Nephrotoxicity of cyclosporin A. A lithium clearance and micropuncture study in rats

Renal function was studied in rats treated with cyclosporin A (CyA). Peroral CyA 25 mg kg-1 day-1 depressed glomerular filtration rate (GFR) from 1284 +/- 429 to 500 +/- 228 microliters min-1 g-1 kidney weight (KW) (P less than 0.01). Absolute rate of proximal tubular reabsorption (APR) decreased from 1075 +/- 437 to 468 +/- 203 microliters min g KW-1 (P less than 0.01). Proximal tubular fractional reabsorption (PFR) was 67.7 and 68.5% measured with the TT/OT and fractional lithium-clearance methods, respectively. Amiloride had no effect on lithium-clearance in CyA treated rats. Acute isotonic volume expansion increased GFR and APR towards normal, while PFR remained increased. Increased sodium clearance did not normalize renal function. CyA intravenously (12.5 mg kg-1) depressed GFR and APR acutely, while PFR increased. Proximal intratubular pressures were low normal (mean 11.6 mmHg). Proximal transit times were prolonged (mean 25.2 s, P less than 0.01). Renal morphology was normal. The data are evidence against a primary tubular damage of CyA, and makes it less likely that the major lesion is located to the glomerular membrane. The results suggest that CyA nephrotoxicity mainly is due to a haemodynamic effect.     

Nephrotoxicity of cyclosporin A in humans: effects on glomerular filtration and tubular reabsorption rates

The contention that cyclosporin A (CyA) nephrotoxicity may be due to renal afferent arteriolar constriction was inferred from rat studies showing CyA to increase renal vascular resistance, to reduce glomerular filtration rate (GFR) and delivery of tubular fluid from the end of the proximal tubule to the loop of Henle (Vprox), and to increase proximal fractional reabsorption. In order to test whether the mechanism of human CyA nephrotoxicity is similar to its rat analogue, and whether CyA treatment causes prolonged renal malfunction after drug withdrawal, renal function was investigated with clearance techniques including lithium clearance (CLi) as a measure of Vprox. The subjects were patients (n = 11) with previously normal renal function, given CyA in the treatment of ocular manifestation of extrarenal disease, or bone-marrow transplant recipients. Nine out of these eleven patients were investigated before and during CyA treatment: GFR (P less than 0.05) and Vprox (P less than 0.005) decreased while proximal fractional reabsorption increased (P less than 0.01). In six patients investigated before CyA was given, and re-examined a mean of 273 days (range 84-384 days) after CyA withdrawal, CLi was reduced (P less than 0.05) while mean GFR was not significantly lowered (0.5 greater than P greater than 0.2). In one of these six patients GFR was reduced to a subnormal value of 26 ml min-1 (1.73 m2 body surface)-1. In conclusion, human and rat CyA nephrotoxicity have the same pattern of renal functional deterioration. Cyclosporin A nephrotoxicity was evident in patients investigated a mean of 9 months after CyA withdrawal.     

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。     

Enhancement of cyclosporin A induced hepato- and nephrotoxicity by glutathione depletion

Abstract The role of glutathione in cyclosporin A (cyclosporin) hepato- and nephrotoxicity has not been clarified yet. The hypothesis that a glutathione deficit enhances the hepato- and nephrotoxicity of cyclosporin was tested in an animal model. Glutathione depletion was achieved by administration of diethyl maleate (DEM). Adult Sprague Dawley rats were divided into four groups (A–D; n≥ 8) and treated for 8 d as follows: group A, glucose 5% (0·4 ml kg^-1, i.p.) + 3 h later olive oil (0·5 ml kg^-1, oral); group B, DEM (0·4 ml kg^-1, i.p.) + 3 h later olive oil (0·5 ml kg^-1, oral); group C, glucose 5% (0·4 ml kg^-1, i.p.) + 3 h later cyclosporin (50 mg kg^-1, oral); group D, DEM (0·4 ml kg^-1, i.p.) + 3 h later cyclosporin (50 mg kg^-1, oral). Cyclosporin alone increased bilirubin concentration from 1·0 ± 0·6 μmol l^-1 to 8·4 ± 1·9 μmol l^-1 (P < 0·05) without changing transaminases. In glutathione depleted rats cyclosporin caused a further elevation of serum bilirubin up to 23·4 ± 5·5 μmol l^-1. This was accompanied by a 50% increase of serum glutamic oxaloacetic transaminase (GOT). Cyclosporin alone significantly decreased creatinine clearance to 50% of controls (P < 0·05). Cyclosporin treatment following glutathione depletion resulted in a further decline of creatinine clearance to 22% of controls. DEM had no effect on kidney or liver function. In conclusion glutathione depletion increases the susceptibility to cyclosporin-induced liver and kidney injury. The results support the hypothesis that sufficient cellular glutathione concentrations may be important to prevent cyclosporin-induced hepato- and nephrotoxicity.     

Effect of endothelin-1 in man: pretreatment with nifedipine, with indomethacin and with cyclosporine A

The rise in blood pressure following the intravenous administration of endothelin-1 remained unchanged in healthy male volunteers pretreated with either the calcium-channel antagonist nifedipine (10 mg orally), the cyclo-oxygenase inhibitor indomethacin (150 mg day-1 for three days) or the immunosuppressive agent cyclosporine (5 mg kg-1 body weight for five days). Following administration of nifedipine the rise in plasma concentrations of endothelin-1 during the infusion of the peptide was markedly higher (P less than 0.01) than during control experiments without nifedipine. It is concluded that, in healthy men, nifedipine, indomethacin and cyclosporine do not exert a major influence on the pressor action of endothelin-1. However, nifedipine apparently influences the elimination of endothelin-1 from the circulation in healthy men.