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This review discusses long-term complications from immunosuppressants after liver transplantation and the management of these complications. Common complications of calcineurin inhibitors include nephrotoxicity and metabolic diseases. Nephrotoxicity can be managed by targeting a lower drug level and/or adding an immunosuppressant of a different class. Metabolic disorders can be managed by treating the underlying condition and targeting a lower drug level. Gastrointestinal adverse effects and myelosuppression are common complications of antimetabolites that are initially managed with dose reduction or discontinuation if adverse events persist. Mammalian targets of rapamycin inhibitors are associated with myelosuppression, proteinuria, impaired wound healing, and stomatitis, which may require dose reduction or discontinuation. Induction agents and agents used for steroid-refractory rejection or antibody-mediated rejection are reviewed. Other rare complications of immunosuppressants are discussed as well., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Evidence suggests that immunosuppressant therapies protect against harmful effects of endotoxaemia. In this study, we tested whether calcineurin-dependent (cyclosporine/tacrolimus) and -independent (sirolimus) immunosuppressants variably influence nephrotoxicity induced by endotoxaemia and whether this interaction is modulated by testosterone. We investigated the effects of immunosuppressants on renal histopathological, biochemical and inflammatory profiles in endotoxic male rats and the role of androgenic state in the interaction. Six-hour treatment of rats with lipopolysaccharide (LPS, 3 mg/kg) increased (i) serum urea/creatinine, (ii) width of proximal/distal tubules, (iii) tubular degeneration and vacuolation, (iv) Western protein expressions of renal toll-like receptor 4, monocyte chemoattractant protein-1, and NADPH oxidase-2, and (v) serum tumour necrosis factor-α and myeloperoxidase. These endotoxic manifestations were intensified and eliminated upon concurrent exposure to cyclosporine and sirolimus, respectively. The cyclosporine actions appear to be a class rather than a drug effect because similar exacerbation of LPS nephrotoxicity was observed in rats treated with tacrolimus, another calcineurin inhibitor (CNI). Moreover, the deteriorated renal outcomes in LPS/tacrolimus-treated rats were reduced after castration or androgen receptor blockade by flutamide. The data suggest opposite effects for calcineurin-dependent (exaggeration) and -independent immunosuppressants (amelioration) on renal defects of endotoxaemia and implicate androgenic pathways in the worsened endotoxic renal profile induced by CNIs., (© 2021 John Wiley & Sons Australia, Ltd.)

Background: A traditional narrative review was performed to evaluate clinical studies that have examined the clinical implications, risk factors, and prevention of calcineurin inhibitors (CNIs) nephrotoxicity with stress on a belatacept-based rescue regimen., Methods: The Cochrane Library, PubMed/MEDLINE, EBSCO (Academic Search Ultimate), ProQuest (Central), and Excerpta Medical databases and Google scholar were searched using the keywords (CNI AND Nephrotoxicity prevention) OR ("Calcineurin inhibitor" AND Nephrotoxicity) OR (Tacrolimus AND Nephrotoxicity) OR (Ciclosporin AND Nephrotoxicity) OR (cyclosporine AND Nephrotoxicity) OR (Belatacept) OR (CNI Conversion) for the period from 1990 to 2020. Fifty-five related articles and reviews were found., Conclusion: A better understanding of the mechanisms underlying calcineurin inhibitor nephrotoxicity could help in the individualization of therapy for and prevention of CNI nephrotoxicity. Identification of high-risk patients for CNI nephrotoxicity before renal transplantation enables better use and selection of immunosuppression with reduced adverse effects and, eventually, successful treatment of the kidney recipients. Belatacept conversion is a good and safe option in patients with deteriorating renal function attributed to CNI nephrotoxicity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Calcineurin inhibitors (CNIs) are vital immunosuppressive therapies in the management of inflammatory conditions. A long-term consequence is nephrotoxicity. In the kidneys, the primary, catalytic calcineurin (CnA) isoforms are CnAα and CnAβ. Although the renal phenotype of CnAα -/- mice substantially mirrors CNI-induced nephrotoxicity, the mechanisms downstream of CnAα are poorly understood. Since NADPH oxidase-2 (Nox2)-derived oxidative damage has been implicated in CNI-induced nephrotoxicity, we hypothesized that CnAα inhibition drives Nox2 upregulation and promotes oxidative stress. To test the hypothesis, Nox2 regulation was investigated in kidneys from CnAα -/- , CnAβ -/- , and wild-type (WT) littermate mice. To identify the downstream mediator of CnAα, nuclear factor of activated T cells (NFAT) and NF-κB regulation was examined. To test if Nox2 is transcriptionally regulated via a NF-κB pathway, CnAα -/- and WT renal fibroblasts were treated with the NF-κB inhibitor caffeic acid phenethyl ester. Our findings showed that cyclosporine A treatment induced Nox2 upregulation and oxidative stress. Furthermore, Nox2 upregulation and elevated ROS generation occurred only in CnAα -/- mice. In these mice, NF-κB but not NFAT activity was increased. In CnAα -/- renal fibroblasts, NF-κB inhibition prevented Nox2 upregulation and reactive oxygen species (ROS) generation. In conclusion, these findings indicate that 1 ) CnAα loss stimulates Nox2 upregulation, 2 ) NF-κB is a novel CnAα-regulated transcription factor, and 3 ) NF-κB mediates CnAα-induced Nox2 and ROS regulation. Our results demonstrate that CnAα plays a key role in Nox2 and ROS generation. Furthermore, these novel findings provide evidence of divergent CnA isoform signaling pathways. Finally, this study advocates for CnAα-sparing CNIs, ultimately circumventing the CNI nephrotoxicity. NEW & NOTEWORTHY A long-term consequence of calcineurin inhibitors (CNIs) is oxidative damage and nephrotoxicity. This study indicates that NF-κB is a novel calcineurin-regulated transcription factor that is activated with calcineurin inhibition, thereby driving oxidative damage in CNI nephropathy. These findings provide additional evidence of divergent calcineurin signaling pathways and suggest that selective CNIs could improve the long-term outcomes of patients by mitigating renal side effects.

Nephrotoxicity is the major adverse reaction to tacrolimus; however, the underlying mechanisms remain to be fully elucidated. Although several tacrolimus-induced nephrotoxicity animal models have been reported, most renal injury rat models contain factors other than tacrolimus. Here, we report the development of a new nephrotoxicity with interstitial fibrosis rat model induced by tacrolimus administration. Thirty Wistar rats were randomly divided into four groups: sham-operated (Sham), vehicle-treated ischemia reperfusion (I/R) injury (IRI), tacrolimus treated (TAC) and tacrolimus treated I/R injury (TAC + IRI). Rats subjected to IR injury and treated with tacrolimus for 2 weeks showed higher serum creatinine (Scr), blood urea nitrogen (BUN), serum magnesium (Mg) and serum potassium (K), indicating decreased renal function. In addition, tacrolimus treatment combined with IR injury increased histological injury (tubular vacuolation, glomerulosclerosis and interstitial fibrosis), as well as α-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-β), and kidney injury molecule-1 (KIM-1) expression in the renal cortex. In summary, we have developed a tacrolimus-induced kidney injury rat model with interstitial fibrosis within 2 weeks by creating conditions mimicking renal transplantation via tacrolimus administration following ischemia-reperfusion., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Intrapatient variability (IPV) in tacrolimus has been increasingly acknowledged as a risk factor for poor graft survival after kidney transplantation. Although past studies have mainly accounted for IPV in acute or chronic rejection states as due to underimmunosuppression, this is not yet clear. So far, tacrolimus IPV for BK virus-associated nephropathy (BKVN) and chronic calcineurin inhibitor toxicity (CNIT) has not been investigated. Here, we evaluated IPV in tacrolimus for BKVN and chronic CNIT, which are mainly considered as overimmunosuppression states. In this case-control study, kidney allograft biopsies conducted between 1998 and 2018 were included, with patients grouped by biopsy results as BKVN alone group, CNIT alone group, and normal graft function (control group). IPV was estimated as mean absolute deviation. Our study groups included 25 kidney transplant recipients with BKVN alone, 91 patients with CNIT alone, and 60 patients with normal 5-year graft survival (control group). In analyses of IPV in tacrolimus six months before graft biopsy, IPV was highest in the BKVN group (P = 0.001). The BKVN group also had the highest IPV in tacrolimus at 12 months after biopsy (P = 0.001), with all pairwise comparisons statistically different between groups. At 12 months after biopsy, five patients (20%) in the BKVN group and 10 patients (10.9%) in the CNIT group had graft loss. Among other risk factors, BKVN and chronic CNIT are consequences related to high IPV. Quantification of IVP for tacrolimus in clinical practice would help to optimize kidney transplant outcomes.

Recently, research has directed its interests into identifying molecular pathways implicated in calcineurin inhibitor (CNI)-induced renal fibrosis. An emerging body of studies investigating calcineurin (CnA) activity has identified distinct actions of two main ubiquitously expressed isoforms: CnAα and CnAβ. CNIs have the capacity to inhibit both of these CnA isoforms. In the kidney, CnAα is required for development, whereas CnAβ predominantly modulates the immune response and glomerular hypertrophic signaling powered by activation of the transcription factor, nuclear factor of activated T lymphocytes (NFAT). Interestingly, data have shown that loss of CnAα activity contributes to the expression of profibrotic proteins in the kidney. Although this finding is of great significance, follow-up studies are needed to identify how loss of the CnAα isoform causes progressive renal damage. In addition, it is also necessary to identify downstream mediators of CnAα signaling that assist in upregulation of these profibrotic proteins. The goal of this review is to provide insight into strides taken to close the gap in elucidating CnA isoform-specific mechanisms of CNI-induced renal fibrosis. It is with hope that these contributions will lead to the development of newer generation CNIs that effectively blunt the immune response while circumventing extensive renal damage noted with long-term CNI use.

Background: Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity., Methods: We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity., Results: DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue., Conclusions: These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.

Background: BK virus (BKV)-associated nephropathy is a significant complication of kidney transplantation that progresses to graft dysfunction and graft loss. The aim of this study was to know the infection rate and progression of BKV according to our strategy., Materials and Methods: This study included 302 patients who received kidney transplantation between August 2010 and October 2012. Patients were divided into 4 groups: no BK infection, BK viruria only, low BK viremia, and high BK viremia., Results: In this study, 57 patients had BK viremia (18.9%), and 18 patients had BK nephropathy (5.9%) during a 2-year follow-up period. Age, sex, cytomegalovirus (CMV) viremia, existence of donor-specific antibodies, type of transplantation, and delayed graft function were not significantly different. Disappearance of BKV infection was better in the viruria and low viremia groups than in the high viremia group (P = .001), and duration of BK infection was longer in the high viremia group than the low viremia group (P = .002)., Conclusion: All diagnosed cases of BKV nephropathy were in the high BK viremia group. For BK viruria and viremia, early detection of BK infection together with early intervention by reduced immunosuppressant is a useful strategy to maintain allograft function. Long-term follow up is required to identify the risk factors for BK infection and graft survival after kidney transplantation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate polymorphisms in genes of drug metabolizing enzymes and transporters involved in cyclosporine and/or voriconazole disposition among patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT)., Methods: DNA from forty patients was genotyped using the DMETPlus array. The average ratio of cyclosporine concentration/dose (C/D in (ng/mL)/(mg/kg)) per participant's weight was computed using available trough levels and daily doses., Results: The C/D cyclosporine ratio was significantly higher when it was administered with voriconazole as compared to when it was administered alone: median: 116.75 vs. 25.40 (ng/mL)/(mg/kg) with and without voriconazole respectively, (P < 0.001). There was also a significant association between the C/D cyclosporine ratio combined with voriconazole and the ABCB1 2677 G > T > A (rs2032582) genetic polymorphism (P = 0.05). In parallel, ABCB1 variant allele carriers had higher creatinine in combination therapy with a median creatinine (mg/dL) of 0.74 vs. 0.56 for variant allele carriers vs. reference; P = 0.003. Interestingly, CYP2C9, CYP2C19, and CYP3A5 extensive metabolizers tended to be associated with lower cyclosporine C/D ratio when combined with voriconazole, but the results were not statistically significant., Conclusion: To the best of our knowledge, this is the first pharmacogenetic study on the interaction between voriconazole and cyclosporine in patients undergoing allo-HCT. Results suggest that the ABCB1 2677 G > T > A genetic polymorphism plays a role in this interaction with cyclosporine related nephrotoxicity. Pre-emptive genotyping for this genetic variant may be warranted for cyclosporine dose optimization. Larger studies are needed to potentially show significant associations with more candidate genes such as CYP3A4/5, CYP2C9, and CYP2C19, among others., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Purpose: Acute nephrotoxicity is a common adverse reaction of tacrolimus therapy; however, its risk factors in pediatric nephrotic syndrome (NS) remain to be evaluated. The objective of this study was to investigate the risk factors and characteristics of tacrolimus-induced acute nephrotoxicity in children with NS., Methods: Past records of children with NS admitted to our hospital from 2014 to 2018 were reviewed. The incidence and characteristics of nephrotoxicity were analyzed. Multivariate logistic regression analysis was used to identify the risk factors of nephrotoxicity. A clinically applicable risk score was developed and validated., Results: Tacrolimus-induced nephrotoxicity occurred in 25 of 129 patients, 13 patients were grade 1, and the renal function was recovered in 22 patients. Multivariate regression analysis showed that the maximum trough concentrations (C 12h ) of tacrolimus (OR, 1.48; 95% CI, 1.16 to 1.88; P < 0.001), huaiqihuang granules (OR, 0.095; 95% CI, 0.014 to 0.66; P = 0.017), and diarrhea (OR, 22.00; 95% CI, 1.58 to 306.92; P = 0.022) were independently associated with tacrolimus-induced nephrotoxicity. The maximum C 12h were significantly higher in patients with nephrotoxicity (median 9.0 ng/ml) and the cut-off value for acute nephrotoxicity was 6.5 ng/ml. The area under the receiver operating characteristic curve was 0.821 for the proposed model based on the observations used to create the model and 0.817 obtained from k-fold cross-validation., Conclusions: High trough concentration of tacrolimus and diarrhea can potentiate the risk of tacrolimus-induced acute nephrotoxicity in children with NS, while huaiqihuang granules can protect this condition.

Tacrolimus (or FK506), a calcineurin inhibitor (CNI) introduced in field of transplantation in the 1990s, is the cornerstone of most immunosuppressive regimens in solid organ transplantation. Its use has revolutionized the future of kidney transplantation (KT) and has been associated with better graft survival, a lower incidence of rejection, and improved drug tolerance with fewer side effects compared to cyclosporine. However, its monitoring remains complicated and underexposure increases the risk of rejection, whereas overexposure increases the risk of adverse effects, primarily nephrotoxicity, neurotoxicity, infections, malignancies, diabetes, and gastrointestinal complaints. Tacrolimus nephrotoxicity can be nonreversible and can lead to kidney graft loss, and its diagnosis is therefore best made with reference to the clinical context and after exclusion of other causes of graft dysfunction. Many factors contribute to its development including: systemic levels of tacrolimus; local renal exposure to tacrolimus; exposure to metabolites of tacrolimus; local susceptibility factors for CNI nephrotoxicity independent of systemic or local tacrolimus levels, such as the age of a kidney; local renal P-glycoprotein, local intestinal and hepatic cytochrome P450A3, and renin angiotensin system activation. The aim of this review is to describe the pharmacokinetics, pharmacodynamics, and mechanisms of acute and chronic tacrolimus nephrotoxicity in adult KT., (© 2019 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc.)

Background: Cyclosporine is a useful immunosuppressive agent for achieving disease control in moderate to severe atopic dermatitis in children and adults. However, it carries the potential for nephrotoxicity. Monitoring of drug levels is performed in other patient groups, such as transplant recipients, but is not commonplace in the management of atopic dermatitis., Objectives: To investigate levels of nephrotoxicity associated with cyclosporine use in atopic dermatitis and assess potential correlation with trough levels of cyclosporine., Methods: An electronic search was conducted on MEDLINE, EMBASE, and Cochrane databases for randomized controlled trials and cohort studies assessing the safety profile of cyclosporine compared to placebo or other atopic dermatitis treatments, in adult and pediatric atopic dermatitis patients from 1966 to May 2019. Studies that did not assess renal toxicity were excluded from analysis., Results: Thirty-eight trials were included for analysis, excluding 11 that did not assess renal toxicity. Descriptive statistical analysis only was performed, due to the high heterogeneity between study methodologies. Significant renal toxicity was seen in 0%-9% of pediatric participants. Monitoring of trough cyclosporine levels was performed in only 10 of the studies, and their correlation to toxicity or disease activity was not explored., Conclusion: There is limited evidence in atopic dermatitis regarding trough level monitoring of cyclosporine. Currently, the practice is not commonplace, particularly in pediatrics, and this is reflected in trial methodology. Monitoring may be useful in specific pediatric groups, such as those on multiple concurrent medications, patients with hepatic or renal dysfunction and non-responders to therapy., (© 2019 Wiley Periodicals, Inc.)

The use of alemtuzumab for induction therapy in orthotopic heart transplantation remains controversial, despite its observed benefits in other transplant populations. This study aimed to evaluate whether alemtuzumab conferred a lower risk of rejection while reducing toxicities commonly attributed to standard immunosuppression in orthotopic heart transplantation. We included adult patients who underwent orthotopic heart transplantation and received induction therapy with alemtuzumab (n = 26) or standard immunosuppression (n = 26). The primary end point was freedom from grade ≥2 rejection at 12 months. Baseline characteristics were similar between the groups with the exception of poorer renal function in the alemtuzumab group ( P < .05). The primary end point of freedom from grade ≥2 rejection at 12 months was not different between alemtuzumab and standard therapy (76.9% vs 96.2%, P = .077), likely due to similarities in the rates of antibody-mediated rejection in the 2 groups. However, grade ≥2 acute cellular rejection was considerably lower with alemtuzumab (0% vs 19.2%, P = .02), as was acute cellular rejection of any severity (50% vs 7.7%, P = .004). Deterioration in renal function was significantly greater among patients receiving standard therapy as evidenced by decreases in glomerular filtration rate (-25.6 vs -9.2 mL/min, P = .032). No differences in hematologic or infectious complications were observed. In conclusion, alemtuzumab reduced several important rejection-related outcomes while ameliorating the toxicities associated with standard immunosuppression therapy, making it a promising agent for induction in orthotopic heart transplantation.

The aim of this study was to investigate effect of nitric oxide (NO) modulation on possible nephroprotective mechanisms of nebivolol (NEB) in cyclosporine A (CsA)-induced nephrotoxicity. Rats were treated with 20 mg/kg/day s.c. of CsA for 21 days, with NEB alone (10 mg/kg/day orally) or together with a NOS inhibitor, L-NAME (10 mg/kg/day i.p.). NEB conferred nephroprotection against CsA-induced toxicity, significantly decreasing serum kidney function tests and improving renal histopathology. NEB showed antioxidant effects, by significantly decreasing renal malondialdehyde levels, while increasing reduced glutathione levels and catalase activity. NEB showed anti-inflammatory and anti-apoptotic effects; reducing renal expression NF-κB and fas ligand. NEB also reversed CsA-induced effects on NO system; increasing renal NO level, with up-regulation of eNOS and down-regulation of iNOS expression. Administering L-NAME with NEB reversed all beneficial effects of NEB. Thus, NEB's modulation of NO system in CsA-induced nephrotoxicity might be the triggering mechanism controlling NEB's nephroprotective effect., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Calcineurin inhibitors (CNIs), which remain the most important immunosuppressants in kidney transplant recipients, are a major cause of renal dysfunction due to CNI-induced nephropathy. However, a safe and effective CNI-sparing protocol is yet to be established. Herein, we report a case series of kidney transplant recipients experiencing CNI nephropathy, whose renal function is improved after conversion from CNIs to everolimus., Cases: The 3 kidney transplant recipients included in this study were diagnosed with CNI arteriolopathy by episode biopsy between 9 months and 11 years after transplantation. All patients received triple immunosuppressive therapy consisting of CNI (tacrolimus or cyclosporine), mycophenolate mofetil, and methylprednisolone. All allografts were transplanted from elderly living donors to ABO-compatible and donor-specific antibody-negative recipients. All allograft biopsy specimens exhibited CNI arteriolopathy with alternative quantitative criteria for hyaline arteriolar thickening (aah score: 2 or 3), according to the Banff classification; however, histopathologic assessment did not show any evidence of allograft rejection. Conversely, total dose and blood concentrations of CNIs were within appropriate ranges. After conversion from CNIs to everolimus (1.5 mg/day, twice daily; trough level, 3-5 ng/mL), serum creatinine levels returned to baseline levels measured before the diagnosis of CNI arteriolopathy. In all patients, renal allograft function remained stable, with no evidence of donor-specific antibodies, 1 year after conversion from CNIs to everolimus., Conclusion: Conversion from CNIs to everolimus can safely and effectively improve renal function in kidney transplant recipients experiencing CNI-induced nephropathy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes., Methods: We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes., Results: Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified., Conclusions: These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.

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., (© 2019 Wiley Periodicals, Inc.)

Background: Cyclosporine A (CsA) is widely used for organ transplantation and autoimmune disorders. However, CsA nephrotoxicity is a serious side effect that limits the clinical use of CsA. The metabolism of CsA has a close relationship with this disease in renal-transplant patients. However, the metabolic pathways of CsA and its metabolizing enzymes have rarely been comprehensively reviewed. In this review, we have summarized the specific metabolic profiles of CsA in humans, especially renal-transplant patients. Moreover, the specific metabolizing enzymes and the potential roles that CsA metabolism plays in CsA nephrotoxicity were summarized and discussed., Methods: Electronic databases including PubMed, Web of Science, and Scifinder were searched with the keywords "Cyclosporine A and metabolism", and "Cyclosporine A and nephrotoxicity", "Cyclosporine A metabolism and nephrotoxicity". All these studies published until 2018 were included in this review., Results: The major metabolic pathways of CsA in humans are hydroxylation and N-demethylation. Normally, these metabolites are relatively less toxic than CsA. However, the metabolism of CsA in the kidneys is much weaker than that in the liver, which explains why CsA is so toxic to the kidneys. CYP3A families, especially CYP3A4 and CYP3A5, play an important role in the biotransformation of CsA. Moreover, increased lines of evidence show that some metabolites (including AM19) associate directly with nephrotoxicity in CsA-treated organ-transplant patients., Conclusion: The findings of this review help to further understand the metabolic activities of CsA in renal-transplant patients and cast some light on the mechanisms of CsA nephrotoxicity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Several drugs commonly used in the management of rheumatic diseases may lead to nephrotoxicity, electrolyte disturbances, and hypertension. Here the authors focus on nonsteroidal antiinflammatory drugs, uric-acid-lowering therapy, and commonly used immunosuppressant therapies. The authors include a drug dosing table for patients with kidney disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Cyclosporine began to be used as one of the immunosuppressive agents in transplantation in the beginning of the 1980s, and in the treatment of nephrotic syndrome in the pediatric nephrology. Therapeutic area of cyclosporine is narrow and its side effects limit its usage. Preference for cyclosporine and tacrolimus as a calcineurin inhibitor is left for the choice of the department. There are still countries with preferred-cyclosporine use because of economic reasons. Cyclosporine is currently being used in the treatment of nephrotic syndrome, but due to its high relapse rates in a short-term use, and nephrotoxicity in long-term use, search for new drugs with fewer side effects keeps continuing. As long as its use is indispensable, it will be necessary to keep track of kidney function and blood level of this medication closely to protect the patients from toxicity.

Calcineurin inhibitors (CNIs, eg, tacrolimus) reduce short-term kidney transplant failure, but chronic nephrotoxicity may contribute to late transplant loss. Elective conversion to inhibitors of the mammalian target of rapamycin (mTOR, eg, sirolimus) pathway might avoid long-term CNI renal damage and improve outcomes. The 3C Study was a pragmatic randomized controlled trial of sequential randomizations between alemtuzumab and basiliximab induction therapy (at the time of surgery) and between tacrolimus and sirolimus maintenance therapy at 6 months posttransplantation. The primary outcome of this analysis was estimated glomerular filtration rate (eGFR) at 18 months after maintenance therapy randomization; 197 patients were assigned sirolimus-based and 197 to tacrolimus-based therapy. Allocation to sirolimus had no significant effect on eGFR at 18 months: baseline-adjusted mean (SEM) eGFR was 53.7 (0.9) mL/min/1.73 m 2 in the sirolimus group versus 54.6 (0.9) mL/min/1.73 m 2 in the tacrolimus group (P = .50). Biopsy-proven acute rejection (29 [14.7%]) vs 6 [3.0%]; P < .001) and serious infections (defined as opportunistic infections or those requiring hospitalization; 95 [48.2%] vs 70 [35.5%]; P = .008) were more common among participants allocated sirolimus. Compared with tacrolimus-based therapy, sirolimus-based maintenance therapy did not improve transplant function at 18 months after conversion and was associated with significant hazards of rejection and infection. ClinicalTrials.gov identifier NCT01120028 and ISRCTN88894088., (© 2017 The Authors. American Journal of Transplantation published by Wiley Periodicals, Inc. on behalf of The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: Calcineurin inhibitors (CNIs) are commonly given to transplant recipients of kidneys and other solid organs and to patients with immune disorders, such as steroid-resistant nephrotic syndrome, steroid-dependent nephrotic syndrome, and frequent relapse nephrotic syndrome. Although CNIs remain the most effective available immunosuppressant agent, there is clinical concern regarding possible long-term nephrotoxicity. This concern is especially significant in children who have a longer life expectancy and greater growth rate., Data Sources: In this review, we analyzed the literatures to identify original articles that examined use of CNIs in children who received organ transplantation and nephropathy to assess the available evidence of their nephrotoxicity. PubMed, Elsevier, and Tompson ISI Web of Knowledge were searched for identifying relevant papers., Results: Clinical research supports the presence of CNI-related nephrotoxicity. However, some researchers have questioned the prevalence and seriousness of chronic CNIs nephrotoxicity, especially because the pathological lesions typically associated with long-term CNI use are nonspecific. Many researchers have focused on early markers of CNI nephrotoxicity, and the methods that may help prevent and manage nephrotoxicity., Conclusions: Future research should focus on investigating early markers of CNI nephrotoxicity and strategies for improved immunosuppressant therapy, and developing alternative treatments. CNI-mediated nephrotoxicity should always be taken seriously in clinic.

Background: Nephrotoxicity of calcineurin inhibitors (CNIs) is the major concern for long-term allograft survival despite its predominant role in current immunosuppressive regime after renal transplantation. CNI nephrotoxicity is multifactorial with demographic, environmental, and pharmacogenetic flexibility, whereas studies indicating risk factors for CNI nephrotoxicity obtained incomplete or conflicting results., Methods: A systematic review and meta-analysis of risk factors for CNI nephrotoxicity was performed on all retrieved studies through a comprehensive research of network database. Data were analyzed by Review Manager 5.2 with heterogeneity assessed using the Cochrane Q and I 2 tests. CNI nephrotoxicity was primarily indicated with protocol biopsy or index-based clinical diagnosis, and the secondary outcome was defined as delayed graft function., Results: Twelve observational studies containing a total of 2,849 cases were identified. Donor age (odds ratio [OR], 1.01; 95% CI, 1.01-1.03; p =0.02), recipient zero-time arteriosclerosis (OR, 1.44; 95% CI, 1.04-1.99; p =0.03), and CYP3A5*3/*3 genotype (OR, 2.80; 95% CI, 2.63-2.98; p =0.00) were confirmed as risk factors for CNI nephrotoxicity. Subgroup and sensitivity analysis claimed donor age as a significant contributor in Asian and Caucasian areas., Conclusion: Older donor age, recipient zero-time arteriosclerosis, and CYP3A5*3/*3 genotype might add up the risk for CNI nephrotoxicity, which could be interpreted into a robust biomarker system., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Introduction: The purpose of this study was to compare the safety and efficacy of generic tacrolimus (Tacrobell [TCB]) and a reference tacrolimus (Prograf [PGF]) in liver transplant recipients., Patients and Methods: We retrospectively analyzed 167 patients who used TCB or PGF between January 2009 and March 2016 for >1 year (TCB group, n=86; PGF group, n=81). To assess the efficacy and safety of TCB, we evaluated the relationship between drug dose and trough level, survival, rejection, infection, kidney function, and side effects., Results: There was no difference in the preoperative demographics between the two groups. Moreover, there was no difference in the drug dose and trough level between the groups at 1 week after surgery. Coefficient of variation (CV) values were obtained at the drug trough level for each patient and no differences in CV values were identified within 1 year ( p =0.587) and up to 5 years ( p =0.824) in both groups. Rehospitalization ( p =0.1) and total rejection ( p =0.915) did not differ between the two groups, but the rejection severity, recorded as the rejection activity index value, was worse in the PGF group ( p =0.039). No difference was found in the infection rate ( p =0.818), and with regard to nephrotoxicity, there was no difference in the rate of patients with chronic kidney disease stage 3 and above during the follow-up period. No differences were found between the two groups in terms of drug side effects and adverse events., Conclusion: The generic tacrolimus, TCB, is a comparable alternative to the original tacrolimus, PGF, as a main immunosuppressive drug for liver transplantation., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Cyclosporine A (CSA) is a widely used immunosuppressant drug known to commonly cause cardio and nephrotoxicity. A study looking at the sex specificity of the cardiotoxicity of CSA revealed that sexual dimorphism existed when looking at the electrocardiographs and left ventricles of CSA-treated rats. We hypothesized that cyclosporine A exhibited gender-specific nephrotoxicity by testing various parameters of kidney function in male and female rats treated for 21 days with 15 mg/kg CSA versus control male and female rats that received a vehicle consisting of 18% kolliphore and 2% ethanol in sterile saline. It was found that male rats treated with CSA had significantly higher levels of serum creatinine and lower creatinine clearance than control males. However, serum creatinine and creatinine clearance were not affected by CSA treatment in females. Histopathological examination of kidney cross-sections revealed a heavy aggregation of inflammatory cells and significant vascular congestion in males treated with CSA, which was less prominent in female rats receiving CSA. In addition CSA treated male rats had higher levels of serum cholesterol compared with control while, CSA did not affect serum cholesterol in female rats. Kidney tumor necrosis factor alpha (TNF-α) levels were found to drop in female rats following CSA treatment, whereas no change was observed in male rats before and after treatment. These results suggest that CSA exhibits gender-related nephrotoxicity in rats that might be mediated by differences in the inflammatory response between males and females., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mammalian target of rapamycin (mTOR) inhibitors, everolimus (EVL) and sirolimus are immunosuppressive agents with a minor nephrotoxic effect, limited to the development of proteinuria in some cases. The combination of EVL and low-dose tacrolimus has proven to be as safe and effective as standard therapy with tacrolimus for the prevention of acute cellular rejection. Early initiation of EVL-based immunosuppressive regimens with reduced exposure to calcineurin inhibitors has been shown to significantly improve renal function of LT recipients during induction and maintenance phases, with comparable efficacy and safety profiles. In patients with established kidney failure, initiating EVL may enable clinicians to reduce calcineurin inhibitors exposure, thereby contributing to the improved renal function of these patients. Although there is not sufficient evidence to recommend their use to prevent the recurrence of hepatocellular carcinoma and the progression of de novo tumours, they are used in this context in routine clinical practice., (Copyright © 2017 Elsevier España, S.L.U., AEEH y AEG. All rights reserved.)

​Introduction: As tolerance is not yet achievable, the kidney-transplanted-patients have to take on a daily-basis immunosuppressive drugs in order to avoid acute rejection-AR-. The cornerstone of immunosuppression relies on tacrolimus-therapy which is potentially nephrotoxic. Areas Covered: We identified from the studies published in the recent years those who were reporting on AR in de novo kidney-transplant recipients under tacrolimus-based therapy, as well as those who reported on the attempt to minimize tacrolimus-therapy., Results: There are many formulations of tacrolimus: immediate-release (Prograf®), slow-release (Advagraf®), or extended-release (Envarsus®). All demonstrate a very good efficacy in preventing AR episodes. Studies in which tacrolimus was minimized or even weaned-off have shown that it was unsafe, i.e. in resulting in AR episode and/or de novo donor-specific alloantibodies. Recent data show that Tacrobell®, a generic of tacrolimus, was as efficient as Prograf® in the short- and long-term. Expert-opinion: Tacrolimus-based immunosuppression is very effective in preventing rejection in kidney-transplant recipients. It might be associated with nephrotoxicity, that can be reduced by avoiding tacrolimus trough levels too high in the long-term. Conversely, tacrolimus ultraminimization should not be attempted.

After immune checkpoint inhibitor therapy was approved for renal cell carcinoma last year, this new immune therapy has spread to urology. Further approvals (atezolizumab, nivolumab, pembrolizumab) are expected in 2017 for metastatic urothelial carcinoma that has progressed following treatment with platinum-based chemotherapy. With expanding use of immune checkpoint inhibitors, experience in diagnosing and managing immune-mediated adverse events increases. Although of low incidence, grade 3/4 toxicities play a central role. Organs most common for immune-mediated adverse events are skin, liver (hepatitis), kidneys (nephritis), gastrointestinal tract (diarrhea and colitis), lungs (pneumonitis), and endocrine organs (hyper-, hypothyroidism and hypophysitis). Diagnostic workup includes routine laboratory tests (including liver function tests) and may be supplemented with hormone values. In cases of pneumonitis or hypophysitis, imaging (high-resolution CT, MRI) can confirm diagnoses. Immune-mediated toxicities are treated with therapy interruption and administration of corticosteroids (and in individual cases additional immunosuppression). Dose modification is not intended!

Aim: Cyclosporin A (CsA) causes renal toxicity. The underlying mechanisms are incompletely understood, but may involve renal hypoxia and hypoxia-inducible factors (Hifs). We sought for hypoxia and Hif in mouse kidneys with CsA-induced toxicity, assessed their time course, Hif-mediated responses and the impact of interventional Hif upregulation., Methods: Mice received CsA or its solvent cremophore for up to 6 weeks. Low salt diet (Na + ↓) was given in combination with CsA to enhance toxicity. We assessed fine morphology, renal function, blood oxygen level-dependent magnetic resonance imaging under room air and following changes in breathing gas composition which correlate with vascular reactivity, pimonidazole adducts (which indicate O 2 tensions below 10 mmHg), Hif-α proteins, as well as expression of Hif target genes. Stable Hif upregulation was achieved by inducible, Pax8-rtTA-based knockout of von Hippel-Lindau protein (Vhl-KO), which is crucial for Hif-α degradation., Results: Cyclosporin A transiently increased renal deoxyhaemoglobin (R2*). Augmented vascular reactivity was observed at 2 h, but decreased at 24 h after CsA treatment. Na + ↓/CsA provoked chronic renal failure with tubular degeneration and interstitial fibrosis. Nephron segments at risk for injury accumulated pimonidazole adducts, as well as Hif-α proteins. Remarkably, Hif target gene expression remained unchanged, while factor-inhibiting Hif (Fih) was enhanced. Na + ↓/CsA/Vhl-KO aggravated morpho-functional outcome of chronic renal CsA toxicity., Conclusions: Cyclosporin A provokes episodic hypoxia in nephron segments most susceptible to chronic CsA toxicity. Fih is upregulated and likely blocks further Hif activity. Continuous tubular Hif upregulation via Vhl-KO worsens the outcome of chronic CsA-induced renal toxicity., (© 2016 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

Background: High intrapatient tacrolimus variability has been associated with worse clinical outcomes postrenal transplantation. Theoretically, tacrolimus levels consistently outside the target therapeutic window may result in allograft dysfunction as subtherapeutic tacrolimus levels predispose to episodes of acute rejection, whereas supratherapeutic levels may cause nephrotoxicity., Methods: We investigated the effect of tacrolimus variability in a "Symphony" style low-dose tacrolimus based regime, by collecting data from 432 patients over a 4-year period.Three hundred seventy-six patients were included, with a mean follow-up of 1495 days. Tacrolimus variability 6 to 12 months after renal transplantation was calculated, and outcomes were compared in low (n = 186) and high variability (n = 190) groups., Results: High variability patients were found to be at increased risk of rejection during the first posttransplant year (P = 0.0054) and to have reduced rejection-free survival (hazard ratio, 1.953; 95% confidence interval, 1.234-3.093; P = 0.0054). High variability patients had significantly worse (P < 0.0001) glomerular filtration rates at 1, 2, 3, and 4 years posttransplant. High variability patients were at increased risk of allograft loss (hazard ratio, 4.928; 95% confidence interval, 2.050-11.85; P = 0.0004)., Conclusions: This suggests that highly variable tacrolimus levels predict worse outcomes postrenal transplantation, although the causal nature of this relationship remains unclear. High tacrolimus variability may identify a subset of patients who warrant increased surveillance and patient education regarding dietary and medication compliance.

Background: The use of calcineurin inhibitor (CNI)-based immunosuppressive regimens following liver transplantation (LTx) has improved the outcomes of the recipients. However, CNI has nephrotoxicity and causes short- and long-term renal complications. The progressive structural changes can be irreversible in the long-term, leading to chronic kidney dysfunction. The present review was to evaluate the different strategies of CNI application to renal function in liver recipients., Data Sources: PubMed database was searched for relevant articles in English on the issue of immunosuppressive regimen and kidney injury that related to early minimization of CNI after LTx., Results: Total avoidance of CNI from post-LTx immunosuppressive regimens has been associated with unacceptable high rates of acute, steroid resistant rejections; late conversion from CNI to non-nephrotoxic immunosuppressant failed to recover renal function. Early CNI minimization and conversion to non-nephrotoxic immunosuppressant, although had no effect on patient survival rates, improved glomerular filtration rate. The combination of everolimus (a mammalian target of rapamycin inhibitor) and tacrolimus not only maintains immunosuppressive efficacy but also minimizes kidney injury., Conclusions: Up to now, protocols entirely avoiding CNI have not passed the primary safety endpoint of patient and graft survival, as well as the FDA mandated endpoint of biopsy proven acute rejection. Thus, early CNI minimization after LTx is the most rational approach preserving post-transplant renal function.

Purpose: The purpose of this study was to investigate the potential impact of FOXP3 and CCDC22 gene polymorphisms on efficacy and safety of tacrolimus (TAC) in renal transplant patients., Methods: Genetic polymorphisms were detected in 114 Chinese renal transplant patients who were on TAC-based maintenance immunosuppression and were followed up for at least 2 years. The relationships between FOXP3 rs3761547, rs3761548, rs3761549, rs2232365, rs2280883, and CCDC22 rs2294021 polymorphisms and clinical outcomes such as acute rejection, TAC-induced acute nephrotoxicity, and pneumonia were investigated by using Kaplan-Meier estimates and multivariate Cox regression analysis. The influence of these gene polymorphisms on the change in estimated glomerular filtration rate over time was evaluated by linear mixed model., Results: Patients with FOXP3 rs3761548 AA and AC genotypes had a 10-fold higher risk for TAC-induced acute nephrotoxicity than those with CC genotype. We did not find any association between other genetic variants and TAC-related outcomes in renal transplant patients., Conclusions: Our study demonstrated the TAC-induced acute nephrotoxicity was associated with FOXP3 rs3761548 polymorphism in renal transplant patients. FOXP3 rs3761548 might serve as a biomarker to prevent TAC toxicity and help progression toward individualized therapy of TAC.

Background: Calcineurin inhibitor-associated chronic nephrotoxicity threatens the prognosis of liver transplant recipients. This study aimed to study the mechanisms involved by identifying the cytokine profiles in tacrolimus (Tac)-induced nephrotoxicity., Methods: We enrolled 125 living-donor liver transplant recipients. All of the recipients had normal serum cystatin (Cys) C and urine microalbumin before transplantation. They received a Tac-based immunosuppressive regimen (Tac + mycophenolate mofetil + prednisone) thereafter. Patients were grouped according to Cys-C results (measured a mean 3.55 ± 1.89 years after transplantation) as a measure of renal injury: the early renal damage group was Cys-C >1 mg/L, and normal renal function was Cys-C ≤1 mg/L. Serum levels of 10 cytokines and chemokines, as well as urine proteins including α1 microglobulin, microalbumin, transferrin, and immunoglobulin G, were compared between groups., Results: In the early renal damage group, the concentration of interferon-γ-induced protein (IP) 10 was higher and monocyte chemotactic protein (MCP) 1 was lower compared with the group with normal renal function (P = .027 and .048, respectively). Multivariate logarithmic regression analysis showed that IP-10 and MCP-1 were independently correlated with renal damage., Conclusions: High level of IP-10 and low level of MCP-1 may be involved in renal injury and therefore may indicate poor prognosis. IP-10 could be a target for renal injury treatment after liver transplantation. Further studies with larger sample sizes are recommended to validate the study results., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The introduction of the calcineurin inhibitors cyclosporine and tacrolimus in the immunosuppressive regimens for kidney transplant has been associated with substantial reductions in the incidence of acute rejection, with a subsequent improvement in 1-year graft survival. However, this has not directly correlated with improvements in long-term allograft survival. Immunosuppressive medications are associated with toxicities related directly to immunosuppressive effects, and these are similar among different agents. In addition, there are other toxicities that are unique for each drug. Immunosuppressive minimization strategies have attempted to address both of these toxicities. Calcineurin inhibitors have been associated with chronic nephrotoxicity, and various calcineurin inhibitor-sparing strategies have been used to address this issue with the aim of improving long-term outcomes. However, there has been a paradigm shift over the past 10 to 15 years, with the appreciation that calcineurin inhibitor nephrotoxicity is not the major cause of late graft failure. Studies have now shown that chronic immune injury mediated by donor-specific antibodies may account for most late graft losses. Although some patients do benefit from calcineurin inhibitor-sparing approaches, others may have late allograft loss from chronic and subacute immune-mediated injury. Unfortunately, the vast majority of calcineurin inhibitor-sparing studies have short-term follow-up and have not explored the change in the donor-specific antibody profile. One of the biggest challenges that we face is being able to distinguish among patients who will benefit from this strategy and those who will not. In this study, we review the various strategies used to limit or avoid the use of calcineurin inhibitors and address the benefits and pitfalls associated in pursuing such strategies.

The kidney is very susceptible to hypoxic injury. Calcineurin inhibitors (CNIs) induce vasoconstriction and might reduce renal tissue oxygenation. We aimed to investigate if the synergistic deleterious effects of CNI-treatment and hypoxia of high altitude living might accelerate the development of arteriolar hyalinosis in kidney allografts. We stratified all patients who received a kidney graft from 2000 to 2010 in our centre (n = 477) in three groups according to the residential elevation (below 400, between 400 to 600 and above 600 m above sea level) and we retrospectively re-evaluated all transplant biopsies performed during follow-up, specifically looking at the degree of arteriolar hyalinosis, the hallmark of chronic CNI nephrotoxicity. Living at high altitude was markedly associated with a higher degree of arteriolar hyalinosis (P < 0.001). Haemoglobin levels confirmed the functional relevance of different arterial oxygenation among the groups (P = 0.01). Thus, patients living at high altitude seem to be more susceptible to the development of arteriolar hyalinosis after kidney transplantation., (© 2016 Asian Pacific Society of Nephrology.)

Background: The contribution of calcineurin inhibitors (CNI) nephrotoxicity to progressive kidney transplant injury remains debated, with little long-term data from the modern tacrolimus (TAC) era using lower doses., Methods: This longitudinal cohort study evaluated histological evidence of CNI nephrotoxicity from normal donor kidneys of successful kidney-pancreas transplant recipients during cyclosporine (CSA) and TAC eras, analyzed by intention-to-treat., Results: From 200 patients, 1622 adequate prospective protocol (84.3%) and indication (15.7%) kidney biopsies yielded 8.1 ± 4.1 samples per patient, over 7.4 ± 4.4 years posttransplant. The TAC era demonstrated less rejection and reduced early immune-mediated tubular damage, compared with CSA (P < 0.001). The incidences of acute mild arteriolopathy, striped interstitial fibrosis, glomerular congestion, and tubular microcalcification were all greater with CSA (hazard ratios of 1.70, 9.35, and 3.78, respectively) and maximal within the first posttransplant year, compared with TAC-treated patients (P < 0.001). However, the 1-, 5-, and 10-year prevalence moderate arteriolar hyalinosis was similar: CSA was 5.4%, 38.4%, and 79.1%; and TAC was 4.3%, 33.6% and 77.2%, respectively (P = NS). Morphometric measurement demonstrated lumenal narrowing from inwards collapse of hyalinized arteriolar walls unable to maintain its structural integrity. Severe hyalinosis was calculated to reduce arteriolar blood flow to 20 ± 34% of normal. Severity of arteriolar hyalinosis correlated with contemporaneous glomerulosclerosis (r = 0.44, P < 0.001), and subsequent progression in 1356 sequential biopsy pairs, consistent with glomerular ischemia., Conclusions: Tacrolimus-based therapy appeared superior to the CSA era, with less early CNI nephrotoxicity and fewer rejection episodes, but comparable chronic arteriolar toxicity. Calcineurin inhibitors are imperfect long-term maintenance immunosuppressive agents because of frequent and irreversible chronic toxicity.

Background: Tacrolimus (Tac) and Cyclosporine A (CyA) calcineurin inhibitors (CNIs) are 2 effective immunosuppressants which are essential to prevent allograft rejection. Calcineurin inhibitors are known to be nephrotoxic. However, the precise mechanism of nephrotoxicity is not fully understood. In this study, we investigated the in vivo effects of CNIs on the local renal renin-angiotensin system in the collecting duct (CD)., Methods: Three-week-old mice were treated with either vehicle, CyA (2 mg/kg per day), Tac (0.075 mg/kg per day), CyA + Aliskiren (25 mg/kg per day), or Tac + Aliskiren for 3 weeks. Serum creatinine was measured. Renin and vascular endothelial growth factor (VEGF) contents in CD were evaluated with flow cytometry and multiphoton microscopy. The diameter of vessels was assessed with multiphoton microscopy, and the amount of renal collagen was determined by real-time polymerase chain reaction and Masson staining., Results: The elevated level of serum creatinine in CNI groups was abolished by Aliskiren. Flow cytometric analysis found elevated renin content in principal cells, which was prevented by Aliskiren. This result was further confirmed with multiphoton microscopy. The VEGF content in CD correlated with reduced capillary diameter and with the formation of fibrotic islands., Conclusions: Calcineurin inhibitors induce production of renin in the CD that may contribute to decreased renal blood flow. In turn, CD responds with increased VEGF production, resulting in disproportional vessel growth, further worsening the local hypoxia and striped fibrosis surrounding the CDs. Aliskiren, a direct renin inhibitor blocks these effects and improves CNI-induced nephropathy by decreasing renin production in the CDs. Our data suggest that Aliskiren may be used for the prevention of CNI nephrotoxicity.

Since its introduction to the antirejection armamentarium in 1994, tacrolimus has become the workhorse of transplant professionals for avoidance of solid organ transplant rejection. Not only does tacrolimus have potent immunosuppressive qualities that prevent rejection, but dosing is straight forward and it is generally well tolerated. However, in the long term, conditions such as calcineurin inhibitor nephrotoxicity can become a problem. A discussion of the compound, the pharmacokinetics, history, and current approved uses for tacrolimus is described. Indeed, tacrolimus is the most important drug for preventing transplant rejection. However, the increased appreciation for significant side effects, particularly in the long term, has led to building interest in new agents with different mechanisms of action and different metabolism.

In recent years a series of trials has sought to define the optimal protocol for everolimus-based immunosuppression in heart transplantation, with the goal of minimizing exposure to calcineurin inhibitors (CNIs) and harnessing the non-immunosuppressive benefits of everolimus. Randomized studies have demonstrated that immunosuppressive potency can be maintained in heart transplant patients receiving everolimus despite marked CNI reduction, although very early CNI withdrawal may be inadvisable. A potential renal advantage has been shown for everolimus, but the optimal time for conversion and the adequate reduction in CNI exposure remain to be defined. Other reasons for use of everolimus include a substantial reduction in the risk of cytomegalovirus infection, and evidence for inhibition of cardiac allograft vasculopathy, a major cause of graft loss. The ongoing MANDELA study is a 12-month multicenter, randomized, open-label, parallel-group study in which efficacy, renal function and safety are compared in approximately 200 heart transplant patients. Patients receive CNI therapy, steroids and everolimus or mycophenolic acid during months 3 to 6 post-transplant, and are then randomized at month 6 post-transplant (i) to convert to CNI-free immunosuppression with everolimus and mycophenolic acid or (ii) to continue reduced-exposure CNI, with concomitant everolimus. Patients are then followed to month 18 post-transplant The rationale and expectations for the trial and its methodology are described herein., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Introduction: Cyclosporine-A and tacrolimus are the cornerstones in modern immunosuppression after organ transplantation. They are potent inhibitors of calcineurin, that is, so-called calcineurin-inhibitors (CNIs). However, because these drugs have narrow therapeutic windows, they are associated with many side-effects, with some being dose related., Areas Covered: The most frequent side-effect of CNIs is nephrotoxicity, which in the long term can contribute, to allograft deterioration. Other frequent side-effects include metabolic disorders (new onset of diabetes, dyslipidemia), neurotoxicity, or promoting of de novo cancers., Expert Opinion: In kidney transplantation, many strategies have been developed to minimize nephrotoxicity while maintaining efficacy of immunosuppression: for example, the minimization of CNI in addition to either full-dose mycophenolic acid or low doses of m-TOR inhibitors, mainly everolimus (EVR). Attempts made to eliminate CNIs by replacing them with m-TOR inhibitors have been unsuccessful because of occurrence of de novo donor-specific alloantibodies in a substantial number of patients, associated with antibody-mediated rejection. Conversely, CNI-avoidance by replacing them by Belatacept is feasible with very good renal function in the long term despite a significant increase in acute cellular rejections within the first-year posttransplantation. Other side-effects of CNIs, such as neurologic disorders, diabetes, dyslipidemia, viral infections, and cancer, seem to be less frequent in low-dose or CNI-free immunosuppressive regimens. Thus, although CNIs remain the major immunosuppressive treatment, their dosage should be minimized by using them with either full-dose MPA or reduced-dose EVR.

Mammalian target of rapamycin inhibitors, such as rapamycin and more recently everolimus, have substituted calcineurin inhibitors in many minimization strategies. Despite their acclaimed renal safety profile, several lines of evidence are emerging on their potential nephrotoxic effect. Predisposing conditions for nephrotoxicity involve a complex interplay between several environmental and genetic factors in the donor-recipient pair. Renal injury may be enhanced by pharmacodynamic interactions when combined with other drugs such as calcineurin inhibitors or nutrients that are predominantly related to an increase in local tissue exposure. These toxic interactions may occur within adequate doses and therapeutic blood levels. This explains the occurrence of nephrotoxicity in some but not all cases. Here, we postulated that activity of a low permeability glycoprotein efflux pump related to low protein expression and/or inhibition enhanced immunosuppressive drug entry in different cells. A rise in intracellular drug concentration increases bioactivity, leading to greater immunosuppression and more immune-related, nonrenal adverse events in the recipient and increased nephrotoxicity in the kidney graft. Under specific isolated or combined environmental and/or genetic conditions in both the recipient and donor affecting the glycoprotein efflux pump and/or the mammalian target of rapamycin pathway, these renal injuries may be aggravated by heightened drug tissue concentrations despite adherence to therapeutic drug and blood levels. Mammalian target of rapamycin inhibitors may induce predominantly a dose-dependent renal epithelial cell injury affecting either the glomerular or the renal tubular epithelial cells, leading to cell death and apoptosis. Epithelial mesenchymal transition mediated interstitial fibrosis and tubular atrophy observed with these drugs may be the result of a cumulative toxic renal tubular injury induced by the direct insult of the drug itself and/or podocytopathy-associated proteinuria. The resulting glomerular tubular damage will ultimately lead to graft failure and loss, if exposure persists.

Cyclosporine A (CsA) is an immunosuppressive drug used in organ transplantation and autoimmune diseases but its clinical uses may be limited due to its dose-related nephrotoxicity. This study was carried out to evaluate the possible protective effects of vildagliptin (VLD) against CsA-induced nephrotoxicity in rats. Animals were divided into four groups treated as follows: control group (CsA & VLD vehicle); VLD group (10mg/kg/day, orally); CsA group (20mg/kg in sunflower oil, S.C.); and CsA-VLD group (CsA &VLD). Induced nephrotoxicity was evidenced by a significant elevation of serum creatinine, blood urea nitrogen (BUN), lactate dehydrogenase (LDH) and urinary micro total proteins (MTP), while serum albumin and urinary creatinine clearance were significantly decreased compared to the control group. Moreover, renal dysfunction was further confirmed by a significant increase in renal lipid peroxide that was measured as renal malondialdehyde (MDA). Renal reduced glutathione (GSH) and superoxide dismutase (SOD) were significantly decreased. Nephrotoxicity was further confirmed by renal tissue histopathology. Also, a high protein expression of Bax with decreased Bcl-2 was revealed in the renal tissue of the CsA treated group. Administration of VLD significantly ameliorated the nephrotoxic effects of CsA suggesting antioxidant, anti-inflammatory and anti-apoptotic benefits of VLD in CsA-induced nephrotoxicity., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Cyclosporine A (CsA) is a powerful immunosuppressive drug. However, nephrotoxicity resulting from its long-term usage has hampered its prolonged therapeutic usage. Schisandra chinensis extracts (SCE) have previously been used in traditional Chinese medicine and more recently coadministered with Western medicine for the treatment of CsA-induced side effects in the People's Republic of China. This study aimed to investigate the possible effects of SCE on the pharmacokinetics of CsA in rats and elucidate the potential mechanisms by which it hinders the development of CsA-induced nephrotoxicity. A liquid chromatography/tandem mass spectrometry method was developed and validated for determining the effect of SCE on the pharmacokinetics of CsA. Male Sprague Dawley rats, which were administered with CsA (25 mg/kg/d) alone or in combination with SCE (54 mg/kg/d and 108 mg/kg/d) for 28 days, were used to evaluate the nephroprotective effects of SCE. Our study showed that SCE increased the mean blood concentration of CsA. Furthermore, we found that the concomitant administration of SCE alongside CsA prevented the disruption of catalase activity and reduction in creatinine, urea, renal malondialdehyde, and glutathione peroxidase levels that would have otherwise occurred in the absence of SCE administration. SCE treatment markedly suppressed the expression of 4-hydroxynonenal, Bcl-2-associated X protein, cleaved caspase 3, and autophagy-related protein LC3 A/B. On the other hand, the expression of heme oxygenase-1, nuclear factor erythroid 2-related factor 2 (Nrf2), and P-glycoprotein was enhanced by the very same addition of SCE. SCE was also able to increase the systemic exposure of CsA in rats. The renoprotective effects of SCE were thought to be mediated by its antiapoptotic and antioxidant abilities, which caused the attenuation of CsA-induced autophagic cell death. All in all, these findings suggest the prospective use of SCE as an effective adjunct in a CsA-based immunosuppressive regimen.

Aim: Calcineurin inhibitors reduce the acute rejection rate and greatly improve renal allograft survival. However, they are associated with some adverse events, including nephrotoxicity, a risk factor for allograft failure. Chronic calcineurin inhibitor-induced nephrotoxicity causes irreversible damage to renal components, such as arteriolar hyaline thickening. The aim of this study is to investigate the risk factors for tacrolimus-induced chronic nephrotoxicity using zero-time biopsy specimens., Methods: Between January 2001 and December 2010, 483 patients who underwent living-related kidney transplantation and had also been placed on a tacrolimus-based regimen were enrolled in this study. There were 1859 specimens evaluated comprising 483 zero-time biopsy specimens and 1376 protocol and for-cause biopsy specimens. De novo arteriolar hyaline thickening due to tacrolimus-induced chronic nephrotoxicity was scored according to the Banff classification aah score. In this study, tacrolimus-induced nephrotoxicity was defined as a positive aah score., Results: Of the 483 patients, 108 patients (22.4%) had biopsy-proven tacrolimus-induced chronic nephrotoxicity. Multivariate analysis showed that interlobular arteriosclerosis proven by zero-time biopsy (OR: 2.23, 95%CI: 1.38-3.58, P < 0.01) and acute rejection episodes (OR: 1.58, 95%CI: 1.00-2.47, P = 0.04) were independent risk factors for tacrolimus-induced chronic nephrotoxicity. However, tacrolimus-induced chronic nephrotoxicity did not affect long-term graft survival., Conclusion: This is the first report showing that arteriosclerosis in zero-time biopsy specimens is a risk factor for histological tacrolimus-induced chronic nephrotoxicity., (© 2015 Asian Pacific Society of Nephrology.)

Polyomavirus-associated nephropathy (PVAN) has become an important cause of kidney failure in kidney transplant recipients. PVAN is reported to affect 1% to 7% of kidney transplant recipients, leading to premature transplant loss in approximately 30% to 50% of diagnosed cases. PVAN occurring in the native kidneys of solid-organ transplant recipients other than kidney only recently has been noted. We report 2 cases of PVAN in heart transplant recipients, which brings the total of reported cases to 7. We briefly review the literature on the hypothesized causes of PVAN in kidney transplant recipients and comment on whether these same mechanisms also may cause PVAN in other solid-organ transplant recipients. PVAN should be considered in the differential diagnosis when evaluating worsening kidney function. BK viremia surveillance studies of nonkidney solid-organ recipients should be conducted to provide data to assist the transplantation community in deciding whether regular monitoring of nonkidney transplant recipients for BK viremia is indicated., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

We investigated the renal protective effects of phophodiesterase type 5 (PDE5) inhibitors in mice with cyclosporine A (CyA; a calcineurin phosphatase inhibitor) induced nephrotoxicity. Fifty male mice were divided into five groups of 10. Group 1 received no treatment, group 2 received only saline orally, group 3 received 30 mg/kg/day CyA by subcutaneous injection, group 4 received only 30 mg/kg/day vardenafil orally, and group 5 received 30 mg/kg/day CyA by subcutaneous injection and 30 mg/kg/day vardenafil orally. At 28 days, platelet-derived growth factor A (PDGF-A) and C (PDGF-C), transforming growth factor-beta 1 (TGF-β1), cyclo-oxygenase 1 and 2 (COX-1 and COX-2), and P glycoprotein (Pgp) expression levels were measured in the renal tissues. In addition, expressions of COX-1 and COX-2 genes were determined using real-time PCR. PDE5 inhibitor administration ameliorated decreased PDGF-A and C, TGF-β1, COX-1 and -2, and Pgp expression levels by modulation of cyclic guanosine monophosphate (cGMP) activity in kidneys. The relative expressions of COX-1 and COX-2 genes to GAPDH revealed that the maximum increase was obtained in the group treated with CyA and vardenafil for both COX-1 and COX-2 genes. Our study revealed that long term oral treatment with vardenafil protects kidneys from CyA induced nephrotoxicity. We showed that long term oral treatment with PDE5 prevents pathological kidney changes caused by CyA induced nephrotoxicity.

Objectives: Tacrolimus is the cornerstone for immunosuppression in renal transplant and is metabolized by the cytochrome P 450 3A (CYP3A) subfamily of enzymes in the liver and small intestine. A polymorphism in intron 3 of the CYP3A5 gene affects the expression of this enzyme and tacrolimus trough blood levels. The purpose of this study was to identify the proportion of CYP3A5 gene polymorphisms in South Indian renal transplant patients and determine the effect of CYP3A5 gene polymorphisms on tacrolimus trough blood levels in patients with and without CYP3A5 expression., Materials and Methods: We included 25 adult patients who underwent renal transplant at Government Medical College, Trivandrum. All patients received tacrolimus (dose, 0.1 mg/kg/body weight, in 2 divided doses). Tacrolimus trough blood levels were determined on postoperative day 6. The CYP3A5 genotype analysis was performed by polymerase chain reaction amplification of target and detection by restriction fragment length polymorphism analysis., Results: The CYP3A5*1/*1 genotype was detected in 5 recipients (20%), *1/*3 genotype in 5 recipients (20%), and *3/*3 genotypes in 15 recipients (60%) of the total 25 graft recipients. Mean tacrolimus level in the CYP3A5*1/*1 group was 5.154 ng/mL (range, 4.42 to 6.5 ng/mL), CYP3A5*1/*3 group was 5.348 ng/mL (range, 3.1 to 9.87 ng/mL), and CYP3A5*3/*3 group was 9.483 ng/mL (range, 4.5 to14.1 ng/mL). Acute rejection episodes were significantly more frequent for CYP3A5*1/*1 homozygous patients (40%) than patients with CYP3A5*1/*3 (20%) or CYP3A5*3/*3 (13%) genotypes., Conclusions: Most patients carried the mutant allele CYP3A5*3 (A6986G). Tacrolimus drug level correlated well with presence or absence of CYP3A5 polymorphisms. Acute rejection episodes were more frequent in expressors, and they may require higher doses of tacrolimus. Similarly, tacrolimus nephrotoxicity was more frequent in non-expressors. Therefore, CYP3A5 polymorphism analysis before renal transplant may help determine the optimal dose of tacrolimus in this population and prevent acute rejection episodes or tacrolimus toxicity.

Background: Visceral leishmaniasis is a disease caused by the protozoan Leishmania sp. and is transmitted by Lutzomyia longipalpis (sand fly). In renal transplant recipients, visceral leishmaniasis causes severe damage to the liver, spleen, and hematopoietic system, as well as poor outcomes for patients with transplanted kidneys. This study describes the largest series of cases of visceral leishmaniasis in renal transplant recipients, providing important information about the diagnostic routines and therapeutic strategies in this patient population., Methods: A retrospective, descriptive study was performed to analyze the distribution and evaluate the extent of the epidemiologic, clinical, diagnostic and therapeutic aspects of 30 renal transplant recipients from endemic regions who presented with visceral leishmaniasis in the post-transplantation period., Results: In this study, visceral leishmaniasis was more frequent in men (80%). The mean age of presentation was 40 ± 10.5 years. The majority of patients worked in urban areas (66.7%), cohabitated with domestic animals (90%), and were from low-income households. In 73.3% of cases, diagnosis was made by direct isolation of Leishmania forms. Patients were treated with liposomal amphotericin, resulting in a high degree of disease remission (80%)., Conclusions: This study describes the largest series of visceral leishmaniasis in renal transplant recipients and expands clinical-epidemiological knowledge for transplantation teams to perform adequate disease management for this specific patient population.