S‐allylcysteine attenuates renal injury by altering the expressions of iNOS and matrix metallo proteinase‐2 during cyclosporine‐induced nephrotoxicity in Wistar rats

Cyclosporine A (CsA) is the first choice immunosuppressant used for the prevention of allograft rejection in solid organ transplantation and immune‐mediated diseases. Reactive oxygen species‐induced oxidative stress and lipid peroxidation are implicated in the pathophysiology of CsA‐induced renal injury. In this work, we have studied the effect of a garlic‐derived compound, S‐allylcysteine (SAC) on CsA‐induced nephrotoxicity. CsA‐induced nephrotoxicity was assessed in terms of increased activities of serum marker enzymes and levels of kidney markers. CsA administration induced significant elevation in lipid peroxidation along with abnormal levels of enzymic and non‐enzymic antioxidants in the kidneys of the rats. SAC administration improved renal function by bringing about a significant decrease in peroxidative levels and increase in antioxidant status. Elevated expressions of inducible nitric oxide synthase (iNOS) and nuclear factor kappa B (NF‐κB) due to CsA administration were reduced by SAC treatment. An increase in the expression of matrix metalloproteinase‐2 (MMP‐2) was evident in CsA‐induced groups of rats, which was moderately reduced in SAC treated rats. An increase in the levels of serum constituent's urea, uric acid and creatinine was observed in the CsA‐induced rats, which was reduced upon treatment with SAC. These results indicate that SAC has a protective action against CsA‐induced nephrotoxicity which is also supported by histopathological studies. A comparative study of the antioxidant vitamin C and SAC is more valuable to assess the efficacy of the drug that can be used for the treatment of nephrotoxicity. Copyright © 2009 John Wiley & Sons, Ltd.     

广防己的肾毒性及代谢组学研究

目的：采用代谢组学方法研究大鼠予广防己灌胃后尿液代谢产物的改变情况。 方法：雄性SD大鼠64只随机分为广防己组和正常对照组,每组32只。广防己组大鼠予广防己8．1g／（kg·d）灌胃,正常对照组灌服等体积蒸馏水,连续灌胃4周。在灌胃前,灌胃2周、4周及停药2周后收集大鼠24h尿液,利用核磁共振（nuclear magnetic resonance,NMR）技术测定大鼠尿液代谢产物^1H NMR谱,进行模式识别分析;取血检测血尿素氮（blood urea nitrogen,BUN）和血清肌酐（serum creatinine,SCr）含量;取肾脏组织行病理学检查。 结果：与正常对照组比较,给药2周时广防己组大鼠血BUN含量明显升高（P〈0．05）;肾组织出现肾小管细胞肿胀,肾小球球囊结构破坏,肾间质炎性细胞浸润。给药4周时,BUN和SCr含量显著升高（P〈0.05）,肾组织病理改变加重。停药恢复2周后,广防己组BUN含量仍较正常对照组明显升高（P〈0．05）,且病理改变与给药4周时无明显差异。大鼠尿样代谢谱经主成分分析提示,广防己组与正常对照组在各时间点代谢物图谱均有差异,整个给药期间,广防己组柠檬酸含量持续下降,牛磺酸含量持续上升。在给药2周时,伴马尿酸盐含量上升;给药4周时伴马尿酸盐、2-酮戊二酸含量下降,氧化三甲胺和肌酐／肌酸含量上升;停药恢复2周后肌酐／肌酸和2-酮戊二酸含量下降,马尿酸盐和氧化三甲胺含量上升。 结论：10倍药典剂量广防己给药2周可造成肾功能损害,随给药时间延长,损伤加重,停药后有一定恢复。广防己可能还具有一定的肝脏毒性作用。     

δ-氨基-γ-酮戊酸脱水酶和维生素D受体基因多态性与铅肾毒性易感性的相关研究

目的探讨δ-氨基-γ-酮戊酸脱水酶(ALAD)和维生素D受体(VDR)基因多态性以及基因-基因、基因-环境之间的联合作用对铅肾毒性的作用。方法选择233名铅作业工人,根据工人接触铅水平是否超过职业接触限值将其分为两组,分别测定血铅、尿N-乙酰-β-D-氨基葡萄糖苷酶(NAG)、尿β2-微球蛋白(β2-MG)和尿肌酐,全血提取DAN基因组,多聚酶链反应-限制性片段长度多态性(PCR-RFLP)法分析ALAD和VDR基因多态性。结果超职业限值组,ALAD1-2/2-2基因型和ALAD1-1基因型工人尿NAG的浓度分别为(2.12±0.07)U/mmol Cr和(1.73±0.03)U/mmol Cr,差异具有显著性P<0.05;VDR-Bb基因型的工人尿β2-MG浓度[(20.94±0.12)μg/mmol Cr]高于携带VDR-bb基因型工人的尿β2-MG浓度[(15.28±0.09)μg/mmol Cr](P=0.01)。多因素Logistic回归分析发现,铅接触、高血铅等环境因素以及环境-基因的联合作用都是铅作业工人肾损害的危险因素,接铅水平、血铅水平、ALAD基因型和接铅水平的联合作用引起尿NAG异常的OR值分别为6.85(2.51～10.87)、2.41(1.70～3.41)、3.01(1.10～8.19)。结论在高铅浓度接触下ALAD和VDR基因型与铅肾毒性有关,ALAD-2等位基因和高铅接触是加重铅肾毒性的危险因素。     

Effect of acute paracetamol overdose on changes in serum and urine electrolytes

What is already known about this subject

• Paracetamol causes renal failure in overdose. Experimental studies have shown that paracetamol can inhibit COX II systemically in a manner similar to selective COX-II inhibitors.
• In overdose nonsteroidal anti-inflammatory drugs such as ibuprofen, cause dose-dependent increase in urinary potassium excretion (FeK) and sodium retention, probably due to vasoconstriction.

What this study adds

• Paracetamol overdose is associated with dose-related hypokalaemia and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose.
• This effect seems likely to be via cyclo-oxygenase inhibition and may be separate from the nephrotoxic effects of paracetamol.

Aims

To investigate the effects of acute paracetamol overdose on renal function, serum and urine electrolyte excretion in man.

Methods

Two studies were performed in patients admitted with paracetamol overdose: a retrospective study examining changes in serum electrolytes, and a prospective study evaluating changes in serum and urine electrolytes. A control group with SSRI overdose was included in the prospective study.

Results

There was a significant dose-dependent relationship between admission (4 h) paracetamol concentration and fall in serum potassium in the retrospective study (P < 0.01) and a significant positive relationship between serum paracetamol at 4 h and fractional excretion of potassium at 12 h postingestion (P < 0.01) in the prospective study. No changes were seen in the control group. No cases developed renal failure.

Conclusions

Paracetamol overdose is associated with dose-related hypokalaemia, and kaliuresis of short duration (<24 h), suggesting a specific renal effect of paracetamol in overdose perhaps via cyclo-oxygenase inhibition. This effect seems distinct from any nephrotoxic effect of paracetamol.     

肾脏转运体和/或代谢酶介导药物排泄及药物相互作用的研究进展

肾脏是人体最重要的排泄器官。肾单元近端小管细胞具有多种药物转运体和代谢酶,在药物及其代谢物处置中发挥关键作用。近端小管细胞中主要转运体包括有机阴离子转运体、有机阳离子转运体、有机阳离子/肉毒碱转运体、多药及毒素外排转运蛋白、P-糖蛋白、乳腺癌耐药蛋白和多药耐药相关蛋白;主要代谢酶包括细胞色素P450酶,UDP-葡萄糖醛酸基转移酶、磺酸基转移酶、谷胱甘肽S-转移酶。肾脏转运体和/或代谢酶介导药物相互作用(DDIs)是临床关注的重要问题。肾脏转运体和代谢酶存在密切协作关系,在肾脏也存在多种相互作用现象(包括转运-转运相互作用,代谢-代谢相互作用和转运-代谢相互作用),其显著影响药物肾脏处置、临床疗效和肾毒性。本文系统阐述了这些相互作用对药物及其代谢物的肾脏排泄、药动学、DDIs和肾毒性的影响。今后需要进一步阐明肾脏转运-代谢相互作用机制,将有助于研究体内药物肾脏处置和DDIs,促进临床合理用药。     

Assessment for Subclinical Kidney Damage in Workers Exposed to Low Concentrations of Hydrocarbons

Abstract

It has been suggested the risk of hydrocarbon-induced chronic nephropathy is negligible at low exposure levels. The first purpose of the study was to test this hypothesis by selecting a population slightly exposed to hydrocarbons. Moreover, as hypertension might be associated with an increased excretion of nephrotoxic mercapturates, the association between blood pressure and urinary concentration of S-phenylmercapturic acid (S-PMA) was also examined. Lifetime exposure assessment, main tests of sub clinical kidney damage, and statistical approach were taken from a previous study that had included primarily moderately or heavily exposed workers and had found hydrocarbon-induced nephrotoxic effects. No nephrotoxic effect of exposure could be ascertained in the present study. S-PMA concentration was not increased in hypertensive workers. Thus, the risk of hydrocarbon-induced chronic nephropathy might be extremely low in workers slightly exposed to hydrocarbons. The negative results of some studies might be due to the low lifetime hydrocarbon exposures of the study populations.     

Light and Electron Microscopic Changes in the Kidney of Wistar Rats following Treatment with Cyclosporine A

The morphological changes found in kidneys of patients undergoing chronic Cyclosporine A (CSA) treatment could, despite of numerous attempts, not yet be reproduced in reliable experimental models. The purpose of the present investigation was to systematically scan the in vivo fixed kidneys in CSA treated Wistar rats at the light and electron microscopic level. The study revealed changes in the proximal tubules, i.e., inclusion bodies, vacuolization, microcalcifications and regeneration. Some glomeruli displayed a thickening of the parietal sheet of Bowman's capsule. At the electron microscopic level, individual necroses of myocytes in the tunica media of afferent arterioles were observed. Thus, at the ultrastructural level, the kidneys of CSA treated normotensive Wistar rats do reveal morphological changes similar to those occurring in man.     

Studies on the comparative toxicity of S-(1,2-dichlorovinyl)-L-cysteine,S-(1,2-dichlorovinyl)-L-homocysteine and 1,1,2-trichloro-3,3,3-trifluoro-1-propene in the Fischer 344 rat

The renal tubular toxicity of various halogenated xenobiotics has been attributed to their enzymatic bioactivation to reactive intermediates by S-conjugation. A combination of high resolution proton nuclear magnetic resonance (¹H NMR) spectroscopy of urine, renal histopathology and more routinely used clinical chemistry methods has been used to explore the acute toxic and biochemical effects of S-(1,2-dichlorovinyl)-L-cysteine (DCVC), S-(1,2-dichlorovinyl)-L-homocysteine (DCVHC) and 1,1,2-trichloro-3,3,3-trifluoro-1-propene (TCTFP) up to 48 h following their administration to male Fischer 344 (F344) rats. In the absence of gross renal pathology, ¹H NMR urinalysis revealed increased excretion of the tricarboxylic acid cycle intermediates citrate and succinate following DCVC administration. In contrast, both DCVHC and TCTFP produced functional defects in the S₂ and S₃ segments of the proximal tubule that were confirmed histologically. In these cases, ¹H NMR urinalysis revealed increased excretion of glucose, L-lactate, acetate and 3-D-hydroxybutyrate (HB) as well as selective amino aciduria (alanine, valine, glutamate and glutamine). The significance of the proximal nephropathies induced by DCVHC and TCTFP is discussed in relation to biochemical observations on other xenobiotics that are toxic by similar mechanisms. Received: 25 April 1994 / Accepted: 13 June 1994