Cyclosporine-induced Nephrotoxicity Research Articles

Mitochondrial SIRT3 as a protective factor against cyclosporine A-induced nephrotoxicity

Sirtuin3 (SIRT3), a mitochondrial deacetylase, has been shown to be involved in various kidney diseases. In this study, we aimed to clarify the role of SIRT3 in cyclosporine-induced nephrotoxicity and the associated mitochondrial dysfunction. Madin-Darby canine kidney (MDCK) cells were transfected with Flag-tagged SIRT3 for SIRT3 overexpression or SIRT3 siRNA for the inhibition of SIRT3. Subsequently, the cells were treated with cyclosporine A (CsA) or vehicle. Wild-type and SIRT3 knockout (KO) mice were randomly assigned to receive cyclosporine A or olive oil. Furthermore, SIRT3 activator, honokiol, was treated alongside CsA to wild type mice. Our results revealed that CsA treatment inhibited mitochondrial SIRT3 expression in MDCK cells. Inhibition of SIRT3 through siRNA transfection exacerbated apoptosis, impaired the expression of the AMP-activated protein kinase-peroxisome proliferator-activated receptor gamma coactivator 1 alpha (AMPK-PGC1α) pathway, and worsened mitochondrial dysfunction induced by CsA treatment. Conversely, overexpression of SIRT3 through Flag-tagged SIRT3 transfection ameliorated apoptosis, increased the expression of mitochondrial superoxide dismutase 2, and restored the mitochondrial regulator pathway, AMPK-PGC1α. In SIRT3 KO mice, CsA treatment led to aggravated kidney dysfunction, increased kidney tubular injury, and accumulation of oxidative end products indicative of oxidative stress injury. Meanwhile, SIRT3 activation in vivo significantly mitigated these adverse effects, improving kidney function, reducing oxidative stress markers, and enhancing mitochondrial health following CsA treatment. Overall, our findings suggest that SIRT3 plays a protective role in alleviating mitochondrial dysfunction caused by CsA through the activation of the AMPK-PGC1α pathway, thereby preventing further kidney injury.

Palliative Role of Zamzam Water against Cyclosporine-Induced Nephrotoxicity through Modulating Autophagy and Apoptosis Crosstalk.

Cyclosporine (CsA) is considered one of the main components of treatment protocols for organ transplantation owing to its immunosuppressive effect. However, its use is very restricted due to its nephrotoxic effect. ZW is an alkaline fluid rich in various trace elements and has a great ability to stimulate antioxidant processes. This study aimed to investigate the possible mitigating effect of ZW on CsA-induced nephrotoxicity and its underlying mechanisms. Forty rats were allocated into four groups (n = 10): a control group, ZW group, cyclosporine A group (injected subcutaneously (SC) with CsA (20 mg/kg/day)), and cyclosporine A+ Zamzam water group (administered CsA (SC) and ZW as their only drinking water (100 mL/cage/day) for 21 days). Exposure to CsA significantly (p < 0.001) increased the serum creatinine level, lipid peroxidation marker level (malondialdehyde; MDA), and the expression of apoptotic markers procaspase-8, caspase-8, caspase- 9, calpain, cytochrome c, caspas-3, P62, and mTOR in renal tissues. Meanwhile, it markedly decreased (p< 0.001) the autophagic markers (AMPK, ULK-I, ATag5, LC3, and Beclin-1), antiapoptotic Bcl-2, and antioxidant enzymes. Moreover, the administration of CsA caused histological alterations in renal tissues. ZW significantly (p < 0.001) reversed all the changes caused by CsA and conclusively achieved a positive outcome in restraining CsA-induced nephrotoxicity, as indicated by the restoration of the histological architecture, improvement of renal function, inhibition of apoptosis, and enhancement of autophagy via the AMPK/mTOR pathway.

Pomegranate attenuates kidney injury in cyclosporine-induced nephrotoxicity in rats by suppressing oxidative stress

Abstract To investigate the effect of pomegranate juice (PJ) on the cyclosporine (CsA)-induced nephrotoxicity in rats, 80 rats were divided into four groups. The first group was regarded a negative control group, and the others were as follows: group 2 (CsA group) received CsA in a dose of 25 mg/kg/day orally, group 3 (treated group) received CsA in a dose of 25 mg/kg/day plus 2.5 mL/day of PJ, and group 4 (PJ group) received 2.5 mL of PJ daily. By the end of the 21st day, plasma creatinine, blood urea nitrogen (BUN), creatinine clearance, urinary KIM-1, and NGAL were determined. Histopathological investigation and the determination of malondialdehyde and antioxidant enzymes were analyzed in kidney tissues. The results show that plasma creatinine, BUN, creatinine clearance, and kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were significantly altered in the CsA group. The supplement of PJ attenuated the alteration in these parameters. The treatment with PJ also prohibits the CsA-induced alteration in the histopathology, lipid peroxidation, and antioxidant enzymes. We can conclude that PJ protects against CsA-induced nephrotoxicity due to its antioxidant effects.

FC074: Mineralocorticoid Receptor Drives Parietal Epithelial Cell Activation and Glomerular Injury During Crescentic Glomerulonephritis

Abstract BACKGROUND AND AIMS We have recently demonstrated that targeting specific pathways in parietal epithelial cells (PEC) can markedly alleviate experimental extracapillary glomerular injury (1). Accumulating evidence has indicated the potential contributions of aldosterone and mineralocorticoid receptor (MR) to the pathophysiology of chronic kidney disease. MR is strongly expressed in endothelial cells, glomerular mesangial cells, podocytes and distal tubular cells. Previous studies have shown that administration of mineralocorticoid receptor antagonists, including spironolactone and eplerenone, has beneficial effects in various renal injury animal models, such as unilateral ureteral obstruction, ischemia-reperfusion, cyclosporine-induced nephrotoxicity and hypertensive renal injury. The role of the MR in extra capillary glomerulopathies is still elusive and mechanistically unclear. METHOD To investigate the cell-specific role of the MR in PEC in the course of crescentic glomerulonephritis, we generated chimeric mice specifically lacking MR (Pec Cre Nr3c2lox/lox) in PECs using an inducible Cre recombinase system. Crescentic glomerulonephritis (GN) was induced using the antiglomerular basement membrane nephrotoxic serum (NTS) model. In vivo, biological parameters (albuminuria, blood urea nitrogen—BUN), glomerular injury, as well as PEC activation (CD44, CD9 and fibronectin staining) were assessed. RESULTS At baseline, Pec Cre Nr3c2wt/wt and Pec Cre Nr3c2lox/lox mice displayed no kidney morphology and function differences. When challenged using the NTS model, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function as compared to Pec Cre Nr3c2 wt/wt counterparts. Crescents were also more numerous and organized in Pec Cre Nr3c2wt/wt mice. Next, we examined whether pharmacological MR inhibition could alleviate the severity of crescentic GN. When Pec Cre Nr3c2wt/wt mice were orally given eplerenone for 14 days after the onset of the crescentic GN, they were significantly protected from renal injury and failure (decreased proteinuria, normal BUN and reduced number of crescent). Such global action was associated with less activation molecule CD44 on PECs. Thus, genetic disruption of MR in PEC as well as pharmacological inhibition using eplerenone reduced glomerular expression of CD44 and crescent formation. Furthermore, kidney biopsies of individuals diagnosed with crescentic glomerulonephritis displayed increased expression of MR in PEC and crescents. CONCLUSION Altogether, these results indicate the critical role of MR in PEC activation during crescentic glomerulonephritis along with the recently discovered CD9/EGFR/PDGFR pathway. This further supports the idea that the PEC phenotype switch is not a bystander event but plays a targetable critical active pathogenic role in crescentic GN. MR modulation using eplerenone may be a new therapeutic option for the management of such severe disease.

Ferulic acid prevents cyclosporine-induced nephrotoxicity in rats through exerting anti-oxidant and anti-inflammatory effects via activation of Nrf2/HO-1 signaling and suppression of NF-κB/TNF-α axis.

Cyclosporine is one of the main immunosuppressive agents used in the treatment of autoimmune diseases or transplantation. Despite the favorable effects, cyclosporine-mediated nephrotoxicity critically restricts the clinical use of the agent. Given this, herein, we aimed to evaluate whether ferulic acid could prevent cyclosporine-mediated nephrotoxicity in rats. A total of 32 Wistar rats were chosen to be treated with cyclosporine, ferulic acid, and the combination of both agents for 21days. To evaluate the nephron-protective mechanism of ferulic acid, the serum levels of biochemical parameters, as well as the tissue levels of several oxidative and anti-oxidative mediators, were examined. The expression and the tissue levels of nuclear factor (NF)-κB, tumor necrosis factor (TNF)-α, heme oxygenase (HO-1), and nuclear factor erythroid 2-related factor 2 (Nrf2) were evaluated using the qRT-PCR and ELISA, respectively. Our results showed while cyclosporine elevated the serum levels of renal-related markers in the rats, in the presence of ferulic acid, there was a significant reduction in the levels of urea, uric acid, creatinine, and sGOT. Moreover, we found that ferulic acid remarkably prevented cyclosporine-mediated nephrotoxicity by restoring the anti-oxidant system through activating the Nrf2/HO-1 axis. By halting the NF-κB-mediated upregulation of TNF-α, it also seems that ferulic acid prevented lymphocytes infiltration into kidney tissue and consequently suppressed inflammatory responses. Overall, the results of the present study suggest that due to the anti-oxidant and anti-inflammatory properties of ferulic acid, this agent could be used alongside cyclosporine to reduce its adverse effects on kidney tissue.

Mechanism and reversal of drug-induced nephrotoxicity on a chip.

The kidney plays a critical role in fluid homeostasis, glucose control, and drug excretion. Loss of kidney function due to drug-induced nephrotoxicity affects over 20% of the adult population. The kidney proximal tubule is a complex vascularized structure that is particularly vulnerable to drug-induced nephrotoxicity. Here, we introduce a model of vascularized human kidney spheroids with integrated tissue-embedded microsensors for oxygen, glucose, lactate, and glutamine, providing real-time assessment of cellular metabolism. Our model shows that both the immunosuppressive drug cyclosporine and the anticancer drug cisplatin disrupt proximal tubule polarity at subtoxic concentrations, leading to glucose accumulation and lipotoxicity. Impeding glucose reabsorption using glucose transport inhibitors blocked cyclosporine and cisplatin toxicity by 1000- to 3-fold, respectively. Retrospective study of 247 patients who were diagnosed with kidney damage receiving cyclosporine or cisplatin in combination with the sodium-glucose cotransporter-2 (SGLT2) inhibitor empagliflozin showed significant (P < 0.001) improvement of kidney function, as well as reduction in creatinine and uric acid, markers of kidney damage. These results demonstrate the potential of sensor-integrated kidney-on-chip platforms to elucidate mechanisms of action and rapidly reformulate effective therapeutic solutions, increasing drug safety and reducing the cost of clinical and commercial failures.

Risk factors for increased serum creatinine level in patients with psoriasis treated with cyclosporine in a real-world practice.

Nephrotoxicity is a major concern for patients with psoriasis using cyclosporine. Here, we evaluated the impact of intermittent cyclosporine treatment on nephrotoxicity risk among patients with psoriasis in real-world clinical practice. We retrospectively reviewed 611 patients with psoriasis treated with cyclosporine between January 2013 and January 2017, 398 of whom were considered eligible for analysis. Eighteen (4.5%) patients showed a greater than 25% increase in serum creatinine levels. Age over 60 years (relative risk [RR], 1.6; p = .015), diabetes (RR, 2.3; p < .001), and obesity (RR, 1.7; p = .011) were the significant risk factors of increased serum creatinine levels in patients with psoriasis. There was no significant association of the treatment duration or cumulative dose of cyclosporine with increased serum creatinine levels. In real clinical practice, intermittent cyclosporine use with regular serum creatinine tests can be used to treat psoriasis relatively safely. Age over 60 years, diabetes and obesity are significant risk factors for cyclosporine-induced nephrotoxicity.

Relationship between allograft cyclosporin concentrations and P-glycoprotein expression in the 1st month following renal transplantation.

The immunosuppressant cyclosporin is a P-glycoprotein (P-gp) substrate whose impaired function has been associated with an increased risk of cyclosporin-induced nephrotoxicity following renal transplantation. This study investigated the relationship between blood and allograft cyclosporin concentration, and the effect of P-gp expression. Fifty biopsy samples were obtained from 39 renal transplant recipients who received cyclosporin as part of maintenance immunosuppression. Blood cyclosporin concentrations (2hours postdose) were obtained from clinical records, matching allograft cyclosporin concentrations were measured in frozen biopsy tissue by liquid chromatography-tandem mass spectrometry, and allograft P-gp expression was assessed by immunohistochemistry. Blood and allograft cyclosporin concentrations in the 1st month post-transplantation ranged from 505-2005μg/L and 0.01-16.7ng/mg tissue, respectively. Dose was the only significant predictor of allograft cyclosporin concentrations (adjusted R2 =.24, F-statistic=11.52, P=.0019), with no effect of P-gp expression or blood cyclosporin concentrations. P-gp expression is not the major determinant of allograft cyclosporin concentrations.

Oxidative stress-induced renal telomere shortening as a mechanism of cyclosporine-induced nephrotoxicity.

Due to the association of oxidative stress and telomere shortening, it was aimed in the present study to investigate the possibility whether cyclosporine-A exerts its nephrotoxic side effects via induction of oxidative stress-induced renal telomere shortening and senescent phenotype in renal tissues of rats. Renal oxidative stress markers, 8-hydroxydeoxyguanosine, malondialdehyde, and protein carbonyl groups were measured by standard methods. Telomere length and telomerase activity were also evaluated in kidney tissue samples. Results showed that cyclosporine-A treatment significantly (P<0.05) enhanced renal malondialdehyde, 8-hydroxydeoxyguanosine, and protein carbonyl groups levels, decreased renal telomere length, and deteriorated renal function compared with the controls. Renal telomerase activity was not affected by cyclosporine-A. Renal telomere length could be considered as an important parameter of both oxidative stress and kidney function. Telomere shortening and accelerated kidney aging may be caused by cyclosporine-induced oxidative stress, indicating the potential mechanism of cyclosporine-induced nephrotoxicity.

Managing a side effect: Cyclosporine-Induced nephrotoxicity

Managing a side effect: Cyclosporine-Induced nephrotoxicity

Defining a microRNA-mRNA interaction map for calcineurin inhibitor induced nephrotoxicity.

Calcineurin inhibitors induce nephrotoxicity through poorly understood mechanisms thereby limiting their use in transplantation and other diseases. Here we define a microRNA (miRNA)-messenger RNA (mRNA) interaction map that facilitates exploration into the role of miRNAs in cyclosporine-induced nephrotoxicity (CIN) and the gene pathways they regulate. Using photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we isolated RNAs associated with Argonaute 2 in the RNA-induced silencing complex (RISC) of cyclosporine A (CsA) treated and control human proximal tubule cells and identified mRNAs undergoing active targeting by miRNAs. CsA causes specific changes in miRNAs and mRNAs associated with RISC, thereby altering post-transcriptional regulation of gene expression. Pathway enrichment analysis identified canonical pathways regulated by miRNAs specifically following CsA treatment. RNA-seq performed on total RNA indicated that only a fraction of total miRNAs and mRNAs are actively targeted in the RISC, indicating that PAR-CLIP more accurately defines meaningful targeting interactions. Our data also revealed a role for miRNAs in calcineurin-independent regulation of JNK and p38 MAPKs caused by targeting of MAP3K1. Together, our data provide a novel resource and unique insights into molecular pathways regulated by miRNAs in CIN. The gene pathways and miRNAs defined may represent novel targets to reduce calcineurin induced nephrotoxicity.

Nebivolol suppresses asymmetric dimethylarginine and attenuates cyclosporine-induced nephrotoxicity and endothelial dysfunction in rats.

Cyclosporine A (CsA)-induced nephrotoxicity is a challenging problem complicating its chronic use in a large array of autoimmune diseases, as well as in organ transplantation. A considerable body of evidence points to the involvement of nitric oxide (NO) and its endogenous synthesis inhibitor, asymmetric dimethylarginine (ADMA), in CsA-induced renal and cardiovascular adverse effects. In this study, the potential of the third generation β-blocker, nebivolol, to modify the NO/ADMA system is hypothesized to play a role in protection against CsA-induced renal injury and endothelial dysfunction. Both in vivo and in vitro studies were carried out on 36 male Wistar rats randomly divided into three groups; normal control, CsA (30mg/kg/day)-treated or CsA+nebivolol (30mg/kg and 1mg/kg daily, respectively)-treated groups. After four weeks, blood pressure, lipid profile, renal functions, renal oxidative status, NO, inducible NO synthase and ADMA were assessed. In vitro evaluation of vascular relaxant responses of norepinephrine pre-contracted aortic rings to acetylcholine (ACh) and sodium nitroprusside were evaluated. Concurrent nebivolol treatment significantly attenuated CsA-induced hypertension, impairment of renal functions, oxidative stress and restored the balance in renal NO system with lowering of the elevated ADMA. This was associated with favourable effects on lipid profile. Nebivolol treatment also abrogated the CsA-induced impairment of relaxant responses of aortic rings to ACh. Nebivolol possesses multifaceted actions that make it advantageous to combat the CsA-induced toxic effects on renal and endothelial functions.

MicroRNA-494 Promotes Cyclosporine-Induced Nephrotoxicity and Epithelial to Mesenchymal Transition by Inhibiting PTEN

A major complication associated with cyclosporine (CsA) treatment is nephrotoxicity. In this study, we examined whether microRNAs play a role in cyclosporine-induced nephrotoxicity. Treatment of mice with CsA resulted in nephrotoxicity that was associated with an early increase in expression of microRNA mmu-miR-494 (miR-494). Similarly, tubular epithelial cell epithelial-mesenchymal transition (EMT) induced by CsA toxicity resulted in the upregulation of microRNA-494 and a decrease in PTEN levels in vitro. miR-494 directly targeted Pten and negatively regulated its expression. Preventing Pten targeting by miR-494 was sufficient to prevent CsA induced EMT. Knockdown of miR-494 prevented the downregulation of PTEN in tubular epithelial cells following CsA treatment and also prevented CsA induced EMT. Thus, miR-494 plays a major role in promoting CsA induced nephrotoxicity through its ability to target Pten thereby contributing to EMT. We suggest that manipulating miR-494 expression may represent a novel approach to preventing EMT associated with CsA induced nephrotoxicity.

Plant flavone apigenin protects against cyclosporine-induced histological and biochemical changes in the kidney in rats

Cyclosporine (CsA) is an immunosuppressant drug universally used for the prevention of transplant rejection and also for the treatment of autoimmune diseases. Use of cyclosporine has been limited by its side effects such as hypertension and renal damage. Antioxidants are known to protect free radical induced damage of tissues during drug toxicity. The aim of this study was to test the role of plant flavone apigenin against cyclosporine-induced nephrotoxicity. Adult male Sprague Dawley rats were randomly divided into control, cyclosporine alone, and cyclosporine with apigenin (10, 15 and 20mg/kg). Cyclosporine treatment was continued for 21days to induce nephrotoxicity. From the blood samples, urea, uric acid, total antioxidants and lipid hydroperoxide assays were done. There was a significant renal damage with cyclosporine alone treatment. Blood urea nitrogen, urea, uric acid and lipid hydroperoxides were significantly elevated whereas there was a significant decrease in the total antioxidant levels. Treatment with apigenin significantly reduced the lipid hydroperoxides and increased the total antioxidant levels. Concurrent apigenin treatment significantly reduced the histopathological changes in the CsA treated groups. In conclusion, the study confirmed the role of oxidative stress in the pathogenesis of cyclosporine-induced nephrotoxicity and protective effects of flavone apigenin against free radical-induced renal damage.

Effects of hydrogen sulphide on cyclosporin induced nephrotoxicity at reperfusion

Effects of hydrogen sulphide on cyclosporin induced nephrotoxicity at reperfusion

0339: Does mineralocorticoid receptor antoganism could alleviate cyclosporin-induced nephrotoxicity in renal transplant recipients?

Cyclosporine-induced Nephrotoxicity (CIN) is a major adverse event but its pathophysiology remains unclear. Mineralocorticoid Receptor (MR) pharmacological antagonism prevents CIN in rats by modulating the expression of vasoactive factors. Our team has shown that MR is expressed in endothelial and vascular smooth muscle cells (VSMC). Therefore, genetic MR manipulations in endothelium or VSMC modify vascular function. Our working hypothesis is that vascular MR activation plays a key role in CIN. Female mice with low-salt diet were used: 1) Pharmacological approach: Control (Vehicle), Cyclosporine-A (CsA, 100 mg/kg/d) and CsA + Can (CsA + Canrenoate 30 mg/kg/d, MR antagonist); 2) Genetic approach: MR KO in VSMC (MRKO-VSMC) or in Endothelial Cells (MRKO-EC) treated or not with CsA. Body weight loss is greater in Cyclosporine-treated groups (p<0.05). Renal function is impaired (p<0.05) and CsA induces renal histological damages that are prevented by MR antagonism or by MR KO in VSMC but not in endothelial cells. Canrenoate and MR KO in VSMC also prevent Cyclosporine-induced renal expression (mRNA) of NGAL (Neutrophil Gelatinase Associated Lipocalin), a kidney damage marker. CsA induced NGAL expression in proximal tubules (immunohistochemistry); this effect is prevented by MR antagonism and MR KO in VSMC but not in endothelial cells. We show that MR antagonism has beneficial effect on Cyclosporine-induced renal damages that, at least partially, involve VSMC MR. The underlying cellular mechanisms are currently under investigation. A clinical trial testing the safety of MR antagonism (Eplerenone) in renal transplant recipients treated with Cyclosporine is currently ongoing.

Statins Against Drug-Induced Nephrotoxicity

Drug-induced nephrotoxicity (DIN) accounts for up to 60% of hospital acquired acute kidney injury with considerable morbidity and mortality. Several efforts have been made to reduce drug-induced nephrotoxicity; however, DIN remains a matter of concern. Statins with their antioxidant, anti-inflammatory and anti-apoptotic effects may have the potential to protect kidney against DIN. The present review evaluated all of the available in vitro and in vivo studies that examined the use of statins as renoprotective agents against nephrotoxic drugs. Materials for this review were obtained by searching Medline, PubMed, Scopus, Cochrane central register of controlled trials, and Cochrane database of systematic reviews. Key words used as search terms included "statin", "3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors, "HMG-CoA reductase inhibitors", "nephroprotective", "renoprotective", "drug-induced renal diseases", "drug-induced nephrotoxicity", "drug-induced renal toxicity", "drug-induced nephropathy", "drug-induced renal side effects", and "contrast-induced nephropathy". This search was performed without time limitation. Only English language articles were included in this review. This review concluded that chronic statin user may be less prone to contrast-induced nephropathy (CIN) compared with statin non-users. Short-term high dose statin administration may also reduce the incidence of CIN in statin naïve patients. This renoprotective effect of statins against CIN is seen in low risk patients with normal kidney function or mild kidney dysfunction, but probably not in patients with moderate to severe renal dysfunction. Based on available animal data, statins may protect kidney against gentamicin-, cisplatin- and cyclosporine-induced nephrotoxicity, however, theses animal results have not yet been confirmed by human data. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

Chronic cyclosporine-induced nephrotoxicity in children with steroid-resistant nephrotic syndrome

Chronic cyclosporine-induced nephrotoxicity in children with steroid-resistant nephrotic syndrome

Previous Exposure to Cigarette Smoke Aggravates Experimental Cyclosporine-Induced Nephrotoxicity

Background/Aims: The effects of cigarette smoke (CS) on cyclosporine (CsA)-induced nephrotoxicity are poorly studied. This study aims to assess the effects of previous exposure to CS on CsA nephrotoxicity. Methods: Rats were either exposed to CS or sham (S) procedures for 10 min twice a day for 20 weeks. From the 16th to the 20th week, they received a low-salt diet. Beginning with the 17th week, they were given 2.5 mg/day CsA or vehicle (VH) for 3 weeks. The final groups were VH/CS, CsA/CS, VH/S, and CsA/S. On day 141, glomerular filtration rate (GFR), renal blood flow (RBF), renal vascular resistance (RVR), tubulointerstitial fibrosis, and CsA blood levels were measured and immunohistochemistry was analyzed for renal α-smooth muscle actin (SMA), nitrotyrosine, and vimentin. Results: CsA decrease in GFR was enhanced by CS exposure. CsA associated with CS induced higher periglomerular α-SMA and renal nitrotyrosine expression. CsA decreased RBF, but increased RVR, tubulointerstitial fibrosis, and α-SMA and renal vimentin expression. These changes and the CsA blood levels were not affected by CS exposure. Conclusion: CS aggravated the CsA-induced impairment of GFR and CS associated with CsA caused the development of periglomerular structural lesions and oxidative stress in a rat model of CsA nephrotoxicity.

ABCB1 polymorphisms are associated with cyclosporine-induced nephrotoxicity and gingival hyperplasia in renal transplant recipients

There is a great deal of controversy regarding the clinical impact of genetic variants in patients receiving cyclosporine (CsA) as immunosuppressant therapy. We have investigated the effect of polymorphisms in the CYP3A and ABCB1 genes on CsA pharmacokinetics, acute rejection incidence and drug-related side effects in renal transplant recipients The presence of CYP3A5*3, CYP3A4*1B and ABCB1 C1236T, G2677T/A and C3435T polymorphisms was assessed in 68 patients and retrospectively associated with pharmacokinetic and clinical parameters at 1 week and 1, 5 and 12 months after transplantation. Only minor associations were found between the tested polymorphisms and CsA pharmacokinetics. Most notably, CYP3A5 expressers showed lower blood trough levels than non-expressers in the first week after grafting (32.5 ± 14.7 vs. 55.1 ± 3.8 ng/ml per mg/day per kilogram). In terms of CsA-induced adverse effects, the incidence of nephrotoxicity was higher in carriers of the ABCB1 3435TT genotype and in those patients carrying four to six variants in the three ABCB1 loci [odds ratio (OR) 4.2, 95 % confidence interval (CI) 1.3-13.9, p = 0.02 and OR 3.6, 95 % CI 1.1-11.8, p = 0.05, respectively]. These subjects with four to six ABCB1 variants were also at higher risk for gingival hyperplasia (OR 3.29, 95 % CI 1.1-10.3, p = 0.04). Renal function and the incidence of neurotoxicity and of acute rejection did not vary across the different genotypes. ABCB1 polymorphisms may be helpful in predicting certain CsA-related side effects in renal transplant recipients. Our results also suggest that the mechanisms underlying these genetic associations are most likely independent of the drug's trough blood concentrations.