Functional Considerations in Aminoglycoside Nephrotoxicity

  • William M. Bennett
  • Donald C. Houghton
  • W. Clayton Elliott


Aminoglycoside nephrotoxicity is a relatively common clinical problem. Well-controlled studies have documented up to a 26% incidence of serum creatinine elevations during therapy despite monitoring by frequent aminoglycoside blood level determinations (Smith et al., 1980). Because of the complex clinical settings in which these antibiotics are prescribed, efforts to study the pathophysiology of nephrotoxicity have involved use of animal models (Kosek et al., 1974; Luft et al., 1975; Houghton et al., 1976; Cronin et al., 1980). In this chapter, an attempt will be made to correlate findings in one such model, the rat, with certain variables which may influence aminoglycoside nephrotoxicity. It has become apparent that studies concerning biochemical and subcellular mechanisms of aminoglycoside nephrotoxicity must take into account the considerable regenerative and functional recovery which occurs during continuous treatment with aminoglycosides. It is not clear at present whether similar caution needs to be exercised in interpreting studies involving other nephrotoxins which cause experimental or clinical acute renal failure. Finally, the consequences of acute nephrotoxic insults on long-term renal functional integrity should be carefully evaluated despite return to normal of such insensitive parameters as serum creatinine after the toxin is withdrawn.


Acute Renal Failure Inulin Clearance Renal Cortical Slice Aminoglycoside Nephrotoxicity Gentamicin Nephrotoxicity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adelman, R. D., Spangler, W. L., Beasom, F., Ishizaki, G., and Conzelman, G. M., 1979, Furosemide enhancement of experimental gentamicin nephrotoxicity: Comparison of functional and morphologic changes with activity of urinary enzymes, J. Infect. Dis. 140:342.CrossRefGoogle Scholar
  2. Bennett, W. M., Hartnett, M. N., Gilbert, D. N., Houghton, D. C., and Porter, G. A., 1976, Effect of sodium intake on gentamicin nephrotoxicity in the rat, Proc. Soc. Exp. Biol. Med. 151:581.Google Scholar
  3. Bennett, W. M., Plamp, C. E., Gilbert, D. N., Parker, R. A., and Porter, G. A., 1979a, The influence of dosage regimen on experimental gentamicin nephrotoxicity: Dissociation of peak serum levels from renal failure, J. Infect. Dis. 140:576.CrossRefGoogle Scholar
  4. Bennett, W. M., Plamp, C. E., Parker, R. A., Gilbert, D. N., Houghton, D. C., and Porter, G. A., 1979b, Renal transport of organic acids and bases in aminoglycoside nephrotoxicity, Antimicrob. Agents Chemother. 16:231.CrossRefGoogle Scholar
  5. Bodey, G. P., Chang, H. Y., Rodriquez, V., and Stewart, D., 1975, Feasibility of administering aminoglycoside antibiotics by continuous intravenous infusion, Antimicrob. Agents Chemother. 8:328.CrossRefGoogle Scholar
  6. Brinker, K., Cronin, R., Bulger, R., Southern, P., and Henrich, W., 1979, Potassium depletion: Risk factor for and consequence of gentamicin nephrotoxicity, Proc. Am. Soc. Nephrol. 12:79A.Google Scholar
  7. Chiu, P. J. S., Miller, G. J., Long, J. F., and Waity, J. A., 1979, Renal uptake and nephrotoxicity of gentamicin during urinary alkalinization in rats, Clin. Exp. Pharmacol. Physiol. 6:317.CrossRefGoogle Scholar
  8. Chonko, A., Savin, V., Stewart, R., Karniski, L., Cuppage, F., and Hodges, G., 1979, The effects of gentamicin on renal function in the mature versus immature rabbit, Proc. Am. Soc. Nephrol. 12:2A.Google Scholar
  9. Cronin, R. E., Bulger, R. E., Southern, P., and Henrich, W. L., 1980, Natural history of aminoglycoside nephrotoxicity in the dog, J. Lab. Clin. Med. 95:463.Google Scholar
  10. Cuppage, F. E., Setter, K., Sullivan, L. P., Reitzes, E. J., and Melnykovych, A. O., 1977, Gentamicin nephrotoxicity. II. Physiological, biochemical and morphological effects of prolonged administration to rats, Virchows Arch. B Cell Pathol. 24:121.Google Scholar
  11. Elliott, W. C., and Bennett, W. M., 1981, Acquired gentamicin insensitivity: Rate of functional recovery with continued drug administration, Clin. Res. 29:72A.Google Scholar
  12. Elliott, W. C., Parker, R. A., Gilbert, D. N., Houghton, D. C., Porter, G. A., DeFehr, J., and Bennett, W. M., 1980a, Effect of compensatory hypertrophy on experimental gentamicin nephrotoxicity, Clin. Res. 28:62A.Google Scholar
  13. Elliott, W. C., Parker, R. A., Houghton, D. C., Gilbert, D. N., Porter, G. A., DeFehr, J., and Bennett, W. M., 1980b, Effect of sodium bicarbonate and ammonium chloride ingestion in experimental gentamicin nephrotoxicity in rats, Res. Commun. Chem. Pathol. Pharmacol. 28:483.Google Scholar
  14. Elliott, W. C., Lynn, R. K., Kennish, J., Houghton, D. C., and Bennett, W. M., 1981, Acute nephrotoxicity of the renal carcinogen TRIS, Clin. Res. 29:72A.Google Scholar
  15. Engle, J. E., Abt, A. B., and Schoolwerth A. C., 1977, Experimental aminoglycoside nephrotoxicity in the isolated perfused rat kidney, in: Proc. Internat. Cong. Nephrol., Volume 7, p. R-9.Google Scholar
  16. Frame, P. T., Phair, J. P., Watanakunakorn, C., and Bannister, T. W. P., 1977, Pharmacologic factors associated with gentamicin nephrotoxicity in rabbits, J. Infect. Dis. 135:852.CrossRefGoogle Scholar
  17. Gilbert, D. N., Houghton, D. C., Bennett, W. M., Plamp, C. E., Reger, K., and Porter, G. A., 1979, Reversibility of gentamicin nephrotoxicity in rats: Recovery during continued drug administration, Proc. Soc. Exp. Biol. Med. 160:99.Google Scholar
  18. Ho, P. W. L., Pien, F. D., and Kominami, N., 1979, Massive amikacin overdose, Ann. Intern. Med. 91:227.Google Scholar
  19. Hook, J. B., and Hewitt, W. R., 1977, Development of mechanisms for drug excretion, Am. J. Med. 62:497.CrossRefGoogle Scholar
  20. Houghton, D. C., Hartnett, M. N., Campbell-Boswell, M., Porter, G. A., and Bennett, W. M., 1976, A light and electron microscopic analysis of gentamicin nephrotoxicity in rats, Am. J. Pathol. 82:589.Google Scholar
  21. Hsu, C. H., Kurtz, G., Easterling, R. E., and Weiler, J. M., 1974, Potentiation of gentamicin nephrotoxicity by metabolic acidosis, Proc. Soc. Exp. Biol. Med. 146:894.Google Scholar
  22. Ilett, K. F., Watson, D. R., Sipes, I. G., and Krishna, G., 1973, Chloroform toxicity in mice: Correlation of renal and hepatic necrosis with covalent binding of metabolites to tissue macromolecules, Exp. Mol. Pathol. 19:215.CrossRefGoogle Scholar
  23. Keating, M. J., Setthi, M. R., Bodey, G. P., and Samaan, N. A., 1977, Hypocalcemia with hypoparathyroidism and renal tubular dysfunction associated with aminoglycoside therapy, Cancer 39:1410.CrossRefGoogle Scholar
  24. Kluwe, W. M., and Hook, J. B., 1980, Metabolic activation of nephrotoxic haloalkanes, Fed. Proc. 39:3129.Google Scholar
  25. Koenig, H., Goldstone, A., Blume, G., and Lu, C. Y., 1980, Testosterone-mediated sexual dimorphism of mitochondria and lysosomes in mouse kidney proximal tubules, Science 209:1023.CrossRefGoogle Scholar
  26. Kosek J. C., Mazze, R. I., and Cousins, M. J., 1974, Nephrotoxicity of gentamicin, Lab. Invest. 30:48.Google Scholar
  27. Kuo, C., and Hook, J. B., 1979, Specificity of gentamicin accumulation by rat renal cortex, Life Sci. 25: 873.CrossRefGoogle Scholar
  28. Luft, F. C., Patel, V., Yum, M. N., Patel, B., and Kleit, S. A., 1975, Experimental aminoglycoside nephrotoxicity, J. Lab. Clin. Med. 86:213.Google Scholar
  29. Luft, F. C., Yum, M. N., and Kleit, S., 1977, The effect of concomitant mercuric chloride and gentamicin on kidney function and structure in the rat, J. Lab. Clin. Med. 89:622.Google Scholar
  30. Lullmann, H., Lullmann-Rauch, R. and Wassermann, O., 1978, Lipidosis induced by amphiphilic cationic drugs, Biochem. Pharmacol. 27:1103.CrossRefGoogle Scholar
  31. MacNider, W., 1929, The functional and pathological response of the kidney in dogs subjected to a second subcutaneous injection of uranium nitrate, J. Exp. Med. 49:411.CrossRefGoogle Scholar
  32. MacNider, W., 1931, The morphological basis for certain tissue resistance, Science 73:103.CrossRefGoogle Scholar
  33. Maunsbach, A. B., 1966, Observations on the segmentation of the proximal tubule in the rat kidney, J. Ultrastruct. Res. 16:239.CrossRefGoogle Scholar
  34. Newman, R., Weinstock, L. B., Gump, D. W., Hacker, M. P., and Yates, J. W., 1980, Effect of osmotic diuresis on gentamicin-induced nephrotoxicity in rats, Arch. Toxicol. 45:213.CrossRefGoogle Scholar
  35. Oken, D. E., Mende, C. W., Taraba, I., and Flamenbaum, W., 1975, Resistance to acute renal failure afforded by prior renal failure, Nephron 15:131.CrossRefGoogle Scholar
  36. Ormsby, A., Parker, R. A., Plamp, C., Stevens, P., Houghton, D. C., Gilbert, D. N., and Bennett, W. M., 1979, Comparison of the nephrotoxic potential of gentamicin, tobramycin and netilmicin in the rat, Curr. Ther. Res. 25:335.Google Scholar
  37. Parker, R. A., Bennett, W. M., Plamp, C. E., Houghton, D. C., Gilbert, D. N., and Porter, G. A., 1980, Resistance of female rats to gentamicin nephrotoxicity, Curr. Chemother. 1:601.Google Scholar
  38. Plamp, C. E., Reger, K., Bennett, W. M., McClung, M. R., and Porter, G. A., 1978, Vasopressin resistant polyuria in gentamicin nephrotoxicity, Clin. Res. 26:151A.Google Scholar
  39. Russo, J., and Adelman, R. D., 1980, Gentamicin induced Fanconi syndrome, J. Pediatr. 96:151.CrossRefGoogle Scholar
  40. Schentag, J. J., and Plaut, M. E., 1980, Patterns of urinary B-2 microglobulin excretion by patients treated with aminoglycosides, Kidney Int. 17:654.CrossRefGoogle Scholar
  41. Simmons, C. F., Bogusky, R. T., and Humes, H. D., 1980, Inhibitory effect of gentamicin on renal cortical mitochondrial oxidative phosphorylation, J. Pharmacol. Exp. Ther. 214:709.Google Scholar
  42. Smith, C. R., Lipsky, J. J., Laskin, O. L., Hellman, D. B., Mellits, E. D., Longstreth, J., and Leitman, P. S., 1980, Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin, N. Engl. J. Med. 302:1106.CrossRefGoogle Scholar
  43. Suzuki, K. T., Yamamura, M., Yamada, Y. K., and Shimizu, F., 1980, Decreased copper content in rat kidney metallothionein and its relation to acute cadmium nephropathy, Toxicol. Lett. 7:137.CrossRefGoogle Scholar
  44. Teixeira, R. B., Morales, J., Kelley, J., Alpert, H., Pardo, V., and Vaamonde, C., 1980, Mechanism of complete protection from gentamicin-induced acute renal failure in the untreated streptozotocin diabetic rat, Clin. Res. 28:463A.Google Scholar
  45. Thiel, G., de Rougemont, D., Konrad, L., Oeschiger, A., Torhorst, J., and Brunner, F., 1978, Gentamicin induced acute renal failure in the rat, in Proc. VII Internat. Cong. Nephrol, Volume 7, p. D45.Google Scholar
  46. Thompson, L., Reiner, N. E., and Bloxham, D. D., 1977, Gentamicin and tobramycin nephrotoxicity in dogs on continuous or once daily intravenous injection, in: Proc. Internat. Cong. Chemother., Volume 10, p. 207.Google Scholar
  47. Vaamonde, C. A., Teixeira, R. B., Morales, J., Kelley, J., Alpert, H., and Pardo, V., 1980, A new model for studying drug-induced nephrotoxicity: The rat with untreated streptozotocin-induced diabetes mellitus, Proc. Am. Soc. Nephrol. 13:108A.Google Scholar
  48. Viotte, G., Morin, J. P., Bendirdjian, J. P., Ducastelle, B., Godin, M., and Fillastre, J. P., 1980, The effects of increasing doses of fosfomycin gentamicin and their association on the rat kidney, Drugs Exp. Clin. Res. 6:317.Google Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • William M. Bennett
    • 1
  • Donald C. Houghton
    • 1
  • W. Clayton Elliott
    • 1
  1. 1.Division of Nephrology, Department of MedicineOregon Health Sciences UniversityPortlandUSA

Personalised recommendations