Co-administration of furosemide augments tacrolimus-induced impairment in kidney function in rats

Sodium-depletion in rats reproduces functional and morphological tacrolimus nephrotoxicity observed in man. Potent diuretics induce sodium-depletion. Our objective was to determine the effect of a loop diuretic furosemide on tacrolimus-mediated functional and pathological impairment of the kidney in rats. Sprague-Dawley rats were divided into four groups; group 1, rats received vehicle (saline) only; group 2, rats were treated with tacrolimus (1 mg/kg body weight) and furosemide (5 mg/kg body weight); group 3, rats were treated with tacrolimus alone; and group 4, rats were treated with furosemide (5 mg/kg body weight) alone. On day 28, tail blood pressure was measured and the rats were placed in metabolic cages for urine collection. After 24 hr the rats were sacrificed. Tacrolimus alone tended to cause growth retardation, hypotension, hypomagnesemia and a rise in blood urea nitrogen. Furosemide co-administration enhanced the effects of tacrolimus on hypotension, hypomagnesemia and a rise in blood urea nitrogen. The renal histology characterized by cytoplasmic vacuolization of the proximal tubules was not different between the rats treated with both tacrolimus and furosemide and the rats treated with tacrolimus alone. A strong immunostaining for FKBP-12, a tacrolimus-binding protein, was observed in the medulla of the kidneys of rats treated with tacrolimus either with or without furosemide. These results indicate that furosemide further augments tacrolimus induced impairment in kidney function, and that furosemide should be used with discretion in patients on tacrolimus therapy.