Smarter Decisions,
Better Care

UpToDate synthesizes the most recent medical information into evidence-based practical recommendations clinicians trust to make the right point-of-care decisions.

  • Rigorous editorial process: Evidence-based treatment recommendations
  • World-Renowned physician authors: over 5,100 physician authors and editors around the globe
  • Innovative technology: integrates into the workflow; access from EMRs

Choose from the list below to learn more about subscriptions for a:


Subscribers log in here


Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity

INTRODUCTION

The main concerns with the use of aminoglycoside antibiotics are nephrotoxicity and ototoxicity. This topic will review what is known about the pathogenesis of these complications and how the nephrotoxicity might be prevented. The manifestations of and risk factors for aminoglycoside nephrotoxicity are discussed separately. (See "Manifestations of and risk factors for aminoglycoside nephrotoxicity".)

NEPHROTOXICITY

Acute kidney injury (AKI) due to acute tubular necrosis is a relatively common complication of aminoglycoside therapy, with a rise in the serum creatinine concentration of more than 0.5 to 1 mg/dL (44 to 88 micromol/L) or a 50 percent increase in serum creatinine concentration from baseline occurring in 10 to 20 percent of patients [1,2]. Aminoglycosides are freely filtered across the glomerulus; almost all of the drug is then excreted, with 5 to 10 percent of a parenteral dose being taken up and sequestered by the proximal tubule cells where the aminoglycoside can achieve concentrations vastly exceeding the concurrent serum concentration [3].

The intracellular accumulation of aminoglycosides is confined primarily to the S1 and S2 segments of the proximal tubule. However, following renal ischemia, the S3 portion is also a site of intracellular aminoglycoside concentrations. AKI can occur even if drug levels are closely monitored [4].

Dose frequency also may be important as multiple human studies suggest that giving a large dose of aminoglycoside once a day is as effective an antimicrobial regimen and less nephrotoxic than giving aminoglycosides in the conventional, divided-dose regimen [5-9]. (See "Dosing and administration of parenteral aminoglycosides".)

Renal transport of aminoglycosides

Proximal tubule cell transport and charge — Multiple amine groups on the aminoglycoside molecule confer a cationic charge at physiologic pH [10,11]. As a result, aminoglycoside molecules readily bind to anion phospholipids within the plasma membrane of the proximal tubule cell (PTC) in a saturable, electrostatic manner [10-13]. The relative affinity of an aminoglycoside for the PTC plasma membrane correlates with the nephrotoxicity observed in clinical practice [4,14-16]:

       

Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Mar 2014. | This topic last updated: Jan 13, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2014 UpToDate, Inc.
References
Top
  1. Humes HD. Aminoglycoside nephrotoxicity. Kidney Int 1988; 33:900.
  2. Moore RD, Smith CR, Lipsky JJ, et al. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984; 100:352.
  3. Galløe AM, Graudal N, Christensen HR, Kampmann JP. Aminoglycosides: single or multiple daily dosing? A meta-analysis on efficacy and safety. Eur J Clin Pharmacol 1995; 48:39.
  4. Smith CR, Lipsky JJ, Laskin OL, et al. Double-blind comparison of the nephrotoxicity and auditory toxicity of gentamicin and tobramycin. N Engl J Med 1980; 302:1106.
  5. Munckhof WJ, Grayson ML, Turnidge JD. A meta-analysis of studies on the safety and efficacy of aminoglycosides given either once daily or as divided doses. J Antimicrob Chemother 1996; 37:645.
  6. Hatala R, Dinh T, Cook DJ. Once-daily aminoglycoside dosing in immunocompetent adults: a meta-analysis. Ann Intern Med 1996; 124:717.
  7. Ferriols-Lisart R, Alós-Almiñana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1996; 53:1141.
  8. Barza M, Ioannidis JP, Cappelleri JC, Lau J. Single or multiple daily doses of aminoglycosides: a meta-analysis. BMJ 1996; 312:338.
  9. Prins JM, Büller HR, Kuijper EJ, et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993; 341:335.
  10. Nagai J, Takano M. Molecular aspects of renal handling of aminoglycosides and strategies for preventing the nephrotoxicity. Drug Metab Pharmacokinet 2004; 19:159.
  11. Sastrasinh M, Knauss TC, Weinberg JM, Humes HD. Identification of the aminoglycoside binding site in rat renal brush border membranes. J Pharmacol Exp Ther 1982; 222:350.
  12. Giuliano RA, Verpooten GA, Verbist L, et al. In vivo uptake kinetics of aminoglycosides in the kidney cortex of rats. J Pharmacol Exp Ther 1986; 236:470.
  13. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother 1999; 43:1003.
  14. Smith CR, Baughman KL, Edwards CQ, et al. Controlled comparison of amikacin and gentamicin. N Engl J Med 1977; 296:349.
  15. Lerner AM, Reyes MP, Cone LA, et al. Randomised, controlled trial of the comparative efficacy, auditory toxicity, and nephrotoxicity of tobramycin and netilmicin. Lancet 1983; 1:1123.
  16. Williams PD, Bennett DB, Gleason CR, Hottendorf GH. Correlation between renal membrane binding and nephrotoxicity of aminoglycosides. Antimicrob Agents Chemother 1987; 31:570.
  17. Moestrup SK, Cui S, Vorum H, et al. Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs. J Clin Invest 1995; 96:1404.
  18. Hammond TG, Majewski RR, Kaysen JH, et al. Gentamicin inhibits rat renal cortical homotypic endosomal fusion: role of megalin. Am J Physiol 1997; 272:F117.
  19. Christensen EI, Birn H. Megalin and cubilin: multifunctional endocytic receptors. Nat Rev Mol Cell Biol 2002; 3:256.
  20. Christensen EI, Birn H. Megalin and cubilin: synergistic endocytic receptors in renal proximal tubule. Am J Physiol Renal Physiol 2001; 280:F562.
  21. Christensen EI, Willnow TE. Essential role of megalin in renal proximal tubule for vitamin homeostasis. J Am Soc Nephrol 1999; 10:2224.
  22. Kerjaschki D, Farquhar MG. The pathogenic antigen of Heymann nephritis is a membrane glycoprotein of the renal proximal tubule brush border. Proc Natl Acad Sci U S A 1982; 79:5557.
  23. Lundgren S, Carling T, Hjälm G, et al. Tissue distribution of human gp330/megalin, a putative Ca(2+)-sensing protein. J Histochem Cytochem 1997; 45:383.
  24. Schmitz C, Hilpert J, Jacobsen C, et al. Megalin deficiency offers protection from renal aminoglycoside accumulation. J Biol Chem 2002; 277:618.
  25. Cui S, Verroust PJ, Moestrup SK, Christensen EI. Megalin/gp330 mediates uptake of albumin in renal proximal tubule. Am J Physiol 1996; 271:F900.
  26. Nagai J, Tanaka H, Nakanishi N, et al. Role of megalin in renal handling of aminoglycosides. Am J Physiol Renal Physiol 2001; 281:F337.
  27. Christensen EI, Birn H, Verroust P, Moestrup SK. Membrane receptors for endocytosis in the renal proximal tubule. Int Rev Cytol 1998; 180:237.
  28. Bennett WM. Mechanisms of aminoglycoside nephrotoxicity. Clin Exp Pharmacol Physiol 1989; 16:1.
  29. Olbricht CJ, Fink M, Gutjahr E. Alterations in lysosomal enzymes of the proximal tubule in gentamicin nephrotoxicity. Kidney Int 1991; 39:639.
  30. Ford DM, Dahl RH, Lamp CA, Molitoris BA. Apically and basolaterally internalized aminoglycosides colocalize in LLC-PK1 lysosomes and alter cell function. Am J Physiol 1994; 266:C52.
  31. Takano M, Ohishi Y, Okuda M, et al. Transport of gentamicin and fluid-phase endocytosis markers in the LLC-PK1 kidney epithelial cell line. J Pharmacol Exp Ther 1994; 268:669.
  32. Hori R, Okuda M, Ohishi Y, et al. Surface binding and intracellular uptake of gentamicin in the cultured kidney epithelial cell line (LLC-PK1). J Pharmacol Exp Ther 1992; 261:1200.
  33. Spiegel DM, Shanley PF, Molitoris BA. Mild ischemia predisposes the S3 segment to gentamicin toxicity. Kidney Int 1990; 38:459.
  34. Wedeen RP, Batuman V, Cheeks C, et al. Transport of gentamicin in rat proximal tubule. Lab Invest 1983; 48:212.
  35. Silverblatt FJ, Kuehn C. Autoradiography of gentamicin uptake by the rat proximal tubule cell. Kidney Int 1979; 15:335.
  36. Servais H, Van Der Smissen P, Thirion G, et al. Gentamicin-induced apoptosis in LLC-PK1 cells: involvement of lysosomes and mitochondria. Toxicol Appl Pharmacol 2005; 206:321.
  37. Sandoval R, Leiser J, Molitoris BA. Aminoglycoside antibiotics traffic to the Golgi complex in LLC-PK1 cells. J Am Soc Nephrol 1998; 9:167.
  38. Sandvig K, Ryd M, Garred O, et al. Retrograde transport from the Golgi complex to the ER of both Shiga toxin and the nontoxic Shiga B-fragment is regulated by butyric acid and cAMP. J Cell Biol 1994; 126:53.
  39. Lord JM, Roberts LM. Toxin entry: retrograde transport through the secretory pathway. J Cell Biol 1998; 140:733.
  40. Sandoval RM, Molitoris BA. Gentamicin traffics retrograde through the secretory pathway and is released in the cytosol via the endoplasmic reticulum. Am J Physiol Renal Physiol 2004; 286:F617.
  41. Sandvig K, Garred O, van Helvoort A, et al. Importance of glycolipid synthesis for butyric acid-induced sensitization to shiga toxin and intracellular sorting of toxin in A431 cells. Mol Biol Cell 1996; 7:1391.
  42. Guo X, Nzerue C. How to prevent, recognize, and treat drug-induced nephrotoxicity. Cleve Clin J Med 2002; 69:289.
  43. Baciewicz AM, Sokos DR, Cowan RI. Aminoglycoside-associated nephrotoxicity in the elderly. Ann Pharmacother 2003; 37:182.
  44. Bailey TC, Little JR, Littenberg B, et al. A meta-analysis of extended-interval dosing versus multiple daily dosing of aminoglycosides. Clin Infect Dis 1997; 24:786.
  45. Bacopoulou F, Markantonis SL, Pavlou E, Adamidou M. A study of once-daily amikacin with low peak target concentrations in intensive care unit patients: pharmacokinetics and associated outcomes. J Crit Care 2003; 18:107.
  46. Ali BH. Agents ameliorating or augmenting experimental gentamicin nephrotoxicity: some recent research. Food Chem Toxicol 2003; 41:1447.
  47. Beauchamp D, Laurent G, Maldague P, et al. Protection against gentamicin-induced early renal alterations (phospholipidosis and increased DNA synthesis) by coadministration of poly-L-aspartic acid. J Pharmacol Exp Ther 1990; 255:858.
  48. Kishore BK, Lambricht P, Laurent G, et al. Mechanism of protection afforded by polyaspartic acid against gentamicin-induced phospholipidosis. II. Comparative in vitro and in vivo studies with poly-L-aspartic, poly-L-glutamic and poly-D-glutamic acids. J Pharmacol Exp Ther 1990; 255:875.
  49. Ramsammy LS, Josepovitz C, Lane BP, Kaloyanides GJ. Polyaspartic acid protects against gentamicin nephrotoxicity in the rat. J Pharmacol Exp Ther 1989; 250:149.
  50. Williams PD, Hottendorf GH, Bennett DB. Inhibition of renal membrane binding and nephrotoxicity of aminoglycosides. J Pharmacol Exp Ther 1986; 237:919.
  51. Kishore BK, Ibrahim S, Lambricht P, et al. Comparative assessment of poly-L-aspartic and poly-L-glutamic acids as protectants against gentamicin-induced renal lysosomal phospholipidosis, phospholipiduria and cell proliferation in rats. J Pharmacol Exp Ther 1992; 262:424.
  52. Josepovitz C, Pastoriza-Munoz E, Timmerman D, et al. Inhibition of gentamicin uptake in rat renal cortex in vivo by aminoglycosides and organic polycations. J Pharmacol Exp Ther 1982; 223:314.
  53. Kishore BK, Kállay Z, Lambricht P, et al. Mechanism of protection afforded by polyaspartic acid against gentamicin-induced phospholipidosis. I. Polyaspartic acid binds gentamicin and displaces it from negatively charged phospholipid layers in vitro. J Pharmacol Exp Ther 1990; 255:867.
  54. Ali BH. Gentamicin nephrotoxicity in humans and animals: some recent research. Gen Pharmacol 1995; 26:1477.
  55. Ben Ismail TH, Ali BH, Bashir AA. Influence of iron, deferoxamine and ascorbic acid on gentamicin-induced nephrotoxicity in rats. Gen Pharmacol 1994; 25:1249.
  56. Ali BH, Bashir AK. Effect of superoxide dismutase treatment on gentamicin nephrotoxicity in rats. Gen Pharmacol 1996; 27:349.
  57. Ali BH, Mousa HM. Effect of dimethyl sulfoxide on gentamicin-induced nephrotoxicity in rats. Hum Exp Toxicol 2001; 20:199.
  58. Sandhya P, Mohandass S, Varalakshmi P. Role of DL alpha-lipoic acid in gentamicin induced nephrotoxicity. Mol Cell Biochem 1995; 145:11.
  59. Mazzon E, Britti D, De Sarro A, et al. Effect of N-acetylcysteine on gentamicin-mediated nephropathy in rats. Eur J Pharmacol 2001; 424:75.
  60. Reiter RJ, Tan DX, Sainz RM, et al. Melatonin: reducing the toxicity and increasing the efficacy of drugs. J Pharm Pharmacol 2002; 54:1299.
  61. Ozbek E, Turkoz Y, Sahna E, et al. Melatonin administration prevents the nephrotoxicity induced by gentamicin. BJU Int 2000; 85:742.
  62. Sandoval RM, Reilly JP, Running W, et al. A non-nephrotoxic gentamicin congener that retains antimicrobial efficacy. J Am Soc Nephrol 2006; 17:2697.
  63. Nudelman I, Glikin D, Smolkin B, et al. Repairing faulty genes by aminoglycosides: development of new derivatives of geneticin (G418) with enhanced suppression of diseases-causing nonsense mutations. Bioorg Med Chem 2010; 18:3735.
  64. Wang D, Belakhov V, Kandasamy J, et al. The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse. Mol Genet Metab 2012; 105:116.
  65. Rowe SM, Sloane P, Tang LP, et al. Suppression of CFTR premature termination codons and rescue of CFTR protein and function by the synthetic aminoglycoside NB54. J Mol Med (Berl) 2011; 89:1149.
  66. Nudelman I, Rebibo-Sabbah A, Cherniavsky M, et al. Development of novel aminoglycoside (NB54) with reduced toxicity and enhanced suppression of disease-causing premature stop mutations. J Med Chem 2009; 52:2836.
  67. Dobie RA, Black FO, Pezsnecker SC, Stallings VL. Hearing loss in patients with vestibulotoxic reactions to gentamicin therapy. Arch Otolaryngol Head Neck Surg 2006; 132:253.
  68. Black FO, Pesznecker S, Stallings V. Permanent gentamicin vestibulotoxicity. Otol Neurotol 2004; 25:559.
  69. Basile AS, Huang JM, Xie C, et al. N-methyl-D-aspartate antagonists limit aminoglycoside antibiotic-induced hearing loss. Nat Med 1996; 2:1338.
  70. Ernfors P, Duan ML, ElShamy WM, Canlon B. Protection of auditory neurons from aminoglycoside toxicity by neurotrophin-3. Nat Med 1996; 2:463.
  71. Wu WJ, Sha SH, Schacht J. Recent advances in understanding aminoglycoside ototoxicity and its prevention. Audiol Neurootol 2002; 7:171.
  72. Sinswat P, Wu WJ, Sha SH, Schacht J. Protection from ototoxicity of intraperitoneal gentamicin in guinea pig. Kidney Int 2000; 58:2525.
  73. Prezant TR, Agapian JV, Bohlman MC, et al. Mitochondrial ribosomal RNA mutation associated with both antibiotic-induced and non-syndromic deafness. Nat Genet 1993; 4:289.
  74. Casano RA, Johnson DF, Bykhovskaya Y, et al. Inherited susceptibility to aminoglycoside ototoxicity: genetic heterogeneity and clinical implications. Am J Otolaryngol 1999; 20:151.
  75. Hamasaki K, Rando RR. Specific binding of aminoglycosides to a human rRNA construct based on a DNA polymorphism which causes aminoglycoside-induced deafness. Biochemistry 1997; 36:12323.
  76. Guan MX, Fischel-Ghodsian N, Attardi G. A biochemical basis for the inherited susceptibility to aminoglycoside ototoxicity. Hum Mol Genet 2000; 9:1787.
  77. Bitner-Glindzicz M, Pembrey M, Duncan A, et al. Prevalence of mitochondrial 1555A-->G mutation in European children. N Engl J Med 2009; 360:640.
  78. Vandebona H, Mitchell P, Manwaring N, et al. Prevalence of mitochondrial 1555A-->G mutation in adults of European descent. N Engl J Med 2009; 360:642.
  79. Aran JM. Current perspectives on inner ear toxicity. Otolaryngol Head Neck Surg 1995; 112:133.
  80. Feldman L, Efrati S, Eviatar E, et al. Gentamicin-induced ototoxicity in hemodialysis patients is ameliorated by N-acetylcysteine. Kidney Int 2007; 72:359.
  81. Tokgoz B, Ucar C, Kocyigit I, et al. Protective effect of N-acetylcysteine from drug-induced ototoxicity in uraemic patients with CAPD peritonitis. Nephrol Dial Transplant 2011; 26:4073.
  82. Tepel M. N-Acetylcysteine in the prevention of ototoxicity. Kidney Int 2007; 72:231.
  83. Chen Y, Huang WG, Zha DJ, et al. Aspirin attenuates gentamicin ototoxicity: from the laboratory to the clinic. Hear Res 2007; 226:178.
  84. Sha SH, Qiu JH, Schacht J. Aspirin to prevent gentamicin-induced hearing loss. N Engl J Med 2006; 354:1856.
  85. Rybak LP, Ramkumar V. Ototoxicity. Kidney Int 2007; 72:931.