Cyclosporine Nephrotoxicity Research Articles

Corticosteroids Augment Cyclosporine Nephrotoxicity in Pediatric Nephrotic Syndrome: Potential Role of CD163+ M2-type Macrophage

Corticosteroids Augment Cyclosporine Nephrotoxicity in Pediatric Nephrotic Syndrome: Potential Role of CD163+ M2-type Macrophage

Adult survivors of childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome treated with cyclosporine: a long-term single-center experience.

Although evidence has confirmed that cyclosporine (CS) is efficacious against childhood-onset steroid-dependent and steroid-resistant nephrotic syndrome (SD/SRNS), some patients may continue to relapse during adulthood. However, predictive factors for adult active disease and kidney complications, such as chronic kidney disease (CKD) and hypertension, in this cohort remain unknown. We conducted a retrospective study on the long-term outcomes of 81 young adults with childhood-onset SD/SRNS treated with CS. The primary endpoint was the probability of active disease into adulthood. The secondary endpoint was the probability of developing kidney complications. At the last follow-up (median age, 23.2 years; median disease duration, 15.8 years), 44 adult patients (54%) continued to have active disease, whereas 16 patients developed CKD or hypertension, respectively. The proportion of patients developing kidney complications was similar between the active disease and long-term remission groups. Young age at NS onset and history of relapse during the initial CS (median, 31 months) were independent predictive factors for active disease. Acute kidney injury at NS onset, focal segmental glomerulosclerosis, and irreversible CS nephrotoxicity were identified as risk factors for the development of CKD, whereas older age was identified as a risk factor for the development of CKD and hypertension. More than 50% of adult survivors treated with CS continued to have active disease, and each 20% developed CKD or hypertension. A long-term follow-up is necessary for patients with SD/SRNS to identify the development of kidney complications later in adulthood that can be attributed to prior disease and CS treatment in childhood, irrespective of disease activity. A higher resolution version of the Graphical abstract is available as Supplementary information.

Cyclosporine A nephropathy, its pathogenesis and management

CsA, obtained from a fungus called Tolypocladium inflatum came into medical use in 1983. Organ transplants have shown great success after the use of Cyclosporine, especially in 3- and 5-year graft survival. However, nephrotoxicity seen in the early and late periods complicates its use. It is very important to distinguish especially early toxicity from rejection attacks; because the treatments of both processes are completely different. While vasocostriction in the renal artery system is prominent in the early period, the underlying factor for late toxicity is the thickening of the arteriolar intima and the consequent decrease in tissue oxygenation. The article discusses the variants of toxicity caused by the use of cyclosporin A. Morphological changes with the use of cyclosporin A are shown in rat models. The results of our own observations on the use of prostaglandin, which demonstrated the effect of vasodilation, are also presented, which can probably be used for further studies in order to reduce the nephrotoxicity of cyclosporin A. In particular, we found that PGE2 significantly reduced vasoconstriction and reduced the toxic effect due to CsA. The limitations was the usage of these agents once, so we couldn’t continue and only gave them intravenously. However, the results obtained were found to be significant.

Geraniol protects against cyclosporine A-induced renal injury in rats: Role of Wnt/β-catenin and PPARγ signaling pathways

AimsThe nephrotoxicity of cyclosporine A (CsA) limits its use as an immunosuppressant. Wnt/β-catenin signaling is involved in the pathogenesis of both acute and chronic kidney disease, and it is inhibited by peroxisome proliferator-activated receptor gamma (PPARγ). We aimed to evaluate if geraniol, which can modulate both PPARγ and Wnt signaling, could protect against CsA-induced nephrotoxicity. Materials and methodsRats (6 groups) received the vehicle or a combination of CsA (30 mg/kg) with the vehicle, geraniol (50, 100, or 200 mg/kg), or the PPARγ agonist pioglitazone for 4 weeks. Blood pressure (BP), markers of renal injury (serum urea, serum creatinine, blood urea nitrogen, and urinary NAG), oxidative stress (glutathione peroxidase), inflammation (ICAM-1, IL-18, and NF-κB), apoptosis (caspase-3), extracellular matrix remodeling [matrix metalloproteinase-9 (MMP-9)], and fibrosis (TGF-β1, Smad3, and Smad7) were assessed. Renal histological analysis, Wnt signaling components (Wnt-4/β-catenin and E-cadherin), and PPARγ expression were evaluated. Key findingsCsA group had renal injury, as well as increased BP, renal oxidative stress, inflammation, and fibrosis. The latter changes were associated with altered renal architecture, active Wnt signaling (higher Wnt-4 and β-catenin expression and E-cadherin down-regulation), and lower PPARγ levels. Geraniol protected against kidney damage and the associated biochemical and histomorphological changes in a dose-dependent manner. The latter effects were comparable or superior to those of pioglitazone. SignificanceThe down-regulation of Wnt/β-catenin and the increase in PPARγ by geraniol suggest that both pathways are involved in its renoprotective potential. The study highlights geraniol as a valuable protective asset against chemically induced nephrotoxicity.

A Novel Dipeptidyl Peptidase-4 Inhibitor DA-1229 Ameliorates Tubulointerstitial Fibrosis in Cyclosporine Nephrotoxicity in Mice.

Cyclosporine A (CyA) is an immunosuppressive agent that induces nephrotoxicity with long-term treatment. The roles of DPP-4 and its inhibitors in cyclosporine nephrotoxicity are not fully understood. Therefore, we investigated the effects of a novel DPP-4 inhibitor, DA-1229, on the progression of renal disease in an experimental cyclosporine nephrotoxicity model. Chronic cyclosporine nephrotoxicity was induced in six-week-old male ICR mice by subcutaneous injections of CyA at a dose of 30 mg/kg for four weeks. Animals were treated with DA-1229 at a dose of 300 mg/kg per day in food for four weeks. Although DPP-4 activity did not increase in the kidneys of mice with induced cyclosporine nephrotoxicity, DA-1229 treatment significantly suppressed DPP-4 activity in both plasma and renal tissues. DPP-4 inhibition by DA-1229 led to significantly decreased albuminuria and urinary excretion of 8-isoprosatane. DPP-4 inhibition also substantially suppressed pro-inflammatory effects, profibrotic molecules, and macrophage infiltration, and led to the improvement in renal structural changes. Our results suggest that DPP-4 inhibition by DA-1229 provides renoprotective effects in an animal model of cyclosporine nephrotoxicity via antioxidant, anti-inflammatory, and anti-fibrotic mechanisms. DPP-4 inhibition may be a useful new therapeutic approach for the management of progressive renal disease in cyclosporine nephrotoxicity.

The Pattern of Cyclosporine Nephrotoxicity and Urinary Kidney Injury Molecule 1 in Allogenic Hematopoietic Stem Cell Transplant Patients

The typical immunosuppressive regimen of hematopoietic stem cell transplant includes cyclosporine. However, cyclosporine nephrotoxicity is a concern. We studied cyclosporine nephrotoxicity epidemiology in hematopoietic stem cell transplant patients and compared the pattern and urinary levels of the KIM-1 kidney injury molecule versus serum and urine creatinine levels. The study covered 10 months at Namazi Hospital, Shiraz, Iran. All patients met the following criteria: > 15 years old, received allogenic hematopoietic stem cell transplant without history of acute or chronic kidney disease, and scheduled for at least 1 week of cyclosporine treatment. Urinary and serum levels of creatinine, urea, sodium, potassium, magnesium, and the KIM-1 kidney injury molecule were measured on days 0, 3, 5, 7, 10, and 14 of cyclosporine treatment. Of 42 patients, one-third developed cyclosporine nephrotoxicity (30.95%), and median onset time was 15 days. Hypokalemia and hypomagnesemia were reported in 76.2% and 53.4% of the cohort, respectively. None of the demographic, clinical, and paraclinical parameters was significantly associated with cyclosporine nephrotoxicity. Median duration of hospital stay for patients with cyclosporine nephrotoxicity (41 days) was significantly higher (P < .001) than those without nephrotoxicity (29 days). Area under the curve for receiver operating characteristic showed that accuracy of serum creatinine (0.267; 95% CI, 0.11-0.43) at day 0 of cyclosporine treatment was significantly lower (P = .017) than the accuracy of urine creatinine (0.477; 95% CI, 0.28-0.67) and urine levels of the KIM-1 kidney injury molecule (0.594; 95% CI, 0.41-0.78). Cyclosporine nephrotoxicity is a common adverse effect in the setting of hematopoietic stem cell transplant and occurs mostly within the first 2 weeks of cyclosporine treatment. Urine KIM-1 kidney injury molecule measurement had no overall superiority and no improved accuracy over serum or urine creatinine measurements for prediction or detection of cyclosporine nephrotoxicity.

Arabic Gum Role In Ameliorating Cyclosporine- A Initiated Nephrotoxicity In Albino Rats

Recently many researchers reported that treatment using cyclosporine A in extended period in order to avoide the rejection of allograft is connected with renal impairment progress. Arabic gum is a valuable antioxidants and anti-carcinogenic factor with a protective effect against renal intoxications. This research aims at assessing the improving function of Arabic gum in ameliorating nephrotoxicity of cyclosporine A in adult rats by measuring urea and creatinine as renal function tests and histopathological changes plus redox status parameters. 80 mature rats males and females were classified into four groups during the period of expirment (45 days) first one act as control given saline; the second one was given 7.5gm/kg/day of Arabic gum ,while third group was given cyclosporine A( 25 mg/kg /day ) finally the fourth one was given 7.5gm/kg/day of Arabic gum together with the 25 mg/kg /day of cyclosporine A. Cyclosporine A group three rats had renal impairment beside injury, when reported by elevated values of urea and creatinine and renal pathological changes, relative to the first group(control) with high level of cyclosporine A in blood and bad parameters of redox status. Receiving of (Arabic gum) accompanied with (cyclosporine A) ameliorating renal damage by decreasing the level of urea and creatinine in the blood, renal histo pathological amelioration, moreover the improved parametersof antioxidant. The levels of catalase, glutathione, peroxidase and superoxide dismutase were statistically reduced as regard group three G3 (cyclosporine) which was significant relative to the control & second groups G1,G2 although significantly elevated in the fourth group which given cyclosporine plus Arabic gum when compared with the third group (cyclosporine). Arabic gum has likely to behave like natural agent opposing cyclosporine A -provoked nephrotoxicity.

MO063CHRONIC INTERSTITIAL NEPHRITIS IN AGRICULTURAL COMMUNITIES IS A TOXIN-INDUCED PROXIMAL TUBULAR NEPHROPATHY

Abstract Background and Aims 30 years after the detection of CINAC, there is no consensus on its etiology. Heat stress/dehydration and toxic exposure are the two most likely etiologies. There are no diagnostic criteria that can directly identify CINAC patients. Method Renal biopsies (RB) (18 Sri Lanka, 10 El Salvador, 1 India, 3 France) of patients with CINAC (CKD2-3) were examined by light (LM) and electron microscopy (EM) in comparison to RB of normal kidneys at implantation and 6 and 12 months of calcineurin inhibitor (CNI) therapy, transplant patients on CNI with indication biopsies (n=24), proteinuric nephropathies (n=15), light chain disease (n=4), cases on nephrotoxic drugs (lomustine, clomiphene, lithium, tenofovir, cisplatinum) and CKD of various causes (n=20). A rat study was conducted comparing histopathology of heat stress/dehydration with cyclosporine nephrotoxicity. Results In addition to previously described histopathological changes, there was a unique constellation of proximal tubular cell (PTC) findings: cellular/tubular atrophy, cell fragment shedding, weak to non-proliferative capacity of the PTC and dysmorphic lysosomes increased in size and number with a light-medium electron-dense matrix containing dispersed dark electron-dense non-membrane bound “aggregates”. Identical renal lesions were observed in 55-80% of renal transplant protocol biopsies taken after 6 and 12 months of calcineurin inhibitor (CNI) therapy and in indication biopsies, in implantation biopsies the prevalence was 6%. Several cases of nephrotoxic drugs (lomustine, clomiphene, lithium) and a subset of patients with light chain disease, all conditions that can be linked to CNI, presented the same lesion. Control RBs (n=66) of normal kidney, toxic nephropathies (tenofovir, cisplatinum), and overt proteinuric patients of different etiology to some extent could demonstrate the tubular cell changes observed by LM, but not or very rarely those that were observed by EM. Rats treated with cyclosporine for 4 weeks developed similar PTC lysosomal alterations, absent in a dehydration group. Conclusion A sensitive constellation of renal PTC lesions was detected associated with CINAC and CNI nephrotoxicity in several countries, suggesting a common new paradigm where CINAC patients are experiencing a tubulotoxic mechanism similar to CNI nephrotoxicity, the latter also being known as a direct or suggested indirect effect of pesticides.

Nephroprotective Potential of Mesenchymal Stromal Cells and Their Extracellular Vesicles in a Murine Model of Chronic Cyclosporine Nephrotoxicity.

BackgroundCell therapies and derived products have a high potential in aiding tissue and organ repairing and have therefore been considered as potential therapies for treating renal diseases. However, few studies have evaluated the impact of these therapies according to the stage of chronic kidney disease. The aim of this study was to evaluate the renoprotective effect of murine bone marrow mesenchymal stromal cells (BM-MSCs), their extracellular vesicles (EVs) and EVs-depleted conditioned medium (dCM) in an aggressive mouse model of chronic cyclosporine (CsA) nephrotoxicity in a preventive and curative manner.MethodsAfter 4 weeks of CsA-treatment (75 mg/kg daily) mice developed severe nephrotoxicity associated with a poor survival rate of 25%, and characterized by tubular vacuolization, casts, and cysts in renal histology. BM-MSC, EVs and dCM groups were administered as prophylaxis or as treatment of CsA nephrotoxicity. The effect of the cell therapies was analyzed by assessing renal function, histological damage, apoptotic cell death, and gene expression of fibrotic mediators.ResultsCombined administration of CsA and BM-MSCs ameliorated the mice survival rates (6–15%), but significantly renal function, and histological parameters, translating into a reduction of apoptosis and fibrotic markers. On the other hand, EVs and dCM administration were only associated with a partial recovery of renal function or histological damage. Better results were obtained when used as treatment rather than as prophylactic regimen i.e., cell therapy was more effective once the damage was established.ConclusionIn this study, we showed that BM-MSCs induce an improvement in renal outcomes in an animal model of CsA nephrotoxicity, particularly if the inflammatory microenvironment is already established. EVs and dCM treatment induce a partial recovery, indicating that further experiments are required to adjust timing and dose for better long-term outcomes.

Long-term functioning of kidney grafts

Purpose of the study. to study the morphological changes of long-functioning kidney transplants and determine the main causes of transplant dysfunction.&#x0D; Materials and methods. A total of 52 recipients aged 20 to 70 years were analyzed retrospectively at different times after transplant surgery (5 to 22 years).Morphological changes in the kidney transplant are comparable according to light microscopy. The morphological changes in the graft were studied in the initial and long-term period. Morphological studies were conducted in monitoring mode.&#x0D; Results. In the early period after transplantation, ischemic injuries, primary graft function, and episodes of acute rejection were taken into account. In the distant period, morphological changes were evaluated in accordance with the recommendations of the Banff-classification.&#x0D; When analyzing long-term results, antigendependent (immune) and antigen-independent (visible) factors that affect the renal transplant are distinguished. The main clinical and laboratory indicators of allografts dysfunction are increased creatinine and proteinuria.&#x0D; In antigen-dependent forms (cellular, humoral and mixed rejection), humoral rejection is the most common (25%) allografts dysfunction.&#x0D; Antigen-independent forms of dysfunction (streptococcal infection 25%, inflammatory diseases 19,2%, recurrent pathology 3,8%, signs of cyclosporine nephrotoxicity in combination with other forms was found in 59,2%, nephrosclerosis 65,4%).&#x0D; Conclusions. The data obtained suggest that antigen-dependent (immune) factors, and in particular humoral rejection, are the most common cause of allografts dysfunction, and antigenindependent factors contribute to the progression of chronic rejection and the development of nephrosclerosis.

Melatonin attenuates vascular calcification by activating autophagy via an AMPK/mTOR/ULK1 signaling pathway

Melatonin has been demonstrated to protect against calcification in cyclosporine nephrotoxicity. Autophagy may affect vascular calcification by inhibiting apoptosis and the transdifferentiation process. This study sought to explore whether melatonin attenuates vascular calcification by regulating autophagy via the AMP-activated protein kinase/mammalian target of rapamycin/Unc-51-like kinase 1 (AMPK/mTOR/ULK1) signaling pathway. The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualised by Alizarin red staining, while calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure expression of runt-related transcription factor 2 (Runx2, an osteogenic transcription factor), light chain 3 (LC3) II/I, and cleaved caspase 3. Melatonin markedly reduced calcium deposition and ALP activity. Runx2 and cleaved caspase 3 were downregulated, whereas LC3 II/I was increased in response to melatonin, and was accompanied by decreased apoptosis. An immunofluorescence assay revealed that melatonin treatment markedly decreased Runx2 expression and upregulated LC3 expression. Treatment with the autophagy inhibitor 3-methyladenine reversed this phenomenon. Melatonin significantly increased expression of p-AMPK and p-ULK1, and decreased mTOR expression. Treatment with compound C (an inhibitor of AMPK) or MHY1485 (an agonist of mTOR) ablated the observed benefits of melatonin treatment. Melatonin protects VSMCs against calcification by activating autophagy via the AMPK/mTOR/ULK1 pathway.

Urinary Concentration Defect and Renal Glycosuria in Cyclosporine-treated Rats.

BackgroundUrinary concentration impairment is a major feature of cyclosporine nephrotoxicity.MethodsWe explored two possible mechanisms that may underlie cyclosporine-induced polyuria; water, and/or osmotic diuresis. Cyclosporine was subcutaneously injected to normal salt-fed Sprague-Dawley rats at a daily dose of 25mg/kg for 2 weeks (Experiment I) and 7.5mg/kg for 6 weeks (Experiment II).ResultsIn Experiment I, cyclosporine treatment caused an increase in urine volume (2.7±0.5 vs. 10.3±1.13mL/d/100 g BW, p<0.001) and a decrease in urine osmolality (2,831±554 vs. 1,379±478mOsm/kg H2O, p<0.05). Aquaporin-2 (AQP2) protein expression decreased in cyclosporine-treated rat kidneys (cortex, 78±8%, p<0.05; medulla, 80±1%, p<0.05). Experiment II also showed that urine volume was increased by cyclosporine treatment (4.97±0.66 vs. 9.65±1.76mL/d/100 g BW, p<0.05). Whereas urine osmolality was not affected, urinary excretion of osmoles was increased (7.5±0.4 vs. 14.9±1.4mosmoles/d/100 g BW, p<0.005). Notably, urinary excretion of glucose increased in cyclosporine-treated rats (7±1 vs. 10,932±2,462 mg/d/100 g BW, p<0.005) without a significant elevation in plasma glucose. In both Experiment I and II, GLUT2 protein expression in the renal cortex was decreased by cyclosporine treatment (Experiment I, 55±6%, p<0.005; Experiment II, 88±3%, p<0.05).ConclusionBoth water diuresis and osmotic diuresis are induced by cyclosporine nephrotoxicity. AQP2 and GLUT2 downregulation may underlie water and osmotic diuresis, respectively.

Melatonin Attenuates β-Glycerophosphate-Induced Calcification of Vascular Smooth Muscle Cells via a Wnt1/β-Catenin Signaling Pathway.

Background Melatonin has been demonstrated to protect against calcification in cyclosporine nephrotoxicity. The wingless-type MMTV integration site family member 1 (Wnt1)/β-catenin pathway is associated with cardiovascular calcification. This study aimed to explore whether melatonin could attenuate VSMC calcification through regulating the Wnt1/β-catenin signaling pathway. Methods The effects of melatonin on vascular calcification were investigated in vascular smooth muscle cells (VSMCs). Calcium deposits were visualized by Alizarin Red Staining. Calcium content and alkaline phosphatase (ALP) activity were used to evaluate osteogenic differentiation. Western blots were used to measure the expression of runt-related transcription factor 2 (Runx2), α-smooth muscle actin (α-SMA), and cleaved caspase-3. Results Melatonin markedly ameliorated calcium deposition and ALP activity. Runx2 and cleaved caspase-3 were found to be reduced and α-SMA was found to be increased by melatonin, together with a decrease in apoptosis. Immunofluorescence assay revealed a lower Runx2 protein level in the melatonin group. Melatonin treatment significantly decreased the expression of Wnt1 and β-catenin. Treatment with lithium chloride or transglutaminase 2 abrogated the protective effects of melatonin. Conclusion Melatonin can attenuate β-GP-induced VSMC calcification through the suppression of Wnt1/β-catenin system.

Tauroursodeoxycholic acid attenuates cyclosporine-induced renal fibrogenesis in the mouse model

Chronic exposure to cyclosporine causes nephrotoxicity and organ damage. Here we show that cyclosporine nephrotoxicity in vivo is associated with the activation of the unfolded protein response (UPR) pathway to initiate tissue fibrosis. We demonstrate that cyclosporine therapy activated the IRE1α branch of the unfolded protein response (UPR) and stimulated the TGFβ1 signaling pathway in the kidneys of male mice. Co-administration of the proteostasis promoter tauroursodeoxycholic acid (TUDCA) with cyclosporine inhibited the UPR pathway in the kidneys of treated male mice as well as decreased the development of renal fibrogenesis.

Magnetic resonance imaging T1- and T2-mapping to assess renal structure and function: a systematic review and statement paper.

This systematic review, initiated by the European Cooperation in Science and Technology Action Magnetic Resonance Imaging Biomarkers for Chronic Kidney Disease (PARENCHIMA), focuses on potential clinical applications of magnetic resonance imaging in renal non-tumour disease using magnetic resonance relaxometry (MRR), specifically, the measurement of the independent quantitative magnetic resonance relaxation times T1 and T2 at 1.5 and 3Tesla (T), respectively. Healthy subjects show a distinguishable cortico-medullary differentiation (CMD) in T1 and a slight CMD in T2. Increased cortical T1 values, that is, reduced T1 CMD, were reported in acute allograft rejection (AAR) and diminished T1 CMD in chronic allograft rejection. However, ambiguous findings were reported and AAR could not be sufficiently differentiated from acute tubular necrosis and cyclosporine nephrotoxicity. Despite this, one recent quantitative study showed in renal transplants a direct correlation between fibrosis and T1 CMD. Additionally, various renal diseases, including renal transplants, showed a moderate to strong correlation between T1 CMD and renal function. Recent T2 studies observed increased values in renal transplants compared with healthy subjects and in early-stage autosomal dominant polycystic kidney disease (ADPKD), which could improve diagnosis and progression assessment compared with total kidney volume alone in early-stage ADPKD. Renal MRR is suggested to be sensitive to renal perfusion, ischaemia/oxygenation, oedema, fibrosis, hydration and comorbidities, which reduce specificity. Due to the lack of standardization in patient preparation, acquisition protocols and adequate patient selection, no widely accepted reference values are currently available. Therefore this review encourages efforts to optimize and standardize (multi-parametric) protocols to increase specificity and to tap the full potential of renal MRR in future research.

Molecular basis of the counteraction by calcium channel blockers of cyclosporine nephrotoxicity.

Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine A(CSA). In this study, we tested the hypothesis that administration of calcium channel blockers such as verapamil or nifedipine ameliorates renal CSA-induced renal dysfunction. Furthermore, our study investigates the roles of inflammatory, oxidative, and fibrotic pathways in CSA-induced renal dysfunction. Six groups of male rats ( n = 6/group) were used and received one of the following treatments for seven consecutive days: vehicle (Cremophor EL ip), CSA (25 mg·kg-1·day-1 ip), verapamil (2 mg·kg-1·day-1 ip), nifedipine (3 mg·kg-1·day-1 ip), CSA in the presence or absence of either verapamil, or nifedipine. Biochemical and histomorphometric analyses showed that rats treated with CSA exhibited clear signs of nephrotoxicity that included 1) proteinuria and elevations in serum creatinine and blood urea nitrogen, 2) mesangial expansion, 3) increases in glomerular and tubular type IV collagen expression, and 4) increases in the glomerulosclerosis and tubulointerstitial fibrosis indices. Although the single administration of nifedipine or verapamil had no significant effect on renal pathology, or its biochemical and physiological function, the concurrent use of either calcium channel blockers significantly and equipotently ameliorated the biochemical, morphological, and functional derangements caused by CSA. More importantly, we report that the oxidative (reactive oxygen species production, NADPH-oxidase activity, and dual oxidase 1/2 levels), fibrotic (transforming growth factor-β1 expression), and inflammatory (NF-κB expression) manifestations of renal toxicity induced by CSA were significantly reversed upon administration of nifedipine or verapamil. Together, these results highlight the efficacy of calcium channel-blocking agents in attenuating CSA-induced nephrotoxicity and predisposing biochemical and molecular machineries.

Effects of Atorvastatin and Carvedilol on Chronic Cyclosporine Nephrotoxicity in Rats

Background: To evaluate possible renoprotective effects of carvedilol and atorvastatin in CsA induced kidney injury in a rat model. Methods: Twenty-two rats were divided into five groups. Control, CsA, CsA+karvedilol, CsA+Atorvastatin, CsA +karvedilol+atorvastatin groups. Drugs were given for 21 days. Results: Serum BUN and creatinine were significantly higher in the CsA group compared to control and were significantly lower in the CsA+carvedilol+atorvastatin group compared to CsA group. Tissue MDA levels were found to be lower in group 3, 4 and 5 than in CsA group. Tissue SOD in CsA +carvedilol and CsA+atorvastatin groups were found higher than the control and CsA groups. Tissue NO levels were found to be higher only in CsA+carvedilol+atorvastatin group compared to CsA group. Apical budding, hyaline casts and apoptosis in the tubular system was significantly higher in the CsA group than in the treatment groups. Osteopontin showed strong positivity especially in the CsA group. Osteopontin density was lower in the treatment group. Conclusions: This is the first study to evaluate MDA, SOD and NO at tissue level for carvedilol in cyclosporine nephrotoxicity. Carvedilol and atorvastatin may contribute to the reduction of renal injury in chronic CsA nehropathy. These agents have provided a protective effect on renal functions especially in combined treatment.

The Effects of Valsartan on Renal Klotho Expression and Oxidative Stress in Alleviation of Cyclosporine Nephrotoxicity: Retraction.

The Effects of Valsartan on Renal Klotho Expression and Oxidative Stress in Alleviation of Cyclosporine Nephrotoxicity: Retraction.

The Effects of Valsartan on Renal Klotho Expression and Oxidative Stress in Alleviation of Cyclosporine Nephrotoxicity.

Nephrotoxicity side effect of the immunosuppressive drug, cyclosporine A (CsA), can be a major issue in transplantation medicine. Cyclosporine A-induced nephrotoxicity is multifactorial but oxidative stress has a critical role in this process. It has been demonstrated that Valsartan (Val) as an angiotensin receptor blocker has renoprotective effects, but the molecular mechanisms responsible for the renal protection, independent from its blood pressure lowering effect, have not yet been fully understood. The present study is aim at evaluating the Val effect in alleviation of CsA nephrotoxicity by probable increase in renal Klotho expression and/or reducing oxidative stress. Thirty-two Sprague-Dawley rats were divided into 4 groups based on the administration of CsA and/or Val: group A (control, 1 mL/kg per day of olive oil as vehicle), group B (CsA, 30 mg/kg per day), group C (CsA + Val, 30 + 30 mg/kg per day), and group D (Val, 30 mg/kg per day). Real-time polymerase chain reaction and Western blotting were used to evaluate Renal Klotho expression. Serum Klotho level was measured by enzyme-linked immunosorbent assay. 8-Hydroxy-deoxy guanosine and malondialdehyde levels as markers of oxidative stress were measured by enzyme-linked immunosorbent assay and spectrophotometrically, respectively. Cyclosporine A treatment reduced renal expression and serum levels of Klotho, improved malondialdehyde and 8-hydroxy-deoxy guanosine levels, and also deteriorated renal function. Valsartan prevented CsA-induced oxidative stress as well as Klotho downregulation and could alleviate CsA-induced renal histological changes and function. Administration of Val might lead to amelioration of CsA nephrotoxicity by probably diminishing CsA-induced renal Klotho downregulation and oxidative stress.

Molecular Mechanisms of the Protective Effects of Calcium Channel Blockers against Cyclosporine Nephrotoxicity in Rats

Nephrotoxicity is a serious side effect for the immunosuppressant drug cyclosporine (CSA). In this study, we tested the hypothesis that the concurrent administration of calcium channel blockers such as verapamil or nifedipine guard against renal dysfunction induced by CSA in rats. Studies were then extended to investigate the roles of inflammatory, oxidative, and fibrotic pathways in the interaction. Six groups of male rats (n=6 each) were employed and allocated to receive one of the following treatments for 7 consecutive days: vehicle (cremophor), CSA (25 mg.kg−1.day−1), verapamil (2 mg.kg−1.day−1), nifedipine (3 mg.kg−1.day−1), CSA plus verapamil, or CSA plus nifedipine. Biochemical and histomorphometric analyses showed that compared with respective vehicle values, rats treated with CSA exhibited clear signs of nephrotoxicity that included: (i) proteinuria and elevations in serum creatinine and blood urea nitrogen, (ii) deposition of collagen IV in glomerular and tubular areas, and (iii) increases in the glomerulosclerosis index. While the single administration of nifedipine or verapamil caused no specific renal effects, the concurrent use of either calcium channel blocker significantly and equipotently ameliorated the biochemical and morphological derangements caused by CSA. We also report that the inflammatory (NF‐κB expression), oxidative (NADPH‐oxidase activity, reactive oxygen species production), and fibrotic (TGF‐β1 expression) manifestations of renal toxicity induced by CSA were eliminated upon concurrent administration of nifedipine or verapamil. Together, these results highlight the usefulness of calcium channel blocking agents in negating the CSA‐induced nephrotoxicity and predisposing biochemical and molecular machinaries.Support or Funding InformationSupported by the Lebanese National Council for Scientific Research (CNRS) Grant Award for Lebanese graduates (Awardee: Safaa Hammoud)