Occupational hydrocarbon exposure and chronic nephropathy

This review aims at discussing the questions raised by the hydrocarbon-related chronic nephropathy and its possible consequence, the hydrocarbon-related chronic renal failure. It has been attempted to adopt the point of view of the clinician. Therefore, the most important part of the review is devoted to a presentation and an analysis of the available data on humans. The main features of the available studies on human subjects are presented, their conclusions discussed in the light of the possible methodological flaws, and practical conclusions drawn. After a discussion of the main difficulties encountered for selecting the suitable exposure indicator, the studies are discussed in order of decreasing quality of the study design (cohort, case-control, cross-sectional studies, and the case reports). It is concluded that a great deal of controversies about chronic hydrocarbon-related nephropathy is explained by differences in the study design and that hydrocarbon-induced nephropathy is probably more than a mere hypothesis, although a causal relationship has not yet been proven. Finally, some practical consequences for dealing with a hydrocarbon-exposed patient diagnosed with a kidney disease and the need for further research are discussed.     

二甲基甲酰胺与乙醇联合毒性初探

经口分别给予Wistar大鼠蒸馏水、DMF 400mg/kg、乙醇1000mg/kg及DMF400mg/kg 乙醇1000mg/kg,染毒21天。结果表明DMF组及联合染毒组大鼠血清ALT明显增高,SLDH在后者也明显升高,且两组肝组织ATP酶及SDH活性明显降低。各染毒组尿LDH活性显著上升,DMF组及联合染毒r-GT活性显著降低,此两组肾脏组织AKP、ATP、SDH活性也明显降低。上述变化联合染毒组较单独作用组明显,因此认为DMF对肝肾具有损伤作用,乙醇可加重DMF的损伤作用。     

Tubulointerstitial nephritis caused by the antiviral agent foscarnet

The antiviral agent foscarnet has long been used in our unit to treat cytomegalovirus (CMV) infections in renal transplant patients. The clinical effect has been convincing and, apart from changes in serum calcium levels, very few side effects have been noted. We have, however, observed a nephrotoxic reaction in a series of patients with initially good renal function who therefore received high doses of foscarnet. Transplant biopsies performed in five of those patients revealed degenerative changes in the tubular epithelial cells as well as tubular calcium deposits and an infiltration of the interstitium by mixed mononuclear and polymorphonuclear leucocytes. Renal insufficiency was accompanied by high fever. After withdrawal of the drug, the temperature rapidly normalized, whereas serum creatinine continued to rise for about 3 days and then fell back towards previous levels. We conclude that transplant biopsies are of great value in distinguishing between a foscarnet nephrotoxic effect and CMV nephritis, various forms of rejection, and other causes of impaired renal function.     

实验性汞中毒时肾组织和尿中碱性磷酸酶活性的变化

本研究采用亚急性汞中毒肾损害的大鼠模型,探讨了汞中毒时血、肾和尿中碱性磷酸酶(ALP)活性的变化关系。结果表明,大鼠肾匀浆中 ALP活性明显低于对照组,尿 ALP活性则显著增加。ALP 活性降低的部位在肾近曲小管。体外实验未发现氯化汞对肾、尿ALP 具有直接抑制作用或激活作用。尿中ALP 活性的增高是汞引起的肾小管上皮细胞损伤所致。它可作为汞中毒肾损害的一个观察指标。     

Effect of buthionine sulfoximine on orthophenylphenol-induced hepato- and nephrotoxic potential in male rats

A single oral administration of orthophenylphenol (OPP, 1400 mg/kg; about half the LD₅₀) to male Fischer 344 rats produced an elevation of serum transaminase activity 24 h later. Pretreatment with l-buthionine-S,R-sulfoximine (BSO, 900 mg/kg) in the OPP-treated rats potentiated the hepatic and renal damage which was accompanied by necrosis. Six hours after the administration of OPP (700 or 1400 mg/kg), hepatic and renal glutathione (GSH) levels decreased with increasing dosage. Hepatic GSH depletion with OPP was enhanced with BSO pretreatment and the recovery of GSH in both organs was slow in the high-dose OPP group. These results suggest that hepatic and renal damage is associated with a serious and prolonged GSH depletion. When either phenyl-p-benzoquinone (PBQ) or phenylhydroquinone (PHQ), which are intermediates of OPP, was administered orally to rats at 700 or 1400 mg/kg, the mortality with the high dose of PBQ was 75% at 24 h. The serum transaminase activity and UN level increased with the low dose of PBQ, accompanied by necrotic hepatocytes. The toxic effects of PHQ on kidney or liver were less than those on PBQ. These observations suggest that the liver and kidney may be target organs for toxic actions of a large dose of OPP and its intermediate, PBQ.Part of this work was presented at IInd International ISSX Meeting Xenobiotic Metabolism and Disposition, May 16–20, 1988, Kobe, Japan     

Deacetylation and further metabolism of the mercapturic acid of hexachloro-1,3-butadiene by rat kidney cytosol in vitro

Hexachloro-1,3-butadiene (HCBD) is more nephrotoxic to female than male rats. Metabolism of HCBD involves conjugation with glutathione followed by formation of the cysteine conjugate S-(pentachloro-1,3-butadienyl) cysteine (PCBD-CYS) and then the mercapturic acid N-acetyl-S-pentachloro-1,3-butadienyl-cysteine (PCBD-NAC). PCBD-NAC is also more nephrotoxic to female rats than male rats. The deacetylation of [¹⁴C]-PCBD-NAC to PCBD-CYS and the binding of radiolabelled metabolites to protein has been studied using renal cytosol preparations from male and female rats in vitro, since a sex-related difference in these reactions could explain the difference in nephrotoxicity found in vivo. PCBD-NAC was rapidly metabolised by renal cytosol. The rate of metabolism was similar with either male or female renal cytosol, and the major metabolite identified was PCBD-CYS. N-Acetylation of PCBD-CYS to PCBD-NAC was not detected in the presence of either male or female renal cytosol. Covalent binding of radioactivity from [¹⁴C]-PCBD-NAC to cytosolic protein could be detected after 5 min incubation, and although the extent of binding was similar for both male and female cytosol at early time periods, after 60 min incubation more binding was found in the presence of male cytosol. Covalent binding was largely prevented by aminooxyacetic acid, an inhibitor of cysteine conjugate -lyase, suggesting a role for this enzyme in the activation of HCBD. These results indicate that the sex differences in the nephrotoxicity of HCBD and PCBD-NAC in the rat are not attributable to differences in the rate of deacetylation of PCBD-NAC to give the proximate nephrotoxin PCBD-CYS.This work was supported by a fellowship from the European Science Foundation granted to I. S. P.     

Induction of light hydrocarbon nephropathy by p-dichlorobenzene

In order to clarify the etiology of a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidney in male rats, the nephrotoxicity of p-dichlorobenzene (p-DCB) was investigated in a subchronic study. Groups of ten male and ten female Fischer 344 rats were dosed by gavage with 0 (controls), 75, 150, 300 or 600 mg p-DCB/kg/day in corn oil. Half of the animals were sacrificed after 4 weeks and the remainder after 13 weeks. Increased urinary LDH and epithelial cell excretion and exacerbation of hyaline droplet accumulation in the cytoplasm of renal cortical cells were observed in male rats over the entire dose range investigated. Tubular single cell necrosis, dilated tubules with granular cast formation in the outer zone of the medulla, were evident in male rats after 4 and 13 weeks of treatment with doses of 150–600 mg/kg/day. In female rats there was no indication of a nephrotoxic action of p-DCB. The effects on the kidney, both in their morphological characteristics and the fact that they occur exclusively in male animals, correspond to the light hydrocarbon nephropathy observed as a result of short-term treatment with a number of aliphatic and cyclic hydrocarbons. The development of cortical renal tumors seems to be associated with this kind of kidney damage which is unique to male rats. The literature on this subject generally regards these renal effects as not predictive for man.     

Biochemical characterisation of para-aminophenol-induced nephrotoxic lesions in the F344 rat

The acute biochemical effects of the nephrotoxin p-aminophenol (PAP) were studied in detail using a combination of conventional bioanalytical and ¹H-NMR spectroscopic methods. Dosing PAP (25–100 mg/kg) to male F344 rats resulted in a dose-related proximal nephropathy with consequent elevations in urinary enzymes, glucose, and urine total protein as shown by conventional methodology. ¹H-NMR spectroscopy at 400 MHz of urine from PAP-treated rats also revealed a characteristic glycosuria, with concomitant amino aciduria. The increased excretion of these compounds indicates functional defects in the proximal tubule and reduced solute reabsorption efficiency. In addition, ¹H-NMR urinalysis and conventional enzymatic analysis showed a dose-related lactic aciduria. Other changes detected by ¹H-NMR included a dose-related reduction in the excretion of citrate (confirmed by a conventional biochemical method) and an increase in the excretion of acetate. The degree of abnormalities shown by ¹H-NMR urinalysis agreed well with histopathological observations and conventional biochemical indices of nephrotoxicity. ¹H-NMR urinalysis therefore serves to highlight changes in the excretion of low MW urine components not routinely studied by conventional biochemical analysis.Abbreviations ALP alkaline phosphatase - APAP paracetamol - BUN blood urea nitrogen - GFR glomerular filtration rate - GOT glutamate oxaloacetate transaminase - LAP leucine aminopeptidase - LDH lactate dehydrogenase - MW molecular weight - NAG N-acetyl--D-glucosaminidase - PAP p-aminophenol - ppm parts per million - TMAO trimethylamine N-oxide - UFR urine flow rate     

老年人应用万古霉素的肾毒性观察(附22例报告)

目的　研究老年患者使用万古霉素的肾毒性及影响肾毒性发生的各种因素。方法　选择 2 2例因肺部感染或肾盂肾炎并且其致病菌对万古霉素敏感 ,而静脉使用万古霉素的老年患者 ,观察用药前后肾功能指标的变化。万古霉素的用量根据血清肌酐清除率相应调整 ,按照 APACHE评分法研究影响万古霉素肾毒性的各种因素。结果　万古霉素的血药浓度不是影响其肾毒性的唯一指标 ,而 APACHE评分有助于预测万古霉素的肾毒性。高龄老年人是万古霉素肾毒性的高危人群。结论　万古霉素对于多数老年患者是安全的。但是对于 APACHE评分大于 40的危重高龄老年患者 ,其肾毒性严重 ,甚至导致肾功能衰竭     

Toxicité rénale des produits de contraste radiologiques

The nephrotoxicity of iodinated contrast agent/media is defined by acute renal failure occurring within 48 to 72 hours after injection of iodized contrast product, in the absence of other etiology. The risk factors for contrast agent renal injury must systematically be sought before the exam. The presence of risk factors, including the existence of a renal failure defined by a creatinine clearance (eGFR) of less than 60 mL/min/1.73 m², requires to take prevention measures including hydration. If eGFR is less than 30 mL/min/1.73 m², the advice of a nephrologist is necessary.