Walev I, Bhakdi S
Institute of Medical Microbiology and Hygiene, University of Mainz, Germany.
Antimicrob Agents Chemother. 1996 May;40(5):1116-20. doi: 10.1128/AAC.40.5.1116.
An important determinant of nephrotoxicity, which is the major complication of long-term amphotericin B treatment, is dysfunction of distal tubular epithelial cells. The underlying cause for this rather selective damage to the cells is unknown. In the present investigation, it was shown that kidney epithelial cells were initially damaged by amphotericin B at concentrations of 2.5 to 10 micrograms/ml, as demonstrable by a dramatic drop in cellular K+ levels. Cells could recover from the initial toxic action of the polyene if they were kept in medium of neutral pH, and cellular K+ levels returned to normal after 6 h. However, the recovery mechanisms failed at lower pHs of 5.6 to 6.0. At low pHs, cells became progressively depleted of ATP; they leaked lactate dehydrogenase and became irreversibly damaged after approximately 6 h. The possibility that the low pH characteristic of the distal tubulus lumen renders the renal epithelial cells particularly vulnerable to the toxic action of amphotericin B is raised. The concept is in line with an earlier report that alkalization ameliorates amphotericin B nephrotoxicity in rats.
肾毒性是长期使用两性霉素B治疗的主要并发症，其一个重要决定因素是远端肾小管上皮细胞功能障碍。这种对细胞具有相当选择性的损伤的根本原因尚不清楚。在本研究中，结果表明，当两性霉素B浓度为2.5至10微克/毫升时，肾上皮细胞最初会受到损伤，这可通过细胞内钾离子水平的急剧下降得到证明。如果将细胞置于中性pH的培养基中，它们可以从多烯的初始毒性作用中恢复，细胞内钾离子水平在6小时后恢复正常。然而，在pH值为5.6至6.0的较低pH条件下，恢复机制失效。在低pH值下，细胞内ATP逐渐耗尽；它们会泄漏乳酸脱氢酶，并在大约6小时后受到不可逆的损伤。由此提出了远端肾小管管腔的低pH特性使肾上皮细胞对两性霉素B的毒性作用特别敏感的可能性。这一概念与早期一份关于碱化可改善大鼠两性霉素B肾毒性的报告一致。
