Sodium status influences chronic amphotericin B nephrotoxicity in rats

Abstract

The nephrotoxic potential of amphotericin B (5 mg/kg per day intraperitoneally for 3 weeks) has been investigated in salt-depleted, normal-salt, and salt-loaded rats. In salt-depleted rats, amphotericin B decreased creatinine clearance linearly with time, with an 85% reduction by week 3. In contrast, in normal-salt rats creatinine clearance was decreased but to a lesser extent at week 2 and 3, and in salt-loaded rats creatinine clearance did not change for 2 weeks and was decreased by 43% at week 3. All rats in the sodium-depleted group had histopathological evidence of patchy tubular cytoplasmic degeneration in tubules that was not observed in any normal-salt or salt-loaded rat. Concentrations of amphotericin B in plasma were not significantly different among the three groups at any time during the study. However, at the end of 3 weeks, amphotericin B levels in the kidneys and liver were significantly higher in salt-depleted and normal-salt rats than those in salt-loaded rats, with plasma/kidney ratios of 21, 14, and 8 in salt-depleted, normal-salt, and salt-loaded rats, respectively. In conclusion, reductions in creatinine clearance and renal amphotericin B accumulation after chronic amphotericin B administration were enhanced by salt depletion and attenuated by sodium loading in rats.Despite recent availability of newer antifungal drugs, amphotericin B remains the broad-spectrum antimycotic antibiotic of choice for the majority of systemic fungal infections. Unfortunately, amphotericin B also induces a variety of adverse effects, including fever, chills, nausea, vomiting, hypokalemia, hypomagnesemia, and phlebitis. The most restrictive adverse effect is its potential for inducing nephrotoxicity, which can occur in up to 80% of patients (6). The mechanism by which amphotericin B induces nephrotoxicity has not been clearly defined, although it is likely that this drug induces primary effects on the kidney, which can be modified by secondary renal responses. The initial renal toxic event may be due to the ability of amphotericin B to bind the sterols in membranes and alter membrane permeability (1, 2), possibly acting as an ionophore. It is unlikely, however, that this is the sole factor that determines the extent of change in renal function, since other factors have been shown to modify the renal response. The most notable of these is the salt status at the time of drug administration.There are observations in humans indicating that nephrotoxicity due to amphotericin B is enhanced when saltdepleted patients receive this drug and that salt supplementation can minimize this response (5, 15). It has also been shown that amphotericin B induces acute renal vasoconstriction in both dogs and rats (7,11,14) and that this response can be attenuated by salt loading (11). No direct evidence is available concerning whether salt loading is associated with maintenance of renal function during chronic administration in experimental animals. In one study, chronic supplements with sodium bicarbonate were shown to provide protec...

Acute and chronic effects of flucytosine on amphotericin B nephrotoxicity in rats

“…3). The ability of sodium chloride alone to reduce the amphotericin B-induced decrease in creatinine clearance confirms previous observations that supplementation with sodium chloride attenuates the nephrotoxic effect of amphotericin B (14). The combination of flucytosine and sodium chloride had no further additive renoprotective effects.…”

“…We have previously shown that levels of amphotericin B in renal tissue during chronic therapy are influenced by salt status. Despite equivalent steady-state trough plasma levels, levels in renal tissue were higher in salt-depleted rats than in salt-loaded rats (14). Furthermore, there was a significant association between the level in tissue and the reduction in creatinine clearance.…”

“…No evidence has yet been provided to suggest metabolism, and the fate of the remaining drug is unknown. It has, however, been established that high renal and tissue-toplasma concentrations occur during chronic amphotericin B administration (14). We have previously shown that levels of amphotericin B in renal tissue during chronic therapy are influenced by salt status.…”

Mechanisms of amphotericin B-induced decrease in glomerular filtration rate in rats

“…In chronic models of nephrotoxicity in the rat, salt loading attenuates the decreases in GFR induced by amphotericin B, while salt depletion potentiates them (16,28). In addition, there are hemodynamic changes similar to those observed after acute infusions of the drug (28).…”

Comparison of nephrotoxicities of different polyoxyethyleneglycol formulations of amphotericin B in rats

“…Both the slow infusion of the antibiotic (45,54) and the administration of the drug on alternate days lower the incidence of nephrotoxicity (32). More recently, sodium loading of the organism which can interfere with the tubuloglomerular feedback response has been shown to reduce the hemodynamic problems associated with antibiotic therapy (2,8,9,(22)(23)(24)(25)42). Another approach to decrease AmB nephrotoxicity consists of acting either on the drug itself to obtain less toxic AmB derivatives or on the galenical preparation of the drug.…”