Possible reason for preferential damage to renal tubular epithelial cells evoked by amphotericin B.
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.
Walev
I
I
Institute of Medical Microbiology and Hygiene, University of Mainz, Germany.
Bhakdi
S
S
D000255:Adenosine Triphosphate / Q000378:metabolism; D000666:Amphotericin B / Q000633:toxicity*; D000818:Animals; D000935:Antifungal Agents / Q000633:toxicity*; D002460:Cell Line; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D006863:Hydrogen-Ion Concentration; D007686:Kidney Tubules, Distal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008253:Macaca mulatta; D011188:Potassium / Q000378:metabolism
D000935:Antifungal Agents; D000666:Amphotericin B; D000255:Adenosine Triphosphate; D007770:L-Lactate Dehydrogenase; D011188:Potassium