Kidney International, Vol. 40 (1991), PP. 302—308 Effect of salt supplementation on amphotericin B nephrotoxicity ALEJANDRO LLANOS, JAVIER CIEZA, JOSE BERNARDO, JUAN ECHEVARRIA, ITALO BIAGGIONI, RAMZI SABRA', and ROBERT A. BRANCH' Instituto de Medicine Tropical "Alexander Von Humboldt", Universidad Peruana Cayetano Heredia, Lima, Peru, and Division of Clinical Pharmacology, Vanderbilt University, Nashville, Tennessee, USA Effect of salt supplementation on amphotericin B nephrotoxicity. It has been suggested that salt loading protects against amphotericin B-in- duced nephrotoxicity. The influence of saline loading on the nephro- toxic response to amphotericin 8 (50 mg/dose given i.v. over 4 hr 3 x/week for 10 weeks) was assessed in two groups of ten patients each who were diagnosed with mucocutaneous leishmaniasis. Patients were randomized to receive either I liter of 0.9% saline or I liter of 5% dextrose in water, administered i.v. over one hour in a double-blinded manner, directly prior to amphotericin B administration. Renal function was monitored on a weekly basis two days after the last dose of amphotericin B. Baseline characteristics were similar in both groups except for a slightly higher serum creatinine concentration (Cr) in the saline group (0.8 0.05 vs. 0.6 0.04 mg/dl). Baseline sodium (Na) excretion was relatively high (262 23 mmol/day in the dextrose group and 224 17 mmollday in the saline group). None of the patients sustained an increase in Cr to values greater than 1.7 mg/dl. Although mean Cr remained within normal, there was a significant difference between the two groups over the ten week period, with the dextrose group sustaining a significant increase in Cr and the saline group remaining unchanged. Serum potassium (K) levels fell in both groups necessitating oral K supplementation. The saline group required signif- icantly greater amounts of K supplementation to maintain a normal serum K. Amphotericin B caused a rapid reduction in the acidification ability of the kidney in response to an ammonium chloride load. Under these conditions, the saline group had a poorer ability to acidify the urine. Urine volumes were not different between the two groups, and the specific gravity of the urine sustained a significant and similar decrease in the two groups. Neither plasma trough amphotericin B levels nor tissue concentrations at the site of the lesion were different between the two groups, suggesting that the effect of salt is probably not on the basis of pharmacokinetic changes. This study supports the hypothesis that salt loading confers protection against reductions in renal function by amphotericin B, but does so at the expense of enhancing K loss. The lower overall incidence of nephrotoxicity in comparison to prior published experience could be due to racial variation in responsiveness, the high baseline salt intake, or lack of coadministration of other nephrotoxic drugs. Nephrotoxicity has been recognized as a serious and com- mon complication of amphotericin B use since the introduction Present address is: Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, 623 Scaife Hall, Pittsburgh, Pa 15261, USA, Received for publication October 9, 1990 and in revised form February 25, 1991 Accepted for publication April 2, 1991 © 1991 by the International Society of Nephrology of this drug in the 1950's. Early reports indicated that as many as 80 to 90% of patients who received the drug developed some degree of renal dysfunction [1—3]. The clinical presentation of nephrotoxicity includes azotemia, renal tubular acidosis, im- paired concentrating ability, and renal sodium, potassium and magnesium wasting, with consequent dehydration, hypokale- mia and hypomagnesemia. The decrease in GFR may be so severe as to necessitate discontinuation of therapy, leading to progression of the underlying disease and extension of the hospital stay. Therefore, any maneuver that decreases the frequency and/or severity of amphotericin B-associated neph- rotoxicity will aid the therapeutic use of this drug. This is especially true considering the increasing frequency of fungal infections, which is now reported at between 5 and 12% of hospitalized patients [4]. Several manipulations have been proposed to try and mini- mize amphotencin B-induced nephrotoxicity. Mannitol co- administration was once suggested as protective based on anecdotal, observational reports [5, 6]. A small prospective and randomized trial, however, did not support a protective effect [7]. More recent reports suggest that liposomal preparations of amphotericin B may have a wider margin of safety [8—10], but the drug has not been approved for use yet, and more definitive statements on its superiority to conventional formulations await larger controlled trials. The maneuver that has received attention involves adminis- tration of a salt load in association with the amphotericin B dose. Unfortunately, there has not been a prospective, random- ized, placebo-controlled trial that would provide a convincing argument for the routine use of such a protective measure. All previous studies have been either case reports [11], retrospec- tive studies [12, 13] or prospective non-controlled studies [12, 14]. Major difficulties are faced in attempting to interpret the results of these studies, namely, that they were uncontrolled, and that certain bias may have been introduced on the basis of selection of patients, their underlying diseases, and the admin- istration of other drugs. The randomized, placebo controlled study would overcome these difficulties and provide a more solid basis to make an informed clinical decision. Studies of the influence of salt loading on amphotericin B nephrotoxicity in the population of patients receiving the drug in the U.S.A. have presented some difficulties in the evaluation of such an intervention, since they involved patients who were 302