Cyclosporine Nephrotoxicity Research Articles

Drug Interaction Between Cyclosporine and Mtor Inhibitors in Experimental Model of Chronic Cyclosporine Nephrotoxicity and Pancreatic Islet Dysfunction

Drug Interaction Between Cyclosporine and Mtor Inhibitors in Experimental Model of Chronic Cyclosporine Nephrotoxicity and Pancreatic Islet Dysfunction

Low-Salt Diet and Cyclosporine Nephrotoxicity: Changes in Kidney Cell Metabolism

Cyclosporine (CsA) is a highly effective immunosuppressant used in patients after transplantation; however, its use is limited by nephrotoxicity. Salt depletion is known to enhance CsA-induced nephrotoxicity in the rat, but the underlying molecular mechanisms are not completely understood. The goal of our study was to identify the molecular effects of salt depletion alone and in combination with CsA on the kidney using a proteo-metabolomic strategy. Rats (n = 6) were assigned to four study groups: (1) normal controls, (2) low-salt fed controls, (3) 10 mg/kg/d CsA for 28 days on a normal diet, (4) 10 mg/kg/d CsA for 28 days on low-salt diet. Low-salt diet redirected kidney energy metabolism toward mitochondria as indicated by a higher energy charge than in normal-fed controls. Low-salt diet alone reduced phospho-AKT and phospho-STAT3 levels and changed the expression of ion transporters PDZK1 and CLIC1. CsA induced macro- and microvesicular tubular epithelial vacuolization and reduced energy charge, changes that were more significant in low-salt fed animals, probably because of their more pronounced dependence on mitochondria. Here, CsA increased phospho-JAK2 and phospho-STAT3 levels and reduced the phospho-IKKγ and p65 proteins, thus activating NF-κB signaling. Decreased expression of lactate transport regulator CD147 and phospho-AKT was also observed after CsA exposure in low-salt rats, indicating a decrease in glycolysis. In summary, our study suggests a key role for PDZK1, CD147, JAK/STAT, and AKT signaling in CsA-induced nephrotoxicity and proposes mechanistic explanations on why rats fed a low-salt diet have higher sensitivity to CsA.

Renal Glycosuria without Hyperglycemia in Cyclosporine-Treated Rats

Background/Aims The pathogenesis of post-transplant diabetes mellitus is thought to be partly related to the direct toxic effect of cyclosporine on pancreatic β-cells and the resultant decrease in insulin synthesis and secretion. As a result of hyperglycemia , glycosuria may be found in cyclosporine administration. However, mechanism of glycosuria in cyclosporine nephrotoxicity was not clear Methods Cyclosporine was subcutaneously injected to male Sprague-Dawley rats at a daily dose of 7.5 mg/kg (n=6) for 6 weeks. Biochemical data were obtained from urine and plasma samples. Results Cyclosporine treatment caused a remarkable increase in urine volume and a decrease in urine osmolality. Urinary excretion of glucose was remarkably elevated by cyclosporine administration (7±3.0 mg/dL versus 12896±3218 mg/dL; P Conclusion Glycosuria may occur without hyperglycemia in cyclosporine administration. We suggest that cyclosporine may decrease tubular reabsorption of glucose in renal tubular epithelial cells, and then glycosuria could be induced by the altered glucose transporter expressions. We will analyze the glucose transporters in proximal tubule of rat kidney.

The Antiproteinuric Effects of Green Tea Extract on Acute Cyclosporine-Induced Nephrotoxicity in Rats

BackgroundIt has been reported that the proteinuria is an early useful marker to detect cyclosporine (CsA) nephrotoxicity. The aim of this study was to investigate the antiproteinuric effects of green tea extract (GTE) on CsA-induced acute renal injury in rats. MethodsThe rats (n = 28) were divided into four groups (n = 7/group); controls intraperitoneally (IP) injected with 0.9% saline; CsA group IP injected CsA (50 mg/kg); inducible nitric oxide synthase (iNOS) inhibitor group administered in addition NG-nitro-L-arginine-methyl ester (12 mmol/L) subcutaneously and CsA-GTE group of CsA IP plus GTE (100 mg/kg) subcutaneously. ResultsThe 24-hour urine proteins were significantly increased among the CsA (22.6 ± 3.1 mg/d) compared with the control (7.1 ± 1.5 mg/d) and significantly decreased in the CsA-GTE group (8.2 ± 1.8 mg/d, P < .01). Nitric oxide production induces by CsA treatment was significantly suppressed by GTE and iNOS inhibitor. Renal tissue malondialdehyde level was significantly increased in the CsA compared with controls and significantly decreased in the CsA-GTE group. The antioxidant enzyme activities of superoxide dysmutase and catalase, which were significantly suppressed in the CsA compared with the control group, were restored in the CsA-GTE cohort. ConclusionGTE treatment of rats showed meaningful antiproteinuric effects through antioxidative activity in kidneys from CsA-induced acute renal injury.

Mapping cyclosporine-induced changes in protein secretion by renal cells using stable isotope labeling with amino acids in cell culture (SILAC)

Nephrotoxicity is an adverse event that strongly limits the use of the immunosuppressant cyclosporine in solid organ transplantation and the precise molecular mechanisms underlying this toxicity remain unclear. MS-based proteomic analysis of the secretome of HEK-293 renal cells exposed to cyclosporine was performed to identify changes in protein secretion, as a first step to discover potential biomarkers of such nephrotoxicity. To detect and quantify the perturbed proteins in the culture medium we used SILAC and nano-scale liquid chromatography followed by MALDI-TOF/TOF mass spectrometry. Among 106 proteins identified, 80 were quantified in both forward/reverse SILAC experiments and quantitative proteomic analysis revealed altered levels of expression for 24 secreted proteins. These included the down-regulation of a number of extracellular matrix/cell adhesion components, and the up-regulation of secreted cyclophilins A and B, macrophage inhibition factor and phosphatidylethanolamine-binding protein 1. These changes in protein secretion were not prevented by co-incubation with the antioxidant N-acetylcysteine, suggesting that they were not triggered by cyclosporine-induced oxidative stress. The results from the present study provide important new knowledge to gain insights into the molecular mechanisms of cyclosporine-related toxicity. Some of the proteins identified here should be tested as potential biomarkers of cyclosporine nephrotoxicity in subsequent clinical studies.

Beneficial effect of ubiquinol, the reduced form of coenzyme Q10, on cyclosporine nephrotoxicity

Cyclosporine (CyA) nephrotoxicity is partly due to some oxidative stress. Ubiquinol, the reduced form of coenzyme Q10 (rCoQ10), has recently gained attention for its anti-oxidative potential. The aim of this study is to evaluate the effect of rCoQ10 on a CyA nephrotoxic rat model. Six-week-old male Wistar rats were divided into three groups (five animals each). Group 1 received a medium only. Group 2 received 30 mg/kg/day of CyA only. Group 3 received both the same dose of CyA and 600 mg/kg/day of rCoQ10. CyA and rCoQ10 were both given orally for four weeks. Systolic blood pressure (BP), daily urinary albumin secretion (u-Alb), serum creatinine (s-Cr) level, and super-oxide anion (SO) level in the renal tissue were measured and compared among those three groups. Immunohistochemistry using an antibody for the transforming growth factor-beta (TGF-beta) was also examined. BPs, u-Albs, s-Crs, and SO levels of groups 1, 2, and 3 were 114 ± 3, 132 ± 4, and 129 ± 5 mmHg, 2.6 ± 0.5, 42.1 ± 7.2, and 22.8 ± 3.4 micro-g/day, 1.1 ± 0.2, 1.7 ± 0.2, and 1.3 ± 0.2 mg/dL, and 224 ± 84, 1251 ± 138, and 512 ± 109 RLU/g kidney respectively. U-Albs, s-Crs, and SO levels were signifi cantly ameliorated by rCoQ10. Micro-vacuolar changes and TGF-beta positive deposits in the proximal renal tubular cells of CyA group rats disappeared in those of CyA and rCoQ10 group rats. RCoQ10, an antioxidants, may have potential for preventing CyA nephrotoxicity.

Genetic and Clinical Determinants of Early, Acute Calcineurin Inhibitor-Related Nephrotoxicity

Calcineurin inhibitor (CNI)-related acute nephrotoxicity is a common complication of transplantation. Clinical factors and elevated CNI levels are associated with nephrotoxicity; however, they do not fully explain the risk. Genetic factors may also predispose individuals to nephrotoxicity. We enrolled 945 kidney recipients into a multicenter, prospective study. DNA was genotyped for 2724 single-nucleotide polymorphisms (SNPs) using a customized chip. Cox models, unadjusted and adjusted for clinical factors, examined the association between SNPs and time to early CNI-related acute nephrotoxicity in the first 6 months posttransplant. Cyclosporine was associated with a 1.49 hazard (95% confidence interval, 1.04-2.14) of acute nephrotoxicity relative to tacrolimus. Acute nephrotoxicity occurred in 22.6% of cyclosporine and 19.8% of tacrolimus recipients. The median (interquartile range) daily dose and trough concentration at time of nephrotoxicity were 400 mg (400-500 mg) and 228 ng/mL (190-272 ng/mL) in the cyclosporine group, and 6 mg (4-8 mg) and 12.6 ng/mL (10.2-15.9 ng/mL) in the tacrolimus group, respectively. In single-SNP adjusted analysis, nine SNPs in the XPC, CYP2C9, PAX4, MTRR, and GAN genes were associated with cyclosporine nephrotoxicity. In a multi-SNP analysis, SNPs from the same genes remained significant after adjusting for the clinical factors, showing that the SNPs are jointly and independently predictive of cyclosporine nephrotoxicity. No SNPs were associated with tacrolimus nephrotoxicity. We identified SNPs that were potentially associated with early, acute cyclosporine-related nephrotoxicity. Identifying risk SNPs before transplantation provides an opportunity for personalization of immunosuppression by identifying those who may benefit from CNI-avoidance or minimization, or assist in selecting CNI type. These SNPs require independent validation.

Drug Interaction Between Cyclosporine and mTOR Inhibitors in Experimental Model of Chronic Cyclosporine Nephrotoxicity and Pancreatic Islet Dysfunction

It is known that sirolimus (SRL) aggravates cyclosporine A (CsA)-induced nephrotoxicity and pancreatic injury, but the influence of everolimus (EVR) on CsA-induced organ injury is undetermined. Rats were treated with CsA (15 mg/kg) and EVR or SRL (0.3 mg/kg) subcutaneously for 4 weeks. The influences of EVR or SRL on CsA-induced nephrotoxicity and pancreatic islet dysfunction were compared, and drug interactions between CsA and EVR or SRL were evaluated at blood and tissue levels. Treatment with EVR or SRL alone did not cause severe pancreatic dysfunction and renal injury, but when combined with CsA they aggravated CsA-induced pancreatic and renal injury. Drug interactions between CsA and EVR or SRL differed at the tissue level. Combined treatment with CsA and SRL significantly increased the CsA or SRL levels in kidney and pancreas compared with CsA or SRL alone. However, combined treatment with CsA and EVR did not increase CsA or EVR levels in kidney and pancreas. Both EVR and SRL aggravate CsA-induced organ injury, but the pharmacologic interaction between EVR and CsA at the tissue level is less than that between CsA and SRL. This finding provides better understanding of the difference between EVR and SRL when combined with CsA treatment.

Cyclosporine lowering with everolimus versus mycophenolate mofetil in heart transplant recipients: Long-term follow-up of the SHIRAKISS randomized, prospective study

Cyclosporine nephrotoxicity negatively impacts long-term outcome after heart transplantation (HT). We previously reported 1-year results from a randomized study showing that cyclosporine-lowering strategies based on everolimus or mycophenolate mofetil (MMF) are equally effective for reducing progression of renal dysfunction. It is unknown whether this efficacy could be maintained over the long term. Thirty-four recipients 1 to 4 years after HT and with 25 to 60 ml/min of creatinine clearance (CrCl) were randomized to everolimus with a very low dose (C(0): 50 to 90 ng/ml, n = 17) or MMF with low dose of cyclosporine (C(0): 100 to 150 ng/ml, n = 17). Follow-up was prolonged up to 3 years, and calculated CrCl was the main efficacy measure. Cyclosporine was maintained at 70% and 30% lower than baseline in the everolimus and MMF arms, respectively, throughout the 3-year study period. CrCl remained stable in the everolimus patients (+7% from baseline; p = 0.7), but improved in the MMF patients (+20% from baseline; p < 0.01), with a trend toward improved values compared with everolimus patients (46 ± 12 vs 56 ± 15 ml/min; p = 0.06). Subgroup analysis revealed that baseline proteinuria markedly influenced the renal function response to everolimus: whereas in patients with baseline proteinuria CrCl significantly worsened (-20%; p = 0.04), it improved in those without (+15%; p = 0.03). Safety was comparable between the two study arms. Cyclosporine nephrotoxicity improved after a prolonged dose reduction in patients receiving MMF. The everolimus-based strategy provided a similar benefit only to patients without baseline proteinuria. While raising caution against the universal use of everolimus for kidney protection, our long-term results support the need for customized approaches in the management of drug toxicities in maintenance HT recipients.

Effect of Reduced Form of Coenzyme Q10 on Cyclosporine Nephrotoxicity

Cyclosporine, a potent immunosuppressant, has nephrotoxic adverse effects that may be mediated by oxidative stress. The reduced form of coenzyme Q10 has antioxidant effects. The aim of the present study was to evaluate the effect of the reduced form of coenzyme Q10 on cyclosporine nephrotoxicity. Six-week-old male Wistar rats were divided into 3 groups (10 animals each). Group 1 (control) received olive oil only. Group 2 received cyclosporine (30 mg/kg/d, which is an experimentally nephrotoxic dose). Group 3 received cyclosporine (30 mg/kg/d) and the reduced form of coenzyme Q10 (600 mg/kg/d). The cyclosporine and the reduced form of coenzyme Q10 were given orally for 4 weeks. Daily urinary albumin excretion, serum creatinine level, and urinary 8-hydroxydeoxyguanosine level were measured, and renal tissue was evaluated by immunohistochemistry. In rats treated with cyclosporine and the reduced form of coenzyme Q10 (group 3), there were significantly less abnormalities in mean urinary albumin excretion (group 1: 2.8 ± 0.5; group 2: 41 ± 7; group 3: 21 ± 4 μg/d), serum creatinine (group 1: 1.0 ± 0.2; group 2: 1.8 ± 0.4; group 3: 1.4 ± 0.3 mg/dL), and urine 8-hydroxydeoxyguanosine levels (group 1: 7 ± 3; group 2: 10 ± 3; group 3: 7 ± 1 mg/mL creatinine) than rats treated with cyclosporine alone (group 2). There were 8-hydroxydeoxyguanosine deposits seen in the proximal tubular cells of group 2 that were not present in rats treated with the reduced form of coenzyme Q10 (group 3). The reduced form of coenzyme Q10 may prevent or minimize cyclosporine nephrotoxicity by an antioxidant effect.

Cyclosporine Effects on Pediatric Kidney Recipients

(1), entitled “Cyclosporine trough and 2 hour post dose monitoring and its contributing factors among pediat-ric kidney recipients,” recently published in the Nephro-Urology Monthly. The authors correctly mentioned that there is a negative relationship between cyclosporine A levels (C0 and C2) and serum creatinine. Based on their data, the mean of C0 levels (118 ± 65 ng/mL) was in the therapeutic range, which is an acceptable level of cyclo-sporine after 6 months using the EMIT (Enzyme multi-plied immunoassay technique) assay method (2). Then lower serum creatinine levels that better reflects graft function are predictable. Although in this study, the mean of C2 levels (471 ± 148 ng/mL) was lower than thera-peutic levels (600-800 ng/mL), patients had good graft function. This result can be explained by previous simi-lar studies in Iran in which most patients at therapeutic C2 levels presented with cyclosporine nephrotoxicity or the recipients did not reach target levels, so they didn’t recommend routine checking of C2 levels (2, 3). This may be due to genetic differences in drug metabolism in dif-ferent races which can lead to different peak levels or dif-ferent peak times (for example 3 or 4 hours after taking) in Iranian patients.Another factor that may impact on graft function con-sists of the donor’s demographic data such as type (ca-daveric

Nephrotoxicity of once-daily cyclosporine A in minimal change nephrotic syndrome

Although once-daily cyclosporine (CsA) therapy may have greater nephrotoxic-sparing effects than standard twice-daily therapy, little information is available in children with steroid-dependent minimal change nephrotic syndrome (MCNS) regarding histological analysis after long-term once-daily administration. A prospective study of the clinical efficacy and comparison between pre- and post-treatment renal biopsy findings in ten children (mean age, 8.8 years) with steroid-dependent MCNS who were administered once-daily CsA therapy for more than 24 months (mean ± SD, 30 ± 3.7) was performed in Saitama Children's Medical Center. Administration of once-daily CsA therapy (mean dose, 2.8 ± 0.6 mg/kg/day; mean C2 levels, 670 ± 64 ng/ml) resulted in a significant reduction in the median relapse rate from 4.6 to 0.2 times per year, and five patients did not experience a relapse of NS. Furthermore, mean threshold of prednisolone dose significantly reduced from 1.2 to 0.02 mg/kg on alternate days. However, two patients showed evidence of chronic CsA nephrotoxicity (CsAN). Once-daily CsA therapy appears to be effective in children with steroid-dependent MCNS. However, follow-up renal biopsies should be performed to investigate the presence of CsAN after more than 24 months of treatment with once-daily regimen as well as with the conventional twice-daily regimen.

Epithelial-to-Mesenchymal Transition Predicts Cyclosporine Nephrotoxicity in Renal Transplant Recipients

Maintenance immunosuppression with cyclosporine A (CsA) can cause nephrotoxicity in renal transplant recipients. Identifying patients at increased risk for CsA nephrotoxicity may allow interventions to prolong graft survival. Here, we studied the effect of early CsA withdrawal or maintenance among 96 kidney recipients at risk for interstitial fibrosis and tubular atrophy (IF/TA) on the basis of tubular expression of vimentin and β-catenin in a protocol biopsy performed 3 months after transplant. In this retrospective analysis of biopsies collected during a randomized trial of early withdrawal of CsA or mycophenolate mofetil, the semiquantitative score of early phenotypic changes suggestive of epithelial-to-mesenchymal transition (EMT) progressed with time among those maintained on a CsA-containing regimen. EMT-positive grafts displayed a significantly higher IF/TA score and greater progression of the IF/TA score at 12 months (P=0.001 and 0.008, respectively). EMT-positive grafts exposed to CsA also had a greater decrease in estimated GFR compared with EMT-negative grafts exposed to CsA and EMT-positive grafts withdrawn from CsA exposure. Multivariable analysis revealed that the presence of EMT was an independent risk factor for a 10% decline in graft function up to 4 years posttransplant (odds ratio 4.49; 95% confidence interval 1.02 to 19.9). Collectively, these data demonstrate that changes consistent with EMT are strong prognostic biomarkers in renal transplant recipients exposed to CsA.

Expression of renal distal tubule transporters TRPM6 and NCC in a rat model of cyclosporine nephrotoxicity and effect of EGF treatment

Renal magnesium (Mg(2+)) and sodium (Na(+)) loss are well-known side effects of cyclosporine (CsA) treatment in humans, but the underlying mechanisms still remain unclear. Recently, it was shown that epidermal growth factor (EGF) stimulates Mg(2+) reabsorption in the distal convoluted tubule (DCT) via TRPM6 (Thébault S, Alexander RT, Tiel Groenestege WM, Hoenderop JG, Bindels RJ. J Am Soc Nephrol 20: 78-85, 2009). In the DCT, the final adjustment of renal sodium excretion is regulated by the thiazide-sensitive Na(+)-Cl(-) cotransporter (NCC), which is activated by the renin-angiotensin-aldosterone system (RAAS). The aim of this study was to gain more insight into the molecular mechanisms of CsA-induced hypomagnesemia and hyponatremia. Therefore, the renal expression of TRPM6, TRPM7, EGF, EGF receptor, claudin-16, claudin-19, and the NCC, and the effect of the RAAS on NCC expression, were analyzed in vivo in a rat model of CsA nephrotoxicity. Also, the effect of EGF administration on these parameters was studied. CsA significantly decreased the renal expression of TRPM6, TRPM7, NCC, and EGF, but not that of claudin-16 and claudin-19. Serum aldosterone was significantly lower in CsA-treated rats. In control rats treated with EGF, an increased renal expression of TRPM6 together with a decreased fractional excretion of Mg(2+) (FE Mg(2+)) was demonstrated. EGF did not show this beneficial effect on TRPM6 and FE Mg(2+) in CsA-treated rats. These data suggest that CsA treatment affects Mg(2+) homeostasis via the downregulation of TRPM6 in the DCT. Furthermore, CsA downregulates the NCC in the DCT, associated with an inactivation of the RAAS, resulting in renal sodium loss.

Tranilast Prevents the Progression of Chronic Cyclosporine Nephrotoxicity Through Regulation of Transforming Growth Factor β/Smad Pathways

Purpose Our aim was to investigate the role of tranilast in transforming growth factor (TGF) β/Smad pathways using a rat model of chronic cyclosporine (CsA) nephrotoxicity. Methods Thirty Sprague-Dawley (SD) rats were equally randomized in to 5 groups for gavage treatments daily for 4 weeks: normal control (N), olive oil; CsA (25 mg/kg), (M) CsA plus low-dose tranilast group (T1; CsA 25 mg/kg and tranilast 100 mg/kg); CsA plus medium-dose tranilast group (T2; CsA 25 mg/kg and tranilast 200 mg/kg); and CsA plus high-dose tranilast group (T4; CsA 25 mg/kg and tranilast 400 mg/kg). Kidneys were harvested at the end of the fourth week. TGF-β1 as well as Smad3 and Smad7 were detected by reverse-transcription polymerase chain reaction and immunohistochemistry. Results The administration of tranilast decreased the expression of TGF-β1 and Smad3 by CsA-treated rats, whereas it increased both mRNA and protein levels of Smad7. Semiquantitative analysis of mRNA production revealed these treatments to markedly reduce the amount of TGF-β1: T1: 0.8452 ± 0.0825 vs 0.8529 ± 0.0606 ( P < .05); T2: 0.8414 ± 0.0696 vs 0.8529 ± 0.0606 ( P < .05); T4: 0.8336 ± 0.0592 vs 0.8529 ± 0.0606 ( P < .05). For Smad3: T1: 0.8581 ± 0.0328 vs 0.8613 ± 0.0542 ( P < .05); T2: 0.8528 ± 0.0599 vs 0.8613 ± 0.0542 ( P < .05); T4: 0.8436 ± 0.0185 vs 0.8613 ± 0.0542 ( P < .05). The significantly elevated dose-dependent amounts of Smad7 were: T1: 0.9026 ± 0.0522 vs 0.8678 ± 0.0246, ( P < .05); T2: 0.9087 ± 0.0506 vs 0.8678 ± 0.0246 ( P < .05); T4: 0.9151 ± 0.0793 vs 0.8678 ± 0.0246 ( P < .05). Conclusion Regulation of TGF-β/Smad pathways is one of the mechanisims by which tranilast mitigates the progression of chronic CsA nephrotoxicity in rats.

The effect of 8-cyclopentyl-1,3-dipropylxanthine on the development of cyclosporin-induced acute renal failure

The effect of the selective A1-adenosine receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (CPX, 0.1 mg kg-1 i.v.) administered twice daily to rats has been assessed on the development of renal dysfunction induced by four daily injections of cyclosporin (60 mg kg-1 i.p.). The series of cyclosporin injections resulted in a polyuria accompanied by a 64-70% increase in plasma urea and creatinine concentrations and a 50% reduction in inulin clearance. However, cyclosporin administration resulted in no change in p-aminohippurate clearance nor was there any evidence of tubular necrosis or vascular damage. CPX treatment did not improve any index of renal function perturbed by cyclosporin. The findings provide evidence that adenosine does not play a role in the pathophysiology of cyclosporin nephrotoxicity.

Clinical evaluation of chronic nephrotoxicity of long‐term cyclosporine A treatment in adult patients with steroid‐dependent nephrotic syndrome

Chronic nephrotoxicity of long-term cyclosporine A (CsA) treatment is a matter of concern in patients with steroid-dependent nephrotic syndrome (SDNS). Twenty-eight adult NS patients (25, minimal-change nephrotic syndrome (NS); three, focal-segmental glomerulosclerosis) were divided into three groups. Group A was continuously treated with CsA for more than 5 years (143 ± 40 months, 1.3 ± 0.4 mg/kg per day at final analysis, n = 12); group B had been previously treated with CsA (70 ± 27 months, n = 6); and group C had been treated with corticosteroids alone (n = 10). The clinical variables related to chronic CsA nephrotoxicity were examined. In groups A and B, estimated glomerular filtration rate decreased from 86 ± 22 and 107 ± 17 to 83 ± 23 and 88 ± 13 mL/min per 1.73 m(2) , respectively, at final analysis (both P < 0.05). Serum magnesium levels in group A were significantly lower than those in group B or C (A, 1.78 ± 0.16 mg/dL; B, 2.00 ± 0.14 mg/dL; C, 2.03 ± 0.10 mg/dL; A vs B, C, P < 0.01), and a significant correlation between these and the duration of CsA treatment was found (r = -0.68, P < 0.001). There was a trend towards a correlation between the duration of CsA administration and urinary α1-microglobulin (r = 0.38, P = 0.07). Mild decrease in renal function and hypomagnesemia were found in adult SDNS patients with long-term CsA treatment. Careful monitoring of renal function, blood pressure and serum magnesium levels is necessary.

Nonrejection pathology of renal allograft biopsies: 10 years experience from a tertiary care center in north India

Renal dysfunction in allograft transplant is common and its assessment is done using Revised Banff '97 working classification, which is the accepted formulation for the evaluation of histological appearance of renal allograft biopsies. The nonrejection category under the Banff working classification of renal allograft pathology forms a large group resulting in allograft dysfunction. To evaluate the spectrum of histopathological changes seen in renal allograft dysfunction. A total of 119 renal biopsies were studied over 10 years presenting with renal allograft dysfunction from a tertiary center in North India. Majority of the biopsies were in the nonrejection category (47.1%), which included few cases of acute tubular necrosis (25.2%), cyclosporine nephrotoxicity (16%), infections (10.9%), and thrombotic microangiopathy (3.4%). The second largest category in our study was acute/active cellular rejection group (31.9%), which displayed moderate to severe tubulitis, mononuclear cell infiltrate in the interstitium, and vasculitis. Antibody-mediated rejection cases were seen in 28.6% of the renal biopsies followed by chronic allograft nephropathy cases (12.6%) showing features of tubular atrophy and interstitial fibrosis. Borderline changes with features of mild tubulitis contributed to 7.6% of the biopsies. The smallest group comprised of only 4.2%, which were within normal histological limits. Timely accurate diagnosis of renal allograft dysfunction is essential for prompt, effective management of renal transplant patients. Thus, nonrejection pathology forms a significant cause of renal dysfunction in patients with renal allograft transplantation.

Long-Term Outcome of Very Early Cyclosporine Minimization and De Novo Everolimus Therapy in Kidney Transplant Recipients: A Pharmacokinetic Guided Approach

Background Cyclosporine (CsA) nephrotoxicity is an important cause of chronic allograft dysfunction. Clinical information concerning the impact of very early CsA dose reduction in kidney transplant recipients is limited. We have examined the long-term outcomes of very early CsA dose reduction. This is synchronized with de novo everolimus and steroid therapy. Methods We enrolled 10 de novo kidney transplant recipients to receive CsA (target C 0 250–350 ng/mL) and prednisolone as initial therapy. CsA dosage was reduced by 50% at posttransplant day 7. Everolimus (target trough level, 3–8 ng/mL) was concomitantly started at the day of CsA reduction. Full pharmacokinetic studies of everolimus and CsA were studied at the period of 4–8 weeks after CsA reduction. CsA was then gradually reduced to maintain a trough level of 50–100 ng/mL and/or C max <600 ng/mL. Results The mean follow-up was 51.2 ± 3.45 months. The nadir serum creatinine was 1.03 ± 0.33 mg/dL. The mean initial estimated glomerular filtration rate (eGFR) was 97.97 ± 23.36 mL/min. The mean initial trough everolimus was 5.2 ± 1.5 ng/mL. The eGFR at 1 year, 3 years, and last follow-up was 82 ± 25, 80 ± 21, and 80 ± 25 mL/min, respectively. Patient and graft survival was 100%. Conclusion Very early CsA dose reduction synchronized with de novo everolimus therapy was associated with good long-term patient and graft survival in kidney transplant recipients. This intervention can lead to 75% CsA minimization and is associated with very good GFR by the modification of Diet in Renal Disease Formula at year 4.

Altered Expression of Tight Junction Proteins in Cyclosporine Nephrotoxicity

Background/Aims: The increased permeability of chloride in the distal cortical nephron in cyclosporine nephrotoxicity may involve the transcellular pathway mediated by the thiazide-sensitive Na⁺-Cl^– cotransporter and/or the paracellular pathway mediated by the tight junctions (TJs). Methods: Cyclosporine was subcutaneously administered to Sprague-Dawley rats for 6 (7.5 mg/kg body weight) and 2 (25 mg/kg body weight) weeks, and immunoblot analysis and immunohistochemistry were carried out from the kidneys. Electrically tight epithelial Madin-Darby canine kidney (MDCK) I cells were exposed to cyclosporine for 72 h to measure changes in transepithelial electrical resistance (ΔTER). Results: Cyclosporine treatment induced a decrease in Na⁺-Cl^– cotransporter in rat renal cortex. WNK4 protein was increased in both rat kidneys and MDCK I cells. Occludin was also increased in rat kidneys and MDCK I cells exposed to 100 ng/ml cyclosporine. In contrast, cyclosporine treatment induced a decrease in zonula occludens 1 protein abundance and no changes in claudin-1 and claudin-4 in both rat kidneys and MDCK I cells. As a measure of the barrier to small ions, ΔTER of MDCK monolayers was decreased by 100 ng/ml cyclosporine. Conclusion: Renal TJ proteins are affected by cyclosporine treatment. Changes in TJ protein assembly induced by altered expression of WNK4, occludin, and zonula occludens 1 may affect paracellular permeability.