Elimination of amphotericin B in impaired renal function

Morgan, Denis J.; Ching, Michael S.; Raymond, Kenneth; Bury, Ross W.; Mashford, Laurence; Kong, Betty; Sabto, J.; Gurr, F. W.; Somogyi, Andrew A.

doi:10.1038/clpt.1983.161

Cited by 33 publications

(10 citation statements)

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“…However, the two features inconsistent with this explanation are as follows. First, renal clearance is only a minor route of amphotericin B elimination, accounting for less than 10% of total clearance (17). Second, levels in plasma, which were in the measurable range of the assay, were not different among the groups.…”

Section: Discussionmentioning

confidence: 94%

“…Amphotericin B is a large molecule and is in part eliminated by excretion into bile (10). Impaired elimination in patients with renal failure has not been observed (17), and dosage modifications in patients with renal failure are not advocated (4,16). It was therefore surprising to find that levels of amphotericin B in tissues were different between salt-depleted and salt-loaded rats in both the kidney and the liver, despite no evidence of accumulation in plasma.…”

Section: Discussionmentioning

confidence: 99%

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Sodium status influences chronic amphotericin B nephrotoxicity in rats

Ohnishi

Stevenhead

et al. 1989

Antimicrob Agents Chemother

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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...

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Sodium status influences chronic amphotericin B nephrotoxicity in rats

Ohnishi

Stevenhead

et al. 1989

Antimicrob Agents Chemother

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“…j In the study by Ohnishi et al (1989), a microbiological assay was used to measure tissue and plasma concentrations of amphotericin B in 3 groups of rats: salt-depleted, normal salt and saltloaded (table III) between kidney concentrations of drug and the deterioration in renal function. Since amphotericin B is not excreted in the kidney to a large extent (Atkinson & Bennett 1978;Morgan et al 1983), this result is presumably not due to the degree of deterioration in renal function. It alternatively suggests that a high salt status may somehow modify the accumulation of the drug in the kidney, thus lowering its nephrotoxic potential.…”

Section: Long Term Effectsmentioning

confidence: 88%

Amphotericin B Nephrotoxicity

1990

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The frequency of fungal infections is increasing. Amphotericin B remains the anti-fungal drug of choice for most systemic infections, but a limiting factor for its use is the development of nephrotoxicity. Amphotericin B-induced nephrotoxicity is manifested as azotaemia, renal tubular acidosis, impaired renal concentrating ability and electrolyte abnormalities like hypokalaemia and sodium and magnesium wasting. All these abnormalities occur to varying degrees in almost all patients receiving the drug. Upon withdrawal of therapy renal function gradually returns to baseline, although in some instances permanent damage is sustained, especially when the cumulative dose exceeds 5g. Salt depletion enhances the development of nephrotoxicity. The mechanism of nephrotoxicity involves direct cell membrane actions to increase permeability, as well as indirect effects secondary to activation of intrarenal mechanisms (tubuloglomerular feedback) and/or release of mediators (thromboxane A2). The latter effects are presumably responsible for the observed acute decreases in renal blood flow and filtration rate, responses that are inhibited by several physiological and pharmacological interventions. Changes in intracellular calcium levels may also contribute to the observed effects. In the clinical situation, and in long term models of nephrotoxicity in the rat, salt loading protects against deterioration in renal function; recommendations are made for the optimisation of amphotericin B therapy by salt loading. New preparations of the drug, such as liposomal amphotericin B, may also prove useful in minimising nephrotoxicity while maintaining antifungal activity, but further research is needed with both salt loading and liposomal amphotericin B to confirm or deny their protective effect on kidney function.

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“…Those effects are selective, as hydralazine, adrenergic ganglionic blockade, sodium nitroprusside, dopamine, and saralasin have no effect (5,10,15 Relatively little information is available concerning the pharmacokinetic disposition of amphotericin B and the role that renal uptake of the drug may have in determining nephrotoxicity. Under normal conditions, less than 10% of administered drug can be recovered in urine and 20% in bile (13). No evidence has yet been provided to suggest metabolism, and the fate of the remaining drug is unknown.…”

Section: Resultsmentioning

confidence: 99%

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

Heidemann

Brune

Sabra

et al. 1992

Antimicrob Agents Chemother

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The combination of intravenous flucytosine (FC) in 0.9%o saline (NaCI) and amphotericin B (AmB) provides synergistic antifungal activity and is associated with a lower incidence of nephrotoxicity than with AmB treatment alone. This study was conducted to examine whether flucytosine can influence renal function and whether it can modify the acute and chronic renal responses to AmB in the rat. In the in situ perfused rat kidney, FC at a concentration of 10 mg/kg/min for 15 min had a vasodilator effect, increasing renal blood flow by 2.5 0.7 ml/min, an effect not observed with vehicle. After the infusion of FC was stopped for 15 min, AmB induced a decrease in renal blood flow similar to that with both FC and vehicle. In a second series of studies, AmB (5 mg/kg/day intraperitoneally) was administered to four groups of rats for 7 days. In addition, the following groups received the intravenous daily interventions indicated: group 1, 5% dextrose in water (15 ml/kg/12 h); group 2, FC (150 mgkg/12 h) in 0.9%o saline (15 mlk12 h); group 3, 0.9%o saline (15 mllkg/12 h); and group 4, FC (150 mglkg/12 h) in 5% dextrose in water. Group 1 sustained a 77% decrease in creatinine clearance over the 7 days and a threefold increase in senrm creatinine concentration (P of <0.05). Groups 2, 3, and 4 sustained signiflicantiy less nephrotoxcity, with no change in serum creatinine concentration and only 38, 41, and 53% decreases in creatinine clearance, respectively (P of <0.05), compared with that for group 1. AmB levels in renal tissue varied inversely to creatinine clearance (r of 0.57, P of s0.005). However, no significant differences were found in levels in tissue between groups (P of 0.06). The results ofthis study suggest that FC has a small but sgnificant effect in reducing chronic AmB-induced nephrotoxicity. This amelioration of renal injury is independent of saline administration. There was evidence that the extent of renal uptake of AmB related to the efficiency of renal function at the end of the experiment.Amphotericin B, a polyene antibiotic, still remains the treatment of choice in the management of systemic fungal infections. The major limitation in its use, however, is its potential to induce adverse effects. Of these, the most dose limiting is the development of nephrotoxicity.In recent years, the frequency of opportunistic mycotic infections occurring in immunocompromised patients, such as AIDS patients, transplant patients, or patients receiving chemotherapy, has resulted in increasing use of amphotericin B. This has prompted attempts to learn how to minimize the nephrotoxic potential of this drug. Empiric observations suggest that sodium depletion enhances nephrotoxicity (11). The mechanisms involved in modifying the renal response are still not clearly understood.The combination of flucytosine (4-amino-5-fluro-2-pyrimadone) and amphotericin B has been advocated for inducing synergistic antifungal activity (1). This combination may also offer the advantage of inducing a lower incidence of amphotericin B-induced ne...

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Elimination of amphotericin B in impaired renal function

Cited by 33 publications

References 0 publications

Sodium status influences chronic amphotericin B nephrotoxicity in rats

Sodium status influences chronic amphotericin B nephrotoxicity in rats

Amphotericin B Nephrotoxicity

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

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