Becker G, Witzke O, Baltes A, Hamar P, Philipp T, Heemann U
Department of Nephrology, University Hospital Essen, Germany.
Transpl Immunol. 1996 Mar;4(1):68-71. doi: 10.1016/s0966-3274(96)80040-2.
We examined the nephrotoxicity of tacrolimus (FK506) in a model of mild warm ischemia. After clamping of both renal arteries of male Sprague-Dawley rats for 20 min, the animals received tacrolimus (3 mg/kg/day i.p.), vehicle of a combination of tacrolimus (3 mg/kg/day i.p.) and diltiazem (12 mg/kg, orally) or vehicle and diltiazem (12 mg/kg, orally). The excretion of urinary enzymes was determined on a daily basis, creatinine clearance at day 10. Tacrolimus significantly increased NAG (N-acetyl-beta-glucosaminidase) excretion and associated histological damage, finally decreasing creatinine clearance. The toxic potential of tacrolimus was markedly enhanced by ischemia. The additional application of diltiazem reduced NAG excretion and histological damage without affecting creatinine clearance. Thus, the protective effect of diltiazem on tacrolimus-induced nephrotoxicity seems to be at least partially a tubular one.
我们在轻度热缺血模型中研究了他克莫司（FK506）的肾毒性。在雄性Sprague-Dawley大鼠的双侧肾动脉夹闭20分钟后，动物接受他克莫司（3mg/kg/天，腹腔注射）、他克莫司（3mg/kg/天，腹腔注射）与地尔硫䓬（12mg/kg，口服）的组合或溶剂以及地尔硫䓬（12mg/kg，口服）。每天测定尿酶排泄量，在第10天测定肌酐清除率。他克莫司显著增加NAG（N-乙酰-β-氨基葡萄糖苷酶）排泄及相关组织学损伤，最终降低肌酐清除率。缺血显著增强了他克莫司的毒性潜力。额外应用地尔硫䓬可减少NAG排泄及组织学损伤，而不影响肌酐清除率。因此，地尔硫䓬对他克莫司诱导的肾毒性的保护作用似乎至少部分是肾小管性的。
