Studies with rabbits have shown a synergistic nephrotoxic interaction of three potential causes of the acute renal failure seen during serious bacterial infections: endotoxemia, produced by infusion of an E. coli lipopolysaccharide, plus cephalosporin administration and/or aminoglycoside administration. Studies of the mechanisms of endotoxic and antibiotic-induced renal injury allow only a preliminary assessment of the mechanisms of this synergy. Endotoxemia may cause: decreased glomerular filtration; decreased, unchanged or increased renal blood flow; and direct tubular cell injury, possibly mediated by mitochondrial respiratory toxicity. These effects of endotoxemia could increase the risk of renal damage by the antibiotics by: increasing their half-lives in serum; increasing or prolonging their concentrations in proximal tubular cells; or increasing their cytotoxicity at the molecular or mitochondrial level. Studies are, therefore, proposed to evaluate the nature and mechanism of the endotoxin-antibiotic nephrotoxic synergy in the rabbit kidney in three general areas: 1) the effects of endotoxin on several components of renal function that may alter the excretion and uptake of the antibiotics; 2a) the specific effects of endotoxemia on cephalosporin and aminoglycoside excretion and renal cortical uptake, and 2b) the toxic interaction of endotoxemia and the antibiotics on cortical mitochondrial respiration and, finally, 3) the scope of the endotoxin-antibiotic synergy, i.e., the degree of toxic interaction of endotoxin with mildly toxic cephalosporins, and with non-lethal as well as lethal endotoxic insults. This last group of studies will examine the comparative effects of several life-preserving measures after lethal endotoxin dosage, because these measures have varying effects upon important functional complications of endotoxemia, such as renal blood flow. In addition to elucidating the causes of the endotoxin-antibiotic nephrotoxic synergy, these studies should identify individual mechanisms of toxicity to the kidney of endotoxin, cephalosporins and aminoglycosides.
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