A Prospective Randomised Comparative Study on the Influence of Cyclosporin and Azathioprine on Renal Allograft Survival and Function

To study the effectiveness and nephrotoxic side-effects of cyclosporinA (CsA) in renal transplant recipients, a prospective randomisedtrial was designed to compare CsA with azathioprine (Aza). Eachtreatment group consisted of 40 patients; in the CsA group,18 were randomly selected for conversion to Aza after 3 months.The 1-year graft survival for CsA-treated patients was 87% comparedwith 66% for the Aza group (P=0.033). Anti-rejection therapywas administrated to 78% of the patients in the Aza group and47% of those in the CsA group (P<0.01). There was no differencein the incidence of primary non-functioning kidneys, cytomegalovirusinfections, hypertension, or degree of proteinuria between thetwo treatment groups. At 3 months the mean creatinine clearance was 42±2 ml/min(mean±SEM) for the CsA group compared with 56±4ml/min for the Aza group (P<0.01), whereas the mean creatinineclearances at 6 months for both the converted and the non-convertedCsA-treated patients did not differ from that found in the Aza-treatedgroup. At 1 year, the mean creatinine clearance for CsA-treatedpatients who were converted to Aza was higher than that foundfor Aza treated patients (62±7 vs 50±6 ml/min;P<0.05). Furthermore, the increment in creatinine clearanceobserved after conversion from CsA to Aza at 3 months showeda linear relationship (r=0.9061) with the CsA trough levelsbefore discontinuation of the drug. This indicates that CsA treatment induces a dose-dependent,nephrotoxic side-effect which is probably reversible.     

乙二醇生产工人尿中酶及低分子蛋白的含量

本文报道了30名乙二醇生产工人三种尿酶及尿中二种微球蛋白排出的变化,并对诸指标的敏感性和应用价值进行了分析。乙二醇接触组工人尿酶及尿中低分子蛋白含量明显高于对照组,说明肾脏功能受到损伤,但无任何临床表现,一般肾功能检查显示正常。研究结果提示长期接触乙二醇可导致慢性肾小管功能障碍。而尿NAG 和α_1-m 是反映乙二醇所致肾损伤较为敏感的二个指标,可用作非损伤性对肾功能的检测手段。     

尿酶检测早期诊断庆大霉素肾脏损害的动物实验与临床研究

采用犬庆大霉素肾中毒模型,结合临床病例,检测尿丙氨酸氨基肽酶、N-乙酰—β—氨基葡萄糖苷酶、γ-谷氨酰转肽酶、乳酸脱氢酶的变化和犬肾超微结构改变。结果显示,治疗剂量庆大霉素对肾脏具有损害作用,中毒量的损害明显加重;处于亚临床期肾病变者,庆大霉素显著加重其毒性损害。检测尿酶的变化可以早期反映出这种肾毒性损害,是一种灵敏的早期监测指标。     

A meta-analysis of the target trough concentration of gentamicin and amikacin for reducing the risk of nephrotoxicity

IntroductionAntimicrobial resistance is one of the biggest threats to public health systems worldwide, and aminoglycosides are key drugs for treating drug-resistant infections. Because of the nephrotoxicity of aminoglycosides, therapeutic drug monitoring is recommended, but few studies of the target trough concentration (Cmin) have been reported. To address the problem, we performed a meta-analysis to confirm the target Cmin of aminoglycosides for minimizing the risk of nephrotoxicity.MethodsWe conducted a literature search using MEDLINE, the Cochrane Library, and Ichushi-Web. In the meta-analysis, nephrotoxicity was compared between the Cmin ≥2 mg/L and Cmin <2 mg/L groups for gentamicin and between the Cmin ≥10 mg/L and Cmin <10 mg/L groups for amikacin.ResultsNo randomized controlled trials were reported for any of the drugs. Five observational studies involving 615 patients were reported for gentamicin, and two observational studies involving 159 patients were identified for amikacin. For gentamicin, Cmin <2 mg/L was linked to a significantly lower rate of nephrotoxicity than Cmin ≥2 mg/L (odds ratio [OR] = 0.22, 95% confidence interval [CI] = 0.12–0.40). For amikacin, Cmin <10 mg/L was associated with a significantly lower rate of nephrotoxicity than Cmin ≥10 mg/L (OR = 0.05, 95% CI = 0.01–0.21).ConclusionsAlthough further well-controlled studies with a low risk of bias are needed, the current meta-analysis demonstrated that Cmin <2 mg/L and Cmin <10 mg/L may reduce the risk of nephrotoxicity linked to gentamicin and amikacin, respectively.     

环孢素A致急性肾损伤及还原性谷胱甘肽的保护作用

目的 进一步探讨环孢素A(CsA)肾毒性的发病机制，并为临床防治CsA所致急性肾损伤提供依据。方法 采用生化、免疫组化和透射电镜方法。结果 CsA使肾皮质内皮素-l(ET-1)水平增高，肾组织中超氧化物歧化酶(SOD)活力下降，丙二醛(MDA)含量增多，肾小管上皮细胞Na^ ，K^ -ATP酶活性降低，并造成肾、肝、肺组织结构破坏，还原性谷胱甘肽(TAD)可使上述病变减轻。结论 血流动力学改变和脂质过氧化损伤是CsA致急性肾损伤的重要原因，TAD有良好的保护作用。     

Tissue oxidative stress induced by patulin and protective effect of crocin

Patulin (PAT) is a secondary toxic metabolite produced principally by Penicillium expansum. This mycotoxin is known to be teratogenic, mutagenic, immunotoxic and neurotoxic, and it has been shown to cause damage in several organs in laboratory animals. This study focuses on the prevention of experimental murine PAT-induced nephrotoxicity and hepatotoxicity. We investigate the ability of a natural product, crocin (CRO), to counteract the toxic effects of PAT. Pre-treatment of mice with CRO prevented PAT-induced oxidative damage in both liver and kidney. CRO reduced lipid peroxidation, protein oxidation and restored redox status by regulating the endogenous antioxidant enzymatic system. These data corroborate and extend findings in PAT-induced nephrotoxicity and hepatotoxicity, and further suggest that preventive effect of CRO towards other forms of PAT toxicity, including neurotoxicity, may be warranted.     

绿茶多酚减轻环孢素A致血管收缩和肾毒性的实验研究

目的探讨绿茶多酚（GTP）对环孢素A（CsA）大鼠胸主动脉环血管舒张功能和肾毒性的作用机制。方法将30只SD大鼠随机平均分为3组：CsA组、对照组和CsA＋GTP组。建立CsA动物模型5周后,检测血尿素氮（BUN）、肌酐（Cr）;取胸主动脉环,观察乙酰胆碱（Ach）诱发的血管舒张反应、L—NAME和吲哚美辛预处理对舒张功能的影响,检测血管组织一氧化氦（NO）水平;并观察各组肾脏组织病理学变化。结果5周后,CsA组大鼠BUN、Cr水平高于对照组和CsA＋GTP组,差异有统计学意义（P〈0．05）。CsA组大鼠Ach引起的胸主动脉环的最大舒张度为（42.5±4．3）％,低于对照组的（81．2±76）％和CsA＋GTP组的（70．1±6．5）％,差异均有统计学意义（P〈0.05）。经L—NAME预处理后,CsA组和CsA＋GTP组动脉环的舒张反应低于对照组;经吲哚美辛预处理后对照组和CsA＋GTP组的舒张反应高于CsA组（均P〈0．05）。CsA组大鼠血管组织中NO含量显著低于对照组和CsA＋GTP组（P〈0．05）。肾脏组织病理学检测：CsA组肾小管、间质损伤评分显著高于对照组,而GTP＋CsA组则显著低于CsA组（均P〈0.05）。结论CsA可对肾脏的结构和功能产生损害,并引起NO介导的内皮依赖性血管舒张功能异常。绿茶多酚能保护肾脏的结构和功能,改善内皮细胞依赖性的血管舒张功能。     

Platycodin D,a triterpenoid sapoinin from Platycodon grandiflorum, ameliorates cisplatin-induced nephrotoxicity in mice

Platycodin D (PD) is well known as a potent triterpenoid saponin having various pharmacological activities isolated from the root of Platycodon grandiflorum (Jacq.) A. DC. (Campanulaceae). We aimed to evaluate protective effect of PD on cisplatin (CDDP)-induced nephrotoxicity. Male ICR mice were allocated into five groups as follows: Negative control, CDDP alone and CDDP with PD (0.1, 1 and 5 mg/kg) treated group. PD was given for three consecutive days before CDDP injection. Increased blood urea nitrogen (BUN) and creatinine (CRE) levels in CDDP alone treated mice were decreased to normal range by pretreatment with PD. It also decreased nitric oxide (NO) and lipid peroxidation with increased antioxidant enzymes such as glutathione (GSH), glutathione peroxidase (GPx) and superoxide dismutase (SOD) in PD pretreated mice. In histopathological examination, pretreatment with PD showed ameliorated renal injury such as intraluminal cast formation and epithelial desquamation. Furthermore, over-expression of nuclear factor-kappa B p65 and apoptotic cells were suppressed by PD pretreatment. Taken together, PD pretreatment might be beneficial to CDDP-induced nephrotoxicity.     

Drug-Induced Nephrotoxicity and Its Biomarkers

Nephrotoxicity occurs when kidney-specific detoxification and excretion do not work properly due to the damage or destruction of kidney function by exogenous or endogenous toxicants. Exposure to drugs often results in toxicity in kidney which represents the major control system maintaining homeostasis of body and thus is especially susceptible to xenobiotics. Understanding the toxic mechanisms for nephrotoxicity provides useful information on the development of drugs with therapeutic benefi ts with reduced side effects. Mechanisms for drug-induced nephrotoxicity include changes in glomerular hemodynamics, tubular cell toxicity, inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy. Biomarkers have been identifi ed for the assessment of nephrotoxicity. The discovery and development of novel biomarkers that can diagnose kidney damage earlier and more accurately are needed for effective prevention of drug-induced nephrotoxicity. Although some of them fail to confer specificity and sensitivity, several promising candidates of biomarkers were recently proved for assessment of nephrotoxicity. In this review, we summarize mechanisms of drug-induced nephrotoxicity and present the list of drugs that cause nephrotoxicity and biomarkers that can be used for early assessment of nephrotoxicity.