Direct amphotericin B-mediated tubular toxicity: Assessments of selected cytoprotective agents

Abstract

Amphotericin B (AB) may induce acute renal failure by vasoconstrictive and tubulo-toxic effects. Although mannitol, Ca2+ channel blockers, and lipid-based AB preparations have been suggested to mitigate in vivo AB nephrotoxicity, whether they confer direct tubular cytoprotection has not been defined. Therefore, this study assessed the impact of mannitol, verapamil/extracellular Ca2+, and cholesteryl sulfate (CS) AB binding on AB cytotoxicity, employing an isolated rat proximal tubular segment (PTS) preparation. After 30 to 60 minutes of incubation, 0.2 mg/ml of AB (Fungizone) caused marked toxicity, as assessed by LDH release (29 to 44%) and ATP depletion (greater than 90%). Approximately 40% of the LDH release could be attributed to deoxycholate, the standard AB (Fungizone) solubilizing agent. Both 100 mM mannitol and 100 mM glucose decreased AB-mediated LDH release, despite having a quantitatively trivial impact on ATP concentrations (increments of less than or equal to 1% at normal values). Dimethylthiourea (25 mM; equipotent to 100 mM mannitol/glucose as a hydroxyl radical scavenger) did not decrease LDH release. Neither verapamil addition (100 microM) nor Ca2+ removal from the PTS buffer had a protective effect. CS binding completely eliminated AB's toxicity (no LDH or ATP losses). The effect of AB and CS-AB on concomitant O2 deprivation/reoxygenation (30 min/15 min) PTS injury was also assessed. AB and hypoxia/reoxygenation caused additive, not synergistic, LDH release whereas CS-AB had no adverse effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Ultrastructural Morphometry of Renal Tubule Epithelium of Rats Treated with Conventional Amphotericin B Deoxycholate or Amphotericin B Colloidal Dispersion

“…It is known that AmB belongs to nephrotoxic drugs and its effects on renal functions were described by many authors (Aronson et al 1979;Cheng et al 1982;Kavlock et al 1985;Zager et al 1991;Inselmann et al 2003 and others). According to Terrel and Hughes (1992) or Zhang et al (2002), AmB acts by binding to sterols, ergosterol in fungal membranes or cholesterol in biological membranes of mammalian cells.…”

Coadministration of Liposomal Amphotericin B and Contrast Medium Does Not Increase Risk of Kidney Injury

“…Much of the initial interest in its nephrotoxicity was driven by the historical use of amphotericin B deoxycholate. Deoxycholate is directly toxic to the tubule and is absent in the liposomal formulation (20). Hence, for liposomal amphotericin B, the amount of attributable nephrotoxicity is not known.…”

Liposomal Amphotericin B and Delayed Presentation of Renal Tubular Acidosis: A Case Report

“…The exact mechanism of amphotericin B induced nephrotoxicity is unclear; it can lead to renal damage either through vasoconstriction, increasing cell membrane permeability through insertion into cell membranes, or through doxycholate, a detergent used as a solubilizing agent for amphotericin [2,3]. Amphotericin B can also cause significant hypokalemia by altering the permeability of distal renal tubular cells, leading to an increase in the passive fluxes of potassium down it electrochemical gradient [4].…”