Low-dose cyclosporine in treatment of membranous nephropathy with nephrotic syndrome: effectiveness and renal safety

Background: To observe effectiveness and renal safety of long-term low-dose cyclosporine in idiopathic membranous nephropathy (IMN).

Methods: Sixty-eight patients were enrolled in this prospective cohort study. Renal endpoint was defined as a decrease in eGFR?≥50% from baseline and a development of eGFR ≤60?ml/min/1.73m².

Results: A cyclosporine dose of 2.0?±?0.5?mg/kg/d and a prednisone of 0.3?±?0.2?mg/kg/d were prescribed. The duration of cyclosporine treatment was 27 (3–80) months. The overall remission rate was 91% with a relapse rate of 42%. Fourteen patients had cyclosporine-related acute renal injury (CsA-ARI) within the first three months, and 16 patients had cyclosporine related chronic renal injury (CsA-CRI) within the first year. At the end of follow-up (50?±?18?months), 16 patients (24%) reached renal endpoint. Presence of intimal fibrosis of small artery and higher time-averaged proteinuria were identified as independent risk factors for renal endpoint. RAS inhibition treatment decreased the risk of poor renal outcome. Patients in CsA-ARI group had the highest proteinuria at the third month, the highest time-average proteinuria and the highest proportion of cases reaching renal endpoint. Patients with CsA-CRI were of the oldest age and with the lowest baseline eGFR.

Conclusions: Low-dose cyclosporine is effective in treating IMN. CsA-ARI and no response in proteinuria during the first three months of cyclosporine treatment had the lowest benefit/risk ratio, and these patients should be switched to non-calcineurin-inhibitor based regimen. Patients of older age, with lower baseline eGFR, or having intimal sclerosis of small artery, are more likely to develop progressive renal dysfunction.     

A new update for radiocontrast-induced nephropathy aggravated with glycerol in rats: the protective potential of epigallocatechin-3-gallate

Contrast media (CM) is known to have nephrotoxic adverse effects. Epigallocatechin-3-gallate (EGCG) is the most abundant and active catechin in green tea, and has strong antioxidant and anti-inflammatory properties. This study investigated whether EGCG can reduce contrast-induced nephrotoxicity (CIN), alone or with glycerol (GLY)-induced renal damage, and to understand its mechanisms of protection against toxicity, using models of GLY and CIN in rats. The rats were separated into eight groups (n?=?6 in each), as follows: Healthy, GLY, CM, GLY?+?CM, CM?+?EGCG 50?mg/kg (po), GLY?+?CM?+?EGCG 50?mg/kg (po), CM?+?EGCG 100?mg/kg (po), and GLY?+?CM?+?EGCG 100?mg/kg (po). Both doses of EGCG protected against CM-induced renal dysfunction, as measured by serum creatinine and blood urea nitrogen (BUN). In addition, EGCG treatment markedly improved CIN-induced oxidative stress, and resulted in a significant down-regulatory effect on tumor necrosis factor (TNF)-α and nuclear factor (NF)-κB mRNA expression. Moreover, histopathological analysis showed that EGCG also attenuated CM-induced kidney damage. Considering the potential clinical use of CM and the numerous health benefits of EGCG, this study showed the protective role of multi-dose EGCG treatment on CIN and GLY-aggravated CIN through different mechanisms.     

Rotenone induces nephrotoxicity in rats: oxidative damage and apoptosis

Previous studies have examined rotenone toxicity on the human central nervous system, especially in the pathogenesis of Parkinson’s disease, but few have investigated the effects of rotenone on the kidney. Here, rotenone-induced nephrotoxicity was evaluated by determining morphological, biochemical, oxidative stress-related, and apoptotic factor alterations in rat renal tissue. Morphological and biochemical analyzes showed that rotenone administration to rats damaged renal tissue. Western blot results revealed that rotenone-induced oxidative damage, causing overproduction of glutathione, malonaldehyde, and reactive oxygen species (ROS), and inhibiting superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity. Rotenone also decreased the mitochondrial membrane potential and increased voltage-dependent anion channel (VDAC), caspase-3, and caspase-9 protein levels, indicating an association of apoptosis with renal damage. Our results suggest that glutathione, malonaldehyde, and ROS may be signals of rotenone-induced oxidative damage, and that the mitochondrial pathway plays a key role in apoptosis of renal cells following rotenone administration.     

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。     

Cyclic adenosine monophosphate protects renal cell lines against amphotericin B toxicity in a PKA-independent manner

Amphotericin B is the “gold standard” agent in the management of serious systemic fungal infections. However, this drug can cause nephrotoxicity, which contributes up to 25% of all acute kidney injuries in critically ill patients. Cyclic adenosine monophosphate can protect kidney cells from death due to injury or drug exposure in some cases. Hence, the objective of this work was to evaluate if cAMP could prevent cell death that occurs in renal cell lines subjected to AmB treatment and, if so, to assess the involvement of PKA in the transduction of this signal. Two different renal cell lines (LLC-PK1 and MDCK) were used in this study. MTT and flow cytometry assays showed increased cell survival when cells were exposed to cAMP in a PKA-independent manner, which was confirmed by western blot. This finding suggests that cAMP (db-cAMP) may prevent cell death caused by exposure to AmB. This is the first time this effect has been identified when renal cells are exposed to AmB’s nephrotoxic potential.     

Evaluation of kidney injury biomarkers in rat amniotic fluid after gestational exposure to cadmium

Cadmium is a well‐characterized nephrotoxic agent that is also capable of accumulating and diffusing across the placenta; however, only a few studies have addressed its effects over fetal kidneys and none of them has used a panel of sensitive and specific biomarkers for the detection of kidney injury. The goal of this study was to determine cadmium renal effects in rat fetuses by the quantification of early kidney injury biomarkers. Pregnant Wistar rats were exposed by inhalation to an isotonic saline solution or to CdCl₂ solution (D_Del=1.48 mg Cd kg^?1 day^?1) during gestational days (GD) 8–20. On GD 21, dams were euthanized and samples obtained. Kidney injury biomarkers were quantified in amniotic fluid samples and fetal kidneys were microscopically evaluated to search for histological alterations. Our results showed that cadmium exposure significantly raised albumin, osteopontin, vascular endothelial growth factor and tissue inhibitor of metalloproteinases‐1 levels in amniotic fluid, whereas it decreased creatinine. Clusterin, calbindin and IFN‐inducible protein 10 did not show any change. Accordingly, histological findings showed tubular damage and precipitations in the renal pelvis. In conclusion, gestational exposure to cadmium induces structural alterations in fetal renal tissue that can be detected by some kidney injury biomarkers in amniotic fluid samples. Copyright © 2016 John Wiley & Sons, Ltd.