Gentamicin and sisomicin — Induced renal tubular damage

Summary Early signs of aminoglycoside — induced renal tubular damage were detected in 26 patients given gentamicin and 23 given sisomicin. The urinary elimination of 3 low molecular weight proteins (LMWP) — beta 2 microglobulin, retinol binding protein and lysozyme (LZM), and the urinary activity of 2 enzymes — alanine aminopeptidase and N-acetylbeta-glucosaminidase — was measured before, during and after treatment. In gentamicin — treated patients LMWP elimination increased, especially LZM which rose markedly during treatment and returned to normal values after its end. Enzyme activities also rose while gentamicin was being given. Sisomicin produced smaller changes. As neither the mean serum creatinine nor the mean urinary elimination of transferrin were increased, glomerular function was probably not affected. However, tubular damage was detected, as shown by the LMWP output (especially LZM) and increased enzyme activity. Urinary LMWP and enzyme measurements are presented as sensitive and reliable methods to monitor early aminoglycoside — induced tubular impairment. It is suggested that the different renal toxicities of gentamicin and sisomicin are related to differences in their accumulation in the renal cortex.     

Comparison of the effect of amphotericin B desoxycholate and amphotericin B colloidal dispersion on renal functions and renal morphology in rats

BACKGROUND AND AIM: Amphotericin B (AmB) desoxycholate remains as one of the most efficacious agents currently available for the treatment of systemic fungal infections; however, amphotericin B colloidal dispersion (ABCD) has been developed because of AmB desoxycholate nephrotoxicity. The goal of our study was to compare the effect of administration of AmB desoxycholate and ABCD on renal functions and renal morphology in rats. RESULTS: Amophotericin B desoxycholate as well as ABCD causes damage to renal tubuli and polyuria. Amophotericin desoxycholate causes considerably more severe damage to tubuli than ABCD, but the morphological damage to renal glomeruli is minimal in both formulas. In tubular cells, AmB desoxycholate causes severe damage to mitochondria, vacuolation of cytoplasm, and increased values of volume density of peroxisomes. CONCLUSION: None of these formulas causes a decrease in glomerular filtration in rats when animals are properly hydrated.     

The natural history of renal function following orthotopic heart transplant

BACKGROUND: The outcome of solid organ transplantation has dramatically improved after the introduction of the calcineurin inhibitor cyclosporine. With the increasing longevity of heart transplant recipients, the long-term effects of cyclosporine on renal function have become more evident. The natural history of kidney function following orthotopic heart transplant is not well defined and long-term follow up studies are scant. METHODS: We conducted an observational study on patients who received a heart transplant at Saint Louis University Hospital between January 1, 1983 and December 31, 1988. Patients were followed up for 15 yr or until death whichever occurred first. In order to assess the effect of heart transplantation and cyclosporine exposure on long-term renal function we restricted the statistical analysis to patients who survived the first year post-transplantation. RESULTS: A total of 68 patients received orthotopic heart transplants at Saint Louis University Hospital between 1983 and 1988. Forty-eight (71%) patients survived for more than 1 yr. All patients were treated with cyclosporine based triple immunosuppressive regimen, with gradual cyclosporine dose reduction over time. The mean duration of follow-up was 8 yr. The estimated GFR at 5 and 10 yr post-transplant were significantly lower than estimated GFR at baseline and 1 yr post-transplant. There was no significant difference between estimated GFR at 15 yr and estimated GFR at baseline or 1 yr post-transplant. The cumulative incidence of chronic renal failure (GFR < or = 29 mL/min/1.73 m2) at 5, 10 and 15 yr was 4.2, 10.4 and 12.5%, respectively (p < 0.05). The cumulative incidence of severe chronic renal failure (GFR < or = 15 mL/min/1.73 m2) at 5, 10 and 15 yr was 2.1, 8.3 and 8.3%, respectively. The mortality rate was 8, 37, and 52% at 5, 10, and 15 yr, respectively. The 10 and 15 yr survivors had an estimated GFR at 1 yr post-transplant that was significantly higher than the non-survivors. Age, pre-transplantation estimated GFR, pre-transplantation diabetes and pre-transplantation hypertension are risk factors associated with > or = 10 mL/min/1.73 m2 decrement in estimated GFR. CONCLUSION: Heart transplant survivors beyond the first year post-transplant have a significant decrease in renal function and significant mortality observed over time. Age, pre-transplant GFR, pre-transplant diabetes and pre-transplant hypertension are important risk factors for decrement in renal function.     

Radiocontrast-induced nephrotoxicity and urinary alpha-glutathione S-transferase levels: Effect of amlodipine administration

AIMS: The exact pathogenesis and prophylaxis concerning radiocontrast-induced nephrotoxicity (RCIN) was unclear. Short-acting calcium antagonists were used to prevent RCIN. This study was designed to evaluate the role of a long-acting calcium antagonist (amlodipine) administration by determining serum creatinine (SCre) levels and 24 hour urinary excretion rates of glutathione S-transferase alpha (GST-alpha) which has a selective localization only to proximal tubular epithelium. METHODS: In a prospective trial, 29 outpatients (19 M, 10 F) undergoing coronary angiography were randomized and either amlodipine 10 mg/day (n = 15) or placebo (n = 14) were administered prior to angiography and continued thereafter. All patients had normal basal renal function and none of them had any risk factor for RCIN. A low osmolar, nonionic contrast media (iopamidol 76%) was administered to all patients. Creatinine clearance (CCre), SCre and 24-hour urinary GST-alpha levels were measured before, 24 hours and 7 days after angiography. RESULTS: SCre and 24 hour urinary GST-alpha values increased on 24th hour following the angiography in both groups (p < 0.017 and 0.001, respectively). Pretreatment with amlodipine created no difference in both variables (p > 0.05). CONCLUSIONS: A reversible tubular dysfunction occurs following radiocontrast administration which was manifested by an increase in urinary GST-alpha excretion rates. Pretreatment with a long acting calcium antagonist amlodipine has no effect on the course of enzyme excretion and alteration observed in SCre.     

番茄红素对环孢素所致大鼠肾毒性的保护作用

目的:研究番茄红素(lycopene,LP)对环孢素(cyclosporine,CsA)所致肾功能衰竭的保护作用及机制。方法:雄性SD大鼠po给予溶媒或LP(10mg/kg)6d后,再联合给予0.9%氯化钠注射液或CsA(50mg/kg)14d,观察大鼠肾功能与肾脏组织的结构改变。结果:连续14d给予CsA可致大鼠体重下降,血清肌酐(creatinine,Crea)和尿素氮(blood urea nitrogen,BUN)水平显著升高、肌酐清除率(creatinine clearance,Ccr)和肾脏抗氧化活性下降,肾脏组织出现大量细胞排列紊乱和小管萎缩。提前给予LP可以有效增加肾脏抗氧化能力,逆转CsA所致的大鼠体重下降和肾功能衰竭,降低大鼠血清Crea和BUN而提高体内Ccr;组织病理学检测也证实LP可有效的拮抗CsA引起的肾小管变性萎缩。结论:LP能有效拮抗CsA所致的大鼠肾功能衰竭,其作用与LP可以增强CsA大鼠抗氧化能力有关。     

Differential effects of cisplatin in proximal and distal renal tubule epithelial cell lines

Pathological studies suggest that cisplatin injures different portions of the nephron to different extents. To investigate this issue further, we examined the cytotoxicity and uptake of cisplatin in cell lines derived from S₁ and S₃ proximal tubule and distal convoluted tubule segments isolated from a mouse carrying the SV40 large T-antigen transgene. S₁ cells displayed the highest sensitivity to cisplatin cytotoxicity, followed by S₃ and distal convuluted tubule (DCT) cells. These differences in cytotoxicity did not correlate with differences in cisplatin uptake. Cytotoxic concentrations of cisplatin triggered apoptosis in all three cell lines. Although BAX and BCL-2 expression was similar among the three cell lines, the expression of the anti-apoptotic protein, BCL-X_L, was significantly lower in S₁ cells than in S₃ and DCT cells, and this may have contributed to the heightened sensitivity of S₁ cells. Cisplatin transport characteristics demonstrated a saturable component of cisplatin uptake and differences in apparent K_M and V_max values among the three cell lines. The three cell lines were 43- to 176-fold more sensitive to cisplatin than to carboplatin. This distinction between the two drugs could not be fully explained by differences in the uptake rates of carboplatin and cisplatin. We conclude that cells from different portions of the nephron display different sensitivities to cisplatin, different transport characteristics for cisplatin and different levels of expression of BCL-X_L. In addition, the relative resistance of renal cells to carboplatin vs cisplatin is mostly due to the differential effects that follow internalization. © 1999 Cancer Research Campaign     

Whortleberry protects kidney against the cisplatin-induced nephrotoxicity: an experimental study

Purpose: This study investigated the antioxidant effects of whortleberry against cisplatin-induced nephrotoxicity in rats.

Material and methods: This study included 48 female Sprague–Dawley rats weighing 263.68?±?8.29?g. The rats were divided into the following six groups, with eight rats in each group: control, ethanol control, whortleberry control, cisplatin control, 16?mg/kg cisplatin +100?mg/kg whortleberry, and 16?mg/kg cisplatin +200?mg/kg whortleberry groups. Biochemical analysis was performed by measuring total oxidant status and total antioxidant status, histopathological analysis was performed by calculating proximal and distal tubule areas (μm²), and immunohistochemical analysis was performed by determining anti-Caspase-3 immunostaining. Differences among the groups were examined using one-way analysis of variance, and p?Results: Cisplatin treatment decreased the total antioxidant status and increased the total oxidant status and Caspase-3 level. Moreover, it resulted in the dilatation, vacuolization and loss of tubular epithelial cells; and glomerular degeneration and edema in the kidney tissues (p?p?Conclusions: Our results indicate that the antioxidant effects of the whortleberry decrease cisplatin-associated nephrotoxicity.     

Nephrotoxicity After the Treatment of Periprosthetic Joint Infection With Antibiotic-Loaded Cement Spacers

Background

Treatment of periprosthetic joint infections commonly involves insertion of an antibiotic-loaded cement spacer (ACS). The risk for acute kidney injury (AKI) related to use of antibiotic spacers has not been well defined. We aimed to identify the incidence of and risk factors for AKI after placement of an ACS.

Curcumin has a palliative action on gentamicin-induced nephrotoxicity in rats

Generation of free radicals in kidney cortex plays an important role in the pathogenesis of gentamicin (GM) nephrotoxicity, and curcumin, the yellow curry pigment isolated from turmeric, has been confirmed to have a strong antioxidant action. Therefore, in the present work, we aimed at testing the possible protective or palliative effect of curcumin on GM nephrotoxicity. Curcumin was given to rats at an oral dose of 200 mg/kg/day for 10 days, and in some of these rats GM was also injected intramuscularly at a dose of 80 mg/kg/day during the last 6 days of the treatment. Nephrotoxicity was evaluated histopathologically by light microscopy, and biochemically by measuring the concentrations of creatinine and urea in serum, and reduced glutathione (GSH) concentration and superoxide dismutase (SOD) activity in renal cortex. The concentration of GM in renal cortex was measured microbiologically. GM significantly increased the concentrations of urea and creatinine (P < 0.05) by about 111 and 97%, respectively. GM treatment reduced cortical GSH concentration by about 31% (P < 0.05), and the activity of SOD by about 27% (P < 0.05). Curcumin significantly mitigated these effects. Sections from saline and curcumin-treated rats showed apparently normal proximal tubules. However, kidneys of GM-treated rats had a moderate degree of necrosis. The degree of necrosis appeared lessened when GM was given simultaneously with curcumin. The concentration of GM in the renal cortex of the rats given GM + curcumin was significantly (P < 0.05) lower than that found in rats treated with GM alone by about 39%. The results suggested that curcumin had ameliorated the histopathological and biochemical indices of nephrotoxicity in rats. Pending further studies, curcumin may potentially be useful as a nephroprotectant agent.     

冬虫夏草对氨基糖甙肾毒性损伤的保护作用

本文前瞻性地观察了冬虫夏草对氨基糖甙(AG)类肾毒性的影响。按随机双盲将54例患者分为冬虫夏草治疗组和安慰剂组。两组同时接受庆大霉素6mg·kg~(-1)/d(18～32岁)或丁胺卡那霉素0.4g/d(55～73岁)注射,连续6天。动态观察尿NAG酶和β_2微球蛋白排泄的结果表明,冬虫夏草治疗组肾毒性损伤要轻于单用AG的对照组。冬虫夏草对临床AG肾毒性损伤具有良好的保护作用。