Chronic Amphotericin B Nephrotoxicity in the Rat, Protective Effect of Prophylactic Salt Loading

Amphotericin B (AMPHO) is the most effective and widely used antifungal agent for the treatment of systemic fungal disease in man. Its use is frequently limited by the development of nephrotoxicity, including renal vasoconstriction with depressed glomerular filtration rate (GFR) and renal plasma flow (RPF), inability to concentrate the urine, and renal potassium wasting. We investigated the effects of oral NaCl loading during chronic administration of AMPHO, on renal function in the rat. Rats were provided 150 mmol/L NaCl (AMPHO plus NaCl) or tap water (AMPHO plus H₂O) as drinking water, 3 days prior to, and during chronic AMPHO (5 mg/kg/d intraperitoneal [IP] for 21 days). At the end of the experimental period, renal functional parameters were determined, including serum creatinine, urinary volume and electrolyte excretion rates, ability to maximally concentrate the urine after water deprivation, and renal hemodynamics. NaCl supplementation prevented the rise in serum creatinine (AMPHO plus NaCl, initial v final, 0.39 ± 0.03 v 0.40 ± 0.03 mg/dL [34.6 ± 2.7 v 35.4 ± 2.7 μmol/L], P = NS) seen in AMPHO plus H₂O (0.34 ± 0.01 v 0.51 ± 0.04 mg/dL [30.0 ± 0.9 v 45.2 ± 3.5 μmol/L], P < 0.05). In AMPHO plus NaCl rats, there was preservation of renal perfusion (AMPHO plus NaCl v AMPHO plus H₂O, renal vascular resistance: 13.39 ± 1.81 v 27.64 ± 2.30 mm Hg min/mL, P < 0.001; renal plasma flow: 5.99 ± 0.52 v 2.99 ± 0.27 mL/min, P < 0.001) and glomerular filtration (AMPHO plus NaCl v AMPHO plus H₂O, 1.30 ± 0.05 v 0.85 ± 0.07 mL/min, P < 0.001) after 21 days of AMPHO. NaCl supplementation did not prevent the development of a concentrating defect (μosmMax, AMPHO plus NaCl v AMPHO plus H₂O, 699 ± 82 v 722 ± 82 mosm/kg, P = NS) or potassium wasting (potassium clearance, AMPHO plus NaCl v AMPHO plus H₂O, 0.53 ± 0.09 v 0.40 ± 0.06 mL/min, P = NS) after AMPHO. NaCl supplementation had no effect on renal hemodynamics or tubular function in rats not receiving AMPHO. Thus, prophylactic NaCl loading prevents renal vasoconstriction and depressed GFR, but not tubular toxicity, in rats receiving chronic AMPHO. This simple therapeutic maneuver warrants study in humans, in whom amphotericin B nephrotoxicity remains a significant clinical problem.