冠状动脉介入治疗中对比剂肾毒性的Meta分析

目的 比较冠状动脉介入治疗中等渗对比剂与低渗对比剂的肾毒性差异.方法 计算机检索CENTRAL、EMbase、PubMed、中国知网(CNKI)、万方数据库(Wanfang Data)、维普数据库(VIP)和中国生物医学文献数据库(CBM),查找比较冠状动脉介入治疗中等渗与低渗对比剂肾毒性差异的随机对照试验(randomized controlled trial,RCT),检索时间均由建库至2014年1月,同时对文献的参考文献进行手检纳入.按照制定的文献纳入与排除标准由两名评价员独立筛选并提取资料,采用Review Manger 5.2软件进行Meta分析.结果 共纳入7项研究,合计2 677名受试者.①诊断标准:以血清肌酐增高超过基线水平的25％为诊断标准,等渗对比剂肾毒性比低渗对比剂低[RR=0.57,95％CI(0.38～0.84),P=0.005];以血清肌酐升高大于44 μmol/L(0.5 mg/dl)为诊断标准,等渗对比剂肾毒性小于低渗对比剂[RR=0.65,95％CI(0.43～0.98);P=0.04].②年龄:患者平均年龄≥65岁,2种对比剂的对比剂肾病(contrast induced nephropathy,CIN)发病率差异无统计学意义RR=0.66,95％CI(0.40～1.09),P=0.10];患者平均年龄60～65岁,2种对比剂肾毒性差异亦无统计学意义[RR=0.64,95％CI(0.19～2.11),P=0.46].③血肌酐基线值:血肌酐基线值偏高,等渗对比剂肾毒性小于低渗对比剂[RR=0.40,95％CI(0.21～0.76);P=0.006];血肌酐基线值正常,2种对比剂肾毒性差异无统计学意义RR=1.14,95％CI(0.39～3.37),P=0.81].④对比剂剂量:对比剂的使用剂量小于200ml的患者,等渗对比剂与低渗对比剂CIN的发病率差异无统计学意义[RR=0.85,95％CI(0.51～1.43),P=0.55],而对比剂使用剂量不低于200ml的患者,等渗对比剂CIN的发病率较低渗对比剂低[RR=0.38,95％CI(0.18～0.80),P=0.01].结论 对于接受冠状动脉介入治疗的患者,无论采用哪种诊断标准,等渗对比剂都较低渗对比剂有较低的肾毒性.对于老年患者,对比剂渗透压是影响CIN发生的因素之一,冠状动脉介入治疗时应尽量使用等渗对比剂并减少剂量,以降低CIN的发生率.     

Protective effect of carnosine against cisplatin-induced nephrotoxicity in mice

The nephroprotective effect of the natural antioxidant carnosine was evaluated in mice with cisplatin-induced acute renal damage, in which generation of reactive oxygen species plays a major role. Nephrotoxicity was induced by a single i.p. injection of cisplatin (20 mg/kg). Carnosine was administered for six consecutive days in a dose of 10 mg/kg/day, i.p., starting 3 days before cisplatin injection. The results revealed that carnosine treatment significantly reduced blood urea nitrogen and serum creatinine levels elevated by cisplatin administration. Also, carnosine significantly attenuated cisplatin-induced increase in malondialdehyde and decrease in reduced glutathione, and catalase and superoxide dismutase activities in renal cortical homogenates. Additionally, histopathological examination and scoring showed that carnosine markedly ameliorated cisplatin-induced renal tubular necrosis. In conclusion, carnosine can be considered a feasible candidate to protect against nephrotoxicity commonly encountered with cisplatin treatment.     

Mechanisms of the ifosfamide-induced inhibition of endocytosis in the rat proximal kidney tubule

The Fanconi syndrome is a common side effect of the chemotherapeutic agent ifosfamide. Current evidences suggest that chloroacetaldehyde (CAA), one of the main metabolites of ifosfamide activation, contributes to its nephrotoxicity. However, the pathophysiology of CAA-induced Fanconi syndrome is not fully understood. The present work examined the adverse effects of CAA on precision-cut rat renal cortical slices, which allowed studying the toxic effect of CAA on proximal endocytosis. We demonstrated that clinically relevant concentrations of CAA (/=75 muM has adverse effects, both on viability parameters and on energy metabolism, as shown by the great decrease in total glutathione and ATP levels. In addition, the V-ATPase, which plays a crucial role in intracellular vesicle trafficking, was inhibited by 100 muM of CAA. By contrast, the slight decrease in Na-K-ATPase activity observed for CAA>/= 125 muM (maximum inhibition: 33%) could not totally explain the inhibition of the reabsorption processes. In conclusion, the addition of the two main adverse effects of CAA (decrease in ATP levels and inhibition of the V-ATPase) could explain the inhibition of endocytosis and the Fanconi syndrome observed during ifosfamide treatments.     

Resveratrol attenuates cisplatin-induced nephrotoxicity in rats

Cisplatin is an antitumor drug widely used in the treatment of many malignant tumors. However, the most common adverse effect, nephrotoxicity, limits the use of this drug in many cancer patients. Resveratrol is a phytoalexin that presents highly efficient protection in experimental nephrotoxicity models. This study evaluated the effect of resveratrol on cisplatin-induced kidney damage. Male Wistar rats were treated with resveratrol (25 mg/kg b.w., i.p.) before the administration of cisplatin (5 mg/kg b.w., i.p.) and killed 2 or 5 days later. Blood and urine samples were collected and the kidneys were removed. Rats from the cisplatin group showed acute tubular cell necrosis and increased immunostaining for ED1 (macrophages/monocytes) and T-lymphocytes in the renal cortex and outer medulla when compared with the control group. These alterations were less intense in animals pre-treated with resveratrol. Moreover, indicators of renal injury such as increased serum creatinine levels, urinary volume and urinary protein caused by the administration of cisplatin, were also significantly reduced with resveratrol. Increased lipid peroxidation and glutathione depletion in tissue were attenuated by resveratrol. In conclusion, resveratrol attenuated the cisplatin-induced structural and functional renal changes by reducing free radicals and inhibiting inflammatory cell infiltrates.     

Ceftazidime does not enhance cyclosporin-a nephrotoxicity in febrile bone marrow transplantation patients

Summary Ceftazidime was used as monotherapy for 30 febrile episodes in 28 patients, who underwent allogeneic bone marrow transplantation and who were treated concomitantly with the immunosuppressive agent cyclosporin-A. Ceftazidime did not enhance the well established nephrotoxicity of cyclosporin-A as measured by serum creatinine levels or creatinine clearnace. Although an increasing number of Gram-positive infections in these patients warrants vigilance, ceftazidime as initial empirical monotherapy proved to be successful in 95% of all febrile post-transplantation patients. All Gram-negative and 69% of the Grampositive infections were cured with ceftazidime alone. The overall clinical cure rate was 72%, with microbiological clearance in 63%. This compares favourably with aminoglycoside containing schedules and avoids the aminoglycoside associated nephrotoxicity.     

Urinary N -acetyl-β-glucosaminidase as an indicator of renal dysfunction in electroplating workers

Objectives: To investigate chromium-induced renal dysfunction in electroplating workers. Methods: A cross-sectional study was used to evaluate four biochemical markers of renal function. A total of 178 workers were divided into 3 comparable groups consisting of 34 hard-chrome plating workers, 98 nickel-chrome electroplating workers, and 46 aluminum anode-oxidation workers, who represented the reference group. Ambient and biological monitoring of urinary chromium were performed to measure exposure concentrations. Results: Overall, urinary chromium concentrations were highest among hard-chrome plating workers (geometric mean 2.44 μg/g creatinine), followed by nickel-chrome electroplating workers (0.31 μg/g creatinine) and aluminum workers (0.09 μg/g creatinine). Airborne chromium concentrations were also highest in the hard-chrome plating area (geometric mean 4.20 μg/m³), followed by the nickel-chrome electroplating area (0.58 μg/m³) and the aluminum area (0.43 μg/m³). A positive correlation was found between urinary chromium and airborne concentrations (r = 0.54, P < 0.01). Urinary concentrations of N-acetyl-β-d-glucosaminidase (NAG) were also highest among hard-chrome plating workers (geometric mean 4.9 IU/g creatinine), followed by nickel-chrome workers (3.4 IU/g creatinine) and aluminum workers (2.9 IU/g creatinine). The prevalence of “elevated” NAG (>7 IU/g creatinine) was significantly highest among hard-chrome plating workers (23.5%), then among nickel-chrome workers (7.1%) and aluminum workers (8.7%). Differences in β₂-microglobulin, total protein, and microalbumin were not significant. Conclusion: The author's evidence indicates that NAG is an early indicator of renal dysfunction in hard-chrome plating workers.     

Cisplatin induces apoptosis through the ERK–p66shc pathway in renal proximal tubule cells

The extracellular signal-regulated kinase (ERK) has been shown to mediate cisplatin (CP)-induced toxicity to renal proximal tubule cells. Here, we demonstrate that ERK serves as the kinase that phosphorylates the pro-apoptotic p66shc protein at its Serine36 residue in CP-treated renal proximal tubule cells. Pharmacologic or dominant-negative inhibition of ERK mitigates cisplatin-induced Ser36 phosphorylation of p66shc. Overexpression of p66shc exacerbates while its knockdown or mutation of the Serine36 site to alanine ameliorates CP-induced nephrotoxicity in vitro. Since p66shc is Serine36 phosphorylated in the kidneys of mice after treatment with CP, a similar mechanism might exist in vivo.     

镉所致肾毒性及氧化性损害机制的研究

目的探讨氯化镉(CdCl2)引起肾脏毒性的氧化性损害机制,为防制镉危害提供实验依据。方法雄性SD大鼠随机分为4组,每组4只,体重200～260g。对照组腹腔内注射生理盐水,染镉组连续3d分别腹腔注射1.25、2.5和5mg/kg的CdCl2溶液。测定体重变化、肾脏系数、血清尿素氮(BUN)和肾皮质脂质过氧化产物丙二醛(MDA)含量,苏木素-伊红(HE)染色观察肾组织形态学,免疫组化的方法检测肾组织中8-羟基脱氧鸟苷(8-OhdG)的表达。结果CdCl2(2.5mg/kg,5mg/kg)可引起明显的肾脏毒性。表现为体重降低,BUN水平升高,肾脏系数升高;组织形态学观察可见肾毒性急性肾小管损害表现。肾皮质匀浆MDA水平升高(P<0.05)。免疫组化结果显示各实验组大鼠肾组织中可检出氧化损伤标志物8-OhdG。结论CdCl2所致大鼠氧化性损伤可能是其肾脏毒性的机制之一。     

顺铂致急性肾损伤的研究进展

顺铂为临床上广泛应用治疗多种实体肿瘤的化疗药物,但在正常组织器官中的不良反应,尤其是肾毒性限制了其临床应用。应用顺铂治疗后,大约1/3的患者可出现肾功能异常,甚至急性肾损伤。近年关于顺铂不良反应的研究聚焦于顺铂肾毒性的发生机制,尤其是在引起肾小管上皮细胞死亡、炎性反应的信号转导通路方面。最近自噬也被证实参与顺铂导致地细胞损伤,虽然已发现一些预防顺铂肾毒性的方法 ,但大多数保护方法均较局限,因此,更好地理解顺铂肾毒性作用机制,对于顺铂肾毒性防治将具有十分重要意义。该文就顺铂致急性肾损伤作用机制研究进展作一综述。     

Reversible nephrotoxicity of onconase and effect of lysine pH on renal onconase uptake

Purpose: To examine the histopathology of the kidney in mice following repeated injections of the antitumor drug onconase, and to determine whether lysine, which reportedly blocks kidney uptake of other basic proteins, blocks the high renal uptake of onconase. Methods: Mice received repeated intraperitoneal onconase injections over 3 weeks. Kidneys were examined by light microscopy after 1 week, 3 weeks, and 5 weeks (2 weeks after cessation of injections) and compared to kidneys from animals receiving a similar schedule of PBS injections. Renal uptake of radioiodinated onconase was measured in animals receiving intraperitoneal injections of lysine solutions of acidic and neutral pH given at −30, 0 and +5 min relative to intravenous onconase injection. Renal onconase uptake was also measured in animals made metabolically acidotic by ingestion of ammonium chloride, arginine chloride or lysine dihydrochloride from the drinking water. Results: Onconase caused acute moderate multifocal proximal renal tubular necrosis, and this toxicity was reversed by 2 weeks after drug withdrawal. Intraperitoneal injections of lysine dihydrochloride in PBS (pH 1.5) reduced renal onconase uptake at 15 min from 67.9 ± 13.4% to 17.0 ± 3.8% of the injected dose without affecting the plasma concentration and also reduced the fraction of degraded onconase in the urine. However, neutral solutions of lysine dihydrochloride at pH 7.4 or lysine acetate at pH 7.1 were ineffective at blocking renal onconase uptake. Furthermore, renal onconase uptake was minimally or not affected by a state of metabolic acidosis. Conclusions: Proximal tubular toxicity of onconase was reversible. Renal onconase uptake was blocked by lysine at pH 1.5 but not at neutral pH. Received: 13 August 1998 / Accepted: 3 December 1998