Reduction of Amphotericin B-Induced Renal Tubular Apoptosis by N -Acetylcysteine

Abstract

The reduction of amphotericin B (AmB)-induced renal tubular apoptosis and nephrotoxicity by N-acetylcysteine (NAC) in a murine model was evaluated. Four groups of rats were treated with AmB for 5 days, and each group concomitantly received two doses of 30, 60, or 120 mg of NAC/kg of body weight/day or sterile water for 5 days. Groups that received concomitant NAC at any dose had significantly decreased levels of apoptosis compared to that in animals receiving AmB only (48.8% versus 27.4, 23.6, or 23.5%, respectively; P < 0.001).Nephrotoxicity is the major dose-limiting side effect of amphotericin B (AmB) deoxycholate (14,16,34). AmB-induced nephrotoxicity is usually reversible; however, up to 15% of patients may require dialysis, resulting in extended hospital stays and increased mortality (3,34). Nephrotoxicty is secondary to renal vasoconstriction, which leads to tubular damage and a decreased glomerular filtration rate (GFR) (11,14,15). The mechanism of renal tubular damage has not been fully elucidated; however, AmB has been suggested previously to induce dose-dependent renal tubular cell apoptosis (32).Several approaches to decreasing the incidence of AmB nephrotoxicity have been proposed. These approaches include prehydrating the drug formulation with saline and prolonging the infusion time (10, 18), infusing the drug in a fat emulsion (Intralipid) solution (7,19,21,25,27), and coadministering the drug with mannitol (6); however, none of these approaches have proven to be effective. While lipid formulations of AmB were found to be less nephrotoxic than other formulations of the drug, these formulations do not completely eliminate nephrotoxicity (9,17,23,35).Recently, Varlam et al. demonstrated that AmB causes a dose-dependent apoptotic effect in rat renal tubular cells, with ensuing nephrotoxicity (32). They also showed that AmB-induced apoptosis and the resulting nephrotoxicity can be reduced by the concomitant use of recombinant human insulinlike growth factor 1 (rhIGF-1), an antiapoptotic agent.N-Acetylcysteine (NAC) is an antiapoptotic and antioxidant drug, and NAC administration prior to the administration of radiocontrast agents prevents the nephrotoxicity associated with these agents (4, 5, 30). The purpose of our study was to evaluate the effect of the concomitant administration of NAC on AmB-induced renal tubular cell apoptosis.(An abstract describing this study was presented at the 46th Interscience Conference on Antimicrobial Agents and Chemotherapy, 2006 [22].)Three-week-old male Sprague-Dawley rats weighing 100 g on average were maintained in individual cages. The animals had free access to a standard diet and received water ad libitum. Prior to the experiments, rats were randomized and divided into four groups consisting of 10 animals each. Animals in each of the groups (A, B, C, and D) were treated with 10 mg of intraperitoneal (i.p.) AmB deoxycholate (Bristol-Myers Squibb)/kg of body weight/day for 5 days. In addition to AmB, group A was given i.p. sterile water and groups B, C, and D were ...

New delivery systems for amphotericin B applied to the improvement of leishmaniasis treatment

“…As new light is shed on the mechanisms of AmpB-induced nephrotoxicity via the signaling pathways that mediate tissue infl ammation, an important goal is to develop novel management and/or delivery strategies that minimize the adverse effects of this time-tested antifungal agent. One such measure might be the use of N-acetylcysteine, which, in accord with its utility in contrast-induced nephropathy, also has anti-infl ammatory and therapeutic properties (74) . In addition, delivery systems based on ChS molecules may be useful, as these molecules also possess anti-infl ammatory activity and may reduce the nephrotoxicity caused by free AmpB.…”

Difficulties in antifungal therapy with amphotericin B and the continuous search for new formulations: A literature review

“…A retrospective study of 22 patients using the liposomal AmB formulation decreased the concentration of hemoglobin and dose-dependent anemia and thrombocytopenia in patients; 50% of patients became likely to develop anemia and thrombocytopenia when using the doses of 3 and 3.3 mg/kg, respectively. Thrombocytopenia occurred in 57.9% of patients, thus confirming the hematological damage caused by such therapy (Odabasi et al, 2009).…”

“…Nephrotoxicity (28%) and an increase of 50-100% in serum creatinine (Patel et al, 2011) was observed in a study of 494 patients using conventional AmB, data similar to that reported by Patel (2011), and demonstrating dose and time dependence effects. The testing of the liposomal formulation in a retrospective analysis of 22 patients showed a similar result in which 27.3% of patients presented renal effects (Odabasi et al, 2009). Therefore, according to these two papers, there was no significant difference in renal toxicity between the conventional and liposomal preparations.…”

Efficacy of N-acetylcysteine in preventing amphotericin B induced acute kidney injury

“…In the same study, they also showed that AmB-induced apoptosis and the resulting nephrotoxicity could be reduced by the concomitant use of recombinant human insulin-like growth factor 1 (rhIGF-1), an anti-apoptotic agent. In our previous studies, we have found that rats that received NAC concomitantly with DAmB had significantly decreased levels of AmB-induced renal tubular cell apoptosis compared to animals that only received DAmB [7].…”

“…We have previously demonstrated in an animal study that renal tubular apoptosis caused by DAmB, is significantly reduced by the concomitant use of NAC [7]. These encouraging findings prompted us to perform this clinical study, in which we aimed to demonstrate NAC's possible beneficial effect in DAmB induced acute kidney injury (AKI), in patients who are under treatment of DAmB for invasive pulmonary aspergillosis.…”