RENAL TUBULAR TRANSPORT AND NEPHROTOXICITY OF BETA-LACTAM ANTIBIOTICS - STRUCTURE-ACTIVITY-RELATIONSHIPS

Several of the cephalosporin and carbapenem antibiotics produce acute renal failure when given in large single doses. Antibiotic concentrations in the tubular cell, determined by the net effects of contraluminal secretory transport and subsequent movement across the luminal membrane, make the proximal tubule the sole target of injury, and are important determinants of the nephrotoxic potentials of different beta-lactams in different animal species. At least three molecular mechanisms of injury have been shown with cephaloridine, the most widely studied nephrotoxic beta-lactam: (1) lipid peroxidation, (2) competitive inhibition of mitochondrial carnitine (zwitterionic) transport and fatty acid oxidation, and (3) acylation and inactivation of tubular cell proteins, most thoroughly evaluated with mitochondrial anionic substrate transporters. The first two of these injuries are dependent upon one or both of cephaloridine's side group substituents, which are not present on the other nephrotoxic cephalosporins or carbapenems. It is not surprising, therefore, that only toxicity to mitochondrial anionic substrate carriers has been found in studies of the other beta-lactams. However, the several effects of cephaloridine on the tubular cell indicate a potential for different mechanisms of attack on different molecular targets. Continuing studies of the effects of existing and newly developed beta-lactams are likely to identify further nephrotoxic mechanisms of this complex and rapidly growing group of antimicrobials.