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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. Differential diagnosis of acute rejection and chronic cyclosporine nephropathy after rat renal transplantation by detection of endothelial microparticles (EMP).

    PubMed

    Cui, Jiewei; Yang, Jing; Cao, Weike; Sun, Yi

    2010-12-01

    Endothelial microparticles (EMP) are small vesicles smaller than 1.0μm, released from endothelial cells (EC) during their activation and (or) apoptosis. The assay of the level of elevated EMP is a new approach to evaluate the dysfunction of endothelial cell. EMP can be classified into several types according to their membrane molecular, and the levels of various types of EMP may be different. As the most cost-effective immunodepressant, cyclosporine A (CsA) has been used widely in organ transplantation. But its dose is hard to control, under-medication may cause the acute rejection (AR) and overdose may cause chronic cyclosporine nephropathy (CCN). The cyclosporine A (CsA) caused CCN and the AR caused renal injury after renal transplantation are both vascular diseases related with endothelial dysfunction, and up to now, there is still no effective method to distinguish the two kinds of diseases. Owing to distinct pathogenesis of the two kinds of vascular diseases, the level of each type of EMP originated from vascular endothelial cells may be different. We hypothesize that maybe we can distinguish them by detecting the different levels of some types of EMP which is also related with vascular disease, and we propose to prove our hypothesis through animal experiment. If our hypothesis is proved, it will be more helpful for clinicians to adjust the dose of CsA promptly according to the differential diagnosis of the two kinds of diseases. Copyright © 2010 Elsevier Ltd. All rights reserved.

  4. 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

  5. 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

  6. 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

  7. [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.

  8. Chronic allograft nephropathy.

    PubMed

    Vadivel, Nidyanandh; Tullius, Stefan G; Chandraker, Anil

    2007-07-01

    Chronic allograft nephropathy (CAN) remains the Achilles heel of renal transplantation. In spite of the significant strides achieved in one-year renal allograft survival with newer immunosuppressant strategies, the fate of long-term renal allograft survival remains unchanged. The number of renal transplant recipients returning to dialysis has doubled in the past decade. This is especially important since these patients pose a significantly increased likelihood of dying while on the waiting list for retransplantation, due to increasing disparity between donor organ availability versus demand and longer waiting time secondary to heightened immunologic sensitization from their prior transplants. In this review we analyze the latest literature in detail and discuss the definition, natural history, pathophysiology, alloantigen dependent and independent factors that play a crucial role in CAN and the potential newer therapeutic targets on the horizon. This article highlights the importance of early identification and careful management of all the potential contributing factors with particular emphasis on prevention rather than cure of CAN as the core management strategy.

  9. 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

  10. 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

  11. The natural history of chronic allograft nephropathy.

    PubMed

    Nankivell, Brian J; Borrows, Richard J; Fung, Caroline L-S; O'Connell, Philip J; Allen, Richard D M; Chapman, Jeremy R

    2003-12-11

    With improved immunosuppression and early allograft survival, chronic allograft nephropathy has become the dominant cause of kidney-transplant failure. We evaluated the natural history of chronic allograft nephropathy in a prospective study of 120 recipients with type 1 diabetes, all but 1 of whom had received kidney-pancreas transplants. We obtained 961 kidney-transplant-biopsy specimens taken regularly from the time of transplantation to 10 years thereafter. Two distinctive phases of injury were evident as chronic allograft nephropathy evolved. An initial phase of early tubulointerstitial damage from ischemic injury (P<0.05), prior severe rejection (P<0.01), and subclinical rejection (P<0.01) predicted mild disease by one year, which was present in 94.2 percent of patients. Early subclinical rejection was common (affecting 45.7 percent of biopsy specimens at three months), and the risk was increased by the occurrence of a prior episode of severe rejection and reduced by tacrolimus and mycophenolate therapy (both P<0.05) and gradually abated after one year. Both subclinical rejection and chronic rejection were associated with increased tubulointerstitial damage (P<0.01). Beyond one year, a later phase of chronic allograft nephropathy was characterized by microvascular and glomerular injury. Chronic rejection (defined as persistent subclinical rejection for two years or longer) was uncommon (5.8 percent). Progressive high-grade arteriolar hyalinosis with luminal narrowing, increasing glomerulosclerosis, and additional tubulointerstitial damage was accompanied by the use of calcineurin inhibitors. Nephrotoxicity, implicated in late ongoing injury, was almost universal at 10 years, even in grafts with excellent early histologic findings. By 10 years, severe chronic allograft nephropathy was present in 58.4 percent of patients, with sclerosis in 37.3 percent of glomeruli. Tubulointerstitial and glomerular damage, once established, was irreversible, resulting in

  12. Cyclosporine

    MedlinePlus

    ... alone. Cyclosporine (modified) is also used to treat psoriasis (a skin disease in which red, scaly patches ... taking cyclosporine (modified) to treat rheumatoid arthritis or psoriasis, your doctor will probably start you on a ...

  13. 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.

  14. Early cyclosporine a withdrawal in kidney-transplant recipients receiving sirolimus prevents progression of chronic pathologic allograft lesions.

    PubMed

    Ruiz, Juan C; Campistol, Josep M; Grinyó, Josep M; Mota, Alfredo; Prats, Dolores; Gutiérrez, Jose A; Henriques, Antonio C; Pinto, Jose R; García, Javier; Morales, Jose M; Gómez, Jose M; Arias, Manuel

    2004-11-15

    Nephrotoxicity of calcineurin inhibitors (CNIs) is partially responsible for the development of chronic allograft nephropathy (CAN). Sirolimus has demonstrated its potential to substitute for CNIs because it lacks significant nephrotoxicity and shows a short-term immunosuppressive capacity comparable with that of cyclosporine. This results in the maintenance of better renal function when cyclosporine is eliminated, but it has not been demonstrated whether this benefit is associated with an improvement in the pathologic substrate and a reduction in CAN. We analyzed pretransplant and 1-year renal-allograft biopsies from 64 patients enrolled in a multicenter trial. Patients received cyclosporine and sirolimus during the first 3 months after transplant and were then randomly assigned to continue with cyclosporine or have it withdrawn. Histologic chronic allograft lesions were compared between groups. The percentage of patients in whom chronic pathologic lesions progressed was lower in the group of cyclosporine elimination. Significant differences were observed in chronic interstitial and tubular lesions (70% vs. 40.9% [P<0.05] and 70% vs. 47.8% [P<0.05], respectively), whereas no differences were observed in acute lesions (subclinical rejection). Prevalence of CAN at 1 year was lower in this group, as was the severity and incidence of new cases (P<0.05). Early cyclosporine withdrawal associated with sirolimus administration is followed by an improvement in renal function, a reduction in the progression of chronic pathologic allograft lesions, and a lower incidence of new cases and severity of CAN during the first year after transplantation. This benefit may result in better long-term graft outcome.

  15. Treatment of chronic urticaria in children with antihistamines and cyclosporine.

    PubMed

    Neverman, Lisa; Weinberger, Miles

    2014-01-01

    Chronic idiopathic urticaria, daily hives that last >6 weeks, can be resistant to antihistamines, even when higher than conventional doses are used. Other pharmacologic agents have been associated with inconsistent benefit. We examined the relationship of clinical characteristics and the presence of autoimmune antibodies to antihistamine resistance in children. We further examined the efficacy and safety of cyclosporine in children whose urticaria was resistant to antihistamine. Patients referred to the pediatric allergy and pulmonary specialty clinic at the University of Iowa Children's Hospital and diagnosed as having chronic idiopathic urticaria were identified during the period from August 2008 to July 2013. A retrospective examination of treatment and outcome was performed. Forty-six patients, 26 female patients and 20 male patients, with chronic idiopathic urticaria were identified. The ages of 16 patients who were antihistamine resistant ranged from 9 to 18 years (median, 12.5 years). Those patients who were antihistamine responsive had a median age of 6 years, significantly lower than those who were antihistamine resistant (P = .0001). There was no significant association between autoimmune antibodies and antihistamine resistance. All the patients who were antihistamine resistant were treated with cyclosporine; all experienced complete resolution of urticaria at times that ranged from 2 days to 3 months (median, 7 days). Relapses responsive to repeated cyclosporine occurred in 5 of the patients after 1 week to 15 months (median, 6 months). Adverse effects were not seen in these patients. Our data were consistent with efficacy and safety of cyclosporine for chronic urticaria in children when even high doses of antihistamines are ineffective. Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.

  16. [Cyclosporine monitoring in patients with chronic uveitis].

    PubMed

    Schmidt, S; Pleyer, U

    2005-04-01

    Cyclosporine (CsA) is a widely used drug in the treatment of posterior uveitis. Whereas treatment with CsA has considerably improved the visual prognosis of uveitis patients, the therapeutic benefits of CsA are partially outweighed by its adverse effects, most notably nephrotoxicity and hypertension. Recently, monitoring the CsA 2-h postdose level (C(2)) has been recommended as the most sensitive assay and predictor of clinical outcome in transplantation. This prospective clinical trial included 15 patients with posterior uveitis who received oral CsA (5 mg/kg BW b.i.d.). The relationship of C(2) to C0 blood levels was analyzed and correlated with clinical safety and efficacy. A high intrapatient and interpatient variability was observed regarding the C0 values depending on several factors including comedication and intestinal resorption. C(2) values corresponded to control measurements of intraocular inflammation. C(2) monitoring offers a simple and accurate alternative for clinical monitoring of CsA. It allows the dose of CsA to be individualized effectively for each patient.

  17. 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.

  18. 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

  19. Expression of fibrosis-associated molecules in IgA nephropathy treated with cyclosporine.

    PubMed

    Lim, Beom Jin; Kim, Ji Hong; Hong, Soon Won; Jeong, Hyeon Joo

    2009-03-01

    Cyclosporine (CsA) treatment in immunoglobulin A nephropathy (IgAN) is controversial and has not been widely studied. The aim of this study was to investigate the effects of CsA on renal histology and the expression of interstitial fibrosis-associated molecules in childhood IgAN. The subjects were 18 children (age 4.2-13.9 years; male:female 13:5) who had been treated with CsA for 8 or 12 months and who had renal biopsies before and after treatment. Renal biopsies were assessed by routine histology and immunohistochemistry against osteopontin (OPN), transforming growth factor-beta (TGF-beta), CD68, and CD34. The degree of proteinuria and mesangial IgA deposits decreased or disappeared after treatment in all cases, and the percentage of patients with diffuse mesangial proliferation decreased from 44.4 to 22.2%. However, interstitial fibrosis developed or was aggravated in nine patients (50%) after treatment and was associated with an increased degree of interstitial inflammation in five patients. Tubular OPN expression (45.3 +/- 23.4 vs. 37.6 +/- 19.3%) and the degree of CD68-positive macrophage infiltration (136.1 +/- 88.2 vs. 132 +/- 86.0/mm(2)) were not increased after CsA treatment, but TGF-beta expression was significantly increased (6.4 +/- 4.2 vs. 13.3 +/- 9.9%; p = 0.025). Microvascular density was increased and peritubular capillaries were of small caliber in inflamed areas. We conclude that increased levels of TGF-beta and the development of interstitial fibrosis limit the long-term use of CsA in IgAN patients. Osteopontin and macrophages may be indirectly involved in renal fibrosis by prolonging interstitial inflammation rather than by directly increasing TGF-beta expression.

  20. 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.

  1. Cyclosporin A for persistent or chronic immune thrombocytopenia in children.

    PubMed

    Liu, Anthony P Y; Cheuk, Daniel K L; Lee, Ana H Y; Lee, Pamela P W; Chiang, Alan K S; Ha, S Y; Tsoi, W C; Chan, Godfrey C F

    2016-10-01

    Twenty percent of children with immune thrombocytopenia (ITP) develop a chronic course where treatment strategy is less established. Cyclosporin A (CSA) has been shown to be effective in small series of children with chronic ITP and might reduce the need for chronic steroid therapy and/or splenectomy. We reviewed consecutive patients below 18 years old with persistent or chronic ITP treated with CSA in our unit between January 1998 and June 2015. Thirty patients (14 boys and 16 girls) were included. The median age at initial diagnosis of ITP was 5 years (range 0.5-16.2 years). CSA was started at a median of 13.9 months (range 3.4-124 months) after initial diagnosis and given for a median duration of 9.3 months (range 0.2-63.9 months). The median platelet count before commencement was 12 × 10(9)/L (range 4-199 × 10(9)/L). The median dose of CSA was 6 mg/kg/day (range 2.4-7.5 mg/kg/day). Complete response (CR) or response (R) was achieved in 17 patients (57 %), and 7 (23 %) had sustained response. Side effects (most commonly hirsutism) were tolerable and reversible. CSA appeared effective in about half of persistent or chronic ITP patients and safe as a second-line agent in managing these children.

  2. 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.

  3. 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

  4. Chronic pyelonephritis: Modulation of host defenses by cyclosporin A

    SciTech Connect

    Findon, G.; Miller, T.E. )

    1989-08-01

    Chronic experimental pyelonephritis is characterized by a stable level of infection, which persists for many months. Administration of cyclosporin A (CsA) reactivated previously healed renal lesions and caused a marked increase in bacterial numbers in the kidney. Studies were then carried out to compare the effects of CsA, and the nonselective cytodepletive agents irradiation and cyclophosphamide, on both host defenses and the bacteriologic status of chronically infected kidneys. Two different responses were observed. In animals treated with CsA, bacterial numbers increased markedly, although circulating neutrophil numbers were relatively unaffected. This observation was in contrast to the severe ablation of leukocyte numbers and competence needed to achieve an equivalent effect when irradiation and cyclophosphamide were used. One possible explanation for the adverse effect of CsA on the host-parasite balance in chronic pyelonephritis is that CsA affects mediators that control the inflammatory response or induces a qualitative change in a critical cellular defense compartment.

  5. Treatment of chronic dry eye: focus on cyclosporine

    PubMed Central

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

    2008-01-01

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

  6. [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

  7. 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

  8. 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.

  9. Oxalate Nephropathy Associated with Chronic Pancreatitis

    PubMed Central

    Cartery, Claire; Karras, Alexandre; Cointault, Olivier; Buscail, Louis; Modesto, Anne; Ribes, David; Rostaing, Lionel; Chauveau, Dominique; Giraud, Patrick

    2011-01-01

    Summary Background and objectives Enteric overabsorption of oxalate may lead to hyperoxaluria and subsequent acute oxalate nephritis (AON). AON related to chronic pancreatitis is a rare and poorly described condition precluding early recognition and treatment. Design, setting, participants, & measurements We collected the clinical characteristics, treatment, and renal outcome of 12 patients with chronic pancreatitis–associated AON followed in four French renal units. Results Before AON, mild to moderate chronic kidney disease was present in all patients, diabetes mellitus in eight (insulin [n = 6]; oral antidiabetic drugs [n = 2]), and known chronic pancreatitis in only eight. At presentation, pancreas imaging showed gland atrophy/heterogeneity, Wirsung duct dilation, calcification, or pseudocyst. Renal findings consisted of rapidly progressive renal failure with tubulointerstitial profile. Acute modification of glomerular filtration preceded the AON (i.e., diarrhea and diuretics). Increase in urinary oxalate excretion was found in all tested patients and hypocalcemia in nine (<1.5 mmol/L in four patients). Renal biopsy showed diffuse crystal deposits, highly suggestive of oxalate crystals, with tubular necrosis and interstitial inflammatory cell infiltrates. Treatment consisted of pancreatic enzyme supplementation, oral calcium intake, and an oxalate-free diet in all patients and renal replacement therapy in five patients. After a median follow-up of 7 months, three of 12 patients reached end-stage renal disease. Conclusion AON is an under-recognized severe crystal-induced renal disease with features of tubulointerstitial nephritis that may occur in patients with a long history of chronic pancreatitis or reveal the pancreatic disease. Extrinsic triggering factors should be prevented. PMID:21737848

  10. [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.

  11. Renoprotective effects of the AGE-inhibitor pyridoxamine in experimental chronic allograft nephropathy in rats.

    PubMed

    Waanders, Femke; van den Berg, Else; Nagai, Ryoji; van Veen, Ingrid; Navis, Gerjan; van Goor, Harry

    2008-02-01

    Advanced glycation end products (AGEs) are involved in diabetic nephropathy (DN). The AGE formation inhibitor pyridoxamine (PM) is renoprotective in DN and in normoglycaemic obese Zucker rats. In chronic allograft nephropathy (CAN), renal AGE accumulation occurs as well. To investigate whether inhibition of AGE formation is renoprotective in CAN, we studied the Fisher 344 to Lewis (F-L) allograft rat model of experimental CAN. Fisher to Fisher (F-F) isografts served as controls. Proteinuria, renal function and renal histology of untreated transplanted rats (F-L n = 8, F-F n = 8) were compared to rats receiving PM 2 g/l in drinking water for 20 weeks starting at transplantation (F-L n = 5, F-F n = 10). All rats received cyclosporin A (1.5 mg/kg/day) for 10 days after transplantation to prevent early acute rejection. Compared to untreated allografts, PM significantly decreased proteinuria (76 +/- 18 vs 29 +/- 3 mg/day), serum creatinine (130 +/- 12 vs 98 +/- 5 micromol/l), focal glomerulosclerosis (116 +/- 27 vs 16 +/- 5 AU), glomerular macrophage influx (5.6 +/- 0.6 vs 3.3 +/- 1.0), interstitial fibrosis (132 +/- 24 vs 76 +/- 2 AU) and interstitial macrophage influx (47.0 +/- 8.7 vs 15.4 +/- 5.0. Moreover, PM significantly ameliorated tubular accumulation of pentosidine, compared to untreated allografts (2.5 +/- 0.6 vs 0.3 +/- 0.3, all p < 0.05). In the isograft controls, these values did not differ between untreated and PM treated rats. PM exerts renoprotective effects and decreases renal pentosidine accumulation in experimental CAN, suggesting a detrimental role for renal AGE accumulation in the pathogenesis of renal damage in this non-diabetic model. These results indicate that inhibition of AGE formation might be a useful adjunct therapy to attenuate CAN.

  12. 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.

  13. 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.

  14. Mechanism of chronic aristolochic acid nephropathy: role of Smad3.

    PubMed

    Zhou, Li; Fu, Ping; Huang, Xiao Ru; Liu, Fei; Chung, Arthur C K; Lai, Kar Neng; Lan, Hui Yao

    2010-04-01

    Aristolochic acid nephropathy (AAN) has become a worldwide disease and is the most severe complication related to the use of traditional Chinese medicine. However, the pathogenic mechanisms of AAN remain unclear and therapies are limited. The present study tested the hypothesis that transforming growth factor (TGF)-beta/Smad3 may be a key pathway leading to chronic AAN. This was examined in vivo in Smad3 wild-type/knockout (WT/KO) mice and in vitro in tubular epithelial cells with knockdown of Smad2 or Smad3. Results revealed that chronic administration of aristolochic acid (AA) resulted in a severe AAN characterized by progressive renal dysfunction and tubulointerstitial fibrosis including epithelial-mesenchymal transition (EMT) in Smad3 WT mice, but not in Smad3 KO mice, suggesting a critical role for Smad3 in the development of AAN. This was further tested in vitro. We found that AA was able to activate Smad signaling to mediate EMT and renal fibrosis via both TGF-beta-dependent and JNK/MAP kinase-dependent mechanisms because blockade of JNK and specific knockdown of Smad3, but not Smad2, were able to attenuate AA-stimulated collagen matrix expression and EMT. In conclusion, TGF-beta/Smad3 may be an essential mediator for chronic AAN. Results from this study indicate that specific blockade of the TGF-beta/Smad3 signaling pathway may have therapeutic potential for chronic AAN.

  15. 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.

  16. 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

  17. 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.

  18. 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

  19. Conversion to Sirolimus Ameliorates Cyclosporine-Induced Nephropathy in the Rat: Focus on Serum, Urine, Gene, and Protein Renal Expression Biomarkers

    PubMed Central

    Sereno, José; Nunes, Sara; Rodrigues-Santos, Paulo; Rocha-Pereira, Petronila; Fernandes, João; Teixeira, Frederico; Reis, Flávio

    2014-01-01

    Protocols of conversion from cyclosporin A (CsA) to sirolimus (SRL) have been widely used in immunotherapy after transplantation to prevent CsA-induced nephropathy, but the molecular mechanisms underlying these protocols remain nuclear. This study aimed to identify the molecular pathways and putative biomarkers of CsA-to-SRL conversion in a rat model. Four animal groups (n = 6) were tested during 9 weeks: control, CsA, SRL, and conversion (CsA for 3 weeks followed by SRL for 6 weeks). Classical and emergent serum, urinary, and kidney tissue (gene and protein expression) markers were assessed. Renal lesions were analyzed in hematoxylin and eosin, periodic acid-Schiff, and Masson's trichrome stains. SRL-treated rats presented proteinuria and NGAL (serum and urinary) as the best markers of renal impairment. Short CsA treatment presented slight or even absent kidney lesions and TGF-β, NF-κ β, mTOR, PCNA, TP53, KIM-1, and CTGF as relevant gene and protein changes. Prolonged CsA exposure aggravated renal damage, without clear changes on the traditional markers, but with changes in serums TGF-β and IL-7, TBARs clearance, and kidney TGF-β and mTOR. Conversion to SRL prevented CsA-induced renal damage evolution (absent/mild grade lesions), while NGAL (serum versus urine) seems to be a feasible biomarker of CsA replacement to SRL. PMID:24971338

  20. Chronic dietary oxalate nephropathy after intensive dietary weight loss regimen

    PubMed Central

    Khneizer, Gebran; Al-Taee, Ahmad; Mallick, Meher S; Bastani, Bahar

    2017-01-01

    Background: Hyperoxaluria has been associated with nephrolithiasis as well as acute and chronic kidney disease. We present a case of end stage renal failure caused by excessive dietary oxalate intake in a dietary weight loss regimen. Case Presentation: A 51-year-old Caucasian male with the past medical history of type 2 diabetes mellitus, gout, hypertension and morbid obesity was referred to the primary care clinic after being found pale and easily fatigued. The patient had lost 36 kg over a 7-month period by implementing exercise and intense dietary measures that included 6 meals of spinach, kale, berries, and nuts. Physical examination revealed a blood pressure of 188/93 mm Hg with sunken eyes and dry mucus membranes. Laboratory workup was notable for blood urea nitrogen of 122 mg/dL, creatinine of 12 mg/dL, and estimated glomerular filtration rate (eGFR) of 4.4 mL/min/1.73m2. Patient denied any history of renal disease or renal stones, or taking herbal products, non-steroidal anti-inflammatory drugs, antifreeze (ethylene glycol), or any type of "diet pills." Family history was unremarkable for any renal diseases. After failing intravenous fluid resuscitation, patient was started on maintenance hemodialysis. Abdominal imaging was consistent with chronic renal parenchymal disease with no evidence of nephrolithiasis. Renal biopsy revealed numerous polarized oxalate crystal deposition and diabetic nephropathy class IIA. At this point the patient was instructed to adopt a low oxalate diet. A 24-hour urine collection was remarkable for pH 4.7, citrate <50 mg, and oxalate 46 mg. Importantly, serum oxalate level was undetectable. Repeat renal biopsy 5 months later while patient was still on maintenance hemodialysis revealed persistence of extensive oxalate crystal deposition. Patient has been referred for evaluation for renal transplantation. Conclusions: Clinicians need to maintain a high index of suspicion for dietary hyperoxaluria as a potential etiology for acute or

  1. [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.

  2. 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.

  3. Urinary uromodulin excretion predicts progression of chronic kidney disease resulting from IgA nephropathy.

    PubMed

    Zhou, Jingjing; Chen, Yuqing; Liu, Ying; Shi, Sufang; Wang, Suxia; Li, Xueying; Zhang, Hong; Wang, Haiyan

    2013-01-01

    Uromodulin, or Tamm-Horsfall protein, is the most abundant urinary protein in healthy individuals. Recent studies have suggested that uromodulin may play a role in chronic kidney diseases. We examined an IgA nephropathy cohort to determine whether uromodulin plays a role in the progression of IgA nephropathy. A total of 344 IgA nephropathy patients were involved in this study. Morphological changes were evaluated with the Oxford classification of IgA nephropathy. Enzyme Linked Immunosorbent Assay (ELISA) measured the urinary uromodulin level on the renal biopsy day. Follow up was done regularly on 185 patients. Time-average blood pressure, time-average proteinuria, estimated glomerular filtration rate (eGFR) and eGFR decline rate were caculated. Association between the urinary uromodulin level and the eGFR decline rate was analyzed with SPSS 13.0. We found that lower baseline urinary uromodulin levels (P = 0.03) and higher time-average proteinuria (P = 0.04) were risk factors for rapid eGFR decline in a follow-up subgroup of the IgA nephropathy cohort. Urinary uromodulin level was correlated with tubulointerstitial lesions (P = 0.016). Patients that had more tubular atrophy/interstitial fibrosis on the surface had lower urinary uromodulin levels (P = 0.02). Urinary uromodulin level is associated with interstitial fibrosis/tubular atrophy and contributes to eGFR decline in IgA nephropathy.

  4. 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.

  5. Protective effect of L-propionylcarnitine in chronic cyclosporine-a induced nephrotoxicity.

    PubMed

    Origlia, Nicola; Migliori, Massimiliano; Panichi, Vincenzo; Filippi, Cristina; Bertelli, Aldo; Carpi, Angelo; Giovannini, Luca

    2006-02-01

    Cyclosporine (CyA) is an immunosuppressive agent used after solid organ transplantation, but its clinical use is limited by side effects, the most important of which is nephrotoxicity. In a previous work we demonstrated that L-propionylcarnitine (L-PC), a propionyl ester of L-carnitine, is able to prevent CyA-induced acute nephrotoxicity reducing lipid peroxidation in the isolated and perfused rat kidney. CyA administration was associated with a dose dependent increase in renovascular resistance prevented by a pretreatment with L-PC. The aim of the present study was to confirm L-PC protective effect, previously described in vitro, in an in vivo rat model. Chronic nephrotoxicity study was carried out for 28 days. L-PC was administered (i.p. 25 mg/kg b.w.) since the first day, while CyA treatment was performed for the last 21 days (by oral administration 25 mg/kg b.w.). We demonstrate that L-PC was able to significantly lower blood pressure in CyA treated animals and to prevent CyA induced decrease in creatinine clearance. Moreover renal tissue analysis revealed that L-PC was able to reduce lipid hydroperoxide content and morphological abnormalities associated to chronic CyA administration. In conclusion our study demonstrated for the first time in vivo that L-PC protects against functional and tissue damage associated to chronic CyA administration.

  6. 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

  7. 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.

  8. Cyclosporin A in treatment of refractory patients with chronic inflammatory demyelinating polyradiculoneuropathy.

    PubMed

    Matsuda, Masayuki; Hoshi, Kenichi; Gono, Takahisa; Morita, Hiroshi; Ikeda, Shu-ichi

    2004-09-15

    To investigate the therapeutic efficacy of cyclosporin A (CyA) in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), a microemulsion form of this drug (Neoral) was orally given to seven patients with the disease who were unresponsive or resistant to conventional therapies. The daily dose of CyA was carefully controlled in order to keep the plasma trough concentration between 100 and 150 ng/ml. Within 1 month of initiation of CyA, all patients subjectively showed improvement of clinical symptoms, while both modified Rankin and INCAT disability scores were significantly decreased (p < 0.05) and grip strength was significantly increased (p < 0.05) 3 months after initiation compared with before. Total protein in the cerebrospinal fluid was significantly decreased 3 and 6 months after starting CyA (p < 0.05). Although the maximal motor nerve conduction velocity showed a significant improvement in the median nerve 1 to 1.5 years after commencement of CyA (p < 0.05), there were no significant changes in any other neurophysiological parameters. One patient with anti-sulphoglucuronyl paragloboside IgM antibodies gradually became resistant to CyA, but the rest have since been in good neurological condition without complications ascribable to this drug. These results suggest that oral CyA may be effective even for refractory cases with CIDP. CyA should be actively considered as a therapeutic option when patients with CIDP are resistant to conventional treatment.

  9. 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.

  10. 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

  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. Conversion to generic cyclosporine A in stable chronic patients after heart transplantation

    PubMed Central

    Kraeuter, Maximilian; Helmschrott, Matthias; Erbel, Christian; Gleissner, Christian A; Frankenstein, Lutz; Schmack, Bastian; Ruhparwar, Arjang; Ehlermann, Philipp; Katus, Hugo A; Doesch, Andreas O

    2013-01-01

    Background Cyclosporine A (CSA) is a narrow therapeutic index drug. Available CSA products differ in the constitution of their emulsion. To compare intra-individual differences after a conversion to a generic CSA, a retrospective single-center study was initiated. Methods Twenty adult stable chronic (>24 months post heart transplant) recipients were included in the present retrospective study. These patients were previously switched from Sandimmune Neoral® to the generic CSA (Equoral®) according to the patients’ preference during the clinical routine. Dose-normalized trough levels (DNL) and trough levels (C0) at 8 months, 4 months, and 2 weeks before the switch were retrospectively compared with the corresponding values at 2 weeks, 4 months, and 8 months after the switch to the generic CSA. Additionally, changes in the routine laboratory parameters, the number of treated rejection episodes, and the adherence to the CSA target levels were compared. Results The mean DNL (adapted to the daily CSA dose in mg) was 0.71±0.26 (ng/mL)/mg on Neoral therapy; on Equoral it was 0.68±0.23 (ng/mL)/mg, (P=0.38). In comparison to the CSA daily dose prior to the conversion, at postconversion, no significant changes of CSA daily dose were observed (Neoral 140.67±39.81 mg versus Equoral 134.58±41.61 mg; P=0.13). No rejection episodes requiring therapy occurred prior to or postconversion (P=0.99). Additionally, no statistically significant changes of routine laboratory parameters regarding the Modification of Diet in Renal Disease or hematological parameters were seen (all P=not significant). No adverse events after the conversion were observed. Conclusion This study in chronic and stable HTx patients demonstrated no statistically significant differences in the CSA DNL after a conversion to generic CSA (Equoral). The generic CSA was generally well-tolerated. We concluded that a conversion from Neoral to Equoral is safe and clinically feasible in this distinct patient

  13. Conversion to generic cyclosporine A in stable chronic patients after heart transplantation.

    PubMed

    Kraeuter, Maximilian; Helmschrott, Matthias; Erbel, Christian; Gleissner, Christian A; Frankenstein, Lutz; Schmack, Bastian; Ruhparwar, Arjang; Ehlermann, Philipp; Katus, Hugo A; Doesch, Andreas O

    2013-01-01

    Cyclosporine A (CSA) is a narrow therapeutic index drug. Available CSA products differ in the constitution of their emulsion. To compare intra-individual differences after a conversion to a generic CSA, a retrospective single-center study was initiated. Twenty adult stable chronic (>24 months post heart transplant) recipients were included in the present retrospective study. These patients were previously switched from Sandimmune Neoral® to the generic CSA (Equoral®) according to the patients' preference during the clinical routine. Dose-normalized trough levels (DNL) and trough levels (C0) at 8 months, 4 months, and 2 weeks before the switch were retrospectively compared with the corresponding values at 2 weeks, 4 months, and 8 months after the switch to the generic CSA. Additionally, changes in the routine laboratory parameters, the number of treated rejection episodes, and the adherence to the CSA target levels were compared. The mean DNL (adapted to the daily CSA dose in mg) was 0.71±0.26 (ng/mL)/mg on Neoral therapy; on Equoral it was 0.68±0.23 (ng/mL)/mg, (P=0.38). In comparison to the CSA daily dose prior to the conversion, at postconversion, no significant changes of CSA daily dose were observed (Neoral 140.67±39.81 mg versus Equoral 134.58±41.61 mg; P=0.13). No rejection episodes requiring therapy occurred prior to or postconversion (P=0.99). Additionally, no statistically significant changes of routine laboratory parameters regarding the Modification of Diet in Renal Disease or hematological parameters were seen (all P=not significant). No adverse events after the conversion were observed. This study in chronic and stable HTx patients demonstrated no statistically significant differences in the CSA DNL after a conversion to generic CSA (Equoral). The generic CSA was generally well-tolerated. We concluded that a conversion from Neoral to Equoral is safe and clinically feasible in this distinct patient population. However, multiple switches between

  14. 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 ...

  15. Cyclosporine Injection

    MedlinePlus

    ... transplanted organ by the immune system of the person receiving the organ) in people who have received kidney, liver, and heart transplants. Cyclosporine injection should only be used to treat people who are unable to take cyclosporine by mouth. ...

  16. 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

  17. 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.

  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. Clinical and pathological analysis of IgA nephropathy with chronic renal failure.

    PubMed

    Liu, Yuyuan; Hu, Qinfeng; Shen, Ping; Tang, Li; Yuan, Gang; Zhou, Yongmei; Chai, Huaqi

    2016-10-01

    To investigative clinical and pathological characteristics of IgA nephropathy with chronic renal failure. Clinical and pathological findings from 65 cases of IgA nephropathy with chronic renal failure were reviewed. Pathological characteristics of all the cases were analyzed according to WHO definition and Oxford Classification. Evaluating the severity of pathological lesions by the Katafuchi R semiquantitative scoring system, and analyzing their relationship with clinical indexes of renal function. Of all 65 cases the male and female ratio was 1.4, and the mean age was 37 ± 13 years old. Levels of systolic pressure, mean arterial pressure (MAP), blood urea nitrogen (BUN), serum creatinine (Scr), uric acid (UA), album (Alb), serum IgG and 24 h urinary protein were related with eGRF level (p < 0.05, respectively). The most common pathological type was proliferative sclerosis glomerulonephritis (PSGN) and M1S1E0T0 according to WHO definition and Oxford Classification, respectively, and most of the 65 cases had glomerulosclerosis. Simple IgA deposition was the most common immunopathologic type. Of all the cases, 44.6% accompanied with C3 while 4.6% with C1q. Further analysis revealed there were no relationships between severity of pathological lesion and levels of clinical indexes (Scr and eGRF) (p > 0.05). IgA nephropathy with chronic renal failure usually occurred in young adults, and it had severe clinical condition and pathological changes, while there was no significant relationship between them.

  20. 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.

  1. 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.

  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. 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.

  4. [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.

  5. 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.

  6. 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

  7. Salutary effects of a novel oxidative stress modulator on adenine-induced chronic progressive tubulointerstitial nephropathy

    PubMed Central

    Nicholas, Susanne B; Yuan, Jun; Aminzadeh, Amin; Norris, Keith C; Crum, Albert; Vaziri, Nosratola D

    2012-01-01

    Background Oxidative stress and inflammation promote the development and progression of chronic kidney disease. Oxidative stress is associated with depletion of tissue glutathione (GSH), the most abundant endogenous intracellular antioxidant, but degradation of oral GSH by digestive enzymes limits its therapeutic use. We hypothesized that GSH repletion with F1, a novel oral GSH precursor containing cystine as a cysteine carrier, would restore tissue GSH and attenuate oxidative stress and inflammation, and thereby reduce the severity of interstitial nephropathy in chronic renal failure (CRF). Methods Male Sprague-Dawley rats (n=5-8) were assigned to 3 groups: Control (regular rat chow), CRF (rat chow containing 0.7% adenine), and F1-treated CRF (rat chow containing 0.7% adenine and F1, 0.5g/kg/day) for 2-weeks. Animals were switched to regular chow and euthanized after 2 additional weeks. Results Consumption of 0.7% adenine-containing diet caused azotemia; severe kidney swelling; heavy tubular and glomerular damage; massive tubulointerstitial nephropathy; impaired urinary concentrating capacity; severe anemia; increased markers of oxidative stress, plasma oxidized glutathione disulfide (GSSG); reduced GSH/GSSG ratio and manganese superoxide dismutase; increased expression of inflammatory mediators (cyclooxygenase-2, cytoplasmic NF-κB, p-IκBα, nuclear NF-κB p65), and 3-nitrotyrosine, p<0.05. Co-treatment with F1 significantly attenuated tubulointerstitial inflammation and edema, improved urinary concentrating capacity, azotemia and anemia, and normalized markers of tissue oxidative and nitrosative stress, p<0.05. Conclusions The novel oxidative stress modulator, F1, markedly attenuated oxidative stress indicators, inflammation, renal injury and dysfunction in the rat model of CRF. Studies to determine the effects of F1 in other models of acute and CRF are warranted. PMID:22937204

  8. 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

  9. 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.

  10. Dahuang Fuzi Decoction Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in Chronic Aristolochic Acid Nephropathy.

    PubMed

    Shui, Guang-Xing; Sang, Dong; Yin, Xun; Cai, Yun; Sun, Wei

    2017-01-01

    Objectives. The effects of the traditional formula Dahuang Fuzi Decoction (DFD) on chronic aristolochic acid nephropathy (AAN) in mice and its underlying mechanisms were studied. Methods. Mice were randomly divided into the following six groups: the control group, the model group (AAN), the saline-treated group (AAN + vehicle), the normal dose DFD-treated group (AAN + NDFD), the high dose DFD-treated group (AAN + HDFD), and the rosiglitazone treated group (AAN + Rosi). After treating for 8 weeks, 24 h urine and blood samples were collected and the mice sacrificed to study the biochemical parameters associated with renal function. The samples were analyzed for renal fibrosis and mitochondrial dysfunction (MtD) markers. To achieve that, collagen III, collagen I, mitochondrial DNA copy numbers (mtDNA), mitochondrial membrane potential (MMP), ATP content, and ROS production were evaluated. Results. Our results showed that proteinuria, kidney function, and the renal pathological characteristics were improved by DFD and rosiglitazone. The expression of collagen III and collagen I decreased after treating with either DFD or rosiglitazone. Mitochondrial dysfunction based on the increase in ROS production, decrease in mitochondrial DNA copy numbers, and reduction of MMP and ATP content was improved by DFD and rosiglitazone. Conclusions. DFD could protect against renal impairments and ameliorate mitochondrial dysfunction in chronic AAN mice.

  11. Dahuang Fuzi Decoction Attenuates Renal Fibrosis and Ameliorates Mitochondrial Dysfunction in Chronic Aristolochic Acid Nephropathy

    PubMed Central

    Shui, Guang-xing; Sang, Dong; Yin, Xun; Cai, Yun

    2017-01-01

    Objectives. The effects of the traditional formula Dahuang Fuzi Decoction (DFD) on chronic aristolochic acid nephropathy (AAN) in mice and its underlying mechanisms were studied. Methods. Mice were randomly divided into the following six groups: the control group, the model group (AAN), the saline-treated group (AAN + vehicle), the normal dose DFD-treated group (AAN + NDFD), the high dose DFD-treated group (AAN + HDFD), and the rosiglitazone treated group (AAN + Rosi). After treating for 8 weeks, 24 h urine and blood samples were collected and the mice sacrificed to study the biochemical parameters associated with renal function. The samples were analyzed for renal fibrosis and mitochondrial dysfunction (MtD) markers. To achieve that, collagen III, collagen I, mitochondrial DNA copy numbers (mtDNA), mitochondrial membrane potential (MMP), ATP content, and ROS production were evaluated. Results. Our results showed that proteinuria, kidney function, and the renal pathological characteristics were improved by DFD and rosiglitazone. The expression of collagen III and collagen I decreased after treating with either DFD or rosiglitazone. Mitochondrial dysfunction based on the increase in ROS production, decrease in mitochondrial DNA copy numbers, and reduction of MMP and ATP content was improved by DFD and rosiglitazone. Conclusions. DFD could protect against renal impairments and ameliorate mitochondrial dysfunction in chronic AAN mice. PMID:28421124

  12. Gremlin: a novel mediator of epithelial mesenchymal transition and fibrosis in chronic allograft nephropathy.

    PubMed

    Carvajal, G; Droguett, A; Burgos, M E; Aros, C; Ardiles, L; Flores, C; Carpio, D; Ruiz-Ortega, M; Egido, J; Mezzano, S

    2008-04-01

    Chronic allograft nephropathy (CAN) is the most frequent cause of chronic dysfunction and late loss of renal allografts. Epithelial mesenchymal transition (EMT) has been identified as responsible for the presence of activated interstitial fibroblasts (myofibroblasts) and transforming growth factor beta (TGF-beta)/Smad is the key signaling mediator. It has been proposed that the bone morphogenetic protein 7 (BMP-7) antagonist, Gremlin, could participate in EMT, as a downstream mediator of TGF-beta. We evaluated 33 renal allograft biopsies, 16 of which showed CAN, versus 17 controls. By in situ hybridization we studied the expression of TGF-beta and Gremlin mRNA. Gremlin, BMP-7, E-cadherin, and alpha-smooth muscle actin (alpha-SMA) proteins were evaluated by immunohistochemistry and Smad3 activation by Southwestern. In cultured human tubuloepithelial cells (HK2 cell line), Gremlin induction by TGF-beta was studied by confocal microscopy. Among renal biopsies of transplanted patients with CAN, we detected up-regulation of TGF-beta in colocalization with Gremlin (RNA and protein), mainly in areas of tubulointerstitial fibrosis. In the same tubules, we observed decreased expression of E-cadherin and induction of vimentin and alpha-SMA. BMP-7 was significantly decreased in the CAN biopsies. In addition, HK2 stimulated with TGF-beta (1 ng/mL) induced Gremlin production at 72 hours. We postulated that Gremlin is a downstream mediator of TGF-beta, suggesting a role for Gremlin in EMT observed in CAN.

  13. 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.

  14. 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.

  15. Update on endemic nephropathies.

    PubMed

    Wernerson, Annika; Wijkström, Julia; Elinder, Carl-Gustaf

    2014-05-01

    A large number of patients worldwide suffer from chronic kidney disease (CKD) of unknown cause. Endemic nephropathies possibly contribute to this. The purpose of this review is to give a brief review of endemic nephropathies and to summarize what is known about their cause. The cause of Balkan endemic nephropathy was eventually resolved, after 50 years of research. The cause was exposure to aristolochic acid from food. A new type of endemic nephropathy has recently been identified in Central America; Mesoamerican nephropathy. This kidney disease mainly affects agricultural workers in hot climates. Renal biopsy studies suggest that repeated dehydration and kidney ischemia is involved in the pathogenesis. Endemic nephropathies may comprise an important cause of CKD. Epidemiological studies are needed to describe the occurrence and distribution of the diseases. However, biopsy studies, in combination with careful clinical evaluation of the patients, are necessary to find out the cause of endemic nephropathies and thereby help in their prevention.

  16. Cyclosporine neurotoxicity.

    PubMed

    Hauben, M

    1996-01-01

    A comprehensive search of the published literature was undertaken to identify reports providing patient-specific data relating to adverse neurologic events with cyclosporine. References cited in the articles identified by the search were manually reviewed to ensure that articles were pertinent. Studies and case reports on cyclosporine neurotoxicity in which individualized patient data were provided were included for review and analysis. Information pertaining to all aspects of cyclosporine neurotoxicity, including epidemiology, clinical manifestations, postulated mechanisms, and management implications, was evaluated. Estimates from case series suggest a 0.5-35% frequency of the disorder. Risk factors include supratherapeutic blood concentrations of cyclosporine, and pharmacokinetic and pharmacodynamic drug interactions, hypocholesterolemia, and other metabolic abnormalities. Postulated mechanisms include a vasculopathy based on cyclosporine's effect on endothelial cell synthesis of prostaglandin, and release and uptake of endothelin as well as inhibition of mitochondrial steroid 26-hydroxylase. Reported adverse events involved all levels of the neuraxis. Associated abnormalities include elevated cerebrospinal fluid protein and pleocytosis, various electroencephalogram abnormalities, and characteristic neuroimaging findings. In most patients these events were reversible with dosage reduction or withdrawal of therapy. Many reports described positive rechallenge, and in rare instances the events regressed despite continuing or reintroducing the drug.

  17. CXC Chemokine Receptor 4 (CXCR4) Antagonist, a Novel Pathway to Prevent Chronic Allograft Nephropathy.

    PubMed

    Xu, Yue; Zhang, Qiang; Xue, Wenrui; Zeng, Song; Zhang, Zijian; Zhang, Xiaodong; Hu, Xiaopeng

    2016-11-25

    BACKGROUND Chronic allograft nephropathy (CAN) remains a major problem for long-term graft survival and different pathways participate in its development. CXC chemokine receptor 4 (CXCR4) is significantly upregulated following renal injury and fibrotic response. We investigated the effect of AMD3100, a CXCR4 antagonist, on the development of CAN in rat models. MATERIAL AND METHODS CAN rat models (n=20) were established using male Fisher 344 to Lewis rats. Rats in the experimental group (n=10) were treated with AMD3100 (1 mg/kg/day subcutaneously, 0-12 weeks), rats in the control group (n=10) were treated with saline. The serum creatinine levels were monitored every week. Kidney grafts were harvested 12 weeks after modeling for histological analysis. We used chronic allograft damage index (CADI) scores to evaluate each group. Q-PCR and Western blotting were used to measure CXCR4, TGF-β1/Smad3 signaling pathway and α-smooth muscle actin (α-SMA) expression in renal allograft tissue. RESULTS CXCR4 expression was increased significantly in the control group which developed intense chronic changes after 12 weeks. Histological changes of CAN in the experimental group were ameliorated by AMD3100 which also had better graft function compare to the control group. AMD3100 significantly blunted the increase in the mRNA expression level of CXCR4, TGF-β1/Smad3, and α-SMA. A significant reduction in TGF-β1 and α-SMA protein content was observed only in the experimental group as shown in a representative Western blot. CONCLUSIONS Based on these findings, CXCR4 expression may mediate in part the development of CAN. AMD3100 may ameliorate histological changes of CAN and maintain better allograft function. It blunts downstream effects of TGF-β1 signaling and fibroblast activation. Therefore, antagonism of CXCR4 may provide a novel way to prevent the development of CAN.

  18. 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.

  19. 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.

  20. Preventing radiocontrast-induced nephropathy in chronic kidney disease patients undergoing coronary angiography

    PubMed Central

    Hung, Yao-Min; Lin, Shoa-Lin; Hung, Shih-Yuan; Huang, Wei-Chun; Wang, Paul Yung-Pou

    2012-01-01

    Radiocontrast-induced nephropathy (RCIN) is an acute and severe complication after coronary angiography, particularly for patients with pre-existing chronic kidney disease (CKD). It has been associated with both short- and long-term adverse outcomes, including the need for renal replacement therapy, increased length of hospital stay, major cardiac adverse events, and mortality. RCIN is generally defined as an increase in serum creatinine concentration of 0.5 mg/dL or 25% above baseline within 48 h after contrast administration. There is no effective therapy once injury has occurred, therefore, prevention is the cornerstone for all patients at risk for acute kidney injury (AKI). There is a small but growing body of evidence that prevention of AKI is associated with a reduction in later adverse outcomes. The optimal strategy for preventing RCIN has not yet been established. This review discusses the principal risk factors for RCIN, evaluates and summarizes the evidence for RCIN prophylaxis, and proposes recommendations for preventing RCIN in CKD patients undergoing coronary angiography. PMID:22655164

  1. 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.

  2. Chronic Nephropathy from Dietary Hyperoxaluria: Sustained Improvement of Renal Function after Dietary Intervention

    PubMed Central

    Sun, Yijuan; Horowitz, Bruce L; Servilla, Karen S; Fair, Joanna R; Vigil, Darlene; Ganta, Kavitha; Massie, Larry

    2017-01-01

    A 56-year-old man with stable chronic kidney disease (CKD) for two years following a single episode of calcium oxalate urolithiasis developed progressive elevation of his serum creatinine concentration. Urinalysis revealed pyuria and white cell casts, a few red blood cells, minimal proteinuria, and no crystals. Urine culture was sterile. Gallium scintigraphy was consistent with interstitial nephritis. Proton pump inhibitor intake was discontinued, and a short course of oral corticosteroids was initiated. Percutaneous kidney biopsy, performed because of the continued deterioration of renal function to a minimum estimated glomerular filtration rate (eGFR) value of 15 mL/min per 1.73 m2 and persistent pyuria, revealed deposition of oxalate crystals in the tubules and interstitium, pronounced tubular changes, and interstitial nephritis and fibrosis. Urinary oxalate excretion was very high, in the range usually associated with primary hyperoxaluria. However, investigations for primary or enteric hyperoxaluria were negative. He reported a diet based on various nuts high in oxalate content. Estimated oxalate content in the diet was, for years, approximately four times higher than that in the average American diet. The institution of a diet low in oxalates resulted in the rapid normalization of urinary oxalate excretion and urinary sediment and in the slow, continuous improvement of renal function to near normal levels (eGFR 59 mL/min/1.73 m2) before his death from a brain malignancy 3.5 years later. The manifestations of nephropathy secondary to dietary hyperoxaluria, including the urine findings, can be indistinguishable from other types of interstitial nephritis. The diagnosis of dietary hyperoxaluria requires careful dietary history and a kidney biopsy. Identifying dietary hyperoxaluria as the cause of CKD is important because the decrease in dietary oxalate intake without any other measures can lead to sustained improvement in renal function. PMID:28435765

  3. 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

  4. 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.

  5. Coronary artery calcification scores improve contrast-induced nephropathy risk assessment in chronic kidney disease patients.

    PubMed

    Osugi, Naohiro; Suzuki, Susumu; Shibata, Yohei; Tatami, Yosuke; Harata, Shingo; Ota, Tomoyuki; Hayashi, Mutsuharu; Yasuda, Yoshinari; Ishii, Hideki; Shimizu, Atsuya; Murohara, Toyoaki

    2017-06-01

    Coronary artery calcification (CAC) is an independent predictor of cardiovascular morbidity and mortality in chronic kidney disease (CKD) patients. The aim of the present study was to evaluate the predictive value of CAC scores for the incidence of contrast-induced nephropathy (CIN) after cardiac catheterization in non-dialyzed CKD patients. The present study evaluated a total of 140 CKD patients who underwent cardiac catheterization. Patients were stratified into two groups based on the optimal cut-off value of the CAC score, which was graded by a non-triggered, routine diagnostic chest computed tomography scan: CAC score ≥8 (high CAC group); and CAC score <8 (low CAC group). CIN was defined as an increase of >10 % in the baseline serum cystatin C level at 24 h after contrast administration. The mean estimated glomerular filtration rate levels were 41.1 mL/min/1.73 m(2), and the mean contrast dose administered was 37.5 mL. Patients with high CAC scores exhibited a higher incidence of CIN than patients with low CAC scores (25.5 vs. 3.2 %, p < 0.001). After multivariate adjustment for confounders, the CAC score predicted CIN (odds ratio 1.68, 95 % confidence interval 1.28-2.21, p < 0.001). Moreover, the C-index for CIN prediction significantly increased when the CAC scores were added to the Mehran risk score (0.855 vs. 0.760, p = 0.023). CAC scores, as evaluated using semi-quantitative methods, are a simple and powerful predictor of CIN. Incorporating the CAC score in the Mehran risk score significantly improved the predictive ability to predict CIN incidence.

  6. Chronic Nephropathy from Dietary Hyperoxaluria: Sustained Improvement of Renal Function after Dietary Intervention.

    PubMed

    Sun, Yijuan; Horowitz, Bruce L; Servilla, Karen S; Fair, Joanna R; Vigil, Darlene; Ganta, Kavitha; Massie, Larry; Tzamaloukas, Antonios H

    2017-03-20

    A 56-year-old man with stable chronic kidney disease (CKD) for two years following a single episode of calcium oxalate urolithiasis developed progressive elevation of his serum creatinine concentration. Urinalysis revealed pyuria and white cell casts, a few red blood cells, minimal proteinuria, and no crystals. Urine culture was sterile. Gallium scintigraphy was consistent with interstitial nephritis. Proton pump inhibitor intake was discontinued, and a short course of oral corticosteroids was initiated. Percutaneous kidney biopsy, performed because of the continued deterioration of renal function to a minimum estimated glomerular filtration rate (eGFR) value of 15 mL/min per 1.73 m(2) and persistent pyuria, revealed deposition of oxalate crystals in the tubules and interstitium, pronounced tubular changes, and interstitial nephritis and fibrosis. Urinary oxalate excretion was very high, in the range usually associated with primary hyperoxaluria. However, investigations for primary or enteric hyperoxaluria were negative. He reported a diet based on various nuts high in oxalate content. Estimated oxalate content in the diet was, for years, approximately four times higher than that in the average American diet. The institution of a diet low in oxalates resulted in the rapid normalization of urinary oxalate excretion and urinary sediment and in the slow, continuous improvement of renal function to near normal levels (eGFR 59 mL/min/1.73 m(2)) before his death from a brain malignancy 3.5 years later. The manifestations of nephropathy secondary to dietary hyperoxaluria, including the urine findings, can be indistinguishable from other types of interstitial nephritis. The diagnosis of dietary hyperoxaluria requires careful dietary history and a kidney biopsy. Identifying dietary hyperoxaluria as the cause of CKD is important because the decrease in dietary oxalate intake without any other measures can lead to sustained improvement in renal function.

  7. Surgical transplant physical examination: correlation of renal resistance index and biopsy-proven chronic allograft nephropathy.

    PubMed

    Elster, Eric A; Hale, Douglas A; Mannon, Roslyn B; Cendales, Linda C; Kleiner, David; Swanson, S John; Kirk, Allan D

    2005-04-01

    Chronic allograft nephropathy (CAN) remains the leading cause of late renal allograft loss that is minimally responsive to therapy once graft dysfunction is clinically evident. A screening test capable of identifying individuals at high risk for CAN would be a valuable adjunct to patient care, but to be cost effective, should be administered during routine evaluations by transplantation clinicians. We have compared the resistive index (RI) as measured by Doppler ultrasonography with subsequent biopsy findings on 91 renal allograft recipients who had a subsequent protocol-directed biopsy at least 3 months after renal transplant. All ultrasonography was performed by the transplantation surgical staff without involving the radiology department or a separate appointment time. Twenty-one patients had RI >/= 80 (average 621 days posttransplantation). Among these individuals, the subsequent incidence of CAN was 38%. Length of time between initial assessment of increased RI and biopsy-proved CAN averaged 233 days. The remaining 70 patients with RI < 80 had an incidence of CAN of 11.4% (p = 0.018). There were minimal complications from these biopsies. Sensitivity and specificity of an elevated RI in predicting CAN were 50% and 83%, respectively. The negative predicted value of an elevated RI in determination of CAN was 89%. These results suggest that elevated RI is an early predictor of histologically relevant CAN, possibly a result of burgeoning vasculopathy. The technical expertise required to make this appraisal is well within the capabilities of transplantation surgeons and trainees. Early evidence of CAN may allow for a targeted change in therapy before clinically significant injury. Ultrasonography should become a routine part of a transplantation clinic evaluation.

  8. 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

  9. Green Tea Polyphenols Stimulate Mitochondrial Biogenesis and Improve Renal Function after Chronic Cyclosporin A Treatment in Rats

    PubMed Central

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

    2013-01-01

    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

  10. Randomized controlled trial: lisinopril reduces proteinuria, ammonia, and renal polypeptide tubular catabolism in patients with chronic allograft nephropathy.

    PubMed

    Amara, Alieu B; Sharma, Asheesh; Alexander, John L; Alfirevic, Ana; Mohiuddin, Atif; Pirmohamed, Munir; Close, Graeme L; Grime, Steve; Maltby, Paul; Shawki, Howida; Heyworth, Sally; Shenkin, Alan; Smith, Linda; Sharma, Ajay K; Hammad, Abdel; Rustom, Rana

    2010-01-15

    Angiotensin-converting enzyme inhibitors in native nephropathies reduce proteinuria and delay progression to renal failure. Data in renal transplantation remain limited. A negative effect on glomerular filtration rate was concluded in a recent systematic review. In this novel randomized controlled trial, 47 patients with chronic allograft nephropathy, severe renal impairment, and more than or equal to 1 g/24 hr proteinuria were randomized to lisinopril (group A) or other hypotensives (group B) for 1 year. Sodium bicarbonate was given to all patients to treat metabolic acidosis prophylactically (acidosis increases significantly with lisinopril). The annual rate of decline of graft function was measured isotopically (primary outcome) and 24 hr proteinuria, genotyping, radiolabeled polypeptide aprotinin proximal tubular catabolic studies (in group A only) as secondary outcome measurements were undertaken. At baseline, groups were comparable except for greater proteinuria in group A. After 1 year, the rate of decline of graft function and graft survival were comparable in both groups. Proteinuria decreased significantly in group A patients only. Lisinopril also significantly reduced radiolabeled aprotinin uptake and metabolism, plasma aldosterone, and ammonia excretion. Plasma potassium, bicarbonate, and mean arterial pressures were comparable in both groups. Patients with more than or equal to 30% reduction in proteinuria had a significant association with rs699 polymorphism in the angiotensinogen gene. The rate of decline of renal graft function in patients with chronic allograft nephropathy was not adversely affected by lisinopril therapy given for 1 year. Lisinopril significantly reduced proteinuria, renal proximal tubular polypeptide catabolism, plasma aldosterone, and ammonia excretion suggesting relative preservation of graft function. Treating metabolic acidosis allowed safe and prolonged use of angiotensinogen-converting enzyme inhibitors.

  11. 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.

  12. Long-Term Gene Therapy with Thrombospondin 2 Inhibits TGF-β Activation, Inflammation and Angiogenesis in Chronic Allograft Nephropathy

    PubMed Central

    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. PMID:24376766

  13. [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.

  14. [Partial clinical remission of chronic IgA nephropathy with therapy of tuberculosis].

    PubMed

    Ortmann, J; Schiffl, H; Lang, S M

    2010-06-01

    A 36-year-old patient suffered from repeated exsudative pleural effusions and renal insufficiency (serum creatinine 1.9 mg/dl) combined with glomerular erythrocyturia, proteinuria and renal hypertension. The diagnosis of the underlying etiology of the pleural effusions was difficult in spite of a thorough diagnostic work-up. Pleural tuberculosis was finally detected by an interferon gamma release assay (IGRA). Kidney biopsy revealed mesangioproliferative glomerulonephritis, immunhistology showed mesangial IgA deposits. Renal insufficiency did not progress when blood pressure control was achieved. The pleural effusions resolved permanently when antituberculous treatment was begun. Eight weeks after initiation of therapy normalization of kidney function (eGFR > 75 ml/min), resolution of hematuria and reduction of proteinuria were observed. This report of a partial remission of IgA nephropathy by treatment of pleural tuberculosis supports the hypothesis that there may be a causal relationship between mycobacterial infections and IgA nephropathy. Georg Thieme Verlag KG Stuttgart New York.

  15. [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.

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

    PubMed Central

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

    2015-01-01

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

  17. 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.

  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. Autophagy protects renal tubular cells against cyclosporine toxicity.

    PubMed

    Pallet, Nicolas; Bouvier, Nicolas; Legendre, Christophe; Gilleron, Jerome; Codogno, Patrice; Beaune, Philippe; Thervet, Eric; Anglicheau, Dany

    2008-08-01

    A major side effect of the powerful immunosuppressive drug cyclosporine (CsA) is the development of a chronic nephrotoxicity whose mechanisms are not fully understood. Recent data suggest that tubular cells play a central role in the pathogenesis of chronic nephropathies. We have shown that CsA is responsible for endoplasmic reticulum (ER) stress in tubular cells. Autophagy has recently been described to be induced by ER stress and to alleviate its deleterious effects. In this study, we demonstrate that CsA induces autophagy in primary cultured human renal tubular cells through LC3II expression and autophagosomes visualization by electron microscopy. Autophagy is dependant on ER stress because various ER stress inducers activate autophagy, and salubrinal, an inhibitor of eIF2alpha dephosphorylation that protects cells against ER stress, inhibited LC3II expression. Furthermore, autophagy inhibition during CsA treatment with beclin1 siRNA significantly increases tubular cell death. Finally, immunohistochemical analysis of rat kidneys demonstrates a positive LC3 staining on injured tubular cells, suggesting that CsA induces autophagy in vivo. Taken together, these results demonstrate that CsA, through ER stress induction, activates autophagy as a protection against cell death.

  20. 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. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. The Oxford Classification predictors of chronic kidney disease in pediatric patients with IgA nephropathy.

    PubMed

    Fabiano, Rafaela C G; Araújo, Stanley A; Bambirra, Eduardo A; Oliveira, Eduardo A; Simões E Silva, Ana Cristina; Pinheiro, Sérgio V B

    The Oxford Classification for Immunoglobulin A nephropathy (IgAN) identifies pathological variables that may predict the decline of renal function. This study aimed to evaluate the Oxford Classification variables as predictors of renal dysfunction in a cohort of Brazilian children and adolescents with IgAN. A total of 54 patients with IgAN biopsied from 1982 to 2010 were assessed. Biopsies were re-evaluated and classified according to the Oxford Classification. Multivariate analysis of laboratory and pathological data was performed. The primary outcomes were decline of baseline estimated glomerular filtration rate (eGFR) greater than or equal to 50%. Mean follow-up was 7.6±5.0 years. Mean renal survival was 13.5±0.8 years and probability of decline ≥50% in baseline eGFR was 8% at five years of follow-up and 15% at ten years. Ten children (18.5%) had a decline of baseline eGFR≥50% and five (9.3%) evolved to end-stage renal disease. Kaplan-Meier analysis showed that baseline proteinuria, proteinuria during follow-up, endocapillary proliferation, and tubular atrophy/interstitial fibrosis were associated with the primary outcome. Multivariate Cox analysis showed that only baseline proteinuria (HR, 1.73; 95% CI, 1.20-2.50, p=0.003) and endocapillary hypercellularity (HR, 37.18; 95% CI, 3.85-358.94, p=0.002) were independent predictors of renal dysfunction. No other pathological variable was associated with eGFR decline in the multivariate analysis. This is the first cohort study that evaluated the predictive role of the Oxford Classification in pediatric patients with IgAN from South America. Endocapillary proliferation was the unique pathological feature that independently predicted renal outcome. Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  2. Mesoamerican nephropathy: geographical distribution and time trends of chronic kidney disease mortality between 1970 and 2012 in Costa Rica.

    PubMed

    Wesseling, Catharina; van Wendel de Joode, Berna; Crowe, Jennifer; Rittner, Ralf; Sanati, Negin A; Hogstedt, Christer; Jakobsson, Kristina

    2015-10-01

    Mesoamerican nephropathy is an epidemic of chronic kidney disease (CKD) unrelated to traditional causes, mostly observed in sugarcane workers. We analysed CKD mortality in Costa Rica to explore when and where the epidemic emerged, sex and age patterns, and relationship with altitude, climate and sugarcane production. SMRs for CKD deaths (1970-2012) among population aged ≥20 were computed for 7 provinces and 81 counties over 4 time periods. Time trends were assessed with age-standardised mortality rates. We qualitatively examined relations between mortality and data on altitude, climate and sugarcane production. During 1970-2012, age-adjusted mortality rates in the Guanacaste province increased among men from 4.4 to 38.5 per 100,000 vs. 3.6-8.4 in the rest of Costa Rica, and among women from 2.3 to 10.7 per 100,000 vs. 2.6-5.0 in the rest of Costa Rica. A significant moderate excess mortality was observed among men in Guanacaste already in the mid-1970s, steeply increasing thereafter; a similar female excess mortality appeared a decade later, remaining stable. Male age-specific rates were high in Guanacaste for age categories ≥30, and since the late 1990s also for age range 20-29. The male spatiotemporal patterns roughly followed sugarcane expansion in hot, dry lowlands with manual harvesting. Excess CKD mortality occurs primarily in Guanacaste lowlands and was already present 4 decades ago. The increasing rates among Guanacaste men in hot, dry lowland counties with sugarcane are consistent with an occupational component. Stable moderate increases among women, and among men in counties without sugarcane, suggest coexisting environmental risk factors. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  3. Chronic renal failure and shortened lifespan in COL4A3+/- mice: an animal model for thin basement membrane nephropathy.

    PubMed

    Beirowski, Bogdan; Weber, Manfred; Gross, Oliver

    2006-07-01

    A heterozygous mutation in autosomal Alport genes COL4A3 and COL4A4 can be found in 20 to 50% of individuals with familial benign hematuria and diffuse glomerular basement membrane thinning (thin basement membrane nephropathy [TBMN]). Approximately 1% of humans are heterozygous carriers of mutations in the autosomal Alport genes and at risk for developing renal failure as a result of TBMN. The incidence and pathogenesis of renal failure in heterozygous COL4A3/4 mutation carriers is still unclear and was examined further in this study using COL4A3 knockout mice. In heterozygous COL4A3(+/-) mice lifespan, hematuria and renal function (serum urea and proteinuria) were monitored during a period of 3 yr, and renal tissue was examined by light and electron microscopy, immunohistochemistry, and Western blot. Lifespan of COL4A3(+/-) mice was found to be significantly shorter than in healthy controls (21.7 versus 30.3 mo). Persistent glomerular hematuria was detected starting in week 9; proteinuria of > 0.1 g/L started after 3 mo of life and increased to > 3 g/L after 24 mo. The glomerular basement membrane was significantly thinned (167 versus 200 nm in wild type) in 30-wk-old mice, coinciding with focal glomerulosclerosis, tubulointerstitial fibrosis, and increased levels of TGF-beta and connective tissue growth factor. The renal phenotype in COL4A3(+/-) mice resembled the clinical and histopathologic phenotype of human cases of TBMN with concomitant progression to chronic renal failure. Therefore, the COL4A3(+/-) mouse model will help in the understanding of the pathogenesis of TBMN in humans and in the evaluation of potential therapies.

  4. Successful use of cyclosporine as treatment for eosinophilic cystitis: a case report.

    PubMed

    Aleem, Sohaib; Kumar, Bharat; Fasano, Mary Beth; Takacs, Elizabeth; Azar, Antoine Emile

    2016-01-01

    Eosinophilic cystitis is a rare inflammatory disorder characterized by eosinophilic infiltration of all layers of the urinary bladder wall. Due to lack of consensus and potential for side effect from various therapeutic options, treatment of the disease is often challenging. A 64-year old woman with hypertensive nephropathy resulting in stage III chronic kidney disease, obstructive sleep apnea, and obstructive lung disease presented with a 4 month history of dysuria, urgency, frequency, and persistent hematuria. Based on eosinophilic infiltration on bladder wall biopsy in the absence of any evidence of infection, malignancy, or immune disorder, she was diagnosed with eosinophilic cystitis. Despite multiple medication regimens, her symptoms persisted, requiring high-dose prednisone with steroid-related side effects. After four months, she was started on cyclosporine, which led to symptomatic improvement and reduction in prednisone dosage. At that time, repeat urine cytology and cystoscopy did not reveal friable tissues or eosinophiluria. This case illustrates the utility of using cyclosporine to treat eosinophilic cystitis in adult patient with multiple comorbid conditions.

  5. 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

  6. [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.

  7. Chronic cadmium treatment induces tubular nephropathy and osteomalacic osteopenia in ovariectomized cynomolgus monkeys.

    PubMed

    Kurata, Y; Katsuta, O; Doi, T; Kawasuso, T; Hiratsuka, H; Tsuchitani, M; Umemura, T

    2014-09-01

    In an attempt to establish a primate model of chronic cadmium toxicosis, we ovariectomized cynomolgus monkeys and treated them with CdCl2 by repeated intravenous injections for 13 to 15 months. The animals showed normocytic-normochromic anemia. The cadmium treatment resulted in increases of urinary enzyme activity indicative of renal tubular degeneration. Histopathology of the kidney revealed renal proximal tubular atrophy accompanied by interstitial fibrosis. Decreased bone mineral density was evident in the trabecular and cortical zones of the lumbar vertebra and femur, with osteoid accumulation around the trabeculae and Haversian canals. Iron deposition at the mineralization front and osteoclasts hyperplasia were indicative of impairment of bone mineralization and an increase of resorption. Blood inorganic phosphorus and 1α,25(OH)2 vitamin D3 levels decreased and urinary deoxypyridinoline level increased in cadmium-treated animals. The renal and bone lesions closely resemble those of itai-itai disease patients, the most severe case of cadmium toxicosis in terms of clinical chemistry and histopathology. Thus, ovariectomized monkeys chronically exposed to cadmium can serve as a primate itai-itai disease model, which is beneficial for developing novel therapeutic methods, investigating the mechanisms of the renal and bone lesions, and establishing more clearly defined criteria for diagnosing the disease. © The Author(s) 2013.

  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. TSI ultrasound elastography for the diagnosis of chronic allograft nephropathy in kidney transplanted patients

    PubMed Central

    Slowinski, Torsten; Thomas, Anke; Filimonow, Sergej; Fischer, Thomas

    2013-01-01

    Purpose To answer the question whether the TSI (tissue strain imaging) sonoelastography technique can contribute to the diagnosis of chronic renal allograft damage. Material and methods A prospective study of 112 patients between June 2010 and April 2011 was conducted to compare elastography data with biopsy results and laboratory parameters in order to determine whether any correlations exist. Elastography parameters were acquired with a high-end ultrasound system and analyzed using the semiquantitative strain ratio. For comparison, patients were divided into three groups based on biopsy findings (Banff classification): group A: biopsy not necessary; group B: Banff grade I; group C: Banff grades II and III. Correlations were assessed by means of correlation (Pearson) and regression analysis. Differences between ordinal groups were tested for statistical significance by the Mann-Whitney U test. Results Mean patient age was 54.2 ± 15.01 years. Fifty-nine percent of the patients were male. The calculated TSI strain ratio of groups A and C differed significantly (p = 0.024). Groups B and C (p = 0.056) and groups A and B (p = 0.88) showed no significant difference. The TSI strain ratio did not correlate with glomerular filtration rate (r = 0.105) or creatinine (r = 0.092). Conclusion The TSI sonoelastography technique can contribute to the differentiation of different stages of renal graft damage (according to Banff classification). However, significant results were not observed for all investigated features. The TSI technique should be further evaluated in future studies including larger numbers of patients. PMID:26674928

  11. Neoral: the new cyclosporine.

    PubMed

    Corbett, J; Ross, K

    1998-02-01

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

  12. 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.

  13. 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.

  14. [Differentiation of mesenchymal stem cells into vascular endothelial cells in treatment of chronic aristolochic acid nephropathy: experiment with rats].

    PubMed

    Zou, Jie; Feng, Jiang-Min; Li, Wei; Guo, Wei; Wang, Li-Ning

    2008-03-11

    To investigate the potentiality of mesenchymal stem cells (MSCs) to differentiate into vascular endothelia cells (ECs) in peritubular capillary (PTC) in chronic aristolochic acid nephropathy (CAAN). MSCs were isolated from a male Wistar rat. The surface markers were identified with flow cytometry. Thirty female Wistar rats were randomly divided into 3 equal groups: Group A, perfused intragastrically with decoction of Caulis Aristolochiae manshuriensis for 12 weeks to establish CAAN models, Group B, perfused intragastrically with decoction of Caulis Aristolochiae manshuriensis for 12 weeks to establish CAAN models and injected with the MSCs by caudal vein in the 12th week, and Group C, perfused intragastrically with drinking water for 12 weeks and then injected with normal saline by caudal vein to be used as normal controls. At week 16, specimens of blood and urine were collected to detect the blood urea nitrogen (BUN), serum creatinine (Scr) and urine protein, and then the rats were killed with their kidneys taken out. Sex-determining region of the Y chromosome-fluorescence in situ hybridization (SRY-FISH) test with carboxyfluorescein (FAM)- was used to detect the cells originated from the source of the male donors. Immunohistochemistry was used to detect CD34, marker antigen pf EC. HE and Masson staining and electron microscope were used to observe the pathology of the kidney. Immunohistochemistry and RT-PCR were used to detect the expression of vascular endothelial growth factor (VEGF). Correlation analysis was conducted to study the relationships among these indices. Y chromosome and CD34 double positive cells could be seen in the renal tissue of Group B. At week 16, the density of PTC and integrated optical density of VEGF of Group A were (5.3 +/- 0.8)/0.13 mm2 and (2.8 +/- 0.4) x 10(3) respectively, both significantly lower than those of Group B [(26.5 +/- 1.6)/0.13 mm2 and (14.7 +/- 1.7) x 10(3) respectively, both P < 0.011]. The Scr and urine protein of

  15. Comparison of the effects of vitamin E and/or quercetin in attenuating chronic cyclosporine A-induced nephrotoxicity in male rats.

    PubMed

    Zal, Fatemeh; Mostafavi-Pour, Zohreh; Vessal, Mahmood

    2007-08-01

    1. The aim of the present study was to investigate the effects of vitamin E and/or quercetin (Q) on renal function, oxygen radical concentrations in the kidney and some anti-oxidant enzyme activities in rats treated with cyclosporine A (CsA). 2. Groups of rats (270 +/- 15 g), on standard rat chow and water, received all their treatments by gavage for either 4 or 8 weeks. Control groups received either olive oil (0.5 mL) or 25% ethanol (0.5 mL) + olive oil (0.5 mL) per day as vehicle. All experimental groups received 25 mg CsA/kg per day in 0.5 mL olive oil. The vitamin E group received 100 mg vitamin E/kg per day in olive oil in addition to CsA treatment. The quercetin group received 15 mg of Q/kg per day in 0.5 mL of 25% ethanol in addition to CsA treatment. The vitamin E + quercetin group received the two anti-oxidants at the concentrations given in addition to CsA treatment. 3. Quercetin, at a concentration less than one-quarter of vitamin E, was more efficient in lowering blood urea nitrogen, serum creatinine and kidney malondialdehyde in CsA-treated rats. However, neither of the two anti-oxidants was able to normalize these analytes to control values after either 4 or 8 weeks treatment. 4. Quercetin (50 micromol/kg per day) elevated all renal anti-oxidant enzyme activities to values observed in the negative controls. However, vitamin E (232 micromol/kg per day) only normalized glutathione peroxidase activity at the end of either 4 or 8 weeks treatment. Combination treatment with the two anti-oxidants abolished all the ill-effects of CsA. 5. Combination treatment with the two anti-oxidants of renal transplant patients receiving CsA may be beneficial in ameliorating the chronic nephrotoxic effects of the important immunosuppressive drug CsA.

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

    PubMed

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

    2016-05-01

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

  17. 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

  18. Clinical use of cyclosporin in rheumatoid arthritis.

    PubMed

    Richardson, C; Emery, P

    1995-01-01

    Rheumatoid arthritis is a chronic immune-mediated disease characterised by an inflammatory synovitis and extra-articular manifestations. There is an expanding body of evidence to indicate that the activation of T lymphocytes is central in the initiation and perpetuation of this disease. Cyclosporin is an immunomodulator and a highly specific inhibitor of T-lymphocyte function, and has demonstrated disease-modifying properties in clinical studies in patients with rheumatoid arthritis. A concern with the use of cyclosporin has been the development of dose-dependent adverse effects, in particular renal dysfunction. Cyclosporin is lipophilic by nature and the conventional oral formulation (Sandimmun) was subject to incomplete and highly variable absorption, resulting in substantial inter- and intrasubject variations in peak concentrations and systemic bioavailability. A microemulsion-based formulation of cyclosporin (Neoral) has recently been developed, and possesses more predictable and improved absorption with a consequent increased peak concentration and systemic bioavailability. The improved predictability of absorption, and hence blood concentrations, facilitates the ability to 'tailor' therapy to an individual patient, which, in theory, could translate into an improved efficacy and safety profile.

  19. [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.

  20. Prevention of Contrast-Induced Nephropathy by Central Venous Pressure-Guided Fluid Administration in Chronic Kidney Disease and Congestive Heart Failure Patients.

    PubMed

    Qian, Geng; Fu, Zhenhong; Guo, Jun; Cao, Feng; Chen, Yundai

    2016-01-11

    This study aimed to explore the hemodynamic index-guided hydration method for patients with congestive heart failure (CHF) and chronic kidney disease (CKD) to reduce the risk of contrast-induced nephropathy (CIN) and at the same time to avoid the acute heart failure. Patients at moderate or high risk for CIN should receive sufficient hydration before contrast application. This prospective, randomized, double-blind, comparative clinical trial enrolled 264 consecutive patients with CKD and CHF undergoing coronary procedures. These patients were randomly assigned to either central venous pressure (CVP)-guided hydration group (n = 132) or the standard hydration group (n = 132). In the CVP-guided group, the hydration infusion rate was dynamically adjusted according to CVP level every hour. CIN was defined as an absolute increase in serum creatinine (SCr) >0.5 mg/dl (44.2 μmol/l) or a relative increase >25% compared with baseline SCr. Baseline characteristics were well-matched between the 2 groups. The total mean volume of isotonic saline administered in the CVP-guided hydration group was significantly higher than the control group (1,827 ± 497 ml vs. 1,202 ± 247 ml; p < 0.001). CIN occurred less frequently in CVP-guided hydration group than the control group (15.9% vs. 29.5%; p = 0.006). The incidences of acute heart failure during the hydration did not differ between the 2 groups (3.8% vs. 3.0%; p = 0.500). CVP-guided fluid administration can safely and effectively reduce the risk of CIN in patients with CKD and CHF. (Central Venous Pressure Guided Hydration Prevention for Contrast-Induced Nephropathy; NCT02405377). Copyright © 2016 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

  1. 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.

  2. 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

  3. 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.

  4. 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.

  5. c-Jun-N-Terminal Kinase Signaling Is Involved in Cyclosporine-Induced Epithelial Phenotypic Changes

    PubMed Central

    Pallet, Nicolas; Thervet, Eric; Anglicheau, Dany

    2012-01-01

    Tubular epithelial cells play a central role in the pathogenesis of chronic nephropathies. Previous toxicogenomic studies have demonstrated that cyclosporine- (CsA-) induced epithelial phenotypic changes (EPCs) are reminiscent of an incomplete epithelial to mesenchymal transition (EMT) in a TGF-β-independent manner. Furthermore, we identified endoplasmic reticulum (ER) stress as a potential mechanism that may participate in the modulation of tubular cell plasticity during CsA exposure. Because c-jun-N-terminal kinase (JNK), which is activated during ER stress, is implicated in kidney fibrogenesis, we undertook the current study to identify the role of JNK signaling in EPCs induced by CsA. In primary cultures of human renal epithelial cells, CsA activates JNK signaling, and the treatment with a JNK inhibitor reduces the occurrence of cell shape changes, E-cadherin downregulation, cell migration, and Snail-1 expression. Our results suggest that CsA activates JNK signaling, which, in turn, may participate in the morphological alterations through the regulation of Snail-1 expression. PMID:22028950

  6. c-Jun-N-Terminal Kinase Signaling Is Involved in Cyclosporine-Induced Epithelial Phenotypic Changes.

    PubMed

    Pallet, Nicolas; Thervet, Eric; Anglicheau, Dany

    2012-01-01

    Tubular epithelial cells play a central role in the pathogenesis of chronic nephropathies. Previous toxicogenomic studies have demonstrated that cyclosporine- (CsA-) induced epithelial phenotypic changes (EPCs) are reminiscent of an incomplete epithelial to mesenchymal transition (EMT) in a TGF-β-independent manner. Furthermore, we identified endoplasmic reticulum (ER) stress as a potential mechanism that may participate in the modulation of tubular cell plasticity during CsA exposure. Because c-jun-N-terminal kinase (JNK), which is activated during ER stress, is implicated in kidney fibrogenesis, we undertook the current study to identify the role of JNK signaling in EPCs induced by CsA. In primary cultures of human renal epithelial cells, CsA activates JNK signaling, and the treatment with a JNK inhibitor reduces the occurrence of cell shape changes, E-cadherin downregulation, cell migration, and Snail-1 expression. Our results suggest that CsA activates JNK signaling, which, in turn, may participate in the morphological alterations through the regulation of Snail-1 expression.

  7. 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.

  8. 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.

  9. Comparative study of bacterial strains and antibiotic susceptibility tests between chronic tonsillitis patients with IgA nephropathy and without nephritis.

    PubMed

    Huang, Hongdong; Sun, Weiming; Liang, Yumei; Peng, Youming; Long, Xi-Dai; Liu, Zhihua; Tian, Ru; Bai, Chengli; Cai, Genshen

    2013-01-01

    The purpose of the present study was to detect bacterial strains and antibiotic susceptibility in chronic tonsillitis patients with IgA nephropathy (IgAN) and without nephritis, in order to provide evidence for clinical therapy and pathogenesis of IgAN. A total of 53 patients with IgAN (group A) and 53 chronic tonsillitis patients without nephritis (group B) underwent tonsillectomy. The tonsil tissues of patients were collected under sterile condition. The bacteria in the tonsil crypt of patients in both groups were isolated and identified for antibiotic susceptibility test by the manual routine of the laboratory and also with the autoScan/Microscan system. There were bacteria in each specimen in both groups. The bacteria detection rate was 100%, but there was no significant difference between two groups (p > 0.05). The 522 strains of bacteria in group A and 494 strains of bacteria in group B were isolated. Streptococcus. Neisseria, Hemophilus parainfluenzae. Staphylococcus. Bacillus proteus and Streptococcus pneumoniae were detected in both groups, but there was no significant difference in the types of bacteria between the two groups (all p > 0.05). Alpha streptococcus was the most common in both groups. The antibiotic susceptibility test showed that there was no significant difference in the susceptibility to penicillin, chloramphenicol, macrolides, cephalosporin, gentamicin, amikacin sulphate, norfloxacin, ciprofloxacin, rifampicin and vancomycin between two groups (all p > 0.05). Alpha streptococcus in both two groups can be detected and is the most common. There was no significant difference in bacterial strains and antibiotic susceptibility between two groups.

  10. 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

  11. 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.

  12. 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

  13. Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate

    PubMed Central

    Brodsky, Sergey V.; Nadasdy, Tibor; Rovin, Brad H.; Satoskar, Anjali A.; Nadasdy, Gyongyi M.; Wu, Haifeng M.; Bhatt, Udayan Y.; Hebert, Lee A.

    2013-01-01

    An acute increase in the international normalized ratio (INR; a comparison of prothrombin time to monitor the effects of warfarin) over 3 in patients with chronic kidney disease (CKD) is often associated with an unexplained acute increase in serum creatinine (SC) and an accelerated progression of CKD. Kidney biopsy in a subset of these patients showed obstruction of the renal tubule by red blood cell casts, and this appears to be the dominant mechanism of the acute kidney injury. We termed this warfarin-related nephropathy (WRN), and previously reported cases of WRN only in patients with CKD. We now assess whether this occurs in patients without CKD, its risk factors, and consequences. In 15,258 patients who initiated warfarin therapy during a 5-year period, 4006 had an INR over 3 and SC measured at the same time; however, the large data set precluded individual patient clinical assessment. A presumptive diagnosis of WRN was made if the SC increased by over 0.3 mg/dl within 1 week after the INR exceeded 3 with no record of hemorrhage. WRN occurred in 20.5% of the entire cohort, 33.0% of the CKD cohort, and 16.5% of the no-CKD cohort. Other risk factors included age, diabetes mellitus, hypertension, and cardiovascular disease. The 1-year mortality was 31.1% with compared with 18.9% without WRN, an increased risk of 65%. Thus, WRN may be a common complication of warfarin therapy in high-risk patients and CKD doubles this risk. The mechanisms of these risks are unclear. PMID:21389969

  14. Reference Renal Artery Diameter Is a Stronger Predictor of Contrast-Induced Nephropathy than Chronic Kidney Disease in Patients with High Cardiovascular Risk

    PubMed Central

    Zanoli, Luca; Rastelli, Stefania; Marcantoni, Carmelita; Blanco, Julien; Capodanno, Davide; Tamburino, Corrado; Castellino, Pietro

    2011-01-01

    Introduction The incidence of contrast-induced nephropathy (CIN) increases in high cardiovascular risk patients. Chronic kidney disease (CKD) is a known risk factor for CIN development. In a previous report, we demonstrated that the mean reference renal artery diameter (RVD) is an important determinant of CKD in patients undergoing coronary angiography for ischemic heart disease. However, RVD was never tested as a predictor of CIN. Aim: To look at the predictors of CIN. Methods A total of 218 consecutive patients undergoing coronary and renal angiography were enrolled from the cohort of the RAS-CAD study (NCT 01173666). CIN was defined as a relative increase in baseline serum creatinine ≥25% within 1 week of contrast administration. Results The incidence of CIN was 22%. In a fully adjusted model, contrast medium dose (20 ml increase, OR 1.12, 95% CI 1.06–1.19, p < 0.001), iso-osmolar contrast media (OR 0.28, 95% CI 0.09–0.99, p < 0.05), atherosclerotic renovascular disease (OR 2.69, 95% CI 1.32–5.48, p < 0.05), and RVD (1 mm/1.73 m2 increase, OR 0.59, 95% CI 0.41–0.86, p < 0.05) had the greatest effect on outcome and were identified as independent predictors of CIN. CKD was selected as a predictor of CIN only in a model without RVD. Conclusions In patients undergoing coronary angiography for ischemic heart disease, RVD is a stronger predictor of CIN than CKD. PMID:22470377

  15. A non-parametric meta-analysis approach for combining independent microarray datasets: application using two microarray datasets pertaining to chronic allograft nephropathy.

    PubMed

    Kong, Xiangrong; Mas, Valeria; Archer, Kellie J

    2008-02-26

    With the popularity of DNA microarray technology, multiple groups of researchers have studied the gene expression of similar biological conditions. Different methods have been developed to integrate the results from various microarray studies, though most of them rely on distributional assumptions, such as the t-statistic based, mixed-effects model, or Bayesian model methods. However, often the sample size for each individual microarray experiment is small. Therefore, in this paper we present a non-parametric meta-analysis approach for combining data from independent microarray studies, and illustrate its application on two independent Affymetrix GeneChip studies that compared the gene expression of biopsies from kidney transplant recipients with chronic allograft nephropathy (CAN) to those with normal functioning allograft. The simulation study comparing the non-parametric meta-analysis approach to a commonly used t-statistic based approach shows that the non-parametric approach has better sensitivity and specificity. For the application on the two CAN studies, we identified 309 distinct genes that expressed differently in CAN. By applying Fisher's exact test to identify enriched KEGG pathways among those genes called differentially expressed, we found 6 KEGG pathways to be over-represented among the identified genes. We used the expression measurements of the identified genes as predictors to predict the class labels for 6 additional biopsy samples, and the predicted results all conformed to their pathologist diagnosed class labels. We present a new approach for combining data from multiple independent microarray studies. This approach is non-parametric and does not rely on any distributional assumptions. The rationale behind the approach is logically intuitive and can be easily understood by researchers not having advanced training in statistics. Some of the identified genes and pathways have been reported to be relevant to renal diseases. Further study on the

  16. 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.

  17. [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.

  18. Endemic Nephropathy Around the World.

    PubMed

    Gifford, Fiona J; Gifford, Robert M; Eddleston, Michael; Dhaun, Neeraj

    2017-03-01

    There have been several global epidemics of chronic kidney disease of unknown etiology (CKDu). Some, such as Itai-Itai disease in Japan and Balkan endemic nephropathy, have been explained, whereas the etiology of others remains unclear. In countries such as Sri Lanka, El Salvador, Nicaragua, and India, CKDu is a major public health problem and causes significant morbidity and mortality. Despite their geographical separation, however, there are striking similarities between these endemic nephropathies. Young male agricultural workers who perform strenuous labor in extreme conditions are the worst affected. Patients remain asymptomatic until end-stage renal failure. Biomarkers of tubular injury are raised, and kidney biopsy shows chronic interstitial nephritis with associated tubular atrophy. In many of these places access to dialysis and transplantation is limited, leaving few treatment options. In this review we briefly describe the major historic endemic nephropathies. We then summarize the epidemiology, clinical features, histology and clinical course of CKDu in Mesoamerica, Sri Lanka, India, Egypt, and Tunisia. We draw comparisons between the proposed etiologies and supporting research. Recognition of the similarities may reinforce the international drive to establish causality and to effect prevention.

  19. 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.

  20. Minimization of maintenance immunosuppressive therapy after renal transplantation comparing cyclosporine A/azathioprine or cyclosporine A/mycophenolate mofetil bitherapy to cyclosporine A monotherapy: a 10-year postrandomization follow-up study.

    PubMed

    Thierry, Antoine; Le Meur, Yannick; Ecotière, Laure; Abou-Ayache, Ramzi; Etienne, Isabelle; Laurent, Charlotte; Vuiblet, Vincent; Colosio, Charlotte; Bouvier, Nicolas; Aldigier, Jean-Claude; Rerolle, Jean-Philippe; Javaugue, Vincent; Gand, Elise; Bridoux, Frank; Essig, Marie; Hurault de Ligny, Bruno; Touchard, Guy

    2016-01-01

    Long-term outcomes in renal transplant recipients withdrawn from steroid and submitted to further minimization of immunosuppressive regimen after 1 year are lacking. In this multicenter study, 204 low immunological risk kidney transplant recipients were randomized 14.2 ± 3.7 months post-transplantation to receive either cyclosporine A (CsA) + azathioprine (AZA; n = 53), CsA + mycophenolate mofetil (MMF; n = 53), or CsA monotherapy (n = 98). At 3 years postrandomization, the occurrence of biopsy for graft dysfunction was similar in bitherapy and monotherapy groups (21/106 vs. 26/98; P = 0.25). At 10 years postrandomization, patients' survival was 100%, 94.2%, and 95.8% (P = 0.25), and death-censored graft survival was 94.9%, 94.7%, and 95.2% (P = 0.34) in AZA, MMF, and CsA groups, respectively. Mean estimated glomerular filtration rate was 70.4 ± 31.1, 60.1 ± 22.2, and 60.1 ± 19.0 ml/min/1.73 m(2), respectively (P = 0.16). The incidence of biopsy-proven acute rejection was 1.4%/year in the whole cohort. None of the patients developed polyomavirus-associated nephropathy. The main cause of graft loss (n = 12) was chronic antibody-mediated rejection (n = 6). De novo donor-specific antibodies were detected in 13% of AZA-, 21% of MMF-, and 14% of CsA-treated patients (P = 0.29). CsA monotherapy after 1 year is safe and associated with prolonged graft survival in well-selected renal transplant recipient (ClinicalTrials.gov number: 980654). © 2015 Steunstichting ESOT.

  1. 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. PMID:28401169

  2. Physical exercise retards the development of chronic nephropathy in the ageing rat as efficiently as food restriction does.

    PubMed

    Loupal, Gerhard; Url, Angelika; Skalicky, Monika; Viidik, Andrus

    2005-01-01

    Obesity combined with decreasing physical fitness in the ageing Western populations promotes a number of degenerative diseases, including chronic kidney disease. It has further been shown in rodent models that prevention of obesity by food restriction mitigates development of kidney lesions. Whether lifelong physical activity also has a positive effect is not known. To compare the effects of physical exercise and food restriction on the development of chronic kidney lesions in ageing rats. Male Sprague-Dawley rats were divided into groups: voluntarily running in wheels (RW), food restriction to the degree necessary to attain pair weight to RW rats (PW), forced running in treadmills (TM) and sedentary controls housed individually (S1) or 4 in each cage (S4). The interventions began at the age of 5 months and kidneys were sampled and analysed histologically at the ages of 15, 19 and 23 months. Total score for kidney lesions (sum of the scores for glomerular changes, interstitial non-purulent inflammation, proteinaceous casts in tubules and increased amount of connective tissue, the possible maximum being 10.0) increased from 0.5 +/- 0.2 at 5 months of age to 1.6 +/- 0.3 for RW, 2.3 +/- 0.4 for PW, 4.5 +/- 0.4 for TM, 3.6 +/- 0.5 for S1 and 5.4 +/- 0.6 for S4 at the age of 23 months. The increase from 5 months of age was gradual for all groups through 15, 19 and 23 months. The patterns for the various lesions followed the same pattern with the exception of connective tissue, which did not increase. Voluntary running in wheels is as effective in mitigating kidney lesions as is food restriction, while forced running in a treadmill is not effective in this respect. Copyright (c) 2005 S. Karger AG, Basel.

  3. 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.

  4. 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.

  5. Prevalence and severity of anaemia in patients with type 2 diabetic nephropathy and different degrees of chronic renal insufficiency.

    PubMed

    Li Vecchi, Maurizio; Fuiano, Giorgio; Francesco, Marino; Mancuso, Domenico; Faga, Teresa; Sponton, Andrea; Provenzano, Rossana; Andreucci, Michele; Tozzo, Carmela

    2007-01-01

    Type 2 diabetes mellitus is the single most common cause of chronic kidney disease (CKD); however its real impact on renal anaemia has not been established. The aim of this study was to evaluate whether onset, severity, and prevalence of anaemia during the course of CKD is different between type 2 diabetic and non-diabetic patients. We enrolled 281 patients with: (1) type 2 diabetes and no CKD (n = 75); (2) type 2 diabetes plus CKD (n = 106), and (3) CKD without type 2 diabetes (n = 100). According to K/DOQI guidelines, the patients with renal insufficiency (i.e., those with a glomerular filtration rate <60 ml/min) were subgrouped into three tertiles of CKD: (1) stage 3 (creatinine clearance 60-30 ml/min); (2) stage 4 (creatinine clearance 29-15 ml/min), and (3) stage 5 (creatinine clearance <15 ml/min). Anaemia was observed in 16% of the diabetic patients without CKD; it was more frequent in the diabetic patients with CKD than in the non-diabetic patients with CKD (61.7 vs. 52%, p < 0.05). The comparison among the tertiles showed that the prevalence of anaemia was significantly higher only in diabetic CKD patients of stages 4 and 5. The prevalence was higher in females independently of type 2 diabetes mellitus. In diabetics with a normal renal function, the haemoglobin levels were higher than in diabetics and non-diabetics with CKD, but the diabetics showed lower levels of haemoglobin than non-diabetics at stage 3 and stage 4 of CKD. Diabetic patients with CKD of stages 4 and 5 have a higher prevalence of anaemia than non-diabetic patients with comparable glomerular filtration rate. A higher awareness of this risk will allow earlier diagnosis and treatment. Copyright 2007 S. Karger AG, Basel.

  6. 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

  7. 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

  8. 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

  9. Cyclosporine for Ocular Inflammatory Diseases

    PubMed Central

    Kaçmaz, R. Oktay; Kempen, John H.; Newcomb, Craig; Daniel, Ebenezer; Gangaputra, Sapna; Nussenblatt, Robert B.; Rosenbaum, James T.; Suhler, Eric B.; Thorne, Jennifer E.; Jabs, Douglas A.; Levy-Clarke, Grace A.; Foster, C. Stephen

    2009-01-01

    Purpose To evaluate the clinical outcomes of cyclosporine treatment for non-infectious ocular inflammation Design Retrospective cohort study Participants Three hundred seventy-three patients with non-infectious ocular inflammation managed at four tertiary ocular inflammation clinics in the United States observed to use cyclosporine as a single non-corticosteroid immunosuppressive agent to their treatment regimen, between 1979-2007 inclusive. Methods Participants were identified from the Systemic Immunosuppressive Therapy for Eye Diseases Cohort Study. Demographic and clinical characteristics, including dosage of cyclosporine and main outcome measures were obtained for every eye of every patient at every visit via medical record review by trained expert reviewers. Main Outcome Measures: Control of inflammation, sustained control after reducing corticosteroid dosages, and discontinuation of therapy because of toxicity. Results Of the 373 patients (681 eyes) initiating cyclosporine monotherapy, 33.4% by six months and 51.9% by one year gained sustained, complete control of inflammation over at least two visits spanning at least 28 days. Approximately 25% more improved to a level of slight inflammatory activity by each of these time points. Corticosteroid-sparing success (completely controlled inflammation for at least 28 days with prednisone 10 mg/day or less) was achieved by 22.1% by six months and 36.1% within one year. Toxicity led to discontinuation of therapy within one year by 10.7% of the population. Patients over 55 years of age were over 3-fold more likely to discontinue therapy because of toxicity than patients ages 18-39 years. Doses of 151-250 mg/day tended to be more successful than lower doses, and were not associated with a higher discontinuation for toxicity rate; higher doses did not appear to offer a therapeutic advantage. Conclusion Cyclosporine, with corticosteroid therapy as indicated, was modestly effective for controlling ocular inflammation

  10. IgA nephropathy and infections.

    PubMed

    Rollino, Cristiana; Vischini, Gisella; Coppo, Rosanna

    2016-08-01

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

  11. Two cases of idiopathic membranous nephropathy treated with rituximab

    PubMed Central

    Young Yoon, Jae; Tae Han, Seung; Cho, Ajin; Ryoun Jang, Hye; Eun Lee, Jung; Huh, Wooseong; Joong Kim, Dae; Young Oh, Ha; Kim, Yoon-Goo

    2013-01-01

    Idiopathic membranous nephropathy is a common cause of nephrotic syndrome, and has been reported as a cause of idiopathic primary glomerulonephropathy in up to 90% of patients. However, the treatment options remain controversial. We report two cases of idiopathic membranous nephropathy that were treated with rituximab. A 54-year-old man and a 64-year old man were admitted for rituximab therapy. They had previously been treated with combinations of immunosuppressive agents including cyclophosphamide, cyclosporine, mycophenolate, and steroids. However, the patients' heavy proteinuria was not resolved. Both patients received rituximab therapy, 2 weeks apart. After several months of follow-up and a second round of rituximab treatment for each patient, their proteinuria decreased and partial remission of disease was achieved in both patients. PMID:26877930

  12. 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

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. Cyclosporine Absorption Following Orthotopic Liver Transplantation

    PubMed Central

    Burckart, Gilbert J.; Venkataramanan, Raman; Ptachcinski, Richard J.; Starzl, Thomas E.; Gartner, J. Carlton; Zitelli, Basil J.; Malatack, Jeffrey J.; Shaw, Byers W.; Iwatsuki, Shunzaburo; Van Thiel, David H.

    2010-01-01

    Blood concentrations of cyclosporine were determined in adult and pediatric patients following orthotopic liver transplantation to quantitate cyclosporine blood clearance and oral absorption. Seventeen bioavailability studies were performed following transplantation surgery in nine children and seven adults. The intravenous cyclosporine study was performed following an average dose of 2.1 mg/kg. The patients were again studied when they received the same intravenous dose plus an oral dose of cyclosporine of 8.6 mg/kg or an oral dose alone. Blood samples were collected and analyzed for cyclosporine using high-performance liquid chromatography. Cyclosporine blood clearance ranged from 29 to 203 mL/min (1.9–21.5 mL/min/kg) in children and from 253 to 680 mL/min (3.2–7.6 mL/min/kg) in adults. The mean cyclosporine clearance value was 9.3 mL/min/kg in the pediatric patients and 5.5 mL/min/kg in the adults. Cyclosporine bioavailability was less than 5% in six studies on five pediatric patients in the immediate postoperative period. The bioavailability varied from 8% to 60% in adult liver transplant patients (mean, 27%). We conclude that: (1) cyclosporine clearance is highly variable between patients, (2) pediatric patients clear the drug more rapidly than adults and therefore need a higher cyclosporine dose on a body weight basis, (3) cyclosporine is poorly and variably absorbed in liver transplant patients, and (4) cyclosporine blood concentration monitoring is essential following orthotopic liver transplantation. PMID:3540030

  18. 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

  19. 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

  20. 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.

  1. Effect of oral administration of cyclosporine on Toxoplasma gondii infection status of cats.

    PubMed

    Lappin, Michael R; VanLare, Karen A; Seewald, Wolfgang; Roycroft, Linda M; Scorza, Andrea V; King, Stephen; Roberts, Elizabeth S

    2015-04-01

    To evaluate whether anti-inflammatory doses of cyclosporine activate Toxoplasma gondii in chronically infected cats or potentiate infection in cats exposed for the first time. 30 T gondii-negative cats. Cats were assigned to 1 of 3 groups (10 cats/group). Group 1 (control) cats were administered a placebo for 126 days; group 2 cats were administered a placebo for 84 days, followed by cyclosporine at 7.5 mg/kg/d, PO, for 42 days; and group 3 cats were administered cyclosporine at 7.5 mg/kg/d, PO, for 126 days. Cats were orally inoculated with T gondii on day 42. Results for fecal flotations, PCR assays, and histologic examinations and IgM and IgG titers were analyzed. Cyclosporine concentrations were measured on selected days. All cats were infected by T gondii and developed signs of self-limiting gastrointestinal tract infection. Group 3 had the highest incidence and severity of CNS and pulmonary histopathologic findings typical of toxoplasmosis. One cat in group 3 died of systemic toxoplasmosis; that cat had a cyclosporine concentration of 1,690 ng/mL. Group 2 cats infected with T gondii before cyclosporine administration did not have repeated oocyst shedding. Group 3 cats shed fewer oocysts for a shorter time than did control cats of group 1. Oral administration of cyclosporine in accordance with the protocol for this study did not potentiate the enteroepithelial phase of T gondii infection. Cats with high cyclosporine blood concentrations at the time of primary T gondii infection may be at risk of developing systemic toxoplasmosis.

  2. 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.

  3. 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.

  4. [Liver damage caused by atorvastatin and cyclosporine in patients with renal transplant].

    PubMed

    Ivandić, Ema; Bašić-Jukić, Nikolina

    2014-04-01

    Kidney transplantation is the preferred method of treatment of end-stage renal disease, which significantly improves the quality of life, but also increases survival when compared to dialysis. Prevention of acute or chronic rejection demands the use of immunosuppression. However, nephrotoxicity, hepatotoxicity, cardiovascular disease, post-transplantation diabetes mellitus, chronic graft dysfunction and dyslipidemia may all occur as complications of immunosuppressive therapy. Dyslipidemia is a significant problem in renal transplant recipients due to the fact that it increases the risk of cardiovascular mortality in patients in whom the risk is already higher than in the general population. Very often, there is an interaction between immunosuppressive drugs, especially cyclosporine, and drugs that are used in the treatment of dyslipidemia. We present a case of a patient who developed severe hepatotoxicity after the introduction of atorvastatin in a cyclosporine-based immunosuppressive regimen. After discontinuation of atorvastatin and replacement of cyclosporine with everolimus, liver chemistries returned to normal values.

  5. 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.

  6. 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.

  7. 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) Specifications...

  8. 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) Specifications...

  9. 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) Specifications...

  10. Lipid mediators in diabetic nephropathy

    PubMed Central

    2014-01-01

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

  11. 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.

  12. 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.

  13. 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

  14. [Diabetic nephropathy: emerging treatments].

    PubMed

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

    2014-07-01

    Diabetic nephropathy is a leading cause of end-stage renal disease worldwide. The mainstay of treatment has been management of hyperglycaemia, blood pressure and proteinuria using hypoglycemic agents, ACE inhibitors, and angiotensin receptor blockers. Since 2000, new therapeutic strategies began to emerge targeting the biochemical activity of glucose molecules on the renal tissue. Various substances have been studied with varying degrees of success, ranging from vitamin B to camel's milk. Silymarin reduces urinary excretion of albumin, tumor necrosis factor (TNF)-α, and malondialdehyde in patients with diabetic nephropathy and may be considered as a novel addition to the anti-diabetic nephropathy armamentarium. Although some results are promising, studies on a larger scale are needed to validate the utility of these molecules in the treatment of the DN. Copyright © 2014 Association Société de néphrologie. Published by Elsevier SAS. All rights reserved.

  15. 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.

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

    PubMed Central

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

    2013-01-01

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

  17. 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.

  18. 1,25-dihydroxyvitamin D synthesis after renal transplantation: the role of fibroblast growth factor 23 and cyclosporine.

    PubMed

    Sato, Tetsuhiko; Fukagawa, Masafumi; Uchida, Kazuharu; Katayama, Akio; Nagasaka, Takaharu; Matsuoka, Susumu; Goto, Norihiko; Tominaga, Yoshihiro; Kobayashi, Takaaki; Nakao, Akimasa

    2009-01-01

    1,25-dihydroxyvitamin D(3) (1,25D) is tightly regulated by circulating factors, containing fibroblast growth factor 23 (FGF23). However, this control is disturbed in chronic kidney disease. Renal transplantation (RTX) alters 1,25D homeostasis. To examine the clinical relevance of 1,25D in RTX, we drew blood samples from 27 renal transplant recipients (20 cyclosporine-based, seven non-cyclosporine-based) and examined serum concentrations of 25-hydroxyvitamin D(3) (25D), 1,25D, and FGF23. Our protocol for cyclosporine was as follows, an initial dose of 8 mg/kg two d before RTX, and subsequently adjusted on the basis of the pharmacokinetic profile. No baseline differences were observed between cyclosporine-based and non-cyclosporine-based regimens before RTX. All variables except 1,25D levels changed similarly between the two groups. In the cyclosporine-based regimen, 1,25D levels increased steeply on day 2 and re-increased from days 7 to 21. Post-transplant FGF23 levels sharply decreased until day 14. Interestingly, the cyclosporine-treated group revealed an unexpected tendency between circulating 1,25D and FGF23 on day 21. Multiple regression analyses indicated the cyclosporine pharmacokinetic profile as a significant predictor for 1,25D levels. Post-transplant 1,25D production is induced by a steep fall in serum FGF23 and prompt graft function on day 2; 1,25D levels thereafter may be stimulated by circulating abundant cyclosporine.

  19. 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.

  20. An interleukin-6-neutralizing antibody prevents cyclosporine-induced nephrotoxicity in mice.

    PubMed

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

    2008-08-01

    Chronic use of cyclosporine A (CyA) induces nephrotoxicity primarily due to endothelial dysfunction. In our previous studies, potential mechanisms were identified in vitro and implicated nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and interleukin-6 (IL-6) as key components in causing endothelial dysfunction. In this study, we tested the hypothesis that NADPH oxidase activity and IL-6 are key components in renal damage in an in vivo model. Male mice C57B/6 mice from Jackson Laboratory (Bar Harbor, ME) at 6-8 wks were subjected to a low-salt diet throughout the trial. After 1 week on a low-salt diet, the mice were injected daily with treatments in 50 muL vehicle composed of 75% cremaphor (Sigma, St. Louis, MO) and ethanol for 5 wks. A vehicle-alone group was also set aside. Mice were weighed and 25 mg/kg/day cyclosporine (Novartis Pharma, St. Louis, MO) was injected daily. Apocynin (Calbiochem, Gibbstown, NJ) 20 mg/kg were injected either alone or concomitantly with CyA. Another group of mice were administered IL-6 antibody (Cat no. MAB406; R&D Systems, Minneapolis, MN) at 2 mug/day along with CyA. The kidneys were removed en bloc immediately and submitted in formalin for paraffin sections. Trichrome stains were performed. Slides were blinded and 10 photographs of cortical areas per treatment group were taken, which covered an estimate of 10% surface area in random fashion. Areas of renal damage, which were determined by tubular necrosis, were identified and quantified by amount of necrosis per photograph. Each photograph was divided into 10 blocks, and the number of blocks that contained necrotic tubules per photo was recorded. The two control mice (low salt only) had no damage. The four vehicle mice had trace amounts of tubular necrosis. CyA treatment group demonstrated the highest amount of damage (29/70; 41%). CyA with apocynin, a specific NADPH oxidase inhibitor, was found to have 36% (22/60) damage, whereas the CyA with IL-6 antibody only was

  1. 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.

  2. [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.

  3. 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

  4. 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 ...

  5. Cyclosporine A causes maturation failure in embryonic-type glomeruli persisting after birth.

    PubMed

    Fujita, Shinsuke; Sugimoto, Keisuke; Miyazawa, Tomoki; Miyazaki, Kohei; Takemura, Yutaka; Yanagida, Hidehiko; Sakata, Naoki; Wada, Norihisa; Okada, Mitsuru; Takemura, Tsukasa

    2011-01-01

    We analyzed renal histologic and immunohistologic findings in children with nephrotic syndrome (NS) who did (n=5) or did not (n=17) develop cyclosporine A (CyA) nephropathy despite appropriately low serum CyA concentrations being maintained over 2 years. To discriminate embryonic-type from mature glomeruli, we performed staining for type IV collagen a1, laminin ß1 and laminin ß2. Staining patterns were used to semiquantitatively assess glomerular immaturity (glomerular immaturity index, or GII). In follow-up biopsy specimens, residual embryonic-type, collapsed embryonic-type and sclerotic glomeruli that had failed to differentiate were observed. Patients with early-onset CyA nephropathy had a high GII. In patients with a high GII, arteriopathy developed early in CyA treatment. Arteriopathy was observed mostly near embryonic-type glomeruli. Taken together, these glomeruli (surviving embryonic-type, collapsing embryonic-type, and sclerotic glomeruli) essentially equaled the total number of embryonic-type glomeruli in specimens obtained before CyA treatment. Our findings indicate a need for caution in CyA therapy for patients with NS, even for a relatively short course of administration, because some patients may have embryonic-type glomeruli or immature arterioles that predispose them to CyA nephropathy.

  6. 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.

  7. 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.

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

    USDA-ARS?s Scientific Manuscript database

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

  9. [Pseudotumor cerebri associated with cyclosporin use following renal transplantation].

    PubMed

    Costa, Kellen Micheline A H; Almeida, José Bruno de; Félix, Ricardo Humberto de M; Silva Júnior, Maurício Ferreira da

    2010-03-01

    Pseudotumor cerebri (PC) is a syndrome characterized by the presence of intracranial hypertension (ICH) and no alteration in the ventricular system. Renal transplanted patients seem more susceptible to develop it due to immunosuppressive therapy. Cyclosporin (CsA) is a rare cause of PC, scarcely reported in the literature, and should be considered in the differential diagnosis of ICH and papilledema in those patients. We report the case of a 10-year-old boy, with a renal allograft for three years, on chronic use of mycophenolate mophetil (MMF), CsA, and low doses of prednisone. The patient presented with headache, vomiting, diplopia, and photophobia. Funduscopy showed bilateral papilledema. Cerebrospinal fluid analysis and imaging tests were normal. After excluding secondary causes, PC was diagnosed based on the chronic use of CsA, which was then replaced by sirolimus. After that, the patient progressively improved, and the papilledema resolved in three months.

  10. A story of microalbuminuria and diabetic nephropathy

    PubMed Central

    Roshan, Bijan; Stanton, Robert C.

    2013-01-01

    Context: It is estimated that more than 346 million people worldwide have diabetes mellitus . By the year 2030, it is predicted that diabetes will become the seventh leading cause of death in the world. Development of chronic kidney disease (CKD) in patients with diabetes adds significantly to the morbidity and mortality and significantly increases health care costs, even before the development of end stage renal disease (ESRD). Evidence  acquisitions: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. Results: Diabetic nephropathy (DN) is increasing rapidly worldwide. It is the leading cause of new cases of ESRD in the USA.  Interestingly, although DN is the most common cause of ESRD in diabetic patients, diabetes mellitus is also an independent and strong risk factor for ESRD ascribed to causes other than DN (e.g. hypertensive nephropathy). Conclusions: It is important to be aware of the pitfalls of using the urine albumin level in predicting development and progression of diabetic nephropathy in order to treat and advise the patients accurately.  Research into finding new markers is rapidly evolving but current progress makes it likely we will be using the urine albumin level for some years into the future. PMID:24475455

  11. A story of microalbuminuria and diabetic nephropathy.

    PubMed

    Roshan, Bijan; Stanton, Robert C

    2013-10-01

    It is estimated that more than 346 million people worldwide have diabetes mellitus . By the year 2030, it is predicted that diabetes will become the seventh leading cause of death in the world. Development of chronic kidney disease (CKD) in patients with diabetes adds significantly to the morbidity and mortality and significantly increases health care costs, even before the development of end stage renal disease (ESRD). Evidence  acquisitions: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. Diabetic nephropathy (DN) is increasing rapidly worldwide. It is the leading cause of new cases of ESRD in the USA.  Interestingly, although DN is the most common cause of ESRD in diabetic patients, diabetes mellitus is also an independent and strong risk factor for ESRD ascribed to causes other than DN (e.g. hypertensive nephropathy). It is important to be aware of the pitfalls of using the urine albumin level in predicting development and progression of diabetic nephropathy in order to treat and advise the patients accurately.  Research into finding new markers is rapidly evolving but current progress makes it likely we will be using the urine albumin level for some years into the future.

  12. Body burdens of lead in hypertensive nephropathy

    SciTech Connect

    Osterloh, J.D.; Selby, J.V.; Bernard, B.P.; Becker, C.E.; Menke, D.J.; Tepper, E.; Ordonez, J.D.; Behrens, B. )

    1989-09-01

    Chronic lead exposure resulting in blood lead concentrations that exceed 1.93 mumol/l (40 micrograms/dl) or chelatable urinary lead excretion greater than 3.14 mumol (650 micrograms) per 72 h has been associated with renal disease. A previous study had found greater chelatable urine lead excretion in subjects with hypertension and renal failure than in controls with renal failure due to other causes, although mean blood lead concentrations averaged 0.92 mumol/l (19 micrograms/dl). To determine if chelatable urinary lead, blood lead, or the hematologic effect of lead (zinc protoporphyrin) were greater in hypertensive nephropathy (when hypertension precedes elevation of serum creatinine) than in other forms of mild renal failure, we compared 40 study subjects with hypertensive nephropathy to 24 controls having a similar degree of renal dysfunction due to causes other than hypertension. Lead burdens were similar in both the study and control groups as assessed by 72-h chelatable urinary lead excretion after intramuscular injection of calcium disodium EDTA (0.74 +/- 0.63 vs. 0.61 +/- 0.40 mumol per 72 h, respectively), and by blood lead (0.35 +/- 0.23 vs. 0.35 +/- 0.20 mumol/l). We conclude that subjects from a general population with hypertensive nephropathy do not have greater body burdens of lead than renal failure controls.

  13. 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

  14. 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

  15. 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

  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. 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

  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. Therapeutic effects of intranasal cyclosporine for eosinophilic rhinosinusitis with nasal polyps in a mouse model.

    PubMed

    Chang, Dong-Yeop; Joo, Yeon-Hee; Kim, Seong-Jae; Kim, Jin Hyun; Jung, Myeong Hee; Kim, Dae Woo; Jeon, Sea-Yuong; Kim, Sang-Wook

    2015-01-01

    Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a principally type 2 T helper cell (Th2)-mediated inflammatory disease. Systemic corticosteroids currently represent the most effective treatment for CRSwNP, but their long-term use is constrained due to their detrimental side effects. Long-term use of topical steroids is safe, but their efficacy is often limited. Topical cyclosporine has proven to be safe and effective for Th2-mediated diseases such as allergic conjunctivitis. It was hypothesized that topical cyclosporine would be an effective novel drug for the treatment of CRSwNP; its therapeutic efficacy was assessed using a previously established mouse model. After induction of eosinophilic CRSwNP in four-week-old BALB/c mice according to previous protocols, the therapeutic effects of intranasal cyclosporine were evaluated and compared with those of triamcinolone acetonide (TAC). Histopathologic changes were evaluated using hematoxylin and eosin for polyp formation and Sirius red staining for eosinophilic infiltration. The production of cytokines in sinonasal tissues, including tumor necrosis factor (TNF), interleukin (IL)-2, interferon (IFN)-γ, IL-4, IL-5, IL-13, and IL-17A, was measured using a cytometric bead array. The number of polyp-like lesions was reduced significantly only by systemic TAC, but the degree of eosinophilic infiltration was decreased significantly by topical cyclosporine, the potency of which was similar to that of topical or systemic TAC. Except for IFN-γ, the majority of measured cytokines were reduced significantly by topical cyclosporine, although their effects on IL-2 and IL-13 were less potent than those of systemic TAC. Topical cyclosporine might be an effective drug for the management of CRSwNP.

  20. 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.

  1. Hypomagnesemia in Type 2 Diabetic Nephropathy

    PubMed Central

    Sakaguchi, Yusuke; Shoji, Tatsuya; Hayashi, Terumasa; Suzuki, Akira; Shimizu, Morihiro; Mitsumoto, Kensuke; Kawabata, Hiroaki; Niihata, Kakuya; Okada, Noriyuki; Isaka, Yoshitaka; Rakugi, Hiromi; Tsubakihara, Yoshiharu

    2012-01-01

    OBJECTIVE There is now growing evidence that magnesium (Mg) deficiency is implicated in type 2 diabetes and its complications. However, it has not been fully elucidated whether hypomagnesemia is a predictor of end-stage renal disease (ESRD) in type 2 diabetic nephropathy. RESEARCH DESIGN AND METHODS This retrospective cohort study included 455 chronic kidney disease (CKD) patients (144 with type 2 diabetic nephropathy and 311 with nondiabetic CKD) who were hospitalized at Osaka General Medical Center for a CKD educational program between April 2001 and December 2007. The primary outcome was progression to renal replacement therapy. Participants were categorized based on serum Mg level into Low-Mg (serum Mg level ≤1.8 mg/dL) and High-Mg (serum Mg level >1.8 mg/dL) groups with the previously published normal lower limit chosen as the cutoff point. RESULTS Of the subjects with type 2 diabetic nephropathy, 102 progressed to ESRD during follow-up (median, 23 months). A multivariate Cox proportional hazards model showed that after adjustment for various demographic factors and laboratory data, the Low-Mg group had a 2.12-fold higher risk of ESRD than the High-Mg group (95% CI 1.28–3.51; P = 0.004). In contrast, 135 of the nondiabetic CKD subjects progressed to ESRD during follow-up (median, 44 months). No significant difference in outcome was found between the Low- and High-Mg groups of this population (adjusted hazard ratio, 1.15; 95% CI 0.70–1.90; P = 0.57). CONCLUSIONS Hypomagnesemia is a novel predictor of ESRD in patients with type 2 diabetic nephropathy. PMID:22498805

  2. 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.

  3. 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

  4. 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

  5. [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.

  6. 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.

  7. 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.

  8. 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. PMID:28401167

  9. 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.

  10. A prospective, randomized therapeutic trial for schistosomal specific nephropathy.

    PubMed

    Sobh, M A; Moustafa, F E; Sally, S M; Foda, M A; Deelder, A M; Ghoneim, M A

    1989-11-01

    In this work 26 patients with schistosomal specific nephropathy were randomly distributed among three groups. Group I cases were given anti-schistosomal drugs (oxamniquine and praziquantel), group II cases were given anti-schistosomal drugs plus prednisolone, and group III cases were given anti-schistosomal drugs plus cyclosporine. The schistosomal specificity of kidney lesions was assessed by detecting the schistosomal specific antigens (CAA and CCA) and antibodies deposited in the renal glomeruli of these patients. Patients who had another etiologic cause which may explain their kidney disease were not admitted to this study. After initiation of the treatment, patients were followed up every other week in the outpatient clinic for 12 months. Follow-up showed complete remission of proteinuria in two cases in group II (duration of remission was 4 and 8 months) and in one case in group III (duration of remission was 6 months) but in none in group I. Partial remission was observed in one case in group I, in three cases in group II and in one case in group III. During the observation period, improvement in kidney function was observed in two cases in group II but deterioration in kidney function was observed in one case in group I and in one other case in group III. We conclude that in patients with schistosomal nephropathy, none of the tried therapeutic regimens produce regression of the disease if given to patients with established disease.

  11. Diagnosis and treatment of patients with IgA nephropathy in Japan.

    PubMed

    Tomino, Yasuhiko

    2016-12-01

    Chronic kidney disease (CKD) is a worldwide public health problem that affects millions of people from all racial and ethnic groups. Although CKD is not one specific disease, it is a comprehensive syndrome that includes IgA nephropathy. As reported by the Japanese Society of Nephrology, 13.0 million people have CKD. In Japan, major causes of end-stage kidney disease are type 2 diabetic nephropathy, chronic glomerulonephritis, especially IgA nephropathy, hypertensive nephrosclerosis, and polycystic kidney disease. IgA nephropathy is characterized by polymeric IgA1 with aberrant galactosylation (galactose-deficient IgA1) increased in the blood and deposited in the glomerular mesangial areas, as well as partially in the capillary walls. The tonsils are important as one of the responsible regions in this disease. The clarification of the mechanism of galactose-deficient IgA1 production will pave the way for the development of novel therapies. The results of future research are eagerly awaited. At present, the most important therapeutic goals in patients with IgA nephropathy are the control of hypertension, the decrease of urinary protein excretion, and the inhibition of progression to end-stage kidney disease. Several investigators have reported that renin-angiotensin-aldosterone system inhibitors reduce levels of urinary protein excretion and preserve renal function in patients with IgA nephropathy. In Japan, tonsillectomy and steroid pulse therapy are more effective for patients with IgA nephropathy.

  12. Spontaneous remission of IgA nephropathy associated with resolution of hepatitis A.

    PubMed

    Han, Seung Hyeok; Kang, Ea Wha; Kie, Jeong Hae; Yoo, Tae Hyun; Choi, Kyu Hun; Han, Dae-Suk; Kang, Shin-Wook

    2010-12-01

    Although most cases of immunoglobulin A (IgA) nephropathy are idiopathic, several diseases are associated with IgA nephropathy. Of these, chronic liver disease resulting from hepatitis B or C virus infection has been reported as a secondary cause of IgA nephropathy. Recently, hepatitis A virus (HAV)-associated kidney disease has received attention because acute kidney injury can occur as a complication of HAV infection, generally caused by acute tubular necrosis or interstitial nephritis. However, unlike IgA nephropathy related to hepatitis B or C, HAV-associated IgA nephropathy is extremely rare and long-term outcomes have not been reported yet. We describe a case of spontaneous remission of IgA nephropathy associated with serologically documented HAV infection. The patient presented with microhematuria and moderate proteinuria, but acute kidney injury did not occur during active hepatic injury. Kidney biopsy specimens clearly showed mesangial IgA deposits with intact tubules and interstitium. Serum liver enzyme levels returned to reference values 1 month after the onset of acute hepatitis, but urinary protein excretion remained increased. Approximately 1 year later, urinary abnormalities were resolved and a second biopsy showed no mesangial IgA deposits. These findings suggest that IgA nephropathy can transiently accompany HAV infection, but may not progress to chronic glomerulonephritis after recovery from HAV. Copyright © 2010 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  13. 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 ...

  14. 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

  15. Immunoexpression of angiogenesis and proliferation markers in patients treated with cyclosporin A.

    PubMed

    Afonso, M; Perrotti, V; Rapani, M; Iaculli, F; Piccirilli, M; Onuma, T; Shibli, J A; De Oliveira Bello, V; Sposto, M R; Artese, L

    2014-03-01

    In the present immunohistochemical study, the expression of vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67 in the gingival tissues of renal transplant patients treated with cyclosporin A was assessed. Gingival overgrowth (GO) frequently occurs in transplant patients receiving immunosuppressive drugs such as cyclosporine and this gingival inflammation might play an important role in the pathogenesis of drug-induced GO. Twenty-eight human gingival biopsies were taken from healthy patients with chronic periodontitis (N.=14 control group), and from renal transplant recipients treated with cyclosporin A (N.=14 test group). The retrieved specimens were immunohistochemically processed and stained for vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67. The levels of vascular endothelial growth factor, nitric oxide synthase 1 and 3, and Ki-67 were found to be significantly different among groups (P>0.001), with patients treated with cyclosporin A showing higher levels of all the analyzed markers compared to control group. In summary, the data from this pilot study suggests that the investigated factors have a role in the inflammation processes associated to immunosuppressive therapy. However, further studies with a larger sample population need to be conducted for an exhaustive knowledge of the mechanisms leading to GO.

  16. 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].

  17. 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.

  18. Scorpion sting nephropathy

    PubMed Central

    Prabhu, Chaitanya

    2011-01-01

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

  19. 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.

  20. 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.

  1. Heroin crystal nephropathy

    PubMed Central

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

    2015-01-01

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

  2. 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.

  3. 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

  4. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor.

    PubMed

    Nkongolo, Shirin; Ni, Yi; Lempp, Florian A; Kaufman, Christina; Lindner, Thomas; Esser-Nobis, Katharina; Lohmann, Volker; Mier, Walter; Mehrle, Stefan; Urban, Stephan

    2014-04-01

    Chronic hepatitis B and hepatitis D are global health problems caused by the human hepatitis B and hepatitis D virus. The myristoylated preS1 domain of the large envelope protein mediates specific binding to hepatocytes by sodium taurocholate co-transporting polypeptide (NTCP). NTCP is a bile salt transporter known to be inhibited by cyclosporin A. This study aimed to characterize the effect of cyclosporin A on HBV/HDV infection. HepaRG cells, primary human hepatocytes, and susceptible NTCP-expressing hepatoma cell lines were applied for infection experiments. The mode of action of cyclosporin A was studied by comparing the effect of different inhibitors, cyclophilin A/B/C-silenced cell lines as well as NTCP variants and mutants. Bile salt transporter and HBV receptor functions were investigated by taurocholate uptake and quantification of HBVpreS binding. Cyclosporin A inhibited hepatitis B and D virus infections during and--less pronounced--prior to virus inoculation. Binding of HBVpreS to NTCP was blocked by cyclosporin A concentrations at 8 μM. An NTCP variant deficient in HBVpreS binding but competent for bile salt transport showed resistance to cyclosporin A. Silencing of cyclophilins A/B/C did not abrogate transporter and receptor inhibition. In contrast, tacrolimus, a cyclophilin-independent calcineurin inhibitor, was inactive. HBV and HDV entry via sodium taurocholate co-transporting polypeptide is inhibited by cyclosporin A. The interaction between the drug and the viral receptor is direct and overlaps with a functional binding site of the preS1 domain, which mediates viral entry. Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

  5. 21 CFR 520.522 - Cyclosporine.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ..., FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.522 Cyclosporine. (a) Specifications... § 510.600(c) of this chapter. (c) [Reserved] (d) Conditions of use in dogs—(1) Amount. 5 mg per kilogram... effect. (2) Indications for use. For the control of atopic dermatitis in dogs weighing at least 4 pounds...

  6. One-year results of the ICON (Ionic versus non-ionic Contrast to Obviate worsening Nephropathy after angioplasty in chronic renal failure patients) Study.

    PubMed

    Giustino, Gennaro; Baber, Usman; Mastoris, Ioannis; Vlachojannis, Georgios J; Yu, Jennifer; Teirstein, Paul S; Downey, William E; Batchelor, Wayne B; Casterella, Peter J; Nikolsky, Eugenia; Wong, S Chiu; Theodoropoulos, Kleanthis N; Dangas, George D; Mehran, Roxana

    2016-03-01

    Long-term clinical outcomes after exposure to non-ionic iso-osmolar contrast medium (IOCM) or ionic low-osmolar CM (LOCM) in patients with chronic kidney disease (CKD) undergoing coronary angiography are unclear. The ICON trial was a prospective, double-blinded, multicentre study that randomly assigned 146 patients with CKD undergoing coronary angiography with or without percutaneous coronary intervention to the non-ionic IOCM Iodixanol or the ionic LOCM Ioxaglate. We report the 1-year clinical outcomes. After randomization, baseline and procedural characteristics were well-matched between the two groups. At 1 year, three deaths (4.1%) occurred in the ioxaglate and nine deaths in the iodixanol group (13.6%, P = 0.07). The cardiac death rate at 1 year was 2.7% in the ioxaglate group and 9.1% in the iodixanol group (P = 0.07). There were no significant differences in the rates of myocardial infarction (1.4% vs. 1.5%; P = 1.00) and repeated revascularization (6.8% vs. 9.1%; P = 0.75). The use of ionic LOCM ioxaglate was associated with a numerically lower mortality at 1 year as compared to iodixanol in patients who underwent cardiac catheterization. Future studies evaluating long-term safety following exposure to different types of CM are warranted. © 2015 Wiley Periodicals, Inc.

  7. [Bioequivalence research of cyclosporin soft capsules].

    PubMed

    Wu, Yue; Mao, Mian; Wang, Ling; Jiang, Xuehua

    2012-04-01

    This paper is aimed to study the bioavailability and bioequivalence of Cyclosporin Soft Capsules (test preparation and reference preparation) in Chinese healthy volunteers. A high performance liquid chromatography-ultraviolet (HPLC-UV) method for determining the concentration of Cyclosporin A in human whole blood was developed and methodological validated. In accordance with the randomized two-period self crossover study, 24 volunteers received a single oral dose of 400 mg of test preparation or reference preparation. Multiple blood samples were collected post dose and then the concentration of Cyclosporin A in human whole blood samples was determined using the validated assay. The pharmacokinetic parameters including AUC0-t, Cmax, Tmax, and T1/2 were calculated using the non-compartmental method. The bioequivalence of the two preparations was evaluated. After receiving single dose of 400 mg of Cyclosporine A, the pharmacokinetic parameters of T1/2, Cmax, Tmax, and AUC0-t, of Cyclosporin A were (10.114 +/- 6.329) h and (9.717 +/- 4.076) h, (2021.235 +/- 298.581) ng x ml(-1) and (1992.192 +/- 1286.923) ng x ml(-1) (1.729 +/- 0.361) h and (1.813 +/- 0.323) h, (9824.811 +/- 1633.026) ng x h x ml(-1) and (10316.514 +/- 1395.955) ng x h x ml(-1) for test preparation and reference preparation, respectively. The statistical results suggested that these parameters were comparable between the two preparations. The results showed that the test preparation was bioequivalent with the reference preparation in healthy volunteers.

  8. 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

  9. The risk of developing endemic nephropathy in subjects with proteinuria.

    PubMed

    Cvitković, Ante; Sonicki, Zdenko; Babus, Vladimir; Cvoriscec, Dubravka

    2014-03-01

    Endemic nephropathy is a chronic tubulointerstitial disease characterized by early damage to the proximal tubule, with low-molecular weight proteinuria being an important hallmark and possible tool for early diagnosis. The aim of this retrospective cohort study was to assess the risk of developing endemic nephropathy in subjects with proteinuria from the endemic region in Croatia. The cohort study included subjects with proteinuria determined by the sulfosalicylic acid method (after 1988 with strip method), involved in the field survey conducted in the Croatian endemic village of Kaniza in 1975 and followed up until 1997. Subjects with endemic nephropathy established at the first visit and patients that failed to present for follow up visits after 1975. were excluded. In the field survey group that consisted of 624 subjects (286 male and 338 female), proteinuria was established in 157 subjects. Upon the application of exclusion and inclusion criteria, the study cohort included 111 of 157 subjects. The mean follow up was 7.26 years (95% confidence interval 4.06-10.46 years). During the follow up period, 19 (17%) subjects with initial proteinuria developed endemic nephropathy. The incidence density of endemic nephropathy among subjects with proteinuria was 1.3 per 100 persons/year. Estimated risk was 0.0137 (confidence interval 0.0087-0.0214) per year of exposure. The presence of proteinuria determined by the sulfosalicylic acid or test strip in subjects from the endemic village indicated that endemic nephropathy would develop in 1.3 of 100 subjects with proteinuria per year.

  10. 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.

  11. 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.

  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. 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

  14. 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.

  15. 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.

  16. Diabetic nephropathy and antioxidants.

    PubMed

    Tavafi, Majid

    2013-01-01

    Oxidative stress has crucial role in pathogenesis of diabetic nephropathy (DN). Despite satisfactory results from antioxidant therapy in rodent, antioxidant therapy showed conflicting results in combat with DN in diabetic patients. Directory of Open Access Journals (DOAJ), Google Scholar,Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. Treatment of DN in human are insufficient with rennin angiotensin system (RAS) blockers, so additional agent ought to combine with this management. Meanwhile based on DN pathogenesis and evidences in experimental and human researches, the antioxidants are the best candidate. New multi-property antioxidants may be improved human DN that show high power antioxidant capacity, long half-life time, high permeability to mitochondrion, improve body antioxidants enzymes activity and anti-inflammatory effects. Based on this review and our studies on diabetic rats, rosmarinic acid a multi-property antioxidant may be useful in DN patients, but of course, needs to be proven in clinical trials studies.

  17. 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

  18. 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.

  19. 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

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

    PubMed

    Sato, Atsuhisa

    2015-06-01

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

  1. Mesoamerican Nephropathy or Global Warming Nephropathy?

    PubMed

    Roncal-Jimenez, Carlos A; García-Trabanino, Ramon; Wesseling, Catharina; Johnson, Richard J

    2016-01-01

    An epidemic of chronic kidney disease (CKD) of unknown cause has emerged along the Pacific Coast of Central America. The disease primarily affects men working manually outdoors, and the major group affected is sugarcane workers. The disease presents with an asymptomatic rise in serum creatinine that progresses to end-stage renal disease over several years. Renal biopsies show chronic tubulointerstitial disease. While the cause remains unknown, recent studies suggest that it is driven by recurrent dehydration in the hot climate. Potential mechanisms include the development of hyperosmolarity with the activation of the aldose reductase-fructokinase pathway in the proximal tubule leading to local injury and inflammation, and the possibility that renal injury may be the consequence of repeated uricosuria and urate crystal formation as a consequence of both increased generation and urinary concentration, similar to a chronic tumor lysis syndrome. The epidemic is postulated to be increasing due to the effects of global warming. An epidemic of CKD has led to the death of more than 20,000 lives in Central America. The cause is unknown, but appears to be due to recurrent dehydration. Potential mechanisms for injury are renal damage as a consequence of recurrent hyperosmolarity and/or injury to the tubules from repeated episodes of uricosuria. The epidemic of CKD in Mesoamerica may be due to chronic recurrent dehydration as a consequence of global warming and working conditions. This entity may be one of the first major diseases attributed to climate change and the greenhouse effect. © 2016 S. Karger AG, Basel.

  2. 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.

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

    PubMed Central

    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. PMID:23202401

  4. [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.

  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. Copyright © 2013 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  6. 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.

  7. Pathogenetic and therapeutic approaches to IgA nephropathy using a spontaneous animal model, the ddY mouse.

    PubMed

    Tomino, Yasuhiko

    2011-02-01

    IgA nephropathy is the most common primary chronic glomerulonephritis in the world and was first described by Berger et al. (J Urol Nephrol 74:694-695;1968). Histopathologically, IgA nephropathy is characterized by expansion of the glomerular mesangial matrix with mesangial cell proliferation. Glomeruli typically contain generalized diffuse granular mesangial deposits of IgA (mainly IgA1), IgG and C3. In advanced patients, global glomerular sclerosis, crescent formation and tubulo-interstitial fibrosis are marked in light microscopy. IgA nephropathy is generally considered to be an immune-complex mediated glomerulonephritis. Although more than 40 years have passed since this disease was firstly described, the pathogenesis/initiation factors of IgA nephropathy are still obscure. The objective of this review is to explain the pathogenesis and treatment based on our previous data of ddY mouse, a spontaneous animal model for IgA nephropathy.

  8. Mechanisms of action of cyclosporine and effects on connective tissues.

    PubMed

    Russell, G; Graveley, R; Seid, J; al-Humidan, A K; Skjodt, H

    1992-06-01

    Cyclosporine is a potent immunomodulatory agent with an increasing number of clinical applications. Its major mode of action is inhibition of the production of cytokines involved in the regulation of T-cell activation. In particular, cyclosporine inhibits the transcription of interleukin 2. Although cyclosporine's major actions are on T cells, there is some evidence that it produces direct effects on other cell types. Its immunosuppressive action is closely linked to its binding of cyclophilin, a member of a family of high-affinity cyclosporine-binding proteins widely distributed in different cell types and in different species. The cyclophilins have been shown to have peptidyl-prolyl cis-trans isomerase enzyme activity that is blocked by cyclosporine. Although this may be a factor in cyclosporine's selective inhibition of cytokine gene transcription, it is still unclear whether inhibition of this activity is the mechanism through which cyclosporine exerts its effects on target cells. The ubiquitous presence of cyclophilins raises the question of why cyclosporine has major effects on T cells. Perhaps the critical proteins affected are transcriptional regulators restricted in their tissue distribution. The effects of cyclosporine on T cells and, directly or indirectly, on connective tissue cells, all of which can produce a range of cytokines, are of interest in relation to the tissue changes that occur in such inflammatory conditions as rheumatoid arthritis.

  9. 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

  10. Nox2 and Cyclosporine-Induced Renal Hypoxia.

    PubMed

    Djamali, Arjang; Wilson, Nancy A; Sadowski, Elizabeth A; Zha, Wei; Niles, David; Hafez, Omeed; Dorn, Justin R; Mehner, Thomas R; Grimm, Paul C; Hoffmann, F Michael; Zhong, Weixiong; Fain, Sean B; Reese, Shannon R

    2016-06-01

    We hypothesized that nicotinamide adenosine diphosphate oxidase 2 (Nox2) plays an important role in cyclosporine A (CsA)-induced chronic hypoxia. We tested this hypothesis in Fisher 344 rats, C57BL/6 J wild type and Nox2-/- mice, and in liver transplant recipients with chronic CsA nephrotoxicity. We used noninvasive molecular imaging (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging) and molecular diagnostic tools to assess intrarenal oxygenation and perfusion, and the molecular phenotype of CsA nephrotoxicity. We observed that chemical and genetic inhibition of Nox2 in rats and mice resulted in the prevention of CsA-induced hypoxia independent of regional perfusion (blood oxygen level-dependent magnetic resonance imaging and dynamic contrast-enhanced magnetic resonance imaging, pimonidazole, HIF-1α). Nicotinamide adenosine diphosphate oxidase 2 knockout was also associated with decreased oxidative stress (Nox2, HIF-1α, hydrogen peroxide, hydroxynonenal), and fibrogenesis (α-smooth muscle actin, picrosirius red, trichrome, vimentin). The molecular signature of chronic CsA nephrotoxicity using transcriptomic analyses demonstrated significant changes in 40 genes involved in injury repair, metabolism, and oxidative stress in Nox2-/- mice. Immunohistochemical analyses of kidney biopsies from liver transplant recipients with chronic CsA nephrotoxicity showed significantly greater Nox2, α-smooth muscle actin and picrosirius levels compared with controls. These studies suggest that Nox2 is a modulator of CsA-induced hypoxia upstream of HIF-1α and define the molecular characteristics that could be used for the diagnosis and monitoring of chronic calcineurin inhibitor nephrotoxicity.

  11. 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

  12. 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.

  13. 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.

  14. 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

  15. Continental variations in IgA nephropathy among Asians.

    PubMed

    Prakash, S; Kanjanabuch, T; Austin, P C; Croxford, R; Hsu, C-Y; Choi, A I; Cattran, D C

    2008-11-01

    Local variations in patient demographics and medical practice can contribute to differences in renal outcomes in patients with IgA nephropathy. We report the experiences of two groups of Asians with IgA nephropathy across continents. We retrospectively examined two cohorts of Asian patients with IgA nephropathy from The King Chulalongkorn Memorial Hospital registry, Thailand (1994 - 2005), and The Metropolitan Toronto Glomerulonephritis registry, Canada (1975 - 2006), and compared their baseline characteristics. Slope of estimated glomerular filtration rate (eGFR) in each group was approximated using separate repeated measures regression models for each country. There were 152 Canadian and 76 Thai patients. At the time of first presentation, Thai patients were more likely to be female (63.2 vs. 44.1%, p = 0.01), have less baseline proteinuria (1.2 vs. 1.7 g/d, p = 0.08) and more likely to receive angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) (64.0 vs. 15.2%, p < 0.01), or prednisone (41.3 vs. 4.6%, p < 0.01). The annual change in estimated glomerular filtration rate (eGFR) for the Thai and Canadian groups were -0.82 ml/min/1.73 m2/year and -3.35 ml/min/1.73 m2/year, respectively, after adjustment for age, sex, mean arterial pressure (MAP), proteinuria, body mass index, Haas histological grade, chronicity scores and baseline medications. Although disease severity was similar among IgA nephropathy patients in Canada and Thailand, more Thai patients were on ACE-I/ARB or prednisone therapy at baseline. Further prospective research is needed to explore international differences in demographic and environmental factors, health resources, and disease management to determine how they may impact long-term outcomes in Asians with IgA nephropathy.

  16. 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.

  17. Cyclosporine therapy monitored with abbreviated area under curve in nephrotic syndrome.

    PubMed

    Rinaldi, Stefano; Sesto, Antonella; Barsotti, Paola; Faraggiana, Tullio; Sera, Francesco; Rizzoni, Gianfranco

    2005-01-01

    Cyclosporin A (CsA) is an effective therapy for children with long-lasting nephrotic syndrome (NS). Long-term treatment can result in chronic CsA nephropathy (CsAN) and there is controversy concerning its incidence and severity. Trough levels are commonly used to monitor the drug concentration. We report a retrospective clinical and histological analysis of 18 children (12 males, 6 females) with steroid-dependent nephrotic syndrome (15 patients) and partially steroid-sensitive nephrotic syndrome (3 patients) treated with CsA for a long-term period (mean 4.9 years, range 2.2-6.9). Before CsA treatment all patients had normal creatinine clearance. CsA was started at a dose of 5 mg/kg per day administered orally in two divided doses and adjusted to maintain the mean CsA blood concentration between 250 and 350 ng/ml obtained from abbreviated area under the curve (AUC). A renal biopsy was performed after a mean period of 3.9 years (range 2.2-6.2) from the start of CsA treatment. Tubular, interstitial, and arteriolar lesions were evaluated in order to assess CsAN. The mean CsA dose and the mean CsA blood concentration were 4.4 mg/kg per day (range 3.6-5.8) and 276.6 ng/ml (range 162-346), respectively. No child had a worsening creatinine clearance during CsA treatment and follow-up after CsA discontinuation. If compared with the year before the start of CsA treatment, NS relapses and prednisone (PDN) dose significantly decreased during CsA treatment, 4/year versus 0.8/year (P <0.0001) and 0.9 mg/kg per day versus 0.2 mg/kg per day (P <0.0001), respectively. Histological analysis showed 15 patients with minimal change disease and 3 with focal segmental glomerulosclerosis. Clear-cut lesions diagnostic of CsAN were never found and only mild lesions were observed in 5 children (suggestive of CsAN in 2 patients and consistent with CsAN in 3 patients). Long-term CsA treatment is confirmed to be effective in preventing NS relapses and reducing PDN dose. Renal function is not a

  18. 21 CFR 524.575 - Cyclosporine ophthalmic ointment.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 21 Food and Drugs 6 2010-04-01 2010-04-01 false Cyclosporine ophthalmic ointment. 524.575 Section... § 524.575 Cyclosporine ophthalmic ointment. (a) Specifications. Each gram of ointment contains 2... use—(1) Amount. Apply a 1/4-inch strip of ointment to the affected eye(s) every 12 hours. (2...

  19. 21 CFR 524.575 - Cyclosporine ophthalmic ointment.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 21 Food and Drugs 6 2013-04-01 2013-04-01 false Cyclosporine ophthalmic ointment. 524.575 Section... § 524.575 Cyclosporine ophthalmic ointment. (a) Specifications. Each gram of ointment contains 2... use—(1) Amount. Apply a 1/4-inch strip of ointment to the affected eye(s) every 12 hours. (2...

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

    PubMed Central

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

    2016-01-01

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

  1. 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.

  2. 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

  3. Transient hyperphosphatasemia in three pediatric patients treated with cyclosporine.

    PubMed

    Mori, Takeshi; Tanaka, Ryojiro; Nishida, Kosuke; Yamamoto, Nobuyuki; Hayakawa, Akira; Nishimura, Noriyuki; Nozu, Kandai; Iijima, Kazumoto

    2016-05-01

    Transient hyperphosphatasemia (TH) is defined as marked elevation of serum alkaline phosphatase (ALP), predominantly its bone or liver isoform. It is a rare condition and is usually detected on laboratory examination in patients without any clinical symptoms. In typical patients with TH, ALP spontaneously normalizes, but no apparent cause of TH has been identified. Some drugs are suspected triggers of TH, but no clear evidence of their association with TH has been shown to date. We herein report three cases of TH in pediatric patients. Two patients were treated with cyclosporine for frequently relapsing nephrotic syndrome, and one was also taking cyclosporine for aplastic anemia. Interestingly, ALP immediately decreased after termination of cyclosporine in two patients, whereas TH lasted 4 months in the one patient who continued cyclosporine. Clearly, cyclosporine is associated with the pathophysiology of TH in children. © 2016 Japan Pediatric Society.

  4. Differentiated transplant derived airway epithelial cell cytokine secretion is not regulated by cyclosporine

    PubMed Central

    2011-01-01

    Background While lung transplantation is an increasingly utilized therapy for advanced lung diseases, chronic rejection in the form of Bronchiolitis Obliterans Syndrome (BOS) continues to result in significant allograft dysfunction and patient mortality. Despite correlation of clinical events with eventual development of BOS, the causative pathophysiology remains unknown. Airway epithelial cells within the region of inflammation and fibrosis associated with BOS may have a participatory role. Methods Transplant derived airway epithelial cells differentiated in air liquid interface culture were treated with IL-1β and/or cyclosporine, after which secretion of cytokines and growth factor and gene expression for markers of epithelial to mesenchymal transition were analyzed. Results Secretion of IL-6, IL-8, and TNF-α, but not TGF-β1, was increased by IL-1β stimulation. In contrast to previous studies using epithelial cells grown in submersion culture, treatment of differentiated cells in ALI culture with cyclosporine did not elicit cytokine or growth factor secretion, and did not alter IL-6, IL-8, or TNF-α production in response to IL-1β treatment. Neither IL-1β nor cyclosporine elicited expression of markers of the epithelial to mesenchymal transition E-cadherin, EDN-fibronectin, and α-smooth muscle actin. Conclusion Transplant derived differentiated airway epithelial cell IL-6, IL-8, and TNF-α secretion is not regulated by cyclosporine in vitro; these cells thus may participate in local inflammatory responses in the setting of immunosuppression. Further, treatment with IL-1β did not elicit gene expression of markers of epithelial to mesenchymal transition. These data present a model of differentiated airway epithelial cells that may be useful in understanding epithelial participation in airway inflammation and allograft rejection in lung transplantation. PMID:21477368

  5. Pathophysiologic insight into MesoAmerican nephropathy.

    PubMed

    Madero, Magdalena; García-Arroyo, Fernando E; Sánchez-Lozada, Laura-Gabriela

    2017-07-01

    Mesoamerican nephropathy (MeN) is an emerging pathophysiological entity of Chronic kidney desease (CKD) not related to traditional risk factors (diabetes and hypertension) that have caused thousands of deaths in Central America, mainly in sugarcane workers. The focus of this review is to discuss the risk factors and probable mechanisms involved in the initiation and progression of this devastating disease. Frequent episodes of subclinical Acute kidney injury caused by repetitive heat stress, dehydration, and strenuous work have been regarded as the main risk factors for MeN. The combination of them chronically activates vasopressin, renin angiotensin aldosterone system, and polyol-fructokinase pathway in the kidney. Also, subclinical rhabdomyolysis compound the framework of the disease by exacerbating systemic inflammation and inducing uricosuria. Exposure to nephrotoxins, high fructose intake, and use of NSAIDs could also contribute to further accelerating the progression of the disease. The evidence supports the notion that recurrent cycles of heat stress, dehydration, and strenuous work may cause CKD. The chronic activation of such mechanisms likely occurs in other conditions of reduced water intake and probably explains why the current management of CKD has not been effective to revert or halt the progression to end-stage CKD.

  6. 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

  7. 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.

  8. 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.

  9. A disease model of diabetic nephropathy in a glomerulus-on-a-chip microdevice.

    PubMed

    Wang, Li; Tao, Tingting; Su, Wentao; Yu, Hao; Yu, Yue; Qin, Jianhua

    2017-05-16

    Diabetic nephropathy is a major chronic renal complication of diabetes mellitus, and is the leading cause of end-stage kidney diseases. Establishing a disease model of diabetic nephropathy in vitro can accelerate the understanding of its mechanisms and pharmaceutical development. We provide the proof-of-principle for using a glomerulus-on-a-chip microdevice that reconstitutes organ-level kidney functions to create a human disease model of early stage diabetic nephropathy on chip. The microfluidic device, which recapitulates the glomerular microenvironment, consists of parallel channels lined by isolated primary glomerular microtissues that experience fluid flow to mimic the glomerular filtration barrier (GFB), including glomerular endothelial cells, 3D basement membrane and podocytes. This device was used to reproduce high glucose-induced critical pathological responses in diabetic nephropathy as observed in humans. The results reveal that hyperglycemia plays a crucial role in the development of increased barrier permeability to albumin and glomerular dysfunction that lead to proteinuria. This organ-on-a-chip microdevice mimics the critical pathological responses of glomerulus that are characteristic of diabetic nephropathy that has not been possible by cell-based and animal models, providing a useful platform for studying the mechanism of diabetic nephropathy and developing an effective therapy in glomerular diseases.

  10. 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.

  11. Blood pressure, proteinuria and nephropathy in Fabry disease.

    PubMed

    Jain, Gaurav; Warnock, David G

    2011-01-01

    Fabry disease is an X-linked disorder leading to abnormal accumulation of glycosphingolipids with multisystem involvement, including cardiac, renal, dermatologic and neurologic manifestations. Fabry nephropathy, specifically proteinuria and progressive chronic kidney disease, have taken center stage over the past decade, defining disease outcomes as well as mortality associated with Fabry disease. Systemic blood pressure among patients with Fabry disease is relatively low, compared to other forms of proteinuric chronic kidney disease. This review is based on a systematic survey of recent publications that describe the diagnosis and treatment of Fabry nephropathy in adults. A high percentage of patients with Fabry disease have been shown to have proteinuria, and a small but significant percentage of Fabry patients have overt hypertension. Recent efforts have focused on the use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEIs/ARBs) in addition to enzyme replacement therapy (ERT) for treatment of Fabry nephropathy. The proven beneficial effects of ACEI/ARBs for more common forms of proteinuric kidney disease have been extrapolated to the treatment of Fabry nephropathy. The overall treatment goal with ACEIs/ARBs, in combination with ERT, is reduction of urinary protein excretion to less than 500 mg/day, and stabilization of the decline of kidney function to -1 ml/min/1.73 m(2)/year. ERT alone, in the absence of ACEIs/ARBs does not decrease proteinuria in Fabry patients. We present the prevalence of proteinuria, kidney disease and hypertension in Fabry disease and discuss treatment goals for the treatment of this unusual form of proteinuric kidney disease. There are some practical challenges to the use of standard antiproteinuric therapy in Fabry disease that need to be addressed to optimize patient outcome, with the expectation that kidney function can be preserved with the combination of ERT and ACEI/ARB therapy. Copyright © 2010 S

  12. 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

  13. Chronic graft-versus-host disease complicated by nephrotic syndrome.

    PubMed

    Wang, Hsin-Hui; Yang, An-Hang; Yang, Ling-Yu; Hung, Giun-Yi; Chang, Jei-Wen; Wang, Chun-Kai; Lee, Tzong-Yann; Tang, Ren-Bin

    2011-09-01

    Chronic graft-versus-host disease (cGVHD) is one of the most frequent and serious complications of allogeneic hematopoietic stem cell transplantation (HSCT). Nephrotic syndrome (NS) is an uncommon and underrecognized manifestation of cGVHD. We report a patient who developed NS 18 months after allogeneic bone marrow transplantation. The onset of NS was accompanied by active manifestations of cGVHD, and immunosuppressants had not been tapered recently. Renal biopsy revealed membranous nephropathy. The patient failed to improve with three combined immunosuppressants (prednisolone, cyclosporine, and mycophenolate mofetil), but achieved partial remission after intravenous immunoglobulin (IVIG) infusion. Twenty-four months after the diagnosis of NS, the patient was still in hematological remission, with normal serum creatinine level, urinary protein loss of 0.7-1.9 g/day and mild oral mucositis. Our report suggests that NS can be a cGVHD-related immune disorder in HSCT patients. Monitoring of renal parameters, especially proteinuria, is important in cGVHD patients. Our case indicated that post-transplant NS, occurring without history of tapering or following immunosuppressant withdrawal, presents a more severe activity of cGVHD and a relatively severe clinical course. IVIG may modify and control the refractory GVHD-related NS, and can be one of the choices of treatment. Copyright © 2011. Published by Elsevier B.V.

  14. Optimization of cyclosporine for liver transplantation.

    PubMed

    Lilly, L B; Grant, D

    2004-03-01

    Our understanding of cyclosporine (CsA) administration for liver transplantation has significantly improved over the past decade. Cyclosporine is a highly lipophilic molecule, and the original galenic formulation, Sandimmune, was highly dependent on bile flow and gut motility for its absorption. Sandimmune's poor absorption profile produced erratic CsA levels after liver transplantation. A new microemulsification formulation of CsA, Neoral (CsA-ME), was developed to overcome these limitations. The NOF-1 study confirmed the superiority of CsA-ME's absorption compared with Sandimmune; CsA-ME had a more consistent and reliable absorption, with lower intrapatient variability and improved dose linearity with drug exposure as measured by area under the concentration-time curve (AUC). These advantages translated into more reliable CsA predose concentrations and less toxicity. An analysis of the pharmacokinetic data showed that 2-hour postdose CsA levels (C2) provided a better measure of immune suppression than did trough levels (C0). The LIS2T study recently confirmed and extended these data by showing equivalent efficacy between CsA-ME using C2 monitoring or tacrolimus in liver transplant patients, with a similar incidence of adverse events except for a higher rate of diabetes mellitus and diarrhea with tacrolimus. These data confirmed that the improved CsA-ME formulation, when used in conjunction with optimized drug-monitoring protocols, is well tolerated after transplantation and provides low rates of graft rejection.

  15. Sulodexide ameliorates early but not late kidney disease in models of radiation nephropathy and diabetic nephropathy

    PubMed Central

    Rossini, Michele; Naito, Takashi; Yang, Haichun; Freeman, Michael; Donnert, Ellen; Ma, Li-Jun; Dunn, Stephen R.; Sharma, Kumar; Fogo, Agnes B.

    2010-01-01

    Background. Sulodexide is a glycosaminoglycan with anticoagulant and antithrombotic activities. Although sulodexide reduced albuminuria in patients with type 1 and type 2 diabetes, long-term effects on chronic renal injury are not established. We investigated sulodexide effects and mechanisms in a rat radiation nephropathy model and in the db/db mouse model of diabetic kidney disease. Methods. Sprague–Dawley rats received kidney radiation and were treated as follows: 15 mg/kg/day sulodexide s.c., 6 day/week (SUL) or no treatment (CONT). Subsets of animals were sacrificed after 8 weeks and 12 weeks. Blood pressure, serum creatinine, creatinine clearance (CrCl) and urinary protein excretion were measured every 4 weeks. Sclerosis and plasminogen activator inhibitor-1 (PAI-1) expression were assessed at 8 and 12 weeks, and collagen I, total collagen content and phospho-smad-2 expressions were determined at 12 weeks. Twelve-week-old db/db mice received sulodexide as above or vehicle. Albuminuria and CrCl were assessed at intervals till sacrifice at week 9 with assessment of urinary transforming growth factor-β (TGF-β) and glomerular lesions. Results. Blood pressure, serum creatinine and CrCl were not different in radiation rat CONT vs SUL at any time. Proteinuria was significantly lower in SUL compared to CONT at 4 and 8 weeks but not at 12 weeks. Sclerosis and PAI-1 expression trended lower in SUL vs CONT at 8 weeks. There was no difference between the groups in sclerosis, collagen I mRNA, total collagen content or PAI-1 expression at 12 weeks. Phospho-smad 2 expression was significantly decreased in SUL compared to CONT at 12 weeks. Db/db mice with or without SUL showed no difference in urinary albumin/creatinine ratio, urine TGF-β or mesangial matrix expansion. Conclusions. Our data show that sulodexide can reduce the early, but not late, proteinuria in radiation nephropathy in rats. In addition, sulodexide did not affect urine TGF-β established albuminuria or

  16. Higher prevalence of nephropathy in young Roma females compared with non-Roma females.

    PubMed

    Rosenberger, Jaroslav; Majerníková, Mária; Jarcuska, Peter; Pella, Daniel; Mareková, Mária; Gecková, Andrea Madarasová; Halánová, Monika

    2014-03-01

    Ethnic differences in the prevalence of various chronic diseases, including end-stage renal disease, have been previously reported. Surprisingly, data focusing on the lower grade of chronic kidney disease (CKD) are scarce. Thus, the aim of this study was to explore differences in the prevalence of nephropathy between the Roma and non-Roma populations. Data from the cross-sectional population based HepaMeta study conducted in Slovakia were used. Nephropathy was defined as: a known history of any kidney disease; or the presence of proteinuria/hematuria; or glomerular filtration rate (GFR) < 60 ml/min. The odds ratio for the prevalence of nephropathy was calculated using binary logistic regression. In an age-adjusted model, Roma females had OR of 1.56 for having nephropathy over non-Roma females (OR 1.56; 95% CI 1.01-2.42; p < 0.05). In addition, Roma females had a significantly lower GFR (mean difference 3.4 ml/min, t = -3.58, p < 0.001); all female patients with proteinuria were Roma. This cross-sectional study on the young general population found that Roma females have half-higher odds for nephropathy than non-Roma females. Therefore, to prevent risks we should focus on searching for ethnic, social and medical determinants of CKD. Interventions to decrease the incidence of CKD in the target population should also address ethnic inequalities as well as female gender.

  17. 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.

  18. 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.

  19. Long-term follow-up after conversion from tacrolimus to cyclosporin in renal transplant patients with new-onset diabetes mellitus after transplantation.

    PubMed

    Batista, F; Auyanet, I; Torregrosa, J-V; Oppenheimer, F

    2012-11-01

    The relationship between anticalcineurin (CNI) drugs and the development new-onset diabetes mellitus after kidney transplantation (NODAT) is well established. Among these agents cyclosporine shows lesser diabetogenicity than tacrolimus. It has been described that conversion from tacrolimus to cyclosporine improves glycemic control; however, there are no studies showing whether this reduced risk is maintained upon long-term follow-up. To evaluate whether CNI drugs conversion from tacrolimus to cyclosporine helps to maintain better glycemic control. We retrospectively evaluated the evolution of glucose metabolism at 5 years after conversion from tacrolimus to cyclosporine in eight patients (six men) with NODAT. Mean age was 42.8 ± 15 years, and time after transplantation to conversion 128 ± 40 months. We analyzed fasting serum glucose, lipid metabolism, renal function, and cyclosporine levels at 0, 6, 12, 24, 36, 48, and 60 months after conversion. At 6 months after conversion, improved glucose metabolism was observed (268 ± 161 versus 121 ± 31 mg/dL; P < .01) although it was minimal in one case with persistent high blood glycemic levels. Only two patients maintained a normal glucose at the end of follow-up. Five subjects showed increased glycemia at 12 to 24 months after conversion requiring antidiabetic therapy: three patients, insulin and two oral antidiabetic agents. Two patients lost their allografts due to chronic rejection at 32 and 50 months respectively. Among the other six patients, renal function remained stable (1.9 ± 0.6 versus 2.11 ± 0.97 mg/dL; P = NS). There was no significant differences among the other variables. Cyclosporine levels remained stable during the follow-up. Conversion of renal transplant patients with NODAT from tacrolimus to cyclosporine improves glucose metabolism in the short term but glycemia increases thereafter. Copyright © 2012 Elsevier Inc. All rights reserved.

  20. Clinical response to combined therapy of cyclosporine and prednisone.

    PubMed

    Gensure, Robert C

    2013-12-01

    Reported is a patient with severe alopecia areata, multiple autoimmune diseases (chronic lymphocytic thyroidis, primary ovarian failure), and Down syndrome. She had a poor response to topical treatment with glucocorticoids and minoxidil, but showed some improvement with glucocorticoid injections. At the time of evaluation, she had hair loss on 85-90% of her scalp. She was treated initially with oral prednisone 50 mg per day for 2 weeks, followed by a 3-month course of prednisone 10 mg per day and cyclosporine 125 mg (4 mg kg(-1)) two times per day. She responded well with excellent regrowth of hair on the scalp, and prednisone was tapered and ultimately discontinued. Importantly, her parents noted marked improvement in sense of well-being. Several months after discontinuing treatment, she developed hyperpigmentation on the trunk consistent with confluent and reticulated papillomatosis; she has several known risk factors for this disorder, but it is not clear if this is related to her previous treatment.

  1. Effects of powdered whole grapefruit and metoclopramide on the pharmacokinetics of cyclosporine in dogs.

    PubMed

    Radwanski, Noel E; Cerundolo, Rosario; Shofer, Frances S; Hanley, Michael J; Court, Michael H

    2011-05-01

    To determine whether oral administration of metoclopramide or a commercially available powdered whole grapefruit (PWG) nutraceutical in combination with cyclosporine enhances systemic availability of cyclosporine in dogs. 8 healthy mixed-breed dogs in part 1 and 6 of these 8 dogs in part 2. Cyclosporine pharmacokinetics were determined over the course of 24 hours after oral administration of cyclosporine (5 mg/kg) alone, cyclosporine with metoclopramide (0.3 to 0.5 mg/kg), cyclosporine with 2 g of PWG, or cyclosporine combined with both metoclopramide and 2 g of PWG by use of a Latin square crossover study with a 14-day washout period between treatments. Sixty days later, 6 of the 8 dogs were given 10 g of PWG followed by cyclosporine, and pharmacokinetic parameters were compared with those previously obtained after administration of cyclosporine alone. Although metoclopramide or coadministration of metoclopramide and 2 g of PWG had no effect on the pharmacokinetic parameters of cyclosporine, compared with results for cyclosporine alone, the higher (10-g) dose of PWG resulted in 29% faster mean time to maximal plasma cyclosporine concentration, 54% larger area under the curve, and 38% lower apparent oral clearance. Adjustment of the cyclosporine dose may not be needed when metoclopramide is coadministered orally to prevent common adverse effects of cyclosporine. Powdered whole grapefruit has the potential to reduce the required orally administered dose of cyclosporine but only when PWG is used in an amount (at least 10 g) that is currently not cost-effective.

  2. 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

  3. Cyclosporine-A induced neurotoxicity after renal transplantation.

    PubMed

    Derici, U; Arinsoy, T; Sindel, S; Tali, T; Leventoglu, A; Sert, S

    2001-06-01

    Cyclosporine-A is a highly potent immunosuppressive agent for solid organ transplantation, but has many side effects including nephrotoxicity, hypertension, gum hyperplasia, hepatotoxicity, and neurotoxicity. Neurotoxicity is a less known toxic effect. The pathogenesis of this effect is unclear. However, it has been postulated that hypomagnesemia, hypocholesterolemia, corticosteroids, and/or neurotoxic substances can induce this syndrome. Also, it has been suggested that the endothelial damage caused by Cyclosporine-A may contribute to neuropeptide-mediated ischemia in the brain and lead to the development of neurological symptoms. In this report, we present a case with reversible neurologic deficits whose symptoms returned to normal after the cessation of cyclosporine-A.

  4. Mechanism of action of cyclosporin in rheumatoid arthritis.

    PubMed

    Bentin, J

    1995-09-01

    Heterogenous population of cells, including macrophages, synoviocytes and lymphocytes play important roles in the immunopathogenesis of rheumatoid arthritis (RA). T cells, however, seem to be a common thread throughout the disease process. In inhibiting T lymphocytes, cyclosporin A presents a more selective form of therapy in RA. The immunosuppressive action of cyclosporin is primarily due to the inhibition of antigen/mitogen-induced secretion of lymphokines at the transcriptional level from T cell. The inhibition of Ca2(+)-dependent signaling pathways by cyclophilin-cyclosporin complexes in T cell appears to shut down lymphokine-gene transcription.

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

    SciTech Connect

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

    1988-08-01

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

  6. 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.

  7. TGF-β: the connecting link between nephropathy and fibrosis.

    PubMed

    Sutariya, Brijesh; Jhonsa, Dimple; Saraf, Madhusudan N

    2016-01-01

    Renal fibrosis is the usual outcome of an excessive accumulation of extracellular matrix (ECM) that frequently occurs in membranous and diabetic nephropathy. The result of renal fibrosis would be end-stage renal failure, which requires costly dialysis or kidney transplantation. Renal fibrosis typically results from chronic inflammation via production of several molecules, such as growth factors, angiogenic factors, fibrogenic cytokines, and proteinase. All of these factors can stimulate excessive accumulation of ECM components through epithelial to mesenchymal transition (EMT), which results in renal fibrosis. Among these, transforming growth factor-beta (TGF-β) is proposed to be the major regulator in inducing EMT. Besides ECM protein synthesis, TGF-β is involved in hypertrophy, proliferation, and apoptosis in renal cells. In particular, TGF-β is likely to be most potent and ubiquitous profibrotic factor acting through several intracellular signaling pathways including protein kinases and transcription factors. Factors that regulate TGF-β expression in renal cell include hyperglycemia, angiotensin II, advance glycation end products, complement activation (C5b-9), and oxidative stress. Over the past several years, the common understanding of the pathogenic factors that lead to renal fibrosis in nephropathy has improved considerably. This review will discuss the recent findings on the mechanisms and role of TGF-β in membranous and diabetic nephropathy.

  8. 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.

  9. 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

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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

  17. 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.

  18. Cyclosporine and tacrolimus for the treatment of rheumatoid arthritis.

    PubMed

    Kitahara, Kanako; Kawai, Shinichi

    2007-05-01

    The calcineurin inhibitors cyclosporine and tacrolimus are important treatments for patients with active rheumatoid arthritis, especially in cases of resistance or intolerance to methotrexate or other disease-modifying antirheumatic drugs. Here, we discuss the mechanism, efficacy and safety of cyclosporine and tacrolimus in the treatment of rheumatoid arthritis. Recent clinical trials of cyclosporine have shown the advantages of its combination with methotrexate, glucocorticoids and leflunomide in the treatment of active rheumatoid arthritis. In Japan, tacrolimus monotherapy was found to be quite effective and combination therapy with methotrexate had positive results in an American study. The inhibitory effects of both drugs not only on T lymphocytes, but also on human osteoclast formation, have been demonstrated in basic studies. Cyclosporine and tacrolimus are clinically available disease-modifying antirheumatic drugs. Numerous clinical studies have shown the usefulness of these calcineurin inhibitors in monotherapy and also when combined with methotrexate. Although these drugs have similar effects, there are some differences in adverse reactions.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. Effects of Nigella sativa and Lepidium sativum on cyclosporine pharmacokinetics.

    PubMed

    Al-Jenoobi, F I; Al-Suwayeh, S A; Muzaffar, Iqbal; Alam, Mohd Aftab; Al-Kharfy, Khalid M; Korashy, Hesham M; Al-Mohizea, Abdullah M; Ahad, Abdul; 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 C(max) and AUC(0-∞) 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 C(max) of cyclosporine, although its absorption was significantly delayed compared with control group. A remarkable change was observed in T(max) and AUC(0-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.

  4. Topical cyclosporine A 0.05% for recurrent anterior uveitis.

    PubMed

    Prabhu, Shreya S; Shtein, Roni M; Michelotti, Monica M; Cooney, Theresa M

    2016-03-01

    To evaluate the effectiveness of treatment with cyclosporine A 0.05% eye drops in reducing frequency and severity of recurrences in patients with recurrent anterior uveitis. A retrospective case-crossover study was conducted by reviewing medical charts of patients treated for recurrent anterior uveitis between 2002 and 2011 at the Kellogg Eye Center by one cornea specialist. We identified patients who had been treated with topical cyclosporine A 0.05% and recorded data regarding demographics, episodes of anterior uveitis, severity of episodes and treatment modalities before and after initiation of cyclosporine A 0.05%. Eight patients were identified as having been treated with topical cyclosporine 0.05% in addition to standard treatment with an average follow-up of 54.9±33.9 months (range: 28-143 months). The patients had statistically significant fewer episodes of anterior uveitis, shorter duration of episodes and fewer total days of inflammation per year while on topical cyclosporine 0.05%. This study showed improvement of recurrent anterior uveitis in patients while on conventional treatment with cyclosporine A 0.05% compared with conventional treatment alone. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/

  5. Administration diluents differentiate Neoral from a generic cyclosporine oral solution.

    PubMed

    Kovarik, John M; Barilla, Denise; McMahon, Louis; Wang, Yibin; Kisicki, James; Schmouder, Robert

    2002-08-01

    A non-microemulsion cyclosporine oral solution was recently recalled from the market because of the lack of bioequivalence when administered with apple juice compared with water as the diluent. This open-label, randomized, two-period, crossover study assessed the effect of apple juice on Neoral, a microemulsion cyclosporine oral solution. The study enrolled 34 subjects who received 180 mg Neoral oral solution diluted in 200 mL tap water or apple juice. Cyclosporine was measured in whole blood by a liquid chromatography method. Pharmacokinetic parameters were compared by standard bioequivalence tests. With water vs. apple juice, cyclosporine Cmax was 1263 +/- 203 vs. 1191 +/- 225 ng/mL and AUC was 4714 +/- 1117 vs. 4788 +/- 1320 ng h/mL, respectively. Bioequivalence was demonstrated for both parameters. These data were comparable with those from a previous study in which subjects received 180 mg Neoral oral solution with orange juice. Cyclosporine bioavailability is unaltered when Neoral is administered diluted in apple juice or orange juice compared with tap water which conforms to the cyclosporine product label.

  6. 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

  7. The treatment of bovine collagen allergy with cyclosporin.

    PubMed

    Baumann, L S; Kerdel, F

    1999-03-01

    Bovine collagen is currently the most common substance used in soft-tissue augmentation. Although patients should undergo routine skin testing for allergy to bovine collagen prior to treatment, hypersensitivity reactions may rarely still occur. Previously, there have been no reliable methods of treatment for these reactions, and physicians could only reassure patients that the reaction would slowly disappear. OBJECTIVE. The use of oral cyclosporin in a patient with hypersensitivity to bovine collagen was evaluated. A patient with an allergic reaction to implanted bovine collagen was started on cyclosporin 175 mg p.o. bid (5 mg/kg/day) after no improvement was seen after treatment with oral and topical steroids. The cyclosporin was started on Day 23 of the allergic reaction. Improvement in the itching and redness was noted by Day 28 of the allergic reaction, and complete clinical resolution of the allergic reaction was noted on Day 41. On Day 47, the cyclosporin was stopped without recurrence of symptoms. The patient did not experience side effects from cyclosporin, and her blood pressure and renal function remained normal. This case report shows that oral cyclosporin A may be a safe and effective treatment for bovine collagen hypersensitivity.

  8. 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

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. 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.

  15. Spectrum of LMX1B mutations: from nail-patella syndrome to isolated nephropathy.

    PubMed

    Harita, Yutaka; Kitanaka, Sachiko; Isojima, Tsuyoshi; Ashida, Akira; Hattori, Motoshi

    2016-07-23

    Nail-patella syndrome (NPS) is an autosomal-dominant disease caused by LMX1B mutations and is characterized by dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. Renal involvement is the major determinant of the prognosis for NPS. Patients often present with varying degrees of proteinuria or hematuria, and can occasionally progress to chronic renal failure. Recent genetic analysis has found that some mutations in the homeodomain of LMX1B cause isolated nephropathy without nail, patellar or skeletal abnormality (LMX1B-associated nephropathy). The classic term "nail-patella syndrome" would not represent disease conditions in these cases. This review provides an overview of NPS, and highlights the molecular genetics of NPS nephropathy and LMX1B-associated nephropathy. Our current understanding of LMX1B function in the pathogenesis of NPS and LMX1B-associated nephropathy is also presented, and its downstream regulatory networks discussed. This recent progress provides insights that help to define potential targeted therapeutic strategies for LMX1B-associated diseases.

  16. 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.

  17. 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.

  18. 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.

  19. Correction of Postkidney Transplant Anemia Reduces Progression of Allograft Nephropathy

    PubMed Central

    Kamar, Nassim; Dussol, Bertrand; Etienne, Isabelle; Cassuto-Viguier, Elisabeth; Toupance, Olivier; Glowacki, François; Moulin, Bruno; Lebranchu, Yvon; Touchard, Guy; Jaureguy, Maïté; Pallet, Nicolas; Le Meur, Yannick; Rostaing, Lionel; Martinez, Frank

    2012-01-01

    Retrospective studies suggest that chronic allograft nephropathy might progress more rapidly in patients with post-transplant anemia, but whether correction of anemia improves renal outcomes is unknown. An open-label, multicenter, randomized controlled trial investigated the effect of epoetin-β to normalize hemoglobin values (13.0–15.0 g/dl, n=63) compared with partial correction of anemia (10.5–11.5 g/dl, n=62) on progression of nephropathy in transplant recipients with hemoglobin <11.5 g/dl and an estimated creatinine clearance (eCrCl) <50 ml/min per 1.73 m2. After 2 years, the mean hemoglobin was 12.9 and 11.3 g/dl in the normalization and partial correction groups, respectively (P<0.001). From baseline to year 2, the eCrCl decreased by a mean 2.4 ml/min per 1.73 m2 in the normalization group compared with 5.9 ml/min per 1.73 m2 in the partial correction group (P=0.03). Furthermore, fewer patients in the normalization group progressed to ESRD (3 versus 13, P<0.01). Cumulative death-censored graft survival was 95% and 80% in the normalization and partial correction groups, respectively (P<0.01). Complete correction was associated with a significant improvement in quality of life at 6 and 12 months. The number of cardiovascular events was low and similar between groups. In conclusion, this prospective study suggests that targeting hemoglobin values ≥13 g/dl reduces progression of chronic allograft nephropathy in kidney transplant recipients. PMID:22193388

  20. 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.

  1. 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

  2. Use of cyclosporine in thoracic transplantation.

    PubMed

    Zuckermann, A; Klepetko, W

    2004-03-01

    The use of cyclosporine (CyA) in clinical thoracic transplantation has markedly improved the survival and quality of life of patients in the past 2 decades. In the mid-1990s a significant advance in formulation design took place with the introduction of Neoral. This new microemulsion formulation of CyA demonstrates reduced intersubject and intrasubject variability in absorption and improved oral bioavailability compared with the oil-based CyA formulation. Moreover, C2 measurements of CyA could result in an even better method to avoid overimmunosuppression. On the other hand, generic alternatives of CyA could potentially reduce costs to transplant recipients as well as to the general community. Since the initiation of tacrolimus, mycophenolate mofetil, and rapamycin, slow but expanding variations of immunosuppressive protocols have taken place. Transplantation medicine is thus becoming an increasingly exciting and innovative field, in which CyA continues to play a central role as the core immunosuppressant of choice for the majority of patients.

  3. 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.

  4. Cyclosporin in Cell Therapy for Cardiac Regeneration

    PubMed Central

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

    2015-01-01

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

  5. [Testament's ability in Balkan endemic nephropathy].

    PubMed

    Novaković, Milan

    2009-01-01

    Testament is a solemn, authentic instrument in writing, by which a person declares his or her will as to disposal of his or her estate, and it has a psychopathological, lawful and ethical importance to a person, family and society. The aim of the study was to assess if the ability to make a testament was more damaged in patients with Balkan Endemic Nephropathy (BEN) than in patients with other diseases that resulted in Chronic Renal Failure in Bosnia and Herzegovina in the period from the 1st January 2001 to 31st December 2006. The 753 respondents were divided into two groups in the study: BEN group (n=150) and control group made of patients with other diseases resulting in CRF (n=150). In a multicentric longitudinal study we used: adapted questionnaire from the Renal Register of Bosnia and Herzegovina, Hamilton Depression Rating Scale, and Mini-Mental State Examination. Descriptive analysis, discriminative function and regression model have been done statistically. In BEN group, heirs are mostly mentioned - 84.0% (t=14.391; P=0.001), and in control group: heirs - 66.6%, relatives - 43.3% (t=7.751; P=0.003), carers - 44.0% (t= 6.678 P=0.032), and institutions 10.0% (t=5.147, P=0.061). The discriminative function shows differences between BEN and control group: canonical correlation (rc) =0.827, Wilkinson lambda (lambda nj) =0.871, Chi-square test =141.575 and significance (P=0.001). The regression course of the analysis can be used for prediction of the ability to make testament for the patients on dialysis. [y=-0.95x + 15.715, and OR = 0.785, (95%) for CI = -0.997 - -0.375); Can Fanc r2=0.861: Significance is P=0.002]. The ability to make a testament is more damaged in patients from the nephropathy group than in the patients from the control group who are on dialysis in Bosnia and Herzegovina. This has been confirmed by socio-demographic and psychological parameters, and it is very important for preservation of the ethic norms of the patients on dialysis

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  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. 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

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

    PubMed Central

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

    2016-01-01

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

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

    PubMed

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

    2016-01-01

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

  15. 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

  16. 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

  17. 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

  18. Patient Age and the Prognosis of Idiopathic Membranous Nephropathy

    PubMed Central

    Yamaguchi, Makoto; Ando, Masahiko; Yamamoto, Ryohei; Akiyama, Shinichi; Kato, Sawako; Katsuno, Takayuki; Kosugi, Tomoki; Sato, Waichi; Tsuboi, Naotake; Yasuda, Yoshinari; Mizuno, Masashi; Ito, Yasuhiko; Matsuo, Seiichi; Maruyama, Shoichi

    2014-01-01

    Background Idiopathic membranous nephropathy (IMN) is increasingly seen in older patients. However, differences in disease presentation and outcomes between older and younger IMN patients remain controversial. We compared patient characteristics between younger and older IMN patients. Methods We recruited 171 Japanese patients with IMN, including 90 (52.6%) patients <65 years old, 40 (23.4%) patients 65–70 years, and 41 (24.0%) patients ≥71 years. Clinical characteristics and outcomes were compared between younger and older IMN patients. Results During a median observation period of 37 months, 103 (60.2%) patients achieved complete proteinuria remission, which was not significantly associated with patient age (P = 0.831). However, 13 (7.6%) patients were hospitalized because of infection. Multivariate Cox proportional hazards models identified older age [adjusted hazard ratio (HR) = 3.11, 95% confidence interval (CI): 1.45–7.49, per 10 years; P = 0.003], prednisolone use (adjusted HR = 11.8, 95% CI: 1.59–242.5; P = 0.014), and cyclosporine used in combination with prednisolone (adjusted HR = 10.3, 95% CI: 1.59–204.4; P = 0.012) as significant predictors of infection. A <25% decrease in proteinuria at 1 month after immunosuppressive therapy initiation also predicted infection (adjusted HR = 6.72, 95% CI: 1.51–37.8; P = 0.012). Conclusions Younger and older IMN patients had similar renal outcomes. However, older patients were more likely to develop infection when using immunosuppressants. Patients with a poor response in the first month following the initiation of immunosuppressive therapy should be carefully monitored for infection and may require a faster prednisolone taper. PMID:25330372

  19. CADAVERIC RENAL TRANSPLANTATION UNDER CYCLOSPORINE-STEROID THERAPY

    PubMed Central

    Rosenthal, J. Thomas; Hakala, Thomas R.; Iwatsuki, Shunzaburo; Shaw, Byers W.; Starzl, Thomas E.

    2009-01-01

    The first clinical trials of renal transplantation with cyclosporine therapy were reported four years ago by Calne and associates (1, 2) who recommended from their experience that the drug should be used alone. In our own pilot trials (3, 4), the alternative was developed of combining cyclosporine with steroid therapy which was administered in large doses on the day of the operation and rapidly reduced to relatively low maintenance levels. Although the results were encouraging, they were not conclusive since there were no patients for comparison who were treated during the same period with conventional immunosuppression. We report herein upon a second trial of cadaveric renal transplantation, in which the results using cyclosporine-steroid therapy for primary cadaveric transplantation could be compared with those in patients treated contemporaneously with azathioprine and prednisone. Experience was also acquired with patients who underwent cadaveric retransplantation. PMID:6353643

  20. 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

  1. 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.

  2. Cyclosporine Amicellar delivery system for dry eyes.

    PubMed

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

    2016-01-01

    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. 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. 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. The results of this study indicate the potential use of a novel MS for the ophthalmic delivery of CsA in treating dry eyes.

  3. 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

  4. 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.

  5. [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.

  6. Cyclosporine and mycophenolate mofetil 48 hours before renal transplantation enables the use of low cyclosporine doses and achieves better graft function.

    PubMed

    Maamoun, H; Soliman, A; Zayed, B

    2010-12-01

    Reducing calcineurin-inhibitor induced nephrotoxicity and simultaneously avoiding long-term side effects are desirable goals in renal transplantation. We examined the hypothesis that administration of cyclosporine and mycophenolate mofetil (MMF) 48 hours before renal transplantation allows reduction in the target cyclosporine C2 concentration, thus decreasing toxicity and improving graft function. We enrolled 80 kidney recipients in a single-center study comparing 2 cyclosporine-based protocols. Group I patients (n = 40) received a standard dose of cyclosporine (blood cyclosporine C2, 800-1500 ng/mL) with MMF and standard doses of corticosteroids. Group II patients (n = 40) were treated with a low dose of cyclosporine (blood cyclosporine C2, 450-800 ng/mL) and MMF plus low doses of corticosteroids after induction 48 hours before surgery with cyclosporine and MMF. Patient (97.5% vs 100%) and graft survivals (92.5% vs 95%) at 1 year were not different between the groups, although patients in group II experienced significantly fewer acute rejection episodes (10% vs 30%; P < .01). Delayed graft function occurred less often among group I than group II (17.5 vs 20%), but the difference was not significant. Graft function at 1 year was significantly better among group II (serum creatinine 1.31 vs 1.64 mg/dL and creatinine clearance 63 mL/min versus 47 mL/min; P < .05). We concluded that administration of cyclosporine and MMF 48 hours before renal transplantation allowed the safe effective use of low target C2 cyclosporine concentrations, enabling an early decrease in cyclosporine dose. These preliminary results indicated better 1-year graft function compared with the normal cyclosporine dose regimen. Copyright © 2010 Elsevier Inc. All rights reserved.

  7. 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

  8. Prophylactic hydration to prevent contrast-induced nephropathy: much ado about nothing?

    PubMed

    Wyatt, Christina M; Camargo, Marianne; Coca, Steven G

    2017-07-01

    Clinical guidelines recommend prophylactic hydration to reduce the risk of contrast-induced nephropathy in high-risk patients, including those with chronic kidney disease. A recent single-center randomized trial showed no significant difference in the incidence of contrast-induced nephropathy in ambulatory patients with stage 3 chronic kidney disease who were randomized to no prophylactic hydration versus normal saline hydration. While these results may identify patients who are less likely to benefit from prophylactic hydration, nephrologists and interventionalists should carefully consider the generalizability of these results to individual patients. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

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

    PubMed

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

    2006-09-01

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

  10. Suppression of hepatitis C virus replication by cyclosporin a is mediated by blockade of cyclophilins.

    PubMed

    Nakagawa, Mina; Sakamoto, Naoya; Tanabe, Yoko; Koyama, Tomoyuki; Itsui, Yasuhiro; Takeda, Yoshie; Chen, Cheng-Hsin; Kakinuma, Sei; Oooka, Shinya; Maekawa, Shinya; Enomoto, Nobuyuki; Watanabe, Mamoru

    2005-09-01

    Cyclosporin A specifically suppresses hepatitis C virus (HCV) replication in vitro at clinically achievable concentrations. In this study, we investigated the mechanisms of action of cyclosporin A against HCV replication. The in vitro effects of cyclosporin A on HCV replication were analyzed using an HCV replicon system that expresses chimeric luciferase reporter protein. The significant effects of cyclosporin A on expression of an HCV replicon and the absence of such effects of FK506, which shares mechanisms of action with cyclosporin A, suggested the involvement of intracellular ligands of cyclosporin A, the cyclophilins. Transient and stable knockdown of the expression of cytoplasmic cyclophilins A, B, and C by short hairpin RNA-expressing vectors suppressed HCV replication significantly. A cyclosporin analogue, cyclosporin D, which lacks immunosuppressive activity but exhibits cyclophilin binding, induced a similar suppression of HCV replication. Furthermore, cyclosporin A treatment of Huh7 cells induced an unfolded protein response exemplified by expression of cellular BiP/GRP78. Treatment of cells with thapsigargin and mercaptoethanol, which induce the unfolded protein responses, suppressed HCV replication, suggesting that the cyclosporin-induced unfolded protein responses might contribute to the suppression of HCV protein processing and replication. The anti-HCV activity of cyclosporin A is mediated through a specific blockade of cyclophilins, and these molecules may constitute novel targets for anti-HCV therapeutics.

  11. Co-administration of cyclosporine and ticagrelor may lead to a higher exposure to cyclosporine: a case report of a 49-year old man.

    PubMed

    van Sloten, T T; de Klaver, P A G; van den Wall Bake, A W L

    2017-09-11

    A drug interaction leading to higher exposure to cyclosporine DRUGS IMPLICATED: Cyclosporine and ticagrelor THE PATIENT: A 49-year old man with a stable renal graft, managed with cyclosporine with stable trough blood concentrations for several years, was treated with ticagrelor for unstable angina pectoris EVIDENCE THAT LINKS THE DRUG TO THE EVENT: The timeline was consistent with the appearance of an interaction, the interaction was confirmed by an increase in trough concentration of cyclosporine, and there were no alternative causes that by themselves could have caused the increase in cyclosporine exposure MANAGEMENT: Cessation of ticagrelor MECHANISM: Inhibition of CYP3A4 and P-glycoprotein by ticagrelor IMPLICATIONS FOR THERAPY: Clinicians should be aware of this potential interaction as ticagrelor is frequently prescribed in individuals using cyclosporine. Close monitoring of cyclosporine serum concentrations is warranted to avoid overdosing of cyclosporine. A pharmacokinetic study is needed to further examine the probable interaction between cyclosporine and ticagrelor. This article is protected by copyright. All rights reserved.

  12. 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

  13. [Low cyclosporin levels induced by the brief use of rifampicin; immunosuppression may fail for several weeks].

    PubMed

    Valk-Swinkels, Corinne G H; Alidjan, Fazil; Rommers, Mirjam K; Bakker, René C; Swen, Jesse J; van 't Veer, Nils E

    2013-01-01

    Cyclosporin is an immunosuppressive agent with a wide range of therapeutic uses. In transplant patients, it is used for the prevention of rejection and graft-versus-host reactions. The metabolism and bioavailability of cyclosporin can be significantly and persistently influenced through induction of CYP3A4 caused by the concomitant use of rifampicin. However, awareness of the need for the timely and frequent monitoring of cyclosporin levels during and especially after treatment with rifampicin has not fully been addressed. Here, we describe 3 patient cases concerning significant episodes of sub-therapeutic cyclosporin levels after short-term rifampicin therapy. Rifampicin was administered for three to five days and decreased cyclosporin levels were observed ± 7 days after the initiation of rifampicin, and continued during the following weeks even after the cessation of rifampicin therapy. Cyclosporin dosage-adjustments were made based on the cyclosporin blood levels and all 3 patients showed good therapeutic and clinical responses.

  14. Clinical Evidence of Acute Mesoamerican Nephropathy.

    PubMed

    Fischer, Rebecca S B; Mandayam, Sreedhar; Chavarria, Denis; Vangala, Chandan; Garcia, Melissa N; Garcia, Linda L; Palma, Lesbia; Garcia, Felix; García-Trabanino, Ramón; Murray, Kristy O

    2017-07-17

    Mesoamerican nephropathy (MeN), an epidemic of unexplained kidney disease in Central America, affects mostly young, healthy individuals. Its etiology is a mystery that requires urgent investigation. Largely described as a chronic kidney disease (CKD), no acute clinical scenario has been characterized. An understanding of the early disease process could elucidate an etiology and guide treatment and prevention efforts. We sought to document the earliest clinical signs in patients with suspected MeN in a high-risk population in Nicaragua. Physicians at a local hospital identified suspect cases and documented clinical/laboratory data, demographics, and medical histories. Over a 1-year period, physicians identified 255 mostly young (median 29 years), male (89.5%) patients with elevated creatinine or reduced creatinine clearance. Mean serum creatinine (2.0 ± 0.6 mg/dL) revealed a 2-fold increase from baseline, and half had stage 2 or 3 acute kidney injury. Leukocyturia (98.4%), leukocytosis (81.4%), and neutrophilia (86.2%) predominated. Nausea (59.4%), back pain (57.9%), fever (54.6%), vomiting (50.4%), headache (47.3%), and muscle weakness (45.0%) were common. A typical case of acute MeN presented with elevated (or increased ≥ 0.3 mg/dL or ≥ 1.5-fold from baseline) creatinine, no hypertension or diabetes, leukocyturia, and at least two of fever, nausea or vomiting, back pain, muscle weakness, headache, or leukocytosis and/or neutrophilia. Rapid progression (median 90 days) to CKD was recorded in 8.5% of patients. This evidence can serve as the basis of a sensitive and urgently needed case definition for disease surveillance of early-stage, acute MeN.

  15. Contrast-induced nephropathy in interventional cardiology

    PubMed Central

    Sudarsky, Doron; Nikolsky, Eugenia

    2011-01-01

    Development of contrast-induced nephropathy (CIN), ie, a rise in serum creatinine by either ≥0.5 mg/dL or by ≥25% from baseline within the first 2–3 days after contrast administration, is strongly associated with both increased inhospital and late morbidity and mortality after invasive cardiac procedures. The prevention of CIN is critical if long-term outcomes are to be optimized after percutaneous coronary intervention. The prevalence of CIN in patients receiving contrast varies markedly (from <1% to 50%), depending on the presence of well characterized risk factors, the most important of which are baseline chronic renal insufficiency and diabetes mellitus. Other risk factors include advanced age, anemia, left ventricular dysfunction, dehydration, hypotension, renal transplant, low serum albumin, concomitant use of nephrotoxins, and the volume of contrast agent. The pathophysiology of CIN is likely to be multifactorial, including direct cytotoxicity, apoptosis, disturbances in intrarenal hemodynamics, and immune mechanisms. Few strategies have been shown to be effective to prevent CIN beyond hydration, the goal of which is to establish brisk diuresis prior to contrast administration, and to avoid hypotension. New strategies of controlled hydration and diuresis are promising. Studies are mixed on whether prophylactic oral N-acetylcysteine reduces the incidence of CIN, although its use is generally recommended, given its low cost and favorable side effect profile. Agents which have been shown to be ineffective or harmful, or for which data supporting routine use do not exist, include fenoldopam, theophylline, dopamine, calcium channel blockers, prostaglandin E1, atrial natriuretic peptide, statins, and angiotensin-converting enzyme inhibitors. PMID:21912486

  16. Contrast-induced nephropathy in interventional cardiology.

    PubMed

    Sudarsky, Doron; Nikolsky, Eugenia

    2011-01-01

    Development of contrast-induced nephropathy (CIN), ie, a rise in serum creatinine by either ≥0.5 mg/dL or by ≥25% from baseline within the first 2-3 days after contrast administration, is strongly associated with both increased inhospital and late morbidity and mortality after invasive cardiac procedures. The prevention of CIN is critical if long-term outcomes are to be optimized after percutaneous coronary intervention. The prevalence of CIN in patients receiving contrast varies markedly (from <1% to 50%), depending on the presence of well characterized risk factors, the most important of which are baseline chronic renal insufficiency and diabetes mellitus. Other risk factors include advanced age, anemia, left ventricular dysfunction, dehydration, hypotension, renal transplant, low serum albumin, concomitant use of nephrotoxins, and the volume of contrast agent. The pathophysiology of CIN is likely to be multifactorial, including direct cytotoxicity, apoptosis, disturbances in intrarenal hemodynamics, and immune mechanisms. Few strategies have been shown to be effective to prevent CIN beyond hydration, the goal of which is to establish brisk diuresis prior to contrast administration, and to avoid hypotension. New strategies of controlled hydration and diuresis are promising. Studies are mixed on whether prophylactic oral N-acetylcysteine reduces the incidence of CIN, although its use is generally recommended, given its low cost and favorable side effect profile. Agents which have been shown to be ineffective or harmful, or for which data supporting routine use do not exist, include fenoldopam, theophylline, dopamine, calcium channel blockers, prostaglandin E(1), atrial natriuretic peptide, statins, and angiotensin-converting enzyme inhibitors.

  17. Nephroprotective Effects of Metformin in Diabetic Nephropathy.

    PubMed

    Ravindran, Sreenithya; Kuruvilla, Vinitha; Wilbur, Kerry; Munusamy, Shankar

    2017-04-01

    Metformin, a well-known anti-diabetic agent, is very effective in lowering blood glucose in patients with type 2 diabetes with minimal side-effects. Metformin is also being recommended in the treatment of obesity and polycystic ovary syndrome. Metformin elicits its therapeutic effects mainly via activation of AMP-activated kinase (AMPK) pathway. Renal cells under hyperglycemic or proteinuric conditions exhibit inactivation of cell defense mechanisms such as AMPK and autophagy, and activation of pathologic pathways such as mammalian target of rapamycin (mTOR), endoplasmic reticulum (ER) stress, epithelial-to-mesenchymal transition (EMT), oxidative stress, and hypoxia. As these pathologic pathways are intertwined with AMPK signaling, the potential benefits of metformin therapy in patients with type 2 diabetes would extend beyond its anti-hyperglycemic effects. However, since metformin is eliminated unchanged through the kidneys and some studies have shown the incidence of lactic acidosis with its use during severe renal dysfunction, the use of metformin was contraindicated in patients with renal disease until recently. With more studies indicating the relatively low incidence of lactic acidosis and revealing the additional benefits with metformin therapy, the US FDA has now approved metformin to be administered in patients with established renal disease based on their renal function. The purpose of this review is to highlight the various mechanisms by which metformin protects renal cells that have lost its functionality in a diabetic or non-diabetic setting and to enlighten the advantages and therapeutic potential of metformin as a nephroprotectant for patients with diabetic nephropathy and other non-diabetic forms of chronic kidney disease. J. Cell. Physiol. 232: 731-742, 2017. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. 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.

  19. Antiphospholipid syndrome (APS) nephropathy in catastrophic, primary, and systemic lupus erythematosus-related APS.

    PubMed

    Tektonidou, Maria G; Sotsiou, Flora; Moutsopoulos, Haralampos M

    2008-10-01

    Renal involvement in antiphospholipid syndrome (APS) has been poorly recognized. A renal small-vessel vasculopathy, defined as APS nephropathy, has recently been observed in small series of patients with primary APS (PAPS) and systemic lupus erythematosus (SLE)-APS. We examined the renal histologic, clinical, and laboratory characteristics of different groups of patients with APS including catastrophic APS (CAPS). Our study included all CAPS (n=6), PAPS (n=8), and SLE-APS (n=23) patients with biopsy-proven renal involvement who were referred to our departments. The kidney biopsy specimens were retrospectively examined by the same renal pathologist. APS nephropathy was diagnosed as previously described. Demographic, clinical, and laboratory data were recorded. All patients with CAPS had acute and chronic renal vascular lesions compatible with diagnosis of APS nephropathy. Thrombotic microangiopathy (TMA), the acute lesion, was observed in all CAPS patients. Fibrous intimal hyperplasia of interlobular arteries (FIH) and focal cortical atrophy (FCA) were the most common chronic vascular lesions, occurring in 4 of 6 (66.7%) and 3 of 6 (50%) patients with CAPS, respectively. TMA was detected in 3 of 8 (37.5%) patients with PAPS and in 8 of 23 (35%) patients with SLE-APS, while FIH and FCA were found with similar frequencies in all 3 groups. Hypertension, proteinuria, hematuria, and renal insufficiency were the most common renal manifestations of all APS groups. Acute and chronic APS nephropathy lesions were detected in all 3 APS groups. Acute lesions were more prominent in CAPS, while chronic lesions were found with similar frequencies in all groups. Hypertension, proteinuria, hematuria, and renal insufficiency were the most common renal manifestations of all APS groups.

  20. 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.

  1. 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 § 862...

  2. 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.

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

    PubMed

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

    2015-04-01

    The aim of this study was to investigate the effect of pomelo pulp on the pharmacokinetics of cyclosporine in healthy male Thai volunteers. The study design was an open-label, randomized, single dose, crossover study with a 2-week washout period. A single oral dose of 2 × 100 mg cyclosporine was administered with 200 mL of water. Each subject received 250 g of pomelo pulp or 250 mL of water 1 hour before drug administration and once again 10 minutes following drug administration. Blood samples were collected over a 24 hour period. The point estimates (90% confidence intervals) of the test/control ratio using logarithmic transformed data for the area under the curve (AUC) for blood concentration from time 0 to infinity (AUC(0- ∞)) and the observed maximum concentration (C(max)) were 128.8% (120.6-137.6) and 136.1% (126.0-146.8), respectively. These 90% confidence intervals were higher than the accepted bioequivalence range defined by the European Medicines Agency guidelines for narrow therapeutic index drugs (90%-111% for AUC and 80%-125% for C(max)). However, the apparent terminal half-life (t(1/2)) was not significantly different. In conclusion, co-administration of cyclosporine and pomelo pulp increased the relative bioavailability of cyclosporine. © 2014, The American College of Clinical Pharmacology.

  4. Successful treatment of metastatic Crohn's disease with cyclosporine.

    PubMed

    Carranza, Dafnis C; Young, Lorraine

    2008-08-01

    Metastatic Crohn's disease refers to cutaneous granulomatous lesions that are noncontiguous to the gastrointestinal tract. The treatment of cutaneous Crohn's disease is challenging. A patient with metastatic Crohn's disease whose lesions cleared after a 3-month course of cyclosporine is reported.

  5. 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 § 862...

  6. 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 § 862...

  7. 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 § 862...

  8. 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 § 862...

  9. 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.

  10. 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.

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

    PubMed Central

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

    2015-01-01

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

  12. 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.

  13. 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.

  14. 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.

  15. 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

  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. 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

  18. 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

  19. Tacrolimus and cyclosporine have differential effects on the risk of development of bronchiolitis obliterans syndrome: results of a prospective, randomized international trial in lung transplantation.

    PubMed

    Treede, Hendrik; Glanville, Allan R; Klepetko, Walter; Aboyoun, Christina; Vettorazzi, Eik; Lama, Raffael; Bravo, Carlos; Knoop, Christiane; Aubert, John-David; Reichenspurner, Hermann

    2012-08-01

    Chronic lung allograft dysfunction, which manifests as bronchiolitis obliterans syndrome (BOS), is recognized as the primary cause of morbidity and mortality after lung transplantation. In this study we assessed the efficacy and safety of two de novo immunosuppression protocols to prevent BOS. Our study approach was a multicenter, prospective, randomized (1:1) open-label superiority investigation of de novo tacrolimus vs cyclosporine, with both study arms given mycophenolate mofetil and prednisolone after lung transplantation. Cytolytic induction therapy was not employed. Patients were stratified at entry for cystic fibrosis. Primary outcome was incidence of BOS 3 years after transplant (intention-to-treat analysis). Secondary outcomes were survival and incidence of acute rejection, infection and other adverse events. Group demographic data were well matched: 110 of 124 tacrolimus vs 74 of 125 cyclosporine patients were treated per protocol (p < 0.01 by chi-square test). Cumulative incidence of BOS Grade ≥1 at 3 years was 11.6% (tacrolimus) vs 21.3% (cyclosporine) (cumulative incidence curves, p = 0.037 by Gray's test, pooled over strata). Univariate proportional sub-distribution hazards regression confirmed cyclosporine as a risk for BOS (HR 1.97, 95% CI 1.04 to 3.77, p = 0.039). Three-year cumulative incidence of acute rejection was 67.4% (tacrolimus) vs 74.9% (cyclosporine) (p = 0.118 by Gray's test). One- and 3-year survival rates were 84.6% and 78.7% (tacrolimus) vs 88.6% and 82.8% (cyclosporine) (p = 0.382 by log-rank test). Cumulative infection rates were similar (p = 0.91), but there was a trend toward new-onset renal failure with tacrolimus (p = 0.09). Compared with cyclosporine, de novo tacrolimus use was found to be associated with a significantly reduced risk for BOS Grade ≥1 at 3 years despite a similar rate of acute rejection. However, no survival advantage was detected. Copyright © 2012 International Society for Heart and Lung Transplantation

  20. BK viremia and polyomavirus nephropathy in 352 kidney transplants; risk factors and potential role of mTOR inhibition.

    PubMed

    Jacobi, Johannes; Prignitz, Antonina; Büttner, Maike; Korn, Klaus; Weidemann, Alexander; Hilgers, Karl F; Heller, Katharina; Velden, Joachim; Knöll, Antje; Wullich, Bernd; May, Christoph; Eckardt, Kai-Uwe; Amann, Kerstin U

    2013-10-02

    Polyomavirus BK nephropathy (PyVAN) remains an important cause of early graft dysfunction and graft loss in kidney transplantation. In this retrospective, single centre cohort study we studied the incidence and outcome of BK viral infection in 352 patients transplanted in 2008-2011. During follow-up viral replication was detected in 48 patients (13.6%); 22 patients (6.2%) had biopsy proven PyVAN.In multivariate logistic regression analyses risk factors for BK-viremia were lack of enrolment into randomized controlled trials (RCTs), biopsy proven acute rejections, cytomegaly virus (CMV) serostatus of both donor and recipient and previous transplantation.In patients without PyVAN reduction or switch of immunosuppression was associated with rapid viral clearance and stable graft function. In contrast, in most patients with PyVAN graft function deteriorated and 5 patients prematurely lost their allograft. Switch of immunosuppression to a low dose cyclosporine plus mTOR inhibitor based regimen in patients with PyVAN was safe, well tolerated and tended to be associated with a better short-term outcome in terms of graft function compared to reduction of existing immunosuppression alone. With the lack of licensed anti-polyoma viral drugs reduction or conversion of immunosuppression remains the mainstay of therapy in patients with PyVAN. The combination of low dose cyclosporine plus mTOR inhibition appears to be safe and warrants further investigation.

  1. Diabetic nephropathy. Prevention and early referral.

    PubMed Central

    Pylypchuk, G.; Beaubien, E.

    2000-01-01

    OBJECTIVE: To review the clinical and pathophysiologic features of diabetic nephropathy and to examine evidence supporting primary, secondary, and tertiary treatment strategies. QUALITY OF EVIDENCE: The medical literature provides both level 1 and level 2 evidence on treatment of diabetic nephropathy, including randomized controlled trials, well-designed clinical trials without randomization, consensus papers, and cohort and case-control analytic studies. MAIN MESSAGE: Diabetes is the most common cause of end-stage renal failure in Canada and the United States, and both diabetes and its renal complications are increasing. Diabetic nephropathy, in both type 1 and type 2 diabetes, usually progresses through five stages. Treatment and prevention strategies depend on stage of disease. Primary prevention includes addressing hyperglycemia, hypertension, and smoking. Secondary prevention adds angiotensin-converting enzyme inhibitors, cholesterol lowering, and perhaps restrictions on dietary protein. Tertiary care, including dialysis or transplantation, is generally managed by nephrologists, but family physicians continue to play an important role in the care of these patients. CONCLUSIONS: Diabetic nephropathy is a serious cause of morbidity and mortality for patients with type 1 and type 2 diabetes. To reduce end-stage diabetic nephropathy and its complications, both specialists and family physicians need to focus efforts on primary and secondary prevention strategies. PMID:10752002

  2. 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.

  3. Pan-European survey of the topical ocular use of cyclosporine A.

    PubMed

    Labbé, A; Baudouin, C; Ismail, D; Amrane, M; Garrigue, J-S; Leonardi, A; Figueiredo, F C; Van Setten, G; Labetoulle, M

    2017-03-01

    To assess medical practices surrounding the use of topical ocular cyclosporine A across European Union nations. Key stakeholders (ophthalmologists, hospital pharmacists, regulatory health authorities) from European Union member states were interviewed by telephone using a semi-structured, open-ended questionnaire. Ophthalmologists responded to questions about practice patterns of cyclosporine A use (prescription frequency, indication, dosage), pharmacists about cyclosporine A formulations (composition, manufacturing process, quality control, distribution), and the regulatory authorities about market authorization and pharmacovigilance for various cyclosporine A products. Over the years, cyclosporine A use for ophthalmic indications has increased across all European Union nations. Prevalence of cyclosporine A use was heterogeneous, with Belgium, France, Germany, Italy, Portugal, Spain and the United Kingdom reporting the highest frequency. Compounded cyclosporine A formulations and other cyclosporine A products were prescribed through temporary authorization on a compassionate use or named-patient basis. Cyclosporine A was prescribed for dry eye disease, atopic and vernal keratoconjunctivitis, corneal graft rejection, and other autoimmune and inflammatory diseases. Concentrations of prescribed topical cyclosporine A ranged between 0.05-2% and formulations were instilled 1-6 times daily. Interviewed stakeholders expressed concern regarding, (1) paucity of product information, (2) lack of standardized manufacturing processes and quality control of cyclosporine A formulations, and (3) poor regulation and pharmacovigilance of ocular cyclosporine A-based products. Medical practice surrounding ocular cyclosporine A use in European Union nations differs based on variations in concentration, dosage, prescription indication, formulation, availability and distribution, manufacturing, quality, and regulatory monitoring. Copyright © 2017 Elsevier Masson SAS. All rights

  4. 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

  5. Non-ischemic cardiomyopathy after rituximab treatment for membranous nephropathy

    PubMed Central

    Cheungpasitporn, Wisit; Kopecky, Stephen L.; Specks, Ulrich; Bharucha, Kharmen; Fervenza, Fernando C.

    2017-01-01

    Rituximab is an anti-CD20 monoclonal antibody frequently used for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), and anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis. In addition, rituximab has recently been increasingly used as an off-label treatment in a number of inflammatory and systemic autoimmune diseases. It is advised that rituximab infusion may cause infusion reactions and adverse cardiac effects including arrhythmia and angina, especially in patients with prior history of cardiovascular diseases. However, its detailed cardiotoxicity profile and effects on cardiac function were not well described. We report a 51-year-old man who developed non-ischemic cardiomyopathy after rituximab treatment for membranous nephropathy. The patient experienced reduced cardiac functions within 48 hours after the initial infusion, which remained markedly reduced at 9-month follow-up. As the utility of rituximab expands, physicians must be aware of this serious cardiovascular adverse effect. PMID:28487867

  6. Diabetic nephropathy among Mexican Americans

    PubMed Central

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

    2012-01-01

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

  7. 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.

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

    PubMed Central

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

    2015-01-01

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

  9. 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

  10. 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.

  11. Behcet's disease and IgA nephropathy.

    PubMed

    Altay, Mustafa; Secilmis, Sema; Unverdi, Selman; Ceri, Mevlut; Duranay, Murat

    2012-07-01

    Although Behçet's disease (BD) is a kind of systemic disease, renal involvement is rare, especially IgA nephropathy (IgAN). Renal manifestations in BD range from mild urinary abnormalities to glomerulonephritis with persistent renal failure, which includes minimal change disease, proliferative glomerulonephritis, rapidly crescentic glomerulonephritis, renal amyloidosis and IgA nephropathy. Amyloidosis seems to be the most common type of renal lesion in BD, and several cases of nephrotic syndrome secondary to amyloidosis have been documented. Co-occurrence of BD and IgA nephropathy has only been reported in only few cases. We describe two patients with the rare association of BD and IgAN. We suggested that it is important to periodically perform renal function assessment in patients with BD, through urinalysis and measurement of serum creatinine for detecting any abnormality and providing an early adequate treatment.

  12. 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.

  13. 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

  14. 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

  15. [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.

  16. Diabetic nephropathy is an independent factor associated to severe subclinical atheromatous disease.

    PubMed

    Barrios, Clara; Pascual, Julio; Otero, Sol; Soler, Maria J; Rodríguez, Eva; Collado, Silvia; Faura, Anna; Mojal, Sergi; Navarro-González, Juan F; Betriu, Angels; Fernandez, Elvira; Valdivielso, Jose M

    2015-09-01

    Atheromatous disease (AD) is a risk factor for death in renal patients. Traditional CV risk factors do not predict the presence of AD in this population. The aim of this study is to analyze whether the etiology of the primary renal disease influences in the risk of having silent AD. Observational cross-sectional study in chronic kidney disease patients without previous cardiovascular events. 2436 CKD subjects without any previous CV event included in the prospective Spanish multicenter NEFRONA study. Patients were classified according to primary renal disease: diabetic nephropathy (n = 347), vascular nephropathy (n = 476), systemic/glomerular disease (n = 447), tubulointerstitial and drug toxicity nephropathy (n = 320), polycystic kidney disease (n = 238), non-filiated nephropathy (n = 406) and other causes (n = 202). B-mode and Doppler ultrasonography analysis of the carotid arteries were performed to measure intima media thickness (IMT) and the presence of plaques. Clinical and laboratory parameters related to CV risk were also determined. AD was scored according with the ultrasonography findings and the ankle-brachial index into two large groups: absence or incipient AD and severe AD. In multivariate regression analysis, older age (OR 1.09/year [1.088-1.108]), smoking habit (OR 2.10 [1.61-2.74]), male gender (OR 1.33 [1.09-1.64]), grade-5D of CKD (OR 2.19 [1.74-2.74]), and diabetic nephropathy (OR 2.59 [1.93-3.48]) are independent risk factors for severe AD. The prevalence of silent AD was highest for diabetic nephropathy with grade-5D of CKD (82.2%) and lowest with stages 2-3 CKD systemic/glomerular disease (36.6%). Observational study with the potential for confounding. In CKD patients without any CV event in the background clinical history, diabetic nephropathy as primary renal disease is the most significant factor associated to severe silent AD. Furthermore, this difference was independent of other conventional risk factors for atherosclerosis and CV events

  17. 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.

  18. [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.

  19. 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

  20. CT and MRI findings of cyclosporine-related encephalopathy and hypertensive encephalopathy.

    PubMed

    Yamamoto, Akira; Hayakawa, Katsumi; Houjyou, Makoto

    2002-05-01

    We present the MRI and CT findings of one child with cyclosporine-related encephalopathy, and one child with hypertensive encephalopathy following cyclosporine-related encephalopathy. The imaging findings were shown well on T2-weighted and fluid-attenuated inversion recovery (FLAIR) MR images. Cyclosporine-related encephalopathy was distributed predominantly in the posterior white matter. Hypertensive encephalopathy showed similar changes of CT attenuation, but with wider distribution. These two disorders seem to have the same pathogenesis.

  1. 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

  2. The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster.

    PubMed

    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

    2013-06-01

    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

  3. 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

  4. 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

  5. Management of Cyclosporine and Nifedipine-Induced Gingival Hyperplasia.

    PubMed

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

    2015-12-01

    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.

  6. [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.

  7. Focus on five patients treated with cyclosporine up to 62 months.

    PubMed

    Bardazzi, Federico; Magnano, Michela; Balestri, Riccardo; Patrizi, Annalisa; Tengattini, Vera

    2016-10-01

    Cyclosporine is a validated treatment for moderate to severe psoriasis. Long-term cyclosporine administration may induce toxic effects. The duration of treatment usually ranges from 10 to 16 weeks. However, some patients may take cyclosporine for a longer time. The objective of the present study is to evaluate the dose, efficacy and safety in long-term cyclosporine therapy. We studied the hospital records of patients with psoriasis treated with cyclosporine between 1 January 2009, and 30 April 2015. We decided to focus on patients who, for different reasons, have continued cyclosporine for more than 2 years. Five patients (2.69%) had been assuming cyclosporine for up to 62 months and had achieved a substantial response with no toxic effects. All of them were concerned about recurrence and all patients had personal reasons to prefer Cyclosporine over other drugs, including: familiar history of neurodegenerative disease, desire for motherhood, easy availability on prescription, systemic scleroderma, belenophobia. Cyclosporine is an acceptable monotherapy for psoriasis in selected patients. The prompt discontinuation of treatment usually results in resolution of any eventual toxicity.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. Monitoring Diabetic Nephropathy by Circulating Gangliosides.

    PubMed

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

    2016-01-01

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

  13. Combination of N-(3'4'-dimethoxycinnamoyl) anthranilic acid with cyclosporin A treatment preserves immunosuppressive effect and reduces the side effect of cyclosporin A in rat.

    PubMed

    Yong-Gang, Xu; Ming-Zhe, Weng; Jin-Yan, Zhang; Zhi-Hai, Peng; Jun-Ming, Xu

    2014-04-05

    Cyclosporin A (CsA), one of the most fundamental immunosuppressive drugs, is routinely used in clinics for the treatment of liver and other organ rejections. However, one of the major challenges of the application of CsA is the occurrence of the serious adverse effects, namely, acute and chronic nephrotoxicity, severe hypertension and neurotoxicity. Although N-(3'4'-dimethoxycinnamoyl) anthranilic acid (3,4-DAA) plays an important role in apoptosis of activated T cells, and is therapeutically used as an orally active anti-allergic drug for the treatment of allergy, it has not been tested for use in the treatment of organ rejection. In this study, we used the dark agouti (DA)-Lewis rat orthotopic liver transplantation (OLT) model to investigate whether the combination of 3,4-DAA with CsA is a promising and useful strategy to lower CsA dosage for reducing CsA side effect and preserve therapeutic effect of CsA. Here, we document that the combination treatment effectively inhibits acute liver rejection in OLT model with only half the normally suggested dosage of CsA that has much less side effect in rats than that of the full dosage. These results indicate that 3,4-DAA may serve as an effective adjunct for a CsA-based immunosuppressive regimen to treat transplant recipients for reducing CsA side effect. Copyright © 2014 Elsevier B.V. All rights reserved.

  14. Outcome of childhood-onset full-house nephropathy.

    PubMed

    Ruggiero, Barbara; Vivarelli, Marina; Gianviti, Alessandra; Pecoraro, Carmine; Peruzzi, Licia; Benetti, Elisa; Ventura, Giovanna; Pennesi, Marco; Murer, Luisa; Coppo, Rosanna; Emma, Francesco

    2017-07-01

    Patients with full-house nephropathy (FHN) present renal lesions that are indistinguishable from those of lupus nephritis (LN) but lack the systemic features necessary to meet diagnostic criteria for systemic lupus erithematosus (SLE). Some have been reported to develop a delayed SLE with time. The clinical outcome of children having FHN without SLE has never been reported. Children with biopsy-proven FHN were selected after excluding SLE cases by the absence of America College of Rheumatology criteria. The proportion of patients with complete (proteinuria <0.5 g/day) or partial remission (proteinuria ≤50% from baseline), relapse (estimated glomerular filtration rate <25% and/or proteinuria ≥50% from baseline) and progression to Stage III chronic kidney disease (CKD) was described according to age and gender groups with the Kaplan-Meier curve and compared with the Log-rank test. Entity of treatment was summarized by a score at induction (0-6 months) and maintenance (6-18 months). Cox-regression model was performed to test predictors of remission, relapse and progression to CKD. Among 42 patients (28 pre-pubertal) who met the inclusion criteria, 39 (92.9%) achieved partial and 32 (76.2%) complete remission of nephropathy over 2.78 and 7.51 months of follow-up. At 10 years, the probability of progressing to CKD was 4.8%. Of those achieving remission, 18% had a renal flare mainly within 4 years after remission. Pre-pubertal males achieved complete remission more frequently than other patients but often relapsed; pre-pubertal females were treated more aggressively. Cox-regression analysis did not find independent predictors of remission or relapse. The outcome of the patients with FHN we investigated was encouraging. Recurrences are limited to the first 4 years following diagnosis, allowing progressive withdrawal of immunosuppression in patients achieving remission. Evaluation of risk factors for adverse outcome is necessary especially in pre-pubertal children.

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

    PubMed Central

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

    2012-01-01

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

  16. Treatment of Chronic Spontaneous Urticaria

    PubMed Central

    2012-01-01

    Chronic spontaneous urticaria is defined as persistent symptoms of urticaria for 6 weeks or more. It is associated with autoimmunity in approximately 45 percent of patients. Therapy is often difficult however the initial approach should employ high-dose non-sedating antihistamines; 4-6 tablets/day may be necessary. It has been shown that the response to 4 tablets/day exceeds 3, and exceeds 2, which exceeds 1. However the dose that corresponds to the maximal dose of first generation antihistamines (hydroxyzine, diphenhydramine) used previously, is 6/day. Yet over half the patients are refractory to antihistamines and other agents should be tried next. Whereas current guidelines (published) often add leukotriene antagonists and/or H2 receptor antogonists next, these are of little utility. Likewise drugs effective for urticarial vasculitis (colchicine, dapsone, sulfasalazine, hydroxychloroquine) are effective in a small percentage of patients and no study suggests that the response rate of any of them exceeds the 30% placebo responses seen in most double-blind, placebo controlled studies. The drugs that are effective for antihistamine-resistant chronic spontaneous urticaria are corticosteroids, cyclosporine, and Omalizumab. Use of steroids is limited by toxicity. If used at all, a dose of no more than 10 mg/day should be employed with a weekly reduction of 1 mg. The response rates to cyclosporine and Omalizumab are each close to 75%. Cyclosporine can be used effectively if care is taken to monitor blood pressure, urine protein, blood urea nitrogen, and creatinine, every 6 weeks. Omalizumab has the best profile in terms of efficacy/toxicity and, once approved by federal agencies for use in chronic spontaneous urticaria, a dramatic change in the treatment paradigm, whether associated with autoimmunity or not, is predicted. A phase 3 trial is currently in place. Refractoriness to both Omalizumab and cyclosporine is expected to be less than 5 percent of patients. Other

  17. CYP3A5 Gene Variation Influences Cyclosporine A Metabolite Formation and Renal Cyclosporine Disposition

    PubMed Central

    Zheng, Songmao; Tasnif, Yasar; Hebert, Mary F.; Davis, Connie L.; Shitara, Yoshihisa; Calamia, Justina C.; Lin, Yvonne S.; Shen, Danny D.; Thummel, Kenneth E.

    2013-01-01

    Background Higher concentrations of AM19 and AM1c9, secondary metabolites of cyclosporine A (CsA), have been associated with nephrotoxicity in organ transplant patients. The risk of renal toxicity may depend upon the accumulation of CsA and its metabolites in the renal tissue. We evaluated the hypothesis that CYP3A5 genotype, and inferred enzyme expression, affects systemic CsA metabolite exposure and intra-renal CsA accumulation. Methods An oral dose of CsA was administered to 24 healthy volunteers who were selected based on their CYP3A5 genotype. CsA and its six main metabolites in whole blood and urine were measured by LC-MS. In vitro incubations of CsA, AM1, AM9 and AM1c with recombinant CYP3A4 and CYP3A5 were performed to evaluate the formation pathways of AM19 and AM1c9. Results The mean CsA oral clearance was similar between CYP3A5 expressors and nonexpressors. However, compared to CYP3A5 nonexpressors, the average blood AUC for AM19 and AM1c9 was 47.4% and 51.3% higher in CYP3A5 expressors (P = 0.040 and 0.011, respectively), corresponding to 30% higher AUCmetabolite/AUCCsA ratios for AM19 and AM1c9 in CYP3A5 expressors. The mean apparent urinary CsA clearance, based on a 48-hour collection, was 20.4% lower in CYP3A5 expressors compared to CYP3A5 nonexpressors (4.2 ± 1.0 and 5.3 ± 1.3 mL/min, respectively, P = 0.037), which is suggestive of CYP3A5-dependent intra-renal CsA metabolism. Conclusions At steady-state, intra-renal accumulation of CsA and its secondary metabolites should depend on the CYP3A5 genotype of the liver and kidneys. This may contribute to inter-patient variability in the risk of CsA-induced nephrotoxicity. PMID:23354298

  18. 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.

  19. 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.

  20. [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.

  1. Pharmacokinetic analysis of cyclosporine in a renal transplant recipient with congenital absence of the portal vein.

    PubMed

    Nakazawa, Ryuto; Sato, Yuichi; Sasaki, Hideo; Shibagaki, Yugo; Kimura, Kenjiro; Chikaraishi, Tatsuya

    2015-08-01

    Here we report therapeutic drug monitoring of cyclosporine in a kidney transplant recipient lacking enterohepatic circulation. The patient developed steroid-resistant nephrotic syndrome at age 14 years, and was medicated with an oral cyclosporine microemulsion. However, her cyclosporine trough level was unexpectedly elevated, and subsequent investigations showed that she was deficient in drug metabolism as a result of the congenital absence of the portal vein. Her renal function gradually decreased and she became dialysis-dependent at the age of 21 years, and kidney transplantation was planned. Based on pretransplant therapeutic drug monitoring, we started cyclosporine microemulsion at half of the conventional dosage. After transplantation, the dosage was successfully adjusted to achieve a target trough level. The post-transplant course was stable with no symptoms of rejection or cyclosporine-associated nephrotoxicity. © 2015 The Japanese Urological Association.

  2. 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

  3. Dyslipidaemia among renal transplant recipients: cyclosporine versus tacrolimus.

    PubMed

    Fazal, Muhammad Asim; Idrees, Muhammad Khalid; Akhtar, Syed Fazal

    2014-05-01

    To compare new onset dyslipidaemia in live-related renal transplant recipients taking cyclosporine versus tacrolimus after 3 months of therapy. The randomised controlled trial was conducted at the Sindh Institute of Urology and Transplantation (SIUT) Karachi, from September 2010 to April 2011, and included 182 End Stage Renal Disease patients on maintenance haemodialysis with pre-transplant normal lipid profile. The patients, who had live-related renal transplant, were randomly allocated to two equal groups using lottery. Group A received cyclosporine (3 mg/kg) and group B was treated with tacrolimus (0.1 mg/kg). All patients had pre-transplant fasting lipid profile checked when they were on maintenance haemodialysis and 3 months after renal transplantation. Serum fasting lipid profile was collected by taking 5 ml blood by venipuncture after an overnight fast of 9-12 hours. SPSS 10 was used for statistical analyses. Of the 182 patients, 144 (79.1%) were males and 38 (20.9%) were females. The overall mean age was 30.18 +/- 9.57 years, and the mean weight was 54.41 +/- 11.144 kg. Significant difference was not observed between the two groups regarding age and weight of the patients. Dyslipidaemia was found in 115(63.2%) subjects; 61(67%) in group A and 54 (59.3%) in group B. There was no statistical difference (p=0.28) when comparison was done after 3 months of therapy. The occurrence of new onset hyperlipidaemia is similar in renal transplant recipients receiving either cyclosporine or tacrolimus in first 3 months post-transplant, but there is room for more research in this field as dyslipidaemia following successful renal transplantation is a frequent and persistent complication.

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

    PubMed

    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.

  5. 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. PMID:28405165

  6. Proteins induced by telomere dysfunction are associated with human IgA nephropathy* #

    PubMed Central

    Lu, Ying-ying; Yang, Xian; Chen, Wen-qing; Ju, Zhen-yu; Shou, Zhang-fei; Jin, Juan; Zhang, Xiao-hui; Chen, Jiang-hua; Jiang, Hong

    2014-01-01

    Aging is one of the contributing risk factors for kidney diseases. Accumulating evidence prompts the view that telomere length in kidney tissue cells is an indicator for organismal aging. Previously identified aging markers (cathelin-related antimicrobial peptide (CRAMP), stathmin, elongation factor-1α (EF-1α), and chitinase) were associated not only with telomere driven aging in mice but also with human aging and chronic diseases. This study focuses on the relationship between these biomarkers and IgA nephropathy (IgAN) progression in the Chinese population. For 260 individuals, the four markers are determined in blind datasets using direct enzyme-linked immunosorbent assay (ELISA) and immunofluorescence staining. The expression levels of CRAMP and chitinase increased in blood plasma, urine, and kidney tissues during human IgAN progression. And for the other nephropathy, such as systemic lupus erythematosus (SLE), diabetic nephropathy (DN), and focal segmental glomerulosclerosis (FSGS), there is no protein upregulation with telomere shortening. Moreover, a combination of CRAMP and chitinase can distinguish patients with IgAN from healthy individuals with 88.2%/92.5% (plasma) and 74.3%/84.2% (urine) sensitivity/specificity. These data provide the experimental evidence that telomere shortening and related inflammatory proteins are associated with human IgAN, and it could be a new direction for the disease progression study. PMID:24903994

  7. 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.

  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. Tacrolimus versus cyclosporin as primary immunosuppression for lung transplant recipients.

    PubMed

    Penninga, Luit; Penninga, Elisabeth I; Møller, Christian H; Iversen, Martin; Steinbrüchel, Daniel A; Gluud, Christian

    2013-05-31

    Lung transplantation is a well-accepted treatment for people with most end-stage lung diseases. Although both tacrolimus and cyclosporin are used as primary immunosuppressive agents in lung transplant recipients, it is unclear which of these drugs is better in reducing rejection and death without causing adverse effects. To assess the benefits and harms of tacrolimus versus cyclosporin for primary immunosuppression in lung transplant recipients. We searched the Cochrane Renal Group's Specialised Register to 10 April 2013 through contact with the Trials Search Co-ordinator using search terms relevant to this review. We also searched Science Citation Index Expanded and the Transplant Library to 20 April 2013. We included all randomised controlled trials (RCT) that compared any dose and duration of administration of tacrolimus versus cyclosporin as primary immunosuppressive treatment in lung transplant recipients. Our selection criteria required that all included patients received the same additional immunosuppressive therapy within each study. Three authors extracted data. For dichotomous data we used risk ratio (RR) and used mean difference (MD) for continuous data, each with 95% confidence intervals (CI). Methodological components of the included studies were used to assess risk of systematic errors (bias). Trial sequential analysis was used to assess risk of random errors (play of chance). We included three studies that enrolled a total of 413 adult patients that compared tacrolimus with microemulsion or oral solution cyclosporin. All studies were found to be at high risk of bias. Tacrolimus seemed to be significantly superior to cyclosporin regarding the incidence of bronchiolitis obliterans syndrome (RR 0.46, 95% CI 0.29 to 0.74), lymphocytic bronchitis score (MD -0.60, 95% CI -1.04 to -0.16), treatment withdrawal (RR 0.27, 95% CI 0.16 to 0.46), and arterial hypertension (RR 0.67, 95% CI 0.50 to 0.89). However, the finding for arterial hypertension was not

  10. 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

  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. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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.

  18. Immunoglobulin A nephropathy complicating pulmonary tuberculosis.

    PubMed

    De Siati, L; Paroli, M; Ferri, C; Muda, A O; Bruno, G; Barnaba, V

    1999-10-01

    A 31-year-old man who presented with smear- and culture-negative pulmonary tuberculosis had associated macroscopic hematuria, elevation of serum creatinine and immunoglobulin A (IgA) levels, overt proteinuria, and peripheral edema. Renal biopsy revealed focal mesangial proliferation with IgA deposits, and a diagnosis of IgA nephropathy was made. The patient received treatment with isoniazide and rifampin. After 4 months, pulmonary lesions were almost completely healed, and a significant improvement of creatinine clearance with normalization of serum creatinine and IgA levels and disappearance of proteinuria were observed. Treatment with isoniazide and rifampin was discontinued after 6 months, without reappearance of either pulmonary or renal symptoms. Two years after the diagnosis of IgA nephropathy, the patient is in good general condition. Serum creatinine and IgA levels are normal, proteinuria is absent, and there is neither macrohematuria nor microhematuria. These findings suggest that IgA nephropathy may be a consequence of tuberculosis, possibly due to an abnormal IgA-mediated immune response against Mycobacterium tuberculosis with formation of nephrotoxic immune complexes.

  19. 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

  20. Urinary semaphorin 3A correlates with diabetic proteinuria and mediates diabetic nephropathy and associated inflammation in mice

    PubMed Central

    Mohamed, Riyaz; Ranganathan, Punithavathi; Jayakumar, Calpurnia; Nauta, Ferdau L.; Gansevoort, Ron T.; Weintraub, Neal L.; Brands, Michael; Ramesh, Ganesan

    2014-01-01

    Semaphorin3A (sema3A) was recently identified as an early diagnostic biomarker of acute kidney injury. However, its role as a biomarker and/or mediator of chronic kidney disease (CKD) related to diabetic nephropathy is unknown. We examined the expression of sema3A in diabetic animal models and in humans and tested whether sema3A plays a pathogenic role in the development of diabetic nephropathy. The expression of sema3A was localized to podocytes and epithelial cells in distal tubules and collecting ducts in control animals, and its expression was increased following induction of diabetes. Quantification of sema3A urinary excretion in three different diabetic mouse models showed that excretion was increased as early as 2 weeks after induction of diabetes and increased over time, in conjunction with the development of nephropathy. Consistent with the mouse data, increased sema3A urinary excretion was detected in diabetic patients with albuminuria, particularly in those with macroalbuminuria. Genetic ablation of sema3A, or pharmacological inhibition with a novel sema3A inhibitory peptide, protected against diabetes-induced albuminuria, kidney fibrosis, inflammation, oxidative stress and renal dysfunction. We conclude that sema3A is both a biomarker and a mediator of diabetic kidney disease and could be a promising therapeutic target in diabetic nephropathy. PMID:25249008

  1. Crystalline nephropathy due to 2,8-dihydroxyadeninuria: an under-recognized cause of irreversible renal failure.

    PubMed

    Nasr, Samih H; Sethi, Sanjeev; Cornell, Lynn D; Milliner, Dawn S; Boelkins, Mark; Broviac, John; Fidler, Mary E

    2010-06-01

    2,8-dihydroxyadeninuria (DHA) disease (also called 2,8 dihydroxyadeninuria) is a rare autosomal recessive disorder caused by complete adenine phosphoribosyltransferase deficiency and typically manifests as recurrent nephrolithiasis. Only rare cases of DHA nephrolithiasis have been reported from the USA. Herein, we report three American patients who developed DHA crystalline nephropathy leading to end-stage renal disease (ESRD) with recurrence in the allograft. Three cases of DHA crystalline nephropathy were identified from the Renal Pathology Laboratory of Mayo Clinic. Detailed clinical and pathologic descriptions are provided. All three patients were Caucasian adults with no history of obstructive nephropathy. Two patients had no history of nephrolithiasis and one had a single episode of stones 36 years prior to presentation. All patients presented with severe renal failure with a mean serum creatinine of 7.5 mg/dl. Renal biopsies revealed numerous tubular and interstitial brown DHA crystals, tubular degenerative changes and moderate to marked tubulointerstitial scarring. Two patients were initially misdiagnosed, one as primary hyperoxaluria and the other as chronic interstitial nephritis. All three patients progressed to ESRD, within 1 month following renal biopsy in two and after 9 months in one. All three patients underwent renal transplantation with early disease recurrence in three allografts in two patients. DHA disease is an under-recognized condition that can lead to irreversible renal failure and frequently recurs in the transplant. It should be included in the differential diagnosis of crystalline nephropathy, even in the absence of history of nephrolithiasis.

  2. 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.

  3. 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.

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

    PubMed

    Meola, Mario; Samoni, Sara; Petrucci, Ilaria

    2016-01-01

    Chronic tubulointerstitial diseases are a common final pathway toward chronic renal failure regardless the primary damage (glomerular, vascular or directly the tubulointerstitium). Chronic tubulointerstitial nephritis (CTN) is characterized by interstitial scarring, fibrosis and tubule atrophy, resulting in progressive chronic kidney disease. Most frequent causes of CTN are drugs, heavy metals, obstructive uropathy, nephrolithiasis, reflux disease, immunologic diseases, neoplasia, ischemia, metabolic diseases, genetics and miscellaneous. At ultrasound (US), kidneys' morphological aspect is similar in all forms of chronic interstitial nephropathy and only chronic pyelonephritis with or without reflux shows distinguishing characteristics. In interstitial nephropathy, kidneys' profiles are finely irregular and corticomedullary differentiation is altered because of a diffused hyperechogenicity. The only indirect sign of chronic interstitial damage can be derived from the value of intrarenal resistive indexes that hardly overcome 0.75. US is mandatory in clinical chronic pyelonephritis work-up because it provides information on kidney's diameter and on growth nomogram in children. Renal profiles can be more or less altered depending on the number of cortical scars and the presence of pseudonodular areas of segmental compensatory hypertrophy. In the early stages, US diagnosis of renal tuberculosis is difficult because parenchymal lesions are non-specific. US sensitivity in the diagnosis of hydronephrosis is very high, close to 100% and, finally, US is the first choice imaging technique in the diagnosis of urinary lithiasis. © 2016 S. Karger AG, Basel.

  5. 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.

  6. Efficacy of dextromethorphan and cyclosporine a for acute encephalopathy.

    PubMed

    Matsuo, Muneaki; Maeda, Toshiyuki; Ono, Nobuyasu; Sugihara, Susumu; Kobayashi, Ikuko; Koga, Daisuke; Hamasaki, Yuhei

    2013-03-01

    Acute encephalopathy with biphasic seizures and late reduced diffusion was recently established clinicoradiologically as an encephalopathy syndrome. The outcome of this encephalopathy is characterized by a low mortality rate and high incidence of neurologic sequelae. Although the exact pathogenesis of this encephalopathy is uncertain, excitotoxic injury with delayed neuronal death is proposed. On the basis of this hypothesis, we tried a combination therapy of N-methyl-D-aspartate receptor antagonist, dextromethorphan, and apoptosis inhibitor, cyclosporine A, in four patients with acute encephalopathy with biphasic seizures and late reduced diffusion. All patients recovered except for hyperactivity in one patient. Furthermore, an additional four patients with near-miss encephalopathy, who showed mild disturbance of consciousness at 24 hours after prolonged febrile seizures associated with exanthem subitum, recovered without secondary seizures by the early administration of dextromethorphan. The combination regimen of dextromethorphan and cyclosporine A could be effective for the treatment and prevention of acute encephalopathy with biphasic seizures and late reduced diffusion. Copyright © 2013 Elsevier Inc. All rights reserved.

  7. Black grape and garlic extracts protect against cyclosporine a nephrotoxicity.

    PubMed

    Durak, Ilker; Cetin, Recep; Candir, Ozden; Devrim, Erdinç; Kiliçoğlu, Bülent; Avci, Aslihan

    2007-01-01

    The aim of this study was to determine if the natural antioxidant foods, dried black grape and garlic, protect against cyclosporine nephrotoxicity. Forty-two Sprague-Dawley rats were given Cyclosporine A (CsA) orally for 10 days, with the antioxidant food supplementation begun 3 days before CsA treatment and continued during the study period (totaling 13 days). In each group (control, CsA alone, CsA plus black grape, CsA plus aqueous garlic extract, aqueous garlic extract alone and black grape alone), there were 7 animals. At the end of the study period, the animals were sacrificed; their kidneys were removed and prepared for biochemical and histopathological investigations. Oxidant (xanthine oxidase enzyme and malondialdehyde) and antioxidant (superoxide dismutase, glutathione peroxidase and catalase enzymes) parameters were measured in the kidney tissues of the groups. Histopathological examinations of the tissues were also performed. It has been found that CsA creates oxidant load to the kidneys through both xanthine oxidase activation and impaired antioxidant defense system, which accelerates oxidation reactions in the kidney tissue. Supplementation with either dried black grape or aqueous garlic extract led to reduced malondialdehyde level in the kidney tissue possibly, by preventing oxidant reactions. In conclusion, the results suggest that impaired oxidant/antioxidant balance may play part in the CsA-induced nephrotoxicity, and some foods with high antioxidant power may ameliorate this toxicity, in agreement with studies with antioxidant vitamins.

  8. Spatial structure of cyclosporin A and insight into its flexibility

    NASA Astrophysics Data System (ADS)

    Efimov, S. V.; Karataeva, F. Kh.; Aganov, A. V.; Berger, S.; Klochkov, V. V.

    2013-03-01

    The molecule of immunosuppressant drug cyclosporin A (CsA) exhibits different properties when dissolved in different media. In apolar solvents it is stabilized by intramolecular hydrogen bonds, but there also exist some less populated conformations. Existence of minor forms is clearly seen from 1H NMR spectra. Using nuclear Overhauser effect (NOE) spectroscopy and analysis of residual dipolar couplings, we obtained data on the molecular structure of the dominant conformers. Based on these data, the spatial structure of the main conformer of cyclosporin in chloroform was determined by molecular dynamics simulation. The kinetics of exchange between the major and minor forms was also studied. Energy barrier (ΔG‡) between the two states is 81 ± 2 kJ/mol. The conformation of CsA in complex with sodium dodecyl sulphate micelles was determined from NOE data. Use of independent structural data improves the reliability of the simulated results. The structure of the minor forms, which exist in organic solvents and also in micellar solution, cannot be assessed by means of nuclear magnetic resonance. Spectroscopic and thermodynamic parameters, however, point to their certain properties. In particular, the minor conformer of CsA in chloroform differs from the main one by a peptide bond (in cis- rather than trans-conformation) in the region of residues from 4 to 7.

  9. 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

  10. 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.

  11. 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.

  12. Cyclosporin A promotes tumor angiogenesis in a calcineurin-independent manner by increasing mitochondrial reactive oxygen species.

    PubMed

    Zhou, Alice Yao; Ryeom, Sandra

    2014-11-01

    The widely used immunosuppressant cyclosporin A, a potent calcineurin inhibitor, significantly increases the incidence of cancer in organ transplant patients. Calcineurin signaling is an important mediator of VEGF signaling in endothelial cells. Negative regulation of calcineurin by its endogenous inhibitor, Down Syndrome Candidate Region-1 (DSCR1), suppresses tumor growth and angiogenesis, in contrast to the effect observed after long-term cyclosporin A treatment. Despite the significance of calcineurin signaling in endothelial cells, the consequences of cyclosporin A on tumor angiogenesis have not been investigated. Using an in vivo model of skin carcinogenesis, prolonged treatment with cyclosporin A promoted tumor growth and angiogenesis. The addition of cyclosporin A to endothelial cells in vitro increased proliferation and migration in a calcineurin-independent manner and is associated with increased mitochondrial reactive oxygen species (ROS). Co-treatment with antioxidants significantly abrogated cyclosporin A-induced endothelial cell activation. Furthermore, mice treated with antioxidants were protected against cyclosporin A-mediated tumor progression. Taken together, these findings suggest that cyclosporin A affects endothelial cells in a calcineurin-independent manner to potentiate tumor growth by promoting tumor angiogenesis through increasing mitochondrial ROS production. This work identifies a previously undescribed mechanism underlying a significantly adverse off-target effect of cyclosporin A and suggests that co-treatment with antioxidants would inhibit the tumor-promoting effects of cyclosporin A. Targeting the proangiogenic effects of cyclosporin A may be useful in the management of transplant-associated cancers. ©2014 American Association for Cancer Research.

  13. 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.

  14. Effectiveness and nephrotoxicity of a 2-year medium dose of cyclosporine in pediatric patients with steroid-dependent nephrotic syndrome: determination of the need for follow-up kidney biopsy.

    PubMed

    Kuroyanagi, Yoshiyuki; Gotoh, Yoshimitsu; Kasahara, Katsuaki; Nagano, China; Fujita, Naoya; Yamakawa, Satoshi; Yamamoto, Masaki; Takeda, Asami; Uemura, Osamu

    2017-07-11

    High dose of cyclosporine (CyA) for ≥2 years in children with steroid-dependent nephrotic syndrome (SDNS) increases the risk for nephropathy. Considering this, risk can be lowered with lower doses of CyA; we evaluated the effects of a medium dose of CyA, with target serum level, C2, of 450 ng/ml, over a 2-year period of observation, to determine the need for follow-up kidney biopsy. We retrospectively evaluated C2 levels in 38 patients (17 males, 5.2 ± 2.9 years old) with SDNS at treatment initiation, at 6, 12 and 18 months during treatment, and at the time of kidney biopsy, 2-year after treatment initiation. Fifteen patients were also treated with mizoribine or mycophenolate mofetil. A number of relapses-per-patient-per-year, relative to SDNS onset and initiation of CyA treatment, were evaluated. Serum levels of total protein, albumin and total cholesterol, blood urea nitrogen level, and the estimated glomerular filtration rate were measured at treatment initiation and at 1- and 2-year post-treatment initiation. Only one very mild case of CyA-associated nephrotoxicity was identified based on biopsy results at 2-year post-treatment initiation. C2 concentrations were maintained at 422.2 ± 133.5 ng/ml and the number of relapses decreased from 3.0 relapses-per-patient-per-year prior to CyA treatment to 0.47 relapses-per-patient-per-year after CyA treatment. No effects of the treatment on the estimated glomerular filtration rate were noted. A 2-year treatment with a medium dose of cyclosporine A with or without other immunosuppressive agents is relatively safe with regard to the development of cyclosporine A nephrotoxicity.

  15. 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

  16. 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.

  17. 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.

  18. 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

  19. 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.

  20. 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.

  1. 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.

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

    PubMed

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

    2016-06-01

    In this study, it was aimed to investigate the toxic and teratogenic effects of cyclosporine A and tacrolimus and their combinations with prednisolone using an in vitro rat embryo culture technique. Cyclosporine A (4-40 μg/ml), tacrolimus (1-20 μg/ml) and combinations of these drugs with prednisolone (20 μg/ml) at different concentrations were tested. Cyclosporine A and its combination with prednisolone were determined to have toxic effects on embryonic growth after 10 μg/ml. When used alone, the lowest dose of tacrolimus had embryotoxic effects on the total morphological score and number of somites. It was determined that cyclosporine A caused hematoma at 4 μg/ml and higher doses, and tacrolimus especially at 20 μg/ml caused an open neural tube beside hematoma. It was observed that cyclosporine A at 40 μg/ml dose initiated apoptotic effects at a very low rate, prednisolone increased this effect, tacrolimus led to excessive apoptosis after 15 μg/ml, and this effect did not change with prednisolone supplement. We are of the opinion that the doses should be determined carefully when cyclosporine A and tacrolimus are required to be administered to pregnant women with prednisolone combination, as prednisolone increases the toxic effects of cyclosporine A, and increases teratogenic effects of tacrolimus. Copyright © 2016 Elsevier Inc. All rights reserved.

  3. 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

  4. Clinical experience with systemic cyclosporine A treatment in severe childhood psoriasis.

    PubMed

    Bulbul Baskan, Emel; Yazici, Serkan; Tunali, Sukran; Saricaoglu, Hayriye

    2016-08-01

    Severe forms of psoriasis including erythrodermic or pustular psoriasis, which require a more aggressive therapeutic approach such as phototherapy or systemic therapies, are rarely seen. Systemic toxicity and long-term safety of these agents are serious concerns in children. We report our experience on the efficacy and safety of cyclosporine A treatment in 22 patients of childhood psoriasis. We retrospectively analyzed the records of all patients less than 18 years of age treated with systemic cyclosporine A therapy at our clinic between January 2000 and March 2009. Demographic features as well as other relevant data including previous therapies, the dosage and duration of cyclosporine A therapy, response to treatment and side effects were retrieved from the patients' records. A total of 22 children were treated with systemic cyclosporine A therapy. Seventeen patients were found to be excellent responders. The mean therapeutic dosage of cyclosporine A was 3.47 ± 0.62 mg/kg/day. The mean duration of cyclosporine A therapy was 5.68 ± 3.29 months. The median time to total clearance of the lesions was 4.0 weeks. We conclude that cyclosporine A therapy is equally effective and safe in pediatric psoriasis patients as in adults.

  5. Cyclosporin A, but not everolimus, inhibits DNA repair mediated by calcineurin: implications for tumorigenesis under immunosuppression.

    PubMed

    Thoms, Kai-Martin; Kuschal, Christiane; Oetjen, Elke; Mori, Toshio; Kobayashi, Nobuhiko; Laspe, Petra; Boeckmann, Lars; Schön, Michael P; Emmert, Steffen

    2011-03-01

    Unlike other immunosuppressive drugs including everolimus, cyclosporin A causes a dramatic increase of UV-induced skin cancer, a feature that is reminiscent of xeroderma pigmentosum (XP), where defective nucleotide excision repair (NER) of UV-induced DNA damage results in cutaneous carcinogenesis. The molecular basis of the clinically important differential activities of cyclosporin A and everolimus is still unclear. We measured post-UV cell survival of cyclosporin A- and everolimus-treated human fibroblasts and lymphoblasts using a cell proliferation assay (MTT). The cellular NER capacity was assessed by host cell reactivation. Using an ELISA and specific antibodies, cyclobutane pyrimidine and pyrimidine-6,4-pyrimidone photoproduct removal from the cellular genome was measured. The effect of calcineurin on NER was investigated using a calcineurin A expression vector and specific RNAi. Cyclosporin A led to a dose dependent decrease in post-UV cell survival, inhibited NER and blocked photoproduct removal. In contrast, none of these effects where seen in everolimus-treated cells. Overexpression of calcineurin A resulted in increased NER and complemented the Cyclosporin A-induced reduction of NER. Downregulation of calcineurin using RNAi inhibited NER comparable to cyclosporin A-treatment. We conclude that cyclosporin A, but not everolimus, leads to an increased skin cancer risk via a calcineurin signalling-dependent impairment of NER. © 2010 John Wiley & Sons A/S.

  6. Renal dysfunction in a renal transplant patient treated concurrently with cyclosporine and imatinib.

    PubMed

    Mulder, Karen E; Egorin, Merrill J; Sawyer, Michael B

    2012-12-01

    Imatinib mesylate has proven activity in treating locally advanced or metastatic gastrointestinal stromal tumors (GIST). Drug interactions are particularly concerning as imatinib is extensively metabolized by the cytochrome P450 enzyme system. We describe the clinical course of a 72 year-old male with a cadaveric renal transplant requiring cyclosporine that presented with a metastatic GIST and was started on imatinib at the standard dose of 400 mg daily. Imatinib initiation resulted in a decline in renal function with the serum creatinine increasing from 123 μmol/L to 196 μmol/L and an elevation in whole blood cyclosporine concentrations from 79 μg/L to 139 μg/L. No other imatinib toxicities were reported. With discontinuation of imatinib, the serum creatinine returned to baseline as did the whole blood cyclosporine levels. Ultimately, decreasing both the cyclosporine and imatinib dosing was associated with stabilized renal function (serum creatinine 150-186 μmol/L) and cyclosporine concentrations (53-97 μg/L). A prolonged partial response to therapy for 19 months was maintained despite low imatinib trough concentrations measured on two separate occasions (127.1 ng/ml and 139 ng/ml). In our patient, imatinib initiation resulted in renal toxicity most likely due to its interaction with cyclosporine resulting in elevation of the whole blood cyclosporine concentration.

  7. Cyclosporine nephrotoxicity and early posttransplant hyperkalemia in living-donor renal recipients: report of 4 cases.

    PubMed

    Pavleska-Kuzmanovska, Svetlana; Popov, Zivko; Ivanovski, Ognen; Ristovska, Vesna; Masin-Spasovska, Jelka; Rambabova-Busljetic, Irena; Ivanovski, Ninoslav

    2014-10-01

    Hyperkalemia is an electrolyte disorder that may occur during the first few months after a renal transplant, in patients undergoing cyclosporine immunosuppression. We present our experience with cyclosporine-associated hyperkalemia in living-donor renal transplant recipients, with isolated clinically relevant hyperkalemia soon after surgery. We report 4 living-donor renal recipients with hyperkalemia soon after transplant. Severe unexpected hyperkalemia (7.5- 9.4 mmol/L) was noted in our patients 12, 20, 22, and 34 days after transplant. The C2 cyclosporine concentration was within recommended range or slightly greater than 1200 ng/mL. The hypertonic glucose/insulin treatment along with potassium diet was without results. A reduction in daily cyclosporine dosages, along with 1- to 2-week administration of fludrocortisone was effective. The patients became normokalemic taking a standard, triple-drug immunosuppression protocol, and were discharged home with normal renal function. There were no repeat episodes of hyperkalemia in any of the patients during 12 months of follow-up. Cyclosporine should be considered a cause of hyperkalemia in renal transplant recipients. Successful treatment with fludrocortisone confirms that transitional pseudohypoaldosteronism has a potential nephrotoxic effect of cyclosporine. We recommend close monitoring of the cyclosporine concentration and administering fludrocortisone when treating hyperkalemia in renal transplant recipients.

  8. Aristolochic acid and the etiology of endemic (Balkan) nephropathy

    PubMed Central

    Grollman, Arthur P.; Shibutani, Shinya; Moriya, Masaaki; Miller, Frederick; Wu, Lin; Moll, Ute; Suzuki, Naomi; Fernandes, Andrea; Rosenquist, Thomas; Medverec, Zvonimir; Jakovina, Krunoslav; Brdar, Branko; Slade, Neda; Turesky, Robert J.; Goodenough, Angela K.; Rieger, Robert; Vukelić, Mato; Jelaković, Bojan

    2007-01-01

    Endemic (Balkan) nephropathy (EN), a devastating renal disease affecting men and women living in rural areas of Bosnia, Bulgaria, Croatia, Romania, and Serbia, is characterized by its insidious onset, invariable progression to chronic renal failure and a strong association with transitional cell (urothelial) carcinoma of the upper urinary tract. Significant epidemiologic features of EN include its focal occurrence in certain villages and a familial, but not inherited, pattern of disease. Our experiments test the hypothesis that chronic dietary poisoning by aristolochic acid is responsible for EN and its associated urothelial cancer. Using 32P-postlabeling/PAGE and authentic standards, we identified dA-aristolactam (AL) and dG-AL DNA adducts in the renal cortex of patients with EN but not in patients with other chronic renal diseases. In addition, urothelial cancer tissue was obtained from residents of endemic villages with upper urinary tract malignancies. The AmpliChip p53 microarray was then used to sequence exons 2–11 of the p53 gene where we identified 19 base substitutions. Mutations at A:T pairs accounted for 89% of all p53 mutations, with 78% of these being A:T → T:A transversions. Our experimental results, namely, that (i) DNA adducts derived from aristolochic acid (AA) are present in renal tissues of patients with documented EN, (ii) these adducts can be detected in transitional cell cancers, and (iii) A:T → T:A transversions dominate the p53 mutational spectrum in the upper urinary tract malignancies found in this population lead to the conclusion that dietary exposure to AA is a significant risk factor for EN and its attendant transitional cell cancer. PMID:17620607

  9. Experimental lead nephropathy: treatment with calcium disodium ethylenediaminetetraacetate.

    PubMed

    Sánchez-Fructuoso, Ana I; Blanco, Julia; Cano, Montserrat; Ortega, Luis; Arroyo, Miguel; Fernández, Christina; Prats, Dolores; Barrientos, Alberto

    2002-07-01

    Chronic lead poisoning may cause hypertension, gout, and renal insufficiency. Most experimental poisoning studies have involved the use of high doses over short periods (ie, acute poisoning). Although chelating treatment leads to remission of acute lead nephropathy, its effects in the treatment of chronic poisoning are unclear. The aims of this study were to evaluate renal alterations produced during chronic lead poisoning and their progression when poisoning was over and to determine the efficiency of chelating treatment with calcium disodium ethylenediaminetetraacetate (EDTA). In this study, 56 male Wistar rats were administered lead in drinking water (500 ppm lead acetate) over 90 days. The control group consisted of 21 nonexposed rats. Seven rats from each group were killed on days 60 and 90. At the end of the 90-day period, 21 of the lead-exposed rats were treated with disodium monocalcium EDTA (50 mg/kg/d x 5 days) intraperitoneally, and 21 were administered serum saline by the same route. Three treatment courses were given separated by 9 days free of treatment. Seven rats from each subgroup were sacrificed at the end of each treatment course. Main findings related to poisoning were hypertrophy and vacuolization of medium and small arteries; mucoid edema and muscular hypertrophy in arterioles; loss of cell brush borders, cell loss, and intranuclear inclusion bodies in the proximal tubule; and fibrosis and the presence of infiltrates in the interstitial component. Treatment with EDTA slowed the progression of most alterations. No damage associated with the use of the chelating agent was observed. Longer term studies of the effects of this drug are required to establish whether the damage caused by lead poisoning may be reversed. Copyright 2002 by the National Kidney Foundation, Inc.

  10. 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