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     

Reversible hypophosphatemic rickets following ifosfamide treatment

A 7-year-old boy developed renal tubular dysfunction and hypophosphatemic rickets following treatment for relapsed embryonal rhabdomyosarcoma. Multi-agent chemotherapy included ifosfamide; the child received a total of 108 g/m². The complete Fanconi syndrome which ensued, including excessive loss of calcium, resolved spontaneously and progressively 18 months after the last dose of ifosfamide. The patient had no further symptoms of rickets and radiological signs had almost completely normalized. Further follow-up was not possible as, despite further treatment, the child died of progressive disease. © 1992 Wiley-Liss, Inc.     

健脾益气利水汤对顺铂所致大鼠肾毒性的预防治疗作用

本实验对中药健脾益气利水汤预防治疗顺铂(PDD)所致大鼠肾毒性的作用机理进行了研究。结果表明:对PDD所致的肾毒性,中药复方能显著降低大鼠血清中尿素氮(BUN)、氨基葡萄糖苷酶(NAG)、β_2-微球蛋白(β_2-mG)的含量(P<0.05),并能减轻PDD对大鼠肾脏Na~ -K~ -ATP酶活性的抑制(P<0.05),病理切片也证实中药对大鼠肾脏有保护作用。提示中药健脾益气利水汤对顺铂所致大鼠肾毒性有明显的预防和治疗作用,其机理之一可能是通过调节机体的能量代谢来实现的。     

Nephrotoxicity of chlorofluoroacetic acid in rats.

Dichloroacetic acid (DCA), chlorofluoroacetic acid (CFA), and difluoroacetic acid (DFA) are inhibitors of pyruvate dehydrogenase kinase. DCA is used for the clinical management of congenital lactic acidosis. Glutathione transferase zeta (GSTZ1-1) catalyzes the biotransformation of DCA and CFA, and DCA is a mechanism-based inactivator of GSTZ1-1. In rodents, DCA causes multiorgan toxicities and is hepatocarcinogenic. The toxic effects of CFA, which is an excellent substrate but a poor inactivator of GSTZ1-1, have not been investigated. The objective of this study was to investigate the nephrotoxicity of CFA. Rats given a single dose of 1.5 mmol/kg CFA became anuric and died within 24 h. Urinalysis and light microscopic analysis showed that rats given 0.6-1.2 mmol/kg CFA developed polyuria, glycosuria, and renal proximal tubular damage. Electron microscopic analysis indicated a role for apoptosis in CFA-induced cell death. The nephrotoxicity of CFA was associated with a dose-dependent increase in inorganic fluoride excretion. Treatment of rats with DCA for 5 days to inactivate GSTZ1-1 failed to prevent metabolism of CFA to fluoride and did not block CFA-induced renal damage. A role for GSTZ1-1-catalyzed release of fluoride from CFA is proposed but a role for other enzymes cannot be excluded. DFA, which is not metabolized to fluoride by GSTZ1-1, was given to rats as a control and was also nephrotoxic: rats given 1.2 mmol DFA/kg/day for 5 days had normal urine volumes but showed proximal and distal tubular damage; fluoride excretion was not elevated. The mechanism of DFA-induced nephrotoxicity is not known but appears to differ from that of CFA.     

L-carnitine ameliorates gentamicin-induced renal injury in rats.

BACKGROUND: This study examined whether administration of L-carnitine ameliorates gentamicin-induced renal injury in rats. METHODS: Male Sprague-Dawley rats were assigned to one of seven treatment groups: group A (control) rats were given normal saline injections daily for 8 consecutive days; group B, C and D rats were given gentamicin injections, 50 mg/kg body weight/day daily for 8 consecutive days; and group E, F and G rats were given gentamicin injections, 80 mg/kg/day daily for 8 consecutive days. Starting 4 days before these injections, all groups were given additional injections, for 12 consecutive days, of normal saline (groups A, B and E) or L-carnitine at 40 mg/kg (groups C and F) or 200 mg/kg (groups D and G). Histological scoring of renal cortical pathology was performed after day 12. RESULTS: Among rats injected with gentamicin 50 mg/kg/day, those given either 40 or 200 mg/kg/day of L-carnitine had higher creatinine clearances at day 12 than the rats not given carnitine. In the rats given 80 mg/kg gentamicin and no carnitine, renal function tended to be lower than in controls. At day 12, the rats given gentamicin 80 mg/kg and L-carnitine 200 mg/kg/day, compared with rats given gentamicin 80 mg/kg and no carnitine, displayed lower serum urea and probably creatinine concentrations, and higher creatinine clearances, and their serum urea was not different from control (group A) rats. Both doses of gentamicin induced renal cortical histopathology. Changes were milder with gentamicin 50 mg/kg/day, and L-carnitine, particularly at 200 mg/kg/day, ameliorated the severity of renal pathology induced by both gentamicin doses. In rats given gentamicin 80 mg/kg/day, the animals treated with carnitine 200 mg/kg/day had significantly less severe proximal tubular necrosis and significantly greater mild proximal tubular necrosis compared with rats receiving L-carnitine 40 mg/kg/day or no carnitine. CONCLUSIONS: In rats receiving gentamicin, daily L-carnitine injections, particularly at 200 mg/kg/day, ameliorate the severity of renal cortical proximal tubular necrosis and maintain greater renal function.     

Network Meta-Analysis of Novel Glucose-Lowering Drugs on Risk of Acute Kidney Injury

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Drug-Induced Glomerular Disease: Attention Required!

Drugs and toxins frequently are associated with the development of various types of acute kidney disease and CKD. Although medications are a widely known cause of tubulointerstitial damage, drug-related glomerular injury is not well appreciated but nonetheless, important. Glomerular damage that occurs after exposure to medications can be caused by direct cellular injury involving the mesangial, endothelial, or visceral epithelial cells (podocytes). Examples include nodular glomerulosclerosis associated with smoking and endothelial injury with thrombotic microangiopathy from a number of medications. Podocyte injury with the development of a minimal change or FSGS lesion has also been described with various medications. Glomerulopathies may also be associated with drug-induced immune-mediated processes. Through various pathways, drugs may promote the formation of a number of antibodies, which may, ultimately, affect the glomerulus. Examples include lupus-like renal lesions and ANCA-related pauci-immune vasculitis. It is critical to recognize these conditions early, because in many patients, there is improvement in renal parameters on stopping the offending medication.     

PCB77 Inducing Renal Tubular Cell Apoptosis

PCBs are a family of persistent environmental toxicants with a wide spectrum of toxic features, such as neurotoxic, hepatoxicity, immunotoxicity, endocrine disruption effects, and oncogenic effects. The kidney is the most important organ involved in the elimination of toxins and drugs. To date, little has been done to investigate the potential influence of nephrotoxicity of 3,3’,4,4’- tetrachlorobiphenyl (PCB77). By assessing cell viability and apoptotic cell death in renal tubular epithelial (NRK-52E) cells cultures, we found that PCB77 could decrease cellular viability at least at 30?μM concentration after 3?h exposure. PCB77 was demonstrated to promote DNA breakage resulting in apoptosis. Moreover, apoptotic subcellular morphological changes administration of PCB77 was observed using transmission electron microscopy. Appearance swelling of mitochondria, endoplasmic reticulum dilation and chromatin agglutinate, and other apoptosis cells morphological characteristics could be visible. Due to increased PCB77 concentration, cells viability was decreased. Collectively, our findings identified the morphological mechanism that PCB77-induced nephrotoxicity via promoting renal tubular epithelial cells apoptosis. It is suggested that using and production of PCB77 should be carefully managed to reduce public health risks.     

Comparison of nephrotoxicity associated to different lipid formulations of amphotericin B: a real‐life study

Amphotericin B (AmB) use is limited by the occurrence of kidney toxicity. Here, we evaluated the incidence and impact of nephrotoxicity in a large series of patients receiving therapy with amphotericin B deoxycholate (d‐AmB), liposomal AmB (L‐AmB), or AmB lipid complex (ABLC), in a clinical practice scenario. In a retrospective cohort study, patients treated with different AmB formulations between 2003 and 2012 were evaluated. Medical records and laboratory data were reviewed. Nephrotoxicity was determined according to modified RIFLE criteria. Predictors of nephrotoxicity and mortality were determined and treatment groups were compared. About 431 patients were studied (d‐AmB, n = 236; L‐AmB, n = 105; ABLC, n = 90). Frequency of severe nephrotoxicity (RIFLE ‘Failure’) was 11.5%, 2.4% and 7.2% for d‐AmB, L‐AmB and ABLC, respectively (P = 0.046). Use of L‐AmB was found to be an independent protective factor (OR: 0.18; 95% CI: 0.03–0.64; P = 0.006) for severe nephrotoxicity, considering d‐AmB as a reference. L‐AmB was also a protective factor for mortality (OR: 0.56; 95% CI: 0.32–0.99; P = 0.046). In addition, in‐hospital overall mortality was associated with cancer, previous dialysis, evolution to dialysis, and stay in the intensive care unit. Patients treated with ABLC showed similar frequency of severe kidney toxicity than those treated with d‐AmB. L‐AmB was associated with better outcomes than other formulations, including severe nephrotoxicity and overall mortality.     

中药马兜铃酸的肾毒性研究

目的：探讨马兜铃酸的毒性作用机制、马兜铃酸肾病发病机制与原因。方法：本文对近年来国内外对于马兜铃酸导致马兜铃酸肾病发生、发展的最新研究进行总结。结果：含马兜铃酸成分中药,与马兜铃酸肾病的发生密切相关。结论：本文为防治马兜铃酸肾病提供参考意见。