Renal dysfunction seen in patients with American cutaneous leishmaniasis (ACL) has been attributed to the use of antimonials for treatment. To determine whether ACL itself causes tubular dysfunction, we measured renal function in 37 patients with ACL prior to their treatment and compared results to that in 10 healthy volunteers of similar mean age. None of the patients presented with glomerular dysfunction; however, 27 had a urinary concentrating defect. There was no statistical difference between groups in the pre- and post-desmopressin test of urine osmolality, but the post-test urine osmolality of the controls was significantly higher. Urinary AQP2 levels, determined by western blot of isolated exosomes, were found to be significantly lower in patients than in controls, whereas that of the cotransporter (NKCC2) was significantly higher. A urinary acidification defect (post-test pH greater than 5.50 following calcium chloride) was found in 15 patients. Pretest plasma bicarbonate was below normal in 12 patients as was the pretest plasma pH in 14. Expression of the Na/H exchanger (NHE3), H(+)-ATPase, and pendrin were all significantly higher in patients with ACL than in controls. A combined urinary concentration and acidification defect was found in 12 patients. Thus, the urinary concentrating defect of ACL may be caused by decreased AQP2, with increased NKCC2 compensatory. Pendrin upregulation may be related to the urinary acidification defect with increased NHE3 and H(+)-ATPase also compensatory. Hence, ACL can cause asymptomatic renal tubular dysfunction.