Science.gov

Sample records for chronic cyclosporine nephropathy

  1. Effects of chronic volume expansion and enalapril on chronic cyclosporine nephropathy.

    PubMed

    Gillum, D M; Truong, L

    1990-04-01

    Prolonged treatment with cyclosporine (CS) results in an irreversible renal lesion consisting of interstitial fibrosis and tubular atrophy, as well as prominent hyperplasia of the juxtaglomerular apparatus (JGA). Ischemia to the tubulointerstitial compartment caused by intense CS-mediated renal vasoconstriction may contribute significantly to the development of this lesion. To explore the potential role of volume contraction and activation of the renin-angiotensin system (RAS) in the genesis of this lesion, we have employed a recently described rodent model of chronic cyclosporine nephropathy (CCN). Over 28 days of CS therapy, animals received plain drinking water, 1% saline, or enalapril (ENAL), 50 mg/l in drinking water. At the end of 28 days, Na+ balance in saline-treated animals was markedly positive, and plasma volume was increased; however, glomerular filtration rate (GFR) did not change, and the tubulointerstitial lesion and JGA hyperplasia as evaluated by morphometric techniques were unaffected. Enalapril-treated animals were relatively hypotensive with lower GFR than CS controls. Enalapril conferred no protection against the development of tubulointerstitial disease and exacerbated the development of JGA hyperplasia and hyperkalemia. We conclude that volume contraction is not an important contributor to the reduced GFR, tubulointerstitial lesion, or JGA hyperplasia associated with long-term CS treatment. Blockade of the RAS also conferred no protection against the development of tubulointerstitial disease but resulted in worsening of JGA hyperplasia and hyperkalemia.

  2. Expression of Ammonia Transporters, Rhbg and Rhcg, in Chronic Cyclosporine Nephropathy in Rats

    PubMed Central

    Lim, Sun Woo; Ahn, Kyung Ohk; Kim, Wan Young; Han, Dong He; Li, Can; Ghee, Jung Yeon; Han, Ki Hwan; Kim, Hye-Young; Handlogten, Mary E.; Kim, Jin; Yang, Chul Woo; Weiner, I. David

    2015-01-01

    Background/Aims Cyclosporine (CsA)-induced renal injury causes renal tubular acidosis. The current study was performed to evaluate the influence of CsA-induced renal injury on the ammonia transporter family members, Rh B-glyco-protein (Rhbg) and Rh C-glycoprotein (Rhcg). Methods Rats were treated daily for 1 or 4 weeks with vehicle (VH) or CsA. Induction of chronic CsA-induced nephropathy was confirmed by demonstrating impaired renal function and characteristic histopathology. Rhbg and Rhcg expression was evaluated with immunoblot, immunohistochemistry, real-time RT-PCR and electron microscopy. Results CsA treatment for 4 weeks developed mild metabolic acidosis and decreased urinary ammonia excretion. Rhcg mRNA expression was unchanged in both the cortex and outer medulla, but Rhcg protein expression in the CsA group was significantly reduced in the cortex and outer medulla. There were no significant differences in Rhbg mRNA and protein expression between the CsA and VH group. Conclusion Long-term treatment with CsA in rats results in decreased urinary ammonia excretion accompanied by decreased expression of Rhcg; these changes are likely to mediate the CsA-induced defect in ammonium excretion in the collecting duct. PMID:18776723

  3. Protective Effect of Edaravone Against Cyclosporine-Induced Chronic Nephropathy Through Antioxidant and Nitric Oxide Modulating Pathways in Rats

    PubMed Central

    Sattarinezhad, Elahe; Panjehshahin, Mohammad Reza; Torabinezhad, Simin; Kamali-Sarvestani, Eskandar; Farjadian, Shirin; Pirsalami, Fatema; Moezi, Leila

    2017-01-01

    Background: Cyclosporine A (CsA) is an immunosuppressant with therapeutic indications in various immunological diseases; however, its use is associated with chronic nephropathy. Oxidative stress has a crucial role in CsA-induced nephrotoxicity. The present study evaluates the protective effect of edaravone on CsA-induced chronic nephropathy and investigates its antioxidant and nitric oxide modulating property. Methods: Male Sprague-Dawley rats (n=66) were distributed into nine groups, including a control (group 1) (n=7). Eight groups received CsA (15 mg/kg) for 28 days while being treated. The groups were categorized as: Group 2: Vehicle (n=10)Groups 3, 4, and 5: Edaravone (1, 5, and 10 mg/kg) (n=7 each)Group 6: Diphenyliodonium chloride, a specific endothelial nitric oxide synthase (eNOS) inhibitor (n=7)Group 7: Aminoguanidine, a specific inducible nitric oxide synthase (iNOS) inhibitor (n=7)Group 8: Edaravone (10 mg/kg) plus diphenyliodonium chloride (n=7)Group 9: Edaravone (10 mg/kg) plus aminoguanidine (n=7) Blood urea nitrogen and serum creatinine levels, malondialdehyde, superoxide dismutase, and glutathione reductase enzyme activities were measured using standard kits. Renal histopathological evaluations and measurements of eNOS and iNOS gene expressions by RT-PCR were also performed. Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s test (SPSS software version 18.0). Results: Edaravone (10 mg/kg) significantly attenuated CsA-induced oxidative stress, renal dysfunction, and kidney tissue injury. Aminoguanidine improved the renoprotective effect of edaravone. Edaravone reduced the elevated mRNA level of iNOS, but could not alter the level of eNOS mRNA significantly. Conclusion: Edaravone protects against CsA-induced chronic nephropathy using antioxidant property and probably through inhibiting iNOS gene expression. PMID:28360443

  4. 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

  5. Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy

    PubMed Central

    Yoon, Hye Eun; Ghee, Jung Yeon; Piao, ShangGuo; Song, Ji-Hyun; Han, Dong He; Kim, Sol; Ohashi, Naro; Kobori, Hiroyuki; Kuro-o, Makoto; Yang, Chul Woo

    2011-01-01

    Background. The Klotho gene plays a role in suppressing ageing-related disorders. It is suggested that activation of renin–angiotensin system (RAS) or oxidative stress suppresses Klotho in the kidney. This study evaluated the association between Klotho expression and RAS in cyclosporine (CsA)-induced renal injury. Methods. Chronic CsA nephropathy was induced by administering CsA (30 mg/kg) to mice on a low-salt diet (LSD) for 4 weeks. A normal-salt diet (NSD) was used as the control. Reverse transcription–polymerase chain reaction, western blot and immunohistochemistry were performed for Klotho and intrarenal RAS activity was measured using immunohistochemistry for angiotensinogen and renin. Oxidative stress was measured with urinary excretion of 8-hydroxy-2′-deoxyguanosine (8-OHdG). Results. CsA treatment decreased Klotho mRNA and protein in mouse kidney in a dose-dependent and time-dependent manner, but a concurrent treatment with losartan, an angiotensin II type 1 (AT1) receptor blocker, reversed the decrease in Klotho expression with histological improvement. This finding was more marked in the LSD than the NSD. Klotho expression was correlated with angiotensinogen and renin expression, tubulointerstitial fibrosis score and urinary 8-OHdG excretion. Conclusions. Angiotensin II may play a pivotal role in regulating Klotho expression in CsA-induced renal injury. AT1 receptor blocker may inhibit the ageing process by decreasing oxidative stress caused by CsA. PMID:20813770

  6. [Chronic transplant nephropathy].

    PubMed

    Campistol Plana, J M

    2008-01-01

    In 2007 there were important scientific contributions in the field of kidney transplant and specifically in chronic transplant nephropathy (interstitial fibrosis and tubular atrophy). A new nomenclature and classification of chronic kidney disease was probably the most important contribution in this entity. Use of the C4d stain has allowed the concepts of glomerulopathy to be updated and to reveal the frequency of this entity and its impact in kidney transplant. Finally, two experimental studies provide new perspectives on the treatment of chronic kidney disease such as the use of statins or the use of pyridoxamine to block glycation end products.

  7. Cyclosporin in the treatment of severe chronic idiopathic uveitis.

    PubMed Central

    de Vries, J; Baarsma, G S; Zaal, M J; Boen-Tan, T N; Rothova, A; Buitenhuis, H J; Schweitzer, C M; de Keizer, R J; Kijlstra, A

    1990-01-01

    In a randomised double-masked study of 27 patients with a severe chronic idiopathic uveitis we evaluated the efficacy, safety, and tolerability of cyclosporin. All received prednisone in a low dose (0.3 mg/kg/day). In 14 patients this was combined with cyclosporin in a single daily dose of 10 mg/kg/day, while 13 patients received a placebo. The dosages were tapered off in accordance with a protocol, and we compared the number of months of successful therapy before the uveitis relapsed. The efficacy results, as expressed in a Kaplan-Meier curve, were in favour of cyclosporin. Owing to the small sample size, however, this difference did not reach statistical significance. The immunosuppressive effect of cyclosporin was not permanent, and in all but one patient the intraocular inflammation relapsed on reduction of dosage. Rather small cumulative doses of cyclosporin proved to be nephrotoxic, but subjective tolerability for cyclosporin was good. PMID:2198928

  8. Nephropathy in Chronic Lead Poisoning

    PubMed Central

    Lilis, Ruth; Gavrilescu, N.; Nestorescu, B.; Dumitriu, C.; Roventa, Ana

    1968-01-01

    This paper presents a study of renal function in 102 patients with lead poisoning admitted to the Occupational Diseases Clinic in Bucharest during the past 10 years; nearly half the patients had no history of lead colic. Every possible cause of renal damage, other than lead, was excluded by a careful differential diagnosis. Renal function was investigated by repeated determinations of blood urea, creatinine and uric acid, urea clearance, and endogenous creatinine clearance tests. Significant decreases of the clearance values (less than 50 ml./min. urea clearance and less than 80 ml./min. creatinine clearance), persistent high blood urea (more than 50 mg./100 ml.), and high blood creatinine (more than 1·2 mg./100 ml.) were found in a significant number of cases. These signs of impaired renal function were more frequent in the group of patients with chronic lead poisoning who had had several episodes of colic and an occupational exposure of more than 10 years. A high blood pressure was also found more frequently in this group of patients. Undercompensated and decompensated renal failure was found in 17 patients, most of whom had been exposed to lead for more than 10 years and had a history of several attacks of colic. Arterial hypertension accompanied the chronic renal failure in 13 patients, the renal impairment generally preceding the rise in blood pressure by several years. The duration of occupational lead exposure, the high absorption in the past, and the long period of observation of these patients, most of whom were repeatedly hospitalized, may explain the relatively high incidence (17 cases) of nephropathy with chronic renal failure in the present group. Impairment of urea clearance seems to be the earliest sign, at a time when the creatinine clearance is still normal. As the duration of exposure lengthens and the patient is subjected to active episodes of poisoning the creatinine clearance also deteriorates. Persistent urea retention and high creatininaemia

  9. Cyclosporine

    MedlinePlus

    ... with methotrexate (Rheumatrex) to treat the symptoms of rheumatoid arthritis (arthritis caused by swelling of the lining of ... If you are taking cyclosporine (modified) to treat rheumatoid arthritis or psoriasis, your doctor will probably start you ...

  10. Angiotensin Type-2 (AT-2)-Receptor activation reduces renal fibrosis in cyclosporine nephropathy: Evidence for blood-pressure independent effect.

    PubMed

    Castoldi, Giovanna; di Gioia, Cira R T; Carletti, Raffaella; Roma, Francesca; Zerbini, Gianpaolo; Stella, Andrea

    2016-09-27

    Compound 21 (C21), selective agonist of AT2 receptors, shows antinflammatory effects in hypertension and nephroprotection in diabetes. The aim of this study was to evaluate the effects of C21 in cyclosporine nephropathy, which is characterized mainly by tubulo-interstitial fibrosis. Ten days before and during the experimental periods, low-salt diet was administered to Sprague Dawley rats. Cyclosporine-A (15mg/kg/day, i.p.) and cyclosporine-A plus C21 (0.3 mg/kg /day, i.p) were administered for 1 and 4 weeks. Control groups was left without any treatment. Blood pressure (plethysmographic method) and 24 hour albuminuria were measured once a week. At the end of the experiments, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and type I and IV collagen expression.
    After 1 and 4 weeks, the rats treated with cyclosporine showed a significant increase (p <0.01) in blood pressure, no significant changes in albuminuria, a significant increase (p <0.01) in glomerular and tubulo-interstitial fibrosis and inflammatory infiltrates as compared to the control rats. Treatment with C21 did not modify the cyclosporine dependent increase of blood pressure, which was higher than in control rats, but after 4 weeks of treatment significantly reduced (p <0.01) glomerular and tubulo-interstitial fibrosis, type 1 collagen expression and macrophage infiltration, as compared to rats treated with cyclosporine.The administration of C21 showed a protective effect on cyclosporine nephropathy, decreasing renal fibrosis and macrophage infiltration. These data suggest that C21 may counteract tubulo-interstitial fibrosis, the most potent predictor of the progression of renal diseases.

  11. Angiotensin type-2 (AT-2)-receptor activation reduces renal fibrosis in cyclosporine nephropathy: evidence for blood pressure independent effect

    PubMed Central

    Castoldi, Giovanna; di Gioia, Cira R.T.; Carletti, Raffaella; Roma, Francesca; Zerbini, Gianpaolo; Stella, Andrea

    2016-01-01

    Compound 21 (C21), selective agonist of angiotensin type-2 (AT-2) receptors, shows anti-inflammatory effects in experimental models of hypertension and nephroprotection in diabetes. The aim of the present study was to evaluate the effects of C21 in cyclosporine nephropathy, which is characterized mainly by tubulo-interstitial fibrosis. Ten days before and during the experimental periods, low-salt diet was administered to Sprague–Dawley rats. Cyclosporine-A (CsA; 15 mg/kg per day, intraperitoneal injection) and CsA plus C21 (0.3 mg/kg per day, intraperitoneal injection) were administered for 1 and 4 weeks. Control groups were left without any treatment. Blood pressure (plethysmographic method) and 24 h urinary albumin excretion were measured once a week. At the end of the experimental protocols, the kidneys were excised for histomorphometric analysis of renal fibrosis and for immunohistochemical evaluation of inflammatory infiltrates and type I and type IV collagen expression. After 1 and 4 weeks, the rats treated with CsA showed a significant increase (P<0.01) in blood pressure, no significant changes in urinary albumin excretion and a significant increase (P<0.01) in glomerular and tubulo-interstitial fibrosis and inflammatory infiltrates as compared with the control rats. Treatment with C21 did not modify the CsA dependent increase of blood pressure, which was higher than in control rats, but after 4 weeks of treatment significantly reduced (P<0.01) glomerular and tubulo-interstitial fibrosis, type 1 collagen expression and macrophage infiltration, as compared with rats treated with cyclosporine. The administration of C21 showed a protective effect on cyclosporine nephropathy, decreasing renal fibrosis and macrophage infiltration. These data suggest that C21 may counteract tubulo-interstitial fibrosis, the most potent predictor of the progression of renal diseases. PMID:27679859

  12. 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.

  13. The effect of prostaglandin E1 analog misoprostol on chronic cyclosporin nephrotoxicity.

    PubMed

    John, E G; Fornell, L C; Radhakrishnan, J; Anutrakulchai, S; Jonasson, O

    1993-11-01

    Cyclosporin A has markedly improved graft survival in transplant patients but its side effects, such as renal toxicity and hypertension, pose management problems in transplant recipients. This toxicity has been attributed to prostaglandin inhibition. Concurrent administration of misoprostol (a prostaglandin E1 analog) prevents chronic cyclosporin A-induced nephrotoxicity but not hypertension in rats.

  14. Impact of cyclosporine reduction with MMF: a randomized trial in chronic allograft dysfunction. The 'reference' study.

    PubMed

    Frimat, L; Cassuto-Viguier, E; Charpentier, B; Noël, C; Provôt, F; Rostaing, L; Glotz, D; Sraer, J D; Bourbigot, B; Moulin, B; Lang, P; Ducloux, D; Pouteil-Noble, C; Girardot-Seguin, S; Kessler, M

    2006-11-01

    Long-term use of calcineurine inhibitors (CNIs) may contribute to the development of chronic allograft dysfunction (CAD). We investigate the impact of the introduction of MMF combined with cyclosporine (CsA) 50% dose reduction. An open, randomized, controlled, multicenter, prospective study was conducted in 103 patients, receiving a CsA-based therapy with a serum creatinine between 1.7-3.4 mg/dL, more than 1 year after transplantation. They were randomized to receive MMF with half dose of CsA (MMF group) or to continue their maintenance CsA dose (control group). A total of 96 weeks after randomization, the evolution of renal function assessed by regression line analysis of 1/SeCr improved in the MMF group (positive slope) vs. the control group (negative slope), 4.2 x 10(-4) vs. -3.0 x 10(-4), respectively (p < 0.001). Concurrently, the absolute renal function improved significantly in the MMF group. No episode of biopsy-proven acute rejection occurred. One patient in each group lost his graft because of biopsy-proven chronic allograft nephropathy. There was a significant decrease of triglycerides level in the MMF group. Anemia and diarrhea were statistically more frequent in the MMF group. In CAD, the reduction of CsA in the presence of MMF results in significant improvement in renal function during a 2-year follow-up.

  15. Urinary proteomic analysis of chronic allograft nephropathy

    PubMed Central

    O’Riordan, Edmond; Orlova, Tatyana N.; Mendelev, Natalia; Patschan, Daniel; Kemp, Rowena; Chander, Praveen N.; Hu, Rena; Hao, Gang; Gross, Steven S.; Iozzo, Renato V.; Delaney, Veronica; Goligorsky, Michael S.

    2015-01-01

    The pathogenesis of progressive renal allograft injury, which is termed chronic allograft nephropathy (CAN), remains obscure and is currently defined by histology. Prospective protocolbiopsy trials have demonstrated that clinical and standard laboratory tests are insufficiently sensitive indicators of the development and progression of CAN. The study aim was to determine if CAN could be characterized by urinary proteomic data and identify the proteins associated with disease. The urinary proteome of 75 renal transplant recipients and 20 healthy volunteers was analyzed using surface enhanced laser desorption and ionization MS. Patients could be classified into subgroups with normal histology and Banff CAN grades 2-3 with a sensitivity of 86% and a specificity of 92% by applying the classification algorithm Adaboost to urinary proteomic data. Several urinary proteins associated with advanced CAN were identified including α1-micro-globulin, β2-micro-globulin, prealbumin, and endorepellin, the antiangiogenic C-terminal fragment of perlecan. Increased urinary endorepellin was confirmed by ELISA and increased tissue expression of the endorepellin/perlecan ratio by immunofluoresence analysis of renal biopsies. In conclusion, analysis of urinary proteomic data has further characterized the more severe CAN grades and identified urinary endorepellin, as a potential biomarker of advanced CAN. PMID:21136903

  16. Can clinical response to cyclosporin in chronic severe asthma be predicted by an in vitro T-lymphocyte proliferation assay?

    PubMed

    Alexander, A G; Barnes, N C; Kay, A B; Corrigan, C J

    1996-07-01

    This study tests the hypothesis that the clinical response to cyclosporin therapy of patients with chronic severe asthma is related to the sensitivity of their T-lymphocytes to the antiproliferative effects of cyclosporin in vitro. In a previous study, we observed such a relationship with glucocorticoids and the same lectin-driven proliferation assay was used in the present study. Peripheral blood mononuclear cells were obtained from 33 patients participating in a cross-over trial of oral cyclosporin therapy during both cyclosporin and placebo treatment periods, and cultured in the presence of phytohaemagglutinin and serial dilutions of cyclosporin and dexamethasone. Proliferation was measured by tritiated thymidine uptake. Both cyclosporin and dexamethasone inhibited T-lymphocyte proliferation in a concentration-dependent manner in vitro at concentrations encompassing those achieved in peripheral blood during therapy in vivo. T-lymphocytes from the asthmatic patients showed a range of sensitivity to the antiproliferative effects of cyclosporin, but this could not be correlated with improvements in peak expiratory flow rate (PEFR) or forced expiratory volume in one second (FEV1) during cyclosporin therapy as compared with placebo. In contrast to previous observations with glucocorticoids, this in vitro T-lymphocyte proliferation assay is not predictive of clinical response to cyclosporin therapy in chronic severe asthmatics.

  17. [Problems with immunosuppressive agents in nephropathies with chronic renal failure].

    PubMed

    Savoldi, S; Mesiano, P; Rocchietti, M

    2008-01-01

    Immunosuppressive treatment is widely used in transplant patients, who often have chronic renal failure, while its use in nephropathies of native kidneys with chronic renal insufficiency is still limited. In recent years a number of papers have reported advantages of its use also in this setting. A prerequisite for immunosuppression in this condition is accurate renal histology, in order to define the etiology, activity/chronicity index and prognosis. Although clinicians agree on the use of aggressive treatment for secondary nephropathies, the approach to primary forms in the presence of chronic renal failure remains controversial, as does the definition of a ''point of no return'' beyond which treatment could be ineffective or unsafe. Nonrandomized studies found that immunosuppressive drugs such as cyclophosphamide can be useful in membranous nephropathy with renal insufficiency. The use of immunosuppressive drugs in IgA nephropathy in the presence of established renal insufficiency seems to improve renal survival with a limited occurrence of side effects. Since the pharmacokinetics of the current immunosuppressive agents (steroids, azathioprine, cyclophosphamide, chlorambucil, mycophenolate mofetil) is modified by renal insufficiency, attention should be paid to reducing drug doses and monitoring toxicity. Immunosuppressive treatment is a critical procedure in patients with chronic renal failure, in whom an increased risk of infection is already present. In conclusion, on the basis of the data of the literature, we can hypothesize that the ''point of no return'' exceeds the threshold generally considered safe by clinicians. Nevertheless, a strict definition of a cutoff value for renal function to establish whether or not a certain treatment should be given is not applicable in clinical practice, where the choice of an immunosuppressive approach must be tailored to the individual patient based on a global evaluation including renal histology, clinical conditions

  18. Long-Term Impact of Cyclosporin Reduction with MMF Treatment in Chronic Allograft Dysfunction: REFERENECE Study 3-Year Follow Up.

    PubMed

    Frimat, L; Cassuto-Viguier, E; Provôt, F; Rostaing, L; Charpentier, B; Akposso, K; Moal, M C; Lang, P; Glotz, D; Caillard, S; Ducloux, D; Pouteil-Noble, C; Girardot-Seguin, S; Kessler, M

    2010-01-01

    Calcineurin inhibitor (CNI) toxicity contributes to chronic allograft nephropathy (CAN). In the 2-year, randomized, study, we showed that 50% cyclosporin (CsA) reduction in combination with mycophenolate mofetil (MMF) treatment improves kidney function without increasing the risk for graft rejection/loss. To investigate the long-term effect of this regimen, we conducted a follow up study in 70 kidney transplant patients until 5 years after REFERENCE initiation. The improvement of kidney function was confirmed in the MMF group but not in the control group (CsA group). Four graft losses occurred, 2 in each group (graft survival in the MMF group 95.8% and 90.9% in control group). One death occurred in the control group. There was no statistically significant difference in the occurrence of serious adverse events or acute graft rejections. A limitation is the weak proportion of patient still remaining within the control group. On the other hand, REFERENCE focuses on the CsA regimen while opinions about the tacrolimus ones are still debated. In conclusion, CsA reduction in the presence of MMF treatment seems to maintain kidney function and is well tolerated in the long term.

  19. 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

  20. [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.

  1. Chronic kidney disease of unknown etiology should be renamed chronic agrochemical nephropathy.

    PubMed

    Jayasinghe, Saroj

    2014-04-01

    Epidemics of chronic kidney disease not attributable to common causes have recently been observed in Central America and Asia. Since the etiology is unclear, the disease is often known by terms such as chronic kidney disease of unknown etiology. There is growing evidence that risk factors include rural agricultural work and agrochemical exposure. The disease should be renamed chronic agrochemical nephropathy to highlight the most likely etiology and draw attention to the condition.

  2. Clinical response to cyclosporin in chronic severe asthma is associated with reduction in serum soluble interleukin-2 receptor concentrations.

    PubMed

    Alexander, A G; Barnes, N C; Kay, A B; Corrigan, C J

    1995-04-01

    Activated T-lymphocytes play an important role in asthma pathogenesis and release soluble interleukin-2 receptor (sIL-2R), which can be detected in the serum. In a recent randomized, cross-over trial we showed that cyclosporin, an inhibitor of T-lymphocyte activation, improved lung function in patients with chronic severe asthma. To investigate whether changes in serum sIL-2R concentration could be related to clinical response we prospectively compared serum sIL-2R concentrations in patients during cyclosporin and placebo treatment. Peripheral venous blood was obtained from 22 patients during the last 4 weeks of both the cyclosporin and placebo treatment periods and serum stored at -80 degrees C pending measurement of sIL-2R concentration by enzyme immunoassay. Soluble IL-2R was detected in all samples at a concentration range of 191-2,297 U.ml-1. Mean serum concentrations of sIL-2R were significantly lower on cyclosporin therapy (560 U.ml-1) as compared with placebo (676 U.ml-1). The decreases in serum sIL-2R concentrations associated with cyclosporin therapy in these patients correlated with the percentage increases in their morning peak expiratory flow rate (PEFR) measurements on cyclosporin as compared with placebo. These data demonstrate that in patients with chronic severe asthma, cyclosporin therapy which results in clinical improvement is associated with a decrease in serum concentrations of sIL-2R. This is compatible with the hypothesis that cyclosporin ameliorates asthma, at least partly, by inhibition of T-lymphocyte activation.

  3. Methenamine silver staining quantitative digital histochemistry in chronic allograft nephropathy.

    PubMed

    Sarioglu, S; Celik, A; Sakar, M; Sonmez, D; Tekis, D

    2004-12-01

    Renal function and final outcome of renal allografts have been correlated with irreversible damage. This study describes a quantitative histochemical method relying on periodic acid methenamine silver (PAMS) staining of all renal compartments. Among 60 renal allograft biopsies from 43 patients, 15 biopsies showing pure chronic allograft nephropathy were selected to determine PAMS-stained area percentage (SAP), using image analysis with quantitative histochemistry. Of the 15 cases, 9 (60%) were grade I and 6 (40%) were grade II chronic allograft nephropathy (CAN). The mean serum creatinine (sCr) value was 1.86 +/- 0.47 for allograft biopsies. The mean (+/-SD) SAP for the implantation biopsies was 10.58 +/- 1.87%, and for allograft biopsies 25.26 +/- 9.67 (P <.000). The serum creatinine (sCr) values for grade I versus II CAN were 1.63 +/- 0.24 versus 2.20 +/- 0.54 mg/dL, respectively (P=.019), and SAP values were 18.97 +/- 0.24 versus 34.7 +/- 5.89 (P=.003). There was a strong positive correlation between sCr values and SAP (P=.005; r=0.64). These findings show the PAMS approach to be a useful alternative method for reflecting damage in more than one compartment of the renal tissue. Also, the method can discriminated implantation and allograft biopsies as well as grade I and II CAN cases. The series is small for a multivariate analysis of the value of SAP measurements in PAMS-stained sections as a prognosticator, but the data support its use.

  4. Color Doppler sonography in the study of chronic ischemic nephropathy.

    PubMed

    Meola, M; Petrucci, I

    2008-06-01

    In western countries, the risk of cardiovascular disease has increased considerably in recent decades. This trend has been paralleled by an increase in cases of atherosclerotic renal disease, which is related to the improved prognosis of cardiovascular diseases, aging, and the increasing mean age of the general population. It is reasonable to expect that in the near future, there will be a sharp increase in the number of elderly patients with atherosclerotic vascular disease in chronic dialysis programs. The result will be a dramatic rise in the social and economic costs of dialysis that could constitute a true clinical emergency. In this epidemiologic scenario, one of the most important targets of 21st century nephrology will be the early diagnosis of chronic ischemic nephropathy and the development of new and more effective strategies for its treatment.Color Doppler (CD) ultrasonography has displayed high sensitivity, specificity, and positive and negative predictive values in the diagnosis of this disease in selected population, making it an ideal tool for use in screening programs. Eligibility for screening should be based on clinical criteria. For the most part, it will be aimed at adults (especially those who are elderly) with atherosclerotic vascular disease involving multiple districts and chronic kidney disease (CKD), stage 2-3, in the absence of a documented history of renal disease. In these patients, hypertension may be a secondary manifestation or a symptom of the ischemic nephropathy itself. The objectives of sonographic screening should be (1) to identify subjects in the population at risk who are affected by stenosis of the main renal artery (RAS); (2) to identify and characterize patients without RAS who have chronic ischemic nephropathy caused by nephroangiosclerosis and/or atheroembolic disease. The former group will require second-level diagnostic studies or angioplasty with stenting; the latter can be managed conservatively. The most important

  5. Efficacy of cyclosporine for chronic, refractory stomatitis in cats: A randomized, placebo-controlled, double-blinded clinical study.

    PubMed

    Lommer, Milinda J

    2013-01-01

    Sixteen cats with chronic stomatitis, that had previously undergone premolar-molar or full-mouth extractions, were randomly assigned a group to receive 2.5 mg/kg cyclosporine or placebo orally twice daily Neither the clinician nor the clients were aware of the group assignments. Cats were evaluated prior to treatment and every 2 weeks for 6 weeks using a 30 point Stomatitis Disease Activity Index (SDAI) score. Mean improvement in SDAI scores among cats in the treatment group after 6 weeks was 52.7 %. This was significantty diffrent fom the mean improvement (12.2 %) of cats in the placebo group. During the 6 week study period, 7 of the 9 cats in the treatment group (77.8 %) showed a > 40 % improvement in SDAI score, while 1 of 7 cats in placebo group (14.3 %) showed a > 40 % improvement in SDAI score. This difference was statistically significant. Individual variability in the absorption of orally-administered cyclosporine was high. Trough whole-blood cyclosporine levels ranged firm 32.1 ng/ml to 1,576.2 ng/ml. At the end of the 6 week observation period, there was a statistically significant diference among cats with trough whole-blood cyclosporine levels >300 ng/ml (72.3 % improvement) compared with cats with cyclosporine levels < 300 ng/ml (28.2 % improvement). Whole-blood cyclosporine levels > 300 ng/ml were associated with significant improvement in oral inflammation in cats with chronic stomatitis that had previously undergone premolar-molar or fuill-mouth extraction.

  6. Prevalence and risk factors for early chronic allograft nephropathy in a live related renal transplant program

    PubMed Central

    Khan, Hamid; Mubarak, Muhammed; Aziz, Tahir; Ahmed, Ejaz; Fazal Akhter, Syed; Kazi, Javed; AA Naqvi, Syed; AH Rizvi, Syed

    2014-01-01

    Background: Chronic allograft nephropathy (CAN) is a common cause of delayed allograft failure throughout the world. Its prevalence and risk factors vary depending on a number of factors. There is little information on the prevalence and risk factors for early CAN in live related renal transplant patients. Objectives: We aimed to determine the prevalence and the risk factors of early CAN in our setup. Patients and Methods: The study was conducted at Sindh Institute of Urology & Transplantation (SIUT), Karachi, from 2002 to 2005 on patients who had live related kidney transplantation and underwent at least one allograft biopsy within 18 months of transplantation. The biopsies were performed and prepared in accordance with established indications and guidelines. The Banff 97 classification and its updates were used to diagnose and categorize the biopsy pathology. Patients were divided into two groups depending on the presence or absence of CAN on biopsies. Following parameters were compared among the groups: age, sex, human leukocyte antigen (HLA) match, immunosuppression used, acute rejection (AR) episodes, urinary tract infections (UTIs), viral infections, cyclosporine levels, early and late graft function monitored by serum creatinine. Results: A total of 164 patients fulfilled the study inclusion criteria. The mean age of recipients and donors was relatively young. The majority of the donors were siblings. The overall prevalence of CAN was 25.6% (42/164), between 3 and 18 months post transplantation. The median time to the appearance of CAN was 9 months post-transplant. The prevalence of CAN increased as post-transplant duration increased. In 39 (92.8%) subjects, CAN was detected on the second or subsequent graft biopsy. Only 3 (7.2%) patients showed CAN on the first graft biopsy. The majority of cases belonged to moderate degree or grade II CAN. The mean serum creatinine values were higher in the CAN group at the time of discharge and all times post

  7. [Reflux and obstructive nephropathy as a cause of renal failure in chronic dialysis children].

    PubMed

    Kałuzyńska, Anna; Jander, Anna; Puczko-Nogal, Barbara; Nowicki, Michał

    2008-01-01

    We carried out a retrospective analysis of medical files to evaluate causes of chronic renal failure in 80 children (M--49, F--31), age 1 month to 20 years) who started renal replacement therapy in the Department of Nephrology and Dialysis of the Polish Mothers Memorial Hospital in the years 1990-2007. In 28 children (35%) reflux and obstructive nephropathy was a cause of renal failure. In 5 children the disease was secondary to the neurogenic bladder. The incidence of these nephropathies in our population was constant in the analyzed years. In our group there were 2 neonates and 7 adolescent who were diagnosed with nephropathy as late as in the endstage phase. Boys with posterior urethral valve required renal replacement therapy earlier (146 +/- 55 months). We conclude that obstructive and reflux nephropathy are still the essential cause of end stage renal disease in children.

  8. Patients with analgetic nephropathy on chronic hemodialysis have a high incidence of severe secondary hyperparathyroidism.

    PubMed

    Pecovnik Balon, B; Krpan, D

    1998-12-01

    Between 1996 and 1997, 86 patients were treated for terminal renal failure by hemodialysis at Maribor Teaching Hospital. Among them were 12 with iPTH over 900 pg/ml and symptoms of bone disease. In these patients bone biopsy was carried out with the aim of determining the type of renal osteodystrophy (RO) and establishing a possible correlation with the clinical picture, with densitometry and laboratory results. Histomorphologically, 6 patients fulfilled the criteria for secondary hyperparathyroidism (HT) - 3 with analgetic nephropathy (AN), one with chronic pyelonephritis (CPN), one with vascular nephropathy (VN), one with chronic glomerulonephritis (CGN). Six patients fulfilled the criteria for mixed osteodystrophy (MO) - 3 AN, 2 CGN, one VN. According to laboratory findings and bone mineral density (BMD), a statistically significant difference between HT and MO was present only in AP (Table 1). The most frequent diagnosis in patients with iPTH >900 pg/ml was analgetic nephropathy.

  9. The Advantage of Cyclosporine A and Methotrexate Rotational Therapy in Long-Term Systemic Treatment for Chronic Plaque Psoriasis in a Real World Practice

    PubMed Central

    Choi, Chong Won; Kim, Bo Ri; Ohn, Jungyoon

    2017-01-01

    Background Psoriasis is a chronic inflammatory disease. In the treatment of psoriasis, cyclosporine is commonly prescribed systemic agents. However, long-term use of cyclosporine is not recommended because of side effects such as nephrotoxicity or hypertension. Objective To ascertain the improved safety of rotational therapy using cyclosporine and methotrexate, we investigated the frequency of abnormal results in laboratory test after long term rotational therapy using cyclosporine and methotrexate. Methods From January 2009 to June 2014, patients who were treated with cyclosporine or methotrexate were enrolled. The clinical data and usage of medications were reviewed. Laboratory tests were conducted before starting the treatment and regularly follow-up. The occurrences of any laboratory abnormalities during the treatments were investigated. Results A total of 21 psoriatic patients were enrolled. The mean of medication period and cumulative dose of cyclosporine and methotrexate were 497.81±512.06 days and 115.68±184.34 g in cyclosporine and 264.19±264.71 days and 448.71±448.63 mg in methotrexate. Laboratory abnormalities were found in total two patients after rotational therapy: two patients (9.5%) in aspartate aminotransferase/alanine aminotransferase and one patient (4.8%) in uric acid. No laboratory abnormalities were found in renal function test. Conclusion We found that the rotational approaches using cyclosporine and methotrexate reduced the possibility of the development of nephrotoxicity. In addition to other advantage such as quick switching from one agent to another, the rotational therapy using cyclosporine and methotrexate can minimize the adverse events during the systemic treatment of chronic plaque psoriasis. PMID:28223747

  10. Hematopoietic Stem Cell Transplantation Nephropathy Associated with Chronic Graft-versus-Host Disease without Extrarenal Involvement

    PubMed Central

    Ishida, Ryo; Shimizu, Akira; Kitani, Takashi; Nakata, Mayumi; Ota, Noriyoshi; Kado, Hiroshi; Shiotsu, Yayoi; Ishida, Mami; Tamagaki, Keiichi

    2016-01-01

    A 30-year-old woman with myelodysplastic syndrome underwent allogeneic hematopoietic stem cell transplantation (HSCT) derived from her HLA-matched sister six years previously. She received preconditioning total body irradiation with renal shielding and was subsequently administered cyclosporin A (CyA) as prophylaxis against graft-versus-host disease (GVHD). Four months after HSCT, asymptomatic proteinuria and glomerular hematuria developed during CyA tapering without obvious extrarenal involvements of GVHD, and persisted for six years. A renal biopsy revealed endothelial injury in the glomeruli, and the deposition of C4d was detected diffusely on glomerular capillaries and focally on peritubular capillaries, suggesting that nephropathy involved antibody- or complement-associated immune reactions. PMID:27725545

  11. Cyclosporin A reduces expression of adhesion molecules in the kidney of rats with chronic serum sickness

    PubMed Central

    Rincón, J; Parra, G; Quiroz, Y; Benatuil, L; Rodríguez-Iturbe, B

    2000-01-01

    Treatment with cyclosporin A (CsA) improves proteinuria and reduces renal cellular infiltration in chronic serum sickness (CSS). We examined if these effects were associated with a reduced renal expression of CD54 and its ligands, interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and MHC class II molecules. We studied two groups of rats in which CSS was induced by daily injections of ovalbumin (OVA): a group treated with CsA (OVA.CsA group, n = 11) and a group that received no treatment (OVA.CSS group, n = 11). An additional group of five rats (control group) received only phosphate buffer. Immunostaining techniques were used to follow CSS and to study the expression of CD54, CD18, CD11b/c, IFN-γ, TNF-α and MHC class molecules. Proteinuria (mg/24 h) was reduced from 248·2 ± 73·1 (OVA.CCS group) to 14·5 ± 13·1 with CsA treatment (P < 0·0001). The renal expression of CD54 and its ligands (CD18 and CD11b/c) was reduced by 50% to 75%. Correspondingly, there was a 60% to 85% reduction in the number of infiltrating leucocytes. The number of cells expressing TNF-α, IFN-γ and MHC II molecules was also reduced. CsA reduces expression of CD54 and its ligands. This effect is associated with a reduction of cellular infiltration, IFN-γ, TNF-α-producing cells and with MHC II expression in the kidney. These findings suggest that expression of adhesion molecules plays a critical role in CSS and underline the importance of cellular immunity in this experimental model. PMID:10931158

  12. Active and chronic phases of Berger's disease (IgA nephropathy).

    PubMed

    Feltis, J T; Churg, J; Holley, K M; Feiner, H; Gallo, G; Ackad, A S

    1984-03-01

    Berger's disease, or IgA nephropathy, is generally considered as pursuing a chronic course, often with recurrent attacks of gross hematuria or persistent microscopic hematuria. However, little attention has been paid to the acute changes that may accompany this nephropathy, and there are few reports of follow-up renal biopsy studies in these patients. We have had the opportunity to study two patients with Berger's disease (IgA nephropathy) in whom initial and follow-up renal biopsy studies were available. Both of these patients presented clinically with gross hematuria and moderately heavy proteinuria. In both cases, the initial renal biopsy disclosed diffuse mesangial proliferation associated with crescent formation, while follow-up biopsy disclosed only mild mesangial proliferation and no crescents. In one case electron microscopy revealed prominent subendothelial and small mesangial deposits in the initial biopsy, which became almost solely large mesangial in the second biopsy. The other case demonstrated only mesangial deposits in both biopsies.

  13. 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 ...

  14. Spanish experience with cyclosporine.

    PubMed

    Pascual, J; Marcén, R; Burgos, F J; Villafruela, J J; Teruel, J L; Mampaso, F; Quereda, C; Ortuño, J

    2004-03-01

    Our experience with cyclosporine (CsA) in de novo renal transplantation (RT) may be systematized in four consecutive periods. From February 1986 to December 1989, patient survival was higher among 128 consecutive CsA-prednisone-treated cadaver allograft recipients than in previous patients on azathioprine. One-year graft survival was significantly higher in CsA patients, a difference that was thereafter progressively reduced: at 10 years graft survivals were 50% versus 45%, and at 15 years 37% versus 35%, respectively. The most frequent cause of graft loss was death with a functioning graft. Acute rejection caused more graft losses among Aza-treated patients than CsA-treated ones. However, chronic allograft nephropathy produced more graft losses in CsA patients. After this initial experience with CsA-based immunosuppression we developed a second phase in which better results were obtained in 209 first cadaveric RT recipients. The use of lower initial CsA doses, more rapid steroid tapering, and a better approach to CsA nephrotoxicity or chronic nephropathy by substantial reductions in CsA exposure and delayed azathioprine addition, lead to these improvements. From March 1995 through 2000, we used the new microemulsion CsA formulation (Neoral) with steroids or azathioprine in 110 first de novo RT recipients. Mean donor and recipient ages were significantly higher in this phase than in previous ones; consequently, survival and function results were slightly worse. Blood CsA concentrations measured 2 hours after administration represent a more precise predictor of exposure than trough concentrations. The last step in optimizing Neoral use in RT on our service was application of reduced-dosage with C2 monitoring instead of classical C0 testing. Acute rejection and treatment failure rates were low and renal allograft function improved with respect to previous full-dose C0 experiences. CsA use has evolved in these two decades in four consecutive phases. Short-term results

  15. The Protective Effects of Cobra Venom from Naja naja atra on Acute and Chronic Nephropathy.

    PubMed

    Wang, Shu-Zhi; He, He; Han, Rong; Zhu, Jia-Li; Kou, Jian-Qun; Ding, Xiao-Lan; Qin, Zheng-Hong

    2013-01-01

    This study investigated the effects of Naja naja atra venom (NNAV) on acute and chronic nephropathy in rats. Rats received 6 mg/kg adriamycin (ADR) once to evoke the chronic nephropathy or 8 ml/kg 50% v/v glycerol to produce acute renal failure (ARF). The NNAV was given orally once a day starting five days prior to ADR or glycerol injection and continued to the end of experiments. The animals were placed in metabolic cages for 24 h for urine collection for urinary protein determination. The kidney function-related biochemical changes and index of oxidative stress were determined with automatic biochemistry analyzer or colorimetric enzyme assay kits. The pathomorphological changes were observed using light and transmission electron microcopies. The levels of inflammatory cytokines and NF- κ B activation were determined using ELISA kits, Western blot analysis, or immunofluorescence. The results showed that NNAV relieved ADR-induced chronic nephropathy and glycerol-triggered acute renal failure syndromes including proteinuria, hypoalbuminemia, hyperlipidemia, serum electrolyte unbalance, renal oxidative stress, and pathological damages. NNAV reduced kidney levels of TNF- α and IL-1 β , but it increased the levels of I κ B- α and inhibited NF- κ B p65 nuclear localization. These findings suggest that NNAV may be a valuable therapeutic drug for acute and chronic kidney diseases.

  16. Multiple papillomavirus-associated epidermal hamartomas and squamous cell carcinomas in situ in a dog following chronic treatment with prednisone and cyclosporine.

    PubMed

    Callan, Mary Beth; Preziosi, Diane; Mauldin, Elizabeth

    2005-10-01

    A 4-year-old, spayed female toy fox terrier developed multiple epidermal hamartomas and squamous cell carcinomas in situ following chronic immunosuppressive therapy with prednisone and cyclosporine for management of an immune-mediated nonregenerative anaemia. Immunohistochemical staining was positive for papillomavirus antigen within both benign (n = 19) and malignant (n = 8) cutaneous lesions that developed during a 3-year period of observation, with positive staining most often seen in keratinocytes in the granular cell layer. Treatment of the papillomavirus infection with interferon-alpha was discontinued after 2 weeks because of diarrhoea and a further increase in liver enzymes. The cutaneous lesions of this dog persisted and new lesions developed during the year following discontinuation of both cyclosporine and prednisone. This is the first reported case of papillomavirus-associated squamous cell carcinoma in situ developing in a dog following chronic administration of cyclosporine and prednisone.

  17. Outcome of anti-thymocyte immunoglobulin plus cyclosporine A for severe aplastic anaemia with chronic hepatitis B virus infection.

    PubMed

    Chen, Miao; Zhuang, Junling; Zhou, Daobin; Xu, Ying; Zhao, Yongqiang; Wang, Shujie; Zhang, Wei; Duan, Minghui; Zhu, Tienan; Li, Jian; Cai, Huacong; Cao, Xinxin; Han, Bing

    2017-04-01

    The influence of chronic hepatitis B virus (HBV) infection on the efficacy of intensive immunosuppressive treatment (IST) of severe aplastic anaemia (SAA) patients remains unclear. Previous reports on this topic have been mostly case reports or have had a relatively short follow-up. Eight SAA patients carrying chronic HBV infection and 24 matched patients without HBV at a ratio of 1:3 were included in this retrospective analysis. The patients were treated with anti-thymocyte globulin (ATG) and cyclosporine A. Entecavir was or was not administered throughout the IST course to patients with positive or negative HBV-DNA results, respectively. No evident HBV reactivation developed. The overall response was 87.5% by 12 months, and the recurrence rate was 12.5%. There were no significant differences in overall response, overall survival and event-free survival between groups. Entecavir can effectively prevent reactivation of HBV in SAA patients with positive HBV-DNA who received intensive IST. Regular surveillance may be sufficient for HBV-DNA negative patients who should receive antiviral drugs immediately when their HBV-DNA status changes from negative to positive. The prognosis of SAA patients with chronic HBV infection after intensive IST treatment is not worse than those without HBV infection.

  18. MRI findings in chronic lithium nephropathy: a case report.

    PubMed

    Slaughter, Aubrey; Pandey, Tarun; Jambhekar, Kedar

    2010-01-01

    Patients on long term lithium therapy for affective disorders may develop renal toxicity. It may manifest as nephrogenic diabetes insipidus with renal biopsy showing interstitial fibrosis, sclerotic glomeruli and cyst formation. Magnetic resonance imaging demonstrates the presence of microcysts in patients on long-term lithium therapy, suggesting a possible cause for their nephrotoxicity. We describe the typical magnetic resonance imaging appearance of renal microcysts in a 53 year old woman on chronic lithium therapy.

  19. Chronic kidney disease in an adolescent with hyperuricemia: familial juvenile hyperuricemic nephropathy.

    PubMed

    Alaygut, Demet; Torun-Bayram, Meral; Soylu, Alper; Kasap, Belde; Türkmen, Mehmet; Kavukçu, Salih

    2013-01-01

    Chronic kidney disease (CKD) is a life-long condition associated with substantial morbidity and premature death due to complications from a progressive decrease in kidney function. Especially in children, early diagnosis and detection of the etiologic factors are important to improve their health outcomes. Familial juvenile hyperuricemic nephropathy (FJHN) is a rare autosomal-dominant disorder characterized by hyperuricemia with renal uric acid under-excretion and CKD. Genetic studies have revealed mutations in the uromodulin (UMOD) gene. Highlighting the importance of CKD in children, a 14-year-old girl with the rare diagnosis of FJHN is reported herein.

  20. Etiopathology of chronic tubular, glomerular and renovascular nephropathies: clinical implications.

    PubMed

    López-Novoa, José M; Rodríguez-Peña, Ana B; Ortiz, Alberto; Martínez-Salgado, Carlos; López Hernández, Francisco J

    2011-01-20

    Chronic kidney disease (CKD) comprises a group of pathologies in which the renal excretory function is chronically compromised. Most, but not all, forms of CKD are progressive and irreversible, pathological syndromes that start silently (i.e. no functional alterations are evident), continue through renal dysfunction and ends up in renal failure. At this point, kidney transplant or dialysis (renal replacement therapy, RRT) becomes necessary to prevent death derived from the inability of the kidneys to cleanse the blood and achieve hydroelectrolytic balance. Worldwide, nearly 1.5 million people need RRT, and the incidence of CKD has increased significantly over the last decades. Diabetes and hypertension are among the leading causes of end stage renal disease, although autoimmunity, renal atherosclerosis, certain infections, drugs and toxins, obstruction of the urinary tract, genetic alterations, and other insults may initiate the disease by damaging the glomerular, tubular, vascular or interstitial compartments of the kidneys. In all cases, CKD eventually compromises all these structures and gives rise to a similar phenotype regardless of etiology. This review describes with an integrative approach the pathophysiological process of tubulointerstitial, glomerular and renovascular diseases, and makes emphasis on the key cellular and molecular events involved. It further analyses the key mechanisms leading to a merging phenotype and pathophysiological scenario as etiologically distinct diseases progress. Finally clinical implications and future experimental and therapeutic perspectives are discussed.

  1. Cyclosporine Injection

    MedlinePlus

    ... injection is used with other medications to prevent transplant rejection (attack of the transplanted organ by the ... people who have received kidney, liver, and heart transplants. Cyclosporine injection should only be used to treat ...

  2. 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.

  3. 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.

  4. Hypokalemic nephropathy in the rat. Role of ammonia in chronic tubular injury.

    PubMed

    Tolins, J P; Hostetter, M K; Hostetter, T H

    1987-05-01

    Chronic potassium deficiency results in progressive tubulointerstitial injury, associated with augmented renal ammoniagenesis. We investigated the role of elevated renal ammonia levels and the interaction of ammonia with the complement system in this injury. Potassium deficiency was induced in rats by feeding a low potassium diet. Experimental animals received 150 mM NaHCO3 or equimolar NaCl, as drinking water. After 3 wk, NaHCO3 supplemented rats demonstrated decreased ammonia production, less renal hypertrophy, less histologic evidence of injury, and less proteinuria. In in vitro studies on normal cortical tubular fragments, the addition of ammonia to serum in concentrations comparable to renal cortical levels in potassium-deficient animals significantly increased tubular deposition of C3 as quantitated by a radiolabeled antibody binding technique. Thus, alkali supplementation reduced chronic tubulointerstitial disease in a rat model of hypokalemic nephropathy. We propose that increased cortical ammonia levels contribute to hypokalemic nephropathy through ammonia-mediated activation of the alternative complement pathway.

  5. 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.

  6. [Clinical studies on chronic diabetic nephropathy and recent data concerning prevention of risks of nephropathy and cardiovascular diseases].

    PubMed

    Esnault, Vincent

    2006-05-01

    Considering the increasing incidence of diabetic nephropathy and its serious complications, the prevention of nephropathy evolution risk in diabetic patients is the subject of several recently initiated studies. In diabetic patients with advanced nephropathy, the lowering of proteinuria by renin angiotensin system blockers induces an evolution risk reduction, which can be further improved by increasing the dose of angiotensin II receptor antagonist (ARA II). Such a synergy can be also obtained with the association of an ARA II and an angiotensin converting enzyme (ACE) inhibitor, provided that the diuretic dose given to the patient is increased. In terms of cardiovascular risk, diabetic patients benefit from this type of treatment, as cardiovascular events increase with the level of proteinuria. In micro-albuminuria patients, sufficient doses of ARA II or ACE inhibitors are needed to avoid relapse after treatment discontinuation. In normo-albuminuria patients also, the treatment with a renin angiotensin system blocker significantly decreases the risk of development of microalbuminuria. Thus, the reduction of proteinuria or the prevention of its appearance with renin angiotensin system blockers is the main therapeutic strategy to prevent the evolution of nephropathy in diabetic patients.

  7. Acute, subacute and chronic effect of cyclosporin-A on mean arterial pressure of rats with severe spinal cord contusion.

    PubMed

    Romero, Samanta E; Bravo, Guadalupe; Hong, Enrique; Rojas, Guillermo; Ibarra, Antonio

    2008-11-07

    Cyclosporin-A (CsA) protects and regenerates the neural tissue after spinal cord (SC) injury. These beneficial effects are achieved when CsA is administered at a dose of 2.5mg/kg/12h during the first 2 days after lesion. In view of these observations, it is realistic to envision that, CsA could be tested in SC-clinical trials. Since CsA is a drug strongly related to hypertension, results imperative to evaluate experimentally the effect of the above CsA-dose regimen on blood pressure. For this purpose, one hundred and twenty adult rats were subjected (10 groups) or not (10 groups) to SC-injury. Five injured and five Sham-operated groups received CsA. The remaining groups received only vehicle. Mean arterial pressure (MAP) was recorded from these animals at acute (6 and 24h post surgery; p.s.), subacute (96h), or chronic (30 days) stages of injury. In the latter, the therapy (CsA or vehicle) was administered only during the first 2 days p.s. or daily during 30 days of follow-up. The results of this study showed that SC-injury by itself induces a significant decrease of MAP during the acute and subacute phases of injury. CsA therapy was able to reestablish MAP parameters to control values in these phases. Regardless the therapy, a reestablishment of MAP was observed in chronic stages. Only the daily administration of CsA induced a significant increase in MAP, however; such variation remained into the normal ranges of MAP for rats. The potential benefits offered by CsA support its usefulness after SC-injury.

  8. The role of Tamm-Horsfall protein in the pathogenesis of reflux nephropathy and chronic pyelonephritis.

    PubMed Central

    Andriole, V. T.

    1985-01-01

    Recurrent bacterial infection of the kidney was previously thought to be responsible for the renal scarring typical of chronic pyelonephritis until recent studies suggested that recurrent bacteriuria rarely produces chronic pyelonephritis in the absence of obstructive uropathy. In contrast, the association between vesicoureteral reflux (VUR) and chronic pyelonephritis has been observed frequently in the absence of urinary infection. Although the mechanism by which VUR injures the kidney has not been defined, recent observations have suggested that some component of urine might serve as an antigenic determinant involved in the immunopathogenesis of renal scarring in VUR. Therefore, the present studies investigated the immunopathogenic role of Tamm-Horsfall protein (THP) in (1) a rabbit model of tubulointerstitial nephritis; (2) a swine model of reflux nephropathy; and (3) patients with recurrent nephrolithiasis. The antigenic similarities between THP and uropathic bacteria were also studied. Our observations indicate that autoimmune responses to THP may occur after exposure to THP by intravenous challenge in rabbits, by urinary reflux in pigs, and in recurrent nephrolithiasis in man. Also, extracts of uropathic coliforms competitively inhibit the binding of human THP to its antibody. These studies suggest that autoimmune responses to THP may be the pathogenetic mechanism by which these factors, including bacteriuria, contribute to "chronic pyelonephritis." PMID:2412354

  9. 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

  10. Increased Expression of p-Akt correlates with Chronic Allograft Nephropathy in a Rat Kidney Model.

    PubMed

    Zhou, Li-Na; Wang, Ning; Dong, Yang; Zhang, Yiqin; Zou, Hequn; Li, Qingqin; Shi, Yangling; Chen, Ling; Zhou, Wenying; Han, Conghui; Wang, Yuxin

    2015-04-01

    Chronic allograft nephropathy (CAN) is the most common cause of chronic graft dysfunction leading to graft failure, our study investigates the expression and significance of p-Akt in the pathogenesis of CAN in rats. Kidneys of Fisher (F344) rats were orthotopically transplanted into Lewis (LEW) rats. The animals were evaluated at 4, 8, 12, 16, and 24 weeks post-transplantation for renal function and histopathology. Phosphorate Akt (p-Akt) protein expression was determined by Western blot and immunohistological assays. Our data show that 24-h urinary protein excretion in CAN rats increased significantly at week 16 as compared with F344/LEW controls. Allografts got severe interstitial infiltration of mononuclear cells at week 4 and week 8, but it was degraded as the time went on after week 16. Allografts markedly presented with severe interstitial fibrosis (IF) and tubular atrophy at 16 and 24 weeks. p-Akt expression was upregulated in rat kidneys with CAN, and the increase became more significant over time after transplantation. p-Akt expression correlated significantly with 24-h urinary protein excretion, serum creatinine levels, tubulointerstitial mononuclear cells infiltration, smooth muscle cells (SMCs) migration in vascular wall, and IF. It was concluded that p-Akt overexpression might be the key event that involved mononuclear cells infiltration and vascular SMCs migration at early stage, and IF and allograft nephroangiosclerosis at the late stage of CAN pathogenesis in rats.

  11. Green tea polyphenols stimulate mitochondrial biogenesis and improve renal function after chronic cyclosporin a treatment in rats.

    PubMed

    Rehman, Hasibur; Krishnasamy, Yasodha; Haque, Khujista; Thurman, Ronald G; Lemasters, John J; Schnellmann, Rick G; Zhong, Zhi

    2014-01-01

    Our previous studies showed that an extract from Camellia sinenesis (green tea), which contains several polyphenols, attenuates nephrotoxicity caused by cyclosporine A (CsA). Since polyphenols are stimulators of mitochondrial biogenesis (MB), this study investigated whether stimulation of MB plays a role in green tea polyphenol protection against CsA renal toxicity. Rats were fed a powdered diet containing green tea polyphenolic extract (0.1%) starting 3 days prior to CsA treatment (25 mg/kg, i.g. daily for 3 weeks). CsA alone decreased renal nuclear DNA-encoded oxidative phosphorylation (OXPHOS) protein ATP synthase-β (AS-β) by 42%, mitochondrial DNA (mtDNA)-encoded OXPHOS protein NADH dehydrogenase-3 (ND3) by 87% and their associated mRNAs. Mitochondrial DNA copy number was also decreased by 78% by CsA. Immunohistochemical analysis showed decreased cytochrome c oxidase subunit IV (COX-IV), an OXPHOS protein, in tubular cells. Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α, the master regulator of MB, and mitochondrial transcription factor-A (Tfam), the transcription factor that regulates mtDNA replication and transcription, were 42% and 90% lower, respectively, in the kidneys of CsA-treated than in untreated rats. These results indicate suppression of MB by chronic CsA treatment. Green tea polyphenols alone and following CsA increased AS-β, ND3, COX-IV, mtDNA copy number, PGC-1α mRNA and protein, decreased acetylated PGC-1α, and increased Tfam mRNA and protein. In association with suppressed MB, CsA increased serum creatinine, caused loss of brush border and dilatation of proximal tubules, tubular atrophy, vacuolization, apoptosis, calcification, and increased neutrophil gelatinase-associated lipocalin expression, leukocyte infiltration, and renal fibrosis. Green tea polyphenols markedly attenuated CsA-induced renal injury and improved renal function. Together, these results demonstrate that green tea polyphenols attenuate Cs

  12. 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

    2016-02-23

    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.

  13. Early treatment with xenon protects against the cold ischemia associated with chronic allograft nephropathy in rats.

    PubMed

    Zhao, Hailin; Luo, Xianghong; Zhou, Zhaowei; Liu, Juying; Tralau-Stewart, Catherine; George, Andrew J T; Ma, Daqing

    2014-01-01

    Chronic allograft nephropathy (CAN) is a common finding in kidney grafts with functional impairment. Prolonged hypothermic storage-induced ischemia-reperfusion injury is associated with the early onset of CAN. As the noble gas xenon is clinically used as an anesthetic and has renoprotective properties in a rodent model of ischemia-reperfusion injury, we studied whether early treatment with xenon could attenuate CAN associated with prolonged hypothermic storage. Exposure to xenon enhanced the expression of insulin growth factor-1 (IGF-1) and its receptor in human proximal tubular (HK-2) cells, which, in turn, increased cell proliferation. Xenon treatment before or after hypothermia-hypoxia decreased cell apoptosis and cell inflammation after reoxygenation. The xenon-induced HK-2 cell proliferation was abolished by blocking the IGF-1 receptor, mTOR, and HIF-1α individually. In the Fischer-to-Lewis rat allogeneic renal transplantation model, xenon exposure of donors before graft retrieval or recipients after engraftment enhanced tubular cell proliferation and decreased tubular cell death and cell inflammation associated with ischemia-reperfusion injury. Compared with control allografts, xenon treatment significantly suppressed T-cell infiltration and fibrosis, prevented the development of CAN, and improved renal function. Thus, xenon treatment promoted recovery from ischemia-reperfusion injury and reduced susceptibility to the subsequent development of CAN in allografts.

  14. Treatment of membranous nephropathy in children.

    PubMed

    Makker, Sudesh P

    2003-07-01

    Membranous nephropathy (MN) is not a common pediatric glomerular disease and not a common cause of idiopathic nephrotic syndrome (NS) in children. Because of the rarity of the disease, there is only a limited amount of uncontrolled data and no controlled data available in children regarding the treatment of MN. Older uncontrolled data indicate that nearly a quarter of children with NS, whether untreated or treated with various immunosuppressive agents, develop chronic renal failure. Current recommendations for treatment both for children presenting with or without NS therefore are based on controlled data obtained in adults with MN. All children should receive angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs). Children with NS may be treated initially with corticosteroids. If a satisfactory response is not obtained with corticosteroids, then treatment with cyclosporine or chlorambucil can be tried. The protocols of treatment with these drugs are described in this article.

  15. Consideration of Rat Chronic Progressive Nephropathy in Regulatory Evaluations for Carcinogenicity

    PubMed Central

    Hard, Gordon C.

    2013-01-01

    Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical. PMID:23104430

  16. Consideration of rat chronic progressive nephropathy in regulatory evaluations for carcinogenicity.

    PubMed

    Hard, Gordon C; Banton, Marcy I; Bretzlaff, Robert S; Dekant, Wolfgang; Fowles, Jefferson R; Mallett, Anthony K; McGregor, Douglas B; Roberts, Kathleen M; Sielken, Robert L; Valdez-Flores, Ciriaco; Cohen, Samuel M

    2013-04-01

    Chronic progressive nephropathy (CPN) is a spontaneous renal disease of rats which can be a serious confounder in toxicology studies. It is a progressive disease with known physiological factors that modify disease progression, such as high dietary protein. The weight of evidence supports an absence of a renal counterpart in humans. There is extensive evidence that advanced CPN, particularly end-stage kidney, is a risk factor for development of a background incidence of atypical tubule hyperplasia and renal tubule tumors (RTT). The likely cause underlying this association with tubule neoplasia is the long-term increased tubule cell proliferation that occurs throughout CPN progression. As a variety of chemicals are able to exacerbate CPN, there is a potential for those exacerbating the severity up to and including end-stage kidney to cause a marginal increase in RTT and their precursor lesions. Extensive statistical analysis of National Toxicology Program studies shows a strong correlation between high-grade CPN, especially end-stage CPN, and renal tumor development. CPN as a mode of action (MOA) for rat RTT has received attention from regulatory authorities only recently. In the absence of toxic effects elsewhere, this does not constitute a carcinogenic effect of the chemical but can be addressed through a proposed MOA approach for regulatory purposes to reach a decision that RTT, developing as a result of CPN exacerbation in rats, have no relevance for human risk assessment. Guidelines are proposed for evaluation of exacerbation of CPN and RTT as a valid MOA for a given chemical.

  17. Long-term gene therapy with thrombospondin 2 inhibits TGF-β activation, inflammation and angiogenesis in chronic allograft nephropathy.

    PubMed

    Daniel, Christoph; Vogelbacher, Regina; Stief, Andrea; Grigo, Christina; Hugo, Christian

    2013-01-01

    We recently identified Thrombospondin-2 (TSP-2) as a regulator of matrix remodelling and inflammation in experimental kidney disease by using TSP-2 null mice and successfully proved TSP-2 overexpression as a therapeutic concept in a short term glomerulonephritis model in the rat. In this current study, we investigated if long-term TSP-2 overexpression is also capable to ameliorate the progression of chronic kidney disease in the setting of the chronic allograft nephropathy F344-Lewis model in the rat. Two weeks after renal transplantation, two rat thigh muscles were transfected once only with either a TSP-2 overexpressing plasmid (n = 8) or a luciferase-expressing plasmid as control (n = 8). Rats were monitored for renal function, histological changes and gene expression in the graft for up to 30 weeks after transplantation. Unexpectedly, only in the TSP-2 treated group 2 rats died before the end of the experiment and renal function tended to be worsened in the TSP-2 group compared to the luciferase-treated controls. In addition, glomerular sclerosis and tubular interstitial injury as well as cortical fibronectin deposition was significantly increased in the TSP-2 treated kidneys despite reduced TGF-β activation and marked anti-inflammatory (macrophages, T-cells and B-cells) effects in this group. Long-term TSP-2 therapy impaired repair of renal endothelium, as demonstrated by significant higher glomerular and peritubular endothelial rarefaction and reduced endothelial cell proliferation in the transplanted kidneys from TSP-2 treated rats compared to controls. This TSP-2 effect was associated with decreased levels of renal VEGF but not VEGF1 receptor. In conclusion, despite its anti-inflammatory and TGF-β activation blocking effects, TSP-2 gene therapy did not ameliorate but rather worsened experimental chronic allograft nephropathy most likely via its anti-angiogenic properties on the renal microvasculature.

  18. The inflammatory state provokes sexual dimorphism in left ventricular and electrocardiographic effects of chronic cyclosporine in rats

    PubMed Central

    El-Bassossy, Hany M.; Banjar, Zainy M.; El-Mas, Mahmoud M.

    2017-01-01

    Although cardiotoxicity has been recognized as an adverse effect of cyclosporine A (CSA), no information exists regarding sex specificity of CSA cardiotoxicity. We tested the hypothesis that left ventricular (LV) and electrocardiographic (ECG) effects of CSA and related inflammatory/histopathological derangements are sex related. CSA reduced the LV slope of end-systolic pressure volume relationship and increased isovolumic relaxation constant. These effects were more pronounced in male compared to female rats, suggesting LV systolic and diastolic dysfunction. ECG recordings showed elevated ST segments and increased QTc and T peak trend intervals in CSA-treated male rats, markers of LV ischemia and arrhythmogenesis. In female rats, CSA delayed AV conduction, as reflected by prolonged PR interval. Other sex-related effects for CSA included (i) increased blood cholesterol, and reduced rates of rise and fall in LV pressure and nuclear factor kappa B and angiotensin receptors type 1 expressions in male rats, and (ii) increased LV adiponectin in females. Histopatholgically, CSA caused vascular congestion, blood extravasation, and pyknotic or even absent nuclei in both sexes. In conclusion, rats exhibit sex-independent susceptibility to negative LV and histopathological influences of CSA. These effects become more intensified in male rats, perhaps on account of aggravated ischemic and inflammatory milieus. PMID:28211883

  19. [Lithium nephropathy].

    PubMed

    Kaczmarczyk, Ireneusz; Sułowicz, Władysław

    2013-01-01

    Lithium salts are the first-line drug therapy in the treatment of uni- and bipolar disorder since the sixties of the twentieth century. In the mid-70s, the first information about their nephrotoxicity appeared. Lithium salts have a narrow therapeutic index. Side effects during treatment are polyuria, polydipsia and nephrogenic diabetes insipidus. Accidental intoxication can cause acute renal failure requiring renal replacement therapy while receiving long-term lithium salt can lead to the development of chronic kidney disease. The renal biopsy changes revealed a type of chronic tubulointerstitial nephropathy. The imaging studies revealed the presence of numerous symmetric microcysts. Care of the patient receiving lithium should include regular determination of serum creatinine, creatinine clearance and monitoring of urine volume. In case of deterioration of renal function reducing the dose should be considered.

  20. Quantitative digital histochemistry with methenamine silver staining in renal allograft biopsies excluding pure chronic allograft nephropathy cases.

    PubMed

    Sarioglu, S; Sis, B; Celik, A; Tekis, D; Kavukcu, S; Bora, S; Camsari, T

    2006-03-01

    Deterioration of renal function is correlated with irreversible damage in chronic diseases. Recently we described a digital quantitative histochemistry method, relying on periodic acid methenamine silver (PAMS) staining to determine the chronic renal lesions. This index was strongly correlated with progressive deterioration of renal function in grafts with chronic allograft nephropathy (CAN). Herein the method has been applied to a cohort of renal allografts which were biopsied for various reasons, we sought to highlight its value to quantify chronic graft damage. Forty-four renal allograft biopsies from 37 patients with elevated serum creatinine values (SCr) underwent light microscopic image analysis (Mediscope, Dokuz Eylül University, Clinical Engineering Department, Izmir, Turkey) of the PAMS-stained area percentage (SAP). SCr was recorded at four intervals to overcome acute effects: the under SCr value before (SCr1) and after a biopsy within 3 months (SCr3), SCr at the time of the biopsy (SCr2), and the latest value (SCr4). The PAMS-SAP scores were strongly associated with increased interstitial fibrosis and tubular atrophy Banff scores (Kruskal-Wallis test, P = .006 and P = .003, respectively). There was a moderate positive correlation between PAMS and SCr3 (Pearson correlation test, P = .04, r = .312), and a strong positive correlation between time from transplantation to biopsy (Pearson correlation test, P < .000, r = .532). The present results show that PAMS-SAP seems to be of value to quantify renal scarring in allograft biopsies, reflecting four compartments. The strong correlation with time is noteworthy especially as a probable reflection of aging of the renal allograft.

  1. [Aristolochic acid nephropathy].

    PubMed

    Witkowicz, Joanna

    2009-01-01

    Aristolochic acid nephropathy is a chronic, fibrosing, interstitial nephritis caused by aristolochic acid (AA), which is a component of the plants of Aristolochiacae family. It was first reported in 1993, in Belgium as a Chinese herb nephropathy, in patients who received a slimming regimen containing AA. The term aristolochic acid nephropathy also includes Balcan endemic nephropathy and other endemic tubulointerstitial fibrosis. Moreover, AA is a human carcinogen which induces urothelial cancer. The AA-containing herbs are banned in many countries and FDA published the warnings concerning the safety of AA-containing botanical remedies in 2000. Regarding the increasing interest in herbal medicines, uncontrolled access to botanical remedies and replacement of one herb by another AA-containing compounds makes thousands of people all around the world at risk of this grave disease.

  2. [Rapid tapering of cyclosporine for cytogenetic relapse shortly after bone marrow transplantation in a patient with chronic myeloid leukemia].

    PubMed

    Kobayashi, Y; Nakata, M; Sato, N; Kamiya, Y; Maeda, A; Togitani, K; Kawahigashi, N; Murayama, T; Yokozawa, T; Takeyama, K; Narabayashi, M; Takenaka, T; Tobinai, K

    1998-06-01

    A 53-year-old female case of cytogenetically relapsed chronic myeloid leukemia after allogeneic bone marrow transplantation (BMT) who achieved remission by withdrawal of immunosuppressant is reported. On day 690 of this presentation she is well and alive with performance status of 100%. She had episodes of cyclic oscillation of her neutrophil count during hydroxyurea therapy lasting 1 year before transplantation. Increase of the neutrophils at the time of BMT might have contributed to her early relapse on day 207. Withdrawal of immunosuppressant was successful at least in this case.

  3. The mineralocorticoid receptor antagonist eplerenone reduces renal interstitial fibrosis after long-term cyclosporine treatment in rat: antagonizing cyclosporine nephrotoxicity

    PubMed Central

    2013-01-01

    Background Chronic cyclosporine-(CsA)-mediated loss of kidney function is a major clinical problem in organ transplantation. We hypothesized that the mineralocorticoid receptor antagonist eplerenone (EPL) prevents chronic CsA-induced renal interstitial volume increase, tubule loss, and functional impairment in a rat model. Methods Sprague–Dawley rats received CsA alone (15 mg/kg/d p.o.), CsA and EPL (approximately 100 mg/kg/day p.o.) or vehicle (control) for 12 weeks. At 11 weeks, chronic indwelling arterial and venous catheters were implanted for continuous measurements of arterial blood pressure (BP) and GFR (inulin clearance) in conscious, freely moving animals. Plasma was sampled for analysis and kidney tissue was fixed for quantitative stereological analyses. Results Compared to controls, CsA-treatment reduced relative tubular volume (0.73±0.03 vs. 0.85±0.01, p<0.05) and increased relative interstitial volume (0.080±0.004 vs. 0.045±0.003, p<0.05); EPL attenuated these changes (0.82±0.02, p<0.05, and 0.060±0.006, p<0.05, respectively). CsA-treated rats had more sclerotic glomeruli and a higher degree of vascular depositions in arterioles; both were significantly reduced in CsA+EPL-treated animals. CsA increased BP and reduced body weight gain and GFR. In CsA+EPL rats, weight gain, GFR and BP at rest (daytime) were normalized; however, BP during activity (night) remained elevated. Plasma sodium and potassium concentrations, kidney-to-body weight ratios and CsA whole blood concentration were similar in CsA and CsA+EPL rats. Conclusions It is concluded that in the chronic cyclosporine rat nephropathy model, EPL reduces renal tissue injury, hypofiltration, hypertension, and growth impairment. MR antagonists should be tested for their renoprotective potential in patients treated with calcineurin inhibitors. PMID:23425330

  4. The impact of ICAM1 and VCAM1 gene polymorphisms on chronic allograft nephropathy and transplanted kidney function.

    PubMed

    Kłoda, K; Domański, L; Pawlik, A; Wiśniewska, M; Safranow, K; Ciechanowski, K

    2013-01-01

    ICAM-1 and VCAM-1 adhesion molecules play important roles in the immune response and emergence of chronic allograft nephropathy (CAN). The several polymorphisms of ICAM1 and VCAM1 genes are associated with changes in molecular expression therefore affecting allograft function and immune responses after kidney transplantation. The aim of this study was to examine the impact of polymorphisms in ICAM1 and VCAM1 genes on biopsy-proven CAN and renal allograft function. The 270 Caucasian renal transplant recipients (166 men and 104 women) were genotyped for the rs5498 ICAM1 and rs1041163 and rs3170794 VCAM1 gene polymorphisms using real-time polymerase chain reaction. There was no correlation between polymorphisms and CAN. Creatinine concentrations in the first month after transplantation differed between the rs5498 ICAM1 genotypes (P = .095), being higher for GG carriers (AA + AG vs GG, P =.07) albeit not with statistical significance. Creatinine concentrations at 12, 24, and 36 months after transplantation differed significantly among rs5498 ICAM1 genotypes (P = .0046, P =.016, and P = .02) and were higher among GG carriers (AA + AG vs GG, P = .001, P = .004, and P = .006). Rs5498 ICAM1 GG genotype and receipient male gender were independent factors associated with higher creatinine concentrations. These results suggest that the rs5498 ICAM1 GG genotype may be associated with long-term allograft function.

  5. Intravenous renal cell transplantation with SAA1-positive cells prevents the progression of chronic renal failure in rats with ischemic-diabetic nephropathy.

    PubMed

    Kelly, Katherine J; Zhang, Jizhong; Han, Ling; Wang, Mingsheng; Zhang, Shaobo; Dominguez, Jesus H

    2013-12-15

    Diabetic nephropathy, the most common cause of progressive chronic renal failure and end-stage renal disease, has now reached global proportions. The only means to rescue diabetic patients on dialysis is renal transplantation, a very effective therapy but severely limited by the availability of donor kidneys. Hence, we tested the role of intravenous renal cell transplantation (IRCT) on obese/diabetic Zucker/SHHF F1 hybrid (ZS) female rats with severe ischemic and diabetic nephropathy. Renal ischemia was produced by bilateral renal clamping of the renal arteries at 10 wk of age, and IRCT with genetically modified normal ZS male tubular cells was given intravenously at 15 and 20 wk of age. Rats were euthanized at 34 wk of age. IRCT with cells expressing serum amyloid A had strong and long-lasting beneficial effects on renal function and structure, including tubules and glomeruli. However, donor cells were found engrafted only in renal tubules 14 wk after the second infusion. The results indicate that IRCT with serum amyloid A-positive cells is effective in preventing the progression of chronic kidney disease in rats with diabetic and ischemic nephropathy.

  6. Cyclosporine in veterinary dermatology.

    PubMed

    Palmeiro, Brian S

    2013-01-01

    Cyclosporine is an immunomodulatory medication that is efficacious and approved for atopic dermatitis in dogs and allergic dermatitis in cats; it has also been used to successfully manage a variety of immune-mediated dermatoses in dogs and cats. This article reviews the use of cyclosporine in veterinary dermatology including its mechanism of action, pharmacokinetics, drug interactions, side effects, and relevant clinical updates. Dermatologic indications including atopic/allergic dermatitis, perianal fistulas, sebaceous adenitis, and other immune-mediated skin diseases are discussed.

  7. Impact of heart failure on the incidence of contrast-induced nephropathy in patients with chronic kidney disease.

    PubMed

    Rosenstock, Jordan L; Gilles, Emmanuelle; Geller, Ari B; Panagopoulos, Georgia; Mathew, Staicy; Malieckal, Deepa; DeVita, Maria V; Michelis, Michael F

    2010-12-01

    We randomized patients with chronic kidney disease (serum creatinine ≥ 1.5 mg/dl or glomerular filtration rate (GFR) <60 ml/min/1.73 m²) in a double-blind fashion to receive saline or sodium bicarbonate prior to and after cardiac or vascular angiography. The primary endpoint was contrast-induced nephropathy (CIN), defined as an increase in serum creatinine by 25% or by 0.5 mg/dl from baseline. Patients with congestive heart failure (CHF), cardiac ejection fraction (EF) <30%, or GFR < 20 ml/min/1.73 m² were excluded. The study was discontinued (after 142 patients were randomized) due to a low incidence of CIN (1.5%). We retrospectively identified all cases of CIN (n = 30) at our institution during the same time period to see if these patients differed from our trial sample. There was no difference in serum creatinine (1.7 ± 0.4 vs. 1.7 ± 0.6 mg/dL), GFR (42.7 ± 9.7 vs. 45.3 ± 3.2 ml/min), incidence of diabetes (51.8% vs. 63.3%), contrast volume (121.7 ± 63.8 vs. 122.7 ± 68.3 ml), ACE inhibitor or angiotensin receptor blocker use (54.0% vs 63.3%), and periprocedure diuretic use (33.1% vs 26.7%). On multivariate analysis, only a cardiac ejection fraction (EF) of less than 40% was significantly associated with CIN (odds ratio, 4.52; 95% confidence interval, 1.30-15.71; P = 0.02). In all, 22/30 patients (73.3%) who developed CIN had at least one or more characteristics that would have excluded their enrollment in our randomized trial including evidence of congestive heart failure (17/30 patients), EF less than 30% (9 patients), age greater than 85 years (2 patients), or advanced renal failure with a baseline GFR of less than 20 cc/min (1 patient). In summary, patients with CKD without evidence of CHF who receive adequate hydration appear to have a very low risk of CIN associated with angiography. A low EF (less than 40%) appeared to be the most significant risk factor for CIN in our population.

  8. 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

  9. Reflux nephropathy

    MedlinePlus

    ... with multiple sclerosis, spinal cord injury, or other nervous system (neurological) conditions Reflux nephropathy can also occur from swelling of the ureters after a kidney transplant or from injury to the ureter. Risk factors ...

  10. N-acetyl cysteine versus allopurinol in the prevention of contrast nephropathy in patients with chronic kidney disease: A randomized controlled trial

    PubMed Central

    Sadineni, R.; Karthik, K. R.; Swarnalatha, G.; Das, U.; Taduri, G.

    2017-01-01

    Contrast media administration can lead to acute deterioration in renal function particularly in patients with pre-existing chronic kidney disease. This prospective, randomized controlled open-label parallel group study was undertaken at Nizam's Institute of Medical Sciences, Hyderabad, from June to December 2015. A total of 95 patients were included, of which 35 received n-acetylcysteine (NAC) + normal saline (NS), 30 patients received allopurinol (ALL) + NS, and 30 patients received placebo. In our study, the overall incidence of CIN was 24%. Incidence of CIN in NAC + NS, ALL + NS, and placebo group were 20%, 16%, and 36%, respectively. The major finding of this study was there was no significant difference between NAC and allopurinol in the prevention of contrast nephropathy. However, only allopurinol was superior to placebo. In our study, hyperuricemia and baseline serum creatinine were the only risk factors associated with CIN. PMID:28356658

  11. Cyclosporin-A associated malignancy

    PubMed Central

    Durnian, Jonathan M; Stewart, Rosalind MK; Tatham, Richard; Batterbury, Mark; Kaye, Stephen B

    2007-01-01

    The use of cyclosporin is well established within the ophthalmology community, especially against sight threatening intraocular inflammation. It is well known however, that immunosuppression in general is a risk factor for the development of malignancy and numerous studies point to the risk imposed by cyclosporin. This article analyses and reviews all relevant studies with regard to the development of malignancy associated with the use of cyclosporin and extrapolates this into the ophthalmic setting. This is to enable clinicians to assess the risks in individual patients and to present a monitoring regime which can be used in patients undergoing cyclosporin treatment. The review is solely concerned with the risk of the development of malignancy following cyclosporin immunosuppression and not with any other adverse effect. PMID:19668519

  12. [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.

  13. Drug-induced nephropathies.

    PubMed

    Paueksakon, Paisit; Fogo, Agnes B

    2017-01-01

    Drugs are associated frequently with the development of various types of acute and chronic kidney diseases. Nephrotoxicity is associated most commonly with injury in the tubulointerstitial compartment manifested as either acute tubular injury or acute interstitial nephritis. A growing number of reports has also highlighted the potential for drug-induced glomerular disease, including direct cellular injury and immune-mediated injury. Recognition of drug-induced nephropathies and rapid discontinuation of the offending agents are critical to maximizing the likelihood of renal function recovery. This review will focus on the pathology and pathogenesis of drug-induced acute interstitial nephritis and drug-induced glomerular diseases.

  14. Chemically exacerbated chronic progressive nephropathy not associated with renal tubular tumor induction in rats: an evaluation based on 60 carcinogenicity studies by the national toxicology program.

    PubMed

    Melnick, Ronald L; Burns, Kathleen M; Ward, Jerrold M; Huff, James

    2012-08-01

    Chronic progressive nephropathy (CPN) is a common age-related degenerative-regenerative disease of the kidney that occurs in both sexes of most strains of rats. Recently, claims have been made that enhanced CPN is a mode of action for chemically induced kidney tumors in male rats and that renal tubular tumors (RTTs) induced by chemicals that concomitantly exacerbate CPN are not relevant for human cancer risk assessments. Although CPN is an observable histopathological lesion that may be modified by diet, the etiology of this disease and the mechanisms for its exacerbation by chemicals are unknown, and it fails to meet fundamental principles for defining carcinogenic modes of action and human relevance. Our comprehensive evaluation of possible relationships between exacerbated CPN and induction of RTTs in 58 carcinogenicity studies, conducted by the National Toxicology Program, in male and 11 studies in female F344 rats using 60 chemicals revealed widespread inconsistency in the claimed association. Because the proposed hypothesis lacks evidence of biological plausibility, and due to inconsistent relationships between exacerbated CPN and kidney tumor incidence in carcinogenicity studies in rats, dismissing the human relevance of kidney tumors induced by chemicals that also exacerbate CPN in rats would be wrong.

  15. Isogenic mesenchymal stem cells transplantation improves a rat model of chronic aristolochic acid nephropathy via upregulation of hepatic growth factor and downregulation of transforming growth factor β1.

    PubMed

    Li, Wei; Jiang, Hong; Feng, Jiang-Min

    2012-09-01

    Chronic aristolochic acid (AA) nephropathy (CAAN) caused by intake of AA-containing herbs is difficult to treat. We evaluated the therapeutic effect of bone marrow (BM) mesenchymal stem cells (MSCs) on a rat model of CAAN. Female Wistar rats were fed with decoction of Caulis Aristolochia manshuriensis by intragastric administration. MSCs were prepared from BM of male Wistar rats and injected into female CAAN rats through tail vein. Body weight, renal function, and urinary excretion of these CAAN rats were monitored before killing at the end of the 20th week. Blood, urine, and tissue samples were collected from experimental (MSC and non-MSC) and normal control groups. All animals developed renal fibrosis after 12 weeks of intake of AA-containing decoction. Fibrosis in the MSC groups was significantly reduced as examined with light and electron microscopy. Blood urea nitrogen, serum creatinine, and urine protein levels were significantly reduced and hemoglobin levels were improved in the MSC group as compared with the non-MSC group (p < 0.01). The expression of TGF-β1 mRNA and protein was reduced but hepatic growth factor (HGF) was increased in the MSC group compared with the non-MSC group, but still higher than the normal control level as measured by immunochemical, RT-PCR, and western blotting assays (p < 0.01). The renal fibrosis of CAAN could be protected by isogenic MSC transplantation, probably via upregulation of HGF and downregulation of TGF-β1.

  16. Association of Hypothyroidism with Body Mass Index, Systolic Blood Pressure and Proteinuria in Diabetic Patients: Does treated Hypothyroidism with Thyroxine Replacement Therapy Prevent Nephropathy/Chronic Renal Disease?

    PubMed

    Aziz, Kamran M A

    2016-01-01

    Untreated or sub-clinical hypothyroidism is associated with insulin resistance, obesity, adverse effects on cardiovascular system, hypertension and in turn risk of nephropathy. However, these changes are reversible with thyroxine replacement therapy (TRT). Current research studied 4235 diabetic patients, divided into two groups, those with clinical hypothyroidism /on TRT, compared to those without thyroid disease or undiagnosed. BMI, blood pressure, creatinine, urine microalbumin and spot urine protein levels were compared between these two groups. Study finding demonstrated that for hypothyroid cases, BMI was higher (32.2 ± 7.44 versus 29.4 ± 5.7; p < 0.0001), serum creatinine was on lower levels (0.75 ± 0.27 versus 1.0 ± 0.74; p = 0.001), systolic BP was on lower side (123.7 ± 15.9 versus 128.13 ± 16.8; p= 0.015); spot urine microalbumin was on lower side (52.58 ± 71.65; versus 87.77 ± 140.86; p=0.010) and spot urine protein had lower levels (25.3 ± 38.3 versus 44.28 ± 123.58; p < 0.0001). Current research also demonstrated that Pearson`s x2 and odds/protective odds for hypothyroidism (on TRT) was strongly associated with obesity (p <0.0001; odds ratio 2.28, 95% CI 1.47 to 3.56). However, they were protected from HTN (p= 0.272; protective odds ratio 1.28, 95%CI 0.824 to 1.98), nephropathy (p=0.386; protective odds 1.36, 95% CI 0.861 to 2.14) and chronic renal disease (p= 0.112; protective odds 3.42, 95% CI 0.83 to 14.13). In conclusion, TRT itself has protective effects on cardiovascular and renal system. Hence, thyroid screening is essential among diabetics to detect sub clinical or clinical hypothyroidism.

  17. Decreased Serum C3 Levels in Immunoglobulin A (IgA) Nephropathy with Chronic Kidney Disease: A Propensity Score Matching Study

    PubMed Central

    Yang, Xi; Wei, Ri-bao; Wang, Yang; Su, Ting-Yu; Li, Qing-Ping; Yang, Ting; Huang, Meng-Jie; Li, Kun-Ying; Chen, Xiang-Mei

    2017-01-01

    Background The effects of low serum C3 levels and the activation of the complement system on the development and the prognosis of IgAN are unclear. The present study aimed to determine whether decreased levels of complement C3 influence the prognosis of IgAN patients with chronic kidney disease. Material/Methods We enrolled a total of 1564 patients with primary IgAN diagnosed by renal biopsy at the Chinese PLA General Hospital from January 2011 to March 2015. The endpoint was end-stage renal disease (ESRD) or a doubling of the baseline serum creatinine (D-SCr) level. All patients were using 1: 1 propensity score matching (PSM), and the baseline values were not significantly different between these 2 groups (P>0.05). Results During a follow-up period, 14 patients in the group with decreased C3 levels reached the endpoint, with 12 patients with normal C3 levels. There was no significant difference between the 2 groups in achieving D-SCr or ESRD (P=0.676). In multivariate Cox analysis, adjusted for demographic and laboratory examination, the risk of reaching the endpoint was comparable in the 2 groups (HR, 0.70; 95% CI, 0.27–1.78; P=0.449;). Furthermore, the risk of reaching ESRD (HR, 0.83; 95% CI, 0.25–2.75; P=0.757) and D-SCr (HR, 1.45; 95% CI, 0.20–10.60; P=0.718) did not differ between the 2 groups. Conclusions Decreased serum C3 levels in IgA nephropathy with chronic kidney disease did not play a decisive role in renal progression. PMID:28166191

  18. Decreased Serum C3 Levels in Immunoglobulin A (IgA) Nephropathy with Chronic Kidney Disease: A Propensity Score Matching Study.

    PubMed

    Yang, Xi; Wei, Ri-Bao; Wang, Yang; Su, Ting-Yu; Li, Qing-Ping; Yang, Ting; Huang, Meng-Jie; Li, Kun-Ying; Chen, Xiang-Mei

    2017-02-06

    BACKGROUND The effects of low serum C3 levels and the activation of the complement system on the development and the prognosis of IgAN are unclear. The present study aimed to determine whether decreased levels of complement C3 influence the prognosis of IgAN patients with chronic kidney disease. MATERIAL AND METHODS We enrolled a total of 1564 patients with primary IgAN diagnosed by renal biopsy at the Chinese PLA General Hospital from January 2011 to March 2015. The endpoint was end-stage renal disease (ESRD) or a doubling of the baseline serum creatinine (D-SCr) level. All patients were using 1: 1 propensity score matching (PSM), and the baseline values were not significantly different between these 2 groups (P>0.05). RESULTS During a follow-up period, 14 patients in the group with decreased C3 levels reached the endpoint, with 12 patients with normal C3 levels. There was no significant difference between the 2 groups in achieving D-SCr or ESRD (P=0.676). In multivariate Cox analysis, adjusted for demographic and laboratory examination, the risk of reaching the endpoint was comparable in the 2 groups (HR, 0.70; 95% CI, 0.27-1.78; P=0.449;). Furthermore, the risk of reaching ESRD (HR, 0.83; 95% CI, 0.25-2.75; P=0.757) and D-SCr (HR, 1.45; 95% CI, 0.20-10.60; P=0.718) did not differ between the 2 groups. CONCLUSIONS Decreased serum C3 levels in IgA nephropathy with chronic kidney disease did not play a decisive role in renal progression.

  19. Lithium nephropathy: unique sonographic findings.

    PubMed

    Di Salvo, Donald N; Park, Joseph; Laing, Faye C

    2012-04-01

    This case series describes a unique sonographic appearance consisting of numerous microcysts and punctate echogenic foci seen on renal sonograms of 10 adult patients receiving chronic lithium therapy. Clinically, chronic renal insufficiency was present in 6 and nephrogenic diabetes insipidus in 2. Sonography showed numerous microcysts and punctate echogenic foci. Computed tomography in 5 patients confirmed microcysts and microcalcifications, which were fewer in number than on sonography. Magnetic resonance imaging in 2 patients confirmed microcysts in each case. Renal biopsy in 1 patient showed chronic interstitial nephritis, microcysts, and tubular dilatation. The diagnosis of lithium nephropathy should be considered when sonography shows these findings.

  20. Mechanism of hypertension in diabetic nephropathy

    PubMed Central

    Nazar, Chaudhary Muhammad Junaid

    2014-01-01

    High prevalence of hypertension is observed in diabetic patients of both the types. Diabetic nephropathy is one of the major reason for high morbidity, mortality and financial burden in such hypertensive diabetic patients. For this review, electronic databases including PubMed/Medline, Embase, Cochrane and Google scholar were searched from 1990-2013. Multiple inter-related factors are responsible for the development of hypertension and therefore nephropathy in the chronic diabetic patients. Majority of such factors are identified to lead to extensive sodium reabsorption and peripheral vasoconstriction and thus leading to microvascular complications like nephropathy. Management of hypertension by targeting such mediators is the highly recommended therapy for controlling and treating diabetic nephropathy. Clinical trials suggests that drugs inhibiting the renin-angiotensin-aldosterone pathway should be used as the first-line agents for the management of hypertensive diabetic nephropathy patients. These agents are effective in slowing the progression of the end-stage kidney disease as well as lowering albuminuria. Researchers are also investigating the effectiveness of drug combination for better management of hypertension and diabetic nephropathy. The present article is a review of the evidences which explains the underlying pathological changes which leads to the development of nephropathy in a hypertensive diabetic patients. The review also observes the clinical trials for different anti-hypertensive drugs which are recommended for the treatment of such patients. PMID:28197463

  1. Detection of anti-HLA antibodies with flow cytometry in needle core biopsies of renal transplants recipients with chronic allograft nephropathy.

    PubMed

    Martin, Laurent; Guignier, Fredy; Bocrie, Olivier; D'Athis, Philippe; Rageot, David; Rifle, Gérard; Justrabo, Eve; Mousson, Christiane

    2005-05-27

    The aim of this study was to assess the feasibility of detecting anti-HLA antibodies in eluates from needle core biopsies of renal transplants with chronic allograft nephropathy. Two methods of screening, the enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FlowPRA) were compared. Twenty renal transplants with CAN were removed after irreversible graft failure. To assess the feasibility of detecting anti-HLA antibodies in small samples, needle core biopsies were sampled at the same place as surgical samples and at a second cortical area. Antibodies were eluted with an acid elution kit and anti-class I and class II IgG HLA antibodies detected using ELISA and flow cytometry. Flow cytometry was found to be more sensitive than ELISA for detecting anti-HLA antibodies in eluates from renal transplants with CAN (95% vs. 75% of positive cases). Detection of anti-HLA antibodies showed good agreement between surgical samples and needle core biopsies performed at the same place for anti-class I (80% vs. 65%, r=0.724 P<0.01) and anti-class II HLA antibodies (70% vs. 55%, r=0.827 P<0.01). In addition, differences in the detection of anti-class I HLA antibodies in needle core biopsies sampled at different sites suggests that immunization to class I donor antigen could be underestimated in needle core biopsy samples. These data indicate that anti-HLA antibodies can be detected in needle core biopsies from renal transplants. Provided further evaluation is done, elution might be a complementary method to detect anti-HLA antibodies when they are bound to the transplant.

  2. Comparison of the pharmacological profiles of cyclosporine, (Nva2)-cyclosporine and (Val2)dihydro-cyclosporine.

    PubMed Central

    Hiestand, P C; Gunn, H C; Gale, J M; Ryffel, B; Borel, J F

    1985-01-01

    The pharmacological profiles of two new derivatives of the immunosuppressive drug, cyclosporine, is presented here. (Nva2)-CS has very similar properties to CS, but lacks the nephrotoxic side-effects. This derivative appears to be a potential successor to cyclosporine. (Val2)DH-CS seems to have a different spectrum of activities. It does not suppress humoral immunity and allograft rejection, but suppresses some types of cell-mediated immune responses. This derivative may prove useful in autoimmune situations where T cells are involved in the disease process. PMID:3891595

  3. [Case report of introducing MMF and steroids as an immunosuppressive therapy after living-donor liver transplantation for a patient with the diabetic nephropathy].

    PubMed

    Kuramitsu, Shotaro; Iguchi, Tomohiro; Ninomiya, Mizuki; Yamashita, Yo-ichi; Harimoto, Norifumi; Ikegami, Toru; Uchiyama, Hideaki; Yoshizumi, Tomoharu; Soejima, Yuji; Shirabe, Ken; Kawanaka, Hirofumi; Ikeda, Tetsuo; Furuta, Toshiya; Tamada, Ryuichiro; Maehara, Yoshihiko

    2014-03-01

    Calcineurin inhibitor (CNI) combined with mycophenolate mofetil (MMF) and steroid is mainly used as immunosuppressive therapy after the living-donor liver transplantation (LDLT). However, the nephrotoxicity caused by CNI remains a critical problem for patients with chronic renal failure, especially on early postoperative period. A 62-year-old woman with decompensated liver cirrhosis secondary to hepatitis B (Child-Pugh C, MELD score 11 points) and chronic renal failure due to diabetic nephropathy (Cr 1.56 mg/dl, GFR 27 ml/min/1.73 m2) experienced LDLT. During the reconstruction of hepatic vein, the supra-and infra-hepatic vena cava was totally clamped. The estimated right lobe liver graft volume was 540 g, representing 51.3% of the standard liver volume of the recipient. Because of the perioperative renal dysfunction due to diabetic nephropathy and the total clamping the vena cava which induced the congestion kidney, MMF (1500 mg/day) and steroid (250 mg/day converted into predonisolone) were mainly introduced as an immunosuppressive therapy after LDLT. The low-dose CNI, tacrolimus also induced the nephrotoxicity and was given for only a short time. Finally, according to the postoperative renal function, the low-dose CNI, cyclosporin (50 mg/day) was able to be added to the introduced immunosuppressive therapy. After having left the hospital, MMF (1500 mg/day), steroid (20 mg/day converted into predonisolone) and cyclosporin (75 mg/day) continued to be given as the immunosuppressive therapy and neither acute graft rejection nor drug-induced renal dysfunction was occurred. This is a case report of introducing with mainly MMF and steroid as an immunosuppressive therapy after LDLT for a patient with perioperative renal dysfunction.

  4. A comparison of the long-term effects of lanthanum carbonate and calcium carbonate on the course of chronic renal failure in rats with adriamycin-induced nephropathy.

    PubMed

    Takashima, Tsuyoshi; Sanai, Toru; Miyazono, Motoaki; Fukuda, Makoto; Kishi, Tomoya; Nonaka, Yasunori; Yoshizaki, Mai; Sato, Sae; Ikeda, Yuji

    2014-01-01

    Lanthanum carbonate (LA) is an effective phosphate binder. Previous study showed the phosphate-binding potency of LA was twice that of calcium carbonate (CA). No study in which LA and CA were given at an equivalent phosphate-binding potency to rats or humans with chronic renal failure for a long period has been reported to date. The objective of this study was to compare the phosphate level in serum and urine and suppression of renal deterioration during long-term LA and CA treatment when they were given at an equivalent phosphate-binding potency in rats with adriamycin (ADR)-induced nephropathy. Rats were divided into three groups: an untreated group (ADR group), a CA-treated (ADR-CA) group and a LA-treated (ADR-LA) group. The daily oral dose of LA was 1.0 g/kg/day and CA was 2.0 g/kg/day for 24 weeks. The serum phosphate was lower in the ADR-CA or ADR-LA group than in the ADR group and significantly lower in the ADR-CA group than in the ADR group at each point, but there were no significant differences between the ADR and ADR-LA groups. The serum phosphate was also lower in the ADR-CA group than in the ADR-LA group, and there was significant difference at week 8. The urinary phosphate was significantly lower in the ADR-CA group than in the ADR or ADR-LA group at each point. The urinary phosphate was also lower in the ADR-LA group than in the ADR group at each point, and significant difference at week 8. There were no significant differences in the serum creatinine or blood urea nitrogen among the three groups. In conclusion, this study indicated the phosphate-binding potency of LA isn't twice as strong as CA, and neither LA nor CA suppressed the progression of chronic renal failure in the serum creatinine and blood urea nitrogen, compared to the untreated group.

  5. Tacrolimus confers lower acute rejection rates and better renal allograft survival compared to cyclosporine

    PubMed Central

    Kamel, Mahmoud; Kadian, Manish; Srinivas, Titte; Taber, David; Posadas Salas, Maria Aurora

    2016-01-01

    AIM To compare the impact of tacrolimus (FK) and cyclosporine (CYA) on acute rejection and graft survival and to assess the predominant causes of graft loss between patients receiving these two calcineurin inhibitors (CNIs). METHODS Retrospective review of 1835 patients who received a kidney transplant (KTX) between 1999-2012. Patients were grouped based on initial CNI utilized: 1195 in FK group, 640 in CYA group. Data on baseline characteristics, clinical outcomes, and causes of graft loss in both groups were analyzed. RESULTS Cumulative acute rejection rates were 14% in the FK vs 24% in the CYA group. Despite more marginal donor characteristics in the FK group, these patients had better graft survival rates compared to the CYA group. Three and five year graft survival rates were 88% and 84% respectively in the FK group compared to 79% and 70% respectively in the CYA group (P < 0.001). After multivariate analysis, which controlled for confounders, FK use was a strong predictor for lower acute rejection rates [odds ratio (OR) 0.60, 95%CI: 0.45-0.79] and better renal allograft survival (OR 0.740, 95%CI: 0.58-0.94). Death with a functioning graft was the most common cause of graft loss in both groups. Common causes of death included cardiovascular disease, infections, and malignancies. Chronic allograft nephropathy was also found to be an important cause of graft loss, being more prevalent in the CYA group. CONCLUSION The use of FK-based maintenance immunosuppression therapy is associated with a significantly lower rate of acute rejection and better graft survival compared to CYA-based regimen. Individualizing immunosuppression through risk-stratified CNI choice may lead to improved outcomes across all spectra of KTX patients. PMID:28058220

  6. Crystalglobulin-induced nephropathy.

    PubMed

    Gupta, Vinay; El Ters, Mireille; Kashani, Kianoush; Leung, Nelson; Nasr, Samih H

    2015-03-01

    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.

  7. Epigenetic Regulations in Diabetic Nephropathy

    PubMed Central

    Lu, Zeyuan

    2017-01-01

    Diabetic nephropathy (DN) is a chronic complication of diabetes and the most common cause of end-stage kidney disease. It has been reported that multiple factors are involved in the pathogenesis of DN, while the molecular mechanisms that lead to DN are still not fully understood. Numerous risk factors for the development of diabetic nephropathy have been proposed, including ethnicity and inherited genetic differences. Recently, with the development of high-throughput technologies, there is emerging evidence that suggests the important role of epigenetic mechanisms in the pathogenesis of DN. Epigenetic regulations, including DNA methylation, noncoding RNAs, and histone modifications, play a pivotal role in DN pathogenesis by a second layer of gene regulation. All these findings can contribute to developing novel therapies for DN.

  8. Cyclosporine increases calcium in kidney medulla

    SciTech Connect

    Borowitz, J.L.

    1988-01-01

    Treatment of rats with 20, 50, or 100 mg/kg of cyclosporine p.o. markedly increased /sup 45/Ca accumulation in kidney slices especially in medulla. The effect was related to dose and duration of treatment, and was also observed in slices of kidney medulla from cyclosporine-treated mice. Total calcium was elevated in kidney medulla of cyclosporine-treated rats so that the effect is not merely an increased exchange but a build-up of calcium in the tissue. No histopathologic evidence of cyclosporine-related cell necrosis was present in mouse kidney, showing that calcium accumulation is not dystrophic in character. Accumulation of /sup 45/Ca in slices of rat heart, liver, or brain was not affected by cyclosporine pretreatment of the animals. It is suggested that cyclosporine-induced changes in calcium metabolism in kidney medulla may influence kidney function.

  9. A new classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy.

    PubMed

    Haneda, Masakazu; Utsunomiya, Kazunori; Koya, Daisuke; Babazono, Tetsuya; Moriya, Tatsumi; Makino, Hirofumi; Kimura, Kenjiro; Suzuki, Yoshiki; Wada, Takashi; Ogawa, Susumu; Inaba, Masaaki; Kanno, Yoshihiko; Shigematsu, Takashi; Masakane, Ikuto; Tsuchiya, Ken; Honda, Keiko; Ichikawa, Kazuko; Shide, Kenichiro

    2015-02-01

    The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease. In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labour and Welfare of Japan. Major revisions to the Classification are summarized as follows: (1) eGFR is substituted for GFR in the Classification; (2) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (3) stage 4 (kidney failure) has been redefined as a GFR less than 30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (4) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

  10. A new Classification of Diabetic Nephropathy 2014: a report from Joint Committee on Diabetic Nephropathy.

    PubMed

    Haneda, Masakazu; Utsunomiya, Kazunori; Koya, Daisuke; Babazono, Tetsuya; Moriya, Tatsumi; Makino, Hirofumi; Kimura, Kenjiro; Suzuki, Yoshiki; Wada, Takashi; Ogawa, Susumu; Inaba, Masaaki; Kanno, Yoshihiko; Shigematsu, Takashi; Masakane, Ikuto; Tsuchiya, Ken; Honda, Keiko; Ichikawa, Kazuko; Shide, Kenichiro

    2015-03-01

    The Joint Committee on Diabetic Nephropathy has revised its Classification of Diabetic Nephropathy (Classification of Diabetic Nephropathy 2014) in line with the widespread use of key concepts, such as the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD). In revising the Classification, the Committee carefully evaluated, as relevant to current revision, the report of a study conducted by the Research Group of Diabetic Nephropathy, Ministry of Health, Labor and Welfare of Japan. Major revisions to the Classification are summarized as follows: (i) eGFR is substituted for GFR in the Classification; (ii) the subdivisions A and B in stage 3 (overt nephropathy) have been reintegrated; (iii) stage 4 (kidney failure) has been redefined as a GFR <30 mL/min/1.73 m(2), regardless of the extent of albuminuria; and (iv) stress has been placed on the differential diagnosis of diabetic nephropathy versus non-diabetic kidney disease as being crucial in all stages of diabetic nephropathy.

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

    PubMed Central

    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

    2016-01-01

    Abstract 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

  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. Renal function in diabetic nephropathy

    PubMed Central

    Dabla, Pradeep Kumar

    2010-01-01

    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

  14. 21 CFR 520.522 - Cyclosporine.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 21 Food and Drugs 6 2014-04-01 2014-04-01 false Cyclosporine. 520.522 Section 520.522 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.522 Cyclosporine. (a)...

  15. 21 CFR 520.522 - Cyclosporine.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Cyclosporine. 520.522 Section 520.522 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.522 Cyclosporine. (a)...

  16. 21 CFR 520.522 - Cyclosporine.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 21 Food and Drugs 6 2012-04-01 2012-04-01 false Cyclosporine. 520.522 Section 520.522 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.522 Cyclosporine. (a)...

  17. 21 CFR 520.522 - Cyclosporine.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 21 Food and Drugs 6 2011-04-01 2011-04-01 false Cyclosporine. 520.522 Section 520.522 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) ANIMAL DRUGS, FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.522 Cyclosporine. (a)...

  18. 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.

  19. BMP-7 PROTEIN EXPRESSION IS DOWNREGULATED IN HUMAN DIABETIC NEPHROPATHY.

    PubMed

    Ivanac-Janković, Renata; Ćorić, Marijana; Furić-Čunko, Vesna; Lovičić, Vesna; Bašić-Jukić, Nikolina; Kes, Petar

    2015-06-01

    Bone morphogenetic protein-7 (BMP-7) is expressed in all parts of the normal kidney parenchyma, being highest in the epithelium of proximal tubules. It protects kidney against acute and chronic injury, inflammation and fibrosis. Diabetic nephropathy is the leading cause of chronic kidney disease, and is characterized by decreased expression of BMP-7. The aim of our study was to analyze whether the expression of BMP-7 is significantly changed in advanced stages of human diabetic nephropathy. Immunohistochemical analysis of the expression of BMP-7 was performed on archival material of 30 patients that underwent renal biopsy and had confirmed diagnosis of diabetic nephropathy. Results showed that BMP-7 was differently expressed in the cytoplasm of epithelial cells of proximal tubules and podocytes among all stages of diabetic nephropathy. At early stages of diabetic nephropathy, BMP-7 was strongly positive in proximal tubules and podocytes, while low expression was recorded in the majority of samples at advanced stages. In conclusion, increased expression of BMP-7 at initial stages of diabetic nephropathy with subsequent decrease at advanced stage highlights the role of BMP-7 in the protection of kidney structure and function. Further investigations should be focused on disturbances of BMP-7 receptors and signaling pathways in patients with diabetic nephropathy.

  20. Nutritional intervention for a patient with diabetic nephropathy.

    PubMed

    Kim, Hee Young

    2014-01-01

    In recent years, several studies have reported that the prevalence of diabetes mellitus is increasing every year, and also the acute and chronic complications accompanying this disease are increasing. Diabetic nephropathy is one of chronic complications of diabetes mellitus, and food intake which is burden to kidney function should be limited. At the same time, diet restriction could deteriorate quality of life of patient with diabetic nephropathy. According to the results of previous studies, the aggressive management is important for delaying of the progression to diabetic nephropathy. Also, the implementation of a personalized diet customized to individuals is an effective tool for preservation of kidney function. This is a case report of a patient with diabetic nephropathy who was introduced to a proper diet through nutrition education to prevent malnutrition, uremia and to maintain blood glucose levels.

  1. Nutritional Intervention for a Patient with Diabetic Nephropathy

    PubMed Central

    2014-01-01

    In recent years, several studies have reported that the prevalence of diabetes mellitus is increasing every year, and also the acute and chronic complications accompanying this disease are increasing. Diabetic nephropathy is one of chronic complications of diabetes mellitus, and food intake which is burden to kidney function should be limited. At the same time, diet restriction could deteriorate quality of life of patient with diabetic nephropathy. According to the results of previous studies, the aggressive management is important for delaying of the progression to diabetic nephropathy. Also, the implementation of a personalized diet customized to individuals is an effective tool for preservation of kidney function. This is a case report of a patient with diabetic nephropathy who was introduced to a proper diet through nutrition education to prevent malnutrition, uremia and to maintain blood glucose levels. PMID:24527422

  2. 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.

  3. Cyclosporin: applications in small animal dermatology.

    PubMed

    Robson, David C; Burton, Gregory G

    2003-02-01

    Cyclosporin has been increasingly used for the treatment of skin diseases in small animals. Reported uses include the treatment of atopy, cutaneous lupus erythematosus, feline acquired alopecia resembling pseudopelade of humans, pemphigus erythematosus, pemphigus foliaceus, perianal fistulae and sebaceous adenitis. In addition, cyclosporin has been used anecdotally for several other skin diseases. Few side effects have been noted at doses therapeutic for dermatologic diseases. Current suggestions for monitoring, and the value of trough cyclosporin serum concentrations for prediction of toxicity and efficacy are discussed.

  4. Smoking in diabetic nephropathy: sparks in the fuel tank?

    PubMed

    Chakkarwar, Vishal Arvind

    2012-12-15

    Diabetic nephropathy is associated with high morbidity and mortality and the prevalence of this disease is continuously increasing worldwide. Long-term diabetes increases the likelihood of developing secondary complications like nephropathy, the most common cause of end stage renal disease. Usually, other factors like hypertension, alcoholism and smoking also partly contribute to the progression of diabetic nephropathy. Among this, cigarette smoking in diabetes has been repeatedly confirmed as an independent risk factor for the onset and progression of diabetic nephropathy. Various studies suggest that smoking is a major fuel in the development of high oxidative stress and subsequently hyperlipidemia, accumulation of advanced glycation end products, activation of the renin angiotensin system and Rho-kinase, which are observed to play a pathogenic role in the progression of diabetic nephropathy. Furthermore, cigarette smoking in diabetic patients with vascular complications produces a variety of pathological changes in the kidney, such as thickening of the glomerular basement membrane and mesangial expansion with progression in glomerulosclerosis and interstitial fibrosis, which ultimately results in end stage renal failure. Strong associations are consistently found between chronic cigarette smoking and diabetic microvascular complications. A diverse group of studies unveil potential mechanisms that may explain the role of cigarette smoking in the progression of diabetic nephropathy. Tremendous efforts are being made to control smoking mediated progression of diabetic nephropathy, but no promising therapy is yet available. The present review critically discusses the possible detrimental role of chronic cigarette smoking in the progression of diabetic nephropathy and various possible pharmacological interventions to attenuate the exacerbation of diabetic nephropathy.

  5. Smoking in diabetic nephropathy: sparks in the fuel tank?

    PubMed Central

    Chakkarwar, Vishal Arvind

    2012-01-01

    Diabetic nephropathy is associated with high morbidity and mortality and the prevalence of this disease is continuously increasing worldwide. Long-term diabetes increases the likelihood of developing secondary complications like nephropathy, the most common cause of end stage renal disease. Usually, other factors like hypertension, alcoholism and smoking also partly contribute to the progression of diabetic nephropathy. Among this, cigarette smoking in diabetes has been repeatedly confirmed as an independent risk factor for the onset and progression of diabetic nephropathy. Various studies suggest that smoking is a major fuel in the development of high oxidative stress and subsequently hyperlipidemia, accumulation of advanced glycation end products, activation of the renin angiotensin system and Rho-kinase, which are observed to play a pathogenic role in the progression of diabetic nephropathy. Furthermore, cigarette smoking in diabetic patients with vascular complications produces a variety of pathological changes in the kidney, such as thickening of the glomerular basement membrane and mesangial expansion with progression in glomerulosclerosis and interstitial fibrosis, which ultimately results in end stage renal failure. Strong associations are consistently found between chronic cigarette smoking and diabetic microvascular complications. A diverse group of studies unveil potential mechanisms that may explain the role of cigarette smoking in the progression of diabetic nephropathy. Tremendous efforts are being made to control smoking mediated progression of diabetic nephropathy, but no promising therapy is yet available. The present review critically discusses the possible detrimental role of chronic cigarette smoking in the progression of diabetic nephropathy and various possible pharmacological interventions to attenuate the exacerbation of diabetic nephropathy. PMID:23301120

  6. Concurrent Drug-Induced Linear Immunoglobulin A Dermatosis and Immunoglobulin A Nephropathy.

    PubMed

    Kim, Ji Seok; Choi, Misoo; Nam, Chan Hee; Kim, Jee Young; Park, Byung Cheol; Kim, Myung Hwa; Hong, Seung Phil

    2015-06-01

    Diseases associated with immunoglobulin A (IgA) antibody include linear IgA dermatosis, IgA nephropathy, Celiac disease, Henoch-Schönlein purpura, etc. Although usually idiopathic, IgA antibody is occasionally induced by drugs (e.g., vancomycin, carbamazepine, ceftriaxone, and cyclosporine), malignancies, infections, and other causes. So far, only a few cases of IgA bullous dermatosis coexisting with IgA nephropathy have been reported. A 64-year-old female receiving intravenous ceftriaxone and metronidazole for liver abscess had purpuric macules and papules on her extremities. One week later, she had generalized edema and skin rash with bullae and was diagnosed with concurrent linear IgA dermatosis and IgA nephropathy. After steroid treatment, the skin lesion subsided within two weeks, and kidney function slowly returned to normal. As both diseases occurred after a common possible cause, we predict their pathogeneses are associated.

  7. Diabetic nephropathy and pregnancy.

    PubMed

    Landon, Mark B

    2007-12-01

    Diabetic nephropathy, the most common etiology for end-stage renal disease, complicates approximately 5% of insulin-dependent diabetic pregnancies. Assessment for vasculopathy is important before pregnancy because nephropathy can increase perinatal risks including potential for preeclampsia and preterm birth. Counseling women receiving renoprotective medications including angiotensin converting enzyme inhibitors has recently become complicated in light of new information suggesting a teratogenic risk for these agents. Most reproductive age women with overt diabetic nephropathy have preserved renal function and do not seem to have the progression of their disease affected by pregnancy. Perinatal outcomes are excellent for these women who have received care in tertiary institutions. However, there are relatively few women with significant renal impairment included in case series of pregnancies complicated by diabetic nephropathy. For these women, adverse perinatal outcomes are more common, and the effect of pregnancy on the course of their disease is less certain.

  8. Acute phosphate nephropathy.

    PubMed

    Monfared, Ali; Habibzadeh, Seyed Mahmoud; Mesbah, Seyed Alireza

    2014-05-01

    We present acute phosphate nephropathy in a 28-year-old man, which was developed after a car accident due to rhabdomyolysis. Treatment of acute kidney injury was done with administration of sodium bicarbonate.

  9. 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.

  10. 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.

  11. Anticoagulation-related nephropathy.

    PubMed

    Wheeler, D S; Giugliano, R P; Rangaswami, J

    2016-03-01

    Anticoagulation-related nephropathy (ARN) is a significant but underdiagnosed complication of anticoagulation that is associated with increased renal morbidity and all-cause mortality. Originally described in patients receiving supratherapeutic doses of warfarin who had a distinct pattern of glomerular hemorrhage on kidney biopsy, ARN is currently defined as acute kidney injury (AKI) without obvious etiology in the setting of an International Normalized Ratio (INR) of > 3.0. The underlying molecular mechanism is thought to be warfarin-induced thrombin depletion; however, newer studies have hinted at an alternative mechanism involving reductions in activated protein C and endothelial protein C receptor signaling. Prompt recognition of ARN is critical, as it is associated with accelerated progression of chronic kidney disease, and significant increases in short-term and long-term all-cause mortality. Prior investigations into ARN have almost universally focused on anticoagulation with warfarin; however, recent case reports and animal studies suggest that it can also occur in patients taking novel oral anticoagulants. Differences in the incidence and severity of ARN between patients taking warfarin and those taking novel oral anticoagulants are unknown; a post hoc analysis of routinely reported adverse renal outcomes in clinical trials comparing warfarin and novel oral anticoagulants found no significant difference in the rates of AKI, a prerequisite for ARN. Given the significant impact of ARN on renal function and all-cause mortality, a thorough understanding of the pathophysiology, molecular mechanisms, clinical spectrum and therapeutic interventions for ARN is crucial to balance the risks and benefits of anticoagulation and optimize treatment.

  12. 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

  13. Arginine feeding modifies cyclosporine nephrotoxicity in rats.

    PubMed Central

    De Nicola, L; Thomson, S C; Wead, L M; Brown, M R; Gabbai, F B

    1993-01-01

    Glycine (G) infusion causes renal vasodilation mediated by nitric oxide (NO). Cyclosporine A (CsA) nephrotoxicity is characterized by preglomerular vasoconstriction and decreased efferent arteriolar tone probably related to reduced NO and angiotensin II, respectively. L-Arginine (ARG) is a precursor to NO. To test the hypothesis that chronic CsA decreases renal NO activity, we compared the glomerular hemodynamic response to glycine infusion in rats after 8 d of CsA (30 mg/kg per d s.c.), CsA and ARG (1.6 g/kg per d p.o.) (A/CsA), and in two groups of pair-fed controls (CON, A/CON). Single nephron GFR (SNGFR), single nephron plasma flow (SNPF), glomerular capillary hydrostatic pressure gradient (delta P), proximal tubular reabsorption (APR), and kidney tissue angiotensin II (AIIk) were measured before and during G. CsA was associated with baseline decrements in SNGFR, SNPF, delta P, and AIIk, and with a blunted hemodynamic response to G. In CON, ARG did not affect baseline hemodynamics or modify the response to G. In CsA, ARG decreased baseline preglomerular resistance and restored the glomerular hemodynamic response to G. G was associated with a significant increase in AIIk in both CON and CsA. These findings suggest that (a) CsA is associated with decreased AIIk, and (b) CsA may diminish NO activity within the kidney, and that this capacity may be partially restored by arginine feeding. PMID:8408638

  14. Cyclosporine and herbal supplement interactions.

    PubMed

    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.

  15. 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

  16. Canine IgA nephropathy: a case report.

    PubMed

    Yabuki, Akira; Shimokawa Miyama, Takako; Kohyama, Moeko; Yamato, Osamu

    2016-03-01

    Immunoglobulin (Ig) A nephropathy is a rare form of canine glomerular disease. This report describes a case of canine IgA nephropathy showing characteristics typical of human IgA nephropathy. An 8-year-old, spayed female Miniature Dachshund showed persistent severe proteinuria without azotemia. She was receiving long-term glucocorticoid therapy due to chronic gastritis and an intra-abdominal suture granuloma. A renal biopsy demonstrated mesangial proliferative glomerulonephritis with predominantly mesangial IgA deposition and electron-dense deposits in the paramesangium. These findings closely resembled those of human IgA nephropathy. Glucocorticoid treatment was discontinued, and the angiotensin-converting enzyme inhibitor enalapril was administrated as an antiproteinuric agent. The proteinuria subsequently went into remission, and the patient has maintained good condition without recurrence.

  17. 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

  18. Conversion from tacrolimus to cyclosporine--a based immunosuppression following liver transplantation.

    PubMed

    Doria, Cataldo; Jain, Ashok Kumar B; Scott, Victor L; Gruttadauria, Salvatore; Marino, Ignazio R; Doyle, Howard R; Fung, John J

    2003-06-01

    We examined the frequency, reasons and outcome after conversion from Tacrolimus to Cyclosporine A. From August 1989 to December 1992, 1000 consecutive liver transplantation patients were studied, which included 834 adults (age>18 yr.) and 166 children with mean follow-up of 77 months (range 56 to 96). A prospectively populated electronic database was queried to identify patients that underwent conversion, the clinical indication and outcomes. Thirty-seven out of 834 adult recipients (4.43%), mean age of 48.4+/-12.9 years, 19 male (51.35%) and 18 females (48.64%) required conversion from Tacrolimus to Cyclosporine A baseline immunosuppressive therapy. No pediatric patient required conversion. The mean time interval from liver transplantation to Cyclosporine A conversion was 443.45+/-441.44 days (range 22 to 1641). The clinical indications for conversion included: 20 neurological (54%), 6 gastrointestinal (16%), 5 hematological (14%), and 6 other (16%) scenarios. Seven of the 37 patients (18.9%) died. The causes of death were multi-organ failure (2), sepsis (2), pancreatitis (1), hepatic failure due to relapse of ethanol abuse (1), and unknown cause (1). Nine out of 37 patients (24.32%) had to be reconverted to Tacrolimus (mean 282.22+/-499.79 days; range 15 to 1583 day with a median of 135) after institution of Cyclosporine A; none showed recurrence of the original symptoms. The reasons for these re-conversions were acute cellular rejection (44%, n=4), chronic rejection (11%, n=1), increased hepatic enzymes (33%, n=3) and progressively worsening neurological symptoms (11%, n=1). The frequency of conversion from Tacrolimus to Cyclosporine A was 4.43%. Conversion is safe and efficacious if done in a controlled setting. Additionally, re-conversion to Tacrolimus for lack of efficacy of Cyclosporine A did not appear to be associated with a recurrence of the condition that caused the initial switch.

  19. Mycotoxic nephropathy in pigs*

    PubMed Central

    Elling, F.; Møller, T.

    1973-01-01

    In Denmark a nephropathy in pigs characterized by tubular atrophy and interstitial fibrosis has been identified frequently during the last 5 decades in the course of meat inspection in slaughterhouses. The disease was first described by Larsen, who recognized the connexion between feeding mouldy rye to pigs and the development of the nephropathy. In this study kidneys were examined from 19 pigs coming from a farm with an outbreak of nephropathy. The barley fed to the pigs was contaminated with the mycotoxin ochratoxin A. Histological examination revealed different degrees of change ranging from slight regressive changes in the tubular epithelium and periglomerular and interstitial fibrosis to tubular atrophy, thickened basement membranes, glomerular sclerosis, and marked fibrosis. These differences were considered to be due to differences in the length of time of exposure to the mouldy barley and differences in the amount of mycotoxin consumed by the individual pig. However, it will be necessary to carry out experiments using crystalline ochratoxin A in order to prove such a relationship. Mycotoxins have also been suggested as etiological factors in Balkan nephropathy in man, which in the initial stages is characterized by tubular lesions similar to those seen in mycotoxic nephropathy in pigs. ImagesFig. 1Fig. 2Fig. 7Fig. 8Fig. 9Fig. 3Fig. 4Fig. 5Fig. 6Fig. 10Fig. 11 PMID:4546872

  20. Possible interaction between cyclosporine and glibenclamide in posttransplant diabetic patients.

    PubMed

    Islam, S I; Masuda, Q N; Bolaji, O O; Shaheen, F M; Sheikh, I A

    1996-10-01

    The possible occurrence of a kinetic interaction between cyclosporine A and glibenclamide was assessed by reviewing data of six posttransplant diabetic patients who received the two drugs concurrently. Coadministration of the two drugs resulted in a 57% increase in the steady-state plasma cyclosporine levels despite normal hepatic and renal functions in the patients. This elevation in cyclosporine level is possibly due to an interaction between the two drugs resulting from an inhibition of CYP3A4-mediated metabolism of cyclosporine by glibenclamide. This observation calls for a closer monitoring of cyclosporine plasma levels during concomitant administration of these two drugs in this group of patients.

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

    PubMed

    Guerra Júnior, 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. Moreover, regimens containing cyclosporine were more cost-effective [corrected].

  2. 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

  3. Predictors of prognosis in IgA nephropathy.

    PubMed

    Tomino, Yasuhiko

    2012-10-01

    IgA nephropathy (nephropathy with mesangial IgA and IgG deposits, so-called Berger's disease) is the most common primary chronic glomerulonephritis worldwide, and was first described in 1968. Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation and/or mononuclear cell infiltration. Glomeruli typically contain generalized-diffuse granular mesangial deposits of IgA (mainly IgA1), IgG and C3. This disease, therefore, is considered to be an immune-complex-mediated glomerulonephritis although the antigenic agents are still obscure. Clinically, patients with IgA nephropathy show microscopic and macroscopic hematuria and/or proteinuria. Although the clinical course is generally gradual in patients with IgA nephropathy, progression to renal hypertension, renal anemia, and end-stage kidney disease is not as rare as originally thought. Since pathogenesis and radical treatment for IgA nephropathy are still not established, it is necessary to study them using various clinical findings.

  4. Absorption of transdermal and oral cyclosporine in six healthy cats.

    PubMed

    Miller, Rose; Schick, Anthea E; Boothe, Dawn M; Lewis, Thomas P

    2014-01-01

    Cyclosporine is commonly used orally to treat feline dermatoses. Due to difficulties administering oral medications, veterinarians sometimes prescribe compounded transdermal cyclosporine, despite studies showing limited absorption. The study objective was to compare cyclosporine blood concentrations after oral administration to concentrations after transdermal application of cyclosporine (prepared in pluronic lecithin organogel [PLO]) in six cats using a controlled, cross-over design with a 2 wk washout period. Cats were dosed at 5.1-7.4 mg/kg of cyclosporine q 24 hr either per os for 7 days or transdermally for 21 days. Cyclosporine blood concentrations were measured q 7 days and after the washout period. A monoclonal-based immunoassay (lower limit of quantitation was 25 ng/mL) was used. Median concentrations on the seventh day were 2,208 ng/mL (range, 1,357-3,419 ng/mL) 2 hr after orally administered cyclosporine and 37 ng/mL (range, 25-290 ng/mL) 2 hr after transdermally applied cyclosporine. Median concentration on day 21 was 58 ng/mL (range, 51-878 ng/mL) 2 hr after transdermally applied cyclosporine. Concentrations were quantifiable for transdermally applied cyclosporine, but considered therapeutic in only one of six cats. Based on those results, transdermally applied cyclosporine was not recommended in cats because of inconsistent absorption.

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

    MedlinePlus

    ... Myeloid Leukemia (CML) About 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 ...

  6. [IgA nephropathy].

    PubMed

    Basta-Jovanović, Gordana

    2004-01-01

    IgA nephropathy is glomerular disease first described in 1968 by Berger, named after him Morbus Berger. The disease is characterized by the presence of IgA dominant or codominant immunoglobulin deposits in glomerular mesangium which can be demonstrated by immunofluorescence. Clinical manifestations of IgA nephropathy in the majority of cases is hematuria which can be macro or microscopic, isolated or combined with proteinuria which can be of nephrotic range. In some cases nephrotic syndrome can be the first clinical presentation. In 10% renal insufficiency can be present at the onset of the disease. By light microscopy IgA can manifest any of the histologic phenotypes of immune complex mediated proliferative glomerulonephritis. According to light microscopy findings a classification system have been used to categorize the histologic patterns of IgA nephropathy. Glomerular changes in IgA nephropathy are proliferative and can be focal or diffuse accompanied by crescentic formation in many cases. Immune deposits seen by electron microscopy appear as electron dense deposits most numerous in mesangium.

  7. Diabetic nephropathy: preventing progression

    PubMed Central

    2010-01-01

    Introduction Up to one third of people with type 1 or 2 diabetes will develop microalbuminuria or macroalbuminuria after 20 years. Methods and outcomes We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatments in people with type 1 diabetes and early nephropathy? What are the effects of treatments in people with type 1 diabetes and late nephropathy? What are the effects of treatments in people with type 2 diabetes and early nephropathy? What are the effects of treatments in people with type 2 diabetes and late nephropathy? We searched: Medline, Embase, The Cochrane Library, and other important databases up to November 2009 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). Results We found 19 systematic reviews, RCTs, or observational studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. Conclusions In this systematic review we present information relating to the effectiveness and safety of the following interventions: angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, glycaemic control, protein restriction, and tight control of blood pressure. PMID:21418671

  8. IgA nephropathy

    MedlinePlus

    ... disease. Causes IgA is a protein, called an antibody , that helps the body fight infections. IgA nephropathy occurs when too much of this protein is deposited in the kidneys. IgA builds up inside the small blood vessels of the kidney. Structures in the kidney called glomeruli become inflamed and ...

  9. Renal involvement in the antiphospholipid syndrome (APS)-APS nephropathy.

    PubMed

    Tektonidou, Maria G

    2009-06-01

    Although the kidney represents a major target organ in antiphospholipid syndrome (APS), renal involvement in APS was poorly recognized until recently. The most well-recognized renal manifestations of APS are the renal artery thrombosis/stenosis, renal infarction, hypertension, renal vein thrombosis, end-stage renal disease, increased allograft vascular thrombosis, some types of glomerular disease, and a small-vessel vaso-occlusive nephropathy, recently defined as APS nephropathy. APS nephropathy was first described in primary APS patients, characterized by acute thrombotic lesions in glomeruli and/or arterioles (thrombotic microangiopathy) and chronic vascular lesions such as fibrous intimal hyperplasia of arterioles and interlobular arteries, organized thrombi with or without recanalization, and fibrous arterial and arteriolar occlusions or focal cortical atrophy. APS nephropathy was also detected in further studies including patients with systemic lupus erythematosus (SLE)-related APS and SLE/non-APS patients with positive antiphospholipid antibodies, independently of lupus nephritis. The same histologic lesions, especially thrombotic mictroangiopathy, were also observed in patients with catastrophic APS. The most frequent clinical and laboratory characteristics of APS nephropathy in all the above groups of patients are hypertension (often severe), proteinuria (ranging from mild to nephrotic range), hematuria, and acute or chronic renal insufficiency.

  10. Quality of life improvement in treatment of psoriasis with intermittent short course cyclosporin (Neoral).

    PubMed

    Salek, M S; Finlay, A Y; Lewis, J J C; Sumner, M I

    2004-02-01

    Due to concern over long term safety of continuous treatment with cyclosporin, the aim of this 1-year study was to assess the effect of intermittent therapy with cyclosporin (Neoral) on the quality of life of patients suffering from chronic plaque psoriasis. A total of 41 patients with chronic plaque psoriasis (26 male, mean age: 36 years, range: 18-61; duration of psoriasis 17 years, range: 2-31) entered a 9-centre open study in which cyclosporin was taken as an initial dose of 5 mg/kg/daily for a maximum of 12 weeks for up to three cycles. Each patient completed a psoriasis specific QOL measure (Psoriasis Disability Index, PDI) at the beginning and end of each treatment cycle and at the end of study. Clinical parameters including Psoriasis Area and Severity Index (PASI) were measured. The PDI scores showed a significant improvement (p < 0.01) between the beginning and end of all three treatment cycles. The various clinical assessments for each treatment period also showed significant improvement (p < 0.001) for all three cycles. When comparing the last follow-up value to baseline there was a clear indication of relapse, but these scores were still significantly better than at baseline (p < 0.01). Notably, the mean PASI score improved by more than 50% (p < 0.001) between first baseline and end of the study. These findings indicate that a short course of intermittent therapy with cyclosporin in microemulsion formulation, used at starting doses of 5 mg/kg/day, improves QOL of patients with chronic plaque psoriasis. Once again, the applicability and validity of the PDI as a useful QOL tool has been demonstrated.

  11. 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

  12. Pathogenesis of IgA nephropathy.

    PubMed

    Lai, Kar Neng

    2012-03-20

    Since its first description in 1968, IgA nephropathy has remained the most common form of idiopathic glomerulonephritis leading to chronic kidney disease in developed countries. The exact pathogenesis of IgA nephropathy is still not well defined. Current data implicate an important genetic factor, especially in promoting the overproduction of an aberrant form of IgA1. The immunochemical aberrancy of IgA nephropathy is characterized by the undergalactosylation of O-glycans in the hinge region of IgA1. However, such aberrant glycosylation alone does not cause renal injury. The next stage of disease development requires the formation of glycan-specific IgG and IgA antibodies that recognize the undergalactosylated IgA1 molecule. These antibodies often have reactivity against antigens from extrinsic microorganisms and might arise from recurrent mucosal infection. B cells that respond to mucosal infections, particularly tonsillitis, might produce the nephritogenic IgA1 molecule. With increased immune-complex formation and decreased clearance owing to reduced uptake by the liver, IgA1 binds to the glomerular mesangium via an as yet unidentified receptor. Glomerular IgA1 deposits trigger the local production of cytokines and growth factors, leading to the activation of mesangial cells and the complement system. Emerging data suggest that mesangial-derived mediators following glomerular deposition of IgA1 lead to podocyte and tubulointerstitial injury via mesangio-podocytic-tubular crosstalk. This Review summarizes the latest findings in the pathogenesis of IgA nephropathy.

  13. [Pathophysiology of diabetic nephropathy: a literature review].

    PubMed

    Meza Letelier, Carlos Eduardo; San Martín Ojeda, Camilo Alfredo; Ruiz Provoste, José Javier; Frugone Zaror, Cristobal Jesus

    2017-01-12

    Chronic kidney disease is a common complication of diabetes. Its importance lies in its high prevalence and future projection. It is associated with high health costs and global cardiovascular deterioration as well. The development of this disease pathophysiology is being studied and it is known that a series of complex molecular pathways determining a microvascular disease are involved. This review addresses the known pathways in the development of diabetic nephropathy aiming to improve the understanding of potential therapeutic targets that could be developed in the future.

  14. 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

  15. Pirfenidone for Diabetic Nephropathy

    PubMed Central

    Ix, Joachim H.; Mathew, Anna V.; Cho, Monique; Pflueger, Axel; Dunn, Stephen R.; Francos, Barbara; Sharma, Shoba; Falkner, Bonita; McGowan, Tracy A.; Donohue, Michael; RamachandraRao, Satish; Xu, Ronghui; Fervenza, Fernando C.; Kopp, Jeffrey B.

    2011-01-01

    Pirfenidone is an oral antifibrotic agent that benefits diabetic nephropathy in animal models, but whether it is effective for human diabetic nephropathy is unknown. We conducted a randomized, double-blind, placebo-controlled study in 77 subjects with diabetic nephropathy who had elevated albuminuria and reduced estimated GFR (eGFR) (20 to 75 ml/min per 1.73 m2). The prespecified primary outcome was a change in eGFR after 1 year of therapy. We randomly assigned 26 subjects to placebo, 26 to pirfenidone at 1200 mg/d, and 25 to pirfenidone at 2400 mg/d. Among the 52 subjects who completed the study, the mean eGFR increased in the pirfenidone 1200-mg/d group (+3.3 ± 8.5 ml/min per 1.73 m2) whereas the mean eGFR decreased in the placebo group (−2.2 ± 4.8 ml/min per 1.73 m2; P = 0.026 versus pirfenidone at 1200 mg/d). The dropout rate was high (11 of 25) in the pirfenidone 2400-mg/d group, and the change in eGFR was not significantly different from placebo (−1.9 ± 6.7 ml/min per 1.73 m2). Of the 77 subjects, 4 initiated hemodialysis in the placebo group, 1 in the pirfenidone 2400-mg/d group, and none in the pirfenidone 1200-mg/d group during the study (P = 0.25). Baseline levels of plasma biomarkers of inflammation and fibrosis significantly correlated with baseline eGFR but did not predict response to therapy. In conclusion, these results suggest that pirfenidone is a promising agent for individuals with overt diabetic nephropathy. PMID:21511828

  16. [Familial juvenile hyperuricemic nephropathy].

    PubMed

    Hummel, Aurélie

    2012-04-01

    Familial juvenile hyperuricemic nephropathy is a rare autosomal dominant disease. It is characterized by abnormal handling of urate responsible for hyperuricaemia often complicated of gouty arthritis. Renal failure is due to tubulointerstitial nephritis. Ultrasonography sometimes finds renal cysts of variable size and number. Renal histology, although not specific, shows interstitial fibrosis, atrophic tubules, sometimes enlarged and with irregular membrane thickening. Renal failure progresses to end stage between 30 and 60 years of age. Allopurinol treatment is recommended at the early stages of the disease, its efficacy on slowing down the progression of the disease is however not proven. There is genetic heterogeneity in familial juvenile hyperuricemic nephropathy. Uromodulin encoding Tamm-Horsfall protein is the only gene to date identified, responsible in less than half of the families. The described mutations most often concern a cystein and are clustering in exon 4. These mutations result in abnormal retention of the protein in endoplasmic reticulum of Henle loop cells and in reduction of its urinary excretion. The pathophysiology of the disease is however still dubious. Indeed, Tamm-Horsfall protein functions are not well known (anti-infectious role, cristallisation inhibition, immunomodulating role). Knock-out mice do not develop renal phenotype but are more prone to E. coli urinary infections. Uromodulin gene mutations have also been described in medullary cystic kidney disease, an autosomal dominant tubulointerstitial nephropathy, considered at first as a distinct disorder. Genetic progress allowed us to consider familial juvenile hyperuricemic nephropathy and medullary cystic kidney disease as the two facets of a same disease, we should call uromodulin associated kidney diseases. At least two other genes have been implicated in similar clinical presentation: TCF2 and the gene encoding renin.

  17. Treatment of ligneous conjunctivitis with amniotic membrane transplantation and topical cyclosporine.

    PubMed

    Tok, Ozlem Yalcin; Kocaoglu, Fatma Akbas; Tok, Levent; Burcu, Ayse; Ornek, Firdevs

    2012-01-01

    Ligneous conjunctivitis (LC) is a rare form of bilateral chronic recurrent disease in which thick membranes form on the palpebral conjunctiva and other mucosal sites. We report the clinical features and describe the management of two cases. Case 1 was an 8-month-old patient with bilateral membranous conjunctivitis. Case 2 was a 5-year-old patient with unilateral membranous conjunctivitis, esotropia, mechanical ptosis and complicated cataract, and had been treated with a number of medications. Histological investigation of the membrane in both cases showed LC. Treatments with amniotic membrane transplantation and institution of topical cyclosporine have shown good response. There has been complete resolution of the membranes with no recurrence at the end of 40- and 28-month follow-ups, respectively. No treatment related side effects were seen. Thus, it appears that amniotic membrane transplantation and topical cyclosporine are effective alternatives for the treatment of LC.

  18. Effects of the N/L-type calcium channel blocker cilnidipine on nephropathy and uric acid metabolism in hypertensive patients with chronic kidney disease (J-CIRCLE study).

    PubMed

    Uchida, Shunya; Takahashi, Masato; Sugawara, Masahiro; Saito, Tomoaki; Nakai, Kazuhiko; Fujita, Masami; Mochizuki, Koichi; Shin, Isu; Morita, Takashi; Hikita, Tomoyuki; Itakura, Hironao; Takahashi, Yuko; Mizuno, Shigeki; Ohno, Yasumi; Ito, Kageki; Ito, Takafumi; Soma, Masayoshi

    2014-10-01

    This study assessed the urinary albumin/creatinine ratio (ACR) and uric acid metabolism in 70 hypertensive patients with chronic kidney disease in whom urinary ACR had remained ≥30 mg/g under the treatment of the L-type calcium channel blocker amlodipine. Three months after switching to the N/L-type calcium channel blocker cilnidipine, blood pressure (BP) did not change; however, urinary ACR significantly decreased with cilnidipine. Serum uric acid levels showed no significant change. In cases where uric acid production had been high (urinary uric acid/creatinine ratio ≥0.5), the urinary uric acid/creatinine ratio decreased significantly after cilnidipine treatment, suggesting that cilnidipine can suppress excessive uric acid formation. These results suggest that switching from amlodipine to cilnidipine results in a significant reduction in urinary ACR as well as significant reduction in uric acid production. Thus, cilnidipine is more useful than amlodipine in improving albuminuria and uric acid metabolism in hypertensive patients with chronic kidney disease.

  19. Herbs and hazards: risk of aristolochic acid nephropathy in Iran.

    PubMed

    Ardalan, Mohammad Reza; Khodaie, Laleh; Nasri, Hamid; Jouyban, Abolghasem

    2015-01-01

    Herbs are usually considered as inherently harmless products. Nonetheless, various renal injuries have been reported in association with several herbs. The best-known herb-induced chronic kidney disease is aristolochic acid nephropathy. Aristolochic acid is found in Chinese slim herbs. Balkan endemic nephropathy is nowadays considered as an aristolochic acid nephropathy. Plants of Aristolochiaceae (also known as birthwort, dutchman's pipe, and somersworth) is named zaravand or chopoghak in Persian and it grows in different mountainous and rural areas of Iran. The fruit and the steam of the Aristolochiacae are named zaravand gerd (nokhod alvand) and zaravand dearaz, respectively, and have different usage in Iranian teadirional such as treatment of headache, back pain, and anxiety. Some patients with end-stage renal disease and bilateral small kidneys have a history of exposure to some herbal remedies. We need to consider the possibility of environmental toxins and even Aristolochia nephrotoxicity as a potential danger in Iran.

  20. Effects of Add-on Fluvastatin Therapy in Patients with Chronic Proteinuric Nephropathy on Dual Renin-Angiotensin System Blockade: The ESPLANADE Trial

    PubMed Central

    Ruggenenti, Piero; Perna, Annalisa; Tonelli, Marcello; Loriga, Giacomina; Motterlini, Nicola; Rubis, Nadia; Ledda, Franca; Rota, Stefano; Satta, Andrea; Granata, Antonio; Battaglia, Giovanni; Cambareri, Francesco; David, Salvatore; Gaspari, Flavio; Stucchi, Nadia; Carminati, Sergio; Ene-Iordache, Bogdan; Cravedi, Paolo

    2010-01-01

    Background and objectives: This open, prospective, randomized trial aimed to assess the effects of statins in chronic kidney disease patients on optimized antiproteinuric treatment with combined angiotensin-converting enzyme inhibition and angiotensin receptor blockade. Design, setting, participants, & measurements: After 1-month benazepril therapy followed by 1-month benazepril-valsartan combined therapy (run-in), 186 consenting patients with residual proteinuria >0.5 g/24 h were randomized to 6-month benazepril-valsartan therapy alone or combined with fluvastatin. Between-groups changes in proteinuria (primary outcome), serum lipids, and GFR were compared by ANCOVA. Analyses were blinded and by intention to treat. Results: During the run-in, proteinuria decreased more on benazepril-valsartan than on benazepril alone. Proteinuria reduction correlated with concomitant reduction in total, LDL, and HDL cholesterol, and apolipoprotein B and apolipoprotein A levels. After randomization, median proteinuria similarly decreased from 1.2 (0.6 to 2.2) to 1.1 (0.5 to 1.7) g/24 h on fluvastatin and from 1.5 (0.8 to 2.7) to 1.0 (0.5 to 2.4) g/24 h on benazapril-valsartan therapy alone. Fluvastatin further reduced total and LDL cholesterol and apolipoprotein B versus benazepril-valsartan alone, but did not affect serum triglycerides and GFR. Treatment was well tolerated. Conclusions: In chronic kidney disease patients with residual proteinuria despite combined angiotensin-converting enzyme inhibitor and angiotensin receptor blockade therapy, add-on fluvastatin does not affect urinary proteins, but further reduces serum lipids and is safe. Whether combined angiotensin-converting enzyme inhibitor, angiotensin receptor blockade, and statin therapy may improve cardiovascular outcomes in this high-risk population is worth investigating. PMID:20671225

  1. Interplay between vesicoureteric reflux and kidney infection in the development of reflux nephropathy in mice.

    PubMed

    Bowen, Samantha E; Watt, Christine L; Murawski, Inga J; Gupta, Indra R; Abraham, Soman N

    2013-07-01

    Vesicoureteric reflux (VUR) is a common congenital defect of the urinary tract that is usually discovered after a child develops a urinary tract infection. It is associated with reflux nephropathy, a renal lesion characterized by the presence of chronic tubulointersitial inflammation and fibrosis. Most patients are diagnosed with reflux nephropathy after one or more febrile urinary tract infections, suggesting a potential role for infection in its development. We have recently shown that the C3H mouse has a 100% incidence of VUR. Here, we evaluate the roles of VUR and uropathogenic Escherichia coli infection in the development of reflux nephropathy in the C3H mouse. We find that VUR in combination with sustained kidney infection is crucial to the development of reflux nephropathy, whereas sterile reflux alone fails to induce reflux nephropathy. A single bout of kidney infection without reflux fails to induce reflux nephropathy. The host immune response to infection was examined in two refluxing C3H substrains, HeN and HeJ. HeJ mice, which have a defect in innate immunity and bacterial clearance, demonstrate more significant renal inflammation and reflux nephropathy compared with HeN mice. These studies demonstrate the crucial synergy between VUR, sustained kidney infection and the host immune response in the development of reflux nephropathy in a mouse model of VUR.

  2. Glycopatterns of Urinary Protein as New Potential Diagnosis Indicators for Diabetic Nephropathy

    PubMed Central

    Zhu, Hanyu; Liu, Moyan; Zhong, Yaogang; Shu, Jian; Fu, Xinle; Cai, Guangyan; Chen, Xiangmei; Geng, Wenjia; Yang, Xiaoli; Wu, Minghui

    2017-01-01

    Diabetic nephropathy is a major cause of chronic kidney disease and end-stage kidney disease. However, so little is known about alterations of the glycopatterns in urine with the development of diabetic nephropathy. Presently, we interrogated glycopatterns in urine specimens using a lectin microarray. The results showed that expression levels of Siaα2-6Gal/GalNAc recognized by SNA exhibited significantly increased tendency with the development of diabetic nephropathy; moreover, SNA blotting indicated glycoproteins (90 kDa, 70 kDa, and 40 kDa) in urine may contribute to this alteration. Furthermore, the glycopatterns of (GlcNAc)2–4 recognized by STL exhibited difference between diabetic and nondiabetic nephropathy. The results of urinary protein microarray fabricated by another 48 urine specimens also indicated (GlcNAc)2–4 is a potential indictor to differentiate the patients with diabetic nephropathy from nondiabetic nephropathy. Furtherly, STL blotting showed that the 50 kDa glycoproteins were correlated with this alteration. In conclusion, our data provide pivotal information to monitor the development of diabetic nephropathy and distinguish between diabetic nephropathy and nondiabetic renal disease based on precise alterations of glycopatterns in urinary proteins, but further studies are needed in this regard.

  3. Preclinical safety evaluation of inhaled cyclosporine in propylene glycol.

    PubMed

    Wang, Tao; Noonberg, Sarah; Steigerwalt, Ronald; Lynch, Maryellen; Kovelesky, Rosemary A; Rodríguez, Carlos A; Sprugel, Katherine; Turner, Nancy

    2007-01-01

    Cyclosporine inhalation solution has the potential to improve outcomes following lung transplantation by delivering high concentrations of an immunosuppressant directly to the allograft while minimizing systemic drug exposure and associated toxicity. The objective of these studies was to evaluate the potential toxicity of aerosolized cyclosporine formulated in propylene glycol when given by inhalation route to rats and dogs for 28 days. Sprague-Dawley rats received total inhaled doses of 0 (air), 0 (vehicle, propylene glycol), 7.4, 24.3, and 53.9 mg cyclosporine/kg/day. In a separate study, beagle dogs were exposed to 0, 4.4, 7.7, and 9.7 mg cyclosporine/kg/day. Endpoints used to evaluate potential toxicity of inhaled cyclosporine were clinical observations, body weight, food consumption, respiratory functions, toxicokinetics, and clinical/anatomic pathology. Daily administration of aerosolized cyclosporine did not result in observable accumulation of cyclosporine in blood or lung tissue. Toxicokinetic analysis from the rat study showed that the exposure of cyclosporine was approximately 18 times higher in the lung tissue compared to the blood. Systemic effects were consistent with those known for cyclosporine. There was no unexpected systemic toxicity or clinically limiting local respiratory toxicity associated with inhalation exposure to cyclosporine inhalation solution at exposures up to 2.7 times the maximum human exposure in either rats or dogs. There were no respiratory or systemic effects of high doses of propylene glycol relative to air controls. These preclinical studies demonstrate the safety of aerosolized cyclosporine in propylene glycol and support its continued clinical investigation in patients undergoing allogeneic lung transplantation.

  4. Neutrophil gelatinase-associated lipocalin (NGAL) fails as an early predictor of contrast induced nephropathy in chronic kidney disease (ANTI-CI-AKI study)

    PubMed Central

    Ribitsch, Werner; Schilcher, Gernot; Quehenberger, Franz; Pilz, Stefan; Portugaller, Rupert H.; Truschnig-Wilders, Martini; Zweiker, Robert; Brodmann, Marianne; Stiegler, Philipp; Rosenkranz, Alexander R.; Pickering, John W.; Horina, Joerg H.

    2017-01-01

    The aim of the study was to evaluate the diagnostic accuracy of urinary neutrophil gelatinase- associated lipocalin (uNGAL) in patients with chronic kidney disease (CKD) as an early biomarker for contrast induced acute kidney injury (CI-AKI) and to investigate whether patients with an uNGAL increase might benefit from an additional intravenous volume expansion with regard to CI-AKI-incidence. We performed a prospective randomized controlled trial in 617 CKD-patients undergoing intra-arterial angiography. Urinary NGAL was measured the day before and 4–6hrs after angiography. In the event of a significant rise of uNGAL patients were randomized either into Group A, who received intravenous saline post procedure or Group B, who did not receive post-procedural i.v. fluids. Ten patients (1.62%) exhibited a significant rise of uNGAL after angiography and were randomized of whom one developed a CI-AKI. In the entire cohort the incidence of CI-AKI was 9.4% (58 patients) resulting in a specificity of 98.4% (95% CI: 97.0–99.3%) and a sensitivity of 1.72% (95% CI: 0.044–9.2%) of uNGAL for the diagnosis of CI-AKI. In this study uNGAL failed to predict CI-AKI and was an inadequate triage tool to guide an early intervention strategy to prevent CI-AKI. Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01292317. PMID:28128223

  5. Heroin crystal nephropathy.

    PubMed

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

    2015-06-01

    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.

  6. 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

  7. IgA Nephropathy.

    PubMed

    Rodrigues, Jennifer C; Haas, Mark; Reich, Heather N

    2017-02-03

    IgA nephropathy (IgAN) is a leading cause of CKD and renal failure. Recent international collaborative efforts have led to important discoveries that have improved our understanding of some of the key steps involved in the immunopathogenesis of IgAN. Furthermore, establishment of multicenter networks has contributed to rigorous design and execution of clinical trials that have provided important insights regarding immunotherapy in IgAN. In this article, we review emerging developments in clinical and translational IgAN research and describe how these novel findings will influence future strategies to improve the outcome of patients with IgAN.

  8. Blood concentration of cyclosporine during early post-transplant period may have influence on the occurrence of chronic graft versus host disease in patients who received allogeneic hematopoietic stem cell transplantation

    PubMed Central

    Park, Silvia; Kim, Kihyun; Jang, Jun Ho; Kim, Seok Jin; Kim, Won Seog; Jung, Chul Won

    2016-01-01

    Introduction It has rarely been studied that how the blood level of CsA affect the incidence of chronic GVHD after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods A total of 183 patients who underwent allo-HSCT from an HLA-matched or haplo matched family donors between 2006 and 2014 were reviewed. Results The average monthly CsA blood concentration (CsAavr, ng/ml) was calculated in each patient: 0-1, 1-2, and 2-3 months after allo-HSCT. CsAavr at the first month showed significant association with the occurrence of moderate to severe cGVHD in multivariate analysis adjusted for gender, age, total body irradiation, anti-thymocyte globulin, acute GVHD ≥ grade 2 and CsAavr levels of other periods. The risk of cGVHD development was lowest in patients with CsAavr of 200-250 ng/ml when compared to those with CsAavr of ≥ 250 or < 200 ng/ml (p=0.003). Conclusions CsA level between 200 and 250 mg/ml during the first month after transplantation was significantly associated with the decreased risk of moderate to severe cGVHD. PMID:27494893

  9. 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.

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

    PubMed

    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.

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. Pharmacokinetics of cyclosporine after renal transplant in children.

    PubMed

    Mochon, M; Cooney, G; Lum, B; Caputo, G C; Dunn, S; Goldsmith, B; Baluarte, H J; Polinsky, M S; Kaiser, B A

    1996-07-01

    The pharmacokinetics of cyclosporine and the relationship between blood levels and average drug concentration were prospectively evaluated in 18 children 1 month after renal transplantation. All children had normal renal function and no hepatic or gastrointestinal dysfunction. Cyclosporine was administered after an overnight fast, and serial blood samples were drawn over a 24-hour period. Analysis of cyclosporine levels was performed by means of monoclonal radio immunoassay on whole blood. Children were divided into three age groups for comparison: 2-5 years, 5-10 years, and > 10 years. There were no differences between age groups in serum protein, serum lipids, or hemoglobin levels, or in the pharmacokinetic parameters of cyclosporine except as follows: significant differences were noted in cyclosporine dose based on body weight, apparent steady-state volume of distribution, and apparent blood clearance, with the youngest children (2-5) requiring higher doses, a relative greater distribution, and exhibiting more rapid drug clearance than those > 10 years of age. In addition, we observed diurnal variation in trough levels, with morning levels (0 hr) significantly higher than those obtained in the evening (12 hours after administration of cyclosporine). Trough levels demonstrated a fair correlation with area under the concentration-time curve (AUC) and average concentration (Cav), but an abbreviated kinetic profile using cyclosporine levels 1 and 3.5 hours after administration accurately predicted AUC.

  17. Pathologic classification of diabetic nephropathy.

    PubMed

    Tervaert, Thijs W Cohen; Mooyaart, Antien L; Amann, Kerstin; Cohen, Arthur H; Cook, H Terence; Drachenberg, Cinthia B; Ferrario, Franco; Fogo, Agnes B; Haas, Mark; de Heer, Emile; Joh, Kensuke; Noël, Laure H; Radhakrishnan, Jai; Seshan, Surya V; Bajema, Ingeborg M; Bruijn, Jan A

    2010-04-01

    Although pathologic classifications exist for several renal diseases, including IgA nephropathy, focal segmental glomerulosclerosis, and lupus nephritis, a uniform classification for diabetic nephropathy is lacking. Our aim, commissioned by the Research Committee of the Renal Pathology Society, was to develop a consensus classification combining type1 and type 2 diabetic nephropathies. Such a classification should discriminate lesions by various degrees of severity that would be easy to use internationally in clinical practice. We divide diabetic nephropathy into four hierarchical glomerular lesions with a separate evaluation for degrees of interstitial and vascular involvement. Biopsies diagnosed as diabetic nephropathy are classified as follows: Class I, glomerular basement membrane thickening: isolated glomerular basement membrane thickening and only mild, nonspecific changes by light microscopy that do not meet the criteria of classes II through IV. Class II, mesangial expansion, mild (IIa) or severe (IIb): glomeruli classified as mild or severe mesangial expansion but without nodular sclerosis (Kimmelstiel-Wilson lesions) or global glomerulosclerosis in more than 50% of glomeruli. Class III, nodular sclerosis (Kimmelstiel-Wilson lesions): at least one glomerulus with nodular increase in mesangial matrix (Kimmelstiel-Wilson) without changes described in class IV. Class IV, advanced diabetic glomerulosclerosis: more than 50% global glomerulosclerosis with other clinical or pathologic evidence that sclerosis is attributable to diabetic nephropathy. A good interobserver reproducibility for the four classes of DN was shown (intraclass correlation coefficient = 0.84) in a test of this classification.

  18. 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

  19. 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.

  20. The absorption site of cyclosporin in the human gastrointestinal tract.

    PubMed Central

    Drewe, J; Beglinger, C; Kissel, T

    1992-01-01

    1. An emulsion preparation of cyclosporin was administered locally to different parts of the small and large intestine by gavage: to the duodenum (opposite to the papilla of Vater), jejunum (150 cm distal to the teeth), ileum (300 cm distal to the teeth), and to the colon descendens (30 cm proximal to the anus). 2. The bioavailability of cyclosporin after these instillations was compared with that after oral administration of a hard gelatine capsule formulation. 3. Cyclosporin was found to be absorbed predominantly in the small intestine. This may have implications for dosage in patients with reduced absorptive surface area. PMID:1540489

  1. Common Analgesic Agents and Their Roles in Analgesic Nephropathy: A Commentary on the Evidence

    PubMed Central

    2016-01-01

    An association between non-opioid analgesic agents and chronic kidney disease has long been suspected. The presumed development of chronic renal impairment following protracted and excessive use of non-opioid analgesia is known as analgesic nephropathy. Many clinicians accept analgesic nephropathy as a real entity despite the paucity of scientific evidence. This narrative review aims to summarize the literature in the field. The weight of available observational literature suggests that long-term ingestion of paracetamol and combination mixtures of aspirin and paracetamol are likely to contribute to chronic renal impairment. However, there is no convincing data to implicate non-steroidal anti-inflammatory drugs or aspirin monotherapy in the development of analgesic nephropathy. In the absence of high-level evidence, while controversy persists, it may be prudent for physicians to consider all non-narcotic analgesics to be nephrotoxic with long-term use. PMID:27900067

  2. 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.

  3. [The role of ramipril in the therapy of diabetic nephropathy].

    PubMed

    Dézsi, Csaba András

    2014-02-16

    In the past two decades the number of diabetic patients has increased dramatically. According to the data of the International Diabetes Federation published in 2012, more than 371 million people suffer from diabetes mellitus, which is responsible for the death of 4.8 million people yearly. Diabetic nephropathy is the most frequent cause of terminal renal failure. The first stage of its development is microalbuminuria. Without an efficient treatment 20-40% of the patients with microalbuminuria suffering from type 2 diabetes mellitus develop chronic renal failure, but only 20% of them become uremic because most of them die beforehand mainly due to cardiovascular disease. The renin-angiotensin-system, which is one of the most important elements of the regulation of blood pressure and water-salt metabolism, plays an important role in the development of diabetic nephropathy. Drugs affecting the function of this system are of great significance in the treatment of hypertension. The author rewiews the results of several important studies and animal experiments to demonstrate the role of ramipril in the therapy of diabetic nephropathy. The author concludes that ramipril is one of the angiotensin-converting enzyme inhibitors with the highest number of evidence based beneficial results. Apart from its blood pressure decreasing effect, ramipril protects target organs and it proved to be effective in the treatment of diabetic nephropathy according to most international multicenter clinical trials. Orv. Hetil., 2014, 155(7), 263-269.

  4. Polyomavirus nephropathy of the native kidney in a patient with rheumatoid arthritis and pulmonary fibrosis.

    PubMed

    Krystel-Whittemore, Melissa; McCarthy, Ellen T; Damjanov, Ivan; Fields, Timothy A

    2015-08-28

    Polyomavirus nephropathy is commonly seen in the renal allograft setting but is uncommon in native kidneys. This paper describes polyomavirus nephropathy that developed in the native kidneys of a patient following immunosuppressive therapy for rheumatoid arthritis/Sjögren's syndrome associated lung disease. The patient presented with dyspnoea and a slow steady rise in serum creatinine. Owing to chronic immunosuppression, calcineurin-inhibitor toxicity was suspected. However, renal biopsy revealed polyomavirus nephropathy. The treatment of choice, lowered immunosuppression, was complicated by exacerbation of the patient's lung disease. This case highlights features of polyomavirus nephropathy in the native kidney, as well as the difficulty in its treatment when immunosuppressive treatment is necessary for medical comorbidities.

  5. A simultaneous liver-kidney transplant recipient with IgA nephropathy limited to native kidneys and BK virus nephropathy limited to the transplant kidney.

    PubMed

    Ujire, Manasa P; Curry, Michael P; Stillman, Isaac E; Hanto, Douglas W; Mandelbrot, Didier A

    2013-08-01

    Immunoglobulin A (IgA) deposition in the native kidneys of patients with liver disease is well described. Secondary IgA nephropathy usually is thought to be benign, but hematuria, proteinuria, and loss of kidney function have been reported in this context. BK virus nephropathy is an important cause of kidney transplant loss; however, BK virus nephropathy is rare in the native kidneys of patients who underwent transplantation of other organs. We report the case of a patient with alcohol-related end-stage liver disease and chronic kidney disease with hematuria who underwent simultaneous liver-kidney transplantation. His kidney function decreased over the course of several weeks posttransplantation. Biopsy of the transplant kidney showed BK virus nephropathy, but no IgA deposits. In contrast, biopsy of the native kidneys showed IgA deposits, but no BK virus nephropathy. To our knowledge, this is the first reported case of a simultaneous liver-kidney transplantation wherein both the native and transplant kidneys were biopsied posttransplantation and showed exclusively different pathologies. These findings confirm the predilection of BK virus nephropathy for transplant rather than native kidneys.

  6. 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

  7. Cyclosporin A in cadaveric organ transplantation.

    PubMed Central

    Calne, R Y; White, D J; Evans, D B; Thiru, S; Henderson, R G; Hamilton, D V; Rolles, K; McMaster, P; Duffy, T J; MacDougall, B R; Williams, R

    1981-01-01

    The use of cyclosporin A (CyA) with a protocol designed to avoid the effects of nephrotoxicity resulted in a one-year survival of 86% in recipients of renal allografts from unmatched cadaveric donors. The drug also controlled rejection of liver and pancreatic allografts. It was possible to change patients initially treated with CyA to azathioprine and corticosteroids and vice versa, thus enlarging the potential value of CyA in organ allografting. Of 34 recipients of renal allografts, 29 were currently receiving only CyA as immunosuppressive treatment. Twelve patients never required any adjuvant steroid treatment. These results suggest that CyA is an effective immunosuppressant, and if used with care side effects need not be severe. PMID:6781658

  8. 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

  9. Effects of cyclosporin on collagen induced arthritis in mice.

    PubMed Central

    Takagishi, K; Kaibara, N; Hotokebuchi, T; Arita, C; Morinaga, M; Arai, K

    1986-01-01

    We have studied the effect of the immunosuppressive agent cyclosporin on collagen induced arthritis in mice. Cyclosporin, when given prophylactically, was capable of suppressing the development of collagen induced arthritis and the immunological response to native type II collagen in a dose dependent manner. Furthermore, treatment with cyclosporin, started on the same day as the booster injection with type II collagen, also resulted in inhibition of development of arthritis and of immunity to collagen. These findings suggest that the time of a booster injection, three weeks after the initial immunisation, might be still within the induction phase of arthritis since reinoculation is required to produce a high incidence of arthritis in mice. In addition, therapeutic treatment with cyclosporin did not affect the clinical course of the disease or the immune response to collagen. PMID:3754714

  10. Combination cyclosporine and (hydroxy)chloroquine in rheumatoid arthritis.

    PubMed

    Dijkmans, B A; Landewé, R B; van den Borne, B E; Breedveld, F C

    1999-01-01

    Antimalarials are attractive candidates for combination therapy. In vitro experiments have revealed a synergistic mode of action of cyclosporine and chloroquine which could not, however, be confirmed in a clinical trial.

  11. Pituitary transplantation: cyclosporine enables transplantation across a minor histocompatibility barrier.

    PubMed

    Tulipan, N B; Huang, S; Allen, G S

    1986-03-01

    Pituitary glands from neonatal donors were transplanted to the median eminence of hypophysectomized adult rats. Rats with transplants were then treated for 2 weeks with the immunosuppressive drug cyclosporine. For 5 weeks thereafter, blood was drawn at regular intervals for determination of serum thyroxine, prolactin, and luteinizing hormone. Cyclosporine-treated recipients of grafts with minor histocompatibility differences had normal levels of thyroxine and prolactin, whereas untreated animals did not. In addition, the treated animals responded to oophorectomy with a marked elevation in serum luteinizing hormone. This evidence indicates that cyclosporine enables successful transplantation across a minor histocompatibility barrier. It also suggests that these grafts interact with the hypothalamus. Transplantation across a major histocompatibility barrier was unsuccessful even in the presence of cyclosporine.

  12. 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.

  13. Impact of cyclosporine in the development of immunosuppressive therapy.

    PubMed

    Chaverri, C

    2004-03-01

    Cyclosporine has been of great interest to the transplant community during the last 20 years. It has permitted an evolution of knowledge through the changes in its original galenic formulation of Sandimmune to Neoral, and now through the recent application of the knowledge of pharmacodynamics and pharmacokinetics to tailor drug doses to each individual. The achievements of cyclosporine are still valid and possibly will be for the next years.

  14. 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

  15. 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

  16. IgA nephropathy.

    PubMed

    Lai, Kar Neng; Tang, Sydney C W; Schena, Francesco Paolo; Novak, Jan; Tomino, Yasuhiko; Fogo, Agnes B; Glassock, Richard J

    2016-02-11

    Globally, IgA nephropathy (IgAN) is the most common primary glomerulonephritis that can progress to renal failure. The exact pathogenesis of IgAN is not well defined, but current biochemical and genetic data implicate overproduction of aberrantly glycosylated IgA1. These aberrant immunoglobulins are characterized by galactose deficiency of some hinge-region O-linked glycans. However, aberrant glycosylation alone is insufficient to induce renal injury: the participation of glycan-specific IgA and IgG autoantibodies that recognize the undergalactosylated IgA1 molecule is required. Glomerular deposits of immune complexes containing undergalactosylated IgA1 activate mesangial cells, leading to the local overproduction of cytokines, chemokines and complement. Emerging data indicate that mesangial-derived mediators that are released following mesangial deposition of IgA1 lead to podocyte and tubulointerstitial injury via humoral crosstalk. Patients can present with a range of signs and symptoms, from asymptomatic microscopic haematuria to macroscopic haematuria. The clinical progression varies, with 30-40% of patients reaching end-stage renal disease 20-30 years after the first clinical presentation. Currently, no IgAN-specific therapies are available and patients are managed with the aim of controlling blood pressure and maintaining renal function. However, new therapeutic approaches are being developed, building upon our ever-improving understanding of disease pathogenesis.

  17. Chinese herb nephropathy

    PubMed Central

    2000-01-01

    In 1994, a 44-year-old woman progressed from normal renal function to advanced renal failure and end-stage renal disease within 8 months. Biopsy revealed extensive interstitial fibrosis with focal lymphocytic infiltration. She received a cadaveric renal transplant in January 1996 and had an uneventful posttransplant course. As a result of a minor motor vehicle accident, the patient had received acupuncture and Chinese herbal medicine for pain relief approximately 5 months before the onset of renal symptoms. After the transplant, analysis of the herbal remedies clearly indicated the presence of aristolochic acid in 2 of the 6 Chinese herbs ingested. Ingestion of aristolochic acid has been linked to a newly defined entity, Chinese herb nephropathy (CHN). This article discusses the history of CHN and its implication in the current case and in other recent similar cases and makes recommendations to avoid future problems caused by unregulated use of herbal medicines. This is the first reported case of CHN in the USA. PMID:16389336

  18. Risk prediction models for contrast induced nephropathy: systematic review

    PubMed Central

    Silver, Samuel A; Shah, Prakesh M; Chertow, Glenn M; Wald, Ron

    2015-01-01

    Objectives To look at the available literature on validated prediction models for contrast induced nephropathy and describe their characteristics. Design Systematic review. Data sources Medline, Embase, and CINAHL (cumulative index to nursing and allied health literature) databases. Review methods Databases searched from inception to 2015, and the retrieved reference lists hand searched. Dual reviews were conducted to identify studies published in the English language of prediction models tested with patients that included derivation and validation cohorts. Data were extracted on baseline patient characteristics, procedural characteristics, modelling methods, metrics of model performance, risk of bias, and clinical usefulness. Eligible studies evaluated characteristics of predictive models that identified patients at risk of contrast induced nephropathy among adults undergoing a diagnostic or interventional procedure using conventional radiocontrast media (media used for computed tomography or angiography, and not gadolinium based contrast). Results 16 studies were identified, describing 12 prediction models. Substantial interstudy heterogeneity was identified, as a result of different clinical settings, cointerventions, and the timing of creatinine measurement to define contrast induced nephropathy. Ten models were validated internally and six were validated externally. Discrimination varied in studies that were validated internally (C statistic 0.61-0.95) and externally (0.57-0.86). Only one study presented reclassification indices. The majority of higher performing models included measures of pre-existing chronic kidney disease, age, diabetes, heart failure or impaired ejection fraction, and hypotension or shock. No prediction model evaluated its effect on clinical decision making or patient outcomes. Conclusions Most predictive models for contrast induced nephropathy in clinical use have modest ability, and are only relevant to patients receiving contrast for

  19. Ochratoxin A levels in human serum and foods from nephropathy patients in Tunisia: where are you now?

    PubMed

    Hmaissia Khlifa, K; Ghali, R; Mazigh, C; Aouni, Z; Machgoul, S; Hedhili, A

    2012-07-01

    Ochratoxin A is a natural mycotoxin with nephrotoxic properties that can contaminate food products. It has been detected in high amount in human serum collected from nephropathy patients, especially those categorized as having a chronic interstitial nephropathy of unknown etiology. In the present study, ochratoxin A levels were measured in commonly consumed food items and in serum samples from nephropathy and healthy subjects in Tunisia. To assess ochratoxin A, a high performance liquid chromatography method was optimized. The ochratoxin A assay showed very different scales of ochratoxin A serum and food contamination from 0.12 to 1.5 ng/mL and 0.11 to 6.1 ng/g respectively, and in healthy subjects and 0.11 to 33.8 ng/g for food and 0.12 to 3.8 ng/mL for serum in nephropathy patients suffering from chronic interstitial nephropathy of unknown etiology. The disease seems related to ochratoxin A serum levels and food contaminations, since the healthy group was significantly different from the nephropathy group (P<0.001) for both food and serum ochratoxin A contamination. Those results combined with data published already, emphasize the likely endemic aspect of ochratoxin A-related nephropathy occurring in Tunisia.

  20. Effects of pregnancy on the onset and progression of diabetic nephropathy and of diabetic nephropathy on pregnancy outcomes.

    PubMed

    Young, Esther Cytrynbaum; Pires, Maria Lucia Elias; Marques, Luiz Paulo José; de Oliveira, José Egídio Paulo; Zajdenverg, Lenita

    2011-01-01

    Controversy exists regarding the effect of pregnancy on the development and course of diabetic nephropathy. This study followed 43 pregnant women with previous diabetes mellitus, 32 without nephropathy (Group I) and 11 with nephropathy (Group II). Urinary albumin excretion (UAE), serum creatinine (Cr) and creatinine clearance (CCr) in the pre-pregnancy (Pre-P), first trimester (1T), third trimester (3T) and 1 year postpartum (PP) were evaluated. In both groups there were an increase in 3T compared to Pre-P of CCr (137 vs. 98 ml/min and 110 vs. 81 ml/min, p=0.0001, respectively) and UAE (7.78 vs. 3.15 mg/24 h and 592 vs. 119 mg/24 h, p=0.0001, respectively). Increase of Cr in the PP compared to 1T in Group II (0.88 vs. 0.70 mg/dL, p=0.031) was observed. There were no difference in UAE, CCr and Cr in the PP when compared to pre-P as well variance over time between groups. Group II showed higher prevalence of chronic hypertension (72.7 vs. 21.9%, p=0.004), preeclampsia (63.6 vs. 6.3%, p=0.0003) and lower gestational age at birth (36 vs. 38 weeks, p=0.003). We conclude that pregnancy was not associated with development and progression of diabetic nephropathy in women with or without mild renal dysfunction. The presence of diabetic nephropathy was associated with increased risk of perinatal complications.

  1. 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

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

    PubMed

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

    2012-01-15

    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.

  3. APOL1 and nephropathy progression in populations of African ancestry.

    PubMed

    Freedman, Barry I

    2013-09-01

    Marked familial aggregation of chronic kidney disease suggests that inherited factors play a major role in nephropathy susceptibility. Molecular genetics analyses have identified a number of genes reproducibly associated with a broad range of renal phenotypes. Most associations show polygenic inheritance patterns with limited effect size. In contrast, genetic association between the apolipoprotein L1 (APOL1) gene and several severe nondiabetic forms of kidney disease in African Americans approach Mendelian inheritance patterns and account for a large proportion of glomerulosclerosis in populations of African ancestry. Emerging data support an important role for APOL1 in the progression of diverse etiologies of kidney disease, in concert with requisite environmental (gene*environment) and inherited (gene*gene) interactions. This article reviews the current status of APOL1-associated nephropathy and discusses research questions under active investigation in the search for a cure for these severe and often progressive kidney diseases.

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

    PubMed

    Kim, Sang Soo; Kim, Jong Ho; Kim, In Joo

    2016-06-01

    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.

  5. CHRONIC URTICARIA AND TREATMENT OPTIONS

    PubMed Central

    Godse, Kiran Vasant

    2009-01-01

    Chronic urticaria has a wide spectrum of clinical presentations and causes. Still, despite our best efforts no cause may be found in the majority of cases. The treatment options are: Primary prevention in the form of avoidance of aggravating factors; counseling; antihistamines; leukotriene receptor antagonists; prednisolone; sulfasalazine and a host of immunosuppressives like methotrexate, cyclosporine, omalizumab etc. PMID:20101328

  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. Oxalate Nephropathy in Systemic Sclerosis: Case Series and Review of the Literature

    PubMed Central

    Ligon, Colin B.; Hummers, Laura K.; McMahan, Zsuzsanna H.

    2015-01-01

    Objective To increase awareness of oxalate nephropathy as a cause of acute kidney injury (AKI) among systemic sclerosis patients with small intestinal dysmotility and malabsorption, and to prompt consideration of dietary modification and early treatment of predisposing causes of oxalate nephropathy in this population. Methods Two cases of biopsy-proven oxalate nephropathy were identified among systemic sclerosis patients in the course of direct clinical care. Subsequently, a retrospective search of the Johns Hopkins Pathology databases identified a third patient with systemic sclerosis who developed oxalate nephropathy. Results Among the three patients with qualifying biopsies, all three had systemic sclerosis with lower gastrointestinal involvement. All three presented with diarrhea, malabsorption, and AKI. In two of the three patients, diarrhea was present for at least two years before the development of AKI; in the third, incidental oxalate nephropathy was noted three years before she developed AKI and extensive oxalate nephropathy in the setting of a prolonged mycobacterium avium-intracellulare enteritis. In one case, oxalate crystals were present by urinalysis months before diagnosis by biopsy, in the second, hyperoxaluria was diagnosed by urine collection immediately after biopsy, and in the third, oxalate crystals had been noted incidentally on post-transplant renal biopsy three years before the development of fulminant oxalate nephropathy. All three patients died within a year of diagnosis. Conclusions Patients with systemic sclerosis and bowel dysmotility associated with chronic diarrhea and malabsorption may be at risk for an associated oxalate nephropathy. Regular screening of systemic sclerosis patients with small bowel malabsorption syndromes through routine urinalysis or 24 hour urine oxalate collection, should be considered. Further studies defining the prevalence of this complication in systemic sclerosis, the benefit of dietary modification on

  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.

  9. Improved dose linearity of cyclosporine pharmacokinetics from a microemulsion formulation.

    PubMed

    Mueller, E A; Kovarik, J M; van Bree, J B; Tetzloff, W; Grevel, J; Kutz, K

    1994-02-01

    The pharmacokinetic dose proportionality and relative bioavailability of cyclosporine from a microemulsion formulation (Sandimmune Neoral) were compared to those of the commercial formulation (Sandimmune) over the dosage range 200 to 800 mg. Single oral administrations were given as soft gelatin capsules in an open randomized study with 48 healthy volunteers. Whole-blood cyclosporine concentrations were determined by a specific monoclonal radioimmunoassay. In comparison to Sandimmune, the absorption rate (maximum concentration) and systemic availability (area under the curve) of cyclosporine were greater for Sandimmune Neoral at all dose levels investigated. The area under the curve for Sandimmune increased in a less than proportional manner with respect to dose, whereas that for Sandimmune Neoral was consistent with linear pharmacokinetics. Because of this difference, no global assessment of relative bioavailability could be performed. The relative bioavailability of cyclosporine from Sandimmune Neoral ranged from 174 to 239% compared to Sandimmune, depending on the dose level. The improvements in oral bioavailability and dose linearity of cyclosporine exposure after administration as Sandimmune Neoral should facilitate more accurate dosage titration in the clinical setting.

  10. The combination of sirolimus plus tacrolimus improves outcome after reduced-intensity conditioning, unrelated donor hematopoietic stem cell transplantation compared with cyclosporine plus mycofenolate

    PubMed Central

    Perez-Simón, Jose Antonio; Martino, Rodrigo; Parody, Rocío; Cabrero, Mónica; Lopez-Corral, Lucía; Valcarcel, David; Martinez, Carmen; Solano, Carlos; Vazquez, Lourdes; Márquez-Malaver, Francisco J.; Sierra, Jordi; Caballero, Dolores

    2013-01-01

    Different types of graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with sirolimus and tacrolimus has recently been tested although comparative studies against the classical combination of a calcineurin inhibitor and mycophenolate mofetil or methotrexate are lacking. We describe the results of a prospective, multicenter trial using sirolimus + tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using cyclosporine + mycophenolate in the setting of unrelated donor transplantation setting after reduced-intensity conditioning. Forty-five patients received cyclosporine + mycophenolate between 2002 and mid-2007, while the subsequent 50 patients, who were transplanted from late 2007, were given sirolimus + tacrolimus. No significant differences were observed in terms of hematopoietic recovery or acute graft-versus-host disease overall, although gastrointestinal acute graft-versus-host disease grade ≥2 was more common in the cyclosporine + mycophenolate group (55% versus 21%, respectively, P=0.003). The 1-year cumulative incidence of chronic graft-versus-host disease was 50% versus 90% for the patients treated with the sirolimus- versus cyclosporine-based regimen, respectively (P<0.001), while the incidence of extensive chronic disease was 27% versus 49%, respectively (P=0.043). The 2-year non-relapse mortality rate was 18% versus 38% for patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively (P=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (P=0.028) and 70% versus 45% (P=0.018) among patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively. In conclusion, in the setting of reduced intensity transplantation from an unrelated donor, promising results can be achieved with the combination of sirolimus + tacrolimus

  11. [Effect of verapamil on cyclosporine-induced vasoconstriction in human or murine isolated glomerules].

    PubMed

    L'Azou, B; Lakhdar, B; Potaux, L; Aparicio, M; Cambar, J

    1991-11-27

    Cyclosporin is a very potent immunosuppressant, but it often produces renal disturbances which limit its clinical use. Using an image analyzer which determines the areas of isolated glomerules, we were able to demonstrate that cyclosporin in various concentrations exerts a direct vasoconstrictive effect on human and murine glomerules. We also showed that verapamil has an almost total inhibitory effect on cyclosporin-induced vasoconstriction. These findings seem to be of interest in clinical practice to reduce the nephrotoxicity of cyclosporin.

  12. 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

  13. 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

  14. Utility of C-2 (Cyclosporine) monitoring in postrenal transplant patients: A study in the Indian population.

    PubMed

    Thakur, V; Kumar, R; Gupta, P N

    2008-07-01

    The study was planned and conducted to assess the benefit of C-2 levels (blood cyclosporine levels two hours postdosing) monitoring over trough (C0) levels (predosing) in postrenal transplant patients. The patient population included 34 postrenal transplant individuals (28 males and six females, mean age of 39.9 +/- 12.3 years). The patients were first-transplant patients and were receiving a microemulsion form of cyclosporine A (CsA) as an immunosuppressant along with azathioprine and prednisolone. In addition, they were not on any enzyme inducer/inhibitor drugs, except for diltiazem. Timed collection of C0 and C-2 samples was done and the samples were immediately processed using the cedia cyclosporine plus assay kit. Estimation was done on a Beckman synchron CX5CE fully automated chemistry analyzer. Serum urea nitrogen and creatinine levels were checked. Poor graft survival was found in this population with 29.3% patients showing graft rejection. The graft rejection patients were assigned to two groups: group I with chronic graft rejection patients (17.6%) and group II with acute graft rejection patients (11.7%). Group III consisted of graft survival patients (70.7%). Mean +/- SD was calculated for C0 and C2 levels. Individual values for C0 and C-2 were plotted on a scatter chart. C0 and C-2 levels were normalized by calculating them as the percentage of their targets (data not shown) and compared using the Kruskal Wallis one-way analysis of variance. C0 levels in all the three groups were within the recommended therapeutic range (150-300 ng/mL) (P < 0.182). Blood C-2 concentrations did not achieve the recommended target levels in these patients. One-way analysis of variance for C-2 values when expressed as the percentage of the target values did not show any significant difference between these groups (P < 0.84). No significant difference was found in C0 levels between groups I, II, and group III patients when expressed as the percentage of the target values (P

  15. Interstitial capillary changes in lithium nephropathy: effects of antihypertensive treatment.

    PubMed

    Skyum, Helle; Marcussen, Niels; Nielsen, Steen Horne; Christensen, Sten

    2004-10-01

    Histopathological changes were investigated in the tubulointerstitium and in the capillaries of male Wistar rats with lithium-induced nephropathy using stereological methods. Two antihypertensive drugs with opposite effects on the renin-angiotensin system, an ACE inhibitor (angiotensin converting enzyme inhibitor) and a thiazide diuretic, modified the nephropathy. Generally, there was a significant positive correlation between the reduction in GFR (glomerular filtration rate) and the reduction in the volume of intact tubular structures and interstitial capillaries. A significant negative correlation was seen between the reduction in GFR and the increase in tubulocapillary distance and the absolute volume of interstitial connective tissue, respectively. Treatment with perindopril, and to some extent hydrochlorothiazide, reversed the rise in systolic blood pressure associated with lithium-induced nephropathy but did not affect the progression to terminal uraemia, the structural renal changes or the mortality. In conclusion, severe tubular and capillary changes are seen in this model of chronic renal failure. Tubular atrophy is associated with a decrease in interstitial capillaries and with an increase in the tubulocapillary distance. Systemic hypertension or activation of the renin-angiotensin system may not be important factors for the progression to terminal renal failure.

  16. [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.

  17. Vesicoureteric reflux and reflux nephropathy: from mouse models to childhood disease.

    PubMed

    Fillion, Marie-Lyne; Watt, Christine L; Gupta, Indra R

    2014-04-01

    Vesicoureteric reflux (VUR) is a common congenital urinary tract defect that predisposes children to recurrent kidney infections. Kidney infections can result in renal scarring or reflux nephropathy defined by the presence of chronic tubulo-interstitial inflammation and fibrosis that is a frequent cause of end-stage renal failure. The discovery of mouse models with VUR and with reflux nephropathy has provided new opportunities to understand the pathogenesis of these conditions and may provide insight on the genes and the associated phenotypes that need to be examined in human studies.

  18. Diabetic nephropathy: a national dialogue.

    PubMed

    Breyer, Matthew D; Coffman, Thomas M; Flessner, Michael F; Fried, Linda F; Harris, Raymond C; Ketchum, Christian J; Kretzler, Matthias; Nelson, Robert G; Sedor, John R; Susztak, Katalin

    2013-09-01

    The National Institute of Diabetes and Digestive and Kidney Diseases-supported Kidney Research National Dialogue (KRND) asked the scientific community to formulate and prioritize research objectives that would improve our understanding of kidney function and disease. Several high-priority objectives for diabetic nephropathy were identified in data and sample collection, hypothesis generation, hypothesis testing, and translation promotion. The lack of readily available human samples linked to comprehensive phenotypic, clinical, and demographic data remains a significant obstacle. With data and biological samples in place, several possibilities exist for using new technologies to develop hypotheses. Testing novel disease mechanisms with state-of-the-art tools should continue to be the foundation of the investigative community. Research must be translated to improve diagnosis and treatment of people. The objectives identified by the KRND provide the research community with future opportunities for improving the prevention, diagnosis, and treatment of diabetic nephropathy.

  19. 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.

  20. Experimental Models of Membranous Nephropathy

    PubMed Central

    Jefferson, J. Ashley; Pippin, Jeffrey W.; Shankland, Stuart J.

    2011-01-01

    Membranous nephropathy (MN) is one of the commonest glomerular diseases, typically presenting in older males with nephrotic syndrome. The development and characterization of animal models of MN, in particular, the passive Heymann nephritis model (PHN), has greatly advanced our understanding of this disease. In this review we discuss the different animal models of human MN that are available, with an emphasis on the PHN model, including technical issues, the typical disease course and its application to human disease. PMID:21359154

  1. Oxidative Stress in Diabetic Nephropathy

    PubMed Central

    Kashihara, N.; Haruna, Y.; Kondeti, V.K.; Kanwar, Y.S.

    2013-01-01

    Diabetic nephropathy is a leading cause of end-stage renal failure worldwide. Its morphologic characteristics include glomerular hypertrophy, basement membrane thickening, mesangial expansion, tubular atrophy, interstitial fibrosis and arteriolar thickening. All of these are part and parcel of microvascular complications of diabetes. A large body of evidence indicates that oxidative stress is the common denominator link for the major pathways involved in the development and progression of diabetic micro- as well as macrovascular complications of diabetes. There are a number of macromolecules that have been implicated for increased generation of reactive oxygen species (ROS), such as, NAD(P)H oxidase, advanced glycation end products (AGE), defects in polyol pathway, uncoupled nitric oxide synthase (NOS) and mitochondrial respiratory chain via oxidative phosphorylation. Excess amounts of ROS modulate activation of protein kinase C, mitogen-activated protein kinases, and various cytokines and transcription factors which eventually cause increased expression of extracellular matrix (ECM) genes with progression to fibrosis and end stage renal disease. Activation of renin-angiotensin system (RAS) further worsens the renal injury induced by ROS in diabetic nephropathy. Buffering the generation of ROS may sound a promising therapeutic to ameliorate renal damage from diabetic nephropathy, however, various studies have demonstrated minimal reno-protection by these agents. Interruption in the RAS has yielded much better results in terms of reno-protection and progression of diabetic nephropathy. In this review various aspects of oxidative stress coupled with the damage induced by RAS are discussed with the anticipation to yield an impetus for designing new generation of specific antioxidants that are potentially more effective to reduce reno-vascular complications of diabetes. PMID:20939814

  2. Successful treatment of autoimmunity in (NZB X NZW)F1 mice with cyclosporin and (Nva2)-cyclosporin: I. Reduction of autoantibodies.

    PubMed Central

    Gunn, H C

    1986-01-01

    Autoimmune (NZB X NZW)F1 mice were treated with the immunosuppressive agent, cyclosporin, and its new derivative (Nva2)-cyclosporin. Both compounds prevented the development of autoantibodies in young mice, and also reduced the levels of the autoantibodies in old mice. These findings established that autoantibodies, at least in the (NZB X NZW)F1 mice, can be controlled pharmacologically. This study supports the possibility that treatment with cyclosporin and (Nva2)-cyclosporin might be effective in the treatment of certain autoimmune diseases in man. PMID:3488856

  3. Assessing genetic susceptibility to diabetic nephropathy.

    PubMed

    Tanaka, Nobue; Babazono, Tetsuya

    2005-10-01

    Diabetic nephropathy is a serious complication of diabetes and the leading cause of end-stage renal disease. Studies indicate both environmental and genetic factors contribute to the development and progression of diabetic nephropathy. In particular, epidemiological evidence shows a familial clustering of nephropathy in siblings with diabetes, supporting an important role of genetic susceptibility in the pathogenesis of diabetic nephropathy. A common approach in genetic research is assessment of candidate gene polymorphisms using case-control analysis; a number of studies have evaluated predictable candidate genes for diabetic nephropathy. In contrast, only a few studies have used a whole genome approach, such as scanning of micro-satellite markers, in the assessment of genetic susceptibility to diabetic nephropathy. A whole genome linkage analysis using families of Pima Indians showed susceptibility loci for diabetic nephropathy on chromosome 3, 7, and 20. Another linkage analysis using discordant sib-pairs of Caucasian families with type 1 diabetes identified a critical area on chromosome 3q. However, these results have been inconclusive and further investigation is required. Recently, a genome-wide, case-control analysis identifying susceptibility genes for diabetic nephropathy was performed. As a result, a single nucleotide polymorphism in exon 23 of the solute carrier family 12 (sodium-chloride cotransporter) member 3 gene was found to be strongly associated with diabetic nephropathy. Although further assessment of this polymorphism is needed, this strategy offers great promise in the identification of genetic factors predisposing patients to diabetic nephropathy. Identification of genetic susceptibility markers may offer new hope in the diagnosis and treatment of diabetic nephropathy.

  4. 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

  5. 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.

  6. Megabladder mouse model of congenital obstructive nephropathy: genetic etiology and renal adaptation.

    PubMed

    McHugh, Kirk M

    2014-04-01

    Congenital obstructive nephropathy remains one of the leading causes of chronic renal failure in children. The direct link between obstructed urine flow and abnormal renal development and subsequent dysfunction represents a central paradigm of urogenital pathogenesis that has far-reaching clinical implications. Even so, a number of diagnostic, prognostic, and therapeutic quandaries still exist in the management of congenital obstructive nephropathy. Studies in our laboratory have characterized a unique mutant mouse line that develops in utero megabladder, variable hydronephrosis, and progressive renal failure. Megabladder mice represent a valuable functional model for the study of congenital obstructive nephropathy. Recent studies have begun to shed light on the genetic etiology of mgb (-/-) mice as well as the molecular pathways controlling disease progression in these animals.

  7. Successful treatment with cyclosporin administration for persistent benign migratory glossitis.

    PubMed

    Abe, Masatoshi; Sogabe, Yoko; Syuto, Tomoko; Ishibuchi, Hirohisa; Yokoyama, Yoko; Ishikawa, Osamu

    2007-05-01

    We herein describe a 54 year-old female patient with a 5-year history of persistent and painful benign migratory glossitis (BMG), which was remarkably improved by systemic administration of cyclosporin. She had noted some white patches leaving smooth denuded red areas with whitish elevated borders on the dorsum of her tongue, and finally felt strong pain. The lesion was refractory to the previous treatment with topical corticosteroid treatment for the last 2 years. Because clinicopathological findings were compatible with BMG, systemic administration of 20 mg/day prednisolone and topical 0.1% dexamethasone application were started, however, she suffered a severe relapse after tapering the dosage of prednisolone to 10 mg/day. Because some investigations have suggested that BMG is an oral manifestation of psoriasis, we introduced cyclosporin administration. The systemic treatment of cyclosporin microemulsion pre-concentrate, 3 mg/kg/day, resulted in a satisfactory improvement. Two months later, we could reduce cyclosporin microemulsion pre-concentrate dosage to 1.5 mg/kg/day for maintenance therapy, and the disease has been well controlled so far.

  8. 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.

  9. 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 §...

  10. 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 §...

  11. 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 §...

  12. 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 §...

  13. 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 §...

  14. Cyclosporin A inhibits DNA synthesis by epidermal Langerhans cells.

    PubMed

    Haftek, M; Urabe, A; Kanitakis, J; Dusserre, N; Thivolet, J

    Cyclosporin A, a potent immunosuppressive drug currently used in organ transplant recipients, has been shown to exert in vitro a direct antiproliferative effect on a number of cell types present in the skin, including keratinocytes, fibroblasts, and endothelial cells. Although in vitro studies suggest that cyclosporin A may interfere with the functional capacities of epidermal Langerhans cells, there is no evidence that the treatment influences the distribution or number of Langerhans cells in vivo. We used a model of normal human skin graft to "nude" mice, which is free of the human systemic control mechanisms, for studies on the DNA synthesis of human Langerhans cells under the influence of cyclosporin A. The grafted animals were given daily subcutaneous (50 mg/kg) or intraperitoneal (5, 12.5, and 25 mg/kg) drug injections during three weeks, which resulted in mean blood levels comparable to those observed in treated patients with organ transplants or psoriasis, respectively. BrdU administered during the last week of the experiment was incorporated by all cells synthesizing DNA, including those passing through S-phase. Langerhans cells were detected on deparaffinized or frozen tissue sections of xenografts with anti-CD1a and anti-HLA DR monoclonal antibodies, and the number of BrdU-positive cells was determined by double labeling. Our results indicate that the Langerhans cell DNA synthesis is impaired by therapeutic levels of cyclosporin A.

  15. Effect of hyperbaric oxygen on cyclosporine-induced nephrotoxicity and oxidative stress in rats.

    PubMed

    Ay, Hakan; Uzun, Gunalp; Onem, Yalcin; Aydinoz, Secil; Yildiz, Senol; Bilgi, Oguz; Topal, Turgut; Atasoyu, Enes Murat

    2007-01-01

    Reactive oxygen species have been suggested to be involved in cyclosporine nephrotoxicity. Hyperbaric oxygen is known to induce the generation of reactive oxygen species in tissues. The aim of this study was to investigate whether the use of hyperbaric oxygen concurrently with cyclosporine potentiates cyclosporine nephrotoxicity by inducing oxidative stress in kidneys. The study consisted of four groups of rats: a control group, a cyclosporine group (15 mg/kg/day intraperitoneally for 14 days), a hyperbaric oxygen group (60 min. every day for five days at 2.5 atmosphere absolute), and a cyclosporine + hyperbaric oxygen group (cyclosporine 15 mg/kg/day intraperitoneally for 14 days + hyperbaric oxygen for 60 min at 2.5 atmosphere absolute every day for five days on the last five days of cyclosporine treatment). Oxidative stress was determined by measuring renal thiobarbituric acid-reactive substances content, renal superoxide dismutase, and glutathione peroxidase activities. Cyclosporine increased serum urea and creatinine levels, indicating the development of nephrotoxicity, and induced significant oxidative stress in rat kidneys. Hyperbaric oxygen alone did not alter any of the biochemical and oxidative stress parameters compared to the control group. When used concurrently with cyclosporine, hyperbaric oxygen significantly reduced cyclosporine-induced oxidative stress, but it neither attenuated nor aggravated cyclosporine-induced nephrotoxicity. These results suggest that reactive oxygen species are involved in cyclosporine nephrotoxicity, but are not the direct cause of the toxicity. Although concurrent use of cyclosporine and hyperbaric oxygen did not exacerbate cyclosporine nephrotoxicity in this model, we recommend that the renal functions of patients be monitored periodically when these treatments are used concurrently.

  16. 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.

  17. IgA nephropathy in a tertiary care center from south India.

    PubMed

    Siddappa, S; Kowsalya, R; Mythri, K M

    2011-10-01

    IgA nephropathy is being recognized as the commonest glomerular disease worldwide. The prevalence and clinical picture varies from region to region. A retrospective analysis of 400 native renal biopsies performed over a period of 3 years at our center was done to know the prevalence and clinicopathological profile of patients with IgA nephropathy. All the biopsies were processed for both light microscopy and immunofluorescence studies. Patients with predominant IgA deposits were labeled as IgA nephropathy and further classified histopathologically into five subclasses according to the Haas classification. We noted a prevalence of 7.8% (31 cases) of IgA nephropathy. Nephrotic syndrome and chronic renal failure were the most common mode of presentation. Majority of cases fell into subclass III (focal segmental glomerular sclerosis) with 35.5% followed by subclasses IV (diffuse proliferative glomerular sclerosis) and V (global sclerosis) with 25.8% and 22.6% prevalence, respectively. As about 50% cases presented with varying degree of renal insufficiency, many ending with ESRD, IgA nephropathy can be considered as a serious problem in India.

  18. Has RAAS Blockade Reached Its Limits in the Treatment of Diabetic Nephropathy?

    PubMed

    Majewski, Collen; Bakris, George L

    2016-04-01

    Medications that block the renin-angiotensin-aldosterone system (RAAS) are a cornerstone of diabetic nephropathy treatment. These agents play an important role in slowing the nephropathy progression in patients with diabetes. Clinical outcome trials that investigated use of these drug classes in patients with diabetic nephropathy have demonstrated clinical significant benefit in slowing nephropathy progression only in people with >300 mg/day of proteinuria. Thus, guidelines mandate their use in such patients. Conversely, combinations of RAAS blocking agents in these patients can worsen renal outcomes. Moreover, use of RAAS blockers in patients with a glomerular filtration rate below 45 mL/min/1.73 m(2) is limited by hyperkalemia. New agents that predictably bind excess potassium in the colon offer the possibility of extending RAAS inhibitor use in advanced chronic kidney disease (CKD) to allow evaluation of RAAS blockade for nephropathy and cardiovascular outcomes. These new potassium-binding agents may provide an opportunity to continue full-dose RAAS inhibition and assess if the benefits of RAAS blockade seen in stage 3 CKD can be extrapolated to persons with stages 4 and 5 CKD, not previously tested due to hyperkalemia.

  19. Association of genetic variants with diabetic nephropathy.

    PubMed

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

    2014-12-15

    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.

  20. 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

  1. Nodular lesions and mesangiolysis in diabetic nephropathy.

    PubMed

    Wada, Takashi; Shimizu, Miho; Yokoyama, Hitoshi; Iwata, Yasunori; Sakai, Yoshio; Kaneko, Shuichi; Furuichi, Kengo

    2013-02-01

    Diabetic nephropathy is a leading cause of end-stage renal failure all over the world. Advanced human diabetic nephropathy is characterized by the presence of specific lesions including nodular lesions, doughnut lesions, and exudative lesions. Thus far, animal models precisely mimicking advanced human diabetic nephropathy, especially nodular lesions, remain to be fully established. Animal models with spontaneous diabetic kidney diseases or with inducible kidney lesions may be useful for investigating the pathogenesis of diabetic nephropathy. Based on pathological features, we previously reported that diabetic glomerular nodular-like lesions were formed during the reconstruction process of mesangiolysis. Recently, we established nodular-like lesions resembling those seen in advanced human diabetic nephropathy through vascular endothelial injury and mesangiolysis by administration of monocrotaline. Here, in this review, we discuss diabetic nodular lesions and its animal models resembling human diabetic kidney lesions, with our hypothesis that endothelial cell injury and mesangiolysis might be required for nodular lesions.

  2. Genetic association studies in diabetic nephropathy.

    PubMed

    Gu, Harvest F; Brismar, Kerstin

    2012-09-01

    Clinical observations and epidemiological studies have shown that there is familial aggregation of diabetic nephropathy in many ethnic groups, indicating the strong contribution of inherited factors in the development of diabetic nephropathy. Identification of the genes involved in the pathogenesis of diabetic nephropathy may provide better knowledge of its pathophysiology and future therapies. To search for the genes involved in susceptibility, resistance or progression to diabetic nephropathy, candidate gene population association, family-based association and genome wide association studies have been widely used. This article reviews genetic polymorphisms, summarizes the data from genetic association studies of diabetic nephropathy in both type 1 and type 2 diabetes, and discusses about the future genetic analyses in the complex diseases.

  3. 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

  4. Oxalate nephropathy due to 'juicing': case report and review.

    PubMed

    Getting, Jane E; Gregoire, James R; Phul, Ashley; Kasten, Mary J

    2013-09-01

    A patient presented with oxalate-induced acute renal failure that was attributable to consumption of oxalate-rich fruit and vegetable juices obtained from juicing. We describe the case and also review the clinical presentation of 65 patients seen at Mayo Clinic (Rochester, MN) from 1985 through 2010 with renal failure and biopsy-proven renal calcium oxalate crystals. The cause of renal oxalosis was identified for all patients: a single cause for 36 patients and at least 2 causes for 29 patients. Three patients, including our index patient, had presumed diet-induced oxalate nephropathy in the context of chronic kidney disease. Identification of calcium oxalate crystals in a kidney biopsy should prompt an evaluation for causes of renal oxalosis, including a detailed dietary history. Clinicians should be aware that an oxalate-rich diet may potentially precipitate acute renal failure in patients with chronic kidney disease. Juicing followed by heavy consumption of oxalate-rich juices appears to be a potential cause of oxalate nephropathy and acute renal failure.

  5. Apoptosis modulated by oxidative stress and inflammation during obstructive nephropathy.

    PubMed

    Manucha, Walter; Vallés, Patricia G

    2012-08-01

    Kidney apoptosis and fibrosis are an inevitable outcome of progressive chronic kidney diseases where congenital obstructive nephropathy is the primary cause of the end-stage renal disease in children, and is also a major cause of renal failure in adults. The injured tubular cells linked to interstitial macrophages, and myofibroblasts produce cytokines and growth factors that promote an inflammatory state in the kidney, induce tubular cell apoptosis, and facilitate the accumulation of extracellular matrix. Angiotensin II plays a central role in the renal fibrogenesis at a very early stage leading to a rapid progression in chronic kidney disease. The increasing levels of angiotensin II induce pro-inflammatory cytokines, NF-κB activation, adhesion molecules, chemokines, growth factors, and oxidative stress. Furthermore, growing evidence reports that angiotensin II (a pro-inflammatory hormone) increases the mitochondrial oxidative stress regulating apoptosis induction. This review summarizes our understanding about possible mechanisms that contribute to apoptosis modulated by inflammation and/or oxidative stress during obstructive nephropathy. The new concept of antiinflammatory tools regulating mitochondrial oxidative stress will directly affect the inflammatory process and apoptosis. This idea could have attractive consequences in the treatment of renal and other inflammatory pathologies.

  6. The role of non-coding RNAs in diabetic nephropathy: potential applications as biomarkers for disease development and progression.

    PubMed

    Alvarez, M Lucrecia; Distefano, Johanna K

    2013-01-01

    Diabetic nephropathy, a progressive kidney disease that develops secondary to diabetes, is the major cause of chronic kidney disease in developed countries, and contributes significantly to increased morbidity and mortality among individuals with diabetes. Although the causes of diabetic nephropathy are not fully understood, recent studies demonstrate a role for epigenetic factors in the development of the disease. For example, non-coding RNA (ncRNA) molecules, including microRNAs (miRNAs), have been shown to be functionally important in modulating renal response to hyperglycemia and progression of diabetic nephropathy. Characterization of miRNA expression in diabetic nephropathy from studies of animal models of diabetes, and in vitro investigations using different types of kidney cells also support this role. The goal of this review, therefore, is to summarize the current state of knowledge of specific ncRNAs involved in the development of diabetic nephropathy, with a focus on the potential role of miRNAs to serve as sensitive, non-invasive biomarkers of kidney disease and progression. Non-coding RNAs are currently recognized as potentially important regulators of genes involved in processes related to the development of diabetic nephropathy, and as such, represent viable targets for both clinical diagnostic strategies and therapeutic intervention.

  7. Membranous nephropathy PLA2R+ associated with Chagas disease

    PubMed Central

    Silva, Vanessa dos Santos; Viero, Rosa Marlene

    2015-01-01

    Chagas disease (CD) — a tropical parasitic disease caused by the protozoan Trypanosoma cruzi — is a major health problem in Latin America. The immune response against the parasite is responsible for chronic CD lesions. Currently, there are no reports of an association between CD and membranous nephropathy (MN). The detection of the phospholipase A2 receptor (PLA2R) as a target antigen in idiopathic MN can improve the differential diagnosis of primary and secondary forms of MN. The authors report the case of a male patient with positive serology for CD who presented sudden death and underwent autopsy. Histological sections of the heart showed multifocal inflammatory infiltrate composed mainly of mononuclear cells, leading to myocardiocytes necrosis and interstitial fibrosis. The kidneys showed a MN with positive expression for PLA2R. As far as we know, this is the first report of a case of primary MN in a patient with CD, with severe chronic cardiomyopathy and heart failure. PMID:26558244

  8. 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

  9. [Pyoderma gangrenosum--positive effect of cyclosporin A therapy ].

    PubMed

    Krauze, Ewa; Lis, Anna; Kamińska-Budzińska, Grazyna; Wygledowska-Kania, Mariola; Pierzchała, Ewa; Brzezińska-Wcisło, Ligia

    2002-10-01

    Although pyoderma gangrenosum is a disorder known since over 70 years, it still remains a diagnostic and therapeutic problem. We describe three subjects with pyoderma gangrenosum; two were females, one was male, one case was associated with colitis ulcerosa, two were without any related disorders. Histopathologic examinations supported the diagnosis in all cases. In spite of intensive topical and systemic treatment with corticosteroids, Dapsone, Clofazimine, no sufficient effects were achieved. Cyclosporin A introduced in the dose of 5 mg/kg/d resulted in dramatic response and complete remission. Serum CyA levels, biochemical parameters of liver and kidney function, blood pressure were monitored during the therapy. No adverse events due to Cyclosporin A were observed.

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

    PubMed Central

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

    2016-01-01

    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

  11. 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.

  12. 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

  13. Multiple Eruptive Sebaceous Hyperplasia Secondary to Cyclosporin in a Patient with Bone Marrow Transplantation

    PubMed Central

    Cortés, Begonia; Kaya, Gürkan

    2016-01-01

    Many cutaneous complications have been described in patients treated with cyclosporin. Alterations of the pilosebaceous unit such as hypertrichosis are particularly frequent. However, the occurrence of sebaceous hyperplasia is exceptional. These lesions seem to be specific to cyclosporin rather than secondary to immunosuppression. Here, we report an exceptional case of eruptive and disseminated sebaceous hyperplasia arising in a bone marrow transplant recipient only a few months after starting immunosuppressive treatment with cyclosporin. PMID:27990417

  14. 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

  15. Chitosan functionalized nanocochleates for enhanced oral absorption of cyclosporine A

    PubMed Central

    Liu, Min; Zhong, Xiaoming; Yang, Zhiwen

    2017-01-01

    It remains a significant challenge to overcome the poor permeability of cyclosporine A and enhance its oral absorption. In this study, we have identified a positively charged chitosan that is able to induce coiling up of anionic lipids to form nanocochleates with an average size of 114.2 ± 0.8 nm, without the need for calcium ions. These functional chitosan-induced nanocochleates enhanced gastrointestinal absorption of cyclosporine A, up to a 3-fold increase in oral bioavailability. A fluorescence-labeling study confirmed that absorption mainly occurred in the duodenum and jejunum. Transport studies indicated that uptake of chitosan-induced nanocochleates by Caco-2 cells was by clathrin- and caveolae-mediated endocytosis, but not by macropinocytosis. Furthermore, three cellular tight junction proteins, ZO-1, F-actin and claudin-4, were significantly down-regulated, suggesting that chitobiose-induced nanocochleates are able to reconstruct and open tight junctions in intestinal epithelial cells to enhance drug absorption. In summary, these novel bifunctional chitosan-induced nanocochleates appear to have potential to facilitate oral delivery of cyclosporine A. PMID:28112262

  16. [Hierba del clavo (Geum chiloense) modifying cyclosporine levels: potential risk for transplanted people].

    PubMed

    Duclos, J; Goecke, H

    2001-07-01

    We report a 54 years old male that received a renal allograft without complications. One year after the transplantation, she was receiving cyclosporine doses of 2 to 3 mg/kg and maintained serum levels of 60 to 90 mg/dl. An abrupt increase in cyclosporine serum levels to 469 and 600 mg/dl was noted after 15 months of transplantation. After a careful interrogation the patient admitted the use of Geum chiloense ("hierba del clavo"). Discontinuing this herbal remedy, cyclosporine levels decreased to 55 mg/dl, despite the maintenance of the same cyclosporine dose. The potential side effects of herbal remedies must be borne in mind.

  17. Safe conversion from cyclosporine to azathioprine with improved renal function in pediatric renal transplantation.

    PubMed

    Kaiser, B A; Lawless, S T; Palmer, J M; Dunn, S P; Polinsky, M S; Baluarte, H J

    1989-10-01

    Although cyclosporine has improved allograft survival in renal transplant patients, problems with drug toxicity remain, raising the question whether cyclosporine should be stopped at some point post-transplant. However, the relative safety of converting from cyclosporine to another immunosuppressive agent, or simply stopping cyclosporine remains an issue of debate and has not been evaluated in children. We have developed a protocol to convert children, who are 6 months post-transplant and have stable kidney function, from cyclosporine and prednisone to azathioprine and prednisone. Eleven children have undergone conversion because of suspected/potential nephrotoxicity or because of other difficulties with cyclosporine (expense, hirsutism). These children were compared with a control group of 12 children who met all criteria for conversion at 6 months but remained on cyclosporine. Allograft survival was similar in both groups but the children converted from cyclosporine experienced an improvement in renal function as measured by calculated creatinine clearance. There were no episodes of rejection for a period of 4 months post-conversion and all rejection episodes that developed subsequently occurred during or after the change from daily to alternate-day prednisone. We believe that conversion from cyclosporine to azathioprine can be accomplished safely in children with stable allograft function but long-term risks and benefits need further evaluation.

  18. Clinical impact of albuminuria in diabetic nephropathy.

    PubMed

    Wada, Takashi; Shimizu, Miho; Toyama, Tadashi; Hara, Akinori; Kaneko, Shuichi; Furuichi, Kengo

    2012-02-01

    Patients suffering from diabetic nephropathy, resulting in end-stage renal failure, are increasing in number. The pathophysiology of diabetic nephropathy remains to be fully investigated. In the clinical setting, the presence of albuminuria/overt proteinuria and a low glomerular filtration rate may predict poor renal prognosis, but the prognosis of the normoalbuminuric renally insufficient diabetic patient remains controversial. In addition to the measurement of urinary albumin excretion, biomarker studies to detect diabetic nephropathy more specifically at the early stage have been performed worldwide. There is a growing body of evidence for remission and/or regression of diabetic nephropathy, which may be an indicator for cardiovascular and renal risk reduction. Deeper insights into the pathological characteristics as well as the clinical impact of albuminuria on renal and cardiovascular outcome are required.

  19. Amadori albumin in diabetic nephropathy

    PubMed Central

    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

  20. Antiphospholipid syndrome nephropathy in systemic lupus erythematosus.

    PubMed

    Daugas, Eric; Nochy, Dominique; Huong, Du Le Thi; Duhaut, Pierre; Beaufils, Hélène; Caudwell, Valérie; Bariety, Jean; Piette, Jean-Charles; Hill, Gary

    2002-01-01

    In the course of the antiphospholipid syndrome (APS), the existence of vaso-occlusive lesions capable of affecting numerous organs is now well established. The renal involvement attributable to primary APS, APS nephropathy (APSN), corresponds to vaso-occlusive lesions of the intrarenal vessels, associating side-by-side, acute thromboses with chronic arterial and arteriolar lesions, leading to zones of cortical ischemic atrophy. A retrospective study of 114 lupus patients undergoing renal biopsy was undertaken to determine the following: (1) if APSN can be found in the course of systemic lupus erythematosus (SLE); (2) if certain clinical and biologic factors can permit the prediction of the presence of APSN; and (3) if APSN is a superadded renal morbidity factor in lupus patients. This study shows the following: (1) APSN occurs in SLE (32% of patients with renal biopsies) in addition to, and independently of, lupus nephritis; (2) APSN is statistically associated with lupus anticoagulant but not with anticardiolipin antibodies; (3) APSN is associated with extrarenal APS, mainly arterial thromboses and obstetrical fetal loss, but not with the venous thromboses of APS; (4) APSN is an independent risk factor, over and above lupus nephritis, that contributes to an elevated prevalence of hypertension, elevated serum creatinine, and increased interstitial fibrosis. Thus, it seems likely that, because of its associations with hypertension, elevated serum creatinine, and increased interstitial fibrosis, APSN may worsen the prognosis in these patients. APSN may also have therapeutic significance in that its recognition should permit a better balance between immunosuppressor and antithrombotic and/or vasoprotective therapy. Finally, this study suggests that APSN should be considered as an element to be included in the classification criteria of APS.

  1. The continuing medical mystery of Balkan Endemic Nephropathy

    USGS Publications Warehouse

    Crosby, Lynn M.; Tatu, Calin A.; Orem, William H.; Pavlovic MD PhD, Nikola

    2015-01-01

    Balkan Endemic Nephropathy (BEN) is a disease of subtle onset and insidious progression that typically occurs between the 4th and 6th decade in long‐resident individuals in highly specific geographic locations of the Balkan region and affects 1 – 5% of the population. Though it does not follow typical Mendelian genetics, there is a familial pattern of occurrence. Although residents may live only a few kilometers apart, certain locations are highly affected while others close by, even as close as across the road, remain unscathed. Because of this geographic selectivity scientists have searched for an environmental cause. It is thought that exposure to the toxic plant Aristolochia clematitis is to blame. Genotoxic N‐heterocyclic or polycyclic aromatic containing coal water leachates entering cultivated soil and drinking water are also a possible cause due to the proximity and predictive power of endemic foci to coal deposits. Evidence for Ochratoxin A fungal poisoning also exists. High levels of phthalates have been measured in BEN‐endemic drinking water. BEN is a probably a multifactorial disease that may result from exposure through some of above‐mentioned environmental sources, with genetic factors contributing. This review will discuss recent research concerning the etiology, potential therapies for the treatment of nephropathy, and unexplored research directions for this chronic kidney disease.

  2. Effects of exogenous desmopressin on a model of heat stress nephropathy in mice.

    PubMed

    Roncal-Jimenez, Carlos A; Milagres, Tamara; Andres-Hernando, Ana; Kuwabara, Masanari; Jensen, Thomas; Song, Zhilin; Bjornstad, Petter; Garcia, Gabriela E; Sato, Yuka; Sanchez-Lozada, Laura G; Lanaspa, Miguel A; Johnson, Richard J

    2017-03-01

    Recurrent heat stress and dehydration have recently been shown experimentally to cause chronic kidney disease (CKD). One potential mediator may be vasopressin, acting via the type 2 vasopressin receptor (V2 receptor). We tested the hypothesis that desmopressin accelerates CKD in mice subjected to heat stress and recurrent dehydration. Recurrent exposure to heat with limited water availability was performed in male mice over a 5-wk period, with one group receiving desmopressin two times daily and the other group receiving vehicle. Two additional control groups were not exposed to heat or dehydration and received vehicle or desmopressin. The effects of the treatment on renal injury were assessed. Heat stress and recurrent dehydration induced functional changes (albuminuria, elevated urinary neutrophil gelatinase-associated protein), glomerular changes (mesangiolysis, matrix expansion), and tubulointerstitial changes (fibrosis, inflammation). Desmopressin also induced albuminuria, glomerular changes, and tubulointerstitial fibrosis in normal animals and also exacerbated injury in mice with heat stress nephropathy. Both heat stress and/or desmopressin were also associated with activation of the polyol pathway in the renal cortex, likely due to increased interstitial osmolarity. Our studies document both glomerular and tubulointerstitial injury and inflammation in heat stress nephropathy and may be clinically relevant to the pathogenesis of Mesoamerican nephropathy. Our data also suggest that vasopressin may play a role in the pathogenesis of the renal injury of heat stress nephropathy, likely via a V2 receptor-dependent pathway.

  3. Interleukin-20 targets podocytes and is upregulated in experimental murine diabetic nephropathy

    PubMed Central

    Hsu, Yu-Hsiang; Li, Hsing-Hui; Sung, Junne-Ming; Chen, Wei-Yu; Hou, Ya-Chin; Weng, Yun-Han; Lai, Wei-Ting; Wu, Chih-Hsing; Chang, Ming-Shi

    2017-01-01

    Interleukin (IL)-20, a proinflammatory cytokine of the IL-10 family, is involved in acute and chronic renal failure. The aim of this study was to elucidate the role of IL-20 during diabetic nephropathy development. We found that IL-20 and its receptor IL-20R1 were upregulated in the kidneys of mice and rats with STZ-induced diabetes. In vitro, IL-20 induced MMP-9, MCP-1, TGF-β1 and VEGF expression in podocytes. IL-20 was upregulated by hydrogen peroxide, high-dose glucose and TGF-β1. In addition, IL-20 induced apoptosis in podocytes by activating caspase-8. In STZ-induced early diabetic nephropathy, IL-20R1-deficient mice had lower blood glucose and serum BUN levels and a smaller glomerular area than did wild-type controls. Anti-IL-20 monoclonal antibody (7E) treatment reduced blood glucose and the glomerular area and improved renal functions in mice in the early stage of STZ-induced diabetic nephropathy. ELISA showed that the serum IL-20 level was higher in patients with diabetes mellitus than in healthy controls. The findings of this study suggest that IL-20 induces cell apoptosis of podocytes and plays a role in the pathogenesis of early diabetic nephropathy. PMID:28360429

  4. Genetics of diabetic nephropathy: a long road of discovery.

    PubMed

    McKnight, Amy Jayne; Duffy, Seamus; Maxwell, Alexander P

    2015-07-01

    The global prevalence of diabetic nephropathy is rising in parallel with the increasing incidence of diabetes in most countries. Unfortunately, up to 40 % of persons diagnosed with diabetes may develop kidney complications. Diabetic nephropathy is associated with substantially increased risks of cardiovascular disease and premature mortality. An inherited susceptibility to diabetic nephropathy exists, and progress is being made unravelling the genetic basis for nephropathy thanks to international research collaborations, shared biological resources and new analytical approaches. Multiple epidemiological studies have highlighted the clinical heterogeneity of nephropathy and the need for better phenotyping to help define important subgroups for analysis and increase the power of genetic studies. Collaborative genome-wide association studies for nephropathy have reported unique genes, highlighted novel biological pathways and suggested new disease mechanisms, but progress towards clinically relevant risk prediction models for diabetic nephropathy has been slow. This review summarises the current status, recent developments and ongoing challenges elucidating the genetics of diabetic nephropathy.

  5. Cutaneous malignant melanomas occurring under cyclosporin A therapy: a report of two cases.

    PubMed

    Mérot, Y; Miescher, P A; Balsiger, F; Magnenat, P; Frenk, E

    1990-08-01

    Two patients are reported with cutaneous malignant melanoma who had been on treatment with cyclosporin A. The first case was a 44-year-old man with systemic sclerosis and the second a 52-year-old woman who had a renal transplant. In both cases cyclosporin A was administered with a low dose of prednisone.

  6. Kimura's disease: case report of an Italian young male and response to oral cyclosporine A in an 8 years follow-up.

    PubMed

    Beccastrini, Enrico; Emmi, Giacomo; Chiodi, Michela; Di Paolo, Camilla; Benedetta Silvestri, Elena; Massi, Daniela; Maggi, Enrico; Liotta, Francesco; Emmi, Lorenzo

    2013-03-01

    Kimura's disease is a benign chronic inflammatory disease, common in Asian males and rare in Western people. Clinically, Kimura's disease is characterized by subcutaneous nodular lesions, usually localised in head and neck, often associated with regional lymphadenopathy. Peripheral blood eosinophilia and elevated serum IgE are often observed. We report a case of a 40-year-old Italian patient presenting with nodular subcutaneous lesions and peripheral eosinophilia. Based on clinical, histopathological and laboratory findings, a diagnosis of Kimura's disease was made. The patient was treated with very low doses of cyclosporine A with no evidence of disease recurrence over the following 8 years. However, the discontinuation of cyclosporine A determined a relapse of the disease. The relevance of this case is due to the rarity of the disease in Italy, to its peculiar clinical presentation and, moreover, it is the first case in literature that has a good response to treatment with low doses of cyclosporine A, documented in an 8-year follow-up.

  7. Edoxaban drug–drug interactions with ketoconazole, erythromycin, and cyclosporine

    PubMed Central

    Parasrampuria, Dolly A.; Mendell, Jeanne; Shi, Minggao; Matsushima, Nobuko; Zahir, Hamim

    2016-01-01

    Aims Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P‐glycoprotein (P‐gp). Three edoxaban drug–drug interaction studies examined the effects of P‐gp inhibitors with varying degrees of CYP3A4 inhibition. Methods In each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P‐gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study. Results Coadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half‐life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9‐fold and peak exposure by 8.7‐fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed. Conclusions Administration of dual inhibitors of P‐gp and CYP3A4 increased edoxaban exposure by less than two‐fold. This effect appears to be primarily due to inhibition of P‐gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects. PMID:27530188

  8. A resistant case of pemphigus gestationis successfully treated with cyclosporine

    PubMed Central

    Özdemir, Özhan; Atalay, Cemal Resat; Asgarova, Vusala; Ilgin, Bunyamin Ugur

    2016-01-01

    Pemphigoid gestationis (PG) is a rare autoimmune blistering disease of pregnancy caused by antibasement membrane zone auto-antibodies. The usual clinical findings are multiple pruritic urticarial papules and plaques, target lesions, vesicles, and blisters that occur during the second and third trimesters of pregnancy or in the immediate postpartum period. The disease is often treated with topical corticosteroids and oral antihistaminics. In more severe cases, systemic corticosteroids are needed. Herein, we report a case of resistant PG that responded to treatment with cyclosporine. PMID:28250977

  9. Enhancement of the oral absorption of cyclosporin in man.

    PubMed Central

    Drewe, J; Meier, R; Vonderscher, J; Kiss, D; Posanski, U; Kissel, T; Gyr, K

    1992-01-01

    1. The oral absorption of cyclosporin from three new semi-solid oral formulations was compared with the standard soft gelatine preparation in twelve healthy male volunteers. One formulation was based on a solid micellar solution, while the other two, with different in vitro release properties, were based on a microemulsion principle. 2. The results showed that the solid micellar solution and the faster releasing microemulsion formulation increased the extent of absorption on average by 45.2 and 49.0%, respectively, compared with the reference soft gelatine capsule. PMID:1633069

  10. 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

  11. Dosing and safety of cyclosporine in patients with severe brain injury

    PubMed Central

    Hatton, Jimmi; Rosbolt, Bonnie; Empey, Philip; Kryscio, Richard; Young, Byron

    2009-01-01

    Object Cyclosporine neuroprotection has been reported in brain injury models but safety and dosing guidelines have not been determined in humans with severe traumatic brain injury (TBI). The purpose of this investigation was to establish the safety of cyclosporine using 4 clinically relevant dosing schemes. Methods The authors performed a prospective, blinded, placebo-controlled, randomized, dose-escalation trial of cyclosporine administration initiated within 8 hours of TBI (Glasgow Coma Scale score range 4–8; motor score range 2–5). Four dosing cohorts (8 patients treated with cyclosporine and 2 receiving placebo treatment per cohort) received cyclosporine (1.25–5 mg/kg/day) or placebo in 2 divided doses (Cohorts I–III) or continuous infusion (Cohort IV) over 72 hours. Adverse events and outcome were monitored for 6 months. Results Forty patients were enrolled over 3 years (cyclosporine cohorts, 24 male and 8 female patients; placebo group, 8 male patients). Systemic trough concentrations were below 250 ng/ml during intermittent doses. Higher blood concentrations were observed in Cohorts III and IV. There was no significant difference in immunological effects, adverse events, infection, renal dysfunction, or seizures. Mortality rate was not affected by cyclosporine administration, independent of dose, compared with placebo (6 of 32 patients receiving cyclosporine and 2 of 8 receiving placebo died, p > 0.05). At 6 months, a dose-related improvement in favorable outcome was observed in cyclosporine-treated patients (p < 0.05). Conclusions In patients with acute TBI who received cyclosporine at doses up to 5 mg/kg/day, administered intravenously, with treatment initiated within 8 hours of injury, the rate of mortality or other adverse events was not significantly different from that of the placebo group. PMID:18826358

  12. The effect of food and bile acid administration on the relative bioavailability of cyclosporin.

    PubMed Central

    Lindholm, A; Henricsson, S; Dahlqvist, R

    1990-01-01

    1. The relative bioavailability of cyclosporin was studied in 11 healthy volunteers after single oral capsule doses of cyclosporin on three separate occasions; fasting, with breakfast and with breakfast together with bile acid tablets (400 mg of cholic acid and 100 mg of dehydrocholic acid). 2. There was a significant increase in the area under the blood concentration vs time curve (AUC) of cyclosporin when the drug was taken together with breakfast and bile acid tablets (9078 ng ml-1 h) as compared with breakfast alone (7453 ng ml-1 h, P less than 0.05) or fasting conditions (7283 ng ml-1 h, P less than 0.01). 3. A blood drug concentration vs time curve displaying two peaks was present in 9/11 subjects when cyclosporin was taken with breakfast or with breakfast and bile acid tablets, but only one peak was present when cyclosporin was taken during fasting, suggesting an enterohepatic circulation of cyclosporin or a second absorption phase after the meal. 4. In a separate study, 12 h trough blood cyclosporin concentrations were measured before and after 1 week of bile acid treatment in 19 clinically stable, out-patient transplant recipients who were treated with oral cyclosporin solution (mean dose 2.0 mg kg-1 twice daily). The administration of cyclosporin was not standardized with regard to food intake. There was no significant difference in the blood concentrations of cyclosporin before and after bile acid treatment (114 +/- 38 ng ml-1 vs 121 +/- 38 ng ml-1).(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2350530

  13. The Role of MicroRNAs in Diabetic Nephropathy

    PubMed Central

    Kong, Lili; Cui, Wenpeng; Li, Xiangqi; Tan, Yi; Miao, Lining

    2014-01-01

    Diabetic nephropathy (DN), as one of the chronic complications of diabetes, is the major cause of end-stage renal disease. However, the pathogenesis of this disease is not fully understood. In recent years, research on microRNAs (miRNAs) has become a hotspot because of their critical role in regulating posttranscriptional levels of protein-coding genes that may serve as key pathogenic factors in diseases. Several miRNAs were found to participate in the pathogenesis of DN, while others showed renal protective effects. Therefore, targeting miRNAs that are involved in DN may have a good prospect in the treatment of the disease. The aim of this review is to summarize DN-related miRNAs and provide potential targets for diagnostic strategies and therapeutic intervention. PMID:25258717

  14. Enhancement of physicochemical properties of nanocolloidal carrier loaded with cyclosporine for topical treatment of psoriasis: in vitro diffusion and in vivo hydrating action

    PubMed Central

    Musa, Siti Hajar; Basri, Mahiran; Fard Masoumi, Hamid Reza; Shamsudin, Norashikin; Salim, Norazlinaliza

    2017-01-01

    Psoriasis is a chronic autoimmune disease that cannot be cured. It can however be controlled by various forms of treatment, including topical, systemic agents, and phototherapy. Topical treatment is the first-line treatment and favored by most physicians, as this form of therapy has more patient compliance. Introducing a nanoemulsion for transporting cyclosporine as an anti-inflammatory drug to an itchy site of skin disease would enhance the effectiveness of topical treatment for psoriasis. The addition of nutmeg and virgin coconut-oil mixture, with their unique properties, could improve cyclosporine loading and solubility. A high-shear homogenizer was used in formulating a cyclosporine-loaded nanoemulsion. A D-optimal mixture experimental design was used in the optimization of nanoemulsion compositions, in order to understand the relationships behind the effect of independent variables (oil, surfactant, xanthan gum, and water content) on physicochemical response (particle size and polydispersity index) and rheological response (viscosity and k-value). Investigation of these variables suggests two optimized formulations with specific oil (15% and 20%), surfactant (15%), xanthan gum (0.75%), and water content (67.55% and 62.55%), which possessed intended responses and good stability against separation over 3 months’ storage at different temperatures. Optimized nanoemulsions of pH 4.5 were further studied with all types of stability analysis: physical stability, coalescence-rate analysis, Ostwald ripening, and freeze–thaw cycles. In vitro release proved the efficacy of nanosize emulsions in carrying cyclosporine across rat skin and a synthetic membrane that best fit the Korsmeyer–Peppas kinetic model. In vivo skin analysis towards healthy volunteers showed a significant improvement in the stratum corneum in skin hydration.

  15. Scoring system for renal pathology in Fabry disease: report of the International Study Group of Fabry Nephropathy (ISGFN)

    PubMed Central

    Fogo, Agnes B.; Bostad, Leif; Svarstad, Einar; Cook, William J.; Moll, Solange; Barbey, Federic; Geldenhuys, Laurette; West, Michael; Ferluga, Dusan; Vujkovac, Bojan; Howie, Alexander J.; Burns, Áine; Reeve, Roy; Waldek, Stephen; Noël, Laure-Hélène; Grünfeld, Jean-Pierre; Valbuena, Carmen; Oliveira, João Paulo; Müller, Justus; Breunig, Frank; Zhang, Xiao; Warnock, David G.

    2010-01-01

    Background. In Fabry nephropathy, alpha-galactosidase deficiency leads to accumulation of glycosphingolipids in all kidney cell types, proteinuria and progressive loss of kidney function. Methods. An international working group of nephrologists from 11 Fabry centres identified adult Fabry patients, and pathologists scored histologic changes on renal biopsies. A standardized scoring system was developed with a modified Delphi technique assessing 59 Fabry nephropathy cases. Each case was scored independently of clinical information by at least three pathologists with an average final score reported. Results. We assessed 35 males (mean age 36.4 years) and 24 females (43.9 years) who mostly had clinically mild Fabry nephropathy. The average serum creatinine was 1.3 mg/dl (114.9 μmol/l); estimated glomerular filtration rate was 81.7 ml/min/1.73 m2 and urine protein to creatinine ratio was 1.08 g/g (122.0 mg/mmol). Males had greater podocyte vacuolization on light microscopy (mean score) and glycosphingolipid inclusions on semi-thin sections than females. Males also had significantly more proximal tubule, peritubular capillary and vascular intimal inclusions. Arteriolar hyalinosis was similar, but females had significantly more arterial hyalinosis. Chronic kidney disease stage correlated with arterial and glomerular sclerosis scores. Significant changes, including segmental and global sclerosis, and interstitial fibrosis were seen even in patients with stage 1–2 chronic kidney disease with minimal proteinuria. Conclusions. The development of a standardized scoring system of both disease-specific lesions, i.e. lipid deposition related, and general lesions of progression, i.e. fibrosis and sclerosis, showed a spectrum of histologic appearances even in early clinical stage of Fabry nephropathy. These findings support the role of kidney biopsy in the baseline evaluation of Fabry nephropathy, even with mild clinical disease. The scoring system will be useful for

  16. Low-protein diet for diabetic nephropathy.

    PubMed

    Otoda, Toshiki; Kanasaki, Keizo; Koya, Daisuke

    2014-01-01

    Diabetic nephropathy is the leading cause of progressive kidney disease, leading to end-stage renal disease and renal replacement therapy. Angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers have been considered effective at slowing the progression of kidney function deterioration. However, these drugs cannot sufficiently halt the progression of nephropathy to the extent that is required. A low-protein diet (LPD) is believed to be a nutritional intervention that may slow kidney disease progression. In fact, preclinical animal experiments have demonstrated excellent renoprotective effects of an LPD. However, in human clinical trials, analyses of the effects of protein restriction on diabetic nephropathy have not yet revealed consistently positive outcomes of this nutritional intervention. In this review, we analyze the potential renoprotective effects of an LPD on diabetic nephropathy and summarize the outcomes of clinical trials that have systematically investigated the efficacy of an LPD in diabetic nephropathy. In addition, we discuss some potential approaches associated with nutritional interventions to combat progressive kidney disease.

  17. Pharmacological inhibition of galectin-3 protects against hypertensive nephropathy.

    PubMed

    Frenay, Anne-Roos S; Yu, Lili; van der Velde, A Rogier; Vreeswijk-Baudoin, Inge; López-Andrés, Natalia; van Goor, Harry; Silljé, Herman H; Ruifrok, Willem P; de Boer, Rudolf A

    2015-03-01

    Galectin-3 activation is involved in the pathogenesis of renal damage and fibrogenesis. Limited data are available to suggest that galectin-3-targeted intervention is a potential therapeutic candidate for the prevention of chronic kidney disease. Homozygous TGR(mREN)27 (REN2) rats develop severe high blood pressure (BP) and hypertensive end-organ damage, including nephropathy and heart failure. Male REN2 rats were treated with N-acetyllactosamine [galectin-3 inhibitor (Gal3i)] for 6 wk; untreated REN2 and Sprague-Dawley rats served as controls. We measured cardiac function with echocardiogram and invasive hemodynamics before termination. BP and proteinuria were measured at baseline and at 3 and 6 wk. Plasma creatinine was determined at 6 wk. Renal damage was assessed for focal glomerular sclerosis, glomerular desmin expression, glomerular and interstitial macrophages, kidney injury molecule-1 expression, and α-smooth muscle actin expression. Inflammatory cytokines and extracellular matrix proteinases were quantified by quantitative real-time PCR. Systolic BP was higher in control REN2 rats, with no effect of Gal3i treatment. Plasma creatinine and proteinuria were significantly increased in control REN2 rats; Gal3i treatment reduced both. Renal damage (focal glomerular sclerosis, desmin, interstitial macrophages, kidney injury molecule-1, α-smooth muscle actin, collagen type I, and collagen type III) was also improved by Gal3i. All inflammatory markers (CD68, IL-68, galectin-3, and monocyte chemoattractant protein-1) were elevated in control REN2 rats and attenuated by Gal3i. Markers of extracellular matrix turnover were marginally altered in untreated REN2 rats compared with Sprague-Dawley rats. In conclusion, galectin-3 inhibition attenuated hypertensive nephropathy, as indicated by reduced proteinuria, improved renal function, and decreased renal damage. Drugs binding to galectin-3 may be therapeutic candidates for the prevention of chronic kidney disease.

  18. 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

  19. IgA nephropathy enigma.

    PubMed

    Mestecky, Jiri; Novak, Jan; Moldoveanu, Zina; Raska, Milan

    2016-11-01

    IgA nephropathy (IgAN) is the leading cause of primary glomerulonephritis in the world. The disease is characterized by the presence of IgA-containing immune complexes in the circulation and in mesangial deposits with ensuing glomerular injury. Although in humans there are two IgA subclasses, only IgA1 molecules are involved. The exclusivity of participation of IgA1 in IgAN prompted extensive structural and immunological studies of the unique hinge region (HR) of IgA1, which is absent in otherwise highly homologous IgA2. HR of IgA1 with altered O-glycans serves as an antigen recognized by autoantibodies specific for aberrant HR glycans leading to the generation of nephritogenic immune complexes. However, there are several unresolved questions concerning the phylogenetic origin of human IgA1 HR, the structural basis of its antigenicity, the origin of antibodies specific for HR with altered glycan moieties, the regulatory defects in IgA1 glycosylation pathways, and the potential approaches applicable to the disease-specific interventions in the formation of nephritogenic immune complexes. This review focuses on the gaps in our knowledge of molecular and cellular events that are involved in the immunopathogenesis of IgAN.

  20. Cyclosporin A and multiple fibroadenomas of the breast.

    PubMed

    Baildam, A D; Higgins, R M; Hurley, E; Furlong, A; Walls, J; Venning, M C; Ackrill, P; Mansel, R E

    1996-12-01

    Multiple bilateral fibroadenomas are uncommon. This finding in four women who had received renal transplants prompted further inquiry. A prospective study was performed on 39 women under the age of 55 years who had received a renal transplant at least 1 year earlier. Clinical examination and breast ultrasonography were performed. Factors considered included immunosuppressive therapy, concurrent medication and renal function. Blood was taken for estimation of oestradiol, prolactin, follicle-stimulating hormone (FSH) and sex hormone binding globulin levels. Fibroadenomas were found in 13 of 29 women who had received cyclosporin A: multiple in ten and bilateral in five. No abnormal breast findings were seen in 10 patients immunosuppressed with steroids and azathioprine alone (chi 2 = 7.30, 1 d.f., P < 0.01). Serum oestradiol concentration was raised in women with fibroadenomas compared with that in those with normal breasts (P < 0.05) and the level of FSH was lower (P < 0.01). Cyclosporin A may act on breast fibroblasts by humoral mechanisms and direct action.

  1. Coexistence of Fabry Disease and Membranous Nephropathy.

    PubMed

    Liu, Ying; Xie, Hua; Lin, Hongli; Chen, Shuni; Wang, Weidong; Zhao, Guangben; Zhang, Xu

    2016-01-01

    A 21-year-old man with no family history or characteristic symptoms of Fabry disease presented with proteinuria. Histological and immunofluorescent analysis of kidney tissue collected revealed stage 1 membranous nephropathy. Electron microscopy of the same tissue revealed a large number of myeloid bodies (zebra bodies) in the glomerular epithelial cytoplasm and a mild irregular thickening of basement membrane. A diagnosis of Fabry disease was supported by the low α-galactosidase A activity detected in the patient's plasma, and confirmed by the detection of a pathogenic homozygous mutation in the α-galactosidase A gene. Therefore, the final diagnosis was of coexistent Fabry disease and stage 1 membranous nephropathy. This is the first case study reporting the coexistence of Fabry disease and membranous nephropathy. Our results emphasize the importance of electron microscopy in Fabry disease diagnosis.

  2. Soybeans Ameliolate Diabetic Nephropathy in Rats

    PubMed Central

    Choi, Young Eun; Ahn, Soo Kyung; Lee, Won Taek; Lee, Jong Eun; Park, Seung Hwa; Yoon, Bang Bu

    2010-01-01

    Diabetic nephropathy is one of the most frequent and serious complications of diabetes mellitus. Soybeans have been shown to reduce urinary albumin excretion and total cholesterol in non-diabetic patients with nephrotic syndrome. However, reports focusing specifically on diabetic nephropathy are scarce and the available results are inconsistent. It was reported that soybean consumption reduced urinary protein excretion in type 1 diabetic patients with diabetic nephropathy, whereas it was found to elicit an increase in urinary protein excretion when soybeans were consumed by type 2 diabetic patients. This study aims to investigate the effects of soybean in diabetic nephropathy, particularly the effects of consuming soybeans on the histopathology of diabetic nephropathy, using aquaporin (AQP) and osteopontin (OPN) expression as diagnostic markers. Male Sprague-Dawley rats were assigned to one of three groups: control, diabetic with red chow diet and diabetic with soybean diet. For histological examination, the expression of OPN and AQP, renal function and hemoglobin A1c were evaluated at the end of the study. Improvements in glomerular and tubulointerstitial lesions were demonstrated in the diabetic rat group given a soybean diet. OPN and AQP expression were suppressed in the kidney specimens of diabetic rats with the soybean diet. In conclusion, soybeans may prevent the weight loss and morphological disruption of the kidney associated with diabetes mellitus. Soybeans also may improve glycemic control. It seems likely that long-term control of blood glucose levels using a soybean diet could prevent the progression of diabetes mellitus, and therefore, nephropathy could be prevented. PMID:18955330

  3. Cellular Cholesterol Transport Proteins in Diabetic Nephropathy

    PubMed Central

    Tsun, Joseph G. S.; Yung, Susan; Chau, Mel K. M.; Shiu, Sammy W. M.; Chan, Tak Mao; Tan, Kathryn C. B.

    2014-01-01

    Background Lipid accumulation has been shown to accelerate renal injury, and the intracellular accumulation of lipids may be caused by alterations in synthesis as well as lipid uptake and efflux. We have investigated the role of cellular cholesterol transport proteins including adenosine triphosphate binding cassette transporter A1 (ABCA1), G1 (ABCG1) and scavenger receptor class B type I (SR-BI) in diabetic nephropathy. Methods Protein expression and the ability to mediate cholesterol efflux of ABCA1, ABCG1 and SR-BI was determined in human renal mesangial cells and proximal tubular epithelial cells cultured under normal or high glucose conditions. Renal expression of these cholesterol transporters was examined in a murine model of streptozotocin-induced type 1 diabetes. Results ABCA1, ABCG1 and SR-BI were expressed in both human renal mesangial cells and proximal tubular epithelial cells, and mediated cholesterol efflux to apolipoprotein AI and HDL. In vitro, hyperglycemia reduced the expression and the ability to mediate cholesterol efflux of all three cholesterol transporters (p<0.05). In vivo studies showed that intra-renal accumulation of lipids was increased in diabetic mice, particularly in mice with nephropathy. This was associated with a significant reduction in the expression of ABCA1, ABCG1 and SR-BI in the kidneys. These changes were already seen in diabetic mice without nephropathy and preceded the development of nephropathy. Diabetic mice with nephropathy had the lowest level of these cholesterol transporters. Conclusion Inducing diabetes with streptozotocin significantly reduced renal expression of ABCA1, ABCG1 and SR-BI. Defects in cholesterol export pathway in renal cells could therefore promote cholesterol accumulation and might contribute to the development of diabetic nephropathy. PMID:25181357

  4. Ca(2+)-loading modulates potencies of cyclosporin A, Mg2+ and ADP to recouple permeabilized rat liver mitochondria.

    PubMed

    Andreyev AYu; Mikhaylova, L M; Starkov, A A; Kushnareva YuE

    1994-09-01

    We studied the relative potencies of cyclosporin A and endogenous effectors (Mg2+ and ADP) to recouple rat liver mitochondria permeabilized by different Ca(2+)-loading in a P(i)-containing medium. Recoupling efficiency of cyclosporin A dramatically decreased at high Ca(2+)-loading (approx. 100 nM of Ca2+/mg protein and more). Mitochondria permeabilized by high Ca2+ were recoupled with approximately equal efficiency by higher cyclosporin A concentrations or by adding 1-5 mM Mg2+ together with low concentrations of cyclosporin A while potentiating effect of ADP on the cyclosporin A recoupling potency was insignificant. Mg2+ ions at concentrations of 3 mM and higher also prevented the carboxyatractylate-induced reversion of cyclosporin A recoupling effect. The data point to competitive relationships between cyclosporin A and/or Mg2+ ions and Ca2+ ions for the site(s) regulating permeability state of the pore.

  5. BIOPSY-PROVEN BK VIRUS NEPHROPATHY WITHOUT DETECTABLE BK VIREMIA IN A ONE-YEAR POST-KIDNEY TRANSPLANT RECIPIENT.

    PubMed

    Ruangkanchanasetr, Prajej; Pumchandh, Norawee; Satirapoj, Bancha; Termmathurapoj, Sumeth; Pongthanapisith, Viroj

    2015-07-01

    BK virus nephropathy (BKVN) is an important clinical problem in kidney transplant (KT) recipients. The sequence of disease is usually viruria, viremia and then nephropathy. Diagnosis of BK virus (BKV) infection includes checking BKV DNA in the urine, in the plasma and histology on renal biopsy. This last method is used to diagnose BKVN. We describe a KT patient with BKVN without detectable BK viremia. A 62-year-old female with hypertensive nephropathy underwent renal transplant from a living relative donor in December 2011. Fourteen months after transplantation, her serum creatinine(SCr) rose up from 1.2 to 1.6 mg/dl with biopsy-proven acute antibody-mediated and cellular rejection. After pulse methylprednisolone, plasmapheresis and intravenous immunoglobulin, her SCr decreased to baseline but she subsequently developed cytomegalovirus infection with pancytopenia and transaminitis. The SCr rose to 1.9 mg/dl despite ganciclovir treatment. Renal ultrasound and antegrade pyelogram showed partial obstruction of the proximal ureter with moderate hydronephrosis. A quantitative polymerase chain reaction (PCR) assay for BKV DNA was negative (less than 10 copies/ml). A renal biopsy was performed and the pathology revealed viral cytopathic changes in the tubular epithelium with interstitial inflammation. The renal biopsy also showed BKV nucleic acid sequences by in-situ hybridization confirming BKVN. Immunosuppression regimen was changed to cyclosporine, low-dose prednisolone and leflunomide. A temporary percutaneous nephrostomy was performed. Her renal function improved within one week. The diagnosis of BKVN should be considered in a KT recipient with a rising SCr with or without BK viremia and should be made by renal biopsy.

  6. [Physiopathology of nephropathy studied with contrast media].

    PubMed

    Morales Buenrostro, L E; Tellez Zenteno, J F; Torre Delgadillo, A

    2000-01-01

    For the technological advances in diagnostic and therapeutic procedures, the use of intravenous contrast media in the hospital is more and more frequent. It can produce acute renal failure secondary to its nephrotoxicity known as contrast media nephropathy. This review describes the pathophysiologic mechanisms of contrast media injury, including cytotoxicity caused by hyperosmoloarity of contrast media, the hemodynamic factors and the role of the renin-angiotensin system, prostaglandins, oxygen free radicals, endothelin-1, adenosine, nitric oxide and others. The understanding of this information is of vital importance for the development of prophylactic strategies for contrast media nephropathy.

  7. Crystal nephropathies: mechanisms of crystal-induced kidney injury.

    PubMed

    Mulay, Shrikant R; Anders, Hans-Joachim

    2017-04-01

    Crystals can trigger a wide range of kidney injuries that can lead to acute kidney injury, chronic kidney disease, renal colic or nephrocalcinosis, depending on the localization and dynamics of crystal deposition. Studies of the biology of crystal handling by the kidney have shown that the formation of different crystals and other microparticles and the associated mechanisms of renal damage share molecular mechanisms, such as stimulation of the NLRP3 inflammasome or direct cytotoxicity through activation of the necroptosis signalling pathway. By contrast, crystal granuloma formation is limited to chronic crystallopathies that lead to chronic kidney disease and renal fibrosis. Here, we discuss current understanding of the pathomechanisms underlying the different types of crystal-induced kidney injury and propose a classification of crystal nephropathies based on the localization of crystal deposits in the renal vasculature (type 1), the nephron (type 2), or the draining urinary tract (type 3). Further exploration of the molecular mechanisms of crystal-induced kidney injury and renal remodelling might aid the development of innovative cures for these diseases.

  8. Molecular mechanisms in the pathogenesis of diabetic nephropathy: an update.

    PubMed

    Arora, Mandeep Kumar; Singh, Umesh Kumar

    2013-04-01

    Diabetes mellitus is known to trigger retinopathy, neuropathy and nephropathy. Diabetic nephropathy, a long-term major microvascular complication of uncontrolled hyperglycemia, affects a large population worldwide. Recent findings suggest that numerous pathways are activated during the course of diabetes mellitus and that these pathways individually or collectively play a role in the induction and progression of diabetic nephropathy. However, clinical strategies targeting these pathways to manage diabetic nephropathy remain unsatisfactory, as the number of diabetic patients with nephropathy is increasing yearly. To develop ground-breaking therapeutic options to prevent the development and progression of diabetic nephropathy, a comprehensive understanding of the molecular mechanisms involved in the pathogenesis of the disease is mandatory. Therefore, the purpose of this paper is to discuss the underlying mechanisms and downstream pathways involved in the pathogenesis of diabetic nephropathy.

  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. Cyclosporin A acute encephalopathy and seizure syndrome in childhood: clinical features and risk of seizure recurrence.

    PubMed

    Gleeson, J G; duPlessis, A J; Barnes, P D; Riviello, J J

    1998-07-01

    Cyclosporin A is associated with an acute encephalopathy including seizures and alterations in mental status, herein referred to as cyclosporin A acute encephalopathy and seizure syndrome. The clinical history, electroencephalogram (EEG), and neuroimaging findings in 19 children with cyclosporin A acute encephalopathy and seizure syndrome over a 10-year period were reviewed in order to delineate clinical characteristics, imaging features, and to determine the risk of seizure recurrence in this population. All 19 had motor seizures associated with other features of cortical and subcortical dysfunction. The acute mean cyclosporin A level was 342 microg/L, but was within the "therapeutic" range in five cases. Brain imaging by computed tomography (CT) or magnetic resonance imaging (MRI) in the acute or subacute phase revealed lesions characteristic of cyclosporin A toxicity in 14 cases. Acute EEG abnormalities were present in all and included epileptiform discharges or focal slowing. Patients were followed for a median of 49 months (1-9 years). Follow-up imaging (n = 10) showed lesion resolution or improvement in the majority while EEG (n = 10) had normalized in only three. Seizures recurred in six patients and only in those with persistent EEG or imaging abnormalities. No patient had a second episode of cyclosporin A associated neurotoxicity or seizure. It appears that a significant risk of seizure recurrence exists following cyclosporin A acute encephalopathy and seizure syndrome and primarily in those children with persistent EEG or imaging abnormalities.

  11. A Comparative Study of Oral Cyclosporine and Betamethasone Minipulse Therapy in the Treatment of Alopecia Areata

    PubMed Central

    Jang, Yong Hyun; Kim, Sang Lim; Lee, Kyou Chae; Kim, Min Ji; Park, Kyung Hea; Lee, Weon Ju; Lee, Seok-Jong

    2016-01-01

    Background Various systemic agents have been assessed for the treatment of alopecia areata (AA); however, there is a paucity of comparative studies. Objective To assess and compare cyclosporine and betamethasone minipulse therapy as treatments for AA with regard to effectiveness and safety. Methods Data were collected from 88 patients who received at least 3 months of oral cyclosporine (n=51) or betamethasone minipulse therapy (n=37) for AA. Patients with ≥50% of terminal hair regrowth in the alopecic area were considered responders. Results The responder of the cyclosporine group was 54.9% and that of the betamethasone minipulse group was 37.8%. In the cyclosporine group, patients with mild AA were found to respond better to the treatment. Based on the patient self-assessments, 70.6% of patients in the cyclosporine group and 43.2% of patients in the betamethasone minipulse group rated their hair regrowth as excellent or good. Side effects were less frequent in the cyclosporine group. Conclusion Oral cyclosporine appeared to be superior to betamethasone minipulse therapy in terms of treatment effectiveness and safety. PMID:27746635

  12. Investigation into the potential of low-frequency ultrasound facilitated topical delivery of Cyclosporin A.

    PubMed

    Liu, Hongzhuo; Li, Sanming; Pan, Weisan; Wang, Yongjun; Han, Fei; Yao, Huimin

    2006-12-01

    The potential for low-frequency ultrasound facilitated topical transport of Cyclosporin A was investigated using rat skin. Studies of intensity and exposure time acting on the deposition of Cyclosporin A into deeper skin of in vitro sonophoresis were performed. Low-frequency ultrasound increased the amount of Cyclosporin A retained in the skin only seven times than the passive diffusion. Furthermore, we also tested the synergistic effect of ultrasound and other approaches such as chemical enhancers and electroporation on topical drug delivery of Cyclosporin A. We found that the efficacy of low-frequency ultrasound in enhancing topical delivery could be further increased by pretreatment of skin with chemical enhancers, such as laurocapram (Azone) and sodium lauryl sulfate (SLS). Meanwhile only a small amount was seen to across the full skin into the receiver compartment. Trimodality treatment comprising of pretreatment with Azone+ultrasound in combination followed by electroporation was not effective in enhancing the topical delivery of Cyclosporin A. However, this combination strategy increased the penetration of Cyclosporin A through rat skin by order of 15. The histopathological findings revealed that there was almost no change observed in the structure of skin after ultrasound or combination with ultrasound and enhancers as compared with the control group. In general, the enhanced skin accumulation of Cyclosporin A by the combination of low-frequency ultrasound and chemical enhancers could help significantly to optimize the targeting of the drug without of a concomitant increase of the systemic side effects.

  13. 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.

  14. Enzyme and combination therapy with cyclosporin A in the rat developing adjuvant arthritis.

    PubMed

    Rovenská, E; Svík, K; Stancíková, M; Rovenský, J

    1999-01-01

    Recent knowledge of the pathophysiology of rheumatoid arthritis and the mechanism of drug effects have enabled the use of new drugs and drug combinations in rheumatoid arthritis therapy. This study investigates the efficacy of both enzyme therapy and combined therapy with cyclosporin in rats with adjuvant arthritis. Rats with adjuvant-induced arthritis were administered either cyclosporin A (2.5 or 5.0 mg/kg/day per os), a mixture of enzymes (Phlogenzym (PHL); 45 mg/kg twice daily intrarectally), or a combination of 2.5 mg cyclosporin A and 90 mg PHL for a period of 40 days from the adjuvant application. Levels of serum albumin, changes in hind paw swelling and bone erosions were measured in rats as variables of inflammation and arthritis-associated destructive changes. Treatment with 5 mg of cyclosporin A, as well as with the combination therapy with cyclosporin A plus PHL, significantly inhibited both the inflammation and destructive arthritis-associated changes. However, 2.5 mg of cyclosporin A and PHL alone inhibited these disease markers, although to a lesser extent and at a later stage of arthritis development. The results show the inhibitory effect of enzyme therapy on rat adjuvant arthritis, as well as the efficacy of a low dose of cyclosporin A given in combination with enzyme therapy, which may be useful in the treatment of rheumatoid arthritis.

  15. Cyclosporin A reduces canalicular membrane fluidity and regulates transporter function in rats.

    PubMed Central

    Yasumiba, S; Tazuma, S; Ochi, H; Chayama, K; Kajiyama, G

    2001-01-01

    Changes of the biliary canalicular membrane lipid content can affect membrane fluidity and biliary lipid secretion in rats. The immunosuppressant cyclosporin A is known to cause intrahepatic cholestasis. This study investigated whether cyclosporin A influenced canalicular membrane fluidity by altering membrane phospholipids or transporter expression. In male Sprague-Dawley rats, a bile-duct cannula was inserted to collect bile, and sodium taurocholate was infused (100 nmol/min per 100 g) for 60 min. During steady-state taurocholate infusion, cyclosporin A (20 mg/kg) or vehicle was injected intravenously and then bile was collected for 80 min. After killing the rats, canalicular membrane vesicles were prepared. Expression of canalicular membrane transporters was assessed by Western blotting and canalicular membrane vesicle fluidity was estimated by fluorescence polarization. Cyclosporin A reduced biliary lipid secretion along with a disproportionate reduction of lipids relative to bile acids. Cyclosporin A significantly decreased canalicular membrane fluidity along with an increase of the cholesterol/phospholipid molar ratio. Only expression of the transporter P-glycoprotein was increased by cyclosporin A. Because canalicular membrane transporter expression was largely unchanged by cyclosporin A despite a marked decrease of biliary lipid secretion, transporter activity may partly depend upon canalicular membrane fluidity. PMID:11237863

  16. Long-term salvage therapy with cyclosporin A in refractory idiopathic thrombocytopenic purpura.

    PubMed

    Emilia, Giovanni; Morselli, Monica; Luppi, Mario; Longo, Giuseppe; Marasca, Roberto; Gandini, Giovanna; Ferrara, Leonardo; D'Apollo, Nicola; Potenza, Leonardo; Bertesi, Marcello; Torelli, Giuseppe

    2002-02-15

    Treatment of severe, chronic idiopathic thrombocytopenic purpura (ITP) refractory to most usual therapies is a difficult challenge. Little information exists on the clinical use of cyclosporin A (CyA) in the treatment of ITP. This report describes long-term treatment with CyA (median, 40 months) and follow-up (median, 36.8 months) in 12 adult patients with resistant ITP. CyA used in relatively low doses (2.5-3 mg/kg of body weight per day) led to a clinical improvement in 10 patients (83.3%). Five had a complete response (41.1%), 4 a complete response to maintenance therapy (33.3%), and one a partial response (8.3%). Two patients had no response. Most patients with a response (60%) had a long-term remission (mean, 28.6 months) after discontinuation of CyA. One patient had a relapse of ITP 4 years after CyA therapy was stopped. Side effects were moderate and transient, even in patients dependent on continued CyA treatment. CyA seems to represent reasonable salvage treatment in severe, potentially life-threatening, refractory ITP.

  17. 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.

  18. Tacrolimus versus cyclosporine after hematopoietic cell transplantation for acquired aplastic anemia

    PubMed Central

    Inamoto, Yoshihiro; Flowers, Mary E.D.; Wang, Tao; Urbano-Ispizua, Alvaro; Hemmer, Michael T.; Cutler, Corey S.; Couriel, Daniel R.; Alousi, Amin M.; Antin, Joseph H.; Gale, Robert Peter; Gupta, Vikas; Hamilton, Betty K.; Kharfan-Dabaja, Mohamed A.; Marks, David I.; Ringdén, Olle T.H.; Socié, Gérard; Solh, Melhem M.; Akpek, Görgün; Cairo, Mitchel S.; Chao, Nelson J.; Hayashi, Robert J.; Nishihori, Taiga; Reshef, Ran; Saad, Ayman; Shah, Ami; Teshima, Takanori; Tallman, Martin S.; Wirk, Baldeep; Spellman, Stephen R.; Arora, Mukta; Martin, Paul J.

    2015-01-01

    Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD and mortality. TAC+MTX was used more frequently in older patients and in recent years in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier ANC recovery in SIB recipients. Other outcomes did not differ statistically between the two regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after HCT for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia. PMID:26033280

  19. Tacrolimus versus Cyclosporine after Hematopoietic Cell Transplantation for Acquired Aplastic Anemia.

    PubMed

    Inamoto, Yoshihiro; Flowers, Mary E D; Wang, Tao; Urbano-Ispizua, Alvaro; Hemmer, Michael T; Cutler, Corey S; Couriel, Daniel R; Alousi, Amin M; Antin, Joseph H; Gale, Robert Peter; Gupta, Vikas; Hamilton, Betty K; Kharfan-Dabaja, Mohamed A; Marks, David I; Ringdén, Olle T H; Socié, Gérard; Solh, Melhem M; Akpek, Görgün; Cairo, Mitchell S; Chao, Nelson J; Hayashi, Robert J; Nishihori, Taiga; Reshef, Ran; Saad, Ayman; Shah, Ami; Teshima, Takanori; Tallman, Martin S; Wirk, Baldeep; Spellman, Stephen R; Arora, Mukta; Martin, Paul J

    2015-10-01

    Combinations of cyclosporine (CSP) with methotrexate (MTX) have been widely used for immunosuppression after allogeneic transplantation for acquired aplastic anemia. We compared outcomes with tacrolimus (TAC)+MTX versus CSP+MTX after transplantation from HLA-identical siblings (SIB) or unrelated donors (URD) in a retrospective cohort of 949 patients with severe aplastic anemia. Study endpoints included hematopoietic recovery, graft failure, acute graft-versus-host disease (GVHD), chronic GVHD, and mortality. TAC+MTX was used more frequently in older patients and, in recent years, in both SIB and URD groups. In multivariate analysis, TAC+MTX was associated with a lower risk of mortality in URD recipients and with slightly earlier absolute neutrophil count recovery in SIB recipients. Other outcomes did not differ statistically between the 2 regimens. No firm conclusions were reached regarding the relative merits of TAC+MTX versus CSP+MTX after hematopoietic cell transplantation for acquired aplastic anemia. Prospective studies would be needed to determine whether the use of TAC+MTX is associated with lower risk of mortality in URD recipients with acquired aplastic anemia.

  20. FTY720 in combination with cyclosporine--an analysis of skin allograft survival and renal function.

    PubMed

    Silva, Francieli Ruiz; Silva, Lea Bueno Lucas; Cury, Patricia Maluf; Burdmann, Emmanuel Almeida; Bueno, Valquiria

    2006-12-20

    Acute and chronic nephrotoxicity caused by CsA continuous administration impair kidney allograft survival. Several clinical and experimental protocols have shown benefits to the kidney after decreasing CsA dose, withdrawing the drug or delaying its introduction after transplantation. FTY720 is a new compound that has immunosuppressive characteristics and increase allograft survival in animal models without causing the side effects of calcineurin inhibitors (CNIs). FTY720 described mechanism of action that consists to alter the lymphocyte migration pattern without impairment of the immune system response against pathogens. In our mice model, FTY720 administered alone or in combination with CsA during 21 days increased skin allograft survival in a fully mismatched strain combination and did not cause significant changes in renal function. Moreover, renal structure was normal in all groups suggesting that at low doses (10 mg/kg/day) CsA can be associated during short-term period to other immunosuppressive drugs, i.e. FTY720 without affecting the kidney. Combination of immunosuppressive compounds with FTY720 and/or delayed introduction of low cyclosporine dose could prevent graft rejection and avoid nephrotoxicity.

  1. Effects of erdosteine on cyclosporine-A-induced hepatotoxicity in rats.

    PubMed

    Erarslan, Elife; Ekiz, Fuat; Uz, Burak; Koca, Cemile; Turkcu, Ummuhani Ozel; Bayrak, Reyhan; Delibasi, Tuncay

    2011-01-01

    Cyclosporine A (CsA) is a potent immunosuppressive agent used for organ transplantations and various autoimmune disorders. However, hepatotoxicity due to CsA remains one of the major side effects. The use of antioxidants reduces the adverse effects of CsA. The aim of this study was to determine the protective effects of erdosteine on CsA-induced liver injury through tissue oxidant/antioxidant parameters and to evaluate light microscopic alterations in rat-liver tissues. Rats were randomly divided into four experimental groups: The control group received sunflower oil (2 mL/kg/day, per orally; p.o.), while the other groups were treated with CsA (25 mg/kg/day, p.o.) or erdosteine (10 mg/kg/day, p.o.) or CsA+erdosteine, respectively. Serum aspartate aminotransferase and alanine aminotransferase levels, tissue malondialdehyde and nitric oxide levels, and superoxide dismutase, glutathione peroxidase and catalase enzyme activities were measured. Histological examination was performed. CsA caused a significant deterioration in the hepatic function tests, morphology, and gave rise to severe oxidative stress in the liver. Erdostein significantly improved the functional and histological parameters and attenuated the oxidative stresss induced by CsA. Erdostein protects liver tissue against oxygen free radicals and prevents hepatic dysfunction and morphological abnormalities associated with chronic CsA administration.

  2. Polyomavirus BK Replication in De Novo Kidney Transplant Patients Receiving Tacrolimus or Cyclosporine: A Prospective, Randomized, Multicenter Study

    PubMed Central

    Hirsch, H H; Vincenti, F; Friman, S; Tuncer, M; Citterio, F; Wiecek, A; Scheuermann, E H; Klinger, M; Russ, G; Pescovitz, M D; Prestele, H

    2013-01-01

    Polyomavirus BK (BKV)-associated nephropathy causes premature kidney transplant (KT) failure. BKV viruria and viremia are biomarkers of disease progression, but associated risk factors are controversial. A total of 682 KT patients receiving basiliximab, mycophenolic acid (MPA), corticosteroids were randomized 1:1 to cyclosporine (CsA) or tacrolimus (Tac). Risk factors were analyzed in 629 (92.2%) patients having at least 2 BKV measurements until month 12 posttransplant. Univariate analysis associated CsA-MPA with lower rates of viremia than Tac-MPA at month 6 (10.6% vs. 16.3%, p = 0.048) and 12 (4.8% vs. 12.1%, p = 0.004) and lower plasma BKV loads at month 12 (3.9 vs. 5.1 log10 copies/mL; p = 0.028). In multivariate models, CsA-MPA remained associated with less viremia than Tac-MPA at month 6 (OR 0.60; 95% CI 0.36–0.99) and month 12 (OR 0.33; 95% CI 0.16–0.68). Viremia at month 6 was also independently associated with higher steroid exposure until month 3 (OR 1.19 per 1 g), and with male gender (OR 2.49) and recipient age (OR 1.14 per 10 years) at month 12. The data suggest a dynamic risk factor evolution of BKV viremia consisting of higher corticosteroids until month 3, Tac-MPA compared to CsA-MPA at month 6 and Tac-MPA, older age, male gender at month 12 posttransplant. PMID:23137180

  3. IgA nephropathy complicating diabetic glomerulosclerosis.

    PubMed

    Orfila, C; Lepert, J C; Modesto, A; Pipy, B; Suc, J M

    1998-01-01

    A retrospective study was done on 66 diabetic patients who had renal biopsies performed during 1979-1994. This review shows 10 patients who presented IgA nephropathy associated with diabetic nephropathy. Six patients had insulin-dependent diabetes mellitus and 4 patients non-insulin-dependent diabetes mellitus. All patients presented with proteinuria and 7 had hematuria. Four patients presented with renal impairment. Histologic evaluation disclosed the presence of thickened glomerular basement membranes and increased mesangial matrix in all cases, associated with nodular sclerosis in 8 cases. By immunofluorescence, diffuse mesangial IgA deposits were observed in all cases. The high incidence of the coexistence of IgA nephropathy and diabetes seems not merely coincidental. Structural and/or functional abnormalities of the glomerular basement membranes might facilitate the development of immune complex glomerular diseases. In patients with diabetes, the appearance of urinary abnormalities and/or deterioration in renal function altered the clinical history of diabetic nephropathy. The disorders are clinically suggestive of the presence of nondiabetic renal disease and raised the possibility of another pathogenetic mechanism.

  4. Formulation and evaluation of Cyclosporin A emulgel for ocular delivery.

    PubMed

    Shen, Yan; Ling, Xiang; Jiang, Weiwei; Du, Shuang; Lu, Yang; Tu, Jiasheng

    2015-01-01

    Emulgels have been extensively covered as a promising drug delivery system for the administration of lipophilic drugs. This work was conducted to develop an emulgel formulation for Cyclosporin A (CsA) employing polycarbophil as the gelling agent for ocular delivery. The prepared emulgels were evaluated for their physical appearance, rheological behavior, drug release, stability, precorneal clearance and irritation. Results showed that CsA emulgel formulations prepared with polycarbophil exhibited acceptable physical properties and drug release, which remained consistent after storage for 3 months. A prolonged retention time was also observed on the ocular surface with improved ocular bioavailability and no irritation. Therefore, the polycarbophil-based emulgel could be exploited as a potential hydrophobic drug carrier for topical ocular drug delivery.

  5. 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

  6. Leaching of diethylhexyl phthalate from polyvinyl chloride bags into intravenous cyclosporine solution

    SciTech Connect

    Venkataramanan, R.; Burckart, G.J.; Ptachcinski, R.J.; Blaha, R.; Logue, L.W.; Bahnson, A.; Giam, C.S.; Brady, J.E.

    1986-11-01

    The release of diethylhexyl phthalate (DEHP) from flexible polyvinyl chloride containers into intravenous cyclosporine solutions was studied. Intravenous cyclosporine solution or solutions containing the vehicle Cremophor EL and alcohol in dextrose were prepared in an all-glass system and stored in polyvinyl chloride (PVC) bags. Four samples were obtained at different time intervals, and DEHP content was analyzed by gas chromatography. The amount of DEHP that was leached into solutions stored in the PVC bags increased as storage time increased. By 48 hours, nearly 33 mg of DEHP had leached into the solution. Intravenous cyclosporine solutions should be prepared in glass containers to minimize patient exposure to DEHP. If plastic bags are used for preparing cyclosporine injections, the injections must be used immediately after preparation.

  7. Treatment of pure red-cell aplasia with cyclosporine in a renal transplant patient.

    PubMed

    Yildirim, Rahsan; Bilen, Yusuf; Keles, Mustafa; Uyanik, Abdullah; Gokbulut, Puren; Aydinli, Bulent

    2013-02-01

    Acquired pure red-cell aplasia is a rare disorder that can be either idiopathic or associated with certain autoimmune diseases, pregnancy, lymphoproliferative disorders, nutritional deficiencies, or medicines. We present a deceased-donor renal transplant patient who developed pure red-cell aplasia associated with mycophenolate mofetil or tacrolimus and was treated with cyclosporine. A 20-year-old woman was transplanted from a deceased donor 1 month earlier and presented to us with symptoms of fatigue, prostration, and palpitation. The results of a laboratory examination revealed anemia. A diagnostic work-up resulted in a diagnosis of pure red-cell aplasia. Mycophenolate mofetil was discontinued. Tacrolimus also was replaced with cyclosporine 2 months after mycophenolate mofetil was halted because of a lack of improvement in anemia. Three months later, her anemia improved with cyclosporine. Starting cyclosporine instead of tacrolimus or mycophenolate mofetil showed good improvement in our patient within 6 months of therapy.

  8. Development and evaluation of in situ gel forming system for sustained delivery of cyclosporine.

    PubMed

    Dhawan, Sanju; Kapil, Rishi; Kapoor, Deepak N; Kumar, Manoj

    2009-10-01

    Phase-sensitive in situ gel forming controlled release formulations of cyclosporine were prepared using poly (lactide-co-glycolide) and a solvent system consisting of various proportions of benzyl benzoate and benzyl alcohol. Uniformity of content of cyclosporine in the formulation and in vitro release samples was determined by radio immune assay (RIA). FTIR and CD spectroscopy ratified the conformational stability of cyclosporine in the formulation and in vitro release samples, respectively. Rheological properties of the formulations, assessed under isothermal conditions, showed dilatant behavior of all the formulations. In vivo studies were carried out on the optimized formulations vis-à-vis pure cyclosporine in rats and drug levels were monitored for 13 days. Mean plasma concentration of cyclosporine was calculated for all the animals and pharmacokinetic parameters were determined using Win NonLin software. The studies construed better regulation of plasma drug levels with the optimized formulation vis-à-vis routine once-a-day administration of cyclosporine. The subcutaneous tissues, further subjected to histopathological examinations ascertained the biocompatibility of the formulation.

  9. Immunosuppressive and antiparasitic effects of cyclosporin A on Hymenolepis nana infection in mice.

    PubMed

    Matsuzawa, K; Nakamura, F; Abe, M; Okamoto, K

    1998-04-01

    The effect of cyclosporin A, which is known to act both as immunosuppressant and as an antiparasitic drug in many host-parasite systems, was examined in a mouse-Hymenolepis nana system. When BDF1 mice were injected s.c. with cyclosporin A (100 mg kg-1 day-1) every 48 h from 11 days p.i. with eggs, expulsion of the adult worms from the intestines of mice was prevented completely until at least 30 days p.i. Worm burden, dry weight and the number of gravid proglottids were not significantly reduced. By contrast, in untreated mice most of the worms were eliminated by 19 days p.i. The drug also completely abolished acquired resistance to a challenge infection with eggs when mice were injected s.c. with cyclosporin A (100 mg kg-1 day-1) around the time of challenge infection (Days -2, -1, 0, 1 and 2 relative to challenge). Such immunosuppressive effects of cyclosporin A on worm expulsion and protective immunity to reinfection were similar to those of another immunosuppressant, cyclophosphamide. As for the antiparasitic action of cyclosporin A against H. nana, a smaller number of cysticercoids developed from eggs in mice given cyclosporin A (100 mg kg-1 day-1) for 5 days beginning 1 day before infection, than in untreated controls.

  10. 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}.

  11. [Berger's disease or primary IgA nephropathy in children].

    PubMed

    Renoult, E; Cochat, P; Jonon, B; Kessler, M

    1989-01-01

    Primary IgA mesangial nephropathy was first described in adults by Berger, and has been increasingly recognized in children. IgA nephropathy is a frequent type of glomerulonephritis in 3 to 15 year-old children in France. Clinical features and outcome have been defined and the progression to renal failure is possible. The pathogeny of IgA nephropathy remains unclear and is under multifactorial control and, at present, no satisfactory specific treatment is available.

  12. Comprehensive genomic profiling in diabetic nephropathy reveals the predominance of proinflammatory pathways.

    PubMed

    Kelly, K J; Liu, Yunlong; Zhang, Jizhong; Goswami, Chirayu; Lin, Hai; Dominguez, Jesus H

    2013-08-15

    Despite advances in the treatment of diabetic nephropathy (DN), currently available therapies have not prevented the epidemic of progressive chronic kidney disease (CKD). The morbidity of CKD, and the inexorable increase in the prevalence of end-stage renal disease, demands more effective approaches to prevent and treat progressive CKD. We undertook next-generation sequencing in a rat model of diabetic nephropathy to study in depth the pathogenic alterations involved in DN with progressive CKD. We employed the obese, diabetic ZS rat, a model that develops diabetic nephropathy, characterized by progressive CKD, inflammation, and fibrosis, the hallmarks of human disease. We then used RNA-seq to examine the combined effects of renal cells and infiltrating inflammatory cells acting as a pathophysiological unit. The comprehensive systems biology analysis of progressive CKD revealed multiple interactions of altered genes that were integrated into morbid networks. These pathological gene assemblies lead to renal inflammation and promote apoptosis and cell cycle arrest in progressive CKD. Moreover, in what is clearly a major therapeutic challenge, multiple and redundant pathways were found to be linked to renal fibrosis, a major cause of kidney loss. We conclude that systems biology applied to progressive CKD in DN can be used to develop novel therapeutic strategies directed to restore critical anomalies in affected gene networks.

  13. T-Cell Proliferation Involving the CD28 Pathway is Associated with Cyclosporine-Resistant Interleukin 2 Gene Expression

    DTIC Science & Technology

    1987-12-01

    Security Classification) T-CELL PROLIFERATION INVOLVING THE CD28 PATHWAY IS ASSOCIATED WITH CYCLOSPORINE-RESISTANT INTERLEUKIN 2 GENE EXPRESSION 12. PERSONAL...Cyclosporins,. T Lymphocytes) r’jh ,,.. "’’ .. - | Gene Expression 19. ABSTRACT (Continue on reverse if necessary and identify by block num’ber) DTIC...American Society tor Microbiology T-Cell Proliferation Involving the CD28 Pathway Is Associated with Cyclosporine-Resistant Interleukin 2 Gene Expression

  14. Natural antioxidants in the treatment and prevention of diabetic nephropathy; a potential approach that warrants clinical trials.

    PubMed

    Al-Waili, Noori; Al-Waili, Hamza; Al-Waili, Thia; Salom, Khelod

    2017-05-01

    Diabetic nephropathy is the major cause of end-stage renal disease and effective and new therapeutic approaches are needed in diabetic nephropathy and chronic kidney diseases. Oxidative stress and inflammatory process are important factors contributing to kidney damage by increasing production of oxidants. KEAP1/Nrf2/ARE pathway regulates the transcription of many antioxidant genes and modulation of the pathway up regulates antioxidants. NFB controls the expression of genes involved in the inflammatory response. Natural substances have antioxidant and anti-inflammatory activities and have an impact on NFB and KEAP1/Nrf2/ARE pathways. The preclinical studies explored the effectiveness of whole herbs, plants or seeds and their active ingredients in established diabetic nephropathy. They ameliorate oxidative stress induced kidney damage, enhance antioxidant system, and decrease inflammatory process and fibrosis; most likely by activating KEAP1/Nrf2/ARE pathway and by deactivating NFB pathway. Whole natural products contain balanced antioxidants that might work synergistically to induce beneficial therapeutic outcome. In this context, more clinical studies involving whole plants or herbal products or mixtures of different herbs and plants and their active ingredients might change our strategies for the management of diabetic nephropathy. The natural products might be useful as preventive interventions and studies are required in this field.

  15. 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.

  16. Complex networks analysis of obstructive nephropathy data.

    PubMed

    Zanin, M; Boccaletti, S

    2011-09-01

    Congenital obstructive nephropathy (ON) is one of the most frequent nephropathy observed among newborns and children, and the first cause of end-stage renal diseases treated by dialysis or transplantation. This pathology is characterized by the presence of an obstacle in the urinary tract, e.g., stenosis or abnormal implantation of the urethra in the kidney. In spite of important advances, pathological mechanisms are not yet fully understood. In this contribution, the topology of complex networks created upon vectors of features for 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.

  17. Classification and Differential Diagnosis of Diabetic Nephropathy

    PubMed Central

    2017-01-01

    Diabetic nephropathy (DN) is a major cause of end-stage renal disease throughout the world in both developed and developing countries. This review briefly introduces the characteristic pathological changes of DN and Tervaert pathological classification, which divides DN into four classifications according to glomerular lesions, along with a separate scoring system for tubular, interstitial, and vascular lesions. Given the heterogeneity of the renal lesions and the complex mechanism underlying diabetic nephropathy, Tervaert classification has both significance and controversies in the guidance of diagnosis and prognosis. Applications and evaluations using Tervaert classification and indications for renal biopsy are summarized in this review according to recent studies. Meanwhile, differential diagnosis with another nodular glomerulopathy and the situation that a typical DN superimposed with a nondiabetic renal disease (NDRD) are discussed and concluded in this review. PMID:28316995

  18. Prevalence of diabetic nephropathy among Type 2 diabetic patients in some of the Arab countries

    PubMed Central

    Aldukhayel, Abdulrhman

    2017-01-01

    Type 2 diabetes mellitus (DM) is a public health concern worldwide and an important cause of morbidity and mortality. Type 2 DM is associated with microvascular and macrovascular complications. Diabetic nephropathy (DN), which is characterized by proteinuria, is one of the most serious long-term microvascular complications of DM. The proportion of DN is increasing worldwide. DN is the leading cause of chronic kidney diseases and end-stage renal disease, which constitutes the major workload of dialysis centers worldwide. Microalbuminuria (MA) is the earliest sign of DN, so the early detection of MA and early control of diabetes retards the progression of DN. PMID:28293155

  19. When "diabetic nephropathy" is not always of diabetic origin: a case report.

    PubMed

    Wróblewski, Krzysztof; Sodolska, Małgorzata; Wągrowska-Danilewicz, Małgorzata; Danilewicz, Marian; Moczulski, Dariusz

    2012-06-01

    The etiology and pathogenesis of fibrillary glomerulonephritis (FGN) remains unknown. The presented case shows an extremely rare FGN in association with commonly diagnosed diabetes. A 74-year-old, non-smoking, obese and diabetic woman was hospitalized due to a progressive and accelerated decrease in the renal function. The primary cause of chronic kidney disease was believed to be of diabetic origin. In the renal biopsy, light microscopy showed glomerular changes resembling diabetic nephropathy, however electron microscopy evaluation revealed linear, randomly arranged fibrils present in the glomerular mesangium and in peripheral capillary loops. The biopsy confirmed fibrillary glomerulopathy.

  20. Human immunodeficiency virus-1 associated nephropathy (HIVAN): epidemiology, pathogenesis, histology, diagnosis, and medical management.

    PubMed

    Lochner, Michelle L; Wolf, Andrea

    2006-01-01

    Human immunodeficiency virus-associated nephropathy (HIVAN) is a very distinct, unique, clinico-pathological syndrome, and a structural type of renal failure that is the most common cause of chronic renal failure in patients who are HIV-seropositive. Early referral and a long-term, primary care approach can improve patient outcomes. Careful adjustments of prescription doses with regularly scheduled, and at times frequent, laboratory testing will yield, optimal health, improve the quality of life, and most importantly, will decrease the incidence of morbidity and mortality in those individuals afflicted with both HIV and HIVAN.

  1. Enzyme replacement therapy and Fabry nephropathy.

    PubMed

    Warnock, David G; Daina, Erica; Remuzzi, Giuseppe; West, Michael

    2010-02-01

    Involvement of the kidneys in Fabry disease ("nephropathy") occurs in male and female individuals. The majority of patients with progressive nephropathy will have significant proteinuria and develop progressive loss of kidney function, leading to ESRD. All too often, treating physicians may ignore "normal" serum creatinine levels or "minimal" proteinuria and fail to assess properly the severity of kidney involvement and institute appropriate management. Fabry nephropathy is treatable, even in patients with fairly advanced disease. Although the cornerstone of therapy remains enzyme replacement therapy with agalsidase, this treatment alone does not reduce urine protein excretion. Treatment with angiotensin receptor blockers or angiotensin-converting enzyme inhibitors must be added to enzyme replacement therapy to reduce urine protein excretion with the hope that this will stabilize kidney function. Kidney function, with at least estimated GFR based on serum creatinine and measurements of urinary protein, should be measured at every clinic visit, and the rate of change of the estimated GFR should be followed over time. Antiproteinuric therapy can be dosed to a prespecified urine protein target rather than a specific BP goal, with the proviso that successful therapy will usually lower the BP below the goal of 130/80 mmHg that is used for other forms of kidney disease. The overall goal for treating Fabry nephropathy is to reduce the rate of loss of GFR to -1 ml/min per 1.73 m(2)/yr, which is that seen in the normal adult population. A systematic approach is presented for reaching this goal in the individual patient.

  2. Pathology of IgA nephropathy.

    PubMed

    Roberts, Ian S D

    2014-08-01

    IgA nephropathy is defined by the presence of IgA-dominant or co-dominant immune deposits within glomeruli. Biopsy specimens meeting these diagnostic criteria have a range of histological changes that are reflected in the variable clinical course of IgA nephropathy. The impact of histology on outcomes in IgA nephropathy has been clarified in a number of large retrospective clinicopathological studies. These studies have consistently demonstrated that the stage of disease at presentation, as indicated by the extent of interstitial fibrosis and tubular atrophy in the biopsy, is the strongest histological predictor of renal survival. The effect of active proliferative lesions on the disease course is less clear cut, owing in part to considerable treatment bias in most published retrospective studies. There is evidence that endocapillary hypercellularity and cellular crescents are responsive to immunosuppressive therapy, but this observation requires confirmation in prospective randomized controlled trials. Future challenges include improving the reproducibility of histological scoring, particularly for the presence and extent of endocapillary lesions, and to improve prognostic modelling by combining histological data with clinical variables and biomarker data.

  3. BASP1 Promotes Apoptosis in Diabetic Nephropathy

    PubMed Central

    Sanchez-Niño, Maria Dolores; Sanz, Ana Belen; Lorz, Corina; Gnirke, Andrea; Rastaldi, Maria Pia; Nair, Viji; Egido, Jesus; Ruiz-Ortega, Marta

    2010-01-01

    Apoptosis contributes to the development of diabetic nephropathy (DN), but the mechanisms that lead to diabetes-induced cell death are not fully understood. Here, we combined a functional genomics screen for cDNAs that induce apoptosis in vitro with transcriptional profiling of renal biopsies from patients with DN. Twelve of the 138 full-length cDNAs that induced cell death in human embryonic kidney cells matched upregulated mRNA transcripts in tissue from human DN. Confirmatory screens identified induction of BASP1 in tubular cross sections of human DN tissue. In vitro, apoptosis-inducing conditions such as serum deprivation, high concentrations of glucose, and proinflammatory cytokines increased BASP1 mRNA and protein in human tubular epithelial cells. In normal cells, BASP1 localized to the cytoplasm, but in apoptotic cells, it colocalized with actin in the periphery. Overexpression of BASP1 induced cell death with features of apoptosis; conversely, small interfering RNA (siRNA)-mediated knockdown of BASP1 protected tubular cells from apoptosis. Supporting possible involvement of BASP1 in renal disease other than DN, we also observed significant upregulation of renal BASP1 in spontaneously hypertensive rats and a trend toward increased tubulointerstitial BASP1 mRNA in human hypertensive nephropathy. In summary, a combined functional genomics approach identified BASP1 as a proapoptotic factor in DN and possibly also in hypertensive nephropathy. PMID:20110383

  4. Cyclosporine-induced gingival overgrowth in New Zealand White rabbits (Oryctolagus cuniculus).

    PubMed

    Jean, Sherrie M; Sharma, Prachi; Taylor, Douglas; Mook, Deborah

    2009-08-01

    A high incidence of gingival overgrowth occurred in a group of New Zealand White rabbits receiving daily cyclosporine (15 mg/kg IM) while on a retinoblastoma study. Over the course of 2 mo, rabbits presented with clinical signs of ptyalism (4 of 18 rabbits), inappetence (3 of 18), or both (3 of 18); facial dermatitis and erythema occurred secondary to ptyalism. Reducing the dose of cyclosporine to 10 mg/kg led to complete resolution of clinical signs in all but 2 rabbits, which then received azithromycin (62.5 mg PO once daily for 7 d), a common treatment for cyclosporine-induced gingival overgrowth in other species. After dose reduction and azithromycin treatment, clinical signs resolved and did not reoccur for the remainder of the study. Fourteen rabbits were necropsied at the end of the study, and gingival width was measured. Although some rabbits were clinically normal, the gingiva in all rabbits was grossly thickened. Rabbits on cyclosporine had molar gingiva that was significantly thicker (4.8 mm) than controls (2.5 mm) not treated with cyclosporine. Histologic analysis of the gingiva revealed mild to moderate gingival epithelial hyperplasia, hyperkeratosis, and mild inflammation. Gingival overgrowth is a known side effect of cyclosporine administration in other species but, to our knowledge, this report is the first description of the condition in rabbits. Because rabbits frequently are used in studies that involve systemic cyclosporine administration, clinicians are advised to include this possibility in their differential list for cases involving hypersalivation, facial dermatitis, or inappetence in rabbits.

  5. [Successful combination therapy of cyclosporine and steroids in two cases with interstitial pneumonitis associated with polymyositis].

    PubMed

    Ando, S; Kobayashi, S; Yamanaka, K; Takasaki, Y; Hashimoto, H

    1995-02-01

    Cyclosporine is an immunosuppressive agent which is well-established in the transplantation of organs including kidney, liver and bone marrow. It acts by inhibiting the production of interleukin 2, thereby blocking both the development of cytotoxic lymphocytes, and the proliferation of helper T cells. T cell-mediated muscle damage is thought to be important in the pathogenesis of polymyositis. And activated cytotoxic T cells are thought to play an important role of polymyositis/dermatomyositis with active pneumonitis. It is thereby likely that cyclosporine would be effective in the management of polymyositis with interstitial pneumonitis. We have used cyclosporine in two cases of corticosteroids resistant polymyositis associated with pneumonitis. The first case was admitted because of the relapse of polymyositis. She was partially responded by the high dose of steroid, but showed decreased %DLCO and increased AaDO2 during the therapy. And oral cyclosporine was given with steroid. Within two weeks, serum creatinine kinase level was reduced to normal range, and the improvement of pneumonitis was observed. The second case was admitted because of the flare of pneumonitis. She was treated with high dose of steroid with insufficient response. And cyclosporine was prescribed. Within two weeks of treatment, her symptom was relieved, and blood gas analysis showed an improvement of pulmonary function. And steroid could be tapered. In both cases, the initial dose of cyclosporine was 200 mg/day, and the optimal trough level was thought to be ranged 100 to 150 ng/ml. In the second case, renal dysfunction was observed but it was recovered by the reduction of the dose of cyclosporine. No other side effect was appeared.(ABSTRACT TRUNCATED AT 250 WORDS)

  6. Cyclosporine-Induced Gingival Overgrowth in New Zealand White Rabbits (Oryctolagus cuniculus)

    PubMed Central

    Jean, Sherrie M; Sharma, Prachi; Taylor, Douglas; Mook, Deborah

    2009-01-01

    A high incidence of gingival overgrowth occurred in a group of New Zealand White rabbits receiving daily cyclosporine (15 mg/kg IM) while on a retinoblastoma study. Over the course of 2 mo, rabbits presented with clinical signs of ptyalism (4 of 18 rabbits), inappetence (3 of 18), or both (3 of 18); facial dermatitis and erythema occurred secondary to ptyalism. Reducing the dose of cyclosporine to 10 mg/kg led to complete resolution of clinical signs in all but 2 rabbits, which then received azithromycin (62.5 mg PO once daily for 7 d), a common treatment for cyclosporine-induced gingival overgrowth in other species. After dose reduction and azithromycin treatment, clinical signs resolved and did not reoccur for the remainder of the study. Fourteen rabbits were necropsied at the end of the study, and gingival width was measured. Although some rabbits were clinically normal, the gingiva in all rabbits was grossly thickened. Rabbits on cyclosporine had molar gingiva that was significantly thicker (4.8 mm) than controls (2.5 mm) not treated with cyclosporine. Histologic analysis of the gingiva revealed mild to moderate gingival epithelial hyperplasia, hyperkeratosis, and mild inflammation. Gingival overgrowth is a known side effect of cyclosporine administration in other species but, to our knowledge, this report is the first description of the condition in rabbits. Because rabbits frequently are used in studies that involve systemic cyclosporine administration, clinicians are advised to include this possibility in their differential list for cases involving hypersalivation, facial dermatitis, or inappetence in rabbits. PMID:19712576

  7. Anticoagulant-related nephropathy in a patient with IgA nephropathy.

    PubMed

    Góis, Mário; Azevedo, Ariana; Carvalho, Fernanda; Nolasco, Fernando

    2017-02-20

    Anticoagulant-related nephropathy is a type of acute kidney injury caused by overcoagulation. We describe a case of an 84-year-old man with arterial hypertension, coronary heart disease and atrial fibrillation treated with acenocoumarol, who presented with haematoproteinuria and acute kidney injury during a phase of excessive anticoagulation. In addition to IgA nephropathy, renal biopsy also revealed acute tubular necrosis, red blood cell casts and positive iron staining in tubular cells. After this acute episode, renal function improved and proteinuria decreased below the nephrotic range.

  8. 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

  9. Cyclosporin A inhibits colon cancer cell growth independently of the calcineurin pathway

    PubMed Central

    Werneck, Miriam B.F.; Hottz, Eugênio; Bozza, Patrícia T.; Viola, João P.B.

    2012-01-01

    Chronic inflammation is a risk factor for the development of colon cancer, providing genotoxic insults, growth and pro-angiogenic factors that can promote tumorigenesis and tumor growth. Immunomodulatory agents can interfere with the inflammation that feeds cancer, but their impact on the transformed cell is poorly understood. The calcium/calcineurin signaling pathway, through activation of NFAT, is essential for effective immune responses, and its inhibitors cyclosporin A (CsA) and FK506 are used in the clinics to suppress immunity. Moreover, the kinases GSK3β and mTOR, modulated by PI-3K/Akt, can inhibit NFAT activity, suggesting a cross-talk between the calcium and growth factor signaling pathways. Both NFAT and mTOR activity have been associated with tumorigenesis. We therefore investigated the impact of calcineurin and PI-3K/mTOR inhibition in growth of human colon carcinoma cells. We show that despite the efficient inhibition of NFAT1 activity, FK506 promotes tumor growth, whereas CsA inhibits it due to a delay in cell cycle progression and induction of necroptosis. We found NFκB activation and mTORC1 activity not to be altered by CsA or FK506. Similarly, changes to mitochondrial homeostasis were equivalent upon treatment with these drugs. We further show that, in our model, NFAT1 activation is not modulated by PI3K/mTOR. We conclude that CsA slows cell cycle progression and induces necroptosis of human carcinoma cell lines in a TGFβ-, NFAT-, NFκB- and PI3K/mTOR-independent fashion. Nevertheless, our data suggest that CsA, in addition to its anti-inflammatory capacity, may target transformed colon and esophagus carcinoma cells without affecting non-transformed cells, promoting beneficial tumoristatic effects. PMID:22992618

  10. 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

  11. Ocular penetration of cyclosporin A. III: The human eye.

    PubMed Central

    BenEzra, D; Maftzir, G; de Courten, C; Timonen, P

    1990-01-01

    The distribution of cyclosporin A (CsA) in the blood, saliva, tears, aqueous humour, vitreous, and cerebrospinal fluid has been studied after oral treatment with 5 mg/kg/day of CsA or application of 2% CsA eye drops in olive oil solution. After oral treatment all patients had high CsA levels in blood. Measurable levels of CsA were also found in the saliva and tears. Patients without any intraocular inflammation or patients with mild uveitis did not have any detectable CsA in the aqueous humour. However, patients with severe uveitis had significant levels of CsA in the aqueous humour and in the vitreous. No CsA was found in the cerebrospinal fluid of two patients with central nervous system manifestations of Behçet's disease. After local treatment with 2% CsA eye drops no detectable levels of CsA were found in the blood, the saliva, the aqueous humour, or the vitreous even in patients with severe uveitis. PMID:2378841

  12. Cyclosporin a. Inhibition of experimental autoimmune uveitis in Lewis rats.

    PubMed Central

    Nussenblatt, R B; Rodrigues, M M; Wacker, W B; Cevario, S J; Salinas-Carmona, M C; Gery, I

    1981-01-01

    Cyclosporin A (CS-A), a selective inhibitor of T lymphocytes, is reported here to prevent S antigen (S-Ag) induced uveitis in Lewis rats. The S-Ag, found in all mammalian retinas, is uveitogenic under experimental conditions and patients with certain uveitic entities demonstrate cell mediated responses to this antigen. Daily treatment with CS-A (10 mg/kg) begun on the same day as S-Ag immunization totally inhibited the development of the uveitis in this experimental autoimmune model. Moreover a greater CS-A dose (40 mg/kg) efficiently prevented the disease process when therapy was started 7 d after S-Ag immunization. Anti-S-Ag antibody titers were observed to be similar in rats either protected or not protected with CS-A. Our data support strongly the need for T cell participation in this disease model. Since ocular inflammatory disease is an important cause of visual impairment, the data further suggest that CS-A may be useful in the treatment of patients with intractable uveitis. Images PMID:7204576

  13. Paradoxical effects of cyclosporin A on collagen arthritis in rats

    PubMed Central

    1983-01-01

    The effect of the immunosuppressive agent cyclosporin A (CS-A) on collagen arthritis in Sprague-Dawley rats is investigated. A 14-d course of CS-A treatment at doses of 15 mg/kg per day or more, begun on the same day as type II collagen immunization, suppressed the development of arthritis as well as humoral and delayed-type hypersensitivity (DTH) skin test responses to type II collagen, possibly by interfering with helper T cells. Additional studies demonstrated that CS-A treatment only during the induction phase of immunity proved to be successful. When CS-A treatment was started only during the immediately preclinical phase of arthritis or after the disease onset, a significant enhancement of the disease was obtained in a dose-dependent manner. This enhancement was accompanied by an augmentation of DTH skin reactions, while antibody responses were either suppressed or unaffected. These results appear to be attributable at least in part to a suppressive effect of CS-A on a population of suppressor T cells, thus resulting in a T cell-mediated helper effect. It is therefore reasonable to assume that the paradoxical effects of CS-A on collagen arthritis in rats might be caused by an altering of the sensitive balance of the two regulatory subpopulations of T cells. It is also possible that cell-mediated immune responses may play an important role in influencing the course of the disease. PMID:6644238

  14. 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.

  15. The use of cyclosporin A in clinical organ grafting.

    PubMed Central

    Calne, R Y; White, D J

    1982-01-01

    Experiments in animals with organ allografts showed that Cyclosporin A (CyA) was an extremely powerful immunosuppressant with a good therapeutic index. A pilot study of the drug in human recipients of renal allografts revealed an unexpected side effect, nephrotoxicity, which made care of patients difficult. Following a policy of deliberate hydration of patients in the perioperative phase and withholding CyA until diuresis was occurring in the graft, excellent results have been obtained in clinical practice. An 82% actuarial functional survival at both one and two years has been obtained in the 59 patients treated with this protocol. A multicenter trial is now in progress in eight centers in Europe, comparing CyA used in the manner described above with conventional azathioprine and steroids. CyA has also been used in 17 recipients of liver allografts, ten of whom are still alive and 11 recipients of segmental pancreatic allografts, one of whom remains off insulin after two and a quarter years. Sudden graft failure occurred between three months and two years in three patients whose pancreatic duct had been occluded. The authors' most recent segmental pancreas graft has been drained into a long roux loop without complications. The main objective in the use of this drug is to obtain consistent immunosuppression without nephrotoxicity. It is possible that maintaining blood level between defined limits would improve results. PMID:7051997

  16. Pharmacokinetic strategies for cyclosporin therapy in organ transplantation.

    PubMed

    Kahan, B D; Welsh, M; Knight, R; Katz, S; Lewis, R; Grevel, J; Van Buren, C T

    1992-04-01

    Marked interindividual variations in cyclosporin (CsA) produce disparate clinical results in organ transplant recipients. In an attempt to eliminate marked deviations of insufficient or excessive CsA concentrations consequent to the administration of uniform drug doses, test dose pharmacokinetics were performed on each potential organ transplant candidate. An intravenous 3 mg/kg test dose delivered over 3 h proved to be readily performed, namely 53% perfect studies, and relatively reliable, namely 73% of observed concentrations within 10% of the predicted values. Furthermore, the use of CsA doses predicted by pretransplant studies reduces the incidence of delayed graft function, early rejection episodes and transplant loss. The oral test dose study predicted a suitable amount of CsA to achieve sufficient gastrointestinal absorption but was less accurate than the iv prediction method: namely, 40% of observed post-transplant concentrations were within 10% of the predicted target value. Furthermore, patients who received oral doses predicted by the test dose strategy showed no improvement in the incidence of acute rejection episodes between 7 and 60 days, and only modestly improved serum creatinine values. The lower accuracy of predictions from oral test dose studies may reflect the impact of non-linear oral (as opposed to iv) drug pharmacokinetics, of variable diet, and/or of altered postoperative gastrointestinal function.

  17. Pharmacokinetics of oral cyclosporin A (Sandimmun) in healthy subjects.

    PubMed

    Grevel, J; Nüesch, E; Abisch, E; Kutz, K

    1986-01-01

    Extensive pharmacokinetic (PK) profiles after oral dosing of 300 mg cyclosporin A (CsA) were determined in whole blood by radioimmunoassay (RIA) in 14 healthy male volunteers, using two-compartment models with either first order (M1) or zero order (M0) absorption. According to zero order absorption the mean of the following PK parameters was determined: terminal half-life = 12.1 +/- 5.0 h, apparent volume of distribution at steady-state = 5.6 +/- 2.11 X kg-1, apparent clearance = 0.51 +/- 0.11 l X h-1 X kg-1. The time lag between drug ingestion and first blood level was short, 0.38 +/- 0.11 h. Drug absorption lasted for 2.8 +/- 1.6 h. The end of absorption was indicated in each individual by a sharp drop in blood levels. The observations support the assumption that CsA is absorbed in the upper part of the small intestine with a clear-cut termination (absorption window). This assumption may explain the high degree of variability in the bioavailability of CsA.

  18. Lipid abnormalities in cyclosporine-prednisone-treated renal transplant recipients.

    PubMed

    Vathsala, A; Weinberg, R B; Schoenberg, L; Grevel, J; Goldstein, R A; Van Buren, C T; Lewis, R M; Kahan, B D

    1989-07-01

    Hyperlipidemia and hypertension, two major risk factors for accelerated atherosclerosis, undoubtedly contribute to the excessive cardiovascular morbidity and mortality experienced by renal transplant recipients. The present survey of posttransplant hyperlipidemia in 500 cyclosporine-treated patients documented a 37.6% incidence of hypercholesterolemia, which occurred within 6 months posttransplant in 82% of patients. An etiologic relation to corticosteroid therapy was suggested by the strong correlation between prednisone doses and cholesterol levels, by the reduced cholesterol levels in patients undergoing steroid withdrawal, and by the reduction in hypercholesterolemia to 13% by 3 years posttransplant when steroid doses were less than 10 mg daily. Hypertriglyceridemia, which was present in 14.7% of the patients, was more severe under CsA-prednisone compared with azathioprine-prednisone therapy. Hypertriglyceridemia, which occurred later in the posttransplant course than hypercholesterolemia, strongly correlated with an excessive percent relative weight and elevated serum creatinine but not with steroid or CsA doses. Increasing age, diabetes mellitus, beta-blockers and nephrotic syndrome contribute to posttransplant hyperlipidemia in the CsA-Pred era as they did in the azathioprine era of immunosuppression.

  19. Risk factor control is key in diabetic nephropathy.

    PubMed

    Lewis, Gareth; Maxwell, Alexander P

    2014-02-01

    Prolonged duration of diabetes, poor glycaemic control and hypertension are major risk factors for both diabetic nephropathy and cardiovascular disease. Optimising blood sugar control together with excellent control of blood pressure can reduce the risk of developing diabetic nephropathy. Diabetic nephropathy should be considered in any patient with diabetes when persistent albuminuria develops. Microalbuminuria is the earliest clinically detectable indicator of diabetic nephropathy risk. The majority of patients with diabetic nephropathy are appropriately diagnosed based on elevated urinary albumin excretion and/or reduced 0032-6518 renal function. Patients with type 2 diabetes should have annual urinary ACR measurements from the time of diabetes diagnosis while those with type 1 diabetes should commence five years after diagnosis. Blood pressure lowering to 130/80mmHg and reduction of proteinuria to <1 g/day retards progression of diabetic nephropathy and reduces the number of cardiovascular events. Drugs that block the renin-angiotensin-aldosterone system (RAAS) are effective in reducing proteinuria, managing hypertension and reducing cardiovascular risk. Unless there are clear contraindications or intolerance all patients with diabetic nephropathy should be prescribed an ACEI or ARB. Stopping an ACEI or ARB during intercurrent illness or times of volume depletion is critically important. Patients with diabetic nephropathy should have at least yearly measurements of blood pressure, renal function and urinary ACR.

  20. 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.

  1. Bromocriptine and low dose cyclosporine in the treatment of experimental autoimmune uveitis in the rat.

    PubMed Central

    Palestine, A G; Muellenberg-Coulombre, C G; Kim, M K; Gelato, M C; Nussenblatt, R B

    1987-01-01

    The immunologic effects of bromocriptine and low dose cyclosporine on experimental autoimmune uveitis (EAU) induced in Lewis rats by S-antigen immunization were studied. Rats treated with a sub-optimal dose (low dose) of cyclosporine (2 mg/kg per d), bromocriptine (1.8 mg/kg per d), or both drugs were compared with untreated rats in regard to the development of EAU, lymphocyte proliferative responses, and anti-S-antigen serum antibodies. Bromocriptine alone decreased the incidence of EAU only in female rats (P less than 0.01), did not effect the lymphocyte proliferative response, but did significantly decrease antibody titers in both males (P less than 0.004) and females (P less than 0.0005). Low dose cyclosporine also partially decreased the incidence of EAU in female rats, but did not decrease antibody titers or lymphocyte proliferative responses. Bromocriptine plus low-dose cyclosporine led to more marked decreases in the incidence of EAU and anti-S-antigen antibody titers as well as in the lymphocyte proliferative assay (P less than 0.01 for males, P less than 0.0005 for females). This study suggests that bromocriptine can enhance the immunosuppression of low dose cyclosporine. PMID:3494043

  2. Accuracy of cyclosporin measurements made in capillary blood samples obtained by skin puncture.

    PubMed

    Merton, G; Jones, K; Lee, M; Johnston, A; Holt, D W

    2000-10-01

    International consensus guidelines suggest that cyclosporin should be measured in whole blood. In some instances it may be advantageous to collect capillary blood, by a finger or ear prick method. However, drug concentrations in skin-puncture blood may not necessarily correlate with those measured in venous blood. This study compared cyclosporin concentrations in blood collected from the fingertip or earlobe with blood collected by standard venipuncture. Patient preference for each of the blood collection methods was also assessed. Specimens were obtained from organ transplant patients receiving cyclosporin, using each of the three methods: venipuncture, finger prick, and earlobe prick. The samples were assayed using a specific radioimmunoassay and the results were compared. In the 102 sets of samples collected, the mean difference (+/- standard deviation) in cyclosporin concentration between finger prick and venipuncture and ear prick and venipuncture was 2.6% (+/- 9.5%) and 2.7% (+/- 12.1%), respectively, while the comparable median (IQR) differences were 1.9% (-3.4% to +6.6%) and -1.1% (-2.8% to +7.2%), respectively. A high degree of correlation was observed between finger prick and venipuncture or ear prick and venipuncture or ear prick and finger prick (r2 > 0.86). Of the three methods of blood collection, finger prick was the patients' preferred method (P < 0.01). These data suggest that capillary blood collected by skin puncture is suitable for use in cyclosporin blood monitoring and acceptable to patients.

  3. Eosinophilic cellulitis (Wells' syndrome) successfully treated with low-dose cyclosporine.

    PubMed Central

    Herr, H.; Koh, J. K.

    2001-01-01

    Eosinophilic cellulitis (Wells'syndrome) is an uncommon skin disorder. We report two adult male patients who had recurrent erythematous plaques and a nodular lesion on the abdomen. The histopathologic feature of their skin biopsies similarly indicated a marked infiltrate of eosinophils in the dermis with the fashion of "flame figures". One of the patients demonstrated blood eosinophilia. Given the clinicohistological findings, the patients fulfilled the criteria for the diagnosis of eosinophilic cellulitis. The skin lesions remained refractory to medications such as corticosteroids, sulfones, antihistamines, and minocycline. Considering the beneficial effect of cyclosporine in the treatment of eosinophilia-associated dermatoses, we speculated that eosinophilic cellulitis might respond to cyclosporine therapy. Thus, each of the two patients was given cyclosporine (microemulsion formulation) at a daily dose of 1.25 or 2.5 mg/kg, i.e., 100 or 200 mg, respectively. Complete remission of the skin eruptions was obtained in both patients during a 3- or 4-week period of treatment. No side effects were observed. Neither of the patients experienced relapse of the disease at least over 10 months after the discontinuation of the cyclosporine therapy. We suggest that administration of low-dose cyclosporine be a safe and useful therapeutic option in patients with eosinophilic cellulitis. PMID:11641541

  4. The kinetics of cyclosporine and its metabolites in bone marrow transplant patients.

    PubMed Central

    Schwinghammer, T L; Przepiorka, D; Venkataramanan, R; Wang, C P; Burckart, G J; Rosenfeld, C S; Shadduck, R K

    1991-01-01

    1. The pharmacokinetics of cyclosporine (CsA) and the time course of CsA metabolites were studied in five bone marrow transplant patients after intravenous (i.v.) administration on two separate occasions and once after oral CsA administration. 2. Cyclosporine and cyclosporine metabolites were measured in whole blood by h.p.l.c. 3. Cyclosporine clearance after i.v. administration decreased from 3.9 +/- 1.7 ml min-1 kg-1 to 2.0 +/- 0.6 ml min-1 kg-1 after 14 days of treatment. The mean +/- s.d. absolute oral bioavailability of cyclosporine was 17 +/- 11%. 4. Hydroxylated CsA (M-17) was the major metabolite in blood. There were no significant differences in the mean metabolite/CsA AUC ratios between the first and second i.v. studies. 5. After oral administration, the metabolite to CsA AUC ratios were higher for most metabolites compared to those observed in the second i.v. study, suggesting a contribution of intestinal metabolism to the clearance of CsA. PMID:1777368

  5. 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

  6. Immunohistochemical diagnosis of Fabry nephropathy and localisation of globotriaosylceramide deposits in paraffin-embedded kidney tissue sections.

    PubMed

    Valbuena, Carmen; Leitão, Dina; Carneiro, Fátima; Oliveira, João Paulo

    2012-02-01

    Fabry disease (FD) is a rare X-linked lysosomal storage disorder of glycosphingolipids, mostly globotriaosylceramide (Gb3). Proteinuric chronic kidney disease develops frequently, and recognition of Fabry nephropathy on a kidney biopsy may be the first clue to the underlying diagnosis. Since the accumulated glycosphingolipids are largely extracted by the paraffin-embedding procedure, the most characteristic feature of Fabry nephropathy on routine light microscopy (LM) is nonspecific cell vacuolization. To test whether residual Gb3 in kidney tissue might be exploited for the specific diagnosis of Fabry nephropathy, paraffin-embedded kidney biopsies of nine FD patients (one boy, four men, four women) and of a female carrier of a mild genetic mutation, with no evidence of Fabry nephropathy, were immunostained with an anti-Gb3 antibody. The adult biopsies were additionally co-stained with a lysosomal marker (anti-lysosomal-associated membrane protein 2 (anti-LAMP2) antibody). The distribution of Gb3 deposits was scored per cell type and compared to the histological scorings of glycosphingolipid inclusions on semi-thin sections. FD patients had residual Gb3 in all types of glomerular, tubular, interstitial and vascular kidney cells. The highest expression of LAMP2 was seen in tubular cells, but there were no meaningful associations between LAMP2 expression and prevalence of Gb3 deposits on different kidney cell types. The histological scorings of glycosphingolipid inclusions were relatively higher than the corresponding immunohistochemical scorings of Gb3 deposits. In the mildly affected female, Gb3 expression was limited to tubular cells, a pattern similar to controls. Gb3 immunostaining allows the specific diagnosis of Fabry nephropathy even in kidney biopsies routinely processed for LM.

  7. Mechanisms of diabetic nephropathy--old buddies and newcomers part 2.

    PubMed

    Nawroth, P P; Isermann, B

    2010-11-01

    The clinical translation of established pathomechanisms of diabetic nephropathy improved the outcome in patients with diabetic nephropathy. However, they fail to halt or even reverse diabetic nephropathy, even though the feasibility of disease reversal has been established. The second part of this review summarizes recent novel insights into the mechanisms of diabetic nephropathy focusing on novel candidate mechanisms of diabetic nephropathy. These studies emphasize a crucial role of endothelial dependent mechanisms, which, however, can not be viewed as independent determinants of diabetic nephropathy. Rather, the endothelial dependent mechanisms act in concert with other cellular systems, establishing an intra-glomerular cross-talk which determines the progression of diabetic nephropathy.

  8. Rodent models of diabetic nephropathy: their utility and limitations

    PubMed Central

    Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

    2016-01-01

    Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2 diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and a decrease in renal function, as well as the characteristic histological changes in the glomeruli and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A rodent model that strongly exhibits all these features of human diabetic nephropathy has not yet been developed. However, the currently available rodent models of diabetes can be useful in the study of diabetic nephropathy by increasing our understanding of the features of each diabetic rodent model. Furthermore, the genetic background and strain of each mouse model result in differences in susceptibility to diabetic nephropathy with albuminuria and the development of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model reproducing human diabetic nephropathy will significantly facilitate our understanding of the underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In this review, we focus on rodent models of diabetes and discuss the utility and limitations of these models for the study of diabetic

  9. Rodent models of diabetic nephropathy: their utility and limitations.

    PubMed

    Kitada, Munehiro; Ogura, Yoshio; Koya, Daisuke

    2016-01-01

    Diabetic nephropathy is the most common cause of end-stage renal disease. Therefore, novel therapies for the suppression of diabetic nephropathy must be developed. Rodent models are useful for elucidating the pathogenesis of diseases and testing novel therapies, and many type 1 and type 2 diabetic rodent models have been established for the study of diabetes and diabetic complications. Streptozotocin (STZ)-induced diabetic animals are widely used as a model of type 1 diabetes. Akita diabetic mice that have an Ins2+/C96Y mutation and OVE26 mice that overexpress calmodulin in pancreatic β-cells serve as a genetic model of type 1 diabetes. In addition, db/db mice, KK-Ay mice, Zucker diabetic fatty rats, Wistar fatty rats, Otsuka Long-Evans Tokushima Fatty rats and Goto-Kakizaki rats serve as rodent models of type 2 diabetes. An animal model of diabetic nephropathy should exhibit progressive albuminuria and a decrease in renal function, as well as the characteristic histological changes in the glomeruli and the tubulointerstitial lesions that are observed in cases of human diabetic nephropathy. A rodent model that strongly exhibits all these features of human diabetic nephropathy has not yet been developed. However, the currently available rodent models of diabetes can be useful in the study of diabetic nephropathy by increasing our understanding of the features of each diabetic rodent model. Furthermore, the genetic background and strain of each mouse model result in differences in susceptibility to diabetic nephropathy with albuminuria and the development of glomerular and tubulointerstitial lesions. Therefore, the validation of an animal model reproducing human diabetic nephropathy will significantly facilitate our understanding of the underlying genetic mechanisms that contribute to the development of diabetic nephropathy. In this review, we focus on rodent models of diabetes and discuss the utility and limitations of these models for the study of diabetic

  10. Early Diabetic Nephropathy in Type 1 Diabetes – New Insights

    PubMed Central

    Bjornstad, Petter; Cherney, David; Maahs, David M.

    2014-01-01

    Purpose of review Despite improvements in glycemic and blood pressure control in patients with T1D, diabetic nephropathy (DN) remains the most common cause of chronic kidney disease worldwide. A major challenge in preventing DN is the inability to identify high-risk patients at an early stage, emphasizing the importance of discovering new therapeutic targets and implementation of clinical trials to reduce DN risk. Recent findings Limitations of managing patients with DN with renin angiotensin aldosterone system (RAAS) blockade have been identified in recent clinical trials, including the failure of primary prevention studies in T1D and the demonstration of harm with dual RAAS blockade. Fortunately, several new targets, including serum uric acid, insulin sensitivity, vasopressin and sodium-glucose cotransporter-2 inhibition are promising in the prevention and treatment of DN. Summary DN is characterized by a long clinically silent period without signs or symptoms of disease. There is an urgent need for improved methods of detecting early mediators of renal injury, to ultimately prevent initiation and progression of DN. In this review, we will focus on early DN and summarize potential new therapeutic targets. PMID:24983394

  11. Vitamin D, proteinuria, diabetic nephropathy, and progression of CKD.

    PubMed

    Agarwal, Rajiv

    2009-09-01

    Although the endocrine effects of vitamin D are widely recognized, somewhat less appreciated is that vitamin D may serve paracrine functions through local activation by 1-alpha-hydroxylase and thus maintain immunity, vascular function, cardiomyocyte health, and abrogate inflammation and insulin resistance. In the kidney, vitamin D may be important for maintaining podocyte health, preventing epithelial-to-mesenchymal transformation, and suppressing renin gene expression and inflammation. Replacement with pharmacologic dosages of vitamin D receptor agonists (VDRA) in animal models of kidney disease consistently show reduction in albuminuria, abrogation of glomerulosclerosis, glomerulomegaly, and glomerular inflammation, effects that may be independent of BP and parathyroid hormone, but the effects of VDRA in preventing tubulointerstitial fibrosis and preventing the progression of kidney failure in these animal models are less clear. Emerging evidence in patients with chronic kidney disease (CKD) show that vitamin D can reduce proteinuria or albuminuria even in the presence of angiotensin-converting enzyme inhibition. In addition to reducing proteinuria, VDRA may reduce insulin resistance, BP, and inflammation and preserve podocyte loss providing biologic plausibility to the notion that the use of VDRA may be associated with salubrious outcomes in patients with diabetic nephropathy. Patients with CKD have a very high prevalence of deficiency of 25-hydroxyvitamin D. Whether pharmacologic dosages of vitamin D instead of VDRA in patients with CKD can overcome the paracrine and endocrine functions of this vitamin remains unknown. To demonstrate the putative benefits of native vitamin D and VDRA among patients with CKD, randomized, controlled trials are needed.

  12. 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.

  13. Feasibility of early tapering of cyclosporine following reduced-intensity stem cell transplantation for advanced hematologic or solid malignancies.

    PubMed

    Hori, Akiko; Kami, Masahiro; Ohnishi, Mutsuko; Murashige, Naoko; Kojima, Rie; Takaue, Yoichi

    2005-07-01

    Although some researchers have reported that early tapering of cyclosporine is feasible and beneficial to augment graft-versus-leukemia effects after conventional stem-cell transplantation, there is little information on the feasibility of this strategy following reduced-intensity stem cell transplantation (RIST). We summarized outcomes of 17 patients who underwent early tapering of cyclosporine following RIST from HLA-identical siblings.

  14. Identification of Spongionella compounds as cyclosporine A mimics.

    PubMed

    Sánchez, Jon Andoni; Alfonso, Amparo; Leirós, Marta; Alonso, Eva; Rateb, Mostafa E; Jaspars, Marcel; Houssen, Wael E; Ebel, Rainer; Tabudravu, J; Botana, Luís M

    2016-05-01

    Marine sponges are found to be a wide source of bioactive compounds with different effects such as anti-inflammatory or anticancer actions among others. Cyclophilin A (Cyp A) is a target protein implicated in the mechanism of action of immunosuppressive compounds such as Cyclosporine A (CsA). In the present paper we studied the binding between 4 Spongionella compounds (Gracilins H, A, L and Tetrahydroaplysulphurin-1) and Cyp A immobilized over a CM5 sensor chip. Thus, we found that Spongionella compounds showed to have similar binding affinities than CsA with dissociation equilibrium constant in the range. Next, the effect of these Spongionella isolated compounds was tested over calcineurin phosphatase activity. The same than CsA, Gracilin H, A and Tetrahydroaplysulphurin-1 were able to inhibit phosphatase activity once the complex between Cyp A-CsA/Spongionella compounds was formed. The ability to avoid the dephosphorylation of NFATc1 was also checked in human T cells isolated from peripheral blood. First, cells were pre-treated with Spongionella compounds or CsA following by Concanavalin A (Con A) stimulation. In these conditions nuclear NFATc1 levels were diminished either by CsA or Gracilin A, L, and Tetrahydroaplysulphurin-1 treatment. Moreover, as happens with CsA due to the inhibition of NFATc1, Interleukine-2 (IL-2) released to the culture medium was significantly decreased with all Spongionella compounds. Results conclude that, Spongionella derivatives preserve T lymphocytes from activation modulating the same pathway than CsA. Thus, this mechanism of action suggests that these compounds could be interesting candidates in drug development as immunosuppressive or anti-inflammatory drugs.

  15. Bioequivalence of a new cyclosporine a formulation to Neoral.

    PubMed

    David-Neto, Elias; Kakehashi, Erica; Alves, Cristiane Feres; Pereira, Lilian M; de Castro, Maria Cristina R; de Mattos, Renata Maciel; Sumita, Nairo Massakazu; Romano, Paschoalina; Mendes, Maria Elizabete; Nahas, William Carlos; Ianhez, Luiz Estevam

    2004-02-01

    New cyclosporine A (CsA) formulations must prove their bioequivalence to Neoral, the reference CsA formulation, to allow free prescription for the patients. The aim of this study was to compare the pharmacokinetics (PK) of a new CsA formulation (Zinograf-ME), produced by Strides-Arcolab, to Neoral and to demonstrate their interchangeability in stable renal transplant recipients. Twelve-hour PK studies were obtained from 18 (13 M/5 F) adult patients (mean age 44.7 +/- 12 years). They received their renal allografts from 13 cadaver and 5 living donors. Before enrollment, all patients were receiving a third generic CsA for a mean of 48 months. Nine patients were also under azathioprine and 9 under mycophenolate mofetil; 17 received prednisone. A single oral dose of either Zinograf or Neoral was administered. The first PK study was performed with one formulation, and 1 week later, a second PK was done with the other formulation. During the washout period, patients continued taking the third CsA formulation. The drug substitution was done milligram-for-milligram. The CsA whole-blood level was measured by TDx immunoassay. Mean +/- SD of area under the curve (AUC), maximum concentration (C(max)), and concentration at the second hour (C2) of Zinograf were not statistically different from those with Neoral (4019 +/- 1466 vs 3971 +/- 1325 ng x h/mL, 998 +/- 376 vs 1021 +/- 356 ng/mL, and 707 +/- 254 vs 734 +/- 229 ng/mL, respectively). In the same way, the Zinograf 90% confidence interval for either C(max) (-123, +77 ng/mL) or AUC (-214, +311 ng.mL/h) were within the Neoral bioequivalence interval for the same parameters (+/-204 ng/mL and +/-794 ng x mL/h, respectively). These data demonstrate that the ZinografME CsA formulation is bioequivalent to Neoral.

  16. 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

  17. Modification of c and n sources for enhanced production of cyclosporin 'a' by Aspergillus Terreus.

    PubMed

    Tanseer, Sundas; Anjum, Tehmina

    2011-10-01

    Most of the studies regarding cyclosporin 'A' production through fungi concentrate around Tolypocladium inflatum. This is mainly due to lower reported production of this drug in other fungi. The present study was therefore conducted to explore indigenous isolates of Aspergillus terreus for synthesis of this drug and defining a production medium for obtaining high yield of cyclosporin 'A'. For this purpose carbon and nitrogen sources were optimized for the selected best strain of A. terreus. Overall results depicted that the best cyclosporin 'A' yield from selected Aspergillus terreus (FCBP58) could be obtained by using production medium containing glucose 10% as carbon source and peptone 0.5% as nitrogen source. This modification in production medium enhanced drug synthesis by selected fungi significantly. The production capabilities when compared with biomass of fungi there was found no relationship between the two confirming that the medium modification increased overall drug synthesis powers of the fungi.

  18. 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.

  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.

  20. Effect of cyclosporin A treatment on the production of antibody in insulin-dependent (type I) diabetic patients.

    PubMed Central

    Boitard, C; Feutren, G; Castano, L; Debray-Sachs, M; Assan, R; Hors, J; Bach, J F

    1987-01-01

    Anti-islet cell and anti-insulin antibody production was studies over a 12-mo period in 82 recently diagnosed diabetics randomly receiving either cyclosporin or placebo. Cyclosporin had only minimal effects on the production of anti-islet cell antibodies whether directed to islet cytoplasmic (immunofluorescence) or membrane (cytotoxicity assay) antigens even in patients undergoing remission. These data suggest that these antibodies do not play a major role in the pathogenesis of the disease particularly since their (irregular) presence is not predictive of the clinical response to cyclosporin. Conversely, cyclosporin completely suppressed the synthesis of antibodies elicited by exogenous insulin irrespective of the insulin doses received, and decreased the autoantibody production against thyroid antigens, indicating that cyclosporin has variable effects on antibody production against various antigens. PMID:3316278

  1. Reversible fibroadenomatous mammary hyperplasia in male and female New Zealand white rabbits associated with cyclosporine A administration.

    PubMed

    Krimer, P M; Harvey, S B; Blas-Machado, U; Lauderdale, J D; Moore, P A

    2009-11-01

    All male and female New Zealand white rabbits in a limbal cell graft study developed marked generalized mammary gland hypertrophy. Postprocedural medications included ophthalmic 0.1% dexamethasone, ophthalmic 0.5% cyclosporine, and subcutaneous cyclosporine A. Cytologic examination revealed epithelial clusters with minimal malignant criteria. On histologic evaluation, there was diffuse glandular hyperplasia with mild cellular atypia and ductal ectasia separated by abundant hypercellular fibrous stroma, consistent with fibroadenomatous mammary gland hyperplasia. The hyperplasia resolved within 2 weeks of cessation of cyclosporine, and at necropsy identifiable mammary masses were not found. Very little has been reported about the use of cyclosporine in laboratory rabbits and its association with development of mammary gland hyperplasia. This is the first report in which administration of cyclosporine to male and female rabbits at a dose as low as 5 mg/kg/day induced benign fibroadenomatous mammary gland hyperplasia. This change regressed after cessation of the drug.

  2. 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)

  3. 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

  4. Membranous nephropathy that first presented in pregnancy.

    PubMed

    Aoshima, Yumie; Iyoda, Masayuki; Nakazawa, Ai; Yamaguchi, Yutaka; Kuroki, Aki; Shibata, Takanori; Akizawa, Tadao

    2013-01-01

    A 37-year-old woman at 17 weeks of gestation who was first noted to have proteinuria and microscopic hematuria at 13 weeks of gestation was admitted to our hospital with proteinuria that progressed to nephrotic syndrome (NS). Despite the treatment with prednisolone, including methylprednisolone pulse therapy, the NS worsened. The patient underwent an elective abortion at 21 weeks of gestation, and the NS then went into partial remission. A renal biopsy revealed membranous nephropathy (MN). There was no evidence of secondary MN. This is the first reported case of subclinical idiopathic MN that first developed in pregnancy.

  5. [Contrast-induced nephropathy: An update].

    PubMed

    Spagnoli, V; Azzalini, L; Tadros, V X; Picard, F; Ly, H Q

    2016-04-01

    Contrast-induced nephropathy (CIN) is common in hospitalized patients. Its occurrence is associated with an increased hospitalization stay and cost, morbidity and mortality. Thus, preventives strategies remain a major issue. Patients that are referred for cardiac catheterization are among the most vulnerable to develop CIN due to their comorbidities. Moreover, in some cases, such preventives measures cannot be introduced due to emergent clinical settings. After a summary regarding the properties of iodinated contrast medium, the aim of this work was to review the definition, pathophysiology, diagnosis and preventive strategies related to CIN.

  6. Gold nephropathy in juvenile rheumatoid arthritis.

    PubMed

    Husserl, F E; Shuler, S E

    1979-01-01

    A 2-year-old girl was treated with gold salts for juvenile rheumatoid arthritis. Treatment had to be discontinued when persistent proteinuria was detected. As this case report indicates, close monitoring of the urine is mandatory during treatment with gold salts to detect early signs of toxicity: hematuria followed by casts and then proteinuria as therapy is continued. Histologic examination with electron microscopy will help to differentiate the different forms of gold toxicity. When the findings are consistent with gold-induced renal involvement, therapy should be discontinued. The gold nephropathy usually resolves in time, with no permanent renal damage.

  7. 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.

  8. Hypertension in Chronic Glomerulonephritis

    PubMed Central

    2015-01-01

    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

  9. Preventive Effect of Salicylate and Pyridoxamine on Diabetic Nephropathy

    PubMed Central

    Abouzed, Tarek Kamal; Munesue, Seiichi; Harashima, Ai; Masuo, Yusuke; Kato, Yukio; Khailo, Khaled; Yamamoto, Hiroshi

    2016-01-01

    Objective. Diabetic nephropathy is a life-threatening complication in patients with long-standing diabetes. Hemodynamic, inflammatory, and metabolic factors are considered as developmental factors for diabetic nephropathy. In this study, we evaluated whether pharmacological interventions with salicylate, compared to pyridoxamine, could prevent diabetic nephropathy in mice. Methods. Male mice overexpressing inducible nitric oxide synthase in pancreatic β-cells were employed as a diabetic model. Salicylate (3 g/kg diet) or pyridoxamine (1 g/L drinking water; ~200 mg/kg/day) was given for 16 weeks to assess the development of diabetic nephropathy. Treatment with long-acting insulin (Levemir 2 units/kg twice a day) was used as a control. Results. Although higher blood glucose levels were not significantly affected by pyridoxamine, early to late stage indices of nephropathy were attenuated, including kidney enlargement, albuminuria, and increased serum creatinine, glomerulosclerosis, and inflammatory and profibrotic gene expressions. Salicylate showed beneficial effects on diabetic nephropathy similar to those of pyridoxamine, which include lowering blood glucose levels and inhibiting macrophage infiltration into the kidneys. Attenuation of macrophage infiltration into the kidneys and upregulation of antiglycating enzyme glyoxalase 1 gene expression were found only in the salicylate treatment group. Conclusions. Treatment with salicylate and pyridoxamine could prevent the development of diabetic nephropathy in mice and, therefore, would be a potentially useful therapeutic strategy against kidney problems in patients with diabetes. PMID:28042580

  10. Preventive Effect of Salicylate and Pyridoxamine on Diabetic Nephropathy.

    PubMed

    Abouzed, Tarek Kamal; Munesue, Seiichi; Harashima, Ai; Masuo, Yusuke; Kato, Yukio; Khailo, Khaled; Yamamoto, Hiroshi; Yamamoto, Yasuhiko

    2016-01-01

    Objective. Diabetic nephropathy is a life-threatening complication in patients with long-standing diabetes. Hemodynamic, inflammatory, and metabolic factors are considered as developmental factors for diabetic nephropathy. In this study, we evaluated whether pharmacological interventions with salicylate, compared to pyridoxamine, could prevent diabetic nephropathy in mice. Methods. Male mice overexpressing inducible nitric oxide synthase in pancreatic β-cells were employed as a diabetic model. Salicylate (3 g/kg diet) or pyridoxamine (1 g/L drinking water; ~200 mg/kg/day) was given for 16 weeks to assess the development of diabetic nephropathy. Treatment with long-acting insulin (Levemir 2 units/kg twice a day) was used as a control. Results. Although higher blood glucose levels were not significantly affected by pyridoxamine, early to late stage indices of nephropathy were attenuated, including kidney enlargement, albuminuria, and increased serum creatinine, glomerulosclerosis, and inflammatory and profibrotic gene expressions. Salicylate showed beneficial effects on diabetic nephropathy similar to those of pyridoxamine, which include lowering blood glucose levels and inhibiting macrophage infiltration into the kidneys. Attenuation of macrophage infiltration into the kidneys and upregulation of antiglycating enzyme glyoxalase 1 gene expression were found only in the salicylate treatment group. Conclusions. Treatment with salicylate and pyridoxamine could prevent the development of diabetic nephropathy in mice and, therefore, would be a potentially useful therapeutic strategy against kidney problems in patients with diabetes.

  11. Diabetic Nephropathy: New Risk Factors and Improvements in Diagnosis.

    PubMed

    Tziomalos, Konstantinos; Athyros, Vasilios G

    2015-01-01

    Diabetic nephropathy is the leading cause of end-stage renal disease. Patients with diabetic nephropathy have a high cardiovascular risk, comparable to patients with coronary heart disease. Accordingly, identification and management of risk factors for diabetic nephropathy as well as timely diagnosis and prompt management of the condition are of paramount importance for effective treatment. A variety of risk factors promotes the development and progression of diabetic nephropathy, including elevated glucose levels, long duration of diabetes, high blood pressure, obesity, and dyslipidemia. Most of these risk factors are modifiable by antidiabetic, antihypertensive, or lipid-lowering treatment and lifestyle changes. Others such as genetic factors or advanced age cannot be modified. Therefore, the rigorous management of the modifiable risk factors is essential for preventing and delaying the decline in renal function. Early diagnosis of diabetic nephropathy is another essential component in the management of diabetes and its complications such as nephropathy. New markers may allow earlier diagnosis of this common and serious complication, but further studies are needed to clarify their additive predictive value, and to define their cost-benefit ratio. This article reviews the most important risk factors in the development and progression of diabetic nephropathy and summarizes recent developments in the diagnosis of this disease.

  12. AGE, RAGE, and ROS in diabetic nephropathy.

    PubMed

    Tan, Adeline L Y; Forbes, Josephine M; Cooper, Mark E

    2007-03-01

    Diabetic nephropathy is a major cause of morbidity and mortality in diabetic patients. Two key mechanisms implicated in the development of diabetic nephropathy include advanced glycation and oxidative stress. Advanced glycation is the irreversible attachment of reducing sugars onto amino groups of proteins to form advanced glycation end products (AGEs). AGE modification of proteins may lead to alterations in normal function by inducing cross-linking of extracellular matrices. Intracellular formation of AGEs also can cause generalized cellular dysfunction. Furthermore, AGEs can mediate their effects via specific receptors, such as the receptor for AGE (RAGE), activating diverse signal transduction cascades and downstream pathways, including generation of reactive oxygen species (ROS). Oxidative stress occurs as a result of the imbalance between ROS production and antioxidant defenses. Sources of ROS include the mitochondria, auto-oxidation of glucose, and enzymatic pathways including nicotinamide adenine dinucleotide phosphate reduced (NAD[P]H) oxidase. Beyond the current treatments to treat diabetic complications such as the optimization of blood pressure and glycemic control, it is predicted that new therapies designed to target AGEs, including AGE formation inhibitors and cross-link breakers, as well as targeting ROS using novel highly specific antioxidants, will become part of the treatment regimen for diabetic renal disease.

  13. 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

  14. Cyclosporin Therapeutic Drug Monitoring - an Established Service Revisited

    PubMed Central

    Morris, Raymond G

    2003-01-01

    Despite the routine application of therapeutic drug monitoring of cyclosporin (CsA) for two decades, there remain significant analytical issues. In addition, new developments have arisen in the delivery of this laboratory service as well as alternative clinical strategies for delivering optimal benefit to organ transplant recipients. Sample collection strategies are evolving away from the traditional pre-dose/trough (C0) sample in favour of estimates of the absorption phase in the first 4–6 hours after the oral dose of CsA. This is based on the recognition of the relatively poor relationship between C0 and CsA exposure indices, such as area under the blood CsA concentration versus time curve (AUC), especially in the first few hours after the dose. By collecting serial blood samples over this limited period (4hr after the dose) and estimating the AUC0-4, one can gain insight into how well CsA has been absorbed for each transplant recipient, and individualise CsA dosage. However, a recent survey of Australasian CsA laboratories revealed that such AUC0-4 sampling strategies in the early post-dose period were poorly accepted in clinics across Australasia. The alternative that has proven to be more clinically acceptable is the use of a single sample 2-hours after the dose (C2). The C2 concentration has been demonstrated (particularly in kidney and liver transplant recipients) as correlating well with AUC0-4, allowing it to be used as a surrogate index of CsA absorption and exposure. The laboratory survey also showed several areas of concern in the analytical sphere. The major one is that the majority of laboratories employ the two immunoassays that deliver the least specific result on C0 samples within the range of monoclonal methods, leading to high variability and clinically significant errors with patient samples. Laboratories have also adopted a range of dilution protocols for the significantly higher C2 concentrations, and this has proved a source of significant

  15. Fresh vein allograft survival in dogs after cyclosporine treatment.

    PubMed

    Mingoli, A; Edwards, J D; Feldhaus, R J; Hunter, W J; Naspetti, R; Cavallari, N; Sapienza, P; Kretchmar, D H; Cavallaro, A

    1996-04-01

    Synthetic grafts are widely used for peripheral arterial reconstructions when autologous veins are not available, but their results have not been satisfactory. Venous allograft may be used as an alternative to synthetic prostheses. The aim of the study was to explore the immunosuppressive efficacy of Cyclosporine A (CyA) as a means of preventing venous allograft failures and rejection. We utilized 56 mongrel dogs. Immunological incompatibility was checked with the skin graft method. Donor inferior vena cava was transplanted into the infrarenal abdominal aorta of recipient animals. One group (group 1, 10 dogs) served as a control and three groups received CyA treatment regimens. Group 2 (10 dogs) received postoperative oral CyA treatment for 30 days. Group 3 (12 dogs) received a vein graft pretreated with a CyA solution without postoperative immunosuppressive therapy. Group 4 (9 dogs) received a vein graft pretreated with a CyA solution and postoperative CyA treatment for 30 days. Allografts were examined at 30 days for patency, aneurysmal dilatation, gross structural changes, inflammatory response, and lymphocytic infiltration. Sex chromatine assessment determined the origin (donor or recipient) of the endothelial cells. The allografts from groups 1 and 3 showed significant aneurysmal dilatation and perivenous inflammation when compared to dogs treated with oral CyA therapy (P < 0.0002). Moreover allografts treated with CyA therapy had a better-developed venous neointima (P < 0.009) with less fibrin (P < 0.02) and thinner medial (P < 0.0009) with less fibrin (P < 0.02), and thinner medial (P < 0.0009) and adventitial layers (P < 0.02). No significant differences were observed in neointimal thickness among the four groups. Lymphocytic infiltration was greater in the group of animals who did not receive oral CyA therapy (P < 0.0004). Barr bodies status showed significant differences between oral CyA treated groups and nontreated groups (P < 0.0003). Oral CyA therapy

  16. Comparative pharmacokinetic profile of cyclosporine (CsA) with a decapeptide and a linear analogue.

    PubMed

    Price, David A; Eng, Heather; Farley, Kathleen A; Goetz, Gilles H; Huang, Yong; Jiao, Zhaodong; Kalgutkar, Amit S; Kablaoui, Natasha M; Khunte, Bhagyashree; Liras, Spiros; Limberakis, Chris; Mathiowetz, Alan M; Ruggeri, Roger B; Quan, Jun-Min; Yang, Zhen

    2017-03-07

    The synthesis and in vivo pharmacokinetic profile of an analogue of cyclosporine is disclosed. An acyclic congener was also profiled in in vitro assays to compare cell permeability. The compounds possess similar calculated and measured molecular descriptors however have different behaviors in an RRCK assay to assess cell permeability.

  17. Urticarial Dermatitis: Clinical Characteristics of Itch and Therapeutic Response to Cyclosporine

    PubMed Central

    Kim, Jeong-Min; Lim, Kyung-Min; Kim, Hoon-Soo; Ko, Hyun-Chang; Kim, Moon-Bum

    2017-01-01

    Background Urticarial dermatitis, which is characterised by persistent wheals with eczematous papules and plaques, is frequently misdiagnosed and difficult to treat. Patients commonly experience intolerable pruritus which may greatly affect their quality of life. Objective The objective of this study is to characterize the clinical patterns of pruritus in patients with urticarial dermatitis and to determine the effectiveness of cyclosporine treatment. Methods This prospective study included 50 histopathologically confirmed patients with urticarial dermatitis. A face-to-face structured questionnaire was given to all patients, and they were treated with low-dose cyclosporine (1~3 mg/kg/d) for at least 2 weeks. Results The majority of patients (80.0%) had moderate to severe pruritus. Most patients experienced exacerbation of the itch in the evening (74.0%), with the extremities (upper, 86.0%; lower, 94.0%) being the most commonly involved sites. Due to severe pruritus, patients complained about reduced social contact, quality of life and difficulties in falling asleep et al. Cyclosporine significantly reduced the mean itch score and extent of erythema, and improved interference with daily activities and sleep. Conclusion Our study highlights the detailed description and characteristics of pruritus in patients with urticarial dermatitis. And we recommend alternative and effective therapeutic option of low-dose cyclosporine. PMID:28392640

  18. 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

    2014-03-03

    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.

  19. Cyclosporine treatment of perianal gland adenoma concurrent with benign prostatic hyperplasia in a dog

    PubMed Central

    Park, Chul; Yoo, Jong-Hyun; Kim, Ha-Jung; Lim, Chae-Young; Kim, Ju-Won; Lee, So-Young; Kim, Jung-Hyun; Jang, Jae-Im; Park, Hee-Myung

    2010-01-01

    A 13-year-old, intact male, mixed-breed dog was evaluated for multiple intradermal nodules around the anus. The nodules were diagnosed as perianal gland adenoma based on histopathologic examination. After therapy with cyclosporin A for 5 wk, the perianal masses were moderately shrunken. The dog’s condition has remained stable over 6 mo. PMID:21286331

  20. Topical cyclosporin as an alternative treatment for vision threatening blepharokeratoconjunctivitis: a case report.

    PubMed

    Ismail, Abdul-Salim; Taharin, Rohana; Embong, Zunaina

    2012-01-01

    Here, a case of vision threatening blepharokeratoconjunctivitis that responded well to topical cyclosporin is reported. A 9-year-old Malay girl with a history of bilateral blepharokeratoconjunctivitis was regularly treated with lid scrubbing using diluted baby shampoo, fusidic acid gel, and topical steroids as well as an intermittent course of oral doxycycline for the past year. She developed acute onset bilateral eye redness associated with poor vision in her right eye. Both eyes showed marked diffuse hyperemic conjunctiva with corneal vascularization. The presence of corneal vascularization obscured the visual axis in the right eye. The condition did not improve with regular intensive lid hygiene using diluted baby shampoo, fusidic acid gel, and topical steroids. She was started on topical cyclosporin A 0.5% every 6 hours. There was a dramatic regression of corneal vascularization after 3 days on topical cyclosporin, with marked improvement in visual acuity. This is a single case in which cyclosporin improved the status of the ocular surface. A large cohort study is required to justify its effectiveness in treating blepharokeratoconjunctivitis and to test its potential as an alternative immunosuppressive agent in comparison to conventional corticosteroids.

  1. Evidence for pre-hepatic metabolism of oral cyclosporine in children.

    PubMed Central

    Hoppu, K; Koskimies, O; Holmberg, C; Hirvisalo, E L

    1991-01-01

    1. The pharmacokinetics of cyclosporine were investigated before renal transplantation in 20 children aged 1.1 to 16.8 years. Cyclosporine was given as a single oral dose (10 mg kg-1) or as a 4 h i.v. infusion (3 mg kg-1). 2. The blood drug concentration was measured by both specific and nonspecific monoclonal radioimmunoassays. 3. The mean oral availability of cyclosporine was 20.6% (range 10.8-34.1%). 4. The mean ratio of AUCs measured by nonspecific and specific r.i.a. was 1.96 (range 1.4-2.7) after oral administration and 1.43 (range 1.1-2.0) after i.v. administration. The mean difference between the ratios was 38.5% (P = 0.0001). The ratio of AUCnonspecific to AUCspecific was inversely related to blood drug clearance (r = 0.57; P = 0.009). 5. The findings are suggestive of presystemic, pre-hepatic metabolism of cyclosporine which could contribute to the low, and highly variable bioavailability of this drug. PMID:1958443

  2. Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats.

    PubMed

    Sullivan, P G; Rabchevsky, A G; Hicks, R R; Gibson, T R; Fletcher-Turner, A; Scheff, S W

    2000-01-01

    Acute neuropathology following experimental traumatic brain injury results in the rapid necrosis of cortical tissue at the site of injury. This primary injury is exacerbated in the ensuing hours and days via the progression of secondary injury mechanism(s) leading to significant neurological dysfunction. Recent evidence from our laboratory demonstrates that the immunosuppressant cyclosporin A significantly ameliorates cortical damage following traumatic brain injury. The present study extends the previous findings utilizing a unilateral controlled cortical impact model of traumatic brain injury in order to establish a dose-response curve and optimal dosing regimen of cyclosporin A. Following injury to adult rats, cyclosporin A was administrated at various dosages and the therapy was initiated at different times post-injury. In addition to examining the effect of cyclosporin A on the acute disruption of the blood-brain barrier following controlled cortical impact, we also assessed the efficacy of cyclosporin A to reduce tissue damage utilizing the fluid percussion model of traumatic brain injury. The findings demonstrate that the neuroprotection afforded by cyclosporin A is dose-dependent and that a therapeutic window exists up to 24h post-injury. Furthermore, the optimal cyclosporin dosage and regimen markedly reduces disruption of the blood-brain barrier acutely following a cortical contusion injury, and similarly affords significant neuroprotection following fluid percussion injury. These findings clearly suggest that the mechanisms responsible for tissue necrosis following traumatic brain injury are amenable to pharmacological intervention.

  3. [Rapamycin: a new immunosuppressive agent capable of inhibiting chronic rejection?].

    PubMed

    Viklický, O; Matl, I

    2001-01-19

    Chronic rejection represents the most common cause of transplanted graft loss in the long term. Rapamycin (sirolimus), and it's derivate RAD, are new and potent, immunosuppressive drugs. They inhibit cell proliferation driven by various growth factors. These drugs were successfully tested in some experimental models of the chronic rejection. Results of the first clinical trials have defined rapamycin pharmacokinetics and proved immunosuppressive efficacy. Rapamycin acts synergistically with cyclosporin A. The side effects are a dose-dependent thrombocytopenia and leukopenia but the most frequent is hyperlipidemia. The question, if rapamycin and RAD inhibit development of chronic rejection in man, will be solved by the prospective clinical trials over years.

  4. DNA vaccination as a treatment for chronic kidney disease.

    PubMed

    Wang, Yuan Min; Alexander, Stephen I

    2014-01-01

    Chronic kidney disease is one of the major health problems worldwide. DNA vaccination delivers plasmid DNA encoding the target gene to induce both humoral and cellular immune responses. Here, we describe the methods of CD40 DNA vaccine enhanced by dendritic cell (DC) targeting on the development of Heymann nephritis (HN), a rat model of human membranous nephropathy.

  5. 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

  6. Prevalence and Determinants of Diabetic Nephropathy in Korea: Korea National Health and Nutrition Examination Survey

    PubMed Central

    Ahn, Jae Hee; Yu, Ji Hee; Ko, Seung-Hyun; Kwon, Hyuk-Sang; Kim, Dae Jung; Kim, Jae Hyeon; Kim, Chul Sik; Song, Kee-Ho; Won, Jong Chul; Lim, Soo; Choi, Sung Hee; Han, Kyungdo; Cha, Bong-Yun

    2014-01-01

    Background Diabetic nephropathy is a leading cause of end stage renal disease and is associated with an increased risk of cardiovascular mortality. It manifests as albuminuria or impaired glomerular filtration rate (GFR), and the prevalence of diabetic nephropathy varies with ethnicity. The prevalence of diabetic nephropathy and its determinants in Korean adults have not previously been studied at the national level. This cross-sectional study was undertaken to ascertain the prevalence and determinants of albuminuria and chronic kidney disease (CKD) in Korean patients with diabetes. Methods The Korea National Health and Nutrition Examination Survey (KNHANES) V, conducted in 2011, was used to define albuminuria (n=4,652), and the dataset of KNHANES IV-V (2008-2011) was used to define CKD (n=21,521). Selected samples were weighted to represent the entire civilian population in Korea. Albuminuria was defined as a spot urine albumin/creatinine ratio >30 mg/g. CKD was defined as a GFR <60 mL/min/1.73 m2. Results Among subjects with diabetes, 26.7% had albuminuria, and 8.6% had CKD. Diabetes was associated with an approximate 2.5-fold increased risk of albuminuria, with virtually no difference between new-onset and previously diagnosed diabetes. Only systolic blood pressure was significantly associated with albuminuria, and old age, high serum triglyceride levels, and previous cardiovascular disease (CVD) were related with CKD in subjects with diabetes. Conclusion Korean subjects with diabetes had a higher prevalence of albuminuria and CKD than those without diabetes. Blood pressure was associated with albuminuria, and age, triglyceride level, and previous CVD were independent determinants of CKD in subjects with diabetes. PMID:24851205

  7. Effects of benidipine on glomerular hemodynamics and proteinuria in patients with nondiabetic nephropathy.

    PubMed

    Morikawa, Takashi; Okumura, Michiaki; Konishi, Yoshio; Okada, Noriyuki; Imanishi, Masahito

    2002-07-01

    Experimental studies suggest that some long-acting calcium antagonists decrease glomerular hypertension and suppress the progression of nephropathy, but clinical evidence is lacking. To investigate clinically whether a long-acting calcium antagonist, benidipine, lowers glomerular capillary hydraulic pressure via a decrease in efferent arteriolar resistance and decreases proteinuria, we examined hypertensive patients with nondiabetic nephropathy. The subjects were 7 patients with chronic glomerulonephritis or glomerulosclerosis. Before and during the administration of benidipine (4 mg/day), systemic pressure, glomerular hemodynamics, the sodium sensitivity index (reciprocal of the pressure-natriuresis curve), and urinary excretion of proteins (total protein, albumin, and immunoglobulin G) were investigated. The glomerular hemodynamics in terms of glomerular capillary hydraulic pressure and resistance of afferent and efferent arterioles were calculated from the renal clearance, plasma total protein concentration, and pressure-natriuresis relationship. Benidipine lowered the mean arterial pressure from 105 +/-5 to 99 +/- 4 mm Hg (p = 0.002; mean +/- SD) and glomerular pressure from 48 +/- 8 to 39 +/- 5 mmHg (p = 0.006) by decreasing the resistance of efferent arterioles. Benidipine made the pressure-natriuresis curve steeper and decreased the median sodium sensitivity index from 0.099 (0.084 and 0.117; 25th and 75th percentiles) to 0.048 (0.017 and 0.058; p = 0.018). Urinary excretion of proteins did not change. Our clinical study showed that benidipine lowered the glomerular pressure by decreasing the resistance of efferent arterioles and decreased the sodium sensitivity of blood pressure, but did not affect proteinuria in patients with nondiabetic nephropathy.

  8. Area under the curve monitoring of cyclosporine therapy: the early posttransplant period.

    PubMed

    Grevel, J; Kahan, B D

    1991-03-01

    The impact of a new monitoring strategy on whole blood concentrations of cyclosporine measured by a specific monoclonal radioimmunoassay was investigated in a group of 37 renal transplant patients. Before transplantation, the patients received a standard intravenous (i.v.) and oral (p.o.) test dose of cyclosporine to calculate their individual i.v. and p.o. starting dose rates to achieve a certain target steady-state cyclosporine concentration. After transplantation, the designated i.v. dose rate was continuously infused for 2 days, at which time the steady-state concentration was measured. Then, the designated oral dose for 24 h was administered while the infusion was continued at an unaltered rate. The oral absorption of cyclosporine was documented by blood samples over the following 8 h. If necessary, this overlap of i.v. and p.o. dosing was repeated until blood concentrations of cyclosporine rose at least 700 ng/ml over the steady-state concentration. By that time, the infusion was stopped and oral dosing continued. Individualized infusions led to steady-state concentrations within a range that did not exceed 1.1 times the median concentration of 472 ng/ml. Standard infusion rates in the past produced a much wider range of steady-state concentrations (9.6 times the median). Individualized infusions reached the target steady-state concentration with a significant positive bias of 17% (SEM = +/- 32%, range of -36 to +105%). Individualized oral doses reached the target average steady-state concentration (calculated by dividing the area under the concentration-time curve by the dosing interval) with an inferior precision (median = 2.6%, range of -54 to +130%) but without a positive or negative bias.(ABSTRACT TRUNCATED AT 250 WORDS)

  9. Telmisartan in the management of diabetic nephropathy: a contemporary view.

    PubMed

    Balakumar, Pitchai; Bishnoi, Harish K; Mahadevan, Nanjaian

    2012-05-01

    Diabetic nephropathy, a complex disorder with heterogeneous etiologies, remains one of the most threatening diseases worldwide. There were around 177 million people with diabetes mellitus worldwide, and it has been estimated to be increased to 360 million by 2030. Given that about 20-30% of these people develop diabetic nephropathy, the present treatment protocols primarily aim for an efficient glucose and blood pressure control to arrest the initiation and progression of diabetic nephropathy. The treatment of diabetic nephropathy near the beginning at microalbuminuria stage with angiotensin-II-AT1 receptor blockers (ARBs) improves blood pressure control and halts disease progression of diabetic nephropathy. In fact, ARBs exert renoprotective effects independently of their blood pressure lowering effect, as they have direct defensive action on the diabetic kidney. Indubitably, it would be better if an ARB has both glucose-lowering and blood pressure controlling potentials efficiently. Intriguingly, telmisartan has such possessions considering its dual role of AT1 receptor blocking action and peroxisome proliferator-activated receptor gamma (PPARγ) partial agonistic property. The additional PPARγ agonistic potential of telmisartan could make it a distinctive intervention in the ARB class to prevent the progression of diabetic nephropathy through activation of PPARγ-mediated insulin sensitization, and renal anti-inflammatory and anti-oxidant actions. Indeed, telmisartan reduced insulin resistance and glucose intolerance, and halted the progressive renal dysfunction associated with diabetic nephropathy by inhibiting the incidence of albuminuria, and preventing the progression of glomerulosclerosis, renal interstitial inflammation and fibrosis. This review will discuss the current status of therapeutic potentials of telmisartan in treating diabetic nephropathy.

  10. Essential hypertension and risk of nephropathy: a reappraisal

    PubMed Central

    Murea, Mariana; Freedman, Barry I.

    2010-01-01

    This manuscript reviews the controversial relationship between hypertension and initiation of kidney disease. We focus on ethnic differences in renal histopathology and associated gene variants comprising the spectrum of MYH9-nephropathy. Purpose of review Treating mild to moderate essential hypertension in non-diabetic African Americans fails to halt nephropathy progression; while hypertension control slows nephropathy progression in European Americans. The pathogenesis of these disparate renal syndromes is reviewed. Recent findings The non-muscle myosin heavy chain 9 gene (MYH9) is associated with a spectrum of kidney diseases in African Americans, including idiopathic focal global glomerulosclerosis historically attributed to hypertension, idiopathic focal segmental glomerulosclerosis, and the collapsing variant of focal segmental glomerulosclerosis (HIV-associated nephropathy). Risk variants in MYH9 likely contribute to the failure of hypertension control to slow progressive kidney disease in non-diabetic African Americans. Summary Early and intensive hypertension control fails to halt progression of “hypertensive nephropathy” in African Americans. Genetic analyses in patients with essential hypertension and nephropathy attributed to hypertension, FSGS and HIVAN reveal that MYH9 gene polymorphisms are associated with a spectrum of kidney diseases in this ethnic group. Mild to moderate hypertension may cause nephropathy in European Americans with intra-renal vascular disease improved by the treatment of hypertension, hyperlipidemia and smoking cessation. PMID:20051853

  11. The kallikrein-kinin system in diabetic nephropathy

    PubMed Central

    Tomita, Hirofumi; Sanford, Ryan B.; Smithies, Oliver; Kakoki, Masao

    2012-01-01

    Diabetic nephropathy is the major cause of end-stage renal disease worldwide. Although the renin-angiotensin system has been implicated in the pathogenesis of diabetic nephropathy, angiotensin I-converting enzyme (ACE) inhibitors have a beneficial effect on diabetic nephropathy independently of their effects on blood pressure and plasma angiotensin II levels. This suggests that the kallikrein-kinin system (KKS) is also involved in the disease. To study the role of the KKS in diabetic nephropathy, mice lacking either the bradykinin B1 receptor (B1R) or the bradykinin B2 receptor (B2R) have been commonly used. However, because absence of either receptor causes enhanced expression of the other, it is difficult to determine the precise functions of each receptor. This difficulty has recently been overcome by comparing mice lacking both receptors with mice lacking each receptor. Deletion of both B1R and B2R reduces nitric oxide (NO) production and aggravates renal diabetic phenotypes, relevant to either lack of B1R or B2R, demonstrating that both B1R and B2R exert protective effects on diabetic nephropathy presumably via NO. Here, we review previous epidemiological and experimental studies, and discuss novel insights regarding the therapeutic implications of the importance of the KKS in averting diabetic nephropathy. PMID:22318421

  12. Role of Toll-like receptors in diabetic nephropathy.

    PubMed

    Mudaliar, Harshini; Pollock, Carol; Panchapakesan, Usha

    2014-05-01

    Diabetic nephropathy is the leading cause of kidney failure and its increasing prevalence and incidence has imposed global socio-economic stress on healthcare systems worldwide. Although historically considered a metabolic disorder, recent studies have established that inflammatory responses are central to the pathogenesis of diabetic nephropathy. TLRs (Toll-like receptors) are a family of pattern recognition receptors responsible for the initiation of inflammatory and immune responses. The regulation of TLR2 and TLR4 have been implicated in the pathogenesis of various kidney diseases, and emerging evidence shows their involvement in the perpetuation of inflammation in the diabetic kidney. The present review focuses on the relative contributions of TLR2 and TLR4 in recognizing endogenous ligands relevant to diabetic nephropathy and their subsequent activation of NF-κB (nuclear factor κB), which results in the synthesis and secretion of pro-inflammatory cytokines and chemokines. Moreover, we discuss the pro-inflammatory signalling pathways of TLR2 and TLR4, in which their interruption or blockade may prove to be important therapeutic targets, potentially translated into clinical treatments for diabetic nephropathy. Currently, inhibitors to TLR2 and TLR4 are undergoing clinical trials in various inflammatory models of disease, but none in patients with diabetic nephropathy. Given the existing literature, there is a fundamental necessity to undertake trials in patients with diabetic nephropathy with a focus on renal end points.

  13. Inherited forms of IgA nephropathy.

    PubMed

    Scolari, Francesco

    2003-01-01

    Simplex and multiplex families with IgA nephropathy (IgAN) have been reported from several ethnic backgrounds, providing the strongest evidence of a role for genetic factors in pathogenesis of IgAN. From a phenotypic point of view, familial and sporadic IgAN cannot be differentiated, and the main clinical and histological features are similar. Traditionally, the case-control study design was employed to identify associations between particular candidate genes, for example, HLA antigens the uteroglobin gene and IgAN, giving conflicting results. Recently, a different approach, using linkage analysis, was undertaken by geneticists at Yale University. A 10-cM genome-wide screen was performed in 30 multiplex IgAN pedigrees, and one locus was mapped (IGAN-1) on chromosome 6q22-23. Future study will be focused on the identification of the gene underlying IGAN-1. This will enable us to understand the molecular pathogenetic basis of IgAN.

  14. 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

  15. 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.

  16. BK Virus Nephropathy in Heart Transplant Recipients.

    PubMed

    Joseph, Alin; Pilichowska, Monika; Boucher, Helen; Kiernan, Michael; DeNofrio, David; Inker, Lesley A

    2015-06-01

    Polyomavirus-associated nephropathy (PVAN) has become an important cause of kidney failure in kidney transplant recipients. PVAN is reported to affect 1% to 7% of kidney transplant recipients, leading to premature transplant loss in approximately 30% to 50% of diagnosed cases. PVAN occurring in the native kidneys of solid-organ transplant recipients other than kidney only recently has been noted. We report 2 cases of PVAN in heart transplant recipients, which brings the total of reported cases to 7. We briefly review the literature on the hypothesized causes of PVAN in kidney transplant recipients and comment on whether these same mechanisms also may cause PVAN in other solid-organ transplant recipients. PVAN should be considered in the differential diagnosis when evaluating worsening kidney function. BK viremia surveillance studies of nonkidney solid-organ recipients should be conducted to provide data to assist the transplantation community in deciding whether regular monitoring of nonkidney transplant recipients for BK viremia is indicated.

  17. Genetic Targeting or Pharmacologic Inhibition of NADPH Oxidase Nox4 Provides Renoprotection in Long-Term Diabetic Nephropathy

    PubMed Central

    Jha, Jay C.; Gray, Stephen P.; Barit, David; Okabe, Jun; El-Osta, Assam; Namikoshi, Tamehachi; Thallas-Bonke, Vicki; Wingler, Kirstin; Szyndralewiez, Cedric; Heitz, Freddy; Touyz, Rhian M.; Cooper, Mark E.; Schmidt, Harald H.H.W.

    2014-01-01

    Diabetic nephropathy may occur, in part, as a result of intrarenal oxidative stress. NADPH oxidases comprise the only known dedicated reactive oxygen species (ROS)–forming enzyme family. In the rodent kidney, three isoforms of the catalytic subunit of NADPH oxidase are expressed (Nox1, Nox2, and Nox4). Here we show that Nox4 is the main source of renal ROS in a mouse model of diabetic nephropathy induced by streptozotocin administration in ApoE−/− mice. Deletion of Nox4, but not of Nox1, resulted in renal protection from glomerular injury as evidenced by attenuated albuminuria, preserved structure, reduced glomerular accumulation of extracellular matrix proteins, attenuated glomerular macrophage infiltration, and reduced renal expression of monocyte chemoattractant protein-1 and NF-κB in streptozotocin-induced diabetic ApoE−/− mice. Importantly, administration of the most specific Nox1/4 inhibitor, GKT137831, replicated these renoprotective effects of Nox4 deletion. In human podocytes, silencing of the Nox4 gene resulted in reduced production of ROS and downregulation of proinflammatory and profibrotic markers that are implicated in diabetic nephropathy. Collectively, these results identify Nox4 as a key source of ROS responsible for kidney injury in diabetes and provide proof of principle for an innovative small molecule approach to treat and/or prevent chronic kidney failure. PMID:24511132

  18. Sodium/glucose cotransporter 2 inhibitors and prevention of diabetic nephropathy: targeting the renal tubule in diabetes.

    PubMed

    De Nicola, Luca; Gabbai, Francis B; Liberti, Maria Elena; Sagliocca, Adelia; Conte, Giuseppe; Minutolo, Roberto

    2014-07-01

    Optimal prevention and treatment of chronic kidney disease in diabetes requires implementing therapies that specifically interfere with the pathogenesis of diabetic nephropathy. In this regard, significant attention has been given to alterations of the proximal tubule and resulting changes in glomerular filtration rate. At the onset of diabetes mellitus, hyperglycemia causes increases in proximal tubular reabsorption secondary to induction of tubular growth with associated increases in sodium/glucose cotransport. The increase in proximal reabsorption leads to a decrease in solute load to the macula densa, deactivation of the tubuloglomerular feedback, and increases in glomerular filtration rate. Because glomerular hyperfiltration currently is recognized as a risk factor for progression of kidney disease in diabetic patients, limiting proximal tubular reabsorption constitutes a potential target to reduce hyperfiltration. The recent introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors opens new therapeutic perspectives for this high-risk patient population. Experimental studies have shown that these new agents attenuate the progressive nature of diabetic nephropathy by blood glucose-dependent and -independent mechanisms. SGLT2 inhibition may prevent glomerular hyperfiltration independent of the effect of lowering blood glucose levels while limiting kidney growth, inflammation, and albuminuria through reductions in blood glucose levels. Clinical data for the potential role of the proximal tubule in the pathophysiology of diabetic nephropathy and the nephroprotective effects of SGLT2 inhibitors currently are limited compared to the more extensive experimental literature. We review the evidence supporting this working hypothesis by integrating the experimental findings with the available clinical data.

  19. The pathology of lithium induced nephropathy: a case report and review, with emphasis on the demonstration of mast cells.

    PubMed

    B N, Kumarguru; M, Natarajan; Nagarajappa, A H

    2013-02-01

    Lithium is a psychotropic agent which is widely employed in the psychiatric practice throughout the world. The therapeutic index of lithium is low and an acute intoxication may appear, which may lead to death or a permanent disability. A frequent side effect of lithium is renal toxicity. The collecting tubules have been identified as the site of action of lithium, due to the down regulation of Acquaporin-2. The mast cells have been associated with a wide range of human renal diseases. They have been documented to be associated with interstitial fibrosis and an impaired renal function. We are reporting a case of a 42 year old male who was admitted with a history of an altered sensorium of short duration. He had bipolar disorder and was on lithium. Investigations revealed a severely compromised renal function. The patient's condition worsened and he expired. A necropsy was performed. The kidneys and the lungs were subjected to a histopathological examination. The kidneys showed a significant Chronic Tubulointerstitial Nephropathy [CTIN] and a considerable glomerular pathology. Toludine blue [1%] staining demonstrated mast cells in the interstitium and the connective tissue of the renal pelvis. This appears to be the first time that mast cells were demonstrated in a case of lithium induced nephropathy in humans. It may be hypothesized that mast cells may possibly play a role in lithium induced nephropathy as a concurrent mechanism.

  20. Association of Diabetic Nephropathy and Liver Disorders

    PubMed Central

    Malawadi, BN

    2016-01-01

    Introduction Liver disorder is known to be a risk factor for Diabetes Mellitus (DM) and diabetic patients are at risk of developing liver disorders. Association of liver and renal disease is less explored in the field of research; hence, we conducted a retrospective study on this. Aim To compare the renal and liver profiles of type II DM patients compared to healthy controls and find the association between the two profiles in diabetics. Materials and Methods The renal and liver profiles of 68 type II DM patients and 58 controls were compared. Estimated Glomerular Filtration Rate (GFR) (eGFR) was calculated using Modification of Diet in Renal Disease (MDRD) formula and was taken as a tool to grade different stages of diabetic nephropathy. Comparison of liver profiles between different stages of diabetic nephropathy was done. Correlations and associations were studied between eGFR and liver enzymes and Bilirubin. Results A significant elevation in Total Bilirubin (TB) (p< 0.15), Direct Bilirubin (DB) (p< 0.0035), Aspartate Amino Transferase (AST) and Alanine Amino Transferase (ALT) (p<0.0001) levels in diabetics was noted. An elevated eGFR and a significant correlation between eGFR and liver enzymes were observed. A significant association between liver and renal disease has been obtained in diabetics (p=0.0136). Conclusion Significantly, high liver function tests and low eGFR were observed in type II diabetics. A significant positive correlation between liver enzymes (AST and ALT) and eGFR suggest a possible association between liver and kidney functions in DM. PMID:27891331

  1. Exogenous kallikrein protects against diabetic nephropathy.

    PubMed

    Liu, Wenjuan; Yang, Yeping; Liu, Yemei; Lu, Xiaolan; Guo, Shizhe; Wu, Meng; Wang, Meng; Yan, Linling; Wang, Qinghua; Zhao, Xiaolong; Tong, Xian; Hu, Ji; Li, Yiming; Hu, Renming; Stanton, Robert C; Zhang, Zhaoyun

    2016-11-01

    The kallikrein-kinin system has been shown to be involved in the development of diabetic nephropathy, but specific mechanisms are not fully understood. Here, we determined the renal-protective role of exogenous pancreatic kallikrein in diabetic mice and studied potential mechanisms in db/db type 2 diabetic and streptozotocin-induced type 1 diabetic mice. After the onset of diabetes, mice were treated with either pancreatic kallikrein (db/db+kallikrein, streptozotocin+kallikrein) or saline (db/db+saline, streptozotocin+saline) for 16 weeks, while another group of streptozotocin-induced diabetic mice received the same treatment after onset of albuminuria (streptozotocin'+kallikrein, streptozotocin'+saline). Db/m littermates or wild type mice were used as non-diabetic controls. Pancreatic kallikrein had no effects on body weight, blood glucose and blood pressure, but significantly reduced albuminuria among all three groups. Pathological analysis showed that exogenous kallikrein decreased the thickness of the glomerular basement membrane, protected against the effacement of foot process, the loss of endothelial fenestrae, and prevented the loss of podocytes in diabetic mice. Renal fibrosis, inflammation and oxidative stress were reduced in kallikrein-treated mice compared to diabetic controls. The expression of kininogen1, tissue kallikrein, kinin B1 and B2 receptors were all increased in the kallikrein-treated compared to saline-treated mice. Thus, exogenous pancreatic kallikrein both prevented and ameliorated diabetic nephropathy, which may be mediated by activating the kallikrein-kinin system.

  2. 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

  3. Differential effects of low-dose fenofibrate treatment in diabetic rats with early onset nephropathy and established nephropathy.

    PubMed

    Kadian, Supriya; Mahadevan, Nanjaian; Balakumar, Pitchai

    2013-01-05

    We have previously shown that low-dose fenofibrate treatment has an ability to prevent diabetes-induced nephropathy in rats. We investigated here the comparative pre- and post-treatment effects of low-dose fenofibrate (30 mg/kg/day p.o.) in diabetes-induced onset of nephropathy. Rats were made diabetics by single administration of streptozotocin (STZ, 55 mg/kg i.p.). The development of diabetic nephropathy was assessed biochemically and histologically. Moreover, lipid profile and renal oxidative stress were assessed. Diabetic rats after 8 weeks of STZ-administration developed apparent nephropathy by elevating serum creatinine, blood urea nitrogen and microproteinuria, and inducing glomerular-capsular wall distortion, mesangial expansion and tubular damage and renal oxidative stress. Fenofibrate (30 mg/kg/day p.o., 4 weeks) pretreatment (4 weeks after STZ-administration) markedly prevented diabetes-induced onset of diabetic nephropathy, while the fenofibrate (30 mg/kg/day p.o., 4 weeks) post-treatment (8 weeks after STZ-administration) was less-effective. However, both pre-and post fenofibrate treatments were effective in preventing diabetes-induced renal oxidative stress and lipid alteration in diabetic rats though the pretreatment was slightly more effective. Conversely, both pre-and post fenofibrate treatments did not alter elevated glucose levels in diabetic rats. It may be concluded that diabetes-induced oxidative stress and lipid alteration, in addition to a marked glucose elevation, play a detrimental role in the onset of nephropathy in diabetic rats. The pretreatment with low-dose fenofibrate might be a potential therapeutic approach in preventing the onset of nephropathy in diabetic subjects under the risk of renal disease induction. However, low-dose fenofibrate treatment might not be effective in treating the established nephropathy in diabetic subjects.

  4. 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.

  5. Immunogenetic differences in subpopulations of patients with IgA nephropathy (Berger's disease).

    PubMed

    Ockhuizen, T; Beukhof, J R; Westra, J; Halie, L M; Beelen, J M; van der Hem, G K

    1984-01-01

    Gm and Km as well as HLA-A, HLA-B, and HLA-DR phenotype frequencies were examined in 64 well-defined IgA nephropathy patients. The patients were divided into subpopulations according to clinical symptoms, e.g. macrohematuria and chronic renal failure (CRF). In patients with CRF the frequency of the Gm1,3,17;5,13,21 phenotype tended to be increased (p = 0.016; pcorr = 0.08). The frequency of the HLA-DR phenotype with only one antigen (HLA-DR-) was increased in the whole population (p less than 0.001; pcorr less than 0.011), which appeared to be confined to the patients with macrohematuria (p less than 0.001; pcorr less than 0.01) and non-CRF (p less than 0.001; pcorr less than 0.011). Patients with the Gm1,3,17;5,13,21 phenotype developed a CRF significantly earlier (p = 0.009; pcorr = 0.045) than patients with other Gm phenotypes. These data suggest that clinically observed subpopulations of IgA nephropathy patients differ in immunogenetic background.

  6. Molecular Basis of Renal Adaptation in a Murine Model of Congenital Obstructive Nephropathy

    PubMed Central

    Allen, Jordan L.; Wilhide, Michael E.; Ingraham, Susan E.; Hains, David S.; McHugh, Kirk M.

    2013-01-01

    Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb−/−) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb−/− kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb−/− kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngalhigh versus Ngallow kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb−/− mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction. PMID:24023768

  7. Why is diabetes mellitus a risk factor for contrast-induced nephropathy?

    PubMed

    Heyman, Samuel N; Rosenberger, Christian; Rosen, Seymour; Khamaisi, Mogher

    2013-01-01

    Contrast-induced nephropathy (CIN) remains a leading cause of iatrogenic acute kidney injury, as the usage of contrast media for imaging and intravascular intervention keeps expanding. Diabetes is an important predisposing factor for CIN, particularly in patients with renal functional impairment. Renal hypoxia, combined with the generation of reactive oxygen species, plays a central role in the pathogenesis of CIN, and the diabetic kidney is particularly susceptible to intensified hypoxic and oxidative stress following the administration of contrast media. The pathophysiology of this vulnerability is complex and involves various mechanisms, including a priori enhanced tubular transport activity, oxygen consumption, and the generation of reactive oxygen species. The regulation of vascular tone and peritubular blood flow may also be altered, particularly due to defective nitrovasodilation, enhanced endothelin production, and a particular hyperresponsiveness to adenosine-related vasoconstriction. In addition, micro- and macrovascular diseases and chronic tubulointerstitial changes further compromise regional oxygen delivery, and renal antioxidant capacity might be hampered. A better understanding of these mechanisms and their control in the diabetic patient may initiate novel strategies in the prevention of contrast nephropathy in these susceptible patients.

  8. Molecular basis of renal adaptation in a murine model of congenital obstructive nephropathy.

    PubMed

    Becknell, Brian; Carpenter, Ashley R; Allen, Jordan L; Wilhide, Michael E; Ingraham, Susan E; Hains, David S; McHugh, Kirk M

    2013-01-01

    Congenital obstructive nephropathy is a common cause of chronic kidney disease and a leading indication for renal transplant in children. The cellular and molecular responses of the kidney to congenital obstruction are incompletely characterized. In this study, we evaluated global transcription in kidneys with graded hydronephrosis in the megabladder (mgb (-/-)) mouse to better understand the pathophysiology of congenital obstructive nephropathy. Three primary pathways associated with kidney remodeling/repair were induced in mgb (-/-) kidneys independent of the degree of hydronephrosis. These pathways included retinoid signaling, steroid hormone metabolism, and renal response to injury. Urothelial proliferation and the expression of genes with roles in the integrity and maintenance of the renal urothelium were selectively increased in mgb (-/-) kidneys. Ngal/Lcn2, a marker of acute kidney injury, was elevated in 36% of kidneys with higher grades of hydronephrosis. Evaluation of Ngal(high) versus Ngal(low) kidneys identified the expression of several novel candidate markers of renal injury. This study indicates that the development of progressive hydronephrosis in mgb (-/-) mice results in renal adaptation that includes significant changes in the morphology and potential functionality of the renal urothelium. These observations will permit the development of novel biomarkers and therapeutic approaches to progressive renal injury in the context of congenital obstruction.

  9. Cordyceps militaris Treatment Preserves Renal Function in Type 2 Diabetic Nephropathy Mice

    PubMed Central

    Yu, Sung-Hsun; Dubey, Navneet Kumar; Li, Wei-Shan; Liu, Ming-Che; Chiang, Han-Sun; Leu, Sy-Jye; Shieh, Ying-Hua; Tsai, Feng-Chou; Deng, Win-Ping

    2016-01-01

    Diabetic nephropathy is derived from long-term effects of high blood glucose on kidney function in type 2 diabetic patients. Several antidiabetic drugs and herbal medications have failed to prevent episodes of DN. Hence, this study aimed to further investigate the renal injury-reducing effect of antidiabetic CmNo1, a novel combination of powders of fruiting bodies and mycelia of Cordyceps militaris. After being administered with streptozotocin-nicotinamide and high-fat-diet, the diabetic nephropathy mouse model displayed elevated blood glucose and renal dysfunction markers including serum creatinine and kidney-to-body weight ratio. These elevated markers were significantly mitigated following 8 weeks CmNo1 treatment. Moreover, the chronic hyperglycemia-induced pathological alteration in renal tissue were also ameliorated. Besides, immunohistochemical study demonstrated a substantial reduction in elevated levels of carboxymethyl lysine, an advanced glycation end product. Elevated collagenous deposition in DN group was also attenuated through CmNo1 administration. Moreover, the enhanced levels of transforming growth factor-β1, a fibrosis-inducing protein in glomerulus were also markedly dampened. Furthermore, auxiliary risk factors in DN like serum triglycerides and cholesterol were found to be increased but were decreased by CmNo1 treatment. Conclusively, the results suggests that CmNo1 exhibit potent and efficacious renoprotective action against hyperglycemia-induced DN. PMID:27832180

  10. Cordyceps militaris Treatment Preserves Renal Function in Type 2 Diabetic Nephropathy Mice.

    PubMed

    Yu, Sung-Hsun; Dubey, Navneet Kumar; Li, Wei-Shan; Liu, Ming-Che; Chiang, Han-Sun; Leu, Sy-Jye; Shieh, Ying-Hua; Tsai, Feng-Chou; Deng, Win-Ping

    2016-01-01

    Diabetic nephropathy is derived from long-term effects of high blood glucose on kidney function in type 2 diabetic patients. Several antidiabetic drugs and herbal medications have failed to prevent episodes of DN. Hence, this study aimed to further investigate the renal injury-reducing effect of antidiabetic CmNo1, a novel combination of powders of fruiting bodies and mycelia of Cordyceps militaris. After being administered with streptozotocin-nicotinamide and high-fat-diet, the diabetic nephropathy mouse model displayed elevated blood glucose and renal dysfunction markers including serum creatinine and kidney-to-body weight ratio. These elevated markers were significantly mitigated following 8 weeks CmNo1 treatment. Moreover, the chronic hyperglycemia-induced pathological alteration in renal tissue were also ameliorated. Besides, immunohistochemical study demonstrated a substantial reduction in elevated levels of carboxymethyl lysine, an advanced glycation end product. Elevated collagenous deposition in DN group was also attenuated through CmNo1 administration. Moreover, the enhanced levels of transforming growth factor-β1, a fibrosis-inducing protein in glomerulus were also markedly dampened. Furthermore, auxiliary risk factors in DN like serum triglycerides and cholesterol were found to be increased but were decreased by CmNo1 treatment. Conclusively, the results suggests that CmNo1 exhibit potent and efficacious renoprotective action against hyperglycemia-induced DN.

  11. BK nephropathy in the native kidneys of patients with organ transplants: Clinical spectrum of BK infection

    PubMed Central

    Vigil, Darlene; Konstantinov, Nikifor K; Barry, Marc; Harford, Antonia M; Servilla, Karen S; Kim, Young Ho; Sun, Yijuan; Ganta, Kavitha; Tzamaloukas, Antonios H

    2016-01-01

    Nephropathy secondary to BK virus, a member of the Papoviridae family of viruses, has been recognized for some time as an important cause of allograft dysfunction in renal transplant recipients. In recent times, BK nephropathy (BKN) of the native kidneys has being increasingly recognized as a cause of chronic kidney disease in patients with solid organ transplants, bone marrow transplants and in patients with other clinical entities associated with immunosuppression. In such patients renal dysfunction is often attributed to other factors including nephrotoxicity of medications used to prevent rejection of the transplanted organs. Renal biopsy is required for the diagnosis of BKN. Quantitation of the BK viral load in blood and urine are surrogate diagnostic methods. The treatment of BKN is based on reduction of the immunosuppressive medications. Several compounds have shown antiviral activity, but have not consistently shown to have beneficial effects in BKN. In addition to BKN, BK viral infection can cause severe urinary bladder cystitis, ureteritis and urinary tract obstruction as well as manifestations in other organ systems including the central nervous system, the respiratory system, the gastrointestinal system and the hematopoietic system. BK viral infection has also been implicated in tumorigenesis. The spectrum of clinical manifestations from BK infection and infection from other members of the Papoviridae family is widening. Prevention and treatment of BK infection and infections from other Papovaviruses are subjects of intense research. PMID:27683628

  12. Protective effects of leflunomide on renal lesions in a rat model if diabetic nephropathy.

    PubMed

    Zhang, Qing; Ji, Yongqiang; Lv, Wei; He, Tianwei; Wang, Jianping

    2016-01-01

    Diabetic nephropathy is one of the most common chronic complications of diabetes with poor efficacy of clinical treatment. This study investigated the protective effects of leflunomide, a new immunosuppressant, on tubulointerstitial lesions in a rat model of diabetic nephropathy. Diabetes was induced with streptozotocin (STZ, 50 mg/kg) by intraperitoneal injection in male Wistar rats. Two weeks after STZ injection, diabetic rats were treated daily for 8 weeks with low (5 mg/kg) and high dose (10 mg/kg) of leflunomide, and benazepril hydrochloride (4 mg/kg) as a positive control. In diabetic rats, the 24-h urine volume, urine protein and microalbumin, blood creatinine and urea nitrogen significantly increased, which were attenuated by leflunomide treatment in a dose-dependent manner (all p < 0.05). The increase of kidney weight/body weight and the histopathological findings of tubulointerstitial lesion in diabetic rats were mitigated by leflunomide treatment. Immunohistochemistry study and real-time polymerase chain reaction results demonstrated that osteopontin (OPN), transforming growth factor beta 1 (TGF-β1), α-smooth muscle actin and CD68 expression in the renal tubulointerstitial region were significantly increased in the diabetic rats, while these increases were inhibited by leflunomide treatment. These findings suggest that leflunomide protects the kidney injury of diabetic rats might through its inhibition of OPN/TGF-β1 mediated extracellular matrix deposition and tubulointerstitial fibrosis, as well as its inhibition on tubular epithelial-myofibroblast transdifferentiation.

  13. Proteases and Protease Inhibitors of Urinary Extracellular Vesicles in Diabetic Nephropathy

    PubMed Central

    Tataruch, Dorota; Gu, Dongfeng; Liu, Xinyu; Forsblom, Carol; Groop, Per-Henrik; Holthofer, Harry

    2015-01-01

    Diabetic nephropathy (DN) is one of the major complications of diabetes mellitus (DM), leads to chronic kidney disease (CKD), and, ultimately, is the main cause for end-stage kidney disease (ESKD). Beyond urinary albumin, no reliable biomarkers are available for accurate early diagnostics. Urinary extracellular vesicles (UEVs) have recently emerged as an interesting source of diagnostic and prognostic disease biomarkers. Here we used a protease and respective protease inhibitor array to profile urines of type 1 diabetes patients at different stages of kidney involvement. Urine samples were divided into groups based on the level of albuminuria and UEVs isolated by hydrostatic dialysis and screened for relative changes of 34 different proteases and 32 protease inhibitors, respectively. Interestingly, myeloblastin and its natural inhibitor elafin showed an increase in the normo- and microalbuminuric groups. Similarly, a characteristic pattern was observed in the array of protease inhibitors, with a marked increase of cystatin B, natural inhibitor of cathepsins L, H, and B as well as of neutrophil gelatinase-associated Lipocalin (NGAL) in the normoalbuminuric group. This study shows for the first time the distinctive alterations in comprehensive protease profiles of UEVs in diabetic nephropathy and uncovers intriguing mechanistic, prognostic, and diagnostic features of kidney damage in diabetes. PMID:25874235

  14. Hydrogen sulfide alleviates diabetic nephropathy in a streptozotocin-induced diabetic rat model.

    PubMed

    Zhou, Xiang; Feng, Yu; Zhan, Zhoubing; Chen, Jianchang

    2014-10-17

    Accumulating evidence has demonstrated that hydrogen sulfide (H2S) plays critical roles in the pathogenesis of chronic kidney diseases. This study was designed to investigate whether H2S has protective effects against diabetic nephropathy. Diabetic rats were induced by intraperitoneal injection of streptozotocin and administrated with H2S donor NaHS for 12 weeks. Rat glomerular mesangial cells were pretreated with NaHS or MAPK inhibitors (U0126, SP600125, and SB203580) prior to high glucose exposure, and cell proliferation was determined. Our findings suggest that H2S can improve renal function and attenuate glomerular basement membrane thickening, mesangial matrix deposition, and renal interstitial fibrosis in diabetic rats. H2S was found to reduce high glucose-induced oxidative stress by activating the Nrf2 antioxidant pathway and to exert anti-inflammatory effects by inhibiting NF-κB signaling. In addition, H2S reduced high glucose-induced mesangial cell proliferation by blockade of MAPK signaling pathways. Moreover, H2S was also found to inhibit the renin-angiotensin system in diabetic kidney. In conclusion, our study demonstrates that H2S alleviates the development of diabetic nephropathy by attenuating oxidative stress and inflammation, reducing mesangial cell proliferation, and inhibiting renin-angiotensin system activity.

  15. Pentraxin-3 Attenuates Renal Damage in Diabetic Nephropathy by Promoting M2 Macrophage Differentiation.

    PubMed

    Sun, Huaibin; Tian, Jun; Xian, Wanhua; Xie, Tingting; Yang, Xiangdong

    2015-10-01

    As one of the most important long-term complications of diabetes, diabetic nephropathy (DN) is the major cause of end-stage renal disease and high mortality in diabetic patients. The long pentraxin 3 (Ptx3) is a member of a superfamily of conserved proteins characterized by a cyclic multimeric structure and a conserved C-terminal domain. Several clinical investigations have demonstrated that elevated plasma Ptx3 levels are associated with cardiovascular and chronic kidney diseases (CKD). However, the therapeutic effect of Ptx3 on DN has never been investigated. In our current study, we showed a crucial role for Ptx3 in attenuating renal damage in DN. In our mouse hyperglycemia-induced nephropathy model, Ptx3 treatment showed significantly increased expression of nephrin, acetylated nephrin, and Wilm's tumor-1 protein (WT-1) when compared with control. The number of CD4(+) T cells, CD8(+) T cells, Ly6G(+) neutrophils, and CD11b(+) macrophages were all significantly lower in the Ptx3-treated group than that in the control group in DN. The IL-4 and IL-13 levels in the Ptx3-treated group were markedly higher than that in the control group in DN. Correspondingly, the Ptx3-treated group showed increased numbers of Arg1- or CD206-expressing macrophages compared with the control group. Furthermore, inhibition of Ptx3-treated macrophages abrogated the alleviated renal damage induced by Ptx3 treatment. In conclusion, Ptx3 attenuates renal damage in DN by promoting M2 macrophage differentiation.

  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.

  17. Association of NFKB1 gene polymorphism (rs28362491) with levels of inflammatory biomarkers and susceptibility to diabetic nephropathy in Asian Indians

    PubMed Central

    Gautam, Amar; Gupta, Stuti; Mehndiratta, Mohit; Sharma, Mohini; Singh, Kalpana; Kalra, Om P; Agarwal, Sunil; Gambhir, Jasvinder K

    2017-01-01

    AIM To investigate the association of NFKB1 gene -94 ATTG insertion/deletion (rs28362491) polymorphism with inflammatory markers and risk of diabetic nephropathy in Asian Indians. METHODS A total of 300 subjects were recruited (100 each), normoglycemic, (NG); type 2 diabetes mellitus (T2DM) without any complications (DM) and T2DM with diabetic nephropathy [DM-chronic renal disease (CRD)]. Analysis was carried out by polymerase chain reaction-restriction fragment length polymorphism and ELISA. Pearson’s correlation, analysis of variance and logistic regression were used for statistical analysis. RESULTS The allelic frequencies of -94 ATTG insertion/deletion were 0.655/0.345 (NG), 0.62/0.38 (DM) and 0.775/0.225 (DM-CRD). The -94 ATTG ins allele was associated with significantly increased levels of urinary monocyte chemoattractant protein-1 (uMCP-1); uMCP-1 (P = 0.026) and plasma tumor necrosis factor-alpha (TNF-α); TNF-α (P = 0.030) and almost doubled the risk of diabetic nephropathy (OR = 1.91, 95%CI: 1.080-3.386, P = 0.025). CONCLUSION -94 ATTG ins/ins polymorphism might be associated with increased risk of developing nephropathy in Asian Indian subjects with diabetes mellitus. PMID:28265344

  18. Membranous nephropathy as a manifestation of graft-versus-host disease: association with HLA antigen typing, phospholipase A2 receptor, and C4d.

    PubMed

    Byrne-Dugan, Cathryn J; Collins, A Bernard; Lam, Albert Q; Batal, Ibrahim

    2014-12-01

    Glomerulopathy is an uncommon but increasingly recognized complication of hematopoietic cell transplantation. It typically manifests as membranous nephropathy, less commonly as minimal change disease, and rarely as proliferative glomerulonephritis. There is evidence to suggest that these glomerulopathies might represent manifestations of chronic graft-versus-host disease. In this report, we focus on membranous nephropathy as the most common form of glomerulopathy after hematopoietic cell transplantation. We present a case of membranous nephropathy that developed 483 days post-allogeneic hematopoietic stem cell transplantation in a patient with a history of acute graft-versus-host disease. We also share our experience with 4 other cases of membranous nephropathy occurring after allogeneic hematopoietic stem cell transplantation. Clinicopathologic correlates, including the association with graft-versus-host-disease, HLA antigen typing, glomerular deposition of immunoglobulin G (IgG) subclasses, subepithelial colocalization of IgG deposits with phospholipase A2 receptor staining, C4d deposition along the peritubular capillaries, and treatment, are discussed with references to the literature.

  19. “Vitamin D supplementation and bone health in adults with diabetic nephropathy: the protocol for a randomized controlled trial”

    PubMed Central

    2014-01-01

    Background Suboptimal vitamin D status is highly prevalent in Northern communities, particularly in those patients with chronic diseases such as diabetes and chronic renal disease. Emerging literature suggests that adherence to daily vitamin D supplementation may be an important factor influencing vitamin D status and overall bone health, but compliance with therapies for bone health is a major challenge. It is unknown what level of vitamin D supplementation will ameliorate or improve suboptimal vitamin D status in patients with diabetic nephropathy or contribute to improved bone health, particularly for those living in northern climates. Methods/Design The study purpose was to examine two different strategies of vitamin D3 supplementation; daily dosing of 2000 IU per day verses monthly dosing of 40,000 IU per month on markers of vitamin D status, bone health and to examine whether adherence, quality of life and patient satisfaction with the supplementation strategy differs between the two vitamin D strategies in adults diagnosed with diabetic nephropathy. Discussion The need for RCTs assessing higher doses of vitamin D3 supplementation at varying frequencies of administration and its impact on bone health in adults with diabetes and chronic kidney disease are needed. Trial registration ClinicalTrials.gov NCT01476501. PMID:25115438

  20. Early detection and prevention of diabetic nephropathy: a challenge calling for mandatory action for Mexico and the developing world.

    PubMed

    Correa-Rotter, Ricardo; González-Michaca, Luis

    2005-09-01

    During the last decades, developing countries have experienced an epidemiologic transition characterized by a reduction of infectious diseases and an increase of chronic degenerative diseases. This situation is generating tormenting public health, financial, and social consequences. Of particular relevance is type 2 diabetes mellitus and its chronic complications, particularly cardiovascular disease and diabetic nephropathy, because mortality of the patient with diabetes is, in most instances, related to these complications. There is a clear need to implement diagnostic and treatment strategies to reduce risk factors for development of diabetes (primary prevention), to detect risk factors of chronic complications in early stages of diabetes (secondary prevention), and to prevent further progression of those that already have renal injury (tertiary prevention). Microalbuminuria is an early marker of renal injury in diabetes, and its early detection can help the timely use of renal preventive measures, which would avoid the extremely high costs of renal replacement treatment for end-stage renal disease as well as that of other cardiovascular complications. Preventive strategies are of very little or no impact, if the primary physician has limited knowledge about the natural history of diabetic nephropathy, the beneficial effect of early preventive maneuvers for delaying its progression, and the social and economic impact of end-stage renal disease. It is therefore imperative to assure in our health systems that general practitioners have the ability and commitment to detect early diabetes complications, in order to promote actions that support regression or retard highly morbid cardiovascular and renal conditions.

  1. Biomarkers in IgA nephropathy: relationship to pathogenetic hits

    PubMed Central

    Hastings, Margaret Colleen; Moldoveanu, Zina; Suzuki, Hitoshi; Berthoux, Francois; Julian, Bruce A; Sanders, John T; Renfrow, Matthew B; Novak, Jan; Wyatt, Robert J

    2015-01-01

    Introduction IgA nephropathy, the most prevalent glomerular disease in the world, requires a renal biopsy for diagnosis. Reliable biomarkers are needed for the non-invasive diagnosis of this disease and to more fully delineate its natural history and risk for progression. Areas covered In this review, the authors examine serum levels of galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG and IgA autoantibodies that are integral to pathogenesis of IgA nephropathy. They also explore biomarkers related to alternative and lectin pathways of complement activation and serum and urinary peptide biomarkers detected by mass spectrometric methods. The literature search included review of all publications having IgA nephropathy in the title that were cited in PubMed and Scopus over the past 10 years and a non-systematic review of abstracts published for the annual meetings of the American Society of Nephrology and the International Symposia on IgA Nephropathy. Expert opinion Serum Gd-IgA1 level and glycan-specific autoantibody levels are prime candidates to become diagnostic biomarkers for IgA nephropathy because of their central role in the earliest stages of disease pathogenesis. Assays for serum levels of complement proteins C3 and factor H are readily available in clinical practice and deserve continued study, either alone or in tandem with total serum IgA or serum Gd-IgA1 levels, as prognostic biomarkers for patients with IgA nephropathy. Urinary peptidomic data are also reviewed because this approach can successfully differentiate patients with IgA nephropathy from healthy controls and from patients with other forms of renal disease. PMID:24175678

  2. 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

    2015-07-03

    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).

  3. Mechanisms of diabetic nephropathy--old buddies and newcomers part 1.

    PubMed

    Nawroth, P P; Isermann, B

    2010-10-01

    Diabetic nephropathy is the most frequent cause of terminal kidney failure in industrialized countries. In addition, the manifestation of diabetic nephropathy is associated with a poor prognosis for affected patients. Current therapies are based on established pathophysiological models. However, despite reflecting significant progress in our understanding of diabetic nephropathy, the translational efforts fell short their expectations. The current review summarizes recent studies which provided new insights into established mechanisms (part 1) and studies identifying new candidate mechanisms (part 2) underlying diabetic nephropathy.

  4. Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy.

    PubMed

    Markowitz, G S; Radhakrishnan, J; Kambham, N; Valeri, A M; Hines, W H; D'Agati, V D

    2000-08-01

    This study examines the clinical features, pathologic findings, and outcome of 24 patients with biopsy-proven lithium toxicity. The patient population was 50% male, 87.5% Caucasian, and had a mean age of 42.5 yr (range, 26 to 57). Mean duration of lithium therapy for bipolar disorder was 13.6 yr (range, 2 to 25). All patients were biopsied for renal insufficiency (mean serum creatinine 2.8 mg/dl; range, 1.3 to 8.0), with associated proteinuria >1.0 g/d in 41.7%. Nephrotic proteinuria (>3.0 g/d) was present in 25%. Other features included nephrogenic diabetes insipidus in 87% and hypertension in 33.3%. Renal biopsy revealed a chronic tubulointerstitial nephropathy in 100%, with associated cortical and medullary tubular cysts (62.5%) or dilatation (33.3%). All of the renal cysts stained for epithelial membrane antigen, while 51.4% stained with lectin Arachis hypogaea, and only 3.8% stained with Tetragonolobus purpureas, indicating they originated from distal and collecting tubules. The degree of tubular atrophy and interstitial fibrosis was graded as severe in 58.3%, moderate in 37.5%, and mild in 4.2% of cases. There was a surprisingly high prevalence of focal segmental glomerulosclerosis (50%) and global glomerulosclerosis (100%), sometimes of equivalent severity to the chronic tubulointerstitial disease. The significant degree of foot process effacement (mean 34%, five of 14 cases with >50%) suggests a potential direct glomerular toxicity. Focal segmental glomerulosclerosis correlated with proteinuria >1.0 g/d (P = 0.0014, Fisher exact test). Despite discontinuation of lithium, seven of nine patients with initial serum creatinine values >2.5 mg/dl progressed to end-stage renal disease (ESRD). Only three patients, all with initial serum creatinine <2.1 mg/dl, had subsequent improvement in renal function. By Kaplan-Meier survival analysis, the only significant predictor of progression to ESRD was serum creatinine >2.5 mg/dl at biopsy (P = 0. 008). In conclusion

  5. 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

  6. Cyclosporine A-Nanosuspension: Formulation, Characterization and In Vivo Comparison with a Marketed Formulation

    PubMed Central

    Nakarani, Mahendra; Patel, Priyal; Patel, Jayvadan; Patel, Pankaj; Murthy, Rayasa S. R.; Vaghani, Subhash S.

    2010-01-01

    Cyclosporine A-nanosuspensions were prepared using zirconium oxide beads as a milling media, Poloxamer 407 as a stabilizer and distilled water as an aqueous medium using the Pearl Milling technique. The optimized formulation was characterized in terms of particle size distribution, surface morphology, drug-surfactant interaction, drug content, saturation solubility, osmolarity, and stability. The nanoparticles consisting of Poloxamer-bound cyclosporin A with a mean diameter of 213 nm revealed a spherical shape and 5.69 fold increased saturation solubility as compared to the parent drug. The formulation was found to be iso-osmolar with blood and stable up to 3 months at 2–8°C. In-vivo studies were carried out in albino rats and the pharmacokinetic parameters were compared with a marketed formulation, which indicated better results of the prepared formulation than the marketed one. PMID:21179351

  7. 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.

  8. 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.

  9. 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.

  10. A Comparative Study of Topical Mitomycin C, Cyclosporine, and Bevacizumab after Primary Pterygium Surgery

    PubMed Central

    Hwang, Shinyoung

    2015-01-01

    Purpose To compare the recurrence rates and complications associated with instillation of topical mitomycin C, cyclosporine, and bevacizumab after primary pterygium surgery. Methods Between July 2013 and June 2014, we performed surgery using the bare sclera method on 132 eyes (132 patients) with primary pterygium. We randomly selected 33 eyes (33 patients) and treated them with artificial tears four times a day for three months, 29 eyes (29 patients) were treated with topical 0.02% mitomycin C four times a day for five days, 34 eyes (34 patients) were treated with topical 0.05% cyclosporine four times a day for three months, and 36 eyes (36 patients) were treated with topical 2.5% bevacizumab four times a day for three months after surgery. We prospectively determined the recurrence rates of pterygium and complications at the six-month follow-up examination. Results At six months after surgery, the recurrence rates in each group were as follows: 45.5% (15 eyes) in the control group, 10.3% (three eyes) in the mitomycin C group, 20.6% (seven eyes) in the cyclosporine group, and 41.7% (15 eyes) in the bevacizumab group (p = 0.004). No serious complications, except subconjunctival hemorrhages, were observed in any group. Conclusions Groups receiving topical 0.02% mitomycin C and 0.05% cyclosporine after surgery showed lower recurrence rates than the control group; however, no difference in recurrence rate was observed between the control group and the group receiving topical 2.5% bevacizumab after surgery. PMID:26635453

  11. Cyclosporine-inhibitable Blood-Brain Barrier Drug Transport Influences Clinical Morphine Pharmacodynamics

    PubMed Central

    Meissner, Konrad; Avram, Michael J.; Yermolenka, Viktar; Francis, Amber M.; Blood, Jane; Kharasch, Evan D.

    2013-01-01

    Background The blood-brain barrier is richly populated by active influx and efflux transporters influencing brain drug concentrations. Morphine, a drug with delayed clinical onset, is a substrate for the efflux transporter P-glycoprotein in vitro and in animals. This investigation tested whether morphine is a transporter substrate in humans. Methods Fourteen healthy volunteers received morphine (0.1 mg/kg, 1 h intravenous infusion) in a crossover study after nothing (control) or the validated P-glycoprotein inhibitor cyclosporine (5 mg/kg, 2 h infusion). Plasma and urine morphine and morphine glucuronide metabolite concentrations were measured by mass spectrometry. Morphine effects were measured by miosis and analgesia. Results Cyclosporine minimally altered morphine disposition, increasing the area under the plasma morphine concentration versus time curve to 100 ± 21 versus 85 ± 24 ng/ml•hr (p < 0.05) without changing maximum plasma concentration. Cyclosporine enhanced (3.2 ± 0.9 vs. 2.5 ± 1.0 mm peak) and prolonged miosis, and increased the area under the miosis-time curve (18 ± 9 vs. 11 ± 5 mm-hr), plasma-effect site transfer rate constant (ke0, median 0.27 vs. 0.17 hr−1), and maximum calculated effect site morphine concentration (11.5 ± 3.7 vs. 7.6 ± 2.9 ng/ml) (all p < 0.05). Analgesia testing was confounded by cyclosporine-related pain. Conclusions Morphine is a transporter substrate at the human blood-brain barrier. Results suggest a role for P-glycoprotein or other efflux transporters in brain morphine access, although the magnitude of the effect is small, and unlikely to be a major determinant of morphine clinical effects. Efflux may explain some variability in clinical morphine effects. PMID:23851346

  12. Membranous nephropathy and nonsteroidal anti-inflammatory agents.

    PubMed

    Nawaz, Fareha A; Larsen, Christopher P; Troxell, Megan L

    2013-11-01

    Membranous nephropathy presents clinically as nephrotic syndrome, with subepithelial immune complex deposits seen on biopsy. Historically, in about three-quarters of membranous cases, no obvious etiologic agent or condition can be identified. More recently, serum antibodies to the phospholipase A2 receptor have been discovered in many patients with primary/idiopathic membranous nephropathy. About one-quarter of patients have membranous nephropathy as a manifestation of another systemic disorder, such as autoimmune conditions, infection, malignancy, toxin exposure, or drugs (classically gold or penicillamine). In this report, we present a case of recurrent nephrotic syndrome with biopsy-proven membranous nephropathy closely associated with use of the nonsteroidal anti-inflammatory drugs (NSAIDs) naproxen and piroxicam. Characterization of the immunoglobulin G (IgG) subclass profile of the deposits showed abundant IgG1, weak IgG4, and positive staining for phospholipase A2 receptor. This case serves to highlight membranous nephropathy as an under-recognized renal complication of NSAID use. Other kidney effects of NSAIDs, such as hemodynamic compromise, interstitial nephritis, and minimal change disease, are more broadly recognized.

  13. Autophagy: A Novel Therapeutic Target for Diabetic Nephropathy.

    PubMed

    Kume, Shinji; Koya, Daisuke

    2015-12-01

    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.

  14. Network-centric Analysis of Genetic Predisposition in Diabetic Nephropathy

    PubMed Central

    Ntemka, A; Iliadis, F; Papanikolaou, NA; Grekas, D

    2011-01-01

    Diabetic nephropathy is a serious, long-term complication of diabetes and the leading cause of end-stage renal disease throughout the world. Although this disease is progressively imposing a heavier burden on the health care system, in many aspects it remains poorly understood. In addition to environmental influences, there is abundant evidence in support of genetic susceptibility to microvascular complications of nephropathy in diabetic patients. Familial clustering of phenotypes such as end-stage renal disease, albuminuria and kidney disease have been reported in large scale population studies throughout the world demonstrating strong contribution of inherited factors. Recent genome-wide linkage scans identified several chromosomal regions that are likely to contain diabetic nephropathy susceptibility genes, and association analyses have evaluated positional candidate genes under linkage peaks. In this review we have extracted from the literature the most promising candidate genes thought to confer susceptibility to diabetic nephropathy and mapped them to affected pathways by using network-centric analysis. Several of the top susceptibility genes have been identified as network hubs and bottlenecks suggesting that they might be important agents in the onset of diabetic nephropathy. PMID:22435020

  15. Treatment of acute kidney injury with cast nephropathy.

    PubMed

    Walther, Carl; Podoll, Amber S; Finkel, Kevin W

    2014-07-01

    Nearly 50% of patients with multiple myeloma develop renal disease; acute kidney injury (AKI) from cast nephropathy, or "myeloma kidney" is the most common type. Development of AKI is associated with worse 1-year survival and reduces the therapeutic options available to patients. Therefore, there is a great need to develop more effective therapies. Cast nephropathy is due to the interaction and aggregation of filtered free light chains (FLCs) and Tamm- Horsfall protein (THP) causing intratubular obstruction and damage. The key to treating cast nephropathy is rapid lowering of FLCs as this correlates with renal recovery. Newer chemotherapy agents lower FLCs and have been referred to as "renoprotective". However there remains great interest in using various extracorporeal therapies to remove serum FLCs. Initially, therapeutic plasma exchange (TPE) was thought to improve renal outcomes in cast nephropathy based on small trials. The largest randomized trial of TPE, however, failed to show any benefit. A newer technique is extended high cut-off hemodialysis (HCO-HD). This modality uses a high molecular weight cut-off filter to remove FLCs. To date, trials with HCO-HD in patients with cast nephropathy have been encouraging. However, there are no randomized trials demonstrating the benefit of HCOHD when used in addition to newer chemotherapeutic regimens. Until these studies are available, HCO-HD cannot be recommended as standard of care.

  16. The role of sulodexide in the treatment of diabetic nephropathy.

    PubMed

    Weiss, Ram; Niecestro, Robert; Raz, Itamar

    2007-01-01

    Diabetic nephropathy is an important cause of morbidity and mortality in patients with either type 1 or type 2 diabetes mellitus. The pathogenesis and natural history of diabetic nephropathy, characterised by a progressive decline in glomerular function, were initially described in patients with type 1 diabetes. Reports that describe the glomerulopathy and progression of renal disease in patients with type 2 diabetes suggest that the disease process is similar to that observed in patients with type 1 diabetes with diabetic nephropathy. An emerging body of evidence supports the notion that glomerular capillary wall and mesangial alterations in diabetic nephropathy involve pathobiochemical alterations of glycoproteins in these structures. Evidence in experimental animals rendered diabetic, reveal that the administration of heparin and other anionic glycoproteins can effectively prevent the biochemical alterations that promote albuminuria. Clinical reports of the use of sulodexide, a preparation of low molecular weight glycosaminoglycan polysaccharides, have shown that proteinuria is significantly diminished in patients with diabetic nephropathy, even when these patients are receiving either an ACE inhibitor or angiotensin receptor antagonist.

  17. Down-regulation of transforming growth factor beta-2 expression is associated with the reduction of cyclosporin induced gingival overgrowth in rats treated with roxithromycin: an experimental study

    PubMed Central

    2009-01-01

    Background Gingival overgrowth (GO) is a common side effect of the chronic use of cyclosporine (CsA), an immunosuppressant widely used to prevent rejection in transplant patients. Recent studies have reported elevated levels of specific cytokines in gingival overgrowth tissue, particularly TGF-beta, suggesting that this growth factor plays a role in the accumulation of extracellular matrix materials. The effectiveness of azithromycin, a macrolide antibiotic, in the regression of this undesirable side effect has also been demonstrated. Methods In this study, we created an experimental model for assessing the therapeutic effect of roxithromycin in GO and the expression of transforming growth factor beta (TGF-beta2) through immunohistochemistry. We used four groups of rats totaling 32 individuals. GO was induced during five weeks and drug treatment was given on the 6th week as follows: group 1 received saline; group 2 received CsA and was treated with saline on the 6th week; group 3 received CsA and, on the 6th week, ampicilin; and group 4 received CsA during 5 weeks and, on the 6th week, was treated with roxithromycin. Results The results demonstrated that roxithromycin treatment was effective in reducing cyclosporine-induced GO in rats. Both epithelial and connective tissue showed a decrease in thickness and a significant reduction in TGF-beta2 expression, with a lower number of fibroblasts, reduction in fibrotic areas and decrease in inflammatory infiltrate. Conclusion The present data suggest that the down-regulation of TGF-beta2 expression may be an important mechanism of action by which roxithromycin inhibits GO. PMID:19995419

  18. Acquired generalized anhidrosis: review of the literature and report of a case with lymphocytic hidradenitis and sialadenitis successfully treated with cyclosporine.

    PubMed

    Fujita, Kumi; Hatta, Kazuhiro

    2013-01-01

    We report a case of acquired generalized anhidrosis successfully treated with cyclosporine. A skin biopsy showed T cell infiltration around the sweat glands and labial biopsy revealed lymphoplasmacytic infiltration around the minor salivary gland, suggesting an underlying autoimmune disease such as Sjögren's syndrome. Administration of cyclosporine markedly improved the patient's condition and sympathetic skin response; thus cyclosporine may be effective for treating anhidrosis in patients with autoimmune disorders.

  19. 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

  20. Surgical treatment of cyclosporine A- and nifedipine-induced gingival enlargement: gingivectomy versus periodontal flap.

    PubMed

    Pilloni, A; Camargo, P M; Carere, M; Carranza, F A

    1998-07-01

    The purpose of this study was to compare probing depth resolution achieved by gingivectomy and periodontal flap techniques in the treatment of cyclosporine A- and nifedipine-induced gingival enlargement. Ten kidney transplant patients who were receiving cyclosporine A and nifedipine for at least 6 months participated in the study. Five patients were randomly assigned to the gingivectomy group and 5 patients to the periodontal flap group. Only anterior segments of the oral cavity (canine to canine) were surgically treated. Clinical measurements, including probing depths, plaque index, and gingival sulcus index, were taken at baseline, 6 weeks, 6 months, and 1 year. Results showed that probing depths, while similar for both groups in the first 6 weeks of the study, were significantly shallower for the periodontal flap group when compared to the gingivectomy group at 6 months (2.48 +/- 0.34 mm versus 4.87 +/- 0.79 mm, respectively) and 1 year (322 +/- 0.65 mm versus 6.40 +/- 1.02 mm, respectively). Within its limitations, this study suggests that the pocket reduction achieved by the periodontal flap may be sustained for longer periods of time than by the gingivectomy technique in the treatment of cyclosporine A- and nifedipine-induced gingival enlargement.

  1. 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

  2. Management of Toxic Epidermal Necrolysis with Plasmapheresis and Cyclosporine A: Our 10 Years’ Experience

    PubMed Central

    Giudice, Giuseppe; Maggio, Giulio; Bufano, Loredana; Memeo, Giuseppe

    2017-01-01

    Background: The management of toxic epidermal necrolysis (TEN) is controversial and there is no uniform strategy. Objective: To share our 10 years’ experience in treating severe TEN with a novel protocol based on the association of cyclosporine A and plasmapheresis. Methods: In this case series, we retrospectively collected and assessed the 12 cases of severe TEN treated from 2005 to 2015 at the Burn Unit of the University of Bari Policlinico hospital. Results: Average body surface area was 77; average SCORETEN was 4.3. The 12 patients had been treated with culprit drug withdrawal, systemic corticosteroids, and/or cyclosporine A with no response. The protocol was successfully administered in all 12 cases. Average time to response from protocol start was 4.9 days. Average time to remission from protocol start was 22 days; average hospital stay at our unit was 24.8 days. Four patients developed severe complications; 1 patient died. No complications linked to the protocol therapeutic measures were observed. The relatively small number of cases given the rarity of the condition is a limitation of this report. Conclusion: Our protocol based on the association of cyclosporine A and plasmapheresis is safe and efficacious in treating severe TEN. PMID:28280663

  3. Consensus document: Hawk's Cay meeting on therapeutic drug monitoring of cyclosporine.

    PubMed

    Kahan, B D; Shaw, L M; Holt, D; Grevel, J; Johnston, A

    1990-08-01

    The optimal measurement method and clinical application of the therapeutic drug monitoring of cyclosporine remain uncertain. At a workshop held at Hawk's Cay, FL, from January 14 to January 17, 1990, 57 scientists presented their latest research findings, either in formal papers or as discussants. Lively debate and discussion followed presentation of extant and new methodologies for drug measurements as well as multicenter validation studies: applications of trough-concentration monitoring in renal, hepatic, and bone-marrow transplants as well as in autoimmune disease; and alternative pharmacokinetic approaches to guide cyclosporine therapy. The process of inducing and maintaining optimal immunosuppression to facilitate graft success is a complex and often challenging task, requiring the combined expertise of multiple disciplines. Thus, the assembly of four of the groups essential to the transplant process--clinicians, laboratory scientists, the pharmaceutical company, and the manufacturers of cyclosporine measurement kits--provided a unique opportunity to evaluate therapeutic drug monitoring issues facing the transplant field. Here we present the major conclusions reached at the meeting, brief discussions of the study data on which they are based, and a summary of unresolved problems that will require further rigorous investigations. The Consensus Document was reviewed by all the workshop participants before we submitted this final manuscript.

  4. Cyclosporine-associated renal arteriopathy resulting in loss of allograft function

    SciTech Connect

    Sommer, B.G.; Innes, J.T.; Whitehurst, R.M.; Sharma, H.M.; Ferguson, R.M.

    1985-06-01

    Cyclosporine-associated arteriopathy was the cause of graft loss in 40 percent of all allografts that failed in a series of 200 consecutive cadaveric renal transplants. Arteriopathy was diagnosed by biopsy and renal uptake of indium 111m labeled platelets in the face of acute renal deterioration. A moderate thrombocytopenia and microangiopathic picture of hemolytic uremia was also present on peripheral blood smear. Immunofluorescence and histologic characteristics of the allograft biopsy specimens failed to show evidence for acute rejection: immunoglobulin M, immunoglobulin A, immunoglobulin G, C1q, C3, and C4 were not present, and there was no evidence of an interstitial or vascular mononuclear cellular infiltrate. Two clinical presentations have been described. In Group I (seven patients), anuria occurred rapidly within the first 2 weeks after transplantation. In Group II (nine patients) renal function gradually diminished 1 to 5 months after starting cyclosporine therapy. Fifteen of the 16 recipients had progressive and irreversible loss of renal function which was pathologically associated with fibrin deposition, intimal proliferation, and thrombotic occlusion of the cortical interlobular and arcuate arteries, with subsequent focal glomerular ischemia and cortical infarction. One recipient with rapid loss of renal function received an intraarterial allograft infusion of streptokinase and subsequent systemic heparinization, which resulted in return of normal allograft function. The syndrome of cyclosporine-associated arteriopathy has been linked to a lack of or reduced amounts of prostacyclin-stimulating factor or prostacyclin.

  5. Cyclosporin A corrects mitochondrial dysfunction and muscle apoptosis in patients with collagen VI myopathies.

    PubMed

    Merlini, Luciano; Angelin, Alessia; Tiepolo, Tania; Braghetta, Paola; Sabatelli, Patrizia; Zamparelli, Alessandra; Ferlini, Alessandra; Maraldi, Nadir M; Bonaldo, Paolo; Bernardi, Paolo

    2008-04-01

    Ullrich congenital muscular dystrophy and Bethlem myopathy are skeletal muscle diseases that are due to mutations in the genes encoding collagen VI, an extracellular matrix protein forming a microfibrillar network that is particularly prominent in the endomysium of skeletal muscle. Myoblasts from patients affected by Ullrich congenital muscular dystrophy display functional and ultrastructural mitochondrial alterations and increased apoptosis due to inappropriate opening of the permeability transition pore, a mitochondrial inner membrane channel. These alterations could be normalized by treatment with cyclosporin A, a widely used immunosuppressant that desensitizes the permeability transition pore independently of calcineurin inhibition. Here, we report the results of an open pilot trial with cyclosporin A in five patients with collagen VI myopathies. Before treatment, all patients displayed mitochondrial dysfunction and increased frequency of apoptosis, as determined in muscle biopsies. Both of these pathologic signs were largely normalized after 1 month of oral cyclosporin A administration, which also increased muscle regeneration. These findings demonstrate that collagen VI myopathies can be effectively treated with drugs acting on the pathogenic mechanism downstream of the genetic lesion, and they represent an important proof of principle for the potential therapy of genetic diseases.

  6. [IgA nephropathy in pediatrics].

    PubMed

    Marinaki, M; Benini, D; Fasoli, E; Fanos, V

    2003-01-01

    IgA nephropathy is a primitive cronic idiopatic glomerulonephritis, characterized by diffuse depositis of IgA in the glomeruler mesangium. Familial cases are also descripted. IgA nephropaty is more frequent in males and in white rase. In Italy it's the most frequently recognized glomerulonephritis in renal biopsia (20%), especially in patients with dismorfic micro or macroematuria and nephrotic proteinuria. Clinical presentation is often in association with respiratory tract or gastrointestinal disorders. The most relevant pathogenetic hypothesis suggest an IgA abnormal glycosilation, with mesangial IgA aggregation, increased mesangial reactivity and release of inflammatory mediators and fibrotic agents. Treatment is considered in rapidly progressing forms. At the present, there is no treatment of proven value in all patients, althoug interesting results have been published with prednison, ACE-inhibitors or fish-oil in decresing renal deterioration rate. Natural history varies in different series. Renal survival at 10 years is 85% in Italy, 94% in France, 97% in the USA. Poor prognostic factor are heavy proteinuria and hypertension. However a wide inter-individual variability is observed.

  7. Resveratrol Attenuates Diabetic Nephropathy via Modulating Angiogenesis

    PubMed Central

    Zhang, Min; Zhang, Liying; Chen, Jing; Gu, Yong; Hao, Chuan-Ming

    2013-01-01

    Angiogenesis plays an important role in the pathogenesis of diabetic nephropathy (DN). In the present study, we investigated the therapeutic potential of resveratrol, a polyphenol with antiangiogenic activity in DN. In a type 1 diabetic rat model, resveratrol treatment blunted the increases of urine albumin excretion, kidney weight and creatinine clearance rate. The increases of glomerular diameter, mesangium accumulation, glomerular basement membrane thickness and renal fibrosis in diabetic rats were also reduced by resveratrol treatment. In the diabetic kidney, increased expression of vascular endothelial growth factor (VEGF), Flk-1 and angiopoietin 2, and reduced expression of Tie-2 were observed. These changes in angiogenic hormones and associated receptors were attenuated by resveratrol treatment. No changes in angiopoietin 1 expression were detected among each group of rats. Resveratrol also significantly downregulated high glucose-induced VEGF and Flk-1 expressions in cultured mouse glomerular podocytes and endothelial cells, respectively. These effects were attenuated by knocking-down silent information regulator 1 (Sirt1) expression. In contrast, upregulation of Sirt1 in cultured endothelial cells reduced Flk-1 expression. Increased permeability and cellular junction disruption of cultured endothelial cells caused by VEGF were also inhibited by resveratrol pretreatment. Taken together, the present study demonstrated that resveratrol may attenuate DN via modulating angiogenesis. PMID:24312656

  8. Oxidative stress in IgA nephropathy.

    PubMed

    Coppo, R; Camilla, R; Amore, A; Peruzzi, L

    2010-01-01

    IgA nephropathy (IgAN) is characterized by mesangial deposits of IgA1, likely due to accumulation of IgA immune complexes. The activation of intracellular signaling mostly results in oxidative stress, as detected in mesangial cells cultured with aberrantly glycosylated IgA or IgA aggregates and in renal biopsies of patients with IgAN. Signs of altered oxidation/antioxidation balance have been detected in sera and/or in erythrocytes of patients with IgAN, including increased levels of lipoperoxide or malondialdehyde and reduced activity of superoxide dismutase, catalase and glutathione peroxidase. Moreover, increased levels of a marker of oxidative stress, advanced oxidation protein products (AOPPs), have been reported to be significantly associated with proteinuria and disease progression in patients with IgAN. AOPPs are often carried by albumin and can in turn enhance the oxidative stress in the circulation. Recent research suggests that the nephrotoxicity of aberrantly glycosylated IgA1 in IgAN is enhanced in the presence of systemic signs of oxidative stress, and it is tempting to hypothesize that the level of the oxidative milieu conditions the different expression and progression of IgAN.

  9. New therapeutic agents in diabetic nephropathy

    PubMed Central

    Kim, Yaeni; Park, Cheol Whee

    2017-01-01

    Studies investigating diabetic nephropathy (DN) have mostly focused on interpreting the pathologic molecular mechanisms of DN, which may provide valuable tools for early diagnosis and prevention of disease onset and progression. Currently, there are few therapeutic drugs for DN, which mainly consist of antihypertensive and antiproteinuric measures that arise from strict renin-angiotensin-aldosterone system inactivation. However, these traditional therapies are suboptimal and there is a clear, unmet need for treatments that offer effective schemes beyond glucose control. The complexity and heterogeneity of the DN entity, along with ambiguous renal endpoints that may deter accurate appraisal of new drug potency, contribute to a worsening of the situation. To address these issues, current research into original therapies to treat DN is focusing on the intrinsic renal pathways that intervene with intracellular signaling of anti-inflammatory, antifibrotic, and metabolic pathways. Mounting evidence in support of the favorable metabolic effects of these novel agents with respect to the renal aspects of DN supports the likelihood of systemic beneficial effects as well. Thus, when translated into clinical use, these novel agents would also address the comorbid factors associated with diabetes, such as obesity and risk of cardiovascular disease. This review will provide a discussion of the promising and effective therapeutic agents for the management of DN. PMID:28049280

  10. 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

  11. [Case of MMF monotherapy for membranous nephropathy].

    PubMed

    Kobayashi, Mioko; Kojima, Chiari; Sugiura, Hidekazu; Aoki, Asuka; Itabashi, Mitsuyo; Tsukada, Misao; Takei, Takashi; Uchida, Keiko; Nitta, Kosaku

    2010-01-01

    We report the case of a 58-year-old male patient who visited our hospital for the management of edema and proteinuria. He was diagnosed as having nephrotic syndrome, with serum total protein and albumin levels of 4.6 g/dL and 2.1 g/dL, respectively, and a urinary protein excretion level of 6.0 g/day. A percutaneous renal biopsy showed features of membranous glomerulonephritis, with capillary-wall granular deposits of IgG and C3 on immunofluorescence and subepithelial immune complex deposits on electron microscopy. No other secondary cause of membranous glomerulopathy was found even after extensive investigations. The patient was started on mycophenolate mofetil (MMF) monotherapy (1,500 mg/day), and 18 months after the start of this therapy, the proteinuria decreased to 0.5 g/day, with return to a normal serum albumin level. No digestive symptoms, kidney function worsening or increase in blood pressure were noted during treatment. These findings suggest that MMF monotherapy is effective and safe for the treatment of membranous nephropathy.

  12. Histone Lysine Methylation in Diabetic Nephropathy

    PubMed Central

    Sun, Guang-dong; Cui, Wen-peng; Guo, Qiao-yan; Miao, Li-ning

    2014-01-01

    Diabetic nephropathy (DN) belongs to debilitating microvascular complications of diabetes and is the leading cause of end-stage renal diseases worldwide. Furthermore, outcomes from the DCCT/EDIC study showed that DN often persists and progresses despite intensive glucose control in many diabetes patients, possibly as a result of prior episode of hyperglycemia, which is called “metabolic memory.” The underlying mechanisms responsible for the development and progression of DN remain poorly understood. Activation of multiple signaling pathways and key transcription factors can lead to aberrant expression of DN-related pathologic genes in target renal cells. Increasing evidence suggests that epigenetic mechanisms in chromatin such as DNA methylation, histone acetylation, and methylation can influence the pathophysiology of DN and metabolic memory. Exciting researches from cell culture and experimental animals have shown that key histone methylation patterns and the related histone methyltransferases and histone demethylases can play important roles in the regulation of inflammatory and profibrotic genes in renal cells under diabetic conditions. Because histone methylation is dynamic and potentially reversible, it can provide a window of opportunity for the development of much-needed novel therapeutic potential for DN in the future. In this minireview, we discuss recent advances in the field of histone methylation and its roles in the pathogenesis and progression of DN. PMID:25215303

  13. 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.

  14. Membranous nephropathy with acquired factor V inhibitor: a case report

    PubMed Central

    2013-01-01

    Background Membranous nephropathy is one of the most common causes of nephrotic syndrome in adults. In contrast, acquired factor V inhibitor is a rare bleeding disorder. Case presentation A 62-year-old Asian man with a history of cerebral hemorrhage, purpura, eosinophilia and hyper immunoglobulin E syndrome developed proteinuria. The bleeding disorder was diagnosed with acquired factor V inhibitors. A renal biopsy revealed that he suffered from membranous nephropathy with glomerular endothelial damage which is reported to be involved in another factor disorder. After the steroid administration, the coagulation test and proteinuria were improved. Conclusions The presence of factor V inhibitors may have been involved in the development of membranous nephropathy. PMID:24360027

  15. Treatment and impact of dyslipidemia in diabetic nephropathy.

    PubMed

    Toyama, Tadashi; Shimizu, Miho; Furuichi, Kengo; Kaneko, Shuichi; Wada, Takashi

    2014-04-01

    Recent epidemiological research revealed that dyslipidemia is a risk factor for development and progression of diabetic nephropathy. Results from interventional studies revealed the possibility that anti-hyperlipidemic agents have a better effect on diabetic nephropathy through improvement of albuminuria and loss of renal function. In addition, dyslipidemia may be a consequence of albuminuria and renal dysfunction, thereby perpetuating kidney damage. Today, the proportion of diabetic patients receiving statins is increasing due to their beneficial effect on cardiovascular mortality. However, treatment for patients should be determined based on consideration of the risk and benefit of the treatment. More insight into the pathogenesis of diabetic nephropathy and the effects of life-style changes is required.

  16. Cyclosporine in the treatment of childhood idiopathic steroid resistant nephrotic syndrome: a single centre experience in Nigeria

    PubMed Central

    Ladapo, Taiwo Augustina; Esezobor, Christopher Imokhuede; Lesi, Foluso Ebunoluwa

    2016-01-01

    Introduction Children with steroid resistant nephrotic syndrome usually require treatment with second-line agents and calcineurin inhibitors such as cyclosporine are now recommended as initial therapy. These agents only recently become available in our environment and their impact on care is unknown. We reviewed the short-term treatment outcomes of their use in comparison with previous outcomes. Methods Medical records of children managed for idiopathic steroid resistant nephrotic syndrome over a 5 year period were reviewed. Remission rates and improvement in renal function following use of various agents were compared. Results Of 103 children with idiopathic nephrotic syndrome, 25(24.3%) were steroid resistant, of whom 17 received additional medications. Full remission rate for cyclosporine was 70% (7/10). Remission rates prior to the availability of cyclosporine were 40% (2/5) for cyclophosphamide and 66% (2/3), (partial remission only) with enalapril, an angiotensin converting enzyme inhibitor used in combination with alternate day prednisolone. One child with cyclophosphamide resistance subsequently achieved remission with cyclosporine. Remission was not related to sex (p=0.96), age (p=0.54), serum albumin (p=0.37) or hypertension (p=0.43) but to serum cholesterol (p= 0.02). The estimated glomerular filteration rate (eGFR) among children treated with cyclosporine ranged from 30-167 ml/min/1.73m2 as follows: >90 (5); 60-89 (3); 30-59 (2) while the mean pre and post treatment eGFR in those with eGFR <90 were 60 and 104ml/min/1.73m2 respectively (p=0.03). Mortality rate was 10% (1/10) in children treated with cyclosporine compared with 28.6% (2/7) in those treated with other medications (p=0.54). Conclusion Cyclosporine resulted in improved treatment outcomes in children with idiopathic steroid resistant nephrotic syndrome. PMID:28293374

  17. Cyclosporine treatment reduces oxygen free radical generation and oxidative stress in the brain of hypoxia-reoxygenated newborn piglets.

    PubMed

    Gill, Richdeep S; Lee, Tze-Fun; 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 (H(2)O(2)) 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 H(2)O(2) 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 H(2)O(2) 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 H(2)O(2) production and minimizes oxidative stress in newborn piglets following hypoxia-reoxygenation.

  18. Cyclosporine pharmacokinetics in liver transplant recipients: evaluation of results using both polyclonal radioimmunoassay and liquid chromatographic analysis.

    PubMed

    Tredger, J M; Grevel, J; Naoumov, N; Steward, C M; Niven, A A; Whiting, B; Williams, R

    1991-01-01

    Pharmacokinetic variables were derived from cyclosporine measurements using liquid chromatography (HPLC) and radioimmunoassay with a non-selective polyclonal antibody (PARIA) in 11 orthotopic liver transplant recipients studied in paired oral and intravenous studies both before and after permanent clamping of the biliary T-tube. After oral drug administration, mean areas under blood cyclosporine concentration versus time curves before clamping were around 5.2-fold greater by PARIA than HPLC but 2.9-fold greater after clamping and closer to comparable values after intravenous cyclosporine (2.5 and 2.3-fold, respectively). Cyclosporine clearance was smaller by PARIA than HPLC (mean 7.3 versus 3.3 ml.min-1.kg-1, respectively, before clamping). Both values decreased by 25% after clamping (to 5.5 and 2.4 ml.min-1.kg-1, respectively), although there was no significant change in distribution or elimination half-lives (around 0.5 and 8 h, respectively). The mean bioavailability of oral cyclosporine increased significantly after clamping in 9 patients (from 10.6% to 28.1% by HPLC and from 14.8 to 35.1% by PARIA) but in two patients who developed the vanishing bile duct syndrome values fell to less than 10% and the proportional overestimation of cyclosporine concentrations by PARIA increased. Clamping had no singificant effect on the mean apparent volumes of distribution but values of Vz were approximately twice those of Vss (around 2.6 and 1.31.kg-1 by PARIA and HPLC respectively). Mean half lives after clamping were shorter following oral than intravenous cyclosporine (t 1/2 lambda 2 around 15 h enterally versus 8 h parenterally).(ABSTRACT TRUNCATED AT 250 WORDS)

  19. Towards microRNA-based therapeutics for diabetic nephropathy.

    PubMed

    Alvarez, M L; DiStefano, J K

    2013-03-01

    There is no cure for diabetic nephropathy and the molecular mechanisms underlying disease aetiology remain poorly understood. While current paradigms for clinical management of diabetic nephropathy are useful in delaying disease onset and preventing its progression, they do not do so for a significant proportion of diabetic individuals, who eventually end up developing renal failure. Thus, novel therapeutic targets are needed for the treatment and prevention of the disease. MicroRNAs (miRNAs), a class of non-coding RNAs that negatively regulate gene expression, have recently been identified as attractive targets for therapeutic intervention. It is widely recognised that dysregulation of miRNA expression or action contributes to the development of a number of different human diseases, and evidence of a role for miRNAs in the aetiology of diabetic nephropathy is emerging. The discovery that modulation of miRNA expression in vivo is feasible, combined with recent results from successful clinical trials using this technology, opens the way for future novel therapeutic applications. For instance, inhibition of miRNAs that are commonly upregulated in diabetic nephropathy decreases albuminuria and mesangial matrix accumulation in animal models, suggesting that a therapeutic agent against these molecules may help to prevent the development of diabetic nephropathy. Certain challenges, including the development of safe and reliable delivery systems, remain to be overcome before miRNA-based therapeutics become a reality. However, the findings accumulated to date, in conjunction with newly emerging results, are expected to yield novel insights into the complex pathogenesis of diabetic nephropathy, and may eventually lead to the identification of improved therapeutic targets for treatment of this disease.

  20. 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.

  1. Decreased incidence of acute graft-versus-host disease by continuous infusion of cyclosporine with a higher target blood level.

    PubMed

    Oshima, Kumi; Kanda, Yoshinobu; Nakasone, Hideki; Arai, Shunya; Nishimoto, Nahoko; Sato, Hiroyuki; Watanabe, Takuro; Hosoya, Noriko; Izutsu, Koji; Asai, Takashi; Hangaishi, Akira; Motokura, Toru; Chiba, Shigeru; Kurokawa, Mineo

    2008-03-01

    Cyclosporine A (CsA) is the mainstay of pharmacologic prevention of acute graft-versus-host disease (GVHD). We previously reported that continuous infusion of CsA with a target blood level between 250 and 400 ng/ml significantly increased the incidence of acute GVHD compared to twice-daily infusion with a target trough level between 150 and 300 ng/ml. Thus, we raised the target level of CsA continuous infusion to 450-550 ng/ml. We treated 33 patients with the higher target level (CsA500) and compared the efficacy and toxicity with those in the 33 historical control patients (CsA300 group). Other transplantation procedures were not changed. The patients' characteristics were equivalent. The average CsA concentration was adjusted around 500 ng/ml and the actual daily dose was maintained at the initial dose (CsA 3mg/kg/day). Toxicities were equivalently observed among the two groups. The incidence of grades II-IV acute GVHD was significantly lower in the CsA500 group (27 vs. 52%, P = 0.033). The target level of CsA was identified as an independent significant risk factor for grades II-IV acute GVHD (P = 0.039), adjusted for the presence of HLA mismatch. The incidence of chronic GVHD was also decreased in the CsA500 group (47 vs. 73%, P = 0.016). We conclude that the toxicity of the continuous CsA infusion with a target level of 450-550 ng/ml is acceptable and the efficacy to prevent acute GVHD is significant. A larger comparative study is warranted to confirm these findings.

  2. Immunoglobulin A nephropathy associated with Plasmodium falciparum malaria.

    PubMed

    Yoo, Dong Eun; Kim, Jeong Ho; Kie, Jeong Hae; Park, Yoonseon; Chang, Tae Ik; Oh, Hyung Jung; Kim, Seung Jun; Yoo, Tae-Hyun; Choi, Kyu Hun; Kang, Shin-Wook; Han, Seung Hyeok

    2012-04-01

    Glomerulonephritis occurs as a rare form of renal manifestation in Plasmodium falciparum malaria. Herein, we report a case of falciparum malaria-associated IgA nephropathy for the first time. A 49-yr old male who had been to East Africa was diagnosed with Plasmodium falciparum malaria. Microhematuria and proteinuria along with acute kidney injury developed during the course of the disease. Kidney biopsy showed mesangial proliferation and IgA deposits with tubulointerstitial inflammation. Laboratory tests after recovery from malaria showed disappearance of urinary abnormalities and normalization of kidney function. Our findings suggest that malaria infection might be associated with IgA nephropathy.

  3. Chronic pancreatitis

    MedlinePlus

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... hospital for: Pain medicines Fluids given through a vein (IV) Stopping food or fluid by mouth to ...

  4. Clearance of BK Virus Nephropathy by Combination Antiviral Therapy With Intravenous Immunoglobulin

    PubMed Central

    Kable, Kathy; Davies, Carmen D.; O'connell, Philip J.; Chapman, Jeremy R.; Nankivell, Brian John

    2017-01-01

    Background Reactivation of BK polyoma virus causes a destructive virus allograft nephropathy (BKVAN) with graft loss in 46%. Treatment options are limited to reduced immunosuppression and largely ineffective antiviral agents. Some studies suggest benefit from intravenous immunoglobulin (IVIG). Methods We evaluated effectiveness of adjuvant IVIG to eliminate virus from blood and tissue, in a retrospective, single-center cohort study, against standard-of-care controls. Both groups underwent reduced immunosuppression; conversion of tacrolimus to cyclosporine; and mycophenolate to leflunomide, oral ciprofloxacin, and intravenous cidofovir. Results Biopsy-proven BKVAN occurred in 50 kidneys at 7 (median interquartile range, 3-12) months after transplantation, predominantly as histological stage B (92%), diagnosed following by dysfunction in 46%, screening viremia in 20%, and protocol biopsy in 34%. After treatment, mean viral loads fell from 1581 ± 4220 × 103 copies at diagnosis to 1434 ± 70 639 midtreatment, and 0.138 ± 0.331 after 3 months (P < 0.001). IVIG at 1.01 ± 0.18 g/kg was given to 22 (44%) patients. The IVIG group more effectively cleared viremia (hazard ratio, 3.68; 95% confidence interval, 1.56-8.68; P = 0.003) and BK immunohistochemistry from repeated tissue sampling (hazard ratio, 2.24; 95% confidence interval, 1.09-4.58; P = 0.028), and resulted in faster (11.3 ± 10.4 months vs 29.1 ± 31.8 months, P = 0.015) and more complete resolution of viremia (33.3% vs 77.3%, P = 0.044). Numerically, fewer graft losses occurred with IVIG (27.3% vs 53.6% for control, P = 0.06), although graft and patient survivals were not statistically different. Acute renal dysfunction requiring pulse corticosteroid was common (59.1% vs 78.6%, P = 0.09), respectively, after immunosuppression reduction. Conclusions Combination treatment incorporating adjuvant IVIG was more effective eliminating virus from BKVAN, compared with conventional therapy. Validation by multicenter

  5. Prediction of area under the cyclosporine concentration versus time curve in children undergoing hematopoietic stem cell transplantation.

    PubMed

    Dupuis, L Lee; Seto, Winnie; Teuffel, Oliver; Gibson, Paul; Schultz, Kirk R; Doyle, John D; Gassas, Adam; Egeler, R Maarten; Sung, Lillian; Schechter, Tal

    2013-03-01

    This prospective study aimed to validate a previously developed first-dose limited sampling strategy (LSS) to predict the area under the cyclosporine concentration-versus-time curve (AUC) and to develop and then validate an LSS to predict cyclosporine AUC at steady state. This two-center Canadian study included children (ages .4 to 17.2 years) undergoing myeloablative allogeneic hematopoietic stem cell transplantation receiving cyclosporine for acute graft-versus-host disease prophylaxis. There were three cohorts, each incorporating 24 AUC determinations: first-dose LSS validation, steady-state LSS development, and steady-state LSS validation. Patients contributing data to either of the development cohorts were excluded from the corresponding validation group. Cyclosporine was given every 12 hours as a 2-hour infusion. Cyclosporine AUC was determined after administration of the first cyclosporine dose (8 samples) and then once weekly (9 samples) until engraftment. Steady-state LSSs were developed using stepwise multiple linear regression. An LSS was considered to provide an acceptable estimate of AUC if the lower limit of the 95% confidence limit (CL) of the intraclass coefficient was .8 or higher and both bias and precision were 15% or less. Fifty-three children age .4 to 18 years participated. Cyclosporine concentrations drawn up to 4 hours from the start of the infusion correlated most strongly with AUC. The previously developed first-dose LSSs and three steady-state LSSs met criteria for acceptability. The intraclass coefficients of the three-point first-dose LSS validation cohort, three-point steady-state LSS development cohort, and three-point steady-state LSS validation cohort were .974 (95% CL: .941 to .988), .984 (95% CL: .965 to .993), and .993 (95% CL: .984 to .997), respectively. The three-point first-dose (2, 6, and 8 hours) and steady-state (2, 2.5, and 8 hours) LSSs are valid measures of cyclosporine AUC after intravenous administration over 2 hours

  6. 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.

  7. Metadherin facilitates podocyte apoptosis in diabetic nephropathy

    PubMed Central

    Liu, Wen-Ting; Peng, Fen-Fen; Li, Hong-Yu; Chen, Xiao-Wen; Gong, Wang-Qiu; Chen, Wen-Jing; Chen, Yi-Hua; Li, Pei-Lin; Li, Shu-Ting; Xu, Zhao-Zhong; Long, Hai-Bo

    2016-01-01

    Apoptosis, one of the major causes of podocyte loss, has been reported to have a vital role in diabetic nephropathy (DN) pathogenesis, and understanding the mechanisms underlying the regulation of podocyte apoptosis is crucial. Metadherin (MTDH) is an important oncogene, which is overexpressed in most cancers and responsible for apoptosis, metastasis, and poor patient survival. Here we show that the expression levels of Mtdh and phosphorylated p38 mitogen-activated protein kinase (MAPK) are significantly increased, whereas those of the microRNA-30 family members (miR-30s) are considerably reduced in the glomeruli of DN rat model and in high glucose (HG)-induced conditionally immortalized mouse podocytes (MPC5). These levels are positively correlated with podocyte apoptosis rate. The inhibition of Mtdh expression, using small interfering RNA, but not Mtdh overexpression, was shown to inhibit HG-induced MPC5 apoptosis and p38 MAPK pathway, and Bax and cleaved caspase 3 expression. This was shown to be similar to the effects of p38 MAPK inhibitor (SB203580). Furthermore, luciferase assay results demonstrated that Mtdh represents the target of miR-30s. Transient transfection experiments, using miR-30 microRNA (miRNA) inhibitors, led to the increase in Mtdh expression and induced the apoptosis of MPC5, whereas the treatment with miR-30 miRNA mimics led to the reduction in Mtdh expression and apoptosis of HG-induced MPC5 cells in comparison with their respective controls. Our results demonstrate that Mtdh is a potent modulator of podocyte apoptosis, and that it represents the target of miR-30 miRNAs, facilitating podocyte apoptosis through the activation of HG-induced p38 MAPK-dependent pathway. PMID:27882943

  8. [Genetics of mesangial IgA nephropathy].

    PubMed

    Delbarba, Elisa; Pedroni, Bruno; Dallera, Nadia; Izzi, Claudia; Scolari, Francesco

    2015-01-01

    IgA nephropathy is the most common form of primary glomerulonephritis, with a variable prevalence depending on the geographic area of examination. Marked differences in disease prevalence has suggested that genetics could play a role in the pathogenesis of the disease, indicating the existence of susceptibility genes detected with different frequencies in geographically separated populations. Moreover, familial forms of IgAN have been reported worldwide, in sibling pairs, families and extended pedigrees belonging to geographically isolated populations. In this article we describe recent discoveries in genetic studies on IgAN. If candidate-gene association studies require first survey on the pathogenesis of the disease, since the candidate loci are selected on the basis of information gathered from traditional biology, the linkage analysis consist in an alternative approach. Several susceptibility loci have been identified in pedigrees segregating for IgAN, but not the causative mutations of the disease. Further progress in the field of knowledge about the genetics of IgAN has recently been obtained by the application of genome-wide association studies (GWAS) in large cohorts of cases and controls of IgAN. GWAS have identified multiple susceptibility loci coding for genes involved in critical mechanisms for the development of IgAN and, accordingly, have shed new light on the biology of the disease, revealing unknown pathogenic pathways. The close connection between IgAN and many autoimmune diseases has been demonstrated. Moreover, these studies have made the correlation of genetic risk score of developing IgAN with the geo-epidemiological aspect of the disease possible. The goal of the integrated genomic approach will be to discover new potential therapeutic targets.

  9. The Nephropathy of Experimental Hepatosplenic Schistosomiasis

    PubMed Central

    Cavallo, Tito; Galvanek, Eleonora G.; Ward, Peter A.; von Lichtenberg, Franz

    1974-01-01

    The glomerular lesions induced in 10 chimpanzees infected with variable numbers of Schistosoma japonicum cercariae were studied by means of light and electron microscopy and fluorescent antibody technic. Ten animals served as controls; 5 were uninfected and 5 were only lightly infected. The animals were observed for periods ranging from 3 to 17 months, and by the time of sacrifice, all had developed advanced liver fibrosis. In general, the degree of glomerular injury was related to infection intensity and degree and duration of portal liver fibrosis. Some animals had terminal BUN elevation and slight proteinuria. By light and electron microscopy, in the initial stages, only part of the glomeruli were involved and exhibited mesangial matrix expansion and mesangial cell proliferation with intracellular hyaline droplets. At later stages, a larger number of glomeruli were affected and exhibited diffuse hypercellularity, glomerular basement thickening, mesangial sclerosis and less often, focal necrosis, crescent formation, synechiae and global hyalinization. In addition, there were discrete electron-dense deposits localized in the mesangial area in some glomeruli. Immunofluorescent studies utilizing antisera to chimpanzee γ-globulin and complement (C3) and to human properdin disclosed only faint deposits of C3, apparently in mesangial areas. The association of hepatosplenic schistosomiasis and nephropathy, the possible role of schistosomal antigen and the mechanism(s) of such glomerular injuries are reviewed and compared with the disease in humans and other host species infected with Schistosoma. ImagesFig 1Fig 2Fig 3Fig 4Figs 5-8Fig 9Fig 10 PMID:4137991

  10. Treatment with rituximab in idiopathic membranous nephropathy

    PubMed Central

    Fiorentino, Marco; Tondolo, Francesco; Bruno, Francesca; Infante, Barbara; Grandaliano, Giuseppe; Gesualdo, Loreto

    2016-01-01

    Background Rituximab represents a valid therapeutic option to induce remission in patients with primary glomerulonephritis. Despite several studies proving its efficacy in improving outcomes in patients with membranous nephropathy (MN), its role in therapeutic protocols is not yet defined. Methods We studied 38 patients with idiopathic MN treated with rituximab (in 13 patients as first-line therapy, in the remaining 25 after conventional immunosuppressive therapy). The patients were analyzed for a 15-month median (interquartile range 7.7–30.2) follow-up, with serial monitoring of 24-h proteinuria, renal function and circulating CD19+ B cells. Results The percentages of patients who achieved complete remission, partial remission and the composite endpoint (complete or partial remission) were 39.5% (15 patients), 36.8% (14 patients) and 76.3% (29 patients), respectively. The 24-h proteinuria was reduced significantly during the entire period of follow-up (from a baseline value of 6.1 to 0.9 g/day in the last visit; P < 0.01), while albuminemia increased constantly (from a baseline value of 2.6 to 3.5 g/dL in the last observation; P < 0.01). Renal function did not significantly change during the observation period. Circulating CD19+ B cells were reduced significantly from the baseline value to the 24-month value (P < 0.01); data about anti-phospholipase A2 receptor antibodies were available in 14 patients, 10 of which experienced a decreasing trend after treatment. No significant adverse events were described during and after infusions. Conclusions The present study confirmed that treatment with rituximab was remarkably safe and allowed for a large percentage of complete or partial remissions in patients with MN. PMID:27994855

  11. Inflammation in IgA nephropathy.

    PubMed

    Rauen, Thomas; Floege, Jürgen

    2017-03-14

    Immunoglobulin A nephropathy (IgAN) is the most frequently occurring primary glomerulonephritis in Caucasian and Asian populations. Nonetheless, therapeutic recommendations are based on weak evidence, large controlled trials are scarce and, in particular, the additional value of immunosuppression beyond comprehensive supportive measures is not well-established. The use of immunosuppressants is supported by experimental insights into IgAN pathogenesis that suggest an autoimmune component in disease development. The so-called "multi-hit" theory comprises multiple steps, starting with defective glycosylation of IgA subclass IgA1 that results in overproduction of galactose-deficient IgA1 (Gd-IgA1), occurrence of anti-Gd-IgA1 autoantibodies, and mesangial deposition of nephritogenic immune complexes. This eventually results in an increased mesangial cell proliferation, inflammatory responses, and complement activation. Recent genome-wide association studies have identified several susceptibility genes, many of which support the "multi-hit" concept. In light of these discoveries, it is astonishing that the vast majority of adult IgAN patients obviously do not need and/or benefit from immunosuppressive therapies in the first place. In fact, a number of supportive measures are highly effective in reducing the risk for disease progression in many patients. These measures need to be optimized before immunosuppression should be considered at all. In this review we focus on the underlying pathogenetic cornerstones and the central question of whether systemic inflammation in adult IgAN patients should be treated. Treatment options in children with IgAN are also discussed.

  12. 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. PMID:27536664

  13. Pyridorin in Type 2 Diabetic Nephropathy

    PubMed Central

    Greene, Tom; Spitalewiz, Samuel; Blumenthal, Samuel; Berl, Tomas; Hunsicker, Lawrence G.; Pohl, Marc A.; Rohde, Richard D.; Raz, Itamar; Yerushalmy, Yair; Yagil, Yoram; Herskovits, Tommy; Atkins, Robert C.; Reutens, Anne T.; Packham, David K.; Lewis, Julia B.

    2012-01-01

    Pyridoxamine dihydrochloride (Pyridorin, NephroGenex) inhibits formation of advanced glycation end products and scavenges reactive oxygen species and toxic carbonyls, but whether these actions translate into renoprotective effects is unknown. In this double-blind, randomized, placebo-controlled trial, we randomly assigned 317 patients with proteinuric type 2 diabetic nephropathy to twice-daily placebo; Pyridorin, 150 mg twice daily; or Pyridorin, 300 mg twice daily, for 52 weeks. At baseline, the mean age ± SD was 63.9±9.5 years, and the mean duration of diabetes was 17.6±8.5 years; the mean serum creatinine level was 2.2±0.6 mg/dl, and the mean protein-to-creatinine ratio was 2973±1932 mg/g. Regarding the primary end point, a statistically significant change in serum creatinine from baseline to 52 weeks was not evident in either Pyridorin group compared with placebo. However, analysis of covariance suggested that the magnitude of the treatment effect differed by baseline renal function. Among patients in the lowest tertile of baseline serum creatinine concentration, treatment with Pyridorin associated with a lower average change in serum creatinine concentration at 52 weeks (0.28, 0.07, and 0.14 mg/dl for placebo, Pyridorin 150 mg, and Pyridorin 300 mg, respectively; P=0.05 for either Pyridorin dose versus placebo); there was no evidence of a significant treatment effect in the middle or upper tertiles. In conclusion, this trial failed to detect an effect of Pyridorin on the progression of serum creatinine at 1 year, although it suggests that patients with less renal impairment might benefit. PMID:22034637

  14. Apelin retards the progression of diabetic nephropathy.

    PubMed

    Day, Robert T; Cavaglieri, Rita C; Feliers, Denis

    2013-03-15

    Apelin and its receptor APJ have pleiotropic effects in mice and humans and play a protective role in cardiovascular diseases at least partially by inhibiting oxidative stress. Our objective was to study the effect of apelin on the progression of kidney disease in mice with established type 1 diabetes. Ove26 mice with type 1 diabetes received daily subcutaneous injections of apelin for 2 or 14 wk. APJ localizes in the glomeruli and blood vessels of kidneys. Renal APJ expression was reduced in diabetic mice but increased after treatment with apelin. Apelin treatment did not affect glycemia, body weight, or blood pressure in diabetic mice. Whole kidney and glomerular hypertrophy, as well as renal inflammation, including monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1 expression, NF-κB activation, and monocyte infiltration, was inhibited after short and long treatment with apelin. Apelin administration significantly reduced albuminuria at 6 mo. Short treatment with apelin was sufficient to reverse the downregulation of the antioxidant enzyme catalase. Expression of angiotensin II and angiotensin type 1 receptor (AT1) in kidneys from diabetic mice treated was not affected by apelin. These findings show for the first time that apelin exerts a protective effect on the diabetic kidney. Short administration is sufficient to reduce kidney and glomerular hypertrophy as well as renal inflammation, but prolonged treatment is required to improve albuminuria. This effect was independent of the activation of the renin angiotensin system but correlated with upregulation of the antioxidant catalase. Apelin may represent a novel tool to treat diabetic nephropathy.

  15. Cyclosporine A decreases the fluconazole minimum inhibitory concentration of Candida albicans clinical isolates but not biofilm formation and cell growth.

    PubMed

    Wibawa, T; Nurrokhman; Baly, I; Daeli, P R; Kartasasmita, G; Wijayanti, N

    2015-03-01

    Among the genus Candida, Candida albicans is the most abundant species in humans. One of the virulent factors of C. albicans is its ability to develop biofilm. Biofilm forming microbes are characterized by decreasing of its susceptibility to antibiotics and antifungal. The fungicidal effect of fluconazole may be enhanced by cyclosporine A in laboratory engineered C. albicans strains. The aim of this work is to analyze the synergistic effect of cyclosporine A with fluconazole in C. albicans clinical isolates and the effect of cycolsporine A alone in the biofilm formation. Six fluconazole resistant and six sensitive C. albicans clinical isolates were analyzed for its minimum inhibitory concentration (MICs), biofilm formation, and cell growths. A semi-quantitative XTT [2,3-bis(2-methoxy-4-nitro-5- sulfo-phenyl)-2H-tetrazolium-5-carboxanilide] reduction assay was conducted to measure the biofilm formation. Cyclosporine A has synergistic effect with fluconazole that was shown by decreasing MICs of both fluconazole resistant and sensitive C. albicans clinical isolates. However, cyclosporine A alone did not influence the biofilm formation and cell growth of both fluconazole resistant and sensitive C. albicans clinical isolates. These results indicated that cyclosporine A might be a promising candidate of adjuvant therapy for fluconazole against both fluconazole resistant and sensitive C. albicans clinical isolates.

  16. Structural characterization of cyclosporin A, C and microbial bio-transformed cyclosporin A analog AM6 using HPLC-ESI-ion trap-mass spectrometry.

    PubMed

    Ahn, Eun Young; Shrestha, Anil; Hoang, Nguyen Huu; Huong, Nguyen Lan; Yoon, Yeo Joon; Park, Je Won

    2014-06-01

    Cyclosporin A (CyA), a cyclic undecapeptide produced by a number of fungi, contains 11 unusual amino acids, and has been one of the most commonly prescribed immunosuppressive drugs. To date, there are over sixty different analogs reported as congeners and analogs resulting from precursor-directed biosynthesis, human CYP-mediated metabolites, or microbial bio-transformed analogs. However, there is still a need for more structurally diverse CyA analogs in order to discover new biological potentials and/or improve the physicochemical properties of the existing cyclosporins. As a result of the complexity of the resulting mass spectrometric (MS) data caused by its unusual amino acid composition and its cyclic nature, structural characterization of these cyclic peptides based on fragmentation patterns using multiple tandem MS analyses is challenging task. Here, we describe, an efficient HPLC-ESI-ion trap MS(n) (up to MS(8)) was developed for the identification of CyA and CyC, a (Thr(2))CyA congener in which L-aminobutyric acid (Abu) is replaced by L-threonine (Thr). In addition, we examined the fragmentation patterns of a CyA analog obtained from the cultivation of a recombinant Streptomyces venezuelae strain fed with CyA, assigning this analog as (γ-hydroxy-MeLeu(6))CyA (otherwise, known as an human CYP metabolite AM6). This is the first report on both the MS(n)-aided identification of CyC and the structural characterization of a CyA analog by employing HPLC-ESI-ion trap MS(n) analysis.

  17. Acute oxalate nephropathy after ingestion of star fruit.

    PubMed

    Chen, C L; Fang, H C; Chou, K J; Wang, J S; Chung, H M

    2001-02-01

    Acute oxalate nephropathy associated with ingestion of star fruit (carambola) has not been reported before. We report the first two cases. These patients developed nausea, vomiting, abdominal pain, and backache within hours of ingesting large quantities of sour carambola juice; then acute renal failure followed. Both patients needed hemodialysis for oliguric acute renal failure, and pathologic examinations showed typical changes of acute oxalate nephropathy. The renal function recovered 4 weeks later without specific treatment. Sour carambola juice is a popular beverage in Taiwan. The popularity of star fruit juice is not compatible with the rare discovery of star fruit-associated acute oxalate nephropathy. Commercial carambola juice usually is prepared by pickling and dilution processes that reduce oxalate content markedly, whereas pure fresh juice or mild diluted postpickled juice for traditional remedies, as used in our cases, contain high quantities of oxalate. An empty stomach and dehydrated state may pose an additional risk for development of renal injury. To avoid acute oxalate nephropathy, pure sour carambola juice or mild diluted postpickled juice should not be consumed in large amounts, especially on an empty stomach or in a dehydrated state.

  18. Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial.

    PubMed

    Praga, M; Barrio, V; Juárez, G Fernández; Luño, J

    2007-05-01

    Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achieve a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patient in the tacrolimus group showed a relapse during the taper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We conclude that tacrolimus is a very useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.

  19. Calorie restriction mimicking effects of roflumilast prevents diabetic nephropathy.

    PubMed

    Tikoo, Kulbhushan; Lodea, Saritha; Karpe, Pinakin Arun; Kumar, Sandeep

    2014-08-08

    Little is known about role of PDE4 in the development and progression of diabetic nephropathy. Here, we investigated the effect of roflumilast, a selective PDE 4 inhibitor in type 1 diabetic nephropathy. Diabetes was induced in male Sprague-Dawley rats using streptozotocin (55 mg/kg). Diabetic rats showed elevated plasma glucose, blood urea nitrogen, creatinine and decrease in plasma albumin confirming signs of nephropathy. Roflumilast at 2 and 3mg/kg normalized these alterations. Roflumilast also suppressed oxidative stress and deposition of an extracellular matrix protein such as fibronectin and collagen in kidney of diabetic rats. TUNEL assay revealed apoptosis in diabetic kidney than control and that roflumilast prevents this effect. We show that kidney of diabetic rats displayed a state of p-AMPK and SIRT1 deficiency and that roflumilast, interestingly, was able to restore their levels. Further, roflumilast prevented an increase in HO-1 and loss in the FoxO1 expression in diabetes. However, it did not improve the reduced NRF2 levels in diabetes. This is the first report to show that, like resveratrol and other SIRT1 activators, roflumilast also mimics calorie restriction effects through activation of AMPK/SIRT1 and protects against diabetic nephropathy. This study unveils the unexplored potential of roflumilast which can be used in treatment of metabolic disorders.

  20. Chronic kidney disease and pregnancy: maternal and fetal outcomes.

    PubMed

    Fischer, Michael J

    2007-04-01

    Chronic kidney disease complicates an increasing number of pregnancies, and at least 4% of childbearing-aged women are afflicted by this condition. Although diabetic nephropathy is the most common type of chronic kidney disease found in pregnant women, a variety of other primary and systemic kidney diseases also commonly occur. In the setting of mild maternal primary chronic kidney disease (serum creatinine <1.3 mg/dL) without poorly controlled hypertension, most pregnancies result in live births and maternal kidney function is unaffected. In cases of more moderate and severe maternal primary chronic kidney disease, the incidence of fetal prematurity, low birth weight, and death increase substantially, and the risk of accelerated irreversible decline in maternal kidney function, proteinuria, and hypertensive complications rise dramatically. In addition to kidney function, maternal hypertension and proteinuria portend negative outcomes and are important factors to consider when risk stratifying for fetal and maternal complications. In the setting of diabetic nephropathy and lupus nephropathy, other systemic disease features such as disease activity, the presence of antiphospholipid antibodies, and glycemic control play important roles in determining pregnancy outcomes. Concomitant with advances in obstetrical management and kidney disease treatments, it appears that the historically dismal maternal and fetal outcomes have greatly improved.

  1. Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients.

    PubMed

    Kishi, Y; Murashige, N; Kami, M; Miyakoshi, S; Shibagaki, Y; Hamaki, T; Takaue, Y; Taniguchi, S

    2005-06-01

    Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n=25), renal dysfunction (n=3), hepatic dysfunction (n=2), and hypertension (n=2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n=4), hyperbilirubinemia (n=2), and hypertension (n=2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

  2. Predicting Diabetic Nephropathy Using a Multifactorial Genetic Model

    PubMed Central

    Blech, Ilana; Wainstein, Julio; Rubinstein, Ardon; Harman-Boehm, Ilana; Cohen, Joseph; Pollin, Toni I.; Glaser, Benjamin

    2011-01-01

    Aims The tendency to develop diabetic nephropathy is, in part, genetically determined, however this genetic risk is largely undefined. In this proof-of-concept study, we tested the hypothesis that combined analysis of multiple genetic variants can improve prediction. Methods Based on previous reports, we selected 27 SNPs in 15 genes from metabolic pathways involved in the pathogenesis of diabetic nephropathy and genotyped them in 1274 Ashkenazi or Sephardic Jewish patients with Type 1 or Type 2 diabetes of >10 years duration. A logistic regression model was built using a backward selection algorithm and SNPs nominally associated with nephropathy in our population. The model was validated by using random “training” (75%) and “test” (25%) subgroups of the original population and by applying the model to an independent dataset of 848 Ashkenazi patients. Results The logistic model based on 5 SNPs in 5 genes (HSPG2, NOS3, ADIPOR2, AGER, and CCL5) and 5 conventional variables (age, sex, ethnicity, diabetes type and duration), and allowing for all possible two-way interactions, predicted nephropathy in our initial population (C-statistic = 0.672) better than a model based on conventional variables only (C = 0.569). In the independent replication dataset, although the C-statistic of the genetic model decreased (0.576), it remained highly associated with diabetic nephropathy (χ2 = 17.79, p<0.0001). In the replication dataset, the model based on conventional variables only was not associated with nephropathy (χ2 = 3.2673, p = 0.07). Conclusion In this proof-of-concept study, we developed and validated a genetic model in the Ashkenazi/Sephardic population predicting nephropathy more effectively than a similarly constructed non-genetic model. Further testing is required to determine if this modeling approach, using an optimally selected panel of genetic markers, can provide clinically useful prediction and if generic models can be developed for

  3. Modification of c and n sources for enhanced production of cyclosporin ‘a’ by Aspergillus Terreus

    PubMed Central

    Tanseer, Sundas; Anjum, Tehmina

    2011-01-01

    Most of the studies regarding cyclosporin ‘A’ production through fungi concentrate around Tolypocladium inflatum. This is mainly due to lower reported production of this drug in other fungi. The present study was therefore conducted to explore indigenous isolates of Aspergillus terreus for synthesis of this drug and defining a production medium for obtaining high yield of cyclosporin ‘A’. For this purpose carbon and nitrogen sources were optimized for the selected best strain of A. terreus. Overall results depicted that the best cyclosporin ‘A’ yield from selected Aspergillus terreus (FCBP58) could be obtained by using production medium containing glucose 10% as carbon source and peptone 0.5% as nitrogen source. This modification in production medium enhanced drug synthesis by selected fungi significantly. The production capabilities when compared with biomass of fungi there was found no relationship between the two confirming that the medium modification increased overall drug synthesis powers of the fungi. PMID:24031766

  4. Glucocorticoid-resistant Th17 cells are selectively attenuated by cyclosporine A.

    PubMed

    Schewitz-Bowers, Lauren P; Lait, Philippa J P; Copland, David A; Chen, Ping; Wu, Wenting; Dhanda, Ashwin D; Vistica, Barbara P; Williams, Emily L; Liu, Baoying; Jawad, Shayma; Li, Zhiyu; Tucker, William; Hirani, Sima; Wakabayashi, Yoshiyuki; Zhu, Jun; Sen, Nida; Conway-Campbell, Becky L; Gery, Igal; Dick, Andrew D; Wei, Lai; Nussenblatt, Robert B; Lee, Richard W J

    2015-03-31

    Glucocorticoids remain the cornerstone of treatment for inflammatory conditions, but their utility is limited by a plethora of side effects. One of the key goals of immunotherapy across medical disciplines is to minimize patients' glucocorticoid use. Increasing evidence suggests that variations in the adaptive immune response play a critical role in defining the dose of glucocorticoids required to control an individual's disease, and Th17 cells are strong candidate drivers for nonresponsiveness [also called steroid resistance (SR)]. Here we use gene-expression profiling to further characterize the SR phenotype in T cells and show that Th17 cells generated from both SR and steroid-sensitive individuals exhibit restricted genome-wide responses to glucocorticoids in vitro, and that this is independent of glucocorticoid receptor translocation or isoform expression. In addition, we demonstrate, both in transgenic murine T cells in vitro and in an in vivo murine model of autoimmunity, that Th17 cells are reciprocally sensitive to suppression with the calcineurin inhibitor, cyclosporine A. This result was replicated in human Th17 cells in vitro, which were found to have a conversely large genome-wide shift in response to cyclosporine A. These observations suggest that the clinical efficacy of cyclosporine A in the treatment of SR diseases may be because of its selective attenuation of Th17 cells, and also that novel therapeutics, which target either Th17 cells themselves or the effector memory T-helper cell population from which they are derived, would be strong candidates for drug development in the context of SR inflammation.

  5. Immunohistochemical Localization of Epithelial Mesenchymal Transition Markers in Cyclosporine A Induced Gingival Overgrowth

    PubMed Central

    Arora, Hitesh; Madapusi, Balaji Thodur; Ramamurti, Anjana; Narasimhan, Malathi; Periasamy, Soundararajan

    2016-01-01

    Introduction Cyclosporine, an immunosuppressive agent used in the management of renal transplant patients is known to produce Drug Induced Gingival Overgrowth (DIGO) as a side effect. Several mechanisms have been elucidated to understand the pathogenesis of DIGO. Recently, epithelial mesenchymal transition has been proposed as a mechanism underlying fibrosis of various organs. Aim The aim of the study was to investigate if Epithelial Mesenchymal Transition (EMT) operates in Cyclosporine induced gingival overgrowth. Materials and Methods The study involved obtaining gingival tissue samples from healthy individuals (n=17) and subjects who exhibited cyclosporine induced gingival overgrowth (n=18). Presence and distribution of E-Cadherin, S100 A4 and alpha smooth muscle actin (α-SMA) was assessed using immunohistochemistry and cell types involved in their expression were determined. The number of α– SMA positive fibroblasts were counted in the samples. Results In control group, there was no loss of E-Cadherin and a pronounced staining was seen in the all layers of the epithelium in all the samples analysed (100%). S100 A4 staining was noted in langerhans cells, fibroblasts, endothelial cells and endothelial lined blood capillaries in Connective Tissue (CT) of all the samples (100%) while α - SMA staining was seen only on the endothelial lined blood capillaries in all the samples (100%). However in DIGO, there was positive staining of E-Cadherin only in the basal and suprabasal layers of the epithelium in all the samples (100%). Moreover there was focal loss of E-Cadherin in the epithelium in eight out of 18 samples (44%). A break in the continuity of the basement membrane was noted in three out of 18 samples (16%) on H & E staining. Conclusion Based on the analysis of differential staining of the markers, it can be concluded that EMT could be one of the mechanistic pathways underlying the pathogenesis of DIGO. PMID:27656563

  6. Immunoglobulin M Nephropathy in a Patient with Wilson's Disease.

    PubMed

    Ul Abideen, Zain; Sajjad, Zoya; Haroon Khan, Asna; Mamoon, Nadira; Bilal, Muhammad; Mujtaba Quadri, Khaja Hameeduddin

    2016-12-13

    Immunoglobulin M nephropathy (IgMN) is characterized by the deposition of immunoglobulin M in a dominant distribution in the renal glomeruli. Primary immunoglobulin M nephropathy is diagnosed after consistent light microscopy (LM), immunofluorescence (IF), electron microscopy (EM) results, and exclusion of known systemic disorders causing immunoglobulin M deposition in the glomeruli. The secondary disease has been reported with a few conditions though it has never been reported with any primary disease of the liver. We report the case of an adolescent male patient who presented with nausea, vomiting, diarrhea, and worsening anasarca. He was found to have nephrotic-range proteinuria that did not respond to conventional corticosteroid treatment. He was subjected to a renal biopsy which revealed a diagnosis of immunoglobulin M nephropathy. His liver function tests were deranged and an ultrasound scan of the abdomen revealed a coarse irregular liver. Workup revealed elevated urine copper excretion and a low ceruloplasmin level. He was diagnosed as a case of Wilson's disease and started on penicillamine and pyridoxine. He was also started on intravenous cyclophosphamide for the corticosteroid-resistant nephrotic syndrome to which he responded remarkably well. His edema settled, proteinuria resolved, and liver functions normalized. Currently, he is in remission and enjoying good health. To the best of our knowledge, we report the first known association between IgM nephropathy and Wilson's disease. It is presently not clear if causation can necessarily be established. This may be the result of defective IgM clearance by the liver or an altered metabolism of the antibody or immune complexes, as with hepatic-associated immunoglobulin M (IgM) nephropathy. Further studies are needed to elucidate the exact mechanism of this disease.

  7. Current concepts in the management of diabetic nephropathy.

    PubMed

    Waanders, F; Visser, F W; Gans, R O B

    2013-11-01

    Although much progress has been made in slowing the progression of diabetic nephropathy, renal dysfunction and development of end-stage renal disease (ESRD) remain major concerns in diabetes. In addition, diabetic patients with microalbuminuria have an increased cardiovascular mortality. Therefore, new treatment modalities or strategies are needed to prevent or slow the progression of diabetic nephropathy and prevent cardiovascular disease in diabetes. In this review we describe current concepts in pathophysiology, treatment goals and we discuss future developments in the treatment of diabetic nephropathy. Common risk factors for diabetic nephropathy and its progression are longer duration, poor glycaemic control, hypertension and the presence of albuminuria. Available treatment options, especially renin-angiotensin aldosterone system (RAAS) blockade, but also better blood pressure and blood glucose control, decrease the incidence of cardiovascular disease and renal disease in diabetes. It is important that treatment goals are tailored to the individual patient with individual treatment goals of glycaemic control and blood pressure, depending on age, type of diabetes and diabetes duration. Aggressive treatment of glucose control and blood pressure might not always be best practice for every patient. Since the proportion of ESRD due to diabetic nephropathy remains high, optimisation of RAAS blockade is advocated and can be achieved by adequate sodium restriction and/or diuretic treatment. Moreover, aldosterone blockade might be a valuable strategy, which has potency to slow the progression of diabetic renal disease. Other possible future interventions are under investigation, but large clinical trials have to be awaited to confirm the safety and efficacy of these drugs.

  8. Improved prognosis of diabetic nephropathy in type 1 diabetes.

    PubMed

    Andrésdóttir, Gudbjörg; Jensen, Majken L; Carstensen, Bendix; Parving, Hans-Henrik; Hovind, Peter; Hansen, Tine W; Rossing, Peter

    2015-02-01

    The natural history of diabetic nephropathy offered an average survival of only 5-7 years. During the past decades, multiple changes in therapy and lifestyle have occurred. The prognosis of diabetic nephropathy after implementing stricter control of blood pressure (including increased use of long-term renin-angiotensin system inhibition), lipids, and glycemia, along with less smoking and other lifestyle and treatment advancements, is inadequately analyzed. To clarify this, we studied 497 patients with type 1 diabetes and diabetic nephropathy at the Steno Diabetes Center and compared them with previous data, obtained using identical criteria at our hospital. The glomerular filtration rate, measured yearly by 51Cr-EDTA plasma clearance, was a mean of 71 ml/min per 1.73 m2 at baseline. The mean glomerular filtration rate decline was significantly reduced by 19% (95% confidence interval 5-34) from previously 4.0 to 3.3 ml/min per 1.73 m2/year. During a median follow-up of 9.1 years, 29% of participants doubled their plasma creatinine or developed end-stage renal disease. Mortality risk was similar to our prior study (hazard ratio 1.05 (0.76-1.43). However, after age adjustment, as both diabetes and nephropathy onset occurred later in life, mortality was reduced by 30%. Risk factors for decline in glomerular filtration rate, death, and other renal end points were generally in agreement with prior studies. Thus, with current treatment of nephropathy in type 1 diabetes, the prognosis and loss of renal function has improved along with better control of modifiable risk factors.

  9. Combining cytochrome P-450 3A4 modulators and cyclosporine or everolimus in transplantation is successful

    PubMed Central

    González, Fernando; Valjalo, Ricardo

    2015-01-01

    AIM: To describe the long term follow-up of kidney allograft recipients receiving ketoconazole with calcineurin inhibitors (CNI) alone or combined with everolimus. METHODS: This is an open-label, prospective observational clinical trial in low immunologic risk patients who, after signing an Institutional Review Board approved consent form, were included in one of two groups. The first one (n = 59) received everolimus (target blood level, 3-8 ng/mL) and the other (n = 114) azathioprine 2 mg/kg per day or mycophenolate mofetyl (MMF) 2 g/d. Both groups also received tapering steroids, the cytochrome P-450 3A4 (CYP3A4) modulator, ketoconazole 50-100 mg/d, and cyclosporine with C0 targets in the everolimus group of 200-250 ng/mL in 1 mo, 100-125 ng/mL in 2 mo, and 50-65 ng/mL thereafter, and in the azathioprine or MMF group of 250-300 ng/mL in 1 mo, 200-250 ng/mL in 2 mo, 180-200 ng/mL until 3-6 mo, and 100-125 ng/mL thereafter. Clinical visits were performed monthly the first year and quarterly thereafter by treating physicians and all data was extracted by the investigators. RESULTS: The clinical characteristics of these two cohorts were similar. During the follow up (66 + 31 mo), both groups showed comparable clinical courses, but the biopsy proven acute rejection rate during the full follow-up period seemed to be lower in the everolimus group (20% vs 36%; P = 0.04). The everolimus group did not show a higher surgical complication rate than the other group. By the end of the follow-up period, the everolimus group tended to show a higher glomerular filtration rate. Nevertheless, we found no evidence of a consistent negative slope of the temporal allograft function estimated by the modification of the diet in renal disease formula in any of both groups. At 6 years of follow-up, the uncensored and death-censored graft survivals were 91% and 93%, and 91% and 83% in the everolimus plus cyclosporine, and cyclosporine alone groups, respectively. The addition of ketoconazole

  10. Oral administration of cyclosporin A for recipients of allogeneic marrow transplants: implications of clinical gut dysfunction.

    PubMed

    Atkinson, K; Biggs, J C; Britton, K; Short, R; Mrongovius, R; Concannon, A; Dodds, A

    1984-02-01

    Cyclosporin A (CyA) was used to minimize graft-versus-host disease (GVHD) in 28 recipients of allogeneic marrow transplants. When given orally, the absorption of CyA was markedly dependent on normal gut function. Patients without gut dysfunction showed normal serum concentration-time curves while those with diarrhoea from any cause (chemo-radiation enteritis, acute GVHD of the gut, infectious enteritis) showed minimal absorption of the drug. These data indicate the desirability of the intravenous administration of CyA during periods of gut dysfunction in marrow transplant recipients.

  11. Cyclosporin A in the treatment of CLL associated PRCA and bone marrow hypoplasia.

    PubMed

    Tura, S; Finelli, C; Bandini, G; Cavo, M; Gobbi, M

    1988-01-01

    Three patients (1 PRCA-T-CLL, 1 PRCA-B-CLL, 1 B-CLL aplasia) were treated with cyclosporin A (CS-A). Patient no 1 had relapsed during steroid therapy and the remaining two patients had been resistant to conventional immunosuppression. CS-A produced in all cases a prompt remission (within 1-4 weeks) of bone marrow failure. Mild reversible renal toxicity was the only side-effect noted. CS-A might be tried in every case of CLL-associated bone marrow failure.

  12. 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

  13. Pneumonia associated with Salmonella spp. infection in a cat receiving cyclosporine.

    PubMed

    Callegari, C; Palermo, G; Greco, M F; Corrente, M; Piseddu, E; Auriemma, E; Zini, E

    2014-10-01

    Salmonellosis is uncommon in cats, usually affects the gastrointestinal tract or skin, and can be fatal. This report describes a domestic shorthair cat with severe pneumonia caused by Salmonella spp. without accompanying gastrointestinal or skin manifestations, in which previous administration of cyclosporine may have played a permissive role in its development. Clinical and laboratory findings as well as follow-up are described from diagnosis until complete recovery. This unusual presentation serves to alert practitioners to consider Salmonella spp. as a possible cause of lung disease in cats, especially if immunocompromised.

  14. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy.

    PubMed

    Ballardie, Francis W; Roberts, Ian S D

    2002-01-01

    In a single-center, multiple-referral source study, 38 patients with progressive IgA nephropathy and controlled hypertension were randomized to treatment with prednisolone and cytotoxic agents, to therapy with low-dose cyclophosphamide then azathioprine, and to control groups. The follow-up period lasted 2 to 6 yr. Renal survival, as assessed by Kaplan-Meier analysis annually to 5 yr, showed significant preservation of function from 3 yr in the treatment group and 82, 82, 72, and 72% for 2, 3, 4, and 5 yr, respectively, compared with 68, 47, 26, and 6% in controls. Rate of loss of renal function, evaluated objectively by least-squares analyses of reciprocal serum creatinine, was reduced-and in one-third of the patients, arrested-during immunosuppressive treatment. Proteinuria, present in all patients at the time of entry into the trial, was reduced by treatment from 12 mo, compared with pretreatment levels or controls; erythrocyturia was reduced from 6 mo. Histologic activity and chronicity indexes were determined in renal biopsies performed at trial entry. Multivariate analysis demonstrated that mesangial cell proliferation and matrix scores were highest in those patients with more rapidly progressive disease. No morphologic variable or residual renal function predicted response to immunosuppressive therapy at entry. Mean arterial pressures did not differ significantly between treatment and control groups. There was thus no explanation other than treatment for the improved outcome in patients who received immunosuppressive therapy. Morbidity attributable to treatment or to renal failure occurred in both groups; an audit showed that benefits of therapy outweighed expected or minor side effects of drugs in this population at risk of end-stage renal failure. Patients selected for moderately progressive IgA nephropathy benefit from treatment with prednisolone and cytotoxic agents; results are consistent with modulation of systemic immune response or nephritic injury

  15. Diabetic nephropathy is resistant to oral l-arginine or l-citrulline supplementation

    PubMed Central

    You, Hanning; Gao, Ting; Cooper, Timothy K.; Morris, Sidney M.

    2014-01-01

    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

  16. Cyclosporin A inhibits HTLV-I tax expression and shows anti-tumor effects in combination with VP-16.

    PubMed

    Ozaki, Atsuo; Arima, Naomichi; Matsushita, Kakushi; Uozumi, Kimiharu; Akimoto, Masaki; Hamada, Heiichiro; Kawada, Hideaki; Horai, Sawako; Tanaka, Yuetsu; Tei, Chuwa

    2007-12-01

    Adult T cell leukemia (ATL) is one of the most refractory malignant hematological diseases. Our previous studies demonstrated HTLV-1Tax protein involvement in clinical manifestation of the aggressive type of ATL and suggested the potential application of agents to inhibit Tax expression for ATL treatment. In the present study, we first examined Tax involvement in the resistance to VP-16-induced apoptosis using four HTLV-1 infected T cell clones and cTax DNA-transfected cells. Next, we examined whether cyclosporin A reduced expression of Tax and its related transfer factors on Western blot and CAT assay. We further investigated whether cyclosporin A in combination with VP-16 can induce apoptosis in HTLV-1 infected T cells. Tax-producing T cells, K3T and F6T, were resistant to VP-16 induced growth inhibition compared with that of the nonproducing cells, S1T and Su9T01. Experiments using S1T and Tax-expressing cDNA-transfected S1T demonstrated Tax-induced resistance to VP-16 induction of apoptosis by DNA ladder formation. Cyclosporin A reduced Tax expression in K3T by Western blot analysis and on CAT assay, showing maximal reduction of 61% and 60% compared to control culture using LTR CAT transfected Jurkat cells and K3T cells, respectively. Cyclosporin A also reduced the nuclear expression of two Tax-related transfer factors, ATF-1 and ATF-2 on Western blot. Cyclosporin A alone did not show any cytotoxicity by itself, but sensitized cells to VP-16 when combined with VP-16. Cyclosporin A may be a useful anti-ATL agent when combined with other anti-cancer agents possibly related to Tax inhibition.

  17. 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

  18. Systematic review and meta-analysis of third-line salvage therapy with infliximab or cyclosporine in severe ulcerative colitis

    PubMed Central

    Feuerstein, Joseph D.; Akbari, Mona; Tapper, Elliot B.; Cheifetz, Adam S.

    2016-01-01

    Background In patients with ulcerative colitis who fail corticosteroids and are treated with rescue therapy (e.g. infliximab or cyclosporine) but fail to respond, salvage therapy with infliximab or cyclosporine can be considered. We sought to assess the efficacy and safety of this third-line salvage therapy. Methods We performed a meta-analysis of trials published in PubMed up to January 2015 relating to the use of third-line salvage therapy following failure of intravenous corticosteroids and infliximab or cyclosporine. Pooled outcome rates for each salvage strategy and pooled odds ratio comparing the two strategies were calculated using the random effects model. Heterogeneity was assessed by the Q and I2 statistics. Results The search strategy yielded 40 articles of which 4 were eligible for inclusion. Four articles assessed patients who were treated with infliximab after failure of cyclosporine and 2 articles assessed the use of cyclosporine after failure of infliximab. There were 138 patients using infliximab as a third-line salvage therapy and 30 patients using cyclosporine. When comparing these two strategies, there was no significant difference in clinical response (RR 1.03, 95%CI 0.7-1.46 P=0.87), clinical remission (RR 0.69, 95%CI 0.30-1.57 P=0.37), or colectomy at 12 months (RR 1.14, 95%CI 0.79-1.67 P=0.48). Similarly, there was no significant difference in total (RR 1.91, 95% CI0.38-9.64 p=0.43) or serious adverse events (RR 1.18, 95%CI 0.34-4.07 P=0.80). Conclusion While third-line salvage therapy may be efficacious in achieving short-term clinical response/remission, there remains a significant risk of colectomy and adverse events. PMID:27366036

  19. Immune-Mediated Nephropathy and Systemic Autoimmunity in Mice Does Not Require Receptor Interacting Protein Kinase 3 (RIPK3)

    PubMed Central

    Corradetti, Chelsea; Jog, Neelakshi R.; Gallucci, Stefania; Madaio, Michael; Balachandran, Siddharth

    2016-01-01

    Immune mediated nephropathy is one of the most serious manifestations of lupus and is characterized by severe inflammation and necrosis that, if untreated, eventually leads to renal failure. Although lupus has a higher incidence in women, both sexes can develop lupus glomerulonephritis; nephritis in men develops earlier and is more severe than in women. It is therefore important to understand the cellular and molecular mechanisms mediating nephritis in each sex. Previous work by our lab found that the absence or pharmacological inhibition of Poly [ADP-ribose] polymerase 1 (PARP-1), an enzyme involved in DNA repair and necrotic cell death, affects only male mice and results in milder nephritis, with less in situ inflammation, and diminished incidence of necrotic lesions, allowing for higher survival rates. A second pathway mediating necrosis involves Receptor-Interacting Serine-Threonine Kinase 3 (RIPK3); in this study we sought to investigate the impact of RIPK3 on the development of lupus and nephritis in both sexes. To this end, we used two inducible murine models of lupus: chronic graft versus host disease (cGvHD) and pristane-induced lupus; and nephrotoxic serum (NTS)-induced nephritis as a model of immune mediated nephropathy. We found that the absence of RIPK3 has neither positive nor negative impact on the disease development or progression of lupus and nephritis in all three models, and in both male and female mice. We conclude that RIPK3 is dispensable for the pathogenesis of lupus and immune mediated nephropathy as to accelerate, worsen or ameliorate the disease. PMID:27669412

  20. Role of galectin-3 in autoimmune and non-autoimmune nephropathies.

    PubMed

    Saccon, Francesca; Gatto, Mariele; Ghirardello, Anna; Iaccarino, Luca; Punzi, Leonardo; Doria, Andrea

    2017-01-01

    Galectins are evolutionary conserved β-galactoside binding proteins with a carbohydrate-recognition domain (CRD) of approximately 130 amino acids. In mammals, 15 members of the galectin family have been identified and classified into three subtypes according to CRD organization: prototype, tandem repeat-type and chimera-type galectins. Galectin-3 (gal-3) is the only chimera type galectin in vertebrates containing one CRD linked to an unusual long N-terminal domain which displays non-lectin dependent activities. Although recent studies revealed unique, pleiotropic and context-dependent functions of gal-3 in both extracellular and intracellular space, gal-3 specific pathways and its ligands have not been clearly defined yet. In the kidney gal-3 is involved in later stages of nephrogenesis as well as in renal cell cancer. However, gal-3 has recently been associated with lupus glomerulonephritis, with Familial Mediterranean Fever-induced proteinuria and renal amyloidosis. Gal-3 has been studied in experimental acute kidney damage and in the subsequent regeneration phase as well as in several models of chronic kidney disease, including nephropathies induced by aging, ischemia, hypertension, diabetes, hyperlipidemia, unilateral ureteral obstruction and chronic allograft injury. Because of the pivotal role of gal-3 in the modulation of immune system, wound repair, fibrosis and tumorigenesis, it is not surprising that gal-3 can be an intriguing prognostic biomarker as well as a promising therapeutic target in a great variety of diseases, including chronic kidney disease, chronic heart failure and cardio-renal syndrome. This review summarizes the functions of gal-3 in kidney pathophysiology focusing on the reported role of gal-3 in autoimmune diseases.

  1. Magnetic resonance histology of age-related nephropathy in the Sprague Dawley rat.

    PubMed

    Xie, Luke; Cianciolo, Rachel E; Hulette, Brian; Lee, Ha Won; Qi, Yi; Cofer, Gary; Johnson, G Allan

    2012-07-01

    Magnetic resonance histology (MRH) has become a valuable tool in evaluating drug-induced toxicity in preclinical models. However, its application in renal injury has been limited. This study tested the hypothesis that MRH could detect image-based biomarkers of chronic disease, inflammation, or age-related degeneration in the kidney, laying the foundation for more extensive use in evaluating drug toxicity. We examined the entire intact kidney in a spontaneous model of chronic progressive nephropathy. Kidneys from male Sprague Dawley rats were imaged at 8 weeks (n = 4) and 52 weeks (n =4) on a 9.4 T system dedicated to MR microscopy. Several potential contrast mechanisms were explored to optimize the scanning protocols. Full coverage of the entire kidney was achieved with isotropic spatial resolution at 31 microns (voxel volume = 30 pL) using a gradient recalled echo sequence. Isotropic spatial resolution of 15 microns (voxel volume < 4 pL) was achieved in a biopsy core specimen. Qualitative age-related structural changes, such as renal cortical microvasculature, tubular dilation, interstitial fibrosis, and glomerular architecture, were apparent. The nondestructive 3D images allowed measurement of quantitative differences of kidney volume, pelvis volume, main vessel volume, glomerular size, as well as thickness of the cortex, outer medulla, and inner medulla.

  2. Inhibition of adriamycin-induced nephropathy in rats by herbs based kangshenoral solution