IFOSFAMIDE METABOLITE CHLOROACETALDEHYDE CAUSES FANCONI SYNDROME IN THE PERFUSED RAT-KIDNEY

Renal proximal tubule dysfunction has been reported in patients treate d with the chemotherapeutic agent ifosfamide. The present study invest igated whether ifosfamide or its metabolites acrolein and chloroacetal dehyde would impair function in the isolated perfused rat kidney. Rena l function was monitored before and after these chemicals were added t o a modified Krebs-Ringer-bicarbonate perfusion medium containing 6.6 g/dl albumin and a mixture of substrates. No functional changes were o bserved when ifosfamide (470 mu M) or acrolein (470 mu M) was added to the perfusate. Addition of chloroacetaldehyde (210 mu M) resulted in significant decreases in the fractional reabsorption of sodium (from 9 2 to 32%), glucose (from 97 to 46%), inorganic phosphate (from 88 to 2 2%), and inorganic sulfate (from 94 to 86%). There were no changes in glomerular filtration rate. PAH clearance also significantly decreased from 4.1 to 0.7 ml/min per gram of kidney weight, indicating impairme nt of proximal tubule organic acid secretion. This impairment was asso ciated with a significant decline in the extraction ratio for PAH, sug gesting abnormal PAH uptake at the basolateral membrane. These results show that chloroacetaldehyde causes generalized renal proximal tubule dysfunction and that it may be the ifosfamide metabolite responsible for nephrotoxic side effects, (C) 1994 Academic Press, Inc.