Studies in this laboratory involve the cellular and molecular mechanisms of the renal injury that complicates serious infections, with an aim toward developing methods of prevention and treatment of this injury. Acute renal failure is a frequent important complication of bacterial infections. Among its causes are the nephrotoxic effects of the antibiotics used to treat these infections. Of the beta-lactim antibiotics, several of the cephalosporins and the new thienamycin, imipenem, are toxic to proximal tubular cells. They may produce acute renal failure after extremely large dosage or, more importantly, after moderate dosage during certain high-risk states: combined use with aminoglycosides, or during endotoxemia or renal ischemia.
The aims of the studies in this proposal are to define the molecular basis of cephalosporin and thienamycin nephrotoxicity. 1) Studies are proposed to test the hypothesis, supported so far by work with mitochondrial uptake of 14-C succinate, that the toxic beta-lactams produce acute renal injury by poisoning cell metabolism through injury to the mitochondrial anionic substrate transporters. Manipulations of antibiotic dose and time of administration will be used to test the pathogenic role of reduced mitochondrial substrate transport in causing tubular necrosis. Different metabolic substrates will be tested at different concentrations to establish whether injury to mitochondrial respiration, which varies in severity between substrates, fits the pattern of injury to mitochondrial transport.l The transition from reversible immediate to irreversible later cephalosporin toxicity to transport acylation of substrate carriers. 2) Further work is planned to pursue preliminary evidence of a link between mitochondrial toxicity and abnormal tubular cell fatty acid metabolism, possibly resulting from decreased oxalacetate caused by reduced mitochondrial uptake of oxalacetate and its precursors, such as succinate. The effects of a ketogenic diet (and a carbohydrate rescue) on beta-lactim nephrotoxicity will be evaluated. The pattern of accumulation in renal cortical mitochondria and cytosol during beta-lactim toxicity of nonesterified fatty acids, beta-hydroxybutyrate, and the intermediates of fatty acid catabolism (including TCA cycle intermediates) will be compared to normal. The fate of the carboxyterminal 14-C of palmitate will be traced in normal and beta-lactim intoxicated mitochondria; this should not reach TCA aminoglycosides (which are toxic to mitochondria),k ischemic injury (which causes potentially cytotoxic intracellular levels of free fatty acids),k and endotoxemia, each one alone and together with the cephalosporins, on the same processes, to determine the mechanisms of the established nephrotoxic synergies of these insults with the toxic beta- lactams.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine B Study Section (GMB)
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Stanford University
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Tune, B M (1997) Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention. Pediatr Nephrol 11:768-72
Tune, B M; Hsu, C Y; Fravert, D (1996) Cephalosporin and carbacephem nephrotoxicity. Roles of tubular cell uptake and acylating potential. Biochem Pharmacol 51:557-61
Tune, B M; Hsu, C Y (1995) Toxicity of cephalosporins to fatty acid metabolism in rabbit renal cortical mitochondria. Biochem Pharmacol 49:727-34
Tune, B M (1995) Effects of L-carnitine on the renal tubular transport of cephaloridine. Biochem Pharmacol 50:562-4
Tune, B M; Hsu, C Y (1995) Effects of nephrotoxic beta-lactam antibiotics on the mitochondrial metabolism of monocarboxylic substrates. J Pharmacol Exp Ther 274:194-9
Tune, B M (1994) Renal tubular transport and nephrotoxicity of beta lactam antibiotics: structure-activity relationships. Miner Electrolyte Metab 20:221-31
Tune, B M; Hsu, C Y (1994) Toxicity of cephaloridine to carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria: structure-activity relationships. J Pharmacol Exp Ther 270:873-80
Schutz, T; Gonzalez-Mendez, R; Nabseth, D C et al. (1991) A study of nephrotoxin-induced acute tubular necrosis with 31P magnetic resonance spectroscopy. Magn Reson Med 18:159-68
Tune, B M; Hsu, C Y (1990) The renal mitochondrial toxicity of cephalosporins: specificity of the effect on anionic substrate uptake. J Pharmacol Exp Ther 252:65-9
Tune, B M; Hsu, C Y (1990) Mechanisms of beta-lactam antibiotic nephrotoxicity. Toxicol Lett 53:81-6

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