after transplantation (early post-operative group; group 2) and 16 at 6 to 32 months after transplantation (late post-operative group; group 3). Nerve conduction studies (median, peroneal and sural nerves) revealed polyneuropathy in 14 out of 16 patients in group 2, significantly more than in group 1 (11 out of 19) and group 3 (9 out of 16). The mean blood cyclosporin concentration was 656 ng/ml in group 2 and 409 ng/ml in group 3 (P less than 0.001). Patients in group 3 with polyneuropathy had significantly higher cyclosporin concentrations than patients without polyneuropathy (505 vs 284 ng/ml; P less than 0.01). Among patients who had undergone operations, there were no noteworthy differences between the mean cyclosporin concentrations and clinical data in those with or without central nervous system lesions. There is preliminary evidence of a neurotoxic effect of cyclosporin on the peripheral but not the central nervous system. PMID:1935623

  6. Cyclosporin C is the main antifungal compound produced by Acremonium luzulae.

    PubMed Central

    Moussaïf, M; Jacques, P; Schaarwächter, P; Budzikiewicz, H; Thonart, P

    1997-01-01

    A strain of Acremonium luzulae (Fuckel) W. Gams was selected in screening new microorganisms for biological control of fruit postharvest diseases, especially gray and blue mold diseases on apples and strawberries. This strain manifests a very strong activity against a large number of phytopathogenic fungi. In this work, the product responsible for this antifungal activity was isolated from modified Sabouraud dextrose broth cultures of A. luzulae. It was purified to homogeneity by reverse-phase column chromatography. On the basis of UV, infrared, and 1H and 13C nuclear magnetic resonance spectra, mass spectral analysis, and the amino acid composition of the acid hydrolysates, the antibiotic was determined to be cyclosporin C. Cyclosporin C showed a broad-spectrum activity against filamentous phytopathogenic fungi but no activity against bacteria or yeasts. Its antifungal activity is only fungistatic. In contrast to Tolypocladium inflatum, another cyclosporin-producing strain, A. luzulae, did not produce additional cyclosporins. This was confirmed by in vivo-directed biosynthesis. PMID:9143111

  7. Recalcitrant pyoderma gangrenosum--two cases successfully treated with cyclosporin A.

    PubMed

    Kavanagh, G M; Ross, J S; Cronin, E; Smith, N P; Black, M M

    1992-01-01

    The successful use of cyclosporin A (CSA) in organ transplantation is now well established. In recent years its usefulness has extended to the treatment of cutaneous autoimmune disorders, including pyoderma gangrenosum (P.G.). We report two further cases of recalcitrant P.G., both associated with rheumatoid arthritis (R.A.) which responded to low dose CSA. PMID:1424262

  8. Quality by design approach for understanding the critical quality attributes of cyclosporine ophthalmic emulsion.

    PubMed

    Rahman, Ziyaur; Xu, Xiaoming; Katragadda, Usha; Krishnaiah, Yellela S R; Yu, Lawrence; Khan, Mansoor A

    2014-03-01

    Restasis is an ophthalmic cyclosporine emulsion used for the treatment of dry eye syndrome. There are no generic products for this product, probably because of the limitations on establishing in vivo bioequivalence methods and lack of alternative in vitro bioequivalence testing methods. The present investigation was carried out to understand and identify the appropriate in vitro methods that can discriminate the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion formulations having the same qualitative (Q1) and quantitative (Q2) composition as that of Restasis. Quality by design (QbD) approach was used to understand the effect of formulation and process variables on critical quality attributes (CQA) of cyclosporine microemulsion. The formulation variables chosen were mixing order method, phase volume ratio, and pH adjustment method, while the process variables were temperature of primary and raw emulsion formation, microfluidizer pressure, and number of pressure cycles. The responses selected were particle size, turbidity, zeta potential, viscosity, osmolality, surface tension, contact angle, pH, and drug diffusion. The selected independent variables showed statistically significant (p < 0.05) effect on droplet size, zeta potential, viscosity, turbidity, and osmolality. However, the surface tension, contact angle, pH, and drug diffusion were not significantly affected by independent variables. In summary, in vitro methods can detect formulation and manufacturing changes and would thus be important for quality control or sameness of cyclosporine ophthalmic products. PMID:24423028

  9. Effect of cyclosporin A particles of varying diameters on gastric cancer cell apoptosis.

    PubMed

    Xing, X L; Lu, Y; Qiu, H L

    2016-01-01

    Human health is significantly threatened by gastric cancer, which is the most common malignant tumor; although drastic, surgery is currently the only way to cure it. However, high recurrence rates and low survival rates are associated with the disease. Therefore, to improve the effectiveness of gastric cancer treatment and to increase the clinical cure rate, we investigated the effect of cyclosporin A particles of varying diameter on gastric cancer cell apoptosis. Flow cytometry was used to detect apoptosis induced by Annexin V-fluorescein isothiocyanate/propidium iodide-double labeling. We also determined the content of reactive oxygen species and the expression level of P-glycoprotein in cells after treatment with cyclosporin A. The results indicated that increases in the concentration and action time of cyclosporin A were associated with statistically significant increases in the apoptosis rate of gastric cancer cells when the experimental and control groups were compared (P < 0.05 and P < 0.01, respectively). In conclusion, during a certain action time and concentration range, cyclosporin A inhibits the proliferation of human gastric cancer cells and can induce their apoptosis. PMID:27173251

  10. Effects of immunosuppressive drugs on gastrointestinal transit of rats: effects of tacrolimus, cyclosporine, and prednisone.

    PubMed

    Dall'Agnol, D J R; Hauschildt, A T; Lima, M B; Corá, L A; Teixeira, M C B; Américo, M F

    2014-01-01

    Triple immunosuppressive therapy after organ transplantation may cause several gastrointestinal disturbances. It is difficult to identify which drug causes more complications, requiring an appropriate animal model. The aim was to compare the gastrointestinal transit in immunosuppressed rats under triple immunosuppressive therapy. Male rats were immunosuppressed by gavage during 14 days with tacrolimus (n = 10), cyclosporine (n = 12), and prednisone (n = 9). Animals received a magnetic pellet before (control) and after treatment that was monitored at predetermined intervals by AC biosusceptometry, a noninvasive and radiation-free technique. The following parameters were measured: creatinine serum, mean time of gastric emptying (MGET), mean time to reach cecum (MCAT), and mean transit time through small bowel (MSBTT). The differences were analyzed by ANOVA (Tukey). Our results showed that MGET of animals treated with prednisone, cyclosporine, and tacrolimus were reduced compared with control subjects (P < .03, P < .009, and P < .002, respectively). There was no difference in MCAT, whereas MSBTT was longer for tacrolimus and prednisone compared with control subjects (P < .004 and P < .004, respectively). Also, prednisone and tacrolimus presented a reduced MGET (P < .05 and P < .01, respectively) compared with cyclosporine. Our data showed a low serum creatinine level and no difference among groups regarding renal function. In summary, cyclosporine has less effect on the gastrointestinal transit; however, all of these drugs should be carefully prescribed to prevent gastrointestinal symptoms and improve quality of life after transplantation. PMID:25131057

  11. Cells of renin lineage take on a podocyte phenotype in aging nephropathy

    PubMed Central

    Pippin, Jeffrey W.; Glenn, Sean T.; Krofft, Ronald D.; Rusiniak, Michael E.; Alpers, Charles E.; Hudkins, Kelly; Duffield, Jeremy S.; Gross, Kenneth W.

    2014-01-01

    Aging nephropathy is characterized by podocyte depletion accompanied by progressive glomerulosclerosis. Replacement of terminally differentiated podocytes by local stem/progenitor cells is likely a critical mechanism for their regeneration. Recent studies have shown that cells of renin lineage (CoRL), normally restricted to the kidney's extraglomerular compartment, might serve this role after an abrupt depletion in podocyte number. To determine the effects of aging on the CoRL reserve and if CoRL moved from an extra- to the intraglomerular compartment during aging, genetic cell fate mapping was performed in aging Ren1cCre × Rs-ZsGreen reporter mice. Podocyte number decreased and glomerular scarring increased with advanced age. CoRL number decreased in the juxtaglomerular compartment with age. There was a paradoxical increase in CoRL in the intraglomerular compartment at 52 and 64 wk of age, where a subset coexpressed the podocyte proteins nephrin, podocin, and synaptopodin. Transmission electron microscopy studies showed that a subset of labeled CoRL in the glomerulus displayed foot processes, which attached to the glomerular basement membrane. No CoRL in the glomerular compartment stained for renin. These results suggest that, despite a decrease in the reserve, a subpopulation of CoRL moves to the glomerulus after chronic podocyte depletion in aging nephropathy, where they acquire a podocyte-like phenotype. This suggests that they might serve as adult podocyte stem/progenitor cells under these conditions, albeit in insufficient numbers to fully replace podocytes depleted with age. PMID:24647714

  12. Diabetic nephropathy is resistant to oral L-arginine or L-citrulline supplementation.

    PubMed

    You, Hanning; Gao, Ting; Cooper, Timothy K; Morris, Sidney M; Awad, Alaa S

    2014-12-01

    Our recent publication showed that pharmacological blockade of arginases confers kidney protection in diabetic nephropathy via a nitric oxide (NO) synthase (NOS)3-dependent mechanism. Arginase competes with endothelial NOS (eNOS) for the common substrate L-arginine. Lack of L-arginine results in reduced NO production and eNOS uncoupling, which lead to endothelial dysfunction. Therefore, we hypothesized that L-arginine or L-citrulline supplementation would ameliorate diabetic nephropathy. DBA mice injected with multiple low doses of vehicle or streptozotocin (50 mg/kg ip for 5 days) were provided drinking water with or without L-arginine (1.5%, 6.05 g·kg(-1)·day(-1)) or L-citrulline (1.66%, 5.73 g·kg(-1)·day(-1)) for 9 wk. Nonsupplemented diabetic mice showed significant increases in albuminuria, blood urea nitrogen, glomerular histopathological changes, kidney macrophage recruitment, kidney TNF-α and fibronectin mRNA expression, kidney arginase activity, kidney arginase-2 protein expression, and urinary oxidative stress along with a significant reduction of nephrin and eNOS protein expression and kidney nitrite + nitrate compared with normal mice after 9 wk of diabetes. Surprisingly, L-arginine or L-citrulline supplementation in diabetic mice did not affect any of these parameters despite greatly increasing kidney and plasma arginine levels. These findings demonstrate that chronic L-arginine or L-citrulline supplementation does not prevent or reduce renal injury in a model of type 1 diabetes. PMID:25320354

  13. Guideline of Chronic Urticaria Beyond

    PubMed Central

    Fine, Lauren M.

    2016-01-01

    Urticaria is a relatively common condition that if chronic can persist for weeks, months or years and affect quality of life significantly. The etiology is often difficult to determine, especially as it becomes chronic. Many cases of chronic urticaria are thought to be autoimmune, although there is no consensus that testing for autoimmunity alters the diagnostic or management strategies or outcomes. Many times, urticaria is easily managed with antihistamines and/or short courses of oral corticosteroids, but too often control is insufficient and additional therapies must be added. For years, immune modulating medications, such as cyclosporine and Mycophenolate Mofetil, have been used in cases refractory to antihistamines and oral corticosteroids, although the evidence supporting their efficacy and safety has been limited. Omalizumab was recently approved for the treatment of chronic urticaria unresponsive to H1-antagonists. This IgG anti-IgE monoclonal antibody has been well demonstrated to safely and effectively control chronic urticaria at least partially in approximately 2/3 of cases. However, the mechanism of action and duration of treatment for omalizumab is still unclear. It is hoped that as the pathobiology of chronic urticaria becomes better defined, future therapies that target specific mechanistic pathways will be developed that continue to improve the management of these often challenging patients. PMID:27334777

  14. Guideline of Chronic Urticaria Beyond.

    PubMed

    Fine, Lauren M; Bernstein, Jonathan A

    2016-09-01

    Urticaria is a relatively common condition that if chronic can persist for weeks, months or years and affect quality of life significantly. The etiology is often difficult to determine, especially as it becomes chronic. Many cases of chronic urticaria are thought to be autoimmune, although there is no consensus that testing for autoimmunity alters the diagnostic or management strategies or outcomes. Many times, urticaria is easily managed with antihistamines and/or short courses of oral corticosteroids, but too often control is insufficient and additional therapies must be added. For years, immune modulating medications, such as cyclosporine and Mycophenolate Mofetil, have been used in cases refractory to antihistamines and oral corticosteroids, although the evidence supporting their efficacy and safety has been limited. Omalizumab was recently approved for the treatment of chronic urticaria unresponsive to H1-antagonists. This IgG anti-IgE monoclonal antibody has been well demonstrated to safely and effectively control chronic urticaria at least partially in approximately 2/3 of cases. However, the mechanism of action and duration of treatment for omalizumab is still unclear. It is hoped that as the pathobiology of chronic urticaria becomes better defined, future therapies that target specific mechanistic pathways will be developed that continue to improve the management of these often challenging patients. PMID:27334777

  15. Cyclosporine and methotrexate-related pharmacogenomic predictors of acute graft-versus-host disease

    PubMed Central

    Laverdière, Isabelle; Guillemette, Chantal; Tamouza, Ryad; Loiseau, Pascale; de Latour, Regis Peffault; Robin, Marie; Couture, Félix; Filion, Alain; Lalancette, Marc; Tourancheau, Alan; Charron, Dominique; Socié, Gérard; Lévesque, Éric

    2015-01-01

    Effective immunosuppression is mandatory to prevent graft-versus-host disease and to achieve a successful clinical outcome of hematopoietic stem cell transplantation. Here we tested whether germline single nucleotide polymorphisms in 20 candidate genes related to methotrexate and cyclosporine metabolism and activity influence the incidence of graft-versus-host disease in patients who undergo stem cell transplantation for hematologic disorders. Recipient genetic status of the adenosine triphosphate-binding cassette sub-family C1 and adenosine triphosphate-binding cassette sub-family C2 transporters, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/ inosine monophosphate cyclohydrolase within the methotrexate pathway, and nuclear factor of activated T cells (cytoplasmic 1) loci exhibit a remarkable influence on severe acute graft-versus-host disease prevalence. Indeed, an increased risk of acute graft-versus-host disease was observed in association with single nucleotide polymorphisms located in 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (hazard ratio=3.04; P=0.002), nuclear factor of activated T cells (cytoplasmic 1) (hazard ratio=2.69; P=0.004), adenosine triphosphate-binding cassette sub-family C2 (hazard ratio=3.53; P=0.0018) and adenosine triphosphate-binding cassette sub-family C1 (hazard ratio=3.67; P=0.0005). While donor single nucleotide polymorphisms of dihydrofolate reductase and solute carrier family 19 (member 1) genes are associated with a reduced risk of acute graft-versus-host disease (hazard ratio=0.32–0.41; P=0.0009–0.008), those of nuclear factor of activated T cells (cytoplasmic 2) are found to increase such risk (hazard ratio=3.85; P=0.0004). None of the tested single nucleotide polymorphisms was associated with the occurrence of chronic graft-versus-host disease. In conclusion, by targeting drug-related biologically relevant genes, this work emphasizes the potential

  16. Cyclosporine A induces apoptotic and autophagic cell death in rat pituitary GH3 cells.

    PubMed

    Kim, Han Sung; Choi, Seung-Il; Jeung, Eui-Bae; Yoo, Yeong-Min

    2014-01-01

    Cyclosporine A (CsA) is a powerful immunosuppressive drug with side effects including the development of chronic nephrotoxicity. In this study, we investigated CsA treatment induced apoptotic and autophagic cell death in pituitary GH3 cells. CsA treatment (0.1 to 10 µM) decreased survival of GH3 cells in a dose-dependent manner. Cell viability decreased significantly with increasing CsA concentrations largely due to an increase in apoptosis, while cell death rates due to autophagy altered only slightly. Several molecular and morphological features correlated with cell death through these distinct pathways. At concentrations ranging from 1.0 to 10 µM, CsA induced a dose-dependent increase in expression of the autophagy markers LC3-I and LC3-II. Immunofluorescence staining revealed markedly increased levels of both LC3 and lysosomal-associated membrane protein 2 (Lamp2), indicating increases in autophagosomes. At the same CsA doses, apoptotic cell death was apparent as indicated by nuclear and DNA fragmentation and increased p53 expression. In apoptotic or autophagic cells, p-ERK levels were highest at 1.0 µM CsA compared to control or other doses. In contrast, Bax levels in both types of cell death were increased in a dose-dependent manner, while Bcl-2 levels showed dose-dependent augmentation in autophagy and were decreased in apoptosis. Manganese superoxide dismutase (Mn-SOD) showed a similar dose-dependent reduction in cells undergoing apoptosis, while levels of the intracellular calcium ion exchange maker calbindin-D9k were decreased in apoptosis (1.0 to 5 µM CsA), but unchanged in autophagy. In conclusion, these results suggest that CsA induction of apoptotic or autophagic cell death in rat pituitary GH3 cells depends on the relative expression of factors and correlates with Bcl-2 and Mn-SOD levels. PMID:25299210

  17. Cyclosporine and methotrexate-related pharmacogenomic predictors of acute graft-versus-host disease.

    PubMed

    Laverdière, Isabelle; Guillemette, Chantal; Tamouza, Ryad; Loiseau, Pascale; Peffault de Latour, Regis; Robin, Marie; Couture, Félix; Filion, Alain; Lalancette, Marc; Tourancheau, Alan; Charron, Dominique; Socié, Gérard; Lévesque, Éric

    2015-02-01

    Effective immunosuppression is mandatory to prevent graft-versus-host disease and to achieve a successful clinical outcome of hematopoietic stem cell transplantation. Here we tested whether germline single nucleotide polymorphisms in 20 candidate genes related to methotrexate and cyclosporine metabolism and activity influence the incidence of graft-versus-host disease in patients who undergo stem cell transplantation for hematologic disorders. Recipient genetic status of the adenosine triphosphate-binding cassette sub-family C1 and adenosine triphosphate-binding cassette sub-family C2 transporters, 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/ inosine monophosphate cyclohydrolase within the methotrexate pathway, and nuclear factor of activated T cells (cytoplasmic 1) loci exhibit a remarkable influence on severe acute graft-versus-host disease prevalence. Indeed, an increased risk of acute graft-versus-host disease was observed in association with single nucleotide polymorphisms located in 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/inosine monophosphate cyclohydrolase (hazard ratio=3.04; P=0.002), nuclear factor of activated T cells (cytoplasmic 1) (hazard ratio=2.69; P=0.004), adenosine triphosphate-binding cassette sub-family C2 (hazard ratio=3.53; P=0.0018) and adenosine triphosphate-binding cassette sub-family C1 (hazard ratio=3.67; P=0.0005). While donor single nucleotide polymorphisms of dihydrofolate reductase and solute carrier family 19 (member 1) genes are associated with a reduced risk of acute graft-versus-host disease (hazard ratio=0.32-0.41; P=0.0009-0.008), those of nuclear factor of activated T cells (cytoplasmic 2) are found to increase such risk (hazard ratio=3.85; P=0.0004). None of the tested single nucleotide polymorphisms was associated with the occurrence of chronic graft-versus-host disease. In conclusion, by targeting drug-related biologically relevant genes, this work emphasizes the potential role of

  18. The novel immunosuppressant SDZ-RAD protects rat brain slices from cyclosporine-induced reduction of high-energy phosphates

    PubMed Central

    Serkova, Natalie; Litt, Lawrence; Leibfritz, Dieter; Hausen, Bernard; Morris, Randall E; James, Thomas L; Benet, Leslie Z; Christians, Uwe

    2000-01-01

    SDZ-RAD, 40-O-(2-hydroxyethyl)-rapamycin, is a novel macrolide immunosuppressant. Because of its synergistic interaction, SDZ-RAD is under clinical investigation as immunosuppressant in combination with cyclosporine after organ transplantation. Neurotoxicity is a critical side-effect of cyclosporine. We studied the effect of SDZ-RAD and its combination with cyclosporine on high-energy phosphates, phosphocreatine (PCr) and nucleoside triphosphates (NTP), in brain slices using 31P-magnetic resonance spectroscopy (MRS). Cyclosporine significantly reduced high-energy phosphates after 2 h in a dose-dependent manner (100 μg l−1: 93±3% of control (NTP), 91±3% (PCr); 500 μg l−1: 84±2% (NTP), 73±2 (PCr); 5000 μg l−1: 68±3% (NTP), 55±5% (PCr); n=6; P<0.02). In contrast, after perfusion for 2 h, SDZ-RAD (500 μg l−1 and 5000 μg l−1) significantly increased high-energy phosphate concentrations in the brain slices (P<0.02). Even at the lowest concentration, SDZ-RAD protected brain energy metabolism against cyclosporine toxicity: 100 μg l−1 SDZ-RAD+5000 μg l−1 cyclosporine: 86±3% (NTP), 83±7% (PCr), n = 3, P<0.03 compared to cyclosporine alone. 5As evaluated using an algorithm based on Loewe isobolograms, the effects of SDZ-RAD/ cyclosporine combinations on brain energy reduction were antagonistic. Both drugs were found in mitochondria using h.p.l.c-MS analysis. We conclude that cyclosporine inhibits mitochondrial high-energy phosphate metabolism, which can be antagonized by SDZ-RAD. PMID:10711346

  19. The risk of recurrent IgA nephropathy in a steroid-free protocol and other modifying immunosuppression.

    PubMed

    Von Visger, J R; Gunay, Y; Andreoni, K A; Bhatt, U Y; Nori, U S; Pesavento, T E; Elkhammas, E A; Winters, H A; Nadasdy, T; Singh, N

    2014-08-01

    Recurrent glomerulonephritis is an important cause of kidney allograft failure. The effect of immunosuppression on recurrent IgA nephropathy (IgAN) is unclear. We analyzed the impact of steroids and other immunosuppression on the risk of recurrent IgAN post-kidney transplantation. Between June 1989 and November 2008, 3311 kidney transplants were performed at our center. IgAN was the primary disease in 124 patients; of these, 75 (60.5%) patients received steroid-based immunosuppression (15 undergoing late steroid withdrawal), and 49 (39.5%) were maintained on steroid-free immunosuppression. Recurrent IgAN was diagnosed in 27 of 124 (22%) patients in clinically indicated kidney allograft biopsies over a median follow-up of 6.86 ± 5.4 yr. On cox proportional hazards model multivariate analysis, the hazard risk (HR) of IgAN recurrence was significantly higher in patients managed with steroid-free (HR 8.59: 3.03, 24.38, p < 0.001) and sirolimus-based (HR = 3.00:1.16, 7.75, p = 0.024) immunosuppression without antilymphocyte globulin induction (HR = 4.5: 1.77, 11.73, p = 0.002). Mycophenolate use was associated with a lower risk (HR = 0.42: 0.19, 0.95, p = 0.036), whereas cyclosporine did not have a significant impact on the risk of IgAN recurrence (p = 0.61). These results warrant future prospective studies regarding the role of steroids and other immunosuppression drugs in reducing recurrence of IgAN and other glomerulonephritis post-transplant. PMID:24869763

  20. Angiotensin-converting enzyme polymorphism and development of diabetic nephropathy in non-insulin-dependent diabetes mellitus.

    PubMed

    Mizuiri, S; Hemmi, H; Inoue, A; Yoshikawa, H; Tanegashima, M; Fushimi, T; Ishigami, M; Amagasaki, Y; Ohara, T; Shimatake, H

    1995-01-01

    We determined the distribution frequency of angiotensin-converting enzyme insertion/deletion (I/D) polymorphism in 111 Japanese patients with non-insulin-dependent diabetes mellitus (NIDDM) of at least 10 years duration (80 patients with diabetic nephropathy and 31 patients without nephropathy) and 76 healthy Japanese controls. Patients with diabetic nephropathy showed an excess of the ID genotype compared with patients without nephropathy (p < 0.02) and less of the II genotype compared with healthy controls (p < 0.01) and patients without nephropathy (p < 0.01). NIDDM patients with the II genotype have a decreased risk for the development of diabetic nephropathy. PMID:7477652

  1. Nicotine worsens the severity of nephropathy in diabetic mice: implications for the progression of kidney disease in smokers

    PubMed Central

    Hua, Ping; Feng, Wenguang; Ji, Shaonin; Raij, Leopoldo

    2010-01-01

    Epidemiological studies have established the role of cigarette smoking as a risk factor in the progression of chronic kidney disease, including diabetic nephropathy. We have previously reported that nicotine promotes mesangial cell proliferation and hypertrophy via activation of nonneuronal nicotinic acetylcholine receptors and that nicotine worsens renal injury in a model of acute glomerulonephritis (Jaimes E, Tian RX, Raij L. Am J Physiol Heart Circ Physiol 292: H76–H82, 2007; Jaimes EA, Tian RX, Joshi M, Raij L. Am J Nephrol 29: 319–326, 2009). These studies were designed to test the hypothesis that nicotine worsens renal injury in db/db mice, a well-established model of diabetic nephropathy, and that reactive oxygen species play an important as mediators of these effects. For these studies, nicotine (100 μg/ml) was administered in the drinking water to control and db/db mice for 10 wk. Blood pressure was measured by the tail-cuff method, and urine was collected for proteinuria. At death, kidneys were collected for histology and molecular biology. The administration of nicotine did not result in significant changes in blood pressure or blood glucose and resulted in cotinine levels similar to those found in the plasma of smokers. In diabetic mice, the administration of nicotine significantly increased urinary protein excretion (1-fold), glomerular hypertrophy, and mesangial area (∼20%). These changes were accompanied by significant increases in NADPH oxidase 4 (∼30%) and increased nitrotyrosine and Akt expression. In vitro, we determined that nicotine has additive effects to high glucose on reactive oxygen species generation and Akt phosphorylation in human mesangial cells. These findings unveil novel mechanisms that may result in the development of novel strategies in the treatment and prevention of diabetic nephropathy in smokers. PMID:20685820

  2. Proteinuria during Follow-Up Period and Long-Term Renal Survival of Childhood IgA Nephropathy

    PubMed Central

    Kamei, Koichi; Harada, Ryoko; Hamada, Riku; Sakai, Tomoyuki; Hamasaki, Yuko; Hataya, Hiroshi; Ito, Shuichi

    2016-01-01

    Background Proteinuria is the most important risk factor for IgA nephropathy progression. The purpose of this study is to evaluate the long-term outcome and risk factors for poor prognosis in childhood IgA nephropathy. Methods Patients who were diagnosed with IgA nephropathy between 1972 and 1992 at the Tokyo Metropolitan Kiyose Children’s Hospital were included. We analyzed risk factors for progression to end-stage kidney disease (ESKD) and chronic renal insufficiency (CRI) using Kaplan-Meier method and multivariate analyses of Cox proportional hazard model. Results One hundred patients were included and the median observation period was 11.8 years. Twelve and 17 patients progressed to ESKD and CRI, respectively. The survival probabilities were 90.0% at 10 years and 79.8% at 20 years for ESKD, and 86.1% at 10 years and 72.3% at 20 years for CRI. Notably, patients with heavy proteinuria with hypoalbuminemia during follow-up period showed extremely poor prognosis. In this group, the survival rate at 10 years from ESKD and CRI was 40.6% and 20.8%, respectively. By multivariate analysis, proteinuria at diagnosis and proteinuria during follow-up period were risk factors for ESKD, whereas glomeruli showing mesangial proliferation ≥50% and proteinuria during follow-up period were risk factors for CRI. Patients without heavy proteinuria during follow-up period did not develop CRI and 63% of patients with mild proteinuria during follow-up period showed no proteinuria at the last observation. Conclusions The degree of proteinuria during follow-up period is the strongest risk factor for ESKD and CRI. PMID:26978656

  3. Effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis in rats.

    PubMed

    Cannon, G W; McCall, S; Cole, B C; Radov, L A; Ward, J R; Griffiths, M M

    1993-03-01

    The prophylactic and therapeutic effects of gold sodium thiomalate, cyclosporin A, cyclophosphamide, and placebo on collagen-induced arthritis (CIA) were evaluated in DA rats. Prophylactic treatment with cyclosporin A and cyclophosphamide suppressed the arthritis incidence, clinical inflammation, destructive bone changes, and development of anti-collagen antibody in DA rats subsequently injected with porcine type-II collagen. Therapeutic treatment with cyclosporin A and cyclophosphamide had a definite suppression on established CIA when started 21 days after the initial collagen injection, but the suppression was less marked than that of prophylactic treatment. Gold had no impact on CIA in DA rats when administered either prophylactically or therapeutically. PMID:8213350

  4. Chronic pancreatitis

    MedlinePlus

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  5. Inhibition of adriamycin-induced nephropathy in rats by herbs based kangshenoral solution

    PubMed Central

    Zhao, Jingsheng; Lin, Xinwei; Xiao, Xueqing; Yang, Jun; Liu, Hong; Yi, Weiguo; Zhang, Zhengchen; Zhang, Xinkuan

    2015-01-01

    The Chronic kidney disease (CKD) is characterized by the progressive loss in renal function over a period. The progression of CKD will finally result the End Stage Renal Disease (ESRD) Symptoms which needs permanent renal replacement therapies. Therefore, control the progression of CKD is necessary. In this study, based on the theory of Traditional Chinese Medicine and the Traditional Chinese Herbology, we developed the Kangshen Oral Solution based ona combination of different herbs for extraction. By utilizing adriamycin (ARD)-induced chronic renal failure in rats as the CKD model, our results demonstrated thatadministration of the Kangshen Oral Solution reduced the kidney disease induced weight loss in rats. The Kangshen Oral Solution could also relieve the proteinuria and kidney index induced by ARD which indicated the partially restoration of the kidney function. The improved kidney function was further supported by biochemical tests for blood total protein level, albumin level as well as cholesterol, triglycerides and Creatinine. Moreover, the histology examination also confirmed the ARD induced pathological changes in kidney was relieved by Kangshen Oral Solution. Taken together, these findings suggested Kangshen Oral solution could reduce ARD-induced nephropathy in rats model and may be employed as an alternative treatment for CKD patients. PMID:26885229

  6. Use of eculizumab in crescentic IgA nephropathy: proof of principle and conundrum?

    PubMed Central

    Ring, Troels; Pedersen, Birgitte Bang; Salkus, Giedrius; Goodship, Timothy H.J.

    2015-01-01

    IgA nephropathy (IgAN) is characterized by a variable clinical course and multifaceted pathophysiology. There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogenesis of the disease. Therefore, complement inhibition using the humanized anti-C5 monoclonal antibody eculizumab could be a rational treatment. We report here a 16-year-old male with the vasculitic form of IgAN who failed to respond to aggressive conventional therapy including high-dose steroids, cyclophosphamide and plasma exchange and who was treated with four weekly doses of 900 mg eculizumab followed by a single dose of 1200 mg. He responded rapidly to this treatment and has had a stable creatinine around 150 µmol/L (1.67 mg/dL) for >6 months. However, proteinuria was unabated on maximal conventional anti-proteinuric treatment, and a repeat renal biopsy 11 months after presentation revealed severe chronic changes. We believe this case provides proof of principle that complement inhibition may be beneficial in IgAN but also that development of chronicity may be independent of complement. PMID:26413271

  7. Use of eculizumab in crescentic IgA nephropathy: proof of principle and conundrum?

    PubMed

    Ring, Troels; Pedersen, Birgitte Bang; Salkus, Giedrius; Goodship, Timothy H J

    2015-10-01

    IgA nephropathy (IgAN) is characterized by a variable clinical course and multifaceted pathophysiology. There is substantial evidence to suggest that complement activation plays a pivotal role in the pathogenesis of the disease. Therefore, complement inhibition using the humanized anti-C5 monoclonal antibody eculizumab could be a rational treatment. We report here a 16-year-old male with the vasculitic form of IgAN who failed to respond to aggressive conventional therapy including high-dose steroids, cyclophosphamide and plasma exchange and who was treated with four weekly doses of 900 mg eculizumab followed by a single dose of 1200 mg. He responded rapidly to this treatment and has had a stable creatinine around 150 µmol/L (1.67 mg/dL) for >6 months. However, proteinuria was unabated on maximal conventional anti-proteinuric treatment, and a repeat renal biopsy 11 months after presentation revealed severe chronic changes. We believe this case provides proof of principle that complement inhibition may be beneficial in IgAN but also that development of chronicity may be independent of complement. PMID:26413271

  8. Increased production of interleukin-2 and IL-2 receptor in primary IgA nephropathy.

    PubMed

    Schena, F P; Mastrolitti, G; Jirillo, E; Munno, I; Pellegrino, N; Fracasso, A R; Aventaggiato, L

    1989-03-01

    The production of interleukin-2 (IL-2) by peripheral blood mononuclear cells (PBMC) in 13 patients with IgA nephropathy (IgAN) and 9 patients with chronic glomerulonephritis was investigated. Moreover, the distribution of IL-2 receptor (IL-2R) expression was studied in the purified T cell population versus the non-T cell population of IgAN patients. The results show a spontaneous significant production of IL-2 in cultures of PBMC from patients with IgAN (P less than 0.025) that increased after PHA stimulation. IgAN patients also had a significantly higher expression of IL-2R on the surface of PBMC than did patients with chronic glomerulonephritis (P less than 0.05). IL-2R was usually detected on unstimulated purified T cells that expressed the activation DR antigen. Moreover, a high number of DR helper T cells was associated to a reduced number of suppressor T cells (OKT8+M1+). These findings suggest that the increased production of IL-2 in patients with IgAN may be responsible for the increased activity of helper T cells. The high number of IL-2R expressed by freshly separated PBMC implies an in vivo continuous stimulation of these cells, and this finding is in agreement with the demonstrated spontaneous hyperproduction of IL-2. Moreover, the low number of suppressor T cells may contribute to the overactivity of helper T cells bearing IL-2R in IgAN patients. PMID:2785227

  9. Inhibition of adriamycin-induced nephropathy in rats by herbs based kangshenoral solution.

    PubMed

    Zhao, Jingsheng; Lin, Xinwei; Xiao, Xueqing; Yang, Jun; Liu, Hong; Yi, Weiguo; Zhang, Zhengchen; Zhang, Xinkuan

    2015-01-01

    The Chronic kidney disease (CKD) is characterized by the progressive loss in renal function over a period. The progression of CKD will finally result the End Stage Renal Disease (ESRD) Symptoms which needs permanent renal replacement therapies. Therefore, control the progression of CKD is necessary. In this study, based on the theory of Traditional Chinese Medicine and the Traditional Chinese Herbology, we developed the Kangshen Oral Solution based ona combination of different herbs for extraction. By utilizing adriamycin (ARD)-induced chronic renal failure in rats as the CKD model, our results demonstrated thatadministration of the Kangshen Oral Solution reduced the kidney disease induced weight loss in rats. The Kangshen Oral Solution could also relieve the proteinuria and kidney index induced by ARD which indicated the partially restoration of the kidney function. The improved kidney function was further supported by biochemical tests for blood total protein level, albumin level as well as cholesterol, triglycerides and Creatinine. Moreover, the histology examination also confirmed the ARD induced pathological changes in kidney was relieved by Kangshen Oral Solution. Taken together, these findings suggested Kangshen Oral solution could reduce ARD-induced nephropathy in rats model and may be employed as an alternative treatment for CKD patients. PMID:26885229

  10. Relationship between P-glycoprotein expression and cyclosporin A in kidney. An immunohistological and cell culture study.

    PubMed Central

    García del Moral, R.; O'Valle, F.; Andújar, M.; Aguilar, M.; Lucena, M. A.; López-Hidalgo, J.; Ramírez, C.; Medina-Cano, M. T.; Aguilar, D.; Gómez-Morales, M.

    1995-01-01

    P-glycoprotein (P-gp), encoded in humans by the mdr-1 gene, acts physiologically as an efflux pump to expel hydrophobic substances from cells. This glycoprotein is closely related to multidrug resistance in tumor cells and can be modulated by cyclosporin A (CsA). We investigated the relationship between CsA and P-gp in 52 renal allograft biopsies and in cultures of Madin-Darby canine kidney (MDCK) renal tubule cells to determine whether the intrarenal accumulation of CsA or chronic stimulation with the drug modified the expression of P-gp. Expression of P-gp and CsA was analyzed by immunohistochemistry. Immunostaining was evaluated semiquantitatively. Modulation of P-gp in MDCK cells after chronic stimulation with CsA for 7, 30, and 60 days was analyzed by flow cytometry. P-gp and CsA immunostaining in renal post-transplant biopsies showed considerable overlap in all cases (Spearman's test, r = 0.577, P < 0.001). After 7 days in vitro, the number of cells expressing P-gp increased progressively; a further increase in mean fluorescence was found after 60 days (P < 0.001, Student's t-test). Our findings suggest that in non-neoplastic cells, CsA may stimulate P-gp as a mechanism of detoxification. Individual differences in the adaptive responses to glycoprotein may be responsible for the appearance of nephrotoxicity or a CsA-resistant rejection reaction in cases of overexpression on lymphocytes and macrophages. Images Figure 1 PMID:7856751

  11. Urinary excretion of guanidinoacetic acid in rats with diabetic nephropathy.

    PubMed

    Kiyatake, I; Nakamura, T; Koide, H

    2006-01-01

    Urinary guanidinoacetic acid (GAA) is a sensitive marker for gentamicin nephrotoxicity in rats. This study assesses the usefulness of GAA concentrations in the diagnosis of renal tubular injury in diabetic nephropathy. Serum, urine, and renal cortex samples were obtained from rats 1, 2, and 3 weeks after streptozotocin injection (65 mg/kg body weight). Guanidinoacetic acid levels were measured by high-performance liquid chromatography. N-acetyl-beta-D-glucosaminidase (NAG) activity in urine was determined by an enzymatic method. GAA levels in serum, urine, and renal cortex were significantly decreased in diabetic rats compared with those in control rats. In contrast, urinary NAG activity was significantly increased in diabetic rats. Decreases in serum, urine, and renal cortical GAA levels were attenuated by insulin treatment. These results indicate that a high serum glucose level may affect GAA synthesis in the renal cortex and that urinary GAA may be a clinically useful indicator of renal tubular injury in diabetic nephropathy. PMID:16538977

  12. Nephropathy in youth and young adults with type 2 diabetes.

    PubMed

    Solis-Herrera, Carolina; Triplitt, Curtis L; Lynch, Jane L

    2014-02-01

    The occurrence and progression of nephropathy associated with early onset type 2 diabetes (T2D) is a consequence of the ongoing epidemic of childhood obesity. Minimal evidence regarding treatment effectiveness of renovascular comorbidities in youth with early onset T2D is available, due to the relatively recent emergence of T2D in youth and young adults. Extrapolation of adult therapy guidelines is not an ideal approach to making therapeutic decisions in this population. Evolving management and intervention strategies are based on accumulating longitudinal data from cohorts of well characterized youth and young adults with T2D. The degree of similarity in histologic findings and disease specific characteristics of kidney disease in patients with early onset T2D and albuminuria compared with affected adults is not well characterized. Early aggressive therapies to minimize the impact of nephropathy are indicated as the evidence for best therapies in youth with T2D are further explored. PMID:24398660

  13. Contrast-Induced Nephropathy: An "All or None" Phenomenon?

    PubMed

    Katsiki, Niki; Athyros, Vasilios G; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-07-01

    Contrast-induced nephropathy (CIN) represents an important adverse effect of contrast media (CM) administration. Contrast-induced nephropathy is associated with prolonged hospitalization as well as increased cardiovascular morbidity, renal morbidity, and all-cause mortality. Several risk factors may predict CIN incidence, and various scores and ratios have been proposed to identify high-risk patients. Novel biomarkers may provide an earlier diagnosis of CIN. A multifactorial approach is required for CIN prevention including hydration, administration of low- or iso-osmolar CM, minimizing CM volume, and statin administration. Renal function may deteriorate after CM administration, even in the absence of CIN. Therefore, this deterioration may not be an "all or none" phenomenon; it may well occur in many patients receiving CM, with/without CIN, and may prove to be an underestimated risk factor. Patients should be followed up for longer periods as outpatients after CM exposure to assess kidney function and predict subsequent increased morbidity and mortality. PMID:25225196

  14. [Mechanism of Chinese herbal medicine delaying glomerulosclerosis in diabetic nephropathy].

    PubMed

    Chen, Jing; Wan, Yigang; Bian, Rongwen; Gu, Liubao; Wang, Chaojun; Zhang, Huilan; Yao, Jian

    2010-02-01

    The pathomechanisms of glomerulosclerosis in diabetic nephropathy (DN) are considered to be related with glycometabolism disorder, podocyte injury, intra-renal hemodynamics abnormality, fibrogenic cytokines over-expression, oxidative stress and inflammatory reaction. Chinese herbal medicine could delay the progression of glomerulosclerosis in DN by ameliorating the harmful factors of these pathological changes. Therefore, it is possible to postpone the progress of DN to end-stage renal disease through the treatment with Chinese herbal medicine. PMID:20450059

  15. Aplastic anemia and membranous nephropathy induced by intravenous mercury

    PubMed Central

    Priya, N.; Nagaprabhu, V. N.; Kurian, G.; Seethalakshmi, N.; Rao, G. G.; Unni, V. N.

    2012-01-01

    Self-injection of mercury can be life-threatening. We report a case of attempted suicide by self-intravenous injection of elemental mercury. The patient suffered from two side effects : membranous nephropathy and aplastic anemia. She was treated and the systemic effects of mercury were reversed after 4 years. The toxicology of mercury, mechanisms of renal and systemic toxicities, and the various therapeutic measures for mercury poisoning are discussed. PMID:23439491

  16. Association of renal adenocarcinoma and BK virus nephropathy post transplantation.

    PubMed

    Kausman, Joshua Yehuda; Somers, Gino Rene; Francis, David Michael; Jones, Colin Lindsay

    2004-04-01

    While most BK virus infections are asymptomatic, immunosuppression has been associated with BK virus reactivation and impaired graft function or ureteric ulceration in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. Oncogenicity is also postulated and this is the first report of a child with a carcinoma of the donor renal pelvis following BK virus allograft nephropathy. Removal of the primary tumor and cessation of immunosuppression led to regression of secondary tumors and a return to health. PMID:14986088

  17. Chryseobacterium meningosepticum bacteremia in diabetic nephropathy patient on hemodialysis

    PubMed Central

    Dias, M.; Prashant, K.; Pai, R.; Scaria, B.

    2010-01-01

    The Chryseobacterium species are inhabitants of soil and water. In the hospital environment, they exist in water systems and wet surfaces. We report here a case of Chryseobacterium meningosepticum bacteremia in a diabetic nephropathy patient on hemodialysis. He was successfully treated with Vancomycin and ceftazidime for three weeks with good clinical outcome. This is the first case reported in dialysis patients from India. PMID:21206682

  18. Metabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms.

    PubMed

    Tonna, Stephen; El-Osta, Assam; Cooper, Mark E; Tikellis, Chris

    2010-06-01

    Many clinical studies have shown that intensive glycemic control in patients with diabetes can reduce the incidence and progression of diabetic nephropathy and can also reduce the incidence of other complications. These beneficial effects persist after patients return to usual (often worse) glycemic control. The Diabetes Control and Complications Trial was the first to refer to this phenomenon as 'metabolic memory'. Many patients with diabetes, however, still develop diabetic nephropathy despite receiving intensified glycemic control. Preliminary work in endothelial cells has shown that transient episodes of hyperglycemia can induce changes in gene expression that are dependent on modifications to histone tails (for example, methylation), and that these changes persist after return to normoglycemia. The persistence of such modifications cannot yet be fully explained, but certain epigenetic changes, as well as biochemical mechanisms such as advanced glycation, may provide new and interesting clues towards explaining the pathogenesis of this phenomenon. Further elucidation of the molecular events that enable prior glycemic control to result in end-organ protection in diabetes may lead to the development of new approaches for reducing the burden of diabetic nephropathy. PMID:20421885

  19. C1q Nephropathy: The Unique Underrecognized Pathological Entity.

    PubMed

    Devasahayam, Joe; Erode-Singaravelu, Gowrishankar; Bhat, Zeenat; Oliver, Tony; Chandran, Arul; Zeng, Xu; Dakshinesh, Paramesh; Pillai, Unni

    2015-01-01

    C1q nephropathy is a rare glomerular disease with characteristic mesangial C1q deposition noted on immunofluorescence microscopy. It is histologically defined and poorly understood. Light microscopic features are heterogeneous and comprise minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS), and proliferative glomerulonephritis. Clinical presentation is also diverse, and ranges from asymptomatic hematuria or proteinuria to frank nephritic or nephrotic syndrome in both children and adults. Hypertension and renal insufficiency at the time of diagnosis are common findings. Optimal treatment is not clear and is usually guided by the underlying light microscopic lesion. Corticosteroids are the mainstay of treatment, with immunosuppressive agents reserved for steroid resistant cases. The presence of nephrotic syndrome and FSGS appear to predict adverse outcomes as opposed to favorable outcomes in those with MCD. Further research is needed to establish C1q nephropathy as a universally recognized distinct clinical entity. In this paper, we discuss the current understanding of pathogenesis, histopathology, clinical features, therapeutic options, and outcomes of C1q nephropathy. PMID:26640759

  20. Involvement of glomerular SREBP-1c in diabetic nephropathy

    SciTech Connect

    Ishigaki, Naomi; Yamamoto, Takashi; Shimizu, Yoshio; Kobayashi, Kazuto; Yatoh, Shigeru; Sone, Hirohito; Takahashi, Akimitsu; Suzuki, Hiroaki; Yamagata, Kunihiro; Yamada, Nobuhiro; Shimano, Hitoshi

    2007-12-21

    The role of glomerular SREBP-1c in diabetic nephropathy was investigated. PEPCK-promoter transgenic mice overexpressing nuclear SREBP-1c exhibited enhancement of proteinuria with mesangial proliferation and matrix accumulation, mimicking diabetic nephropathy, despite the absence of hyperglycemia or hyperlipidemia. Isolated transgenic glomeruli had higher expression of TGF{beta}-1, fibronectin, and SPARC in the absence of marked lipid accumulation. Gene expression of P47phox, p67phox, and PU.1 were also activated, accompanying increased 8-OHdG in urine and kidney, demonstrating that glomerular SREBP-1c could directly cause oxidative stress through induced NADPH oxidase. Similar changes were observed in STZ-treated diabetic mice with activation of endogenous SREBP-1c. Finally, diabetic proteinuria and oxidative stress were ameliorated in SREBP-1-null mice. Adenoviral overexpression of active and dominant-negative SREBP-1c caused consistent reciprocal changes in expression of both profibrotic and oxidative stress genes in MES13 mesangial cells. These data suggest that activation of glomerular SREBP-1c could contribute to emergence and/or progression of diabetic nephropathy.

  1. Renal ACE immunohistochemical localization in NIDDM patients with nephropathy.

    PubMed

    Mizuiri, S; Yoshikawa, H; Tanegashima, M; Miyagi, M; Kobayashi, M; Sakai, K; Hayashi, I; Aikawa, A; Ohara, T; Hasegawa, A

    1998-02-01

    A role of renal angiotensin-converting enzyme (ACE) in diabetic nephropathy has been suggested. Immunohistochemical localization of ACE was studied in 20 non-insulin-dependent diabetes mellitus patients with diabetic nephropathy and 17 healthy kidney transplant donors, with ACE gene insertion/deletion (I/D) polymorphism also examined in the latter. Immunohistochemical studies indicated that ACE staining was significantly (P < 0.01) enhanced in glomeruli and slightly decreased in proximal tubules in diabetic patients. Glomeruli positive for ACE immunostaining were observed in 23.5% of the healthy subjects and in 80% of the diabetic patients. All patients with nodular lesions had ACE-positive glomeruli and showed significantly (P < 0.01) more intense glomerular ACE immunostaining than patients without nodular lesions. Among healthy controls, subjects with the DD genotype had ACE-positive glomeruli more frequently and tended to show slightly increased intensity on proximal tubule ACE immunostaining compared with subjects with other genotypes. These observations suggest that increased ACE localization in glomeruli is likely to be one of the factors in the increased renin-angiotensin system activity in glomeruli in patients with diabetic nephropathy. There is a possibility that ACE gene I/D polymorphism may be related to renal ACE immunohistochemical localization. PMID:9469501

  2. A Glimpse of Matrix Metalloproteinases in Diabetic Nephropathy

    PubMed Central

    Xu, X.; Xiao, L.; Xiao, P.; Yang, S.; Chen, G.; Liu, F.; Kanwar, Y.Y.; Sun, L.

    2014-01-01

    Matrix metalloproteinases (MMPs) are proteolytic enzymes belonging to the family of zinc-dependent endopeptidases that are capable of degrading almost all the proteinaceous components of the extracellular matrix (ECM). It is known that MMPs play a role in a number of renal diseases, such as, various forms of glomerulonephritis and tubular diseases, including some of the inherited kidney diseases. In this regard, ECM accumulation is considered to be a hallmark morphologic finding of diabetic nephropathy, which not only is related to the excessive synthesis of matrix proteins, but also to their decreased degradation by the MMPs. In recent years, increasing evidence suggest that there is a good correlation between the activity or expression of MMPs and progression of renal disease in patients with diabetic nephropathy in humans and in various experimental animal models. In such a diabetic milieu, the expression of MMPs is modulated by high glucose, advanced glycation end products (AGEs), TGF-β, reactive oxygen species (ROS), transcription factors and some of the microRNAs. In this review, we focused on the structure and functions of MMPs, and their role in the pathogenesis of diabetic nephropathy. PMID:25039784

  3. Role of upstream stimulatory factor 2 in diabetic nephropathy

    PubMed Central

    Wang, Shuxia

    2015-01-01

    Diabetic nephropathy (DN) is the most common cause of end-stage renal disease (ESRD). About 20%–30% of people with type 1 and type 2 diabetes develop DN. DN is characterized by both glomerulosclerosis with thickening of the glomerular basement membrane and mesangial matrix expansion, and tubulointerstitial fibrosis. Hyperglycemia and the activation of the intra-renal renin-angiotensin system (RAS) in diabetes have been suggested to play a critical role in the pathogenesis of DN. However, the mechanisms are not well known. Studies from our laboratory demonstrated that the transcription factor—upstream stimulatory factor 2 (USF2) is an important regulator of DN. Moreover, the renin gene is a downstream target of USF2. Importantly, USF2 transgenic (Tg) mice demonstrate a specific increase in renal renin expression and angiotensin II (AngII) levels in kidney and exhibit increased urinary albumin excretion and extracellular matrix deposition in glomeruli, supporting a role for USF2 in the development of diabetic nephropathy. In this review, we summarize our findings of the mechanisms by which diabetes regulates USF2 in kidney cells and its role in regulation of renal renin-angiotensin system and the development of diabetic nephropathy. PMID:26494984

  4. Climate Change and the Emergent Epidemic of CKD from Heat Stress in Rural Communities: The Case for Heat Stress Nephropathy.

    PubMed

    Glaser, Jason; Lemery, Jay; Rajagopalan, Balaji; Diaz, Henry F; García-Trabanino, Ramón; Taduri, Gangadhar; Madero, Magdalena; Amarasinghe, Mala; Abraham, Georgi; Anutrakulchai, Sirirat; Jha, Vivekanand; Stenvinkel, Peter; Roncal-Jimenez, Carlos; Lanaspa, Miguel A; Correa-Rotter, Ricardo; Sheikh-Hamad, David; Burdmann, Emmanuel A; Andres-Hernando, Ana; Milagres, Tamara; Weiss, Ilana; Kanbay, Mehmet; Wesseling, Catharina; Sánchez-Lozada, Laura Gabriela; Johnson, Richard J

    2016-08-01

    Climate change has led to significant rise of 0.8°C-0.9°C in global mean temperature over the last century and has been linked with significant increases in the frequency and severity of heat waves (extreme heat events). Climate change has also been increasingly connected to detrimental human health. One of the consequences of climate-related extreme heat exposure is dehydration and volume loss, leading to acute mortality from exacerbations of pre-existing chronic disease, as well as from outright heat exhaustion and heat stroke. Recent studies have also shown that recurrent heat exposure with physical exertion and inadequate hydration can lead to CKD that is distinct from that caused by diabetes, hypertension, or GN. Epidemics of CKD consistent with heat stress nephropathy are now occurring across the world. Here, we describe this disease, discuss the locations where it appears to be manifesting, link it with increasing temperatures, and discuss ongoing attempts to prevent the disease. Heat stress nephropathy may represent one of the first epidemics due to global warming. Government, industry, and health policy makers in the impacted regions should place greater emphasis on occupational and community interventions. PMID:27151892

  5. A Patient with Refractory Psoriasis Who Developed Sebaceous Carcinoma on the Neck during Cyclosporine Therapy and Showed Rapid Progression

    PubMed Central

    Shima, Tomoko; Yamamoto, Yuki; Okuhira, Hisako; Mikita, Naoya; Furukawa, Fukumi

    2016-01-01

    We report a patient who developed sebaceous carcinoma on the neck during therapy with immunosuppressive agents (cyclosporine, corticosteroid, methotrexate) for refractory psoriasis vulgaris, which showed rapid enlargement, leading to a fatal outcome. Multiple-organ metastases were detected. Weekly carboplatin + paclitaxel therapy resulted in the disappearance of tumor cells, but the patient died of febrile neutropenia. The development of sebaceous carcinoma is rare among psoriasis patients receiving immunosuppressive agents including cyclosporine. PMID:27462222

  6. Atypical dissemination of the highly neurotropic Borna disease virus during persistent infection in cyclosporine A-treated, immunosuppressed rats.

    PubMed Central

    Stitz, L; Schilken, D; Frese, K

    1991-01-01

    In adult rats infected with Borna disease virus, the virus was found exclusively in the brain, whereas in cyclosporine A-treated rats, infectious virus was also detected in peripheral nerve fibers and, unexpectedly, in adjacent organ-specific cells. In contrast to untreated virus-infected rats, no major histocompatibility complex class II expression was found in the brain of cyclosporine A-treated animals. Images PMID:1985209

  7. A Patient with Refractory Psoriasis Who Developed Sebaceous Carcinoma on the Neck during Cyclosporine Therapy and Showed Rapid Progression.

    PubMed

    Shima, Tomoko; Yamamoto, Yuki; Okuhira, Hisako; Mikita, Naoya; Furukawa, Fukumi

    2016-01-01

    We report a patient who developed sebaceous carcinoma on the neck during therapy with immunosuppressive agents (cyclosporine, corticosteroid, methotrexate) for refractory psoriasis vulgaris, which showed rapid enlargement, leading to a fatal outcome. Multiple-organ metastases were detected. Weekly carboplatin + paclitaxel therapy resulted in the disappearance of tumor cells, but the patient died of febrile neutropenia. The development of sebaceous carcinoma is rare among psoriasis patients receiving immunosuppressive agents including cyclosporine. PMID:27462222

  8. Cyclosporine A affects the in vitro expression of T cell activation-related molecules and cytokines in dogs.

    PubMed

    Fellman, C L; Stokes, J V; Archer, T M; Pinchuk, L M; Lunsford, K V; Mackin, A J

    2011-04-15

    Cyclosporine is a powerful immunosuppressive drug that is being used with increasing frequency to treat a wide range of immune-mediated diseases in the dog. To date, ideal dosing protocols that will achieve immunosuppression with cyclosporine in dogs remain unclear, and standard methods that can measure effectiveness of immunosuppression have not been established. The aim of our study was to evaluate the effects of in vitro cyclosporine exposure on a panel of molecules expressed by activated T cells to ascertain their potential as biomarkers of immunosuppression in dogs. Blood was drawn from six healthy dogs, and peripheral blood mononuclear cells (PBMC) were isolated and activated. Half of the cells were incubated with 200 ng/mL cyclosporine prior to activation, and the other half were not exposed to cyclosporine. Samples were analyzed using flow cytometry, and the expression of intracellular cytokines IL-2, IL-4, and IFN-γ was evaluated after 6, 12, and 24h of drug exposure. Each cytokine exhibited a time-dependent suppression profile, and all but two samples activated in the presence of cyclosporine showed lower cytokine expression than untreated controls. We also evaluated the expression of the surface T cell activation molecules CD25 and CD95 by flow cytometry after 36 h of drug exposure. Expression of these surface molecules decreased significantly when activated in the presence of cyclosporine. Our results suggest that suppressed expression of the markers related to T cell activation could potentially be utilized as an indicator of the efficacy of cyclosporine therapy in dogs. PMID:21227512

  9. Endothelial Cell Autoantibodies in Predicting Declining Renal Function, End-Stage Renal Disease, or Death in Adult Type 2 Diabetic Nephropathy

    PubMed Central

    Zimering, Mark B.; Zhang, Jane H.; Guarino, Peter D.; Emanuele, Nicholas; McCullough, Peter A.; Fried, Linda F.

    2014-01-01

    Albuminuria is a strong predictor of diabetic nephropathy chronic kidney disease outcomes. Yet, therapeutic albuminuria-lowering has not consistently translated into a reduction in clinical events suggesting the involvement of additional pathogenic factors. Our hypothesis is that anti-endothelial cell autoantibodies play a role in development and progression in diabetic nephropathy. We determined anti-endothelial cell antibody (AECA) bioactivity in protein A-elutes of baseline plasma in 305 participants in the VA NEPHRON-D study, a randomized trial of angiotensin receptor blocker (ARB) or dual ARB plus angiotensin-converting enzyme inhibitor therapy in type 2 diabetes with proteinuric nephropathy. Thirty-eight percent (117/305) of participants had significantly reduced endothelial cell survival ( ≤80%) in the IgG fraction of plasma. A VA NEPHRON-D primary endpoint [end-stage renal disease (ESRD), significant reduction in estimated glomerular filtration rate, or death] was experienced by 58 individuals. In adjusted Cox regression analysis, there was a significant interaction effect of baseline anti-endothelial cell-mediated cell survival and albuminuria on the hazard rate (HR) for primary composite endpoint (P = 0.017). Participants lacking strongly inhibitory antibodies with albuminuria ≥1 g/g creatinine had a significantly increased primary event hazard ratio, 3.41 – 95% confidence intervals (CI 1.84–6.33; P < 0.001) compared to those lacking strongly inhibitory antibodies with lower baseline albuminuria ( <1 g/g creatinine). These results suggest that anti-endothelial cell antibodies interact significantly with albuminuria in predicting the composite endpoint of death, ESRD, or substantial decline in renal function in older, adult type 2 diabetic nephropathy. PMID:25157242

  10. FTO modulates fibrogenic responses in obstructive nephropathy

    PubMed Central

    Wang, Chao-Yung; Shie, Shian-Sen; Tsai, Ming-Lung; Yang, Chia-Hung; Hung, Kuo-Chun; Wang, Chun-Chieh; Hsieh, I-Chang; Wen, Ming-Shien

    2016-01-01

    Genome-wide association studies have shown that variants in fat mass and obesity-associated (FTO) gene are robustly associated with body mass index and obesity. These FTO variants are also associated with end stage renal disease and all-cause mortality in chronic kidney diseases. However, the exact role of FTO in kidneys is currently unknown. Here we show that FTO expression is increased after ureteral obstruction and renal fibrosis. Deficiency of the FTO gene attenuates the fibrogenic responses induced by ureteral obstruction in the kidney. Renal tubular cells deficient of FTO produce less α-SMA after TGF-β stimulation. FTO is indispensable for the extracellular matrix synthesis after ureteral obstruction in kidneys. Indeed, global gene transcriptions amplitude is reduced in FTO deficient kidneys after ureteral obstruction. These data establish the importance of FTO in renal fibrosis, which may have potential therapeutic implications. PMID:26727661

  11. The Spectrum of MYH9-Associated Nephropathy

    PubMed Central

    Bostrom, Meredith A.; Freedman, Barry I.

    2016-01-01

    Causes of the excess incidence rates of chronic kidney disease in the African American population have long been under study. Recently, polymorphisms in the nonmuscle myosin heavy chain 9 gene (MYH9) have been associated with nondiabetic kidney diseases in African- and European-derived populations. Risk variants in MYH9 contribute to approximately 70% of nondiabetic forms of ESRD in African Americans and 40 to 45% of all ESRD in this ethnic group, with lesser effects in European Americans. It is clear that MYH9 polymorphisms have a significant impact on the incidence rates of kidney disease in African Americans. This article describes the current spectrum of biopsy-proven MYH9-associated kidney diseases, along with potential effects of MYH9 on ethnic differences in clinical outcome. MYH9 risk variants exhibit the most impressive association with any common complex kidney disease yet identified. PMID:20299374

  12. Methotrexate and Cyclosporine Treatments Modify the Activities of Dipeptidyl Peptidase IV and Prolyl Oligopeptidase in Murine Macrophages

    PubMed Central

    Olivo, R. A.; Nascimento, N. G.; Teixeira, C. F. P.; Silveira, P. F.

    2008-01-01

    Analysis of the effects of cyclosporine A (25–28 mgkg−1) and/or methotrexate (0.1 mgkg−1) treatments on dipeptidyl peptidase IV (DPPIV) and prolyl oligopeptidase (POP) activities and on algesic response in two distinct status of murine macrophages (Mφs) was undertaken. In resident Mφs, DPPIV and POP were affected by neither individual nor combined treatments. In thioglycolate-elicited Mφs, methotrexate increased DPPIV (99–110%) and POP (60%), while cyclosporine inhibited POP (21%). Combined treatment with both drugs promoted a rise (51–84%) of both enzyme activities. Only cyclosporine decreased (42%) the tolerance to algesic stimulus. Methotrexate was revealed to exert prevalent action over that of cyclosporine on proinflammatory Mφ POP. The opposite effects of methotrexate and cyclosporine on POP activity might influence the availability of the nociceptive mediators bradykinin and substance P in proinflammatory Mφs. The exacerbated response to thermally induced algesia observed in cyclosporine-treated animals could be related to upregulation of those mediators. PMID:18354729

  13. Severe Intimal Thickening of Interlobular Arteries Revealed by a Renal Biopsy in an Adult with Prader-Willi Syndrome Complicated by IgA Nephropathy.

    PubMed

    Ito, Takayasu; Ishikawa, Eiji; Fujimoto, Mika; Murata, Tomohiro; Yamada, Norikazu; Ito, Masaaki

    2016-01-01

    Renal complications are rare in patients with Prader-Willi syndrome (PWS). We herein experienced a 31-year-old woman with PWS, in whom a renal biopsy showed IgA nephropathy and severe intimal thickening of the interlobular arteries. The patient was admitted to our hospital due to proteinuria and microscopic hematuria after an upper respiratory infection. The occurrence of cardiovascular events has been reported as a cause of death in obese PWS patients. Because chronic kidney disease is generally a risk factor for cardiovascular disease, early detection checkups are essential in obese PWS patients to monitor the possible development of cardiovascular disease. PMID:26781016

  14. Cyclosporine in the management of impetigo herpetiformis: a case report and review of the literature.

    PubMed

    Patsatsi, Aikaterini; Theodoridis, Theodoros D; Vavilis, Dimitrios; Tzevelekis, Vasilios; Kyriakou, Aikaterini; Kalabalikis, Dimitrios; Sotiriadis, Dimitrios

    2013-01-01

    A 27-year-old female, gravida 1, para 0, in week 22 of pregnancy, presented with an eruption consisting of annular erythematosquamous plaques with an active polycyclic elevated border comprised of superficial micropustules. Clinical and histological features were typical of impetigo herpetiformis (IH). Systemic steroids resulted in an unstable condition, with no resolution of lesions. Resistance to the above therapeutic scheme served as a stimulus to discuss the use of cyclosporine as a therapeutic option in this condition. Reviewing the limited literature, cyclosporine seems to serve not as a monotherapy in the management of IH but as an additional medication, in order to achieve a stable course of the disease and avoid high doses of systemic steroids. PMID:23626548

  15. [Hair-like hyperkeratoses in patients with kidney transplants. A new cyclosporin side-effect].

    PubMed

    Izakovic, J; Büchner, S A; Düggelin, M; Guggenheim, R; Itin, P H

    1995-12-01

    We report a 31-year-old renal transplant patient treated with cyclosporin A who developed an unusual sebaceous gland hyperplasia accompanied by a disseminated follicular spiny hyperkeratosis. Those alterations were most evident on his face and limbs. In some locations hairy hyperkeratosis with authentic hair neogenesis was found. The histology of these alterations showed a marked hyperkeratosis of the hair follicles with formation of hair-like spikes either alone or in connection with hairs. The presence of true hairs distinguishes our case from the morphologically similar disseminated spiked hyperkeratosis and other spiny keratinization disorders. Scanning electron microscopy helped to demonstrate the hair-like structure of these keratoses. Some of the sebaceous glands showed cystic widening of their lumina, which were filled with abundant amorphous eosinophilic material, a finding similar to earlier observations. Our case demonstrates that these skin alterations should be classified as side effects of cyclosporin A and that they are apparently dose-dependent. PMID:8567267

  16. The influence of cyclosporin A on experimental autoimmune thyroid disease in the rat

    SciTech Connect

    McGregor, A.M.; Rennie, D.P.; Weetman, A.P.; Hassman, R.A.; Foord, S.M.; Dieguez, C.; Hall, R.

    1983-01-01

    Female PVG/c rats, thymectomised on weaning and given 4 courses of whole body irradiation to a total dose of 1000 rads, developed experimental autoimmune thyroid disease (EAITD) as assessed by histological evidence of thyroiditis and circulating levels of antithyroglobulin antibodies. Hypothyroidism resulted. Induction of the disease was associated with a highly significant fall in T lymphocyte numbers. Eight weeks after their last dose of irradiation the animals commenced treatment with cyclosporin A (10 mg/kg rat/day, intragastrically) and were treated for varying time intervals thereafter. The reversal of the T lymphocyte helper: suppressor ratio on cyclosporin A therapy was associated with a significant improvement in the disease process. The alterations in the T cell subsets and in the disease lasted only as long as the drug was administered and thereafter reverted towards that seen in the control groups of animals receiving no treatment.

  17. Tacrolimus Versus Cyclosporine as Primary Immunosuppressant After Renal Transplantation: A Meta-Analysis and Economics Evaluation.

    PubMed

    Liu, Jin-Yu; You, Ru-Xu; Guo, Min; Zeng, Lu; Zhou, Pu; Zhu, Lan; Xu, Gang; Li, Juan; Liu, Dong

    2016-01-01

    Tacrolimus and cyclosporine are the major immunosuppressants for renal transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this study was to evaluate the efficacy, safety, and pharmacoeconomics of cyclosporine and tacrolimus in the treatment of renal transplantation and provide evidence for the selection of essential drugs. Trials were identified through a computerized literature search of PubMed, EMBASE, Cochrane Controlled Trials Register, Cochrane Renal Group Specialized Register of randomized controlled trials, and Chinese Biomedical database. Two independent reviewers assessed trials for eligibility and quality and then extracted data. Data were extracted for patient and graft mortality, acute rejection, and adverse events. Dichotomous outcomes were reported as relative risk with 95% confidence intervals. A decision tree model was populated with data from a literature review and used to estimate costs and quality-adjusted life years gained and incremental cost-effectiveness. Altogether, 6137 patients from 27 randomized controlled trials were included. The results of our analysis were that tacrolimus reduced the risks after renal transplantation of patient mortality, graft loss, acute rejection, and hypercholesterolemia. Nevertheless, tacrolimus increased the risk of new-onset diabetes. Pharmacoeconomic analysis showed that tacrolimus represented a more cost-effective treatment than does cyclosporine for the prevention of adverse events following renal transplant. Tacrolimus is an effective and safe immunosuppressive agent and it may be more cost-effective than cyclosporine for the primary prevention of graft rejection in renal transplant recipients. However, new-onset diabetes should be closely monitored during the medication period. PMID:25299636

  18. Topical cyclosporin stimulates neovascularization in resolving sterile rheumatoid central corneal ulcers.

    PubMed Central

    Gottsch, J D; Akpek, E K

    2000-01-01

    OBJECTIVE: To report the successful use of topical cyclosporin for treatment of central sterile corneal ulcers associated with rheumatoid disease. DESIGN: Retrospective, noncomparative case series. PARTICIPANTS/INTERVENTION: Five patients (7 eyes) with collagen vascular disorders presented with central, sterile corneal ulcers. An extensive medical evaluation did not reveal active underlying rheumatoid disease in any patient. Inadequate clinical response with use of topical steroids and lubricants led to corneal perforations requiring multiple tectonic procedures. Systemic immunosuppressive therapy either could not be initiated owing to a systemic contraindication or was discontinued owing to intolerance and side effects. The patients were ultimately treated with topical cyclosporin. RESULTS: Six of the 7 eyes responded favorably. An intense limbal vascularization began within 48 hours of treatment. The neovascularization progressed centrally with the simultaneous arresting of epithelial and stromal ulceration. Over a 2-week period, re-epithelization occurred with vascularization proceeding throughout the cornea. After several months, the corneal vessels attenuated, and all signs of inflammation subsided. Intrastromal bleeding with corneal blood staining occurred in 1 patient; this resolved over several months. No recurrences of corneal ulceration occurred in a mean follow-up period of 28 months (range, 7 to 60 months). None of the 5 patients have had a reactivation of their rheumatoid disease in the follow-up period. CONCLUSION: The clinical response in these patients contrasts with previous animal studies demonstrating an anti-angiogenic property of cyclosporin. We report that an immediate intense neovascularization is the first sign of a favorable clinical response. Treatment with topical cyclosporin alone may be considered in patients with sterile corneal ulcers associated with rheumatoid disease in the absence of systemic activation. Images FIGURE 1 FIGURE 2

  19. Anorexia nervosa in a pediatric renal transplant recipient and its reversal with cyclosporine.

    PubMed

    Okechuku, Gyongyi; Boulos, Andrew K; Herman, Lettie; Upadhyay, Kiran

    2015-05-01

    We report a 16-yr-old female who developed AN within a month after renal transplantation and its resolution after switching from tacrolimus to cyclosporine. Her initial maintenance immunosuppressive regimen after renal transplantation consisted of tacrolimus, mycophenolate, and steroid. She had 7 kg weight loss within the first month of transplant with subsequent 10, 12, 17, and 19 kg loss after three, five, seven, and nine months of transplant, respectively. Besides weight loss and disturbances in body image, the patient developed alopecia, bradycardia, and persistent secondary amenorrhea. Upon switching to cyclosporine from tacrolimus nine months after transplant, she started regaining weight with 5 kg gain within two months and 10 kg after four months. She restarted her menstrual cycle, alopecia and bradycardia resolved, and her body image disturbance improved. Here, we describe a very unusual neuropsychiatric side effect of tacrolimus and its resolution with another calcineurin inhibitor, cyclosporine, in an adolescent renal transplant recipient. PMID:25661468

  20. Localization of gingival overgrowth in heart transplant patients undergoing cyclosporin therapy.

    PubMed

    Somacarrera, M L; Hernández, G; Acero, J; Moskow, B S

    1994-07-01

    This research was aimed at determining and comparing the pattern of localization of both cyclosporin-induced gingival overgrowth and associated periodontal variables in heart transplant patients. Thirty-nine patients undergoing cyclosporin treatment were studied for 6 months following transplant surgery. Oral hygiene and gingivitis were evaluated using the Silness-Löe and Löe-Silness indices. Gingival overgrowth was measured using a periodontal probe to determine the height of the gingiva at six points per tooth. Statistical hypothesis testing was applied to calculate the significance of the results. Overgrowth average showed a steady and significant growth. The graphs depicting average overgrowth localization, "standard periodontograms," showed remarkable symmetry, and a significantly anterior mandibular papillary distribution. No overgrowth was observed in edentulous areas. The localization of plaque and gingivitis followed a similar pattern; a highly significant correlation was found with the overgrowth localization pattern. It was concluded that the elimination of plaque is an important preventive measure for cyclosporin-induced gingival overgrowth, and that tooth or periodontium related factors have a significant impact on its pathogenesis. PMID:7608842

  1. Cyclosporin A and tissue antigen matching in bone transplantation. Fibular allografts studied in the dog.

    PubMed

    Welter, J F; Shaffer, J W; Stevenson, S; Davy, D T; Field, G A; Klein, L; Li, X Q; Zika, J M; Goldberg, V M

    1990-12-01

    We studied the mechanical, metabolic, and histologic properties of short-term nonvascularized cortical bone grafts in a canine fibular graft model. Sham operated nonvascularized autotransplanted and allotransplanted bones were compared. The allografts were performed between dog leukocyte antigen (DLA) class I and II matched; DLA class I and II mismatched; and cyclosporin A (CsA) treated, DLA class I and II mismatched animals. Cyclosporin was given for 1 month, and all the animals were followed for 3 months after surgery. Mechanical properties were investigated using standard torsional tests, metabolic kinetics were assessed using isotopic prelabeling techniques, and histomorphometric analysis of cross-sectional area properties and sequential fluorochrome labels were performed. Autografts were mechanically stronger and stiffer than all the types of allograft. CsA-treated, DLA-mismatched allografts performed better than matched allografts. These in turn were stronger than non-CsA-treated, mismatched allografts, which underwent nearly complete resorption. These relationships were preserved in the metabolic and histologic analyses. In this short-term animal study, although DLA matching resulted in a slight improvement in graft outcome, mismatched grafts in dogs receiving a short course of cyclosporin A fared even better. PMID:2281759

  2. Development and characterization of mucoadhesive chitosan films for ophthalmic delivery of cyclosporine A.

    PubMed

    Hermans, Kris; Van den Plas, Dave; Kerimova, Sabina; Carleer, Robert; Adriaensens, Peter; Weyenberg, Wim; Ludwig, Annick

    2014-09-10

    Ocular chitosan films were prepared in order to prolong ocular delivery of cyclosporine A. The mucoadhesive films were prepared using the solvent casting evaporation method. A 2(4) full factorial design was used to evaluate the effect of 4 preparation parameters on the film thickness, swelling index and mechanical properties. Moreover, uniformity of content and in vitro drug release were investigated. Possible interactions between the film excipients were studied by FTIR analysis. In vitro experiments were performed in order to evaluate the cytotoxicity and anti-inflammatory activity of the chitosan films. Film thickness, water uptake, mechanical properties and in vitro release of cyclosporine A were dependent on film composition, especially on the amount of plasticizer. Lower drug release was measured from chitosan films containing a higher amount of plasticizer as glycerol decreased the swelling of chitosan films. FTIR spectra suggest a reorganization of hydrogen bonds between chitosan chains in the presence of glycerol and cyclodextrins. None of the film formulations showed significant cytotoxicity as compared to the negative control using human epithelial cells (HaCaT). Cyclosporine A dispersed in the various film formulations remained anti-inflammatorily active as significant suppression of interleukin-2 secretion in concanavalin A stimulated Jurkat T cells was measured. PMID:24929014

  3. Effect of Cyclosporin A on the Uptake of D3-Selective PET Radiotracers in Rat Brain

    PubMed Central

    Tu, Zhude; Li, Shihong; Xu, Jinbin; Chu, Wenhua; Jones, Lynne A.; Luedtke, Robert R.; Mach, Robert H.

    2011-01-01

    Introduction Four benzamide analogs having a high affinity and selectivity for D3 versus D2 receptors were radiolabeled with 11C or 18F for in vivo evaluation. Methods Precursors were synthesized and the four D3 selective benzamide analogs were radiolabeled. The tissue distribution and brain uptake of the four compounds were evaluated in control rats and rats pretreated with cyclosporin A, a modulator of P-glycoprotein and an inhibitor of other ABC efflux transporters that contribute to the blood brain barrier. MicroPET imaging was carried out for [11C]6 in a control and a cyclosporin A pre-treated rat. Results All four compounds showed low brain uptake in control rats at 5 and 30 min post-injection; despite recently reported rat behavioral studies conducted on analogs 6 (WC-10) and 7 (WC-44). Following administration of cyclosporin A, increased brain uptake was observed with all four PET radiotracers at both 5 and 30 min post-i.v. injection. An increase in brain uptake following modulation/inhibition of the ABC transporters was also observed in the microPET study. Conclusions These data suggest that D3 selective conformationally-flexible benzamide analogs which contain a N-2-methoxyphenylpiperazine moiety are substrates for P-glycoprotein or other ABC transporters expressed at the blood-brain barrier, and that PET radiotracers containing this pharmacophore may display low brain uptake in rodents due to the action of these efflux transporters. PMID:21718948

  4. Cyclosporine A: Novel concepts in its role in drug-induced gingival overgrowth

    PubMed Central

    Ponnaiyan, Deepa; Jegadeesan, Visakan

    2015-01-01

    Cyclosporine is a selective immunosuppressant that has a variety of applications in medical practice. Like phenytoin and the calcium channel blockers, the drug is associated with gingival overgrowth. This review considers the pharmacokinetics, pharmacodynamics, and unwanted effects of cyclosporine, in particular the action of the drug on the gingival tissues. In addition, elucidates the current concepts in mechanisms of cyclosporine-induced gingival overgrowth. Clinical and cell culture studies suggest that the mechanism of gingival overgrowth is a result of the interaction between the drug and its metabolites with susceptible gingival fibroblasts. Plaque-induced gingival inflammation appears to enhance this interaction. However, understanding of the pathogenesis of gingival overgrowth is incomplete at best. Hence, it would be pertinent to identify and explore possible risk factors relating to both prevalence and severity of drug-induced gingival overgrowth. Newer molecular approaches are needed to clearly establish the pathogenesis of gingival overgrowth and to provide novel information for the design of future preventive and therapeutic modalities. PMID:26759584

  5. FAT1 mutations cause a glomerulotubular nephropathy

    PubMed Central

    Gee, Heon Yung; Sadowski, Carolin E.; Aggarwal, Pardeep K.; Porath, Jonathan D.; Yakulov, Toma A.; Schueler, Markus; Lovric, Svjetlana; Ashraf, Shazia; Braun, Daniela A.; Halbritter, Jan; Fang, Humphrey; Airik, Rannar; Vega-Warner, Virginia; Cho, Kyeong Jee; Chan, Timothy A.; Morris, Luc G. T.; ffrench-Constant, Charles; Allen, Nicholas; McNeill, Helen; Büscher, Rainer; Kyrieleis, Henriette; Wallot, Michael; Gaspert, Ariana; Kistler, Thomas; Milford, David V.; Saleem, Moin A.; Keng, Wee Teik; Alexander, Stephen I.; Valentini, Rudolph P.; Licht, Christoph; Teh, Jun C.; Bogdanovic, Radovan; Koziell, Ania; Bierzynska, Agnieszka; Soliman, Neveen A.; Otto, Edgar A.; Lifton, Richard P.; Holzman, Lawrence B.; Sibinga, Nicholas E. S.; Walz, Gerd; Tufro, Alda; Hildebrandt, Friedhelm

    2016-01-01

    Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function. PMID:26905694

  6. FAT1 mutations cause a glomerulotubular nephropathy.

    PubMed

    Gee, Heon Yung; Sadowski, Carolin E; Aggarwal, Pardeep K; Porath, Jonathan D; Yakulov, Toma A; Schueler, Markus; Lovric, Svjetlana; Ashraf, Shazia; Braun, Daniela A; Halbritter, Jan; Fang, Humphrey; Airik, Rannar; Vega-Warner, Virginia; Cho, Kyeong Jee; Chan, Timothy A; Morris, Luc G T; ffrench-Constant, Charles; Allen, Nicholas; McNeill, Helen; Büscher, Rainer; Kyrieleis, Henriette; Wallot, Michael; Gaspert, Ariana; Kistler, Thomas; Milford, David V; Saleem, Moin A; Keng, Wee Teik; Alexander, Stephen I; Valentini, Rudolph P; Licht, Christoph; Teh, Jun C; Bogdanovic, Radovan; Koziell, Ania; Bierzynska, Agnieszka; Soliman, Neveen A; Otto, Edgar A; Lifton, Richard P; Holzman, Lawrence B; Sibinga, Nicholas E S; Walz, Gerd; Tufro, Alda; Hildebrandt, Friedhelm

    2016-01-01

    Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease (CKD). Here we show that recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of SRNS, tubular ectasia, haematuria and facultative neurological involvement. Loss of FAT1 results in decreased cell adhesion and migration in fibroblasts and podocytes and the decreased migration is partially reversed by a RAC1/CDC42 activator. Podocyte-specific deletion of Fat1 in mice induces abnormal glomerular filtration barrier development, leading to podocyte foot process effacement. Knockdown of Fat1 in renal tubular cells reduces migration, decreases active RAC1 and CDC42, and induces defects in lumen formation. Knockdown of fat1 in zebrafish causes pronephric cysts, which is partially rescued by RAC1/CDC42 activators, confirming a role of the two small GTPases in the pathogenesis. These findings provide new insights into the pathogenesis of SRNS and tubulopathy, linking FAT1 and RAC1/CDC42 to podocyte and tubular cell function. PMID:26905694

  7. Polyoma (BK) virus associated urothelial carcinoma originating within a renal allograft five years following resolution of polyoma virus nephropathy.

    PubMed

    Salvatore, Steven P; Myers-Gurevitch, Patricia M; Chu, Stacy; Robinson, Brian D; Dadhania, Darshana; Seshan, Surya V

    2016-03-01

    A direct role for BK polyomavirus infection in malignant tumors of renal allografts and urinary tract is emerging. Case reports suggest a link between BK virus (BKV) reactivation and development of malignancy in renal allograft recipients. Herein we describe the first case of BKV positive invasive urothelial carcinoma within the renal allograft, presenting with chronic diarrhea and weight loss 5 years following resolution of BK viremia/nephropathy (BKVN). Unique to our case was the remote history of BK viremia/BKVN, rising titer of anti-HLA antibody and presence of renal limited urothelial carcinoma with microinvasion of malignant cells staining positive for SV40 large T antigen (T-Ag). These findings suggest that persistence of subclinical BKV infection within the renal allograft may play a role in the malignant transformation of epithelial cells. Patients with history of BKVN may be at risk for kidney and urinary tract malignancy despite resolution of BK viremia/BKVN. PMID:26709521

  8. Is Collapsing C1q Nephropathy Another MYH9-Associated Kidney Disease? A Case Report

    PubMed Central

    Reeves-Daniel, Amber M.; Iskandar, Samy S.; Bowden, Donald W.; Bostrom, Meredith A.; Hicks, Pamela J.; Comeau, Mary E.; Langefeld, Carl D.; Freedman, Barry I.

    2009-01-01

    C1q nephropathy is a rare kidney disease that can present with nephrotic syndrome and typically has the histological phenotype of either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Disagreement exists as to whether it is a distinct immune complex-mediated glomerulopathy or whether it resides in the spectrum of FSGS-MCD. Two African American patients with C1q nephropathy histologically presenting as the collapsing variant of FSGS (collapsing C1q nephropathy) and rapid loss of kidney function were genotyped for polymorphisms in the non-muscle myosin heavy chain 9 gene (MYH9). Both cases were homozygous for the MYH9 E1 risk haplotype; the variant strongly associated with idiopathic FSGS, collapsing FSGS in Human Immunodeficiency Virus-associated nephropathy and focal global glomerulosclerosis (historically attributed to hypertensive nephrosclerosis). Collapsing C1q nephropathy with rapid progression to ESRD appears to reside in the MYH9-associated disease spectrum. PMID:20116156

  9. Historical chronology of basic and clinical research in diabetic nephropathy and contributions of Japanese scientists.

    PubMed

    Wada, Jun; Makino, Hirofumi

    2009-10-01

    The most problematic issue in clinical nephrology worldwide is the relentless and progressive increase in patients with end-stage renal disease (ESRD). Diabetic nephropathy has considerable impact on society in the areas of public health and social economy; many scientists are involved in research for the elucidation of the pathogenesis of diabetic nephropathy and for the prevention and cure of the disease. In contrast, diabetic nephropathy was a neglected or ignored disease in the historical era, and few dedicated physicians recognized the disease process of diabetic nephropathy. In this review, we look back on the history of basic and clinical research on diabetic nephropathy and survey the recent progress of the research, especially focusing on the contribution of Japanese scientists. PMID:19363645

  10. [Ultrasound and color Doppler applications in chronic kidney disease].

    PubMed

    Meola, Mario; Petrucci, Ilaria

    2012-01-01

    Chronic kidney disease (CKD) encompasses all clinical features and complications during the progression of various kidney conditions towards end-stage renal disease. These conditions include immune and inflammatory diseases such as primary and HCV-related glomerulonephritis; infectious diseases such as pyelonephritis with or without reflux and tuberculosis; vascular diseases such as chronic ischemic nephropathy; hereditary and congenital diseases such as polycystic disease and congenital cystic dysplasia; metabolic diseases including diabetes and hyperuricemia; and systemic diseases (collagen disease, vasculitis, myeloma). During the progression of CKD, ultrasound imaging can differentiate the nature of the renal damage in only 50-70% of cases. Infact, the end-stage kidney appears shrunken, reduced in volume (Ø <9 cm), unstructured, amorphous, with acquired cystic degeneration (small and multiple cysts involving the cortex and medulla) or nephrocalcinosis, but there are rare exceptions, such as polycystic kidney disease, diabetic nephropathy, and secondary inflammatory nephropathies. The main difficulties in the differential diagnosis are encountered in multifactorial CKD, which is commonly presented to the nephrologist at stage 4-5, when the kidney is shrunken, unstructured and amorphous. As in acute renal injury and despite the lack of sensitivity, ultrasonography is essential for assessing the progression of the renal damage and related complications, and for evaluating all conditions that increase the risk of CKD, such as lithiasis, recurrent urinary tract infections, vesicoureteral reflux, polycystic kidney disease and obstructive nephropathy. The timing and frequency of ultrasound scans in CKD patients should be evaluated case by case. In this review we will consider the morphofunctional features of the kidney in all nephropathies that may lead to progressive CKD. PMID:23229668

  11. Measurement of cyclosporine concentrations in whole blood: HPLC and radioimmunoassay with a specific monoclonal antibody and /sup 3/H- or /sup 125/I-labeled ligand compared

    SciTech Connect

    Wolf, B.A.; Daft, M.C.; Koenig, J.W.; Flye, M.W.; Turk, J.W.; Scott, M.G.

    1989-01-01

    We compared cyclosporine concentrations in whole blood as measured by HPLC and by RIA with a monoclonal antibody specific for cyclosporine with /sup 3/H- or /sup 125/I-labeled cyclosporine ligand. The /sup 3/H-RIA kit slightly underestimated cyclosporine concentrations (greater than 600 micrograms/L) in comparison with HPLC. Over a wide range of concentrations, cyclosporine measured with the /sup 125/I-RIA kit correlated well with HPLC (slope = 0.99, n = 301, r = 0.98), observed for samples from recipients of kidney, heart, or liver allografts (respective slopes: 1.01, 0.93, and 1.00). The /sup 125/I-RIA standard curve was linear to 1000 micrograms of cyclosporine per liter. Inter- and intra-assay CVs for /sup 125/I-RIA measurements of cyclosporine were less than or equal to 7%. Evidently, the /sup 125/I-RIA kit involving a monoclonal antibody specific for cyclosporine is equivalent to the HPLC assay and can replace it for therapeutic drug monitoring of cyclosporine therapy.

  12. Acute oxalate nephropathy associated with orlistat

    PubMed Central

    Humayun, Youshay; Ball, Kenneth C.; Lewin, Jack R.; Lerant, Anna A.; Fülöp, Tibor

    2016-01-01

    Background: Obesity is a major world-wide epidemic which has led to a surge of various weight loss-inducing medical or surgical treatments. Orlistat is a gastrointestinal lipase inhibitor used as an adjunct treatment of obesity and type 2 diabetes mellitus to induce clinically significant weight loss via fat malabsorption. Case Presentation: We describe a case of a 76-year-old female with past medical history of chronic kidney disease (baseline serum creatinine was 1.5-2.5 mg/dL), hypertension, gout and psoriatic arthritis, who was admitted for evaluation of elevated creatinine, peaking at 5.40 mg/dL. She was started on orlistat 120 mg three times a day six weeks earlier. Initial serologic work-up remained unremarkable. Percutaneous kidney biopsy revealed massive calcium oxalate crystal depositions with acute tubular necrosis and interstitial inflammation. Serum oxalate level returned elevated at 45 mm/l (normal <27). Timed 24-hour urine collection documented increased oxalate excretion repeatedly (54-96 mg/24 hour). After five renal dialysis sessions in eighth days she gradually regained her former baseline kidney function with creatinine around 2 mg/dL. Given coexisting proton-pump inhibitor therapy, only per os calcium-citrate provided effective intestinal oxalate chelation to control hyperoxaluria. Conclusions: Our case underscores the potential of medically induced fat malabsorption to lead to an excessive oxalate absorption and acute kidney injury (AKI), especially in subjects with pre-existing renal impairment. Further, it emphasizes the importance of kidney biopsy to facilitate early diagnosis and treatment. PMID:27152294

  13. Procarcinogenic effects of cyclosporine A are mediated through the activation of TAK1/TAB1 signaling pathway

    SciTech Connect

    Xu, Jianmin; Walsh, Stephanie B.; Verney, Zoe M.; Kopelovich, Levy; Elmets, Craig A.; Athar, Mohammad

    2011-05-13

    Research highlights: {yields} Organ transplant recipients are highly susceptible to early skin cancer development. {yields} CsA-mediated TGFB1-dependent TAK1/TAB1 signaling augments invasive tumor growth. {yields} CsA enhances accumulation of upstream kinases, ZMP, AMPK and IRAK to activate TAK1. {yields} TAK1 mediates enhanced proliferation and reduced apoptosis via CsA-dependent NF{kappa}B. -- Abstract: Cyclosporine A (CsA) is an immunosuppressive drug commonly used for maintaining chronic immune suppression in organ transplant recipients. It is known that patients receiving CsA manifest increased growth of aggressive non-melanoma skin cancers. However, the underlying mechanism by which CsA augments tumor growth is not fully understood. Here, we show that CsA augments the growth of A431 epidermoid carcinoma xenograft tumors by activating tumor growth factor {beta}-activated kinase1 (TAK1). The activation of TAK1 by CsA occurs at multiple levels by kinases ZMP, AMPK and IRAK. TAK1 forms heterodimeric complexes with TAK binding protein 1 and 2 (TAB1/TAB2) which in term activate nuclear factor {kappa}B (NF{kappa}B) and p38 MAP kinase. Transcriptional activation of NF{kappa}B is evidenced by IKK{beta}-mediated phosphorylation-dependent degradation of I{kappa}B and consequent nuclear translocation of p65. This also leads to enhancement in the expression of its transcriptional target genes cyclin D1, Bcl2 and COX-2. Similarly, activation of p38 leads to enhanced inflammation-related signaling shown by increased phosphorylation of MAPKAPK2 and which in turn phosphorylates its substrate HSP27. Activation of both NF{kappa}B and p38 MAP kinase provide mitogenic stimuli to augment the growth of SCCs.

  14. Cyclosporine Treatment Reduces Oxygen Free Radical Generation and Oxidative Stress in the Brain of Hypoxia-Reoxygenated Newborn Piglets

    PubMed Central

    Liu, Jiang-Qin; Chaudhary, Hetal; Brocks, Dion R.; Bigam, David L.; Cheung, Po-Yin

    2012-01-01

    Oxygen free radicals have been implicated in the pathogenesis of hypoxic-ischemic encephalopathy. It has previously been shown in traumatic brain injury animal models that treatment with cyclosporine reduces brain injury. However, the potential neuroprotective effect of cyclosporine in asphyxiated neonates has yet to be fully studied. Using an acute newborn swine model of hypoxia-reoxygenation, we evaluated the effects of cyclosporine on the brain, focusing on hydrogen peroxide (H2O2) production and markers of oxidative stress. Piglets (1–4 d, 1.4–2.5 kg) were block-randomized into three hypoxia-reoxygenation experimental groups (2 h hypoxia followed by 4 h reoxygenation)(n = 8/group). At 5 min after reoxygenation, piglets were given either i.v. saline (placebo, controls) or cyclosporine (2.5 or 10 mg/kg i.v. bolus) in a blinded-randomized fashion. An additional sham-operated group (n = 4) underwent no hypoxia-reoxygenation. Systemic hemodynamics, carotid arterial blood flow (transit-time ultrasonic probe), cerebral cortical H2O2 production (electrochemical sensor), cerebral tissue glutathione (ELISA) and cytosolic cytochrome-c (western blot) levels were examined. Hypoxic piglets had cardiogenic shock (cardiac output 40–48% of baseline), hypotension (mean arterial pressure 27–31 mmHg) and acidosis (pH 7.04) at the end of 2 h of hypoxia. Post-resuscitation cyclosporine treatment, particularly the higher dose (10 mg/kg), significantly attenuated the increase in cortical H2O2 concentration during reoxygenation, and was associated with lower cerebral oxidized glutathione levels. Furthermore, cyclosporine treatment significantly attenuated the increase in cortical cytochrome-c and lactate levels. Carotid blood arterial flow was similar among groups during reoxygenation. Conclusively, post-resuscitation administration of cyclosporine significantly attenuates H2O2 production and minimizes oxidative stress in newborn piglets following hypoxia

  15. Long-term antihypertensive treatment inhibiting progression of diabetic nephropathy

    PubMed Central

    Mogensen, C E

    1982-01-01

    Six men aged 26-35 years with proteinuria due to insulindependent juvenile-onset diabetes were treated for moderate hypertension (mean blood pressure 162/103 mm Hg) and studied for a mean of 73 months for the effect on the progression of nephropathy. All patients were of normal weight. During a mean control period of 28 months before treatment the mean glomerular filtration rate (three or four measurements) was 86·1 ml/min and mean 24-hour urinary albumin excretion (also three or four measurements) 3·9 g (range 0·5-8·8 g). During antihypertensive treatment the mean systolic blood pressure fell to 144 mm Hg and mean diastolic pressure to 95 mm Hg. In the control period five patients had shown a mean monthly decline in glomerular filtration rate of 1·23 ml/min; with antihypertensive treatment, however, this decline fell to 0·49 ml/min (2p=0·042). In the remaining patient the glomerular filtration rate was 137 ml/min before treatment and 135 ml/min at the end of the treatment period. In all patients the mean yearly increase in albumin clearance (expressed as a percentage of the glomerular filtration rate) fell from 107% before treatment to 5% during treatment (2p=0·0099). This small study indicates that antihypertensive treatment slows the decline in renal function in diabetic nephropathy. Clinical trials beginning treatment in the incipient phase of diabetic nephropathy will define the optimal modality of treatment in this large patient population. PMID:6809187

  16. [Chronic kidney disease associated with Poems syndrome: Report of one case].

    PubMed

    Vega, Jorge

    2016-04-01

    POEMS syndrome is characterized by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein and Skin changes. We report a woman with the syndrome, who had peripheral polyneuropathy, osteosclerotic myeloma, monoclonal IgA elevation, hypothyroidism, hypogonadotrophic hypogonadism, hyperprolactinemia, adrenal insufficiency, hepatosplenomegaly, lymphadenopathy, thyroid and parotid enlargement, Castleman’s disease, papilledema, stiff and hyperpigmented skin, white nails, clubbing, ascites and chronic diarrhea. She had also a nephropathy characterized by microscopic hematuria, proteinuria, renal insufficiency and a unilateral kidney retraction. She was treated with melphalan and prednisone, achieving remission of the disease and nephropathy. She survived twelve years and died due to a myocardial infarction 20 years after POEMS diagnosis. PMID:27401385

  17. Morphologic aspects of low-potassium and low-sodium nephropathy.

    PubMed

    Riemenschneider, T; Bohle, A

    1983-06-01

    Renal biopsies from 40 patients with hypokalemia and hyponatremia of an average of 10 years' duration due to abuse of laxatives or diuretics, anorexia nervosa, or chronic vomiting were examined with morphometric methods. Light microscopy revealed the following alterations in the renal cortex as compared with 36 normal kidney: JGC were sometimes slightly and sometimes enormously enlarged (mean, 217%). Smaller glomeruli were found with reduction in the area of the glomerular capillaries and of Bowman's capsule (+/- 7%) but an increase in the area of the mesangial matrix by 25%. The proximal and distal tubules contained nonspecific vacuoles in only 8 of 40 biopsy specimens. Only minor, age-dependent arteriolosclerosis was demonstrable. In 75% of the cases, the interstitial surface area was increased (by 107%) with predominantly focal lymphocytic cellular infiltration. Interstitial fibrosis was more pronounced in emaciated patients. The morphologic-functional correlation between the increase of interstitial surface area and the rise in serum creatinine concentration was highly significant. Typical kaliopenic nephropathy is therefore detectable by light microscopy. GFR impairment correlates with the extent of interstitial fibrosis. PMID:6872364

  18. Prevention of contrast induced nephropathy: recommendations for the high risk patient undergoing cardiovascular procedures.

    PubMed

    Schweiger, Marc J; Chambers, Charles E; Davidson, Charles J; Zhang, Shaoheng; Blankenship, James; Bhalla, Narinder P; Block, Peter C; Dervan, John P; Gasperetti, Christine; Gerber, Lowell; Kleiman, Neal S; Krone, Ronald J; Phillips, William J; Siegel, Robert M; Uretsky, Barry F; Laskey, Warren K

    2007-01-01

    Contrast induced nephropathy (CIN) is the third leading cause of hospital acquired renal failure and is associated with significant morbidity and mortality. Chronic kidney disease is the primary predisposing factor for CIN. As estimated glomerular filtration rate<60 ml/1.73 m2 represents significant renal dysfunction and defines patients at high risk. Modifiable risk factors for CIN include hydration status, the type and amount of contrast, use of concomitant nephrotoxic agents and recent contrast administration. The cornerstone of CIN prevention, in both the high and low risk patients, is adequate parenteral volume repletion. In the patient at increased risk for CIN it is often appropriate to withhold potentially nephrotoxic medications, and consider the use of n-acetylcysteine. In patients at increased risk for CIN the use of low or iso-osomolar contrast agents should be utilized and strategies employed to minimize contrast volume. In these patients serum creatinine should be obtained forty-eight hours post procedure and it is often appropriate to continue withholding medications such as metformin or non steroidal anti-inflammatories until renal function returns to normal. PMID:17139671

  19. Evaluating Weight of Evidence in the Mystery of Balkan Endemic Nephropathy

    PubMed Central

    Bui-Klimke, Travis; Wu, Felicia

    2014-01-01

    Balkan Endemic Nephropathy (BEN) is a chronic, progressive wasting disease of the kidneys, endemic in certain rural regions of the Balkan nations Croatia, Serbia, Bulgaria, and Romania. It is irreversible, and ultimately fatal. Though this disease was first described in the 1920s, its causes have been a mystery and a source of much academic and clinical contention. Possible etiologic agents that have been explored include exposure to metals and metalloids, viruses and bacteria, and the environmental toxins aristolochic acid (AA) and ochratoxin A (OTA). Aristolochic acid is a toxin produced by weeds of the genus Aristolochia, common in Balkan wheat fields. Aristolochia seeds may intermingle with harvested grains and thus inadvertently enter human diets. Ochratoxin A is a mycotoxin (fungal toxin) common in many foods, including cereal grains. In this study, we analyzed the weight of evidence for each of the suspected causes of BEN using the Bradford Hill Criteria (BHC): nine conditions that determine weight of evidence for a causal relationship between an agent and a disease. Each agent postulated to cause BEN was evaluated using the nine criteria, and for each criterion was given a rating based on the strength of the association between exposure to the substance and BEN. From the overall available scientific evidence for each of these suspected risk factors, aristolochic acid is the agent with the greatest weight of evidence in causing BEN. We describe other methods for testing causality from epidemiological studies, which support this conclusion of AA causing BEN. PMID:24954501

  20. MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy.

    PubMed

    Popovska-Jankovic, Katerina; Noveski, Predrag; Jankovic-Velickovic, Ljubinka; Stojnev, Slavica; Cukuranovic, Rade; Stefanovic, Vladisav; Toncheva, Draga; Staneva, Rada; Polenakovic, Momir; Plaseska-Karanfilska, Dijana

    2016-01-01

    Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups. PMID:27218105

  1. Prevention of Contrast-Induced Nephropathy through a Knowledge of Its Pathogenesis and Risk Factors

    PubMed Central

    Faga, Teresa; Pisani, Antonio; Russo, Domenico; Michael, Ashour

    2014-01-01

    Contrast-induced nephropathy (CIN) is an iatrogenic acute renal failure (ARF) occurring after the intravascular injection of iodinated radiographic contrast media. During the past several years, in many patients undergoing computed tomography, iodinated contrast media have not been used for the fear of ARF, thereby compromising the diagnostic procedure. But recent studies have demonstrated that CIN is rarely occurring in patients with normal renal function and that preexisting chronic renal failure and/or diabetes mellitus represent(s) predisposing condition(s) for its occurrence. After the description of CIN and its epidemiology and pathophysiology, underlying the important role played by dehydration and salt depletion, precautions for prevention of CIN are listed, suggested, and discussed. Maximum priority has to be given to adequate hydration and volume expansion prior to radiographic procedures. Other important precautions include the need for monitoring renal function before, during, and after contrast media injection, discontinuation of potentially nephrotoxic drugs, use of either iodixanol or iopamidol at the lowest dosage possible, and administration of antioxidants. A long list of references is provided that will enable readers a deep evaluation of the topic. PMID:25525625

  2. Review of Herbal Traditional Chinese Medicine for the Treatment of Diabetic Nephropathy

    PubMed Central

    Sun, Guang-dong; Li, Chao-yuan; Cui, Wen-peng; Guo, Qiao-yan; Dong, Chang-qing; Zou, Hong-bin; Liu, Shu-jun; Dong, Wen-peng; Miao, Li-ning

    2016-01-01

    Diabetic nephropathy (DN) is the most serious chronic complications of diabetes; 20–40% of diabetic patients develop into end stage renal disease (ESRD). However, exact pathogenesis of DN is not fully clear and we have great difficulties in curing DN; poor treatment of DN led to high chances of mortality worldwide. A lot of western medicines such as ACEI and ARB have been demonstrated to protect renal function of DN but are not enough to delay or retard the progression of DN; therefore, exploring exact and feasible drug is current research hotspot in medicine. Traditional Chinese medicine (TCM) has been widely used to treat and control diabetes and its complications such as DN in a lot of scientific researches, which will give insights into the mechanism of DN, but they are not enough to reveal all the details. In this paper, we summarize the applications of herbal TCM preparations, single herbal TCM, and/or monomers from herbal TCM in the treatment of DN in the recent 10 years, depicting the renal protective effects and the corresponding mechanism, through which we shed light on the renal protective roles of TCM in DN with a particular focus on the molecular basis of the effect and provide a beneficial supplement to the drug therapy for DN. PMID:26649322

  3. Limitations and plausibility of the Pliocene lignite hypothesis in explaining the etiology of Balkan endemic nephropathy

    PubMed Central

    Maharaj, S V M

    2014-01-01

    Background: Balkan endemic nephropathy (BEN) is a chronic, tubulointerstitial renal disease often accompanied by urothelial cancer that has a lethality of nearly 100%. Introduction: One of the many factors that have been proposed to play an etiological role in BEN is exposure to organic compounds from Pliocene lignite coal deposits via the drinking water in endemic areas. Objectives: The objective of this study was to systematically evaluate the role of the tenets of the Pliocene lignite hypothesis in the etiology of BEN in order to provide an improved understanding of the hypothesis for colleagues and patients alike. Methods: A comprehensive compilation of the possible limitations of the hypothesis, with each limitation addressed in turn is presented. Results: The Pliocene lignite hypothesis can best account for, is consistent with, or has the potential to explain the evidence associated with the myriad of factors related to BEN. Conclusions: Residents of endemic areas are exposed to complex mixtures containing hundreds of organic compounds at varying doses and their potentially more toxic (including nephrotoxic) and/or carcinogenic metabolites; however, a multifactorial etiology of BEN appears most likely. PMID:24075451

  4. New Insights into the PPAR γ Agonists for the Treatment of Diabetic Nephropathy.

    PubMed

    Jia, Zhanjun; Sun, Ying; Yang, Guangrui; Zhang, Aihua; Huang, Songming; Heiney, Kristina Marie; Zhang, Yue

    2014-01-01

    Diabetic nephropathy (DN) is a severe complication of diabetes and serves as the leading cause of chronic renal failure. In the past decades, angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs) based first-line therapy can slow but cannot stop the progression of DN, which urgently requests the innovation of therapeutic strategies. Thiazolidinediones (TZDs), the synthetic exogenous ligands of nuclear receptor peroxisome proliferator-activated receptor- γ (PPAR γ ), had been thought to be a promising candidate for strengthening the therapy of DN. However, the severe adverse effects including fluid retention, cardiovascular complications, and bone loss greatly limited their use in clinic. Recently, numerous novel PPAR γ agonists involving the endogenous PPAR γ ligands and selective PPAR γ modulators (SPPARMs) are emerging as the promising candidates of the next generation of antidiabetic drugs instead of TZDs. Due to the higher selectivity of these novel PPAR γ agonists on the regulation of the antidiabetes-associated genes than that of the side effect-associated genes, they present fewer adverse effects than TZDs. The present review was undertaken to address the advancements and the therapeutic potential of these newly developed PPAR γ agonists in dealing with diabetic kidney disease. At the same time, the new insights into the therapeutic strategies of DN based on the PPAR γ agonists were fully addressed. PMID:24624137

  5. Renin-Angiotensin-Aldosterone System Blockade in Diabetic Nephropathy. Present Evidences

    PubMed Central

    Lozano-Maneiro, Luz; Puente-García, Adriana

    2015-01-01

    Diabetic Kidney Disease (DKD) is the leading cause of chronic kidney disease in developed countries and its prevalence has increased dramatically in the past few decades. These patients are at an increased risk for premature death, cardiovascular disease, and other severe illnesses that result in frequent hospitalizations and increased health-care utilization. Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and the development of end-stage renal disease remain major concerns in diabetes. Dysregulation of the renin-angiotensin-aldosterone system (RAAS) results in progressive renal damage. RAAS blockade is the cornerstone of treatment of DKD, with proven efficacy in many arenas. The theoretically-attractive option of combining these medications that target different points in the pathway, potentially offering a more complete RAAS blockade, has also been tested in clinical trials, but long-term outcomes were disappointing. This review examines the “state of play” for RAAS blockade in DKD, dual blockade of various combinations, and a perspective on its benefits and potential risks. PMID:26569322

  6. MicroRNA Profiling in Patients with Upper Tract Urothelial Carcinoma Associated with Balkan Endemic Nephropathy

    PubMed Central

    Popovska-Jankovic, Katerina; Noveski, Predrag; Jankovic-Velickovic, Ljubinka; Stojnev, Slavica; Cukuranovic, Rade; Stefanovic, Vladisav; Toncheva, Draga; Staneva, Rada; Polenakovic, Momir; Plaseska-Karanfilska, Dijana

    2016-01-01

    Balkan endemic nephropathy (BEN) is a disease that affects people that live in the alluvial plains along the tributaries of the Danube River in the Balkan region. BEN is a chronic tubulointerstitial disease with a slow progression to terminal renal failure and has strong association with upper tract urothelial carcinoma (UTUC). There are several hypotheses about the etiology of BEN, but only the toxic effect of aristolochic acid has been confirmed as a risk factor in the occurrence of the disease. Aberrantly expressed miRNAs have been shown to be associated with many types of cancers. A number of studies have investigated the expression of microRNAs in urothelial carcinoma, mainly on urothelial bladder cancer, and only a few have included patients with UTUC. Here we present the first study of microRNA profiling in UTUC tissues from patients with BEN (BEN-UTUC) and patients with UTUC from nonendemic Balkan regions (non-BEN-UTUC) in comparison to normal kidney tissues. We found 10 miRNAs that were differentially expressed in patients with BEN-UTUC and 15 miRNAs in patients with non-BEN-UTUC. miRNA signature determined in BEN-UTUC patients differs from the non-BEN-UTUC patients; only miR-205-5p was mutual in both groups. PMID:27218105

  7. A Meta-Analysis of Antiviral Therapy for Hepatitis B Virus-Associated Membranous Nephropathy.

    PubMed

    Yang, Yue; Ma, Ye-Ping; Chen, Da-Peng; Zhuo, Li; Li, Wen-Ge

    2016-01-01

    Hepatitis B virus-associated membranous nephropathy (HBV-MN) is the most common renal extra-hepatic manifestation in patients with chronic HBV infection. In September 2015, we searched the MEDLINE, EMBASE, and CENTRAL databases, and the reference lists of retrieved articles, to identify relevant studies. Descriptions of antiviral drugs used to treat HBV-MN were included in our review. Two authors independently screened all relevant articles, extracted data, and assessed the risk of bias. Nine hundred and fifty-four papers have been considered after electronic and manual searching, only five relevant studies were identified. Complete remission (OR = 26.87, 95% CI: 8.06 to 89.52), total remission (OR = 10.31, 95% CI: 3.59 to 29.63) of proteinuria and HBeAg clearance (OR = 20.91, 95% CI: 6.90 to 63.39) increased significantly after antiviral therapy. No significant differences were seen between interferon and nucleoside analog treatments. Our study found that antiviral therapy was an effective treatment in HBV-MN patients; interferon and nucleoside analogs were equally effective at causing proteinuria remission and HBeAg clearance. PMID:27598699

  8. Prevention of contrast-induced nephropathy through a knowledge of its pathogenesis and risk factors.

    PubMed

    Andreucci, Michele; Faga, Teresa; Pisani, Antonio; Sabbatini, Massimo; Russo, Domenico; Michael, Ashour

    2014-01-01

    Contrast-induced nephropathy (CIN) is an iatrogenic acute renal failure (ARF) occurring after the intravascular injection of iodinated radiographic contrast media. During the past several years, in many patients undergoing computed tomography, iodinated contrast media have not been used for the fear of ARF, thereby compromising the diagnostic procedure. But recent studies have demonstrated that CIN is rarely occurring in patients with normal renal function and that preexisting chronic renal failure and/or diabetes mellitus represent(s) predisposing condition(s) for its occurrence. After the description of CIN and its epidemiology and pathophysiology, underlying the important role played by dehydration and salt depletion, precautions for prevention of CIN are listed, suggested, and discussed. Maximum priority has to be given to adequate hydration and volume expansion prior to radiographic procedures. Other important precautions include the need for monitoring renal function before, during, and after contrast media injection, discontinuation of potentially nephrotoxic drugs, use of either iodixanol or iopamidol at the lowest dosage possible, and administration of antioxidants. A long list of references is provided that will enable readers a deep evaluation of the topic. PMID:25525625

  9. Cellular and molecular aspects of diabetic nephropathy; the role of VEGF-A.

    PubMed

    Carranza, Katherine; Veron, Dolores; Cercado, Alicia; Bautista, Noemi; Pozo, Wilson; Tufro, Alda; Veron, Delma

    2015-01-01

    The prevalence of diabetes mellitus increased during the last century and it is estimated that 45% of the patients are not diagnosed. In South America the prevalence of diabetes and chronic kidney disease (CKD) increased, with a great disparity among the countries with respect to access to dialysis. In Ecuador it is one of the main causes of mortality, principally in the provinces located on the coast of the Pacific Ocean. The greatest single cause of beginning dialysis is diabetic nephropathy (DN). Even using the best therapeutic options for DN, the residual risk of proteinuria and of terminal CKD remains high. In this review we indicate the importance of the problem globally and in our region. We analyse relevant cellular and molecular studies that illustrate the crucial significance of glomerular events in DN development and evolution and in insulin resistance. We include basic anatomical, pathophysiological and clinical concepts, with special attention to the role of angiogenic factors such as the vascular endothelial growth factor (VEGF-A) and their relationship to the insulin receptor, endothelial isoform of nitric oxide synthase (eNOS) and angiopoietins. We also propose various pathways that have therapeutic potential in our opinion. Greater in-depth study of VEGF-A and angiopoietins, the state of glomerular VEGF resistance, the relationship of VEGF receptor 2/nephrin, VEGF/insulin receptors/nephrin and the relationship of VEGF/eNOS-NO at glomerular level could provide solutions to the pressing world problem of DN and generate new treatment alternatives. PMID:26300505

  10. The genetics and immunobiology of IgA nephropathy

    PubMed Central

    Kiryluk, Krzysztof; Novak, Jan

    2014-01-01

    IgA nephropathy (IgAN) represents the leading cause of kidney failure among East Asian populations and the most frequent form of primary glomerulonephritis among Europeans. Patients with IgAN develop characteristic IgA1-containing immune complexes that deposit in the glomerular mesangium, producing progressive kidney injury. Recent studies define IgAN as an autoimmune trait of complex architecture with a strong genetic determination. This Review summarizes new insights into the role of the O-glycosylation pathway, anti-glycan immune response, mucosal immunity, antigen processing and presentation, and the alternative complement pathway in the pathogenesis of IgAN. PMID:24892706

  11. Acute oxalate nephropathy due to 'Averrhoa bilimbi' fruit juice ingestion.

    PubMed

    Bakul, G; Unni, V N; Seethaleksmy, N V; Mathew, A; Rajesh, R; Kurien, G; Rajesh, J; Jayaraj, P M; Kishore, D S; Jose, P P

    2013-07-01

    Irumban puli (Averrhoa bilimbi) is commonly used as a traditional remedy in the state of Kerala. Freshly made concentrated juice has a very high oxalic acid content and consumption carries a high risk of developing acute renal failure (ARF) by deposition of calcium oxalate crystals in renal tubules. Acute oxalate nephropathy (AON) due to secondary oxalosis after consumption of Irumban puli juice is uncommon. AON due to A. bilimbi has not been reported before. We present a series of ten patients from five hospitals in the State of Kerala who developed ARF after intake of I. puli fruit juice. Seven patients needed hemodialysis whereas the other three improved with conservative management. PMID:23960349

  12. Methyl isobutyl ketone exposure-related increases in specific measures of α2u-globulin (α2u) nephropathy in male rats along with in vitro evidence of reversible protein binding.

    PubMed

    Borghoff, S J; Poet, T S; Green, S; Davis, J; Hughes, B; Mensing, T; Sarang, S S; Lynch, A M; Hard, G C

    2015-07-01

    Chronic exposure to methyl isobutyl ketone (MIBK) resulted in an increase in the incidence of renal tubule adenomas and occurrence of renal tubule carcinomas in male, but not female Fischer 344 rats. Since a number of chemicals have been shown to cause male rat renal tumors through the α2u nephropathy-mediated mode of action, the objective of this study is to evaluate the ability of MIBK to induce measures of α2u nephropathy including renal cell proliferation in male and female F344 rats following exposure to the same inhalation concentrations used in the National Toxicology Program (NTP) cancer bioassay (0, 450, 900, or 1800ppm). Rats were exposed 6h/day for 1 or 4 weeks and kidneys excised approximately 18h post exposure to evaluate hyaline droplet accumulation (HDA), α2u staining of hyaline droplets, renal cell proliferation, and to quantitate renal α2u concentration. There was an exposure-related increase in all measures of α2u nephropathy in male, but not female rat kidneys. The hyaline droplets present in male rat kidney stained positively for α2u. The changes in HDA and α2u concentration were comparable to d-limonene, an acknowledged inducer of α2u nephropathy. In a separate in vitro study using a two-compartment vial equilibration model to assess the interaction between MIBK and α2u, the dissociation constant (Kd) was estimated to be 1.27×10(-5)M. This Kd is within the range of other chemicals known to bind to α2u and cause nephropathy. Together, the exposure-related increase in measures of α2u nephropathy, sustained increase in renal cell proliferation along with an indication of reversible binding of MIBK to α2u, support the inclusion of MIBK in the category of chemicals exerting renal effects through a protein droplet α2u nephropathy-mediated mode of action (MoA). PMID:25797582

  13. Race/ethnicity and disease severity in IgA nephropathy

    PubMed Central

    Hall, Yoshio N; Fuentes, Eloisa F; Chertow, Glenn M; Olson, Jean L

    2004-01-01

    Background Relatively few U.S.-based studies in chronic kidney disease have focused on Asian/Pacific Islanders. Clinical reports suggest that Asian/Pacific Islanders are more likely to be affected by IgA nephropathy (IgAN), and that the severity of disease is increased in these populations. Methods To explore whether these observations are borne out in a multi-ethnic, tertiary care renal pathology practice, we examined clinical and pathologic data on 298 patients with primary glomerular lesions (IgAN, focal segmental glomerulosclerosis, membranous nephropathy and minimal change disease) at the University of California San Francisco Medical Center from November 1994 through May 2001. Pathologic assessment of native kidney biopsies with IgAN was conducted using Haas' classification system. Results Among individuals with IgAN (N = 149), 89 (60%) were male, 57 (38%) white, 53 (36%) Asian/Pacific Islander, 29 (19%) Hispanic, 4 (3%) African American and 6 (4%) were of other or unknown ethnicity. The mean age was 37 ± 14 years and median serum creatinine 1.7 mg/dL. Sixty-six patients (44%) exhibited nephrotic range proteinuria at the time of kidney biopsy. The distributions of age, gender, mean serum creatinine, and presence or absence of nephrotic proteinuria and/or hypertension at the time of kidney biopsy were not significantly different among white, Hispanic, and Asian/Pacific Islander groups. Of the 124 native kidney biopsies with IgAN, 10 (8%) cases were classified into Haas subclass I, 12 (10%) subclass II, 23 (18%) subclass III, 30 (25%) subclass IV, and 49 (40%) subclass V. The distribution of Haas subclass did not differ significantly by race/ethnicity. In comparison, among the random sample of patients with non-IgAN glomerular lesions (N = 149), 77 (52%) patients were male, 51 (34%) white, 42 (28%) Asian/Pacific Islander, 25 (17%) Hispanic, and 30 (20%) were African American. Conclusions With the caveats of referral and biopsy biases, the race

  14. Genetic variants and cell-free hemoglobin processing in sickle cell nephropathy

    PubMed Central

    Saraf, Santosh L.; Zhang, Xu; Shah, Binal; Kanias, Tamir; Gudehithlu, Krishnamurthy P.; Kittles, Rick; Machado, Roberto F.; Arruda, Jose A.L.; Gladwin, Mark T.; Singh, Ashok K.; Gordeuk, Victor R.

    2015-01-01

    Intravascular hemolysis and hemoglobinuria are associated with sickle cell nephropathy. ApoL1 is involved in cell-free hemoglobin scavenging through association with haptoglobin-related protein. APOL1 G1/G2 variants are the strongest genetic predictors of kidney disease in the general African-American population. A single report associated APOL1 G1/G2 with sickle cell nephropathy. In 221 patients with sickle cell disease at the University of Illinois at Chicago, we replicated the finding of an association of APOL1 G1/G2 with proteinuria, specifically with urine albumin concentration (β=1.1, P=0.003), observed an even stronger association with hemoglobinuria (OR=2.5, P=4.3×10−6), and also replicated the finding of an association with hemoglobinuria in 487 patients from the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy study (OR=2.6, P=0.003). In 25 University of Illinois sickle cell disease patients, concentrations of urine kidney injury molecule-1 correlated with urine cell-free hemoglobin concentrations (r=0.59, P=0.002). Exposing human proximal tubular cells to increasing cell-free hemoglobin led to increasing concentrations of supernatant kidney injury molecule-1 (P=0.01), reduced viability (P=0.01) and induction of HMOX1 and SOD2. HMOX1 rs743811 associated with chronic kidney disease stage (OR=3.0, P=0.0001) in the University of Illinois cohort and end-stage renal disease (OR=10.0, P=0.0003) in the Walk-Treatment of Pulmonary Hypertension and Sickle cell Disease with Sildenafil Therapy cohort. Longer HMOX1 GT-tandem repeats (>25) were associated with lower estimated glomerular filtration rate in the University of Illinois cohort (P=0.01). Our findings point to an association of APOL1 G1/G2 with kidney disease in sickle cell disease, possibly through increased risk of hemoglobinuria, and associations of HMOX1 variants with kidney disease, possibly through reduced protection of the kidney from hemoglobin

  15. Gelatin-stabilised microemulsion-based organogels facilitates percutaneous penetration of Cyclosporin A in vitro and dermal pharmacokinetics in vivo.

    PubMed

    Liu, Hongzhuo; Wang, Yongjun; Han, Fei; Yao, Huimin; Li, Sanming

    2007-11-01

    Gelatin-stabilised microemulsion-based organogels (MBGs) are very useful in transdermal and topical delivery of hydrophobic drugs because of their lipophilic nature. MBGs systems possessing a potentially improved skin bioavailability of Cyclosporin A were designed and explored for some characteristics. The release characteristics of drug from MBGs were studied according to drug concentration. As the concentration of drug increased, the release of drug from gel increased, showing concentration dependency. Percutaneous penetration studies using rat skin in vitro showed that the deposition of Cyclosporin A was significantly improved by MBGs compared to the control. We also evaluated the therapeutic advantage of dermal administration of Cyclosporin A in rat model. Local (subcutaneous and skin), systemic concentrations and organ distribution (liver and kidney) were evaluated serially following topical and oral application of the drug. In rat dermal applied with the MBGs containing Cyclosporin A, the deposition of the drug into skin and subcutaneous fat was, respectively, almost 55- and 3-fold higher than the concentrations compared with oral administration. Systemic distribution in blood, liver and kidney was much lower following topical than following oral administration. With high local concentrations and minimal distribution to other organs via the circulation, topical applied MBGs loaded with Cyclosporin A might deliver maximal therapeutic effect to local tissue while avoiding the side effects seen with systemic therapy. The histopathological findings revealed that the new MBGs vehicle was a safe vehicle for topical drug delivery systems. PMID:17705159

  16. Short-term nitric oxide inhibition induces progressive nephropathy after regression of initial renal injury.

    PubMed

    Fujihara, Clarice K; Sena, Claudia R; Malheiros, Denise M A C; Mattar, Ana L; Zatz, Roberto

    2006-03-01

    Chronic nitric oxide (NO) inhibition and salt overload (HS) promote severe hypertension and renal injury, which regress quickly, although not completely, on treatment withdrawal. We investigated whether renal function and structure remain stable 6 mo after cessation of these treatments. Adult male Munich-Wistar rats were distributed among three groups: HS, receiving 3.1% Na diet; HS+N, receiving HS and the NO inhibitor N(omega)-nitro-l-arginine methyl ester (l-NAME; 30 mg.kg(-1).day(-1) orally); and HS+N+L, receiving HS+N and the ANG II blocker losartan (L; 50 mg.kg(-1).day(-1) orally). In studies performed after 20 days of treatment (protocol 1), HS+N rats exhibited severe glomerular and systemic hypertension, massive albuminuria, glomerular and interstitial injury, and infiltration by macrophages and cells expressing ANG II. These abnormalities were largely prevented in the HS+N+L group. A second cohort (protocol 2) received HS+N for 20 days, followed by a conventional (0.5% Na) diet and no l-NAME treatment during the subsequent 30 days. At this time, systemic and glomerular pressure, along with parameters of renal injury and inflammation, were still higher than in HS or HS+N+L rats, although differences were much smaller than in protocol 1. Six months after 20-day l-NAME/salt overload treatment was ceased (protocol 3), severe albuminuria, hypertension, and renal injury developed in HS+N rats. Again, losartan prevented most of these changes. We conclude 1) short-term HS+N treatment triggers the autonomous development of progressive glomerulosclerosis; 2) this process may involve activation of the AT(1) receptor; and 3) temporary HS+N treatment may represent a new model of slowly progressive chronic nephropathy. PMID:16204410

  17. The protective effects of oral low-dose quercetin on diabetic nephropathy in hypercholesterolemic mice

    PubMed Central

    Gomes, Isabele B. S.; Porto, Marcella L.; Santos, Maria C. L. F. S.; Campagnaro, Bianca P.; Gava, Agata L.; Meyrelles, Silvana S.; Pereira, Thiago M. C.; Vasquez, Elisardo C.

    2015-01-01

    Aims: Diabetic nephropathy (DN) is one of the most important causes of chronic renal disease, and the incidence of DN is increasing worldwide. Considering our previous report (Gomes et al., 2014) indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg) demonstrated anti-oxidative, anti-apoptotic and renoprotective effects in the C57BL/6J model of DN, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE−/−). Methods: Streptozotocin was used to induce diabetes (100 mg/kg/day, 3 days) in male apoE−/− mice (8 week-old). After 6 weeks, the mice were randomly separated into DQ: diabetic apoE−/− mice treated with quercetin (10 mg/kg/day, 4 weeks, n = 8), DV: diabetic ApoE−/− mice treated with vehicle (n = 8) and ND: non-treated non-diabetic mice (n = 8). Results: Quercetin treatment diminished polyuria (~30%; p < 0.05), glycemia (~25%, p < 0.05), normalized the hypertriglyceridemia. Moreover, this bioflavonoid diminished creatininemia (~30%, p < 0.01) and reduced proteinuria but not to normal levels. We also observed protective effects on the renal structural changes, including normalization of the index of glomerulosclerosis and kidney weight/body weight. Conclusions: Our data revealed that quercetin treatment significantly reduced DN in hypercholesterolemic mice by inducing biochemical changes (decrease in glucose and triglycerides serum levels) and reduction of glomerulosclerosis. Thus, this study highlights the relevance of quercetin as an alternative therapeutic option for DN, including in diabetes associated with dyslipidemia. PMID:26388784

  18. Effect of Cordyceps sinensis and Tripterygium wilfordii polyglycosidium on podocytes in rats with diabetic nephropathy.

    PubMed

    Hao, Li; Pan, Meng-Shu; Zheng, Yun; Wang, Rui-Feng

    2014-06-01

    The aim of the present study was to investigate the effects of Cordyceps sinensis (CS) and Tripterygium wilfordii polyglycosidium (TWP) on podocytes in rats with diabetic nephropathy (DN). DN rat models were established and divided randomly into normal control (group A), DN (group B), CS (group C), TWP (group D) and CS and TWP groups (group E). After 12 weeks, levels of 24-h urinary protein, blood urea nitrogen (BUN), serum creatinine (SCR), white blood cells, blood glucose (GLU), aspartate aminotransferase, alanine aminotransferase and kidney weight (KW)/body weight (BW) were determined. Renal pathological changes were evaluated using hematoxylin and eosin staining, whereas the structural changes in the podocytes were observed under a transmission electron microscope. The expression levels of nephrin and podocin were evaluated using immunofluorescence staining. Compared with group A, the SCR and BUN levels in group B were higher (P<0.05) and the GLU, KW/BW and the 24-h urine protein were markedly higher (P<0.01). Moreover, incidences of glomerular disorders, chronic tubulointerstitial damage and glomerular podocyte lesions in groups B, C, D and E were observed, compared with group A. The high cortical expression of nephrin and podocin protein decreased. Compared with group B, the KW/BW and 24-h urinary protein level in groups C, D and E were lower (P<0.01). The glomeruli, tubules and podocytes exhibited pathomorphological improvements and the nephrin and podocin protein expression levels were higher in the nephridial tissue. A decrease in KW/BW and the 24-h urinary protein level, as well as improvements in glomerular disorder, chronic tubulointerstitial damage and glomerular podocyte lesions, were observed in groups C, D and E. Therefore, the results demonstrated that CS and TWP exhibited a protective effect on the podocytes of rats with DN. Moreover, CS combined with TWP increased this protective effect. PMID:24926327

  19. Resolving the enigma of the mesoamerican nephropathy: a research workshop summary.

    PubMed

    Wesseling, Catharina; Crowe, Jennifer; Hogstedt, Christer; Jakobsson, Kristina; Lucas, Rebekah; Wegman, David H

    2014-03-01

    The First International Research Workshop on Mesoamerican Nephropathy (MeN) met in Costa Rica in November 2012 to discuss how to establish the extent and degree of MeN, examine relevant causal hypotheses, and focus efforts to control or eliminate the disease burden. MeN describes a devastating epidemic of chronic kidney disease of unknown origin predominantly observed among young male sugarcane cutters. The cause of MeN remains uncertain; however, the strongest hypothesis pursued to date is repeated episodes of occupational heat stress and water and solute loss, probably in combination with other potential risk factor(s), such as nonsteroidal anti-inflammatory drug and other nephrotoxic medication use, inorganic arsenic, leptospirosis, or pesticides. At the research workshop, clinical and epidemiologic case definitions were proposed in order to facilitate both public health and research efforts. Recommendations emanating from the workshop included measuring workload, heat, and water and solute loss among workers; quantifying nephrotoxic agents in drinking water and food; using biomarkers of early kidney injury to explore potential causes of MeN; and characterizing social and working conditions together with methods for valid data collection of exposures and personal risk factors. Advantages and disadvantages of different population study designs were detailed. To elucidate the etiology of MeN, multicountry studies with prospective cohort design, preferably integrating an ecosystem health approach, were considered the most promising. In addition, genetic, experimental, and mechanistic methods and designs were addressed, specifically the need for kidney biopsy analysis, studies in animal models, advances in biomarkers, genetic and epigenetic studies, a common registry and repository of biological and demographic data and/or specimens, and other areas of potential chronic kidney disease experimental research. Finally, in order to improve international collaboration on

  20. Redox Signaling in Diabetic Nephropathy: Hypertrophy versus Death Choices in Mesangial Cells and Podocytes

    PubMed Central

    Manda, Gina; Checherita, Alexandru-Ionel; Comanescu, Maria Victoria; Hinescu, Mihail Eugen

    2015-01-01

    This review emphasizes the role of oxidative stress in diabetic nephropathy, acting as trigger, modulator, and linker within the complex network of pathologic events. It highlights key molecular pathways and new hypothesis in diabetic nephropathy, related to the interferences of metabolic, oxidative, and inflammatory stresses. Main topics this review is addressing are biomarkers of oxidative stress in diabetic nephropathy, the sources of reactive oxygen species (mitochondria, NADPH-oxidases, hyperglycemia, and inflammation), and the redox-sensitive signaling networks (protein kinases, transcription factors, and epigenetic regulators). Molecular switches deciding on the renal cells fate in diabetic nephropathy are presented, such as hypertrophy versus death choices in mesangial cells and podocytes. Finally, the antioxidant response of renal cells in diabetic nephropathy is tackled, with emphasis on targeted therapy. An integrative approach is needed for identifying key molecular networks which control cellular responses triggered by the array of stressors in diabetic nephropathy. This will foster the discovery of reliable biomarkers for early diagnosis and prognosis, and will guide the discovery of new therapeutic approaches for personalized medicine in diabetic nephropathy. PMID:26491232

  1. Diabetic Nephropathy Amelioration by a Low-Dose Sitagliptin in an Animal Model of Type 2 Diabetes (Zucker Diabetic Fatty Rat)

    PubMed Central

    Mega, Cristina; Teixeira de Lemos, Edite; Vala, Helena; Fernandes, Rosa; Oliveira, Jorge; Mascarenhas-Melo, Filipa; Teixeira, Frederico; Reis, Flávio

    2011-01-01

    This study was performed to assess the effect of chronic low-dose sitagliptin, a dipeptidyl peptidase 4 inhibitor, on metabolic profile and on renal lesions aggravation in a rat model of type-2 diabetic nephropathy, the Zucker diabetic fatty (ZDF) rat. Diabetic and obese ZDF (fa/fa) rats and their controls ZDF (+/+) were treated for 6 weeks with vehicle (control) or sitagliptin (10 mg/kg/bw). Blood/serum glucose, HbA1c, insulin, Total-c, TGs, urea, and creatinine were assessed, as well as kidney glomerular and tubulointerstitial lesions (interstitial fibrosis/tubular atrophy), using a semiquantitative rating from 0 (absent/normal) to 3 (severe and extensive damage). Vascular lesions were scored from 0–2. Sitagliptin in the diabetic rats promoted an amelioration of glycemia, HbA1c, Total-c, and TGs, accompanied by a partial prevention of insulinopenia. Furthermore, together with urea increment prevention, renal lesions were ameliorated in the diabetic rats, including glomerular, tubulointerstitial, and vascular lesions, accompanied by reduced lipid peroxidation. In conclusion, chronic low-dose sitagliptin treatment was able to ameliorate diabetic nephropathy, which might represent a key step forward in the management of T2DM and this serious complication. PMID:22203828

  2. Autoimmunity in Membranous Nephropathy Targets Aldose Reductase and SOD2

    PubMed Central

    Prunotto, Marco; Carnevali, Maria Luisa; Candiano, Giovanni; Murtas, Corrado; Bruschi, Maurizio; Corradini, Emilia; Trivelli, Antonella; Magnasco, Alberto; Petretto, Andrea; Santucci, Laura; Mattei, Silvia; Gatti, Rita; Scolari, Francesco; Kador, Peter; Allegri, Landino

    2010-01-01

    Glomerular targets of autoimmunity in human membranous nephropathy are poorly understood. Here, we used a combined proteomic approach to identify specific antibodies against podocyte proteins in both serum and glomeruli of patients with membranous nephropathy (MN). We detected specific anti–aldose reductase (AR) and anti–manganese superoxide dismutase (SOD2) IgG4 in sera of patients with MN. We also eluted high titers of anti-AR and anti-SOD2 IgG4 from microdissected glomeruli of three biopsies of MN kidneys but not from biopsies of other glomerulonephritides characterized by IgG deposition (five lupus nephritis and two membranoproliferative glomerulonephritis). We identified both antigens in MN biopsies but not in other renal pathologies or normal kidney. Confocal and immunoelectron microscopy (IEM) showed co-localization of anti-AR and anti-SOD2 with IgG4 and C5b-9 in electron-dense podocyte immune deposits. Preliminary in vitro experiments showed an increase of SOD2 expression on podocyte plasma membrane after treatment with hydrogen peroxide. In conclusion, our data support AR and SOD2 as renal antigens of human MN and suggest that oxidative stress may drive glomerular SOD2 expression. PMID:20150532

  3. Vitamin E and diabetic nephropathy in mice model and humans

    PubMed Central

    Farid, Nakhoul; Inbal, Dahan; Nakhoul, Nakhoul; Evgeny, Farber; Miller-Lotan, Rachel; Levy, Andrew P; Rabea, Asleh

    2013-01-01

    Diabetes mellitus (DM) is associated with increased oxidative stress due to elevated glucose levels in the plasma. Glucose promotes glycosylation of both plasma and cellular proteins with increased risk for vascular events. Diabetic patients suffer from a higher incidence of cardiovascular complications such as diabetic nephropathy. Haptoglobin (Hp) is an antioxidant plasma protein which binds free hemoglobin, thus preventing heme-iron mediated oxidation. Two alleles exist at the Hp gene locus (1 and 2) encoding three possible Hp genotypes that differ in their antioxidant ability, and may respond differently to vitamin E treatment. Several clinical studies to have shown that Hp 1-1 genotype is a superior antioxidant to the Hp 2-2 genotype and Hp 2-2 genotype is associated with a higher incidence of cardiovascular disease. Vitamin E was found to have beneficial effect in patient and mice with Hp 2-2 genotype. In this review we have summarized the results of our studies in patients with diabetic nephropathy treated with vitamin E and in diabetic mice with different haptoglobin genotypes. PMID:24255894

  4. Reactive oxygen species in diabetic nephropathy: friend or foe?

    PubMed

    Bondeva, Tzvetanka; Wolf, Gunter

    2014-11-01

    Based on the numerous cellular and animal studies over the last decades, it has been postulated that reactive oxygen species (ROS) are important secondary messengers for signalling pathways associated with apoptosis, proliferation, damage and inflammation. Their adverse effects were considered to play a leading role in the onset and progression of type 1 and type 2 diabetes mellitus as well as in the complication of diabetic disease leading to vascular-, cardiac-, neuro-degeneration, diabetic retinopathy and diabetic nephropathy. All these complications were mostly linked to the generation of the superoxide anion, due to a prolonged hyperglycaemia in diabetes, and this anion was almost 'blamed for everything', despite the fact that its measurement and detection in life systems is extremely complicated due to the short lifespan of the superoxide anion. Therefore, a tremendous amount of research has been focused on finding ways to suppress ROS production. However, a recent report from Dugan et al. shed new insights into the life detection of superoxide generation in diabetes and raised the question of whether we treat the diabetes-related complications correctly or the target is somewhat different as thought. This review will focus on some aspects of this novel concept for the role of ROS in diabetic nephropathy. PMID:24589719

  5. Living donor kidney transplantation in patients with hereditary nephropathies.

    PubMed

    Niaudet, Patrick

    2010-12-01

    Patients with some hereditary nephropathies-including autosomal dominant polycystic kidney disease (ADPKD), Fabry disease and Alport syndrome-can progress to end-stage renal disease (ESRD) and are candidates for kidney transplantation. When considering whether a potential living donor is appropriate for a particular patient, clinicians should be aware of the increased risk of adverse outcomes for the donor and the recipient. Renal transplantation from a living related donor is not contraindicated in most nephropathies that have an autosomal recessive mode of inheritance (for example, autosomal recessive polycystic kidney disease and cystinosis). Renal transplant recipients with ADPKD, however, should only receive a kidney from a related donor if the disease has been excluded in the donor by imaging and/or genetic testing. Potential living related donors for patients with Alport syndrome should be evaluated carefully for the presence of microhematuria and microalbuminuria before a decision is made to perform transplantation, and mothers or heterozygous sisters of affected male recipients with X-linked Alport syndrome should be informed about the possible long-term increased risk of renal dysfunction associated with donation. Most patients with atypical hemolytic uremic syndrome should not receive a kidney transplant from a living donor because there is a high risk of disease recurrence and graft loss. PMID:20877305

  6. Rutin ameliorates kidney interstitial fibrosis in rats with obstructive nephropathy.

    PubMed

    Wang, Bin; Liu, Ding; Zhu, Qiu-Hua; Li, Min; Chen, Hua; Guo, Ying; Fan, Li-Pei; Yue, Liang-Sheng; Li, Liu-Yang; Zhao, Ming

    2016-06-01

    Rutin reportedly conveys many beneficial effects, including renoprotection; however, it has not yet been demonstrated to have a renoprotective effect against obstructive nephropathy. The present study is the first to show a protective effect of rutin against obstructive renal injury induced by unilateral ureteral obstruction (UUO). A total of 24 male Wistar rats were randomly divided into four groups of six rats each, including vehicle- or rutin-treated sham operated groups, and vehicle- or rutin-treated UUO groups. Rats received daily oral gavage of rutin (100mg/kg) for 2weeks. All rats were euthanized on postoperative day 14. Histological findings showed that rutin administration significantly reduced renal interstitial injury and suppressed interstitial collagen deposits in UUO rats. Moreover, rutin decreased macrophage infiltration, proinflammatory cytokine expression and phosphorylation of nuclear factor-κB p65. Furthermore, rutin inhibited extracellular matrix accumulation by reducing expression of type I/III collagen and fibronectin. Rutin also prevented the epithelial-mesenchymal transition processes of renal tubular cells by decreasing α-smooth muscle actin expression and retaining E-cadherin expression. These effects of rutin were in parallel with the reductions in Smad3 activity and pivotal to the fibrogenic potential of TGF-β1. Taken together, the renoprotective effects of rutin in obstructive nephropathy were likely due to anti-inflammatory effects and inhibition of TGF-β1/Smad3 signaling. PMID:27035719

  7. Mesoamerican nephropathy: a neglected tropical disease with an infectious etiology?

    PubMed

    Murray, Kristy O; Fischer, Rebecca S B; Chavarria, Denis; Duttmann, Christiane; Garcia, Melissa N; Gorchakov, Rodion; Hotez, Peter J; Jiron, William; Leibler, Jessica H; Lopez, Job E; Mandayam, Sreedhar; Marin, Alejandro; Sheleby, Jessica

    2015-10-01

    An outbreak of unexplained and severe kidney disease, "Mesoamerican Nephropathy," in mostly young, male sugar cane workers emerged in Central America in the late 1990's. As a result, an estimated 20,000 individuals have died, to date. Unfortunately, and with great consequence to human life, the etiology of the outbreak has yet to be identified. The sugarcane fields in Chichigalpa, Chinandega, Nicaragua, have been involved in the outbreak, and during our initial investigation, we interviewed case patients who experienced fever, nausea and vomiting, arthralgia, myalgia, headache, neck and back pain, weakness, and paresthesia at the onset of acute kidney disease. We also observed a heavy infestation of rodents, particularly of Sigmodon species, in the sugarcane fields. We hypothesize that infectious pathogens are being shed through the urine and feces of these rodents, and workers are exposed to these pathogens during the process of cultivating and harvesting sugarcane. In this paper, we will discuss the epidemic in the Chichigalpa area, potential pathogens responsible for Mesoamerican Nephropathy, and steps needed in order to diagnose, treat, and prevent future cases from occurring. PMID:26320026

  8. Low molecular weight proteinuria in Chinese herbs nephropathy.

    PubMed

    Kabanda, A; Jadoul, M; Lauwerys, R; Bernard, A; van Ypersele de Strihou, C

    1995-11-01

    Urinary excretion of five low molecular weight proteins (LMWP) [beta 2-microglobulin (beta 2m), cystatin C (cyst C), Clara cell protein (CC16), retinol-binding protein (RBP) and alpha 1-microglobulin (alpha 1m)], albumin and N-acetyl-beta-D-glucosaminidase (NAG) were quantified in 16 patients who followed a weight reduction program which included Chinese herbs, which have been incriminated in the genesis of Chinese herbs nephropathy (CHN). An additional group of four patients transplanted for CHN were investigated. Urinary data were obtained for comparison purpose in five groups of proteinuric patients: two groups with normal serum creatinine (SCr) and glomerular albuminura [12 patients with diabetes mellitus and microalbuminuria (DN), 10 patients with primary nephrotic syndrome (NS)]; two groups with normal SCr and toxic nephropathy [6 patients with analgesic (AN), 9 patients with cadmium nephropathy (CdN)]; and one group of seven patients with glomerular diseases and increased SCr (GN). Patients were classified according to serum level S beta 2m to take into account the possibility of overflow proteinuria at S beta 2m > or = 5 mg/liter. Three patients (CHN0) with a S beta 2m < 5 mg/liter, had a normal urinary protein pattern including NAG and a normal S beta 2m. Eight patients (CHN1) with a S beta 2m < 5 mg/liter had various abnormalities of their urinary protein pattern. In four of them (CHN1a) only beta 2m, RBP and CC16 were increased while total proteinuria and SCr were normal. In the other four (CHN1b and c) albumin, cyst C, alpha 1m and NAG were also elevated, while total proteinuria and SCr were moderately raised. Five patients (CHN2) with a S beta 2m > or = 5 mg/liter had a markedly increased excretion of all LMWP, albumin and NAG (CHN1 vs. CHN2, P < 0.05) as well as a further increase in total proteinuria and SCr. The urinary LMWP/albumin concentration ratio was strikingly higher in CHN patients than in patients with glomerular albuminuria (CHN1 vs. DN

  9. NMR studies of (U- sup 13 C)cyclosporin A bound to cyclophilin: Bound conformation and protions of cyclosporin involved in binding

    SciTech Connect

    Fesik, S.W.; Gampe, R.T. Jr.; Eaton, H.L.; Gemmecker, G.; Olejniczak, E.T.; Neri, P.; Holzman, T.F.; Egan, D.A.; Edalji, R.; Simmer, R.; Helfrich, R.; Hochlowski, J.; Jackson, M. )

    1991-07-02

    Cyclosporin A (CsA), a potent immunosuppressant, is known to bind with high specificity to cyclophilin (CyP), a 17.7 kDa protein with peptidyl-prolyl isomerase activity. In order to investigate the three-dimensional structure of the CsA/CyP complex, the authors have applied a variety of multidimensional NMR methods in the study of uniformly {sup 13}C-labeled CsA bound to cyclophilin. The {sup 1}H and {sup 13}C NMR signals of cyclosporin A in the bound state have been assigned, and, from a quantitative interpretation of the 3D NOE data, the bound conformation of CsA has been determined. Three-dimensional structures of CsA calculated from the NOE data by using a distance geometry/simulated annealing protocol were found to be very different form previously determined crystalline and solution conformations of uncomplexed CsA. In addition, from CsA/CyP NOEs, the portions of CsA that interact with cyclophilin were identified. For the most part, those CsA residues with NOEs to cyclophilin were the same residues important for cyclophilin binding and immunosuppressive activity as determined from sturcture/activity relationships. The structural information derived in this study together with the known structure/activity relationships for CsA analogues may prove useful in the design of improved immunosuppressants. Moreover, the approach that is described for obtaining the structural information is widely applicable to the study of small molecule/large molecule interactions.

  10. Recent Advances in the Pathogenesis and Management of Cast Nephropathy (Myeloma Kidney)

    PubMed Central

    Stringer, Stephanie; Basnayake, Kolitha; Hutchison, Colin; Cockwell, Paul

    2011-01-01

    Multiple myeloma is an incurable plasma cell malignancy that is often accompanied by renal failure; there are a number of potential causes of this, of which cast nephropathy is the most important. Renal failure is highly significant in myeloma, as patient survival can be stratified by the severity of the renal impairment. Consequently, there is an ongoing focus on the pathological basis of cast nephropathy and the optimal treatment regimens in this setting, including effective chemotherapy regimens to reduce light chain production and emerging extracorporeal techniques to remove circulating light chains. This paper bridges recent advances in the pathogenesis and management of cast nephropathy in multiple myeloma. PMID:22046563

  11. Balkan (endemic) nephropathy and foodborn ochratoxin A: preliminary results of a survey of foodstuffs.

    PubMed

    Krogh, P; Hald, B; Plestina, R; Ceović, S

    1977-06-01

    Ochratoxin A is a nephrotoxic fungal metabolite (mycotoxin) occurring in foodstuffs. The compound is causally associated with mycotoxic porcine nephropathy, a disease comparable with a human kidney disease, Balkan endemic nephropathy. A preliminary survey of home-produced foodstuffs in areas of Yugoslavia revealed that contamination with ochratoxin A is more frequent in an area where Balkan endemic nephropathy is prevalent (endemic area) than in area where this disease is absent. This indicates higher exposure to foodborn ochratoxin A in the endemic area. Thus further evidence is provided supporting the hypothesis that ochratoxin A is a disease determinant of Balkan endemic nephropathyk0 PMID:888703

  12. A novel calcineurin-independent activity of cyclosporin A in Saccharomyces cerevisiae.

    PubMed

    Singh-Babak, Sheena D; Shekhar, Tanvi; Smith, Andrew M; Giaever, Guri; Nislow, Corey; Cowen, Leah E

    2012-10-01

    Fungi rely on regulatory networks to coordinate sensing of environmental stress with initiation of responses crucial for survival. Antifungal drugs are a specific type of environmental stress with broad clinical relevance. Small molecules with antifungal activity are ubiquitous in the environment, and are produced by a myriad of microbes in competitive natural communities. The echinocandins are fungal fermentation products and the most recently developed class of antifungals, with those in clinical use being semisynthetic derivatives that target the fungal cell wall by inhibiting 1,3-β-D-glucan synthase. Recent studies implicate the protein phosphatase calcineurin as a key regulator of cellular stress responses required for fungal survival of echinocandin-induced cell wall stress. Pharmacological inhibition of calcineurin can be achieved using the natural product and immunosuppressive drug cyclosporin A, which inhibits calcineurin by binding to the immunophilin Cpr1. This drug-protein complex inhibits the interaction between the regulatory and catalytic subunits of calcineurin, an interaction necessary for calcineurin function. Here, we report on potent activity of cyclosporin A when combined with the echinocandin micafungin against the model yeast Saccharomyces cerevisiae that is independent of its known mechanism of action of calcineurin inhibition. This calcineurin-independent synergy does not involve any of the 12 immunophilins known in yeast, individually or in combination, and is not mediated by any of the multidrug transporters encoded or controlled by YOR1, SNQ2, PDR5, PDR10, PDR11, YCF1, PDR15, ADP1, VMR1, NFT1, BPT1, YBT1, YNR070w, YOL075c, AUS1, PDR12, PDR1 and/or PDR3. Genome-wide haploinsufficiency profiling (HIP) and homozygous deletion profiling (HOP) strongly implicate the cell wall biosynthesis and integrity pathways as being central to the calcineurin-independent activity of cyclosporin A. Thus, systems level chemical genomic approaches implicate

  13. Cyclosporine-impregnated allograft bone sterilized with low-temperature plasma.

    PubMed

    Lu, Haibo; Pei, Guoxian; Zhao, Peiran; Liang, Shuangwu; Jin, Dan; Jiang, Shan

    2010-12-01

    Deep-freezing, freeze-drying and gamma (γ)-irradiation have deleterious effects on bone healing and mechanical properties of allograft bones. We tried preparing bone allografts using cyclosporine plus low-temperature-plasma sterilization. To explore the feasibility of this method of preparation, segmental defects in the right radii of rabbits were repaired with cyclosporine-impregnated allograft bones (CABs) sterilized with low-temperature-plasma (in the study group) and deep-frozen/freeze-dried irradiated allograft bones (D/FIABs) (in the control group). X-ray and quantitative histological analysis, peripheral blood T lymphocyte subset analysis and CD₂₅ molecule immunohistochemistry stain, the four-point bending test and safety evaluations were respectively conducted to compare bone-healing, immunosuppression, mechanical properties and safety between the two groups. X-ray scores were higher in the study group than those in the control (p = 0.032). There were significant differences in new bone areas at most repairs in both groups (p < 0.05). There were no significant differences in the percentages of CD₄(+) T, CD₈(+) T, ratios of CD₄(+) T:CD₈(+) T or serum concentrations of GPT/Cr in both groups (p > 0.05). At 16 weeks postoperatively, the density of CD₂₅ molecules in the control group was higher than that in the study group. The ultimate loading in the study group was significantly higher than that in the control (p = 0.048). Bone marrow stromal cells (BMSCs) grew thickly around and on the surface of a cyclosporine-impregnated allograft. Livers and kidneys in the study and control groups remained histologically normal at 7 days postoperatively. These results indicate that the CAB might be a better material than the D/FIAB in terms of bone healing, preservation of mechanical properties and immunosuppression without severe side-effects. PMID:20665654

  14. Skeletal muscle ischemia-reperfusion injury and cyclosporine A in the aging rat.

    PubMed

    Pottecher, Julien; Kindo, Michel; Chamaraux-Tran, Thiên-Nga; Charles, Anne-Laure; Lejay, Anne; Kemmel, Véronique; Vogel, Thomas; Chakfe, Nabil; Zoll, Joffrey; Diemunsch, Pierre; Geny, Bernard

    2016-06-01

    Old patients exhibit muscle impairments and increased perioperative risk during vascular surgery procedures. Although aging generally impairs protective mechanisms, data are lacking concerning skeletal muscle in elderly. We tested whether cyclosporine A (CsA), which protects skeletal muscle from ischemia-reperfusion (IR) in young rats, might reduce skeletal muscle mitochondrial dysfunction and oxidative stress in aging rats submitted to hindlimb IR. Wistar rats aged 71-73 weeks were randomized to IR (3 h unilateral tourniquet application and 2 h reperfusion) or IR + CsA (10 mg/kg cyclosporine IV before reperfusion). Maximal oxidative capacity (VM ax ), acceptor control ratio (ACR), and relative contribution of the mitochondrial respiratory chain complexes II, III, IV (VS ucc ), and IV (VTMPD /Asc ), together with calcium retention capacity (CRC) a marker of apoptosis, and tissue reactive oxygen species (ROS) production were determined in gastrocnemius muscles from both hindlimbs. Compared to the nonischemic hindlimb, IR significantly reduced mitochondrial coupling, VMax (from 7.34 ± 1.50 to 2.87 ± 1.22 μMO2 /min/g; P < 0.05; -70%), and VS ucc (from 6.14 ± 1.07 to 3.82 ± 0.83 μMO2 /min/g; P < 0.05; -42%) but not VTMPD /Asc . IR also decreased the CRC from 15.58 ± 3.85 to 6.19 ± 0.86 μMCa(2+) /min/g; P < 0.05; -42%). These alterations were not corrected by CsA (-77%, -49%, and -32% after IR for VM ax, VS ucc , and CRC, respectively). Further, CsA significantly increased ROS production in both hindlimbs (P < 0.05; +73%). In old rats, hindlimb IR impairs skeletal muscle mitochondrial function and increases oxidative stress. Cyclosporine A did not show protective effects. PMID:26787364

  15. Clinical variability of cyclosporine pharmacokinetics in adult and pediatric patients after renal, cardiac, hepatic, and bone-marrow transplants.

    PubMed

    Clardy, C W; Schroeder, T J; Myre, S A; Wadhwa, N K; Pesce, A J; First, M R; McEnery, P T; Balistreri, W F; Harris, R E; Melvin, D B

    1988-10-01

    The most important limitation associated with the clinical use of cyclosporine is the narrow therapeutic range between its efficacy and toxicity. Effective treatment is further complicated by significant variation in intrapatient and interpatient pharmacokinetics of the drug. We describe a practical approach to pharmacokinetic analysis that does not interfere with the cyclosporine dosage regimen or with clinical management of the patient. To optimize therapy, we individualized patient management by using noncompartmental pharmacokinetic analysis. Mean residence time (MRT) and volume of distribution at steady-state were calculated from data on concentration vs time after dose. We applied this approach to 24 kidney, 12 heart, 8 bone-marrow, 7 liver, and 5 pancreas transplants. Individualized requirements for cyclosporine dose and dosage interval can be predicted from these parameters. MRT is the most useful pharmacokinetic parameter, because it allows prediction of the optimal dosage interval. PMID:3048779

  16. A case report of an anorexia nervosa patient with end-stage renal disease due to pseudo Bartter's syndrome and Chinese herb nephropathy requiring maintenance hemodialysis.

    PubMed

    Wada, Kentaro; Shinoda, Toshio

    2008-10-01

    The extent of end stage renal disease (ESRD) has not been well documented in anorexia nervosa (AN). We herein describe a 47-year-old female with ESRD who required maintenance hemodialysis (HD) following a 27 year history of AN, and seven years of diuretic and purgative abuse. In spite of HD treatment, her serum inorganic phosphorus level remained elevated (10.2-15.8 mg/dL). Tissue degradation due to catabolism, insufficient dialysis treatment, and use of Chinese herbal medicine, including aristolochic acid, are speculated as the cause of her hyperphosphatemia. We also speculated that the causes of her renal dysfunction are as follows: chronic interstitial nephritis caused by pseudo Bartter's syndrome resulting from chronic abuse of diuretics and purgatives, and Chinese herb nephropathy. PMID:18937729

  17. SUCCESSFUL SMALL BOWEL ALLOTRANSPLANTATION IN DOGS WITH CYCLOSPORINE AND PREDNISONE1

    PubMed Central

    Diliz-Perez, Hector S.; McClure, John; Bedetti, Carlos; Hong, He-Qun; de Santibanes, Eduardo; Shaw, Byers W.; Van Thiel, David; Iwatsuki, Shunzaburo; Starzl, Thomas E.

    2010-01-01

    Twelve dogs had transplantation of almost the entire small intestine in the orthotopic location; immunosuppression was with cyclosporine and prednisone. Half the dogs had survival of at least one month, and a third lived for at least four months. Two of the animals are still living after 550 and 555 days. Maintenance of nutrition, and absorption of D-xylose and fat were better than in control animals with an iatrogenic short gut syndrome, but distinctly worse than that of normal dogs. PMID:6695451

  18. Induction therapy with a combination of fumarates and cyclosporine: A benefit for the patient?

    PubMed

    Fallah Arani, S; Neumann, H A M; Thio, H B

    2016-08-01

    Fumarates or fumaric acid esters derivates (FAED) have appeared to be effective and less toxic than other systemic treatments for psoriasis. Due to its safe adverse event profile, FAED can be used as a long-term maintenance therapy. One of the greatest reasons why FAED are not preferred as a first-line treatment is that according to the recommended dosing schedule, clinically meaningful improvement is seen just after 6 to 8 weeks of therapy. In this manuscript, we suppose an alternative induction scheme with a combination therapy of fumarates and cyclosporine for a more rapid improvement and better compliance. PMID:26651839

  19. Interaction between castanospermine an immunosuppressant and cyclosporin A in rat cardiac transplantation

    PubMed Central

    Hibberd, Adrian D; Clark, David A; Trevillian, Paul R; Mcelduff, Patrick

    2016-01-01

    AIM: To investigate the interaction between castanospermine and cyclosporin A (CsA) and to provide an explanation for it. METHODS: The alkaloid castanospermine was prepared from the seeds of Castanospermum austral consistently achieving purity. Rat heterotopic cardiac transplantation and mixed lymphocyte reactivity were done using genetically inbred strains of PVG (donor) and DA (recipient). For the mixed lymphocyte reaction stimulator cells were irradiated with 3000 rads using a linear accelerator. Cyclosporin A was administered by gavage and venous blood collected 2 h later (C2). The blood levels of CsA (Neoral) were measured by immunoassay which consisted of a homogeneous enzyme assay (EMIT) on Cobas Mira. Statistical analyses of interactions were done by an accelerated failure time model with Weibull distribution for allograft survival and logistic regression for the mixed lymphocyte reactivity. RESULTS: Castanospermine prolonged transplant survival times as a function of dose even at relatively low doses. Cyclosporin A also prolonged transplant survival times as a function of dose particularly at doses above 2 mg/kg. There were synergistic interactions between castanospermine and CsA in the prolongation of cardiac allograft survival for dose ranges of CsA by castanospermine of (0 to 2) mg/kg by (0 to 200) mg/kg (HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) and (0 to 3) mg/kg by (0 to 100) mg/kg (HR = 0.986; 95%CI: 0.981-0.992; P < 0.001) respectively. The addition of castanospermine did not significantly increase the levels of cyclosporin A on day 3 or day 6 for all doses of CsA. On the contrary, cessation of castanospermine in the presence of CsA at 2 mg/kg significantly increased the CsA level (P = 0.002). Castanospermine inhibited mixed lymphocyte reactivity in a dose dependent manner but without synergistic interaction. CONCLUSION: There is synergistic interaction between castanospermine and CsA in rat cardiac transplantation. Neither the mixed lymphocyte

  20. The effect of cyclosporin A on peripheral blood T cell subpopulations in renal allografts.

    PubMed Central

    Sweny, P; Tidman, N

    1982-01-01

    Treatment with cyclosporin A (CyA) produces a reversal of the normal ratio of OKT4+ (inducer type) to OKT84 (suppressor-cytotoxic type) cells so that renal allograft recipients on CyA alone develop a four-fold increase in the absolute number of circulating OKT8 positive cells. Conventional immunosuppression with azathioprine and prednisolone reduces both populations of T cells without altering the ratio of OKT4+ to OKT8+ cells. This effect of CyA may help to explain its action as an immunosuppressive agent. PMID:6210475

  1. Successful treatment of severe arthralgia associated with palmoplantar pustulosis with low-dose oral cyclosporine A.

    PubMed

    Yamamoto, T; Kimura, K; Katayama, I; Nishioka, K

    1995-07-01

    Two patients with severe arthralgia associated with palmoplantar pustulosis (PPP) were treated with oral cyclosporine A (CsA). Clinical efficacy was assessed on a 0-4 point scale for erythema, desquamation, infiltration, and pustulation, and on a 0-3 point pain scale. Skin lesions and arthralgia improved within twelve weeks with low dose CsA ranging from 2.1 to 2.2 mg/kg/day. High levels of plasma interleukin-6 (IL-6) were reduced to the normal range. PMID:7560444

  2. Higher plasma bilirubin predicts veno-occlusive disease in early childhood undergoing hematopoietic stem cell transplantation with cyclosporine

    PubMed Central

    Kim, Kwi Suk; Moon, Aree; Kang, Hyoung Jin; Shin, Hee Young; Choi, Young Hee; Kim, Hyang Sook; Kim, Sang Geon

    2016-01-01

    AIM: To analyze the association between plasma bilirubin levels and veno-occlusive disease (VOD) in non-adult patients undergoing hematopoietic stem cell transplantation (HSCT) during cyclosporine therapy. METHODS: A total of 123 patients taking cyclosporine were evaluated using an electronic medical system at the Seoul National University Children’s Hospital from the years 2004 through 2011. Patients were grouped by age and analyzed for incidence and type of adverse drug reactions (ADRs) including VOD. RESULTS: The HSCT patients were divided into three age groups: G#1 ≥ 18; 9 ≤ G#2 ≤ 17; and G#3 ≤ 8 years of age). The majority of transplant donor types were cord blood transplantations. Most prevalent ADRs represented acute graft-vs-host disease (aGVHD) and VOD. Although the incidences of aGVHD did not vary among the groups, the higher frequency ratios of VOD in G#3 suggested that an age of 8 or younger is a risk factor for developing VOD in HSCT patients. After cyclosporine therapy, the trough plasma concentrations of cyclosporine were lower in G#3 than in G#1, indicative of its increased clearance. Moreover, in G#3 only, a maximal total bilirubin level (BILmax) of ≥ 1.4 mg/dL correlated with VOD incidence after cyclosporine therapy. CONCLUSION: HSCT patients 8 years of age or younger are more at risk for developing VOD, diagnosed as hyperbilirubinemia, tender hepatomegaly, and ascites/weight gain after cyclosporine therapy, which may be represented by a criterion of plasma BILmax being ≥ 1.4 mg/dL, suggestive of more sensitive VOD indication in this age group. PMID:27358786

  3. Abbott’s Fluorescence Polarization Immunoassay for Cyclosporine and Metabolites Compared with the Sandoz “Sandimmune” RIA

    PubMed Central

    Sanghvi, Ajit; Diven, Warren; Seltman, Howard; Starzl, Thomas

    2010-01-01

    A new procedure for measuring cyclosporine in plasma has been introduced by Abbott Laboratories, involving their TDx instrumentation and fluorescence polarization immunoassay. Radioimmunoassay (RIA) and high-performance liquid chromatography are currently the conventional methods for measuring cyclosporine in plasma and whole blood. In an effort to find a method that will decrease the radioactive hazard, the reagent and supply cost, and the labor requirements associated with RIA procedures, we used specimens from transplantation patients to compare the Abbott assay with the Sandoz Sandimmune assay. We believe that the Abbott assay offers some advantages over the Sandimmune RIA procedure, providing a reliable but simpler and less hazardous technology. PMID:3416444

  4. Differential effects of cyclosporin A on transport of bile acids by rat hepatocytes: relationship to individual serum bile acid levels.

    PubMed

    Azer, S A; Stacey, N H

    1994-02-01

    Cyclosporin A treatment has been reported to induce hepatotoxicity marked by a rise in total serum bile acid and total bilirubin. The mechanism of cyclosporin A-induced hepatotoxicity seems to be related to interference with hepatocellular transport of these substrates although this remains to be fully substantiated. The purpose of this study was to investigate whether the hepatocellular uptake of the different bile acids, in the presence of cyclosporin A, is consistent with the changes in their respective individual serum bile acid concentrations. High-performance liquid chromatography has been used to assay individual serum bile acids in cyclosporin A-treated rats at doses of 0.1, 1, and 10 mg/kg/day for 4 days. Control rats were treated with Cremophor (1 ml/kg/day). At the higher doses, cyclosporin A produced a significant increase in levels of cholic acid, taurocholic acid, chenodeoxycholic acid, and deoxycholic acid compared with controls. Serum glycocholate was unaffected even at the highest dose. Inhibition of initial rate of uptake and accumulation of [14C]cholic acid, [14C]chenodeoxycholic acid, and [14C]deoxycholic acid by isolated rat hepatocytes was consistent with the changes in their respective serum bile acids. Coincubation of rat hepatocytes with unlabeled cholic acid (100 microM), the major serum bile acid in cyclosporin A-treated rats, showed a further inhibitory effect on [14C]cholic acid and [14C]deoxycholic acid accumulation. The initial rate of uptake of [14C]glycocholate was also inhibited. However, accumulation of glycocholic acid did not show significant changes at the longer incubation times (2-30 min). In addition, coincubation of rat hepatocytes with unlabeled cholic acid (100 microM) plus cyclosporin A did not induce any inhibition of glycocholate accumulation. Together, these differences provide an explanation for the unchanged serum levels of glycocholate. In conclusion, the changes in individual serum bile acids in cyclosporin A

  5. Association Analysis of Dyslipidemia-Related Genes in Diabetic Nephropathy

    PubMed Central

    McKay, Gareth J.; Savage, David A.; Patterson, Christopher C.; Lewis, Gareth; McKnight, Amy Jayne; Maxwell, Alexander P.

    2013-01-01

    Type 1 diabetes (T1D) increases risk of the development of microvascular complications and cardiovascular disease (CVD). Dyslipidemia is a common risk factor in the pathogenesis of both CVD and diabetic nephropathy (DN), with CVD identified as the primary cause of death in patients with DN. In light of this commonality, we assessed single nucleotide polymorphisms (SNPs) in thirty-seven key genetic loci previously associated with dyslipidemia in a T1D cohort using a case-control design. SNPs (n = 53) were genotyped using Sequenom in 1467 individuals with T1D (718 cases with proteinuric nephropathy and 749 controls without nephropathy i.e. normal albumin excretion). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK to compare allele frequencies in cases and controls. In a sensitivity analysis, samples from control individuals with reduced renal function (estimated glomerular filtration rate<60 ml/min/1.73 m2) were excluded. Correction for multiple testing was performed by permutation testing. A total of 1394 samples passed quality control filters. Following regression analysis adjusted by collection center, gender, duration of diabetes, and average HbA1c, two SNPs were significantly associated with DN. rs4420638 in the APOC1 region (odds ratio [OR]  = 1.51; confidence intervals [CI]: 1.19–1.91; P = 0.001) and rs1532624 in CETP (OR = 0.82; CI: 0.69–0.99; P = 0.034); rs4420638 was also significantly associated in a sensitivity analysis (P = 0.016) together with rs7679 (P = 0.027). However, no association was significant following correction for multiple testing. Subgroup analysis of end-stage renal disease status failed to reveal any association. Our results suggest common variants associated with dyslipidemia are not strongly associated with DN in T1D among white individuals. Our findings, cannot entirely exclude these key genes which are central to the process of

  6. Alterations of urinary metabolite profile in model diabetic nephropathy

    SciTech Connect

    Stec, Donald F.; Wang, Suwan; Stothers, Cody; Avance, Josh; Denson, Deon; Harris, Raymond; Voziyan, Paul

    2015-01-09

    Highlights: • {sup 1}H NMR spectroscopy was employed to study urinary metabolite profile in diabetic mouse models. • Mouse urinary metabolome showed major changes that are also found in human diabetic nephropathy. • These models can be new tools to study urinary biomarkers that are relevant to human disease. - Abstract: Countering the diabetes pandemic and consequent complications, such as nephropathy, will require better understanding of disease mechanisms and development of new diagnostic methods. Animal models can be versatile tools in studies of diabetic renal disease when model pathology is relevant to human diabetic nephropathy (DN). Diabetic models using endothelial nitric oxide synthase (eNOS) knock-out mice develop major renal lesions characteristic of human disease. However, it is unknown whether they can also reproduce changes in urinary metabolites found in human DN. We employed Type 1 and Type 2 diabetic mouse models of DN, i.e. STZ-eNOS{sup −/−} C57BLKS and eNOS{sup −/−} C57BLKS db/db, with the goal of determining changes in urinary metabolite profile using proton nuclear magnetic resonance (NMR). Six urinary metabolites with significantly lower levels in diabetic compared to control mice have been identified. Specifically, major changes were found in metabolites from tricarboxylic acid (TCA) cycle and aromatic amino acid catabolism including 3-indoxyl sulfate, cis-aconitate, 2-oxoisocaproate, N-phenyl-acetylglycine, 4-hydroxyphenyl acetate, and hippurate. Levels of 4-hydroxyphenyl acetic acid and hippuric acid showed the strongest reverse correlation to albumin-to-creatinine ratio (ACR), which is an indicator of renal damage. Importantly, similar changes in urinary hydroxyphenyl acetate and hippurate were previously reported in human renal disease. We demonstrated that STZ-eNOS{sup −/−} C57BLKS and eNOS{sup −/−} C57BLKS db/db mouse models can recapitulate changes in urinary metabolome found in human DN and therefore can be

  7. The Application of AN Electronic Nose as a Predictive Technique against Human Diabetic Nephropathy

    NASA Astrophysics Data System (ADS)

    Mohamed, E. I.; Festuccia, A. M.; Martinelli, E.; Andreoli, A.; Martini, A.; di Natale, C.; de Lorenzo, A.

    2000-12-01

    The aim of this study is to apply electronic nose (EN) technology as an alternative method for fast monitoring of metabolic clearances and nephropathy insurgence in diabetics. This will be performed through urine analyses of diabetic patients and healthy subjects.

  8. Molecular Insights into the Pathogenesis of IgA Nephropathy.

    PubMed

    Robert, Thomas; Berthelot, Laureline; Cambier, Alexandra; Rondeau, Eric; Monteiro, Renato C

    2015-12-01

    Immunoglobulin IgA nephropathy (IgAN) is the leading form of primary glomerulonephritis associated with end-stage renal failure, requiring either dialysis or renal transplantation. Microscopic hematuria and proteinuria are the most common presentations, and mesangial cell proliferation with IgA deposition are found in renal biopsies. There is growing evidence that IgAN is an immune complex (IC)-mediated disease. To date, three key molecules have been implicated in IC formation, correlating with disease progression/recurrence after transplantation: galactose-deficient IgA1 (Gd-IgA1), IgG anti-Gd-IgA1 antibodies, and soluble CD89 (an Fc receptor for IgA). This review examines recent data on the role of these molecular players in IgAN. Understanding these factors is essential because such knowledge could lead to improved strategies for the future management of patients with IgAN. PMID:26614735

  9. Membranous nephropathy in the cat: a clinical and pathological study.

    PubMed

    Nash, A S; Wright, N G; Spencer, A J; Thompson, H; Fisher, E W

    1979-07-28

    A series of 13 cases of feline membranous nephropathy is presented. Two groups were distinguished clinically; eight cats had the nephrotic syndrome and five others were in renal failure but not nephrotic. The definitive diagnosis was based on histological, immunofluorescence and ultrastructural examinations of renal tissue obtained at renal biopsy or necropsy. Glomerular lesions were classified according to the degree of glomerular change into three distinct groups; mild, moderately severe and advanced. A relationship was established between the mild and moderately severe groups and cats with the nephrotic syndrome, and the advanced group and cats in renal failure. Diuretic therapy was satisfactory in initial control of oedema in the nephrotic cases. Monitoring of previously nephrotic cats for up to three years indicated that the disease is progressive, although in some cases it is sufficiently slow for a cat to live a relatively normal life without continuing treatment. The prognosis for cats presented in renal failure is hopeless. PMID:552741

  10. Prevention of contrast-induced nephropathy: an overview.

    PubMed

    Ellis, James H; Cohan, Richard H

    2009-09-01

    Many unknowns remain concerning how best to reduce a patient's risk of contrast-induced nephropathy (CIN). Many interventions have been proposed, but few have gone unchallenged, and new questions have arisen from analysis of serum creatinine variations in patients who have not been exposed to radiographic iodinated contrast media (RICM). Use of alternate imaging tests that do not use RICM is the most direct way to avoid CIN. Hydration remains the bulwark of intervention when RICM must be administered. The administration of N-acetylcysteine is a popular pharmacologic prophylaxis against CIN but its efficacy is unclear. Hemodialysis has not been effective, but hemofiltration has shown good results in limited series. PMID:19744595

  11. The clinical features of thin basement membrane nephropathy.

    PubMed

    Gregory, Martin C

    2005-05-01

    Thin basement membrane nephropathy (TBMN) is a common, lifelong condition affecting the kidneys that is characterized by microscopic glomerular hematuria, minimal or no proteinuria, and normal renal function. It often is discovered incidentally, and usually has an excellent prognosis. Many cases are familial and show autosomal-dominant inheritance. The defining characteristic is a glomerular basement membrane (GBM) that is thinned to about half its normal thickness on ultrastructural examination of the renal biopsy specimen. However, occasionally patients with TBMN develop marked proteinuria or renal impairment. It is unclear whether individuals with TBMN and impaired renal function represent part of the spectrum of TBMN associated with heterozygous COL4A3 or COL4A4 mutations, or if their disease is caused by mutations of other genes, or whether it is caused by a second coexistent renal lesion or is misdiagnosed Alport syndrome. PMID:15880323

  12. Membranous nephropathy, leiomyoma and autoimmune myasthenia: more than a coincidence?

    PubMed

    Calviño, Jesus; Adeva, Magdalena; Sobrido, Maria-Jesus

    2012-12-01

    Membranous nephropathy (MN) has been associated with several infectious, immunological and malignant conditions, but had only rarely been reported with malignant and other immune disorders in the same patient. We describe the case of a 56-year-old male with MN who was also diagnosed with a gastrointestinal stromal tumour (GIST), myasthenia gravis (MG) and thymic hyperplasia. Thus, we report here for the first time the coincidence of these conditions in the same patient. There was a recurrence of nephrotic syndrome without impairment of renal function 5 years after removal of the GIST (3 years after thymectomy). The possible basis for the relationship between these diseases is discussed, and some common genetic and immune physiopathological pathways are hypothesized. PMID:26069802

  13. Membranous nephropathy, leiomyoma and autoimmune myasthenia: more than a coincidence?

    PubMed Central

    Calviño, Jesus; Adeva, Magdalena; Sobrido, Maria-Jesus

    2012-01-01

    Membranous nephropathy (MN) has been associated with several infectious, immunological and malignant conditions, but had only rarely been reported with malignant and other immune disorders in the same patient. We describe the case of a 56-year-old male with MN who was also diagnosed with a gastrointestinal stromal tumour (GIST), myasthenia gravis (MG) and thymic hyperplasia. Thus, we report here for the first time the coincidence of these conditions in the same patient. There was a recurrence of nephrotic syndrome without impairment of renal function 5 years after removal of the GIST (3 years after thymectomy). The possible basis for the relationship between these diseases is discussed, and some common genetic and immune physiopathological pathways are hypothesized. PMID:26069802

  14. Treatment of progressive IgA nephropathy: an update.

    PubMed

    Wang, Weiming; Chen, Nan

    2013-01-01

    IgA nephropathy (IgAN) is the most common primary glomerular disease worldwide. About 25-30% of IgAN patients will progress to end-stage kidney disease in 20-25 years. Early-onset symptoms that are highly suggestive of progressive IgAN include massive proteinuria, hypertension, renal damage, glomerular sclerosis, crescent formation, and tubulointerstitial fibrosis. Progressive IgAN may progress to renal failure in a short time. Optimized supportive therapy is the fundamental treatment for progressive IgAN patients, and includes renin-angiotensin system blockers, blood pressure control, antiplatelet and anticoagulant drugs, statins, and allopurinol. In progressive IgAN patients whose clinical and pathological manifestations are more severe, active therapy may be considered including glucocorticoid therapy, cyclophosphamide, azathioprine, mycophenolate mofetil, tacrolimus, and other immunosuppressants. However, there are currently controversies on the definition and treatment of progressive IgAN. PMID:23689569

  15. Significance of unilateral radiation nephropathy. [/sup 60/Co; Linear accelerator

    SciTech Connect

    Kim, T.H.; Freeman, C.R.; Webster, J.H.

    1980-11-01

    Thirteen patients with non-Hodgkin's lymphoma with residual disease in the abdomen were treated by irradiation to the whole abdomen and left upper quadrant. The entire or half of the left kidney received between 2550 rad in 6 weeks and 4900 rad in 5 weeks. Seven of 12 patients evaluated showed functional and/or morphological changes in the left kidney on renal function studies and renal scan at various intervals. None of these patients clinically demonstrated overt acute radiation nephropathy. Three patients developed elevated blood pressure; the plasma renin level was markedly elevated in one of these patients. With the possible exception of one patient, no patient was discovered to have any functional morphological changes in the right kidney. The lymphoma in the abdomen was under control in 12 out of 13 patients treated at this writing.

  16. Canine mammary carcinoma cell line are resistant to chemosensitizers: verapamil and cyclosporin A.

    PubMed

    Król, M; Pawłowski, K M; Majchrzak, K; Mucha, J; Motyl, T

    2014-01-01

    Cancer chemotherapy can fail in many ways. One of the most significant is the development of multiple drug resistance (MDR), which constitutes a serious clinical problem. The development of MDR relates to the expression of a major membrane pump, P-glycoprotein (P-gp). Thus, currently one of the goals of experimental and clinical oncology is to decrease its activity. So far, many different P-gp inhibitors are available, but their efficacy is still questionable and requires further study. The aim of our study was to assess an impact of classical P-gp inhibitors (verapamil and cyclosporin A) in the reversion of multidrug resistance in canine mammary cancer cells. We used two cell lines isolated from mammary tumors and two cell lines isolated from their lung metastases. All of them showed P-gp over-expression confirmed using Real-time rt-PCR, Skan(R) screening station and confocal microscopy. The FACS analysis showed that in three of the examined cell lines, treatment with verpamil/cyclosporin A was ineffective to reverse cancer chemoresistance. However, more studies in this field are required. PMID:24724465

  17. Early non-steady-state population pharmacokinetics of oral cyclosporine in renal transplant recipients

    PubMed Central

    Baek, Hyunjeong; Han, Seunghoon; Yim, Dong-Seok; Kim, Sung Joo; Lee, Soo-Youn; Jang, Hye Ryoun; Lee, Jung Eun; Kim, Dae Joong; Kim, Yoon-Goo; Oh, Ha Young; Huh, Wooseong

    2014-01-01

    This study aimed to evaluate the change in the pharmacokinetics (PK) of cyclosporine in the non-steady-state period in the first week after renal transplantation; the factors influencing this change, including genetic variability; and the time point concentration that correlated best with drug exposure. Data were obtained from 69 patients, and PK studies were conducted on postoperative days (PODs) 2, 3, and 7. Samples were taken pre-dose and at 1, 2, 3, 4, 6, 8, and 12 hours after drug administration. MDR1, CYP3A4, and CYP3A5 were genotyped. A population PK analysis and correlational analysis between the concentration at each time point and the area under the time–concentration curve were performed. A two-compartment model with first-order absorption was chosen. The rate and extent of drug absorption showed a significant increase on POD3, followed by a slight decrease on POD7. Until POD3, 8 hours post-dose was the single time point concentration that correlated best with drug exposure and 3 hours was the best time point on POD7. In both analyses, the MDR1 genotype showed potential as a factor influencing PK change. We conclude that oral administration of cyclosporine and dose adjustment based on a single concentration measurement might result in unexpected drug exposure during this early posttransplantation period. PMID:25422583

  18. Oxidative Stress and Liver Morphology in Experimental Cyclosporine A-Induced Hepatotoxicity

    PubMed Central

    Czechowska, Grażyna; Irla-Miduch, Joanna

    2016-01-01

    Cyclosporine A is an immunosuppressive drug used after organ's transplantation. The adverse effects on such organs as kidney or liver may limit its use. Oxidative stress is proposed as one of the mechanisms of organs injury. The study was designed to elucidate CsA-induced changes in liver function, morphology, oxidative stress parameters, and mitochondria in rat's hepatocytes. Male Wistar rats were used: group A (control) receiving physiological saline, group B cyclosporine A in a dose of 15 mg/kg/day subcutaneously, and group C the CsA-vehicle (olive oil). On the 28th day rats were anesthetized. The following biochemical changes were observed in CsA-treated animals: increased levels of ALT, AST, and bilirubin in the serum, statistically significant changes in oxidative stress parameters, and lipid peroxidation products in the liver supernatants: MDA+4HAE, GSH, GSSG, caspase 3 activity, and ADP/ATP, NAD+/NADH, and NADP+/NADPH ratios. Microscopy of the liver revealed congestion, sinusoidal dilatation, and focal hepatocytes necrosis with mononuclear cell infiltration. Electron microscope revealed marked mitochondrial damage. Biochemical studies indicated that CsA treatment impairs liver function and triggers oxidative stress and redox imbalance in rats hepatocytes. Changes of oxidative stress markers parallel with mitochondrial damage suggest that these mechanisms play a crucial role in the course of CsA hepatotoxicity. PMID:27298826

  19. Biological conversion of a water-soluble prodrug of cyclosporine A.

    PubMed

    Lallemand, F; Varesio, E; Felt-Baeyens, O; Bossy, Leila; Hopfgartner, G; Gurny, R

    2007-09-01

    UNIL088 is a water-soluble prodrug of cyclosporine A (CsA) designed for topical ocular delivery. The pro-moiety is grafted via an ester function to CsA and the solubilizing group is a phosphate ion. The aim of this study was to elucidate the conversion mechanisms by which UNIL088 generates CsA. UNIL088 was incubated in rabbit tears at physiological temperature to study its enzymatic and chemical conversion, respectively. Metabolites and intermediates were identified using a quadrupole-time of flight (QqTOF) mass spectrometer, which allowed biotransformation pathways to be deduced. Conversion is activated by the chemical or enzymatic hydrolysis of the terminal ester function of the pro-moiety, leading to the phospho-serine-sarcosine-cyclosporine A that spontaneously converts into CsA. In addition to the main biotransformation pathway, a secondary reaction involved hydrolysis of the phosphate ester group of the pro-moiety, probably by phosphatases present in tears. PMID:17475453

  20. Expression of amelogenin and effects of cyclosporin A in developing hair follicles in rats.

    PubMed

    Yoo, Hong-Il; Lee, Gye-Hyeok; Lee, Su-Young; Kang, Jee-Hae; Moon, Jung-Sun; Kim, Min-Seok; Kim, Sun-Hun

    2016-01-01

    Amelogenin, an enamel matrix protein has been considered to be exclusively expressed by ameloblasts during odontogenesis. However, burgeoning evidence indicates that amelogenin is also expressed in non-mineralizing tissues. Under the hypothesis that amelogenin may be a functional molecule in developing hair follicles which share developmental features with odontogenesis, this study for the first time elucidated the presence and functional changes of amelogenin and its receptors during rat hair follicle development. Amelogenin was specifically localized in the outer epithelial root sheath of hair follicles. Its expression appeared in the deeper portion of hair follicles, i.e. the bulbar and suprabulbar regions rather than the superficial region. Lamp-1, an amelogenin receptor, was localized in either follicular cells or outer epithelial sheath cells, reflecting functional changes during development. The expression of amelogenin splicing variants increased in a time-dependent manner during postnatal development of hair follicles. Amelogenin expression was increased by treatment with cyclosporin A, which is an inducer of anagen in the hair follicle, whereas the level of Lamp-1 and -2 was decreased by cyclosporin A treatment. These results suggest that amelogenin may be a functional molecule involved in the development of the hair follicle rather than an inert hair shaft matrix protein. PMID:26426935

  1. Human Recombinant ACE2 Reduces the Progression of Diabetic Nephropathy

    PubMed Central

    Oudit, Gavin Y.; Liu, George C.; Zhong, JiuChang; Basu, Ratnadeep; Chow, Fung L.; Zhou, Joyce; Loibner, Hans; Janzek, Evelyne; Schuster, Manfred; Penninger, Josef M.; Herzenberg, Andrew M.; Kassiri, Zamaneh; Scholey, James W.

    2010-01-01

    OBJECTIVE Diabetic nephropathy is one of the most common causes of end-stage renal failure. Inhibition of ACE2 function accelerates diabetic kidney injury, whereas renal ACE2 is downregulated in diabetic nephropathy. We examined the ability of human recombinant ACE2 (hrACE2) to slow the progression of diabetic kidney injury. RESEARCH DESIGN AND METHODS Male 12-week-old diabetic Akita mice (Ins2WT/C96Y) and control C57BL/6J mice (Ins2WT/WT) were injected daily with placebo or with rhACE2 (2 mg/kg, i.p.) for 4 weeks. Albumin excretion, gene expression, histomorphometry, NADPH oxidase activity, and peptide levels were examined. The effect of hrACE2 on high glucose and angiotensin II (ANG II)–induced changes was also examined in cultured mesangial cells. RESULTS Treatment with hrACE2 increased plasma ACE2 activity, normalized blood pressure, and reduced the urinary albumin excretion in Akita Ins2WT/C96Y mice in association with a decreased glomerular mesangial matrix expansion and normalization of increased α-smooth muscle actin and collagen III expression. Human recombinant ACE2 increased ANG 1–7 levels, lowered ANG II levels, and reduced NADPH oxidase activity. mRNA levels for p47phox and NOX2 and protein levels for protein kinase Cα (PKCα) and PKCβ1 were also normalized by treatment with hrACE2. In vitro, hrACE2 attenuated both high glucose and ANG II–induced oxidative stress and NADPH oxidase activity. CONCLUSIONS Treatment with hrACE2 attenuates diabetic kidney injury in the Akita mouse in association with a reduction in blood pressure and a decrease in NADPH oxidase activity. In vitro studies show that the protective effect of hrACE2 is due to reduction in ANG II and an increase in ANG 1–7 signaling. PMID:19934006

  2. Contribution of glomerular morphometry to the diagnosis of pediatric nephropathies.

    PubMed

    Marini, Mariana Barreto; Rocha, Laura Penna; Machado, Juliana Reis; Ramalho, Fernando Silva; Dos Reis, Marlene Antônia; Corrêa, Rosana Rosa Miranda

    2016-05-01

    Only a few studies describe histopathological changes in renal biopsies performed in pediatric patients. This study was conducted to identify an association between morphometric data in renal biopsies and renal function of these patients. Fifty-nine individuals with ages between 2 and 18 years old were selected, who were divided into six groups consisting of frequent nephropathies in children and adolescents and one control group. Proteinuria, urea, and creatinine values of the patients were recorded. Interactive image analysis software Leica QWin[®]was used for morpho- metric analysis of Bowman's capsule, glomerular capillary tuft, and Bowman's space area. The mean glomerular tuft area was higher in the membranous glomerulopathy group than in the podo- cytopathy group (57,101 ± 25,094 vs. 27,420 c ± 6279 µm(2); P <0.05). The median of Bowman's space area was higher in the control group than in the podocytopathy group and in the thin basement membrane/Alport syndrome group [12,210 (7676-26,945) vs. 5801 (3031-7852) µm(2); P <0.01 and 12210 (7676-26,945) vs. 4183 (3797-7992) µm(2); P <0.01, respectively]. There was a positive and significant correlation between Bowman's capsule area and the levels of proteinuria, creatinine, and urea of the patients, as well as between the glomerular tuft area and the levels of proteinuria, creatinine, and urea in the patients, regardless of their nephropathy. Glomerular morphometry may contribute to the diagnosis of some glomerulopathies and the association between glomerular morphometric parameters, and laboratory data may promote a better understanding of the prognosis of these patients. PMID:27215240

  3. The Clinical Epidemiology of Contrast-Induced Nephropathy

    SciTech Connect

    Parfrey, Patrick

    2005-12-15

    Recent improvements in contrast agents and radiologic imaging tools have resulted in an increasing number of patients undergoing contrast media (CM)-enhanced examinations. Although the majority of patients undergoing these diagnostic and therapeutic procedures experience only mild adverse events, some patient subpopulations are at risk for developing contrast-induced nephropathy (CIN), an adverse event that is associated with high morbidity and mortality. Contrast-induced nephropathy is usually defined as an increase of {>=}25% in the serum creatinine level relative to baseline. Pathophysiologic mechanisms underlying this disorder are not fully understood, but it is currently believed that disturbances in renal hemodynamics and a direct effect of CM on renal tubules are involved. In the general population, the incidence of CIN is estimated to be 1% to 6%. However, the risk may be as high as 50% in some patient subgroups. Patients with diabetes and pre-existing renal impairment are at high risk, and CIN incidence increases in patients with multiple comorbidities. The volume and osmolality of CM used also play a role in the development of CIN. Patients who develop CIN are more likely to die in-hospital and, for those who are discharged, 1-year mortality rates are high. Whether this is due to CM, comorbidity, or concurrent comorbid events is unclear. Randomized controlled trials that measure non-renal clinical outcomes are necessary to determine whether interventions that prevent CIN can also prevent non-renal adverse events. A review of the incidence, pathogenesis, and clinical consequences of CIN is provided.

  4. Renal ultrastructural markers in AIDS-associated nephropathy.

    PubMed Central

    Chander, P.; Soni, A.; Suri, A.; Bhagwat, R.; Yoo, J.; Treser, G.

    1987-01-01

    Renal tissues from two groups of patients with acquired immune deficiency syndrome (AIDS) were examined: Group A had severe proteinuria and varying degrees of renal insufficiency, designated AIDS-associated nephropathy (AAN), and Group B had no renal involvement. Control Group C consisted of patients with heroin-associated nephropathy (HAN) with proteinuria comparable to patients in Group A but without AIDS or its related complex (ARC). The most frequent finding, common to both AAN and HAN, was focal glomerular sclerosis. In contrast to HAN, AAN tissue showed mesangial hypocellularity, sparse interstitial infiltrates, severe tubular degenerative changes, tubular microcystic ectasia, Bowman's space dilatation, and presence of multiple complex inclusions both in the nuclei and cytoplasm in a variety of cells. Abundant tubuloreticular inclusions were found in the endothelial and occasionally in the interstitial cell cytoplasm. Nuclear bodies (NBs) were seen in greater frequency, complexity, size, and heterogeneity, and of budding configuration in Group A as compared with Groups B and C; NBs in Group C were mostly of simple types (I and II). In addition, a peculiar granulofibrillary transformation in many tubular and interstitial cell nuclei was observed in Group A. This transformation was rarely present in Group B and was never seen in Group C. Because complex NBs (Types III to V) and various intracytoplasmic and intranuclear inclusions present in Group A are often associated with viral invasion, their presence in kidneys of AIDS patients with proteinuria suggests a viral etiology for AAN. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Figure 10 Figure 11 Figure 12 Figure 13 Figure 14 PMID:3548410

  5. Pathophysiology of radiocontrast nephropathy: a role for medullary hypoxia.

    PubMed

    Heyman, S N; Reichman, J; Brezis, M

    1999-11-01

    Recent experimental data underlies the role of hypoxic tubular injury in the pathophysiology of radiocontrast nephropathy. Although systemic transient hypoxemia, increased blood viscosity, and a leftward shift of the oxygen-hemoglobin dissociation curve may all contribute to intrarenal hypoxia, imbalance between oxygen demand and supply plays a major role in radiocontrast-induced outer medullary hypoxic damage. Low oxygen tension normally exists in this renal region, reflecting the precarious regional oxygen supply and a high local metabolic rate and oxygen requirement, resulting from active salt reabsorption by medullary thick ascending limbs of Henle's loop. Radiologic contrast agents markedly aggravate outer medullary physiologic hypoxia. This results from enhanced metabolic activity and oxygen consumption (as a result of osmotic diuresis and increased salt delivery to the distal nephron) because the regional blood flow and the oxygen supply actually increase. The latter effect may result in part from the activation of various regulatory mediators of outer medullary blood flow to ensure maximal regional oxygen supply. Low-osmolar radiocontrast agents may be less nephrotoxic because of the smaller osmotic load and vasomotor alterations. Experimental radiocontrast-induced renal failure requires preconditioning of animals with various insults (for example, congestive heart failure, reduced renal mass, salt depletion, or inhibition of nitric oxide and prostaglandin synthesis). In all these perturbations, which resemble clinical conditions that predispose to contrast nephropathy, outer medullary hypoxic injury results from insufficiency or inactivation of mechanisms designed to preserve regional oxygen balance. This underlines the importance of identifying and ameliorating predisposing factors in the prevention of this iatrogenic disease. PMID:10548380

  6. Markers for the progression of IgA nephropathy.

    PubMed

    Maixnerova, Dita; Reily, Colin; Bian, Qi; Neprasova, Michaela; Novak, Jan; Tesar, Vladimir

    2016-08-01

    We have summarized the latest findings on markers for progression of immunoglobulin A (IgA) nephropathy (IgAN), the most common primary glomerulonephritis with a high prevalence among end-stage renal disease (ESRD) patients. The clinical predictors of renal outcome in IgAN nephropathy, such as proteinuria, hypertension, and decreased estimated glomerular filtration rate (eGFR) at the time of the diagnosis, are well known. The Oxford classification of IgAN identified four types of histological lesions (known as the MEST score) associated with the development of ESRD and/or a 50 % reduction in eGFR. In addition, the role of genetic risk factors associated with IgAN is being elucidated by genome-wide association studies, with multiple risk alleles described. Recently, biomarkers in serum (galactose-deficient IgA1, IgA/IgG autoantibodies against galactose-deficient IgA1, and soluble CD 89-IgA complexes) and urine (soluble transferrin receptor, interleukin-6/epidermal growth factor ratio, fractalkine, laminin G-like 3 peptide, κ light chains, and mannan-binding lectin) have been identified. Some of these biomarkers may represent candidates for the development of noninvasive diagnostic tests, that would be useful for detection of subclinical disease activity, monitoring disease progression, assessment of treatment, and at the same time circumventing the complications associated with renal biopsies. These advances, along with future disease-specific therapy, will be helpful in improving the treatment effectiveness, prognosis, and the quality of life in connection with IgAN. PMID:27142988

  7. Renal histology in diabetic nephropathy: A novel perspective.

    PubMed

    Sahay, M; Mahankali, R K; Ismal, K; Vali, P S; Sahay, R K; Swarnalata, G

    2014-07-01

    Diabetic nephropathy (DN) is the leading cause of end-stage renal disease all over the world. India has a high incidence and prevalence of diabetes and >30% have nephropathy. Recently, a histological classification has been proposed. This study analyzed the renal histology in 114 diabetic patients with renal dysfunction. Nearly 75% of patients had DN. Fifty five (63.95%) were males. Mean duration of diabetes was 7.04 ± 4.9 years. Mean serum creatinine in study group was 5.2 ± 2.9 mg/dl, with mean estimated glomerular filtration rate of 23.43 ± 21.48 ml/min/1.732 m(2). Forty eight patients (55.81%) had diabetic retinopathy (DR); prevalence of DR was more in patients who had diabetes for > 10 years than patients who had diabetes for <6 years (P = 0.022). The most common histological class was Class IV observed in 37 (43.02. %) cases, Class III DN in 24 (27.90%) cases, Class IIa and Class IIb in 11 (12.79%) cases each and Class I DN in 3 (3.48%) cases. Higher histological class was associated with higher proteinuria, lower glomerular filtration rate (P < 0.001) and was more likely to be associated with retinopathy (P = 0.012) and hypertension (P = 0.0003) but did not correlate with duration of diabetes (P = 0.85). There was a poor correlation between retinopathy and DN. Biopsy helps to stage the renal lesions in diabetics with renal dysfunction. PMID:25097335

  8. Reducing the Risks for Contrast-Induced Nephropathy

    SciTech Connect

    Stacul, Fulvio

    2005-12-15

    Contrast-induced nephropathy (CIN) is one of the most serious adverse events associated with the use of contrast media (CM). Patients who develop this complication can have increased morbidity, higher rates of mortality, lengthy hospital stays, and poor long-term outcomes. Although CIN cannot be eliminated, the chances of developing this condition can be reduced by using appropriate prevention strategies. An important first step to reduce the chance of CIN is to identify risk factors associated with this condition. Patients with a previously elevated serum creatinine level, especially when secondary to diabetic nephropathy, are at great risk for developing CIN. Other patient-related risk factors include concurrent use of nephrotoxic medications, dehydration, congestive heart failure, age greater than 70 years, and probably the presence of diabetes mellitus even if serum creatinine is normal. Adequate hydration is widely accepted as an important prophylactic measure for preventing CIN, but the optimal hydration regimen is still debatable. The risk of CIN increases with greater doses of CM, as well as with the type of CM used. A high-osmolar CM poses a greater risk of CIN than does a low-osmolar CM and, as recent but limited data suggest, the use of an iso-osmolar CM is less nephrotoxic than a low-osmolar CM in patients with renal impairment following intra-arterial procedures, although this finding needs to be verified in future clinical studies. Pharmacologic agents such as calcium channel blockers, dopamine, atrial natriuretic peptide, fenoldopam, prostaglandin E1, and endothelin receptor antagonist have not been proven effective against CIN development. Controversies still exist on the possible effectiveness of theophylline and N-acetylcysteine. Simple strategies for the prevention of CIN in at-risk patients are reviewed and unproven interventions are discussed.

  9. Obstetric nephrology: pregnancy in women with diabetic nephropathy--the role of antihypertensive treatment.

    PubMed

    Mathiesen, Elisabeth R; Ringholm, Lene; Feldt-Rasmussen, Bo; Clausen, Peter; Damm, Peter

    2012-12-01

    This review highlights factors of importance for the clinical care of pregnant women with pregestational diabetes and microalbuminuria or diabetic nephropathy with particular focus on the role of intensive antihypertensive treatment during pregnancy. Most information in the literature comes from women with type 1 diabetes and diabetic nephropathy, but this is probably also valid for women with type 2 diabetes. Careful counseling of women with diabetic nephropathy before pregnancy with estimation of the risk for the mother and fetus is important. Pregnancy does not result in worsening of kidney function in women with diabetic nephropathy and normal serum creatinine, but pregnancy complications such as pre-eclampsia and preterm delivery are common. Intensive metabolic control before and during pregnancy, low-dose aspirin from 12 gestational weeks onward, and intensive antihypertensive treatment are important. Methyldopa, labetalol, and nifedipine are regarded safe in pregnancy, whereas angiotensin converting enzyme inhibitors, AngII antagonists, or statins should be paused before pregnancy. Case series and pathophysiological studies support the use of a stringent goal for BP and albumin excretion in pregnant women with diabetic nephropathy. Screening for diabetic retinopathy before and during pregnancy is mandatory and laser treatment should be performed if indicated. Pregnancy outcome in women with diabetic nephropathy has improved considerably with a take-home-baby rate of approximately 95%. Further research on the benefits and risks of intensive antihypertensive treatment in this population is needed. PMID:22917698

  10. Diabetic nephropathy--a review of the natural history, burden, risk factors and treatment.

    PubMed Central

    Ayodele, Olugbenga E.; Alebiosu, C. Olutayo; Salako, Babatunde L.

    2004-01-01

    The earliest clinical evidence of diabetic nephropathy is microalbuminuria. Progression from microalbuminuria to overt nephropathy occurs in 20-40% within a 10-year period with approximately 20% of these patients progressing to end-stage renal disease. End-stage renal disease develops in 50% of type-1 diabetes patients with overt nephropathy within 10 years and in more than 75% by 20 years in the absence of treatment. In type-2 diabetes, a greater proportion of patients have microalbuminuria and overt nephropathy at or shortly after diagnosis of diabetes. The incidence of diabetes is increasing worldwide, with subsequent increase in the incidence of diabetic nephropathy. The risk factors identified in the development of DN from longitudinal and cross-sectional studies include race, genetic susceptibility, hypertension, hyperglycemia, hyperfiltration, smoking, advanced age, male sex, and high-protein diet. Treatment interventions in diabetic nephropathy include glycemic control, treatment of hypertension, hyperlipidemia, cessation of smoking, protein restriction, and renal replacement therapy. Multifactorial approach includes combined therapy targeting hyperglycemia, hypertension, microalbuminuria, and dyslipidemia. PMID:15586648

  11. Growth Factor Midkine Is Involved in the Pathogenesis of Diabetic Nephropathy

    PubMed Central

    Kosugi, Tomoki; Yuzawa, Yukio; Sato, Waichi; Kawai, Hanayo; Matsuo, Seiichi; Takei, Yoshifumi; Muramatsu, Takashi; Kadomatsu, Kenji

    2006-01-01

    Diabetic nephropathy is a life-threatening disease associated with diabetes mellitus. Longstanding hyperglycemia induces pathological reactions of glomerular mesangial cells, such as overproduction of extracellular matrix, which finally lead to nephropathy. However, the mechanisms underlying its pathogenesis have not been completely elucidated. Using the Streptozotocin-induced model of diabetes, we report that mice deficient in the growth factor midkine (Mdk−/−) exhibited strikingly milder nephropathy than Mdk+/+ mice, even though both mice showed similar extents of hyperglycemia after Streptozotocin injection. Midkine expression was induced in the glomerular mesangium of Mdk+/+ mice with diabetic nephropathy and in primary cultured mesangial cells exposed to high glucose. Mdk−/− mesangial cells exhibited reduced phosphorylation of protein kinase C and extracellular signal-regulated kinase as well as reduced production of transforming growth factor-β1 on high glucose loading. Addition of exogenous midkine restored extracellular signal-regulated kinase phosphorylation in Mdk−/− cells under high glucose conditions, whereas a midkine antisense oligodeoxynucleotide suppressed midkine in Mdk+/+ cells. Therefore, this study identifies midkine as a key molecule in diabetic nephropathy and suggests that midkine accelerates the intracellular signaling network evoked by hyperglycemia in nephropathy. PMID:16400005

  12. Cell biology of diabetic nephropathy: Roles of endothelial cells, tubulointerstitial cells and podocytes

    PubMed Central

    Maezawa, Yoshiro; Takemoto, Minoru; Yokote, Koutaro

    2015-01-01

    Diabetic nephropathy is the major cause of end-stage renal failure throughout the world in both developed and developing countries. Diabetes affects all cell types of the kidney, including endothelial cells, tubulointerstitial cells, podocytes and mesangial cells. During the past decade, the importance of podocyte injury in the formation and progression of diabetic nephropathy has been established and emphasized. However, recent findings provide additional perspectives on pathogenesis of diabetic nephropathy. Glomerular endothelial damage is already present in the normoalbuminuric stage of the disease when podocyte injury starts. Genetic targeting of mice that cause endothelial injury leads to accelerated diabetic nephropathy. Tubulointerstitial damage, previously considered to be a secondary effect of glomerular protein leakage, was shown to have a primary significance in the progression of diabetic nephropathy. Emerging evidence suggests that the glomerular filtration barrier and tubulointerstitial compartment is a composite, dynamic entity where any injury of one cell type spreads to other cell types, and leads to the dysfunction of the whole apparatus. Accumulation of novel knowledge would provide a better understanding of the pathogenesis of diabetic nephropathy, and might lead to a development of a new therapeutic strategy for the disease. PMID:25621126

  13. Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND).

    PubMed

    Iyengar, Sudha K; Sedor, John R; Freedman, Barry I; Kao, W H Linda; Kretzler, Matthias; Keller, Benjamin J; Abboud, Hanna E; Adler, Sharon G; Best, Lyle G; Bowden, Donald W; Burlock, Allison; Chen, Yii-Der Ida; Cole, Shelley A; Comeau, Mary E; Curtis, Jeffrey M; Divers, Jasmin; Drechsler, Christiane; Duggirala, Ravi; Elston, Robert C; Guo, Xiuqing; Huang, Huateng; Hoffmann, Michael Marcus; Howard, Barbara V; Ipp, Eli; Kimmel, Paul L; Klag, Michael J; Knowler, William C; Kohn, Orly F; Leak, Tennille S; Leehey, David J; Li, Man; Malhotra, Alka; März, Winfried; Nair, Viji; Nelson, Robert G; Nicholas, Susanne B; O'Brien, Stephen J; Pahl, Madeleine V; Parekh, Rulan S; Pezzolesi, Marcus G; Rasooly, Rebekah S; Rotimi, Charles N; Rotter, Jerome I; Schelling, Jeffrey R; Seldin, Michael F; Shah, Vallabh O; Smiles, Adam M; Smith, Michael W; Taylor, Kent D; Thameem, Farook; Thornley-Brown, Denyse P; Truitt, Barbara J; Wanner, Christoph; Weil, E Jennifer; Winkler, Cheryl A; Zager, Philip G; Igo, Robert P; Hanson, Robert L; Langefeld, Carl D

    2015-08-01

    Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD. PMID:26305897

  14. Clinical outcomes of kidney transplants on patients with end-stage renal disease secondary to lupus nephritis, polycystic kidney disease and diabetic nephropathy

    PubMed Central

    Nieto-Ríos, John Fredy; Builes-Rodriguez, Sheila Alexandra; Restrepo-Correa, Ricardo Cesar; Aristizabal-Alzate, Arbey; Ocampo-Kohn, Catalina; Serna-Campuzano, Angélica; Cardona-Díaz, Natalia; Giraldo-Ramirez, Nelson Darío; Zuluaga-Valencia, Gustavo Adolfo

    2016-01-01

    Background: Patients with lupus nephritis could progress to end-stage renal disease (10-22%); hence, kidney transplants should be considered as the treatment of choice for these patients. Objective: To evaluate the clinical outcomes after kidney transplants in patients with chronic kidney diseases secondary to lupus nephritis, polycystic kidney disease and diabetes nephropathy at Pablo Tobon Uribe Hospital. Methods: A descriptive and retrospective study performed at one kidney transplant center between 2005 and 2013. Results: A total of 136 patients, 27 with lupus nephritis (19.9%), 31 with polycystic kidney disease (22.8%) and 78 with diabetes nephropathy (57.4%), were included in the study. The graft survivals after one, three and five years were 96.3%, 82.5% and 82.5% for lupus nephritis; 90%, 86% and 76.5% for polycystic kidney disease and 91.7%, 80.3% and 67.9% for diabetes nephropathy, respectively, with no significant differences (p= 0.488); the rate of lupus nephritis recurrence was 0.94%/person-year. The etiology of lupus vs diabetes vs polycystic disease was not a risk factor for a decreased time of graft survival (Hazard ratio: 1.43; 95% CI: 0.52-3.93). Conclusion: Kidney transplant patients with end stage renal disease secondary to lupus nephritis has similar graft and patient survival success rates to patients with other kidney diseases. The complication rate and risk of recurrence for lupus nephritis are low. Kidney transplants should be considered as the treatment of choice for patients with end stage renal disease secondary to lupus nephritis. PMID:27226665

  15. Genome-Wide Association and Trans-ethnic Meta-Analysis for Advanced Diabetic Kidney Disease: Family Investigation of Nephropathy and Diabetes (FIND)

    PubMed Central

    Kretzler, Matthias; Keller, Benjamin J.; Adler, Sharon G.; Best, Lyle G.; Bowden, Donald W.; Burlock, Allison; Chen, Yii-Der Ida; Cole, Shelley A.; Comeau, Mary E.; Curtis, Jeffrey M.; Divers, Jasmin; Drechsler, Christiane; Duggirala, Ravi; Elston, Robert C.; Guo, Xiuqing; Huang, Huateng; Hoffmann, Michael Marcus; Howard, Barbara V.; Ipp, Eli; Kimmel, Paul L.; Klag, Michael J.; Knowler, William C.; Kohn, Orly F.; Leak, Tennille S.; Leehey, David J.; Li, Man; Malhotra, Alka; März, Winfried; Nair, Viji; Nelson, Robert G.; Nicholas, Susanne B.; O’Brien, Stephen J.; Pahl, Madeleine V.; Parekh, Rulan S.; Pezzolesi, Marcus G.; Rasooly, Rebekah S.; Rotimi, Charles N.; Rotter, Jerome I.; Schelling, Jeffrey R.; Seldin, Michael F.; Shah, Vallabh O.; Smiles, Adam M.; Smith, Michael W.; Taylor, Kent D.; Thameem, Farook; Thornley-Brown, Denyse P.; Truitt, Barbara J.; Wanner, Christoph; Weil, E. Jennifer; Winkler, Cheryl A.; Zager, Philip G.; Igo, Robert P.; Hanson, Robert L.; Langefeld, Carl D.

    2015-01-01

    Diabetic kidney disease (DKD) is the most common etiology of chronic kidney disease (CKD) in the industrialized world and accounts for much of the excess mortality in patients with diabetes mellitus. Approximately 45% of U.S. patients with incident end-stage kidney disease (ESKD) have DKD. Independent of glycemic control, DKD aggregates in families and has higher incidence rates in African, Mexican, and American Indian ancestral groups relative to European populations. The Family Investigation of Nephropathy and Diabetes (FIND) performed a genome-wide association study (GWAS) contrasting 6,197 unrelated individuals with advanced DKD with healthy and diabetic individuals lacking nephropathy of European American, African American, Mexican American, or American Indian ancestry. A large-scale replication and trans-ethnic meta-analysis included 7,539 additional European American, African American and American Indian DKD cases and non-nephropathy controls. Within ethnic group meta-analysis of discovery GWAS and replication set results identified genome-wide significant evidence for association between DKD and rs12523822 on chromosome 6q25.2 in American Indians (P = 5.74x10-9). The strongest signal of association in the trans-ethnic meta-analysis was with a SNP in strong linkage disequilibrium with rs12523822 (rs955333; P = 1.31x10-8), with directionally consistent results across ethnic groups. These 6q25.2 SNPs are located between the SCAF8 and CNKSR3 genes, a region with DKD relevant changes in gene expression and an eQTL with IPCEF1, a gene co-translated with CNKSR3. Several other SNPs demonstrated suggestive evidence of association with DKD, within and across populations. These data identify a novel DKD susceptibility locus with consistent directions of effect across diverse ancestral groups and provide insight into the genetic architecture of DKD. PMID:26305897

  16. Relation of contrast induced nephropathy to new onset atrial fibrillation in acute coronary syndrome.

    PubMed

    Raposeiras Roubín, Sergio; Abellas-Sequeiros, Rosa Alba; Abu Assi, Emad; Yousef-Abumuaileq, Rami Riziq; Rodríguez Mañero, Moisés; Iglesias Álvarez, Diego; González-Salvado, Violeta; González Ferreiro, Rocío; Redondo Diéguez, Alfredo; Ocaranza Sánchez, Raymundo; Virgós Lamela, Alejandro; Peña Gil, Carlos; García Acuña, José María; González Juanatey, José Ramón

    2015-03-01

    Chronic renal failure has been described as a risk factor for the development of atrial fibrillation (AF). The aim of this study was to examine the association between contrast-induced nephropathy (CIN) and new-onset AF in patients with acute coronary syndromes. A total of 1,520 consecutive patients (mean age 67.1 ± 12.7 years) with acute coronary syndromes (34.4% with ST-segment elevation myocardial infarctions) who underwent coronary angiography were studied. CIN was defined as an increase in serum creatinine of 0.5 mg/dl within 72 hours of contrast exposure. The independent effect of AF history (chronic or paroxysmal AF before catheterization) on the development of CIN, as well as the independent effect of CIN on the development of new-onset AF (after catheterization, during the in-hospital phase), were tested by using different logistic regression models. One hundred thirty-nine patients (9.1%) had histories of AF before catheterization (60 with paroxysmal and 79 with chronic AF), and 56 (4.1%) developed new-onset AF after catheterization. Eighty-seven patients (5.7%) had CIN. AF history was a predictor of CIN in univariate analysis (odds ratio 2.19, 95% confidence interval 1.22 to 3.95, p = 0.007) but not in multivariate analysis, after adjusting for confounding variables (odds ratio 1.69, 95% confidence interval 0.89 to 3.22, p = 0.111). In contrast, those with CIN had an increased prevalence of new-onset AF (15.3% vs 3.4%, p <0.001). After adjusting for those variables associated with new-onset AF in the univariate analysis, CIN continued to show a significant association with new-onset AF, with a twofold increased risk (odds ratio 2.45, 95% confidence interval 1.07 to 5.64, p = 0.035). In conclusion, the development of CIN is an independent predictor of new-onset AF in the context of acute coronary syndromes. PMID:25591897

  17. The epidermal growth factor receptor pathway in chronic kidney diseases.

    PubMed

    Harskamp, Laura R; Gansevoort, Ron T; van Goor, Harry; Meijer, Esther

    2016-08-01

    The epidermal growth factor receptor (EGFR) pathway has a critical role in renal development, tissue repair and electrolyte handling. Numerous studies have reported an association between dysregulation of this pathway and the initiation and progression of various chronic kidney diseases such as diabetic nephropathy, chronic allograft nephropathy and polycystic kidney disease through the promotion of renal cell proliferation, fibrosis and inflammation. In the oncological setting, compounds that target the EGFR pathway are already in clinical use or have been evaluated in clinical trials; in the renal setting, therapeutic interventions targeting this pathway by decreasing ligand availability with disintegrin and metalloproteinase inhibitors or with ligand-neutralizing antibodies, or by inhibiting receptor activation with tyrosine kinase inhibitors or monoclonal antibodies are only just starting to be explored in animal models of chronic kidney disease and in patients with autosomal dominant polycystic kidney disease. In this Review we focus on the role of the EGFR signalling pathway in the kidney under physiological conditions and during the pathophysiology of chronic kidney diseases and explore the clinical potential of interventions in this pathway to treat chronic renal diseases. PMID:27374915

  18. TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model.

    PubMed

    Yadav, Raj Kumar; Lee, Geum-Hwa; Lee, Hwa-Young; Li, Bo; Jung, Han-Eul; Rashid, Harun-Or; Choi, Min Kyung; Yadav, Binod Kumar; Kim, Woo-Ho; Kim, Kyung-Woon; Park, Byung-Hyun; Kim, Won; Lee, Yong-Chul; Kim, Hyung-Ryong; Chae, Han-Jung

    2015-01-01

    Cyclosporine A (CsA) is widely used as an immunosuppressor in transplantation. Previous studies reported that CsA induces autophagy and that chronic treatment with CsA results in accumulation of autophagosomes and reduced autophagic clearance. Autophagy is a prosurvival process that promotes recovery from acute kidney injury by degrading misfolded proteins produced in the kidney. In the present study, we used TMBIM6-expressing HK-2, human kidney tubular cells (TMBIM6 cells) and Tmbim6 knockout (tmbim6(-/-)) mice. When exposed to CsA, the TMBIM6 cells maintained autophagy activity by preventing autophagosome accumulation. With regard to signaling, PRKKA/AMPK phosphorylation and mechanistic target of rapamycin (serine/threonine kinase) complex 1 (MTORC1) expression and its downstream target TFEB (transcription factor EB), a lysosome biogenesis factor, were regulated in the TMBIM6 cells. Lysosomal activity was highly increased or stably maintained in the presence of TMBIM6. In addition, treatment of tmbim6(-/-) mice with CsA resulted in increased autophagosome formation and decreased lysosome formation and activity. We also found that tmbim6(-/-) mice were susceptible to CsA-induced kidney injury. Taken together, these results indicate that TMBIM6 protects against CsA-induced nephrotoxicity both in vitro and in vivo by inducing autophagy and activating lysosomes. PMID:26305401

  19. Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy.

    PubMed

    Oltean, Sebastian; Qiu, Yan; Ferguson, Joanne K; Stevens, Megan; Neal, Chris; Russell, Amy; Kaura, Amit; Arkill, Kenton P; Harris, Kirstie; Symonds, Clare; Lacey, Katja; Wijeyaratne, Lihini; Gammons, Melissa; Wylie, Emma; Hulse, Richard P; Alsop, Chloe; Cope, George; Damodaran, Gopinath; Betteridge, Kai B; Ramnath, Raina; Satchell, Simon C; Foster, Rebecca R; Ballmer-Hofer, Kurt; Donaldson, Lucy F; Barratt, Jonathan; Baelde, Hans J; Harper, Steven J; Bates, David O; Salmon, Andrew H J

    2015-08-01

    Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy. PMID:25542969

  20. Vascular Endothelial Growth Factor-A165b Is Protective and Restores Endothelial Glycocalyx in Diabetic Nephropathy

    PubMed Central

    Oltean, Sebastian; Qiu, Yan; Ferguson, Joanne K.; Stevens, Megan; Neal, Chris; Russell, Amy; Kaura, Amit; Arkill, Kenton P.; Harris, Kirstie; Symonds, Clare; Lacey, Katja; Wijeyaratne, Lihini; Gammons, Melissa; Wylie, Emma; Hulse, Richard P.; Alsop, Chloe; Cope, George; Damodaran, Gopinath; Betteridge, Kai B.; Ramnath, Raina; Satchell, Simon C.; Foster, Rebecca R.; Ballmer-Hofer, Kurt; Donaldson, Lucy F.; Barratt, Jonathan; Baelde, Hans J.; Harper, Steven J.; Bates, David O.

    2015-01-01

    Diabetic nephropathy is the leading cause of ESRD in high-income countries and a growing problem across the world. Vascular endothelial growth factor-A (VEGF-A) is thought to be a critical mediator of vascular dysfunction in diabetic nephropathy, yet VEGF-A knockout and overexpression of angiogenic VEGF-A isoforms each worsen diabetic nephropathy. We examined the vasculoprotective effects of the VEGF-A isoform VEGF-A165b in diabetic nephropathy. Renal expression of VEGF-A165b mRNA was upregulated in diabetic individuals with well preserved kidney function, but not in those with progressive disease. Reproducing this VEGF-A165b upregulation in mouse podocytes in vivo prevented functional and histologic abnormalities in diabetic nephropathy. Biweekly systemic injections of recombinant human VEGF-A165b reduced features of diabetic nephropathy when initiated during early or advanced nephropathy in a model of type 1 diabetes and when initiated during early nephropathy in a model of type 2 diabetes. VEGF-A165b normalized glomerular permeability through phosphorylation of VEGF receptor 2 in glomerular endothelial cells, and reversed diabetes-induced damage to the glomerular endothelial glycocalyx. VEGF-A165b also improved the permeability function of isolated diabetic human glomeruli. These results show that VEGF-A165b acts via the endothelium to protect blood vessels and ameliorate diabetic nephropathy. PMID:25542969