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Possible reason for preferential damage to renal tubular epithelial cells evoked by amphotericin B
Abstract:
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.
Insights
Amphotericin B causes kidney damage by depleting cellular potassium. This nephrotoxicity is worsened in acidic conditions, hindering cell recovery and leading to irreversible damage.
Area of Science:
- Nephrology
- Cell Biology
- Pharmacology
Background:
- Amphotericin B is a critical antifungal medication.
- Nephrotoxicity is a significant complication of long-term amphotericin B therapy.
- The precise mechanisms underlying amphotericin B-induced nephrotoxicity, particularly the selective damage to distal tubular epithelial cells, remain unclear.
Purpose of the Study:
- To investigate the impact of pH on amphotericin B-induced kidney epithelial cell damage.
- To elucidate the cellular mechanisms responsible for amphotericin B nephrotoxicity.
Main Methods:
- Exposure of kidney epithelial cells to amphotericin B at varying concentrations (2.5-10 µg/ml).
- Assessment of cellular potassium (K+) levels and adenosine triphosphate (ATP) depletion.
- Monitoring of lactate dehydrogenase (LDH) leakage as an indicator of cell damage.
- Evaluation of cell recovery at neutral and acidic pH levels (pH 5.6-6.0).
Main Results:
- Amphotericin B caused an initial drop in cellular K+ levels at concentrations of 2.5-10 µg/ml.
- Cells recovered normal K+ levels at neutral pH within 6 hours.
- At acidic pH (5.6-6.0), recovery mechanisms failed, leading to progressive ATP depletion, LDH leakage, and irreversible cell damage within approximately 6 hours.
Conclusions:
- The acidic environment of the distal tubule lumen may increase renal epithelial cell susceptibility to amphotericin B.
- Low pH exacerbates amphotericin B nephrotoxicity by impairing cellular recovery mechanisms.
- These findings support the hypothesis that alkalization could mitigate amphotericin B-induced kidney damage.