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.     

他克莫司慢性肾毒性机制及其防治药物的研究进展

他克莫司（tacrolimus）作为常用的免疫抑制剂,广泛用于器官移植术后和多种自身免疫性疾病。但长期服用他克莫司可导致慢性肾毒性,引起器官存活率下降、死亡率升高等,极大影响临床结局。近年研究表明,氧化应激、细胞自噬、细胞凋亡、肾素-血管紧张素系统（renin-angiotensin-system,RAS）以及炎症介导他克莫司慢性肾毒性（tacrolimus-induced chronic nephrotoxicity,TICN）的发生发展。相应地,抗氧化剂、RAS抑制剂、钙离子通道阻滞剂及某些天然药物等对TICN显示出了一定的防治效果。基于此,该文综述了TICN的发生机制和防治药物的研究进展,以期为TAC的临床安全使用和未来研究提供参考。     

Curcumin has a palliative action on gentamicin-induced nephrotoxicity in rats

Generation of free radicals in kidney cortex plays an important role in the pathogenesis of gentamicin (GM) nephrotoxicity, and curcumin, the yellow curry pigment isolated from turmeric, has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of curcumin on GM nephrotoxicity. Curcumin was given to rats at an oral dose of 200 mg/kg/day for 10 days, and in some of these rats GM was also injected intramuscularly at a dose of 80 mg/kg/day during the last 6 days of the treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, and reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex. The concentration of GM in renal cortex was measured microbiologically. GM significantly increased the concentrations of urea and creatinine (P < 0.05) by about 111 and 97%, respectively. GM treatment reduced cortical GSH concentration by about 31% (P < 0.05), and the activity of SOD by about 27% (P < 0.05). Curcumin significantly mitigated these effects. Sections from saline and curcumin-treated rats showed apparently normal proximal tubules. However, kidneys of GM-treated rats had a moderate degree of necrosis. The degree of necrosis appeared lessened when GM was given simultaneously with curcumin. The concentration of GM in the renal cortex of the rats given GM + curcumin was significantly (P < 0.05) lower than that found in rats treated with GM alone by about 39%. The results suggested that curcumin had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further studies, curcumin may potentially be useful as a nephroprotectant agent.     

C-Phycocyanin Attenuates Cisplatin-Induced Nephrotoxicity in Mice

Although cisplatin is a highly effective antineoplastic agent, nephrotoxicity is its major clinical problem. Recently, it was reported that Spirulina, a blue-green algae, has potent antioxidant properties. The aim of this study was to establish the possible protective role of C-phycocyanin (PC), one of the active ingredients of Spirulina, against cisplatin-induced nephrotoxicity. This study was carried out using human kidney-2 (HK-2) cells and male C57BL6 mice. Cells and mice were divided into four groups; untreated control group, PC-treated control group, cisplatin-treated group, and PC plus cisplatin-treated group. The molecular, functional, and structural parameters were measured. PC significantly attenuated blood urea nitrogen, serum creatinine, renal histological damages, and apoptotic cell death in cisplatin-treated mice. The cisplatin-induced cell death was significantly attenuated in cells pretreated with PC. PC also significantly attenuated the elevation of p-ERK, p-JNK, and p-p38 induced by cisplatin treatment. The expression of Bax, caspase-9, and caspase-3 in cisplatin-treated cells were also decreased by PC treatment. In conclusion, PC ameliorates cisplatin-induced nephrotoxicity and, at least in part, suppression of p-ERK, p-JNK, p-p38, Bax, caspase-9, and caspase-3 may be involved in this mechanism.     

Protective effect of trapidil and l-arginine against renal and hepatic toxicity induced by cyclosporine in rats

Rationale: Cyclosporine A (CsA) leads to renal and liver injury, production of free radicals and nitric oxide (NO) deficiency. This study investigates the possible protective effects of trapidil and l-arginine against CsA-induced tissue injury. Objectives: Forty adult male Wistar rats (180 ± 20 g) were divided into five groups, eight animals in each. The first group served as control, second group served as CsA group, third group served as CsA + trapidil group, fourth group served as CsA + l-arginine group, and fifth group served as CsA + trapidil + l-arginine group. Kidney and liver functions, inflammatory mediators, cytokines, oxidant and antioxidant parameters as well as histopathological studies of renal and liver tissue were assessed in all groups. Main findings: CsA induced renal and hepatic dysfunction, which was confirmed by laboratory and histopathological examination. Administration of trapidil diminished the renal and liver injury and significantly attenuated the levels of serum creatinine, urea, aspartate aminotransferase (AST), alanine aminotransferase (ALT), interleukin-1β (IL-1β), tumor necrosis factor alpha (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and oxidative stress, while it significantly elevated the level of serum nitric oxide and the activity of antioxidative stress. l-Arginine gave the same trend as trapidil, but trapidil effect was more pronounced. Coadministration of trapidil + l-arginine significantly ameliorated the toxic effect of CsA, but did not differ significantly from the effect of trapidil alone. Conclusions: Treatment with trapidil or l-arginine diminished the renal and hepatic CsA-induced toxicity. However, the effect of trapidil was more pronounced. Therefore, treatment with trapidil alone may be the most economic and effective as a potential therapeutic agent in CsA injury.     

Calcium Channel Blockade in Rats with Cyclosporine-Induced Vasoconstriction

Calcium channel blockade has been found to attenuate nephrotoxicity of cyclosporine. However, it is not known whether intrarenal vasoconstriction caused by cyclosporine is totally mediated by vascular smooth muscle calcium influx. To study the protective effects of two calcium blockers on cyclosporine-induced intrarenal vasoconstriction and renal microvascular blood flow, hydronephrotic rat kidneys were suspended in an environmentally controlled tissue bath. Renal microvessel diameters and microvascular blood flow were determined by in vivo videomicroscopy and Doppler velocimetry. Calcium channel blockade was achieved by adding verapamil hydrochloride (5.6 ± 10-⁵ M) or diltiazem hydrochloride (2.8 × 10-⁵ M) to the tissue bath, which respectively resulted in a 15 ± 2% and 16 ± 3% interlobular arteriolar dilation, a 13 ± 3% and 12 ± 2% afferent arteriolar dilation, and a 60 ± 8% and 46 ± 14% increase in interlobular blood flow. When cyclosporine (1.7 × 10-³ M) was added to the tissue bath, there was a constriction of the interlobular arterioles to 4 ± 3% below baseline in rats receiving verapamil and 9 ± 3% below baseline in rats receiving diltiazem. Microvascular blood flow was reduced by the addition of cyclosporine to 3 ± 4% above original baseline values in the verapamil group and 22 ± 6% below baseline in the diltiazem group. Afferent arterioles were similarly constricted by cyclosporine. The results indicate that calcium blockade causes preglomerular vasodilation and protects the microvascular blood flow induced by cyclosporine. Since verapamil or diltiazem did not prevent arteriolar constriction as observed when cyclosporine was added, it was concluded that the mechanism of acute cyclosporine-induced vasoconstriction is not solely mediated by vascular smooth muscle calcium influx through potential dependent channels.     

Sirolimus conversion regimen versus continued calcineurin inhibitors in liver allograft recipients: a randomized trial

A large prospective, open-label, randomized trial evaluated conversion from calcineurin inhibitor (CNI)- to sirolimus (SRL)-based immunosuppression for preservation of renal function in liver transplantation patients. Eligible patients received liver allografts 6-144 months previously and maintenance immunosuppression with CNI (cyclosporine or tacrolimus) since early posttransplantation. In total, 607 patients were randomized (2:1) to abrupt conversion (<24 h) from CNI to SRL (n = 393) or CNI continuation for up to 6 years (n = 214). Between-group changes in baseline-adjusted mean Cockcroft-Gault GFR at month 12 (primary efficacy end point) were not significant. The primary safety end point, noninferiority of cumulative rate of graft loss or death at 12 months, was not met (6.6% vs. 5.6% in the SRL and CNI groups, respectively). Rates of death at 12 months were not significantly different, and no true graft losses (e.g. liver transplantation) were observed during the 12-month period. At 52 weeks, SRL conversion was associated with higher rates of biopsy-confirmed acute rejection (p = 0.02) and discontinuations (p < 0.001), primarily for adverse events. Adverse events were consistent with known safety profiles. In conclusion, liver transplantation patients showed no demonstrable benefit 1 year after conversion from CNI- to SRL-based immunosuppression.