To investigate the potential direct nephrotoxicity of Shiga toxin, a putative mediator for hemolytic uremic syndrome, purified toxin (10(-11) M) was added to isolated rat kidneys perfused for 160 min with a Krebs-Henseleit acellular medium enriched with albumin and amino acids. Kidney function and morphology were examined after perfusion with the Shiga toxin vs controls. Shiga toxin did not significantly alter renal perfusion flow, glomerular filtration rate, or tubular sodium reabsorption, but it significantly increased urinary protein excretion (from 61 +/- 23 to 169 +/- 28 microg/min, P < 0.01). On renal morphologic study, Shiga toxin did not induce gross glomerular damage but increased markedly the injury to the medullary thick ascending limbs. In conclusion, Shiga toxin is toxic to rat kidneys ex vivo and in the absence of platelets. Renal damage is manifested by proteinuria and medullary tubular injury. The distribution of this injury suggests a possible synergism between local medullary hypoxia and the toxic tubular or endothelial effects of the toxin. These effects may play a pathogenic role in the tubulo-interstitial injury observed in hemolytic uremic syndrome associated with severe renal failure.