Manifestations of and risk factors for aminoglycoside nephrotoxicity
- Brian S Decker, MD, PharmD
Brian S Decker, MD, PharmD
- Assistant Professor of Clinical Medicine
- Indiana University Department of Medicine
- Bruce A Molitoris, MD
Bruce A Molitoris, MD
- Professor of Medicine
- Indiana University School of Medicine
Acute kidney injury is a relatively common complication of therapy with the aminoglycoside antibiotics, with a rise in the plasma creatinine concentration of more than 0.5 to 1 mg/dL (44 to 88 micromol/L) or 50 percent increase in plasma creatinine concentration from baseline occurring in 10 to 20 percent of patients [1-4].
Aminoglycosides are freely filtered across the glomerulus and then partially taken up by, concentrated in, and produce damage to proximal tubular cells. The renal injury induced by these drugs is related to their preferential accumulation in the renal cortex. After administration, up to 5 to 10 percent of the parenteral dose is retained in the renal cortex, where it can achieve concentrations greatly exceeding the concurrent serum concentration . This preferential sequestration of aminoglycosides in proximal tubule cells accounts for the observation that renal failure may become clinically apparent as late as several days after the drug has been discontinued. (See "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)
The manifestations of and risk factors for aminoglycoside nephrotoxicity are reviewed here. Acute tubular necrosis due to ischemia or other insults and the pathogenesis and potential therapy of aminoglycoside nephrotoxicity are discussed separately. (See "Etiology and diagnosis of prerenal disease and acute tubular necrosis in acute kidney injury (acute renal failure)" and "Pathogenesis and etiology of postischemic (ischemic) acute tubular necrosis" and "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity".)
Nonoliguric acute kidney injury — Acute kidney injury from aminoglycoside exposure typically manifests after five to seven days of therapy. The nonoliguric aspect of the renal failure is secondary to a loss in renal concentrating ability believed to be the result of distal tubular damage.
The acute tubular necrosis that occurs from aminoglycoside exposure is rarely severe, with incremental increases in the plasma creatinine that are usually mild (0.5 to 2.0 mg/dL [44 to 177 micromol/liter]) . However, aminoglycosides can result in toxicity, mandating renal replacement therapy in patients who already have chronic kidney disease (CKD). The urine sediment most commonly shows mild proteinuria, hyaline, and granular casts. The fractional excretion of sodium is generally above 1 percent (calculator 1) or, for standard units, (calculator 2). (See "Fractional excretion of sodium, urea, and other molecules in acute kidney injury (acute renal failure)".)
- Humes HD. Aminoglycoside nephrotoxicity. Kidney Int 1988; 33:900.
- Moore RD, Smith CR, Lipsky JJ, et al. Risk factors for nephrotoxicity in patients treated with aminoglycosides. Ann Intern Med 1984; 100:352.
- Meyer RD. Risk factors and comparisons of clinical nephrotoxicity of aminoglycosides. Am J Med 1986; 80:119.
- Bell S, Davey P, Nathwani D, et al. Risk of AKI with gentamicin as surgical prophylaxis. J Am Soc Nephrol 2014; 25:2625.
- Laurent G, Kishore BK, Tulkens PM. Aminoglycoside-induced renal phospholipidosis and nephrotoxicity. Biochem Pharmacol 1990; 40:2383.
- Chambers HF. Aminoglycosides. In: Goodman and Gilman's The Pharmacological Basis of Therapeutics, 11th ed, Hardman JG, Limbird LE, Molinoff PB, et al. (Eds), McGraw-Hill, New York 2006.
- Patel R, Savage A. Symptomatic hypomagnesemia associated with gentamicin therapy. Nephron 1979; 23:50.
- Houghton DC, English J, Bennett WM. Chronic tubulointerstitial nephritis and renal insufficiency associated with long-term "subtherapeutic" gentamicin. J Lab Clin Med 1988; 112:694.
- Schentag JJ, Jusko WJ. Renal clearance and tissue accumulation of gentamicin. Clin Pharmacol Ther 1977; 22:364.
- Dahlgren JG, Anderson ET, Hewitt WL. Gentamicin blood levels: a guide to nephrotoxicity. Antimicrob Agents Chemother 1975; 8:58.
- Prins JM, Büller HR, Kuijper EJ, et al. Once versus thrice daily gentamicin in patients with serious infections. Lancet 1993; 341:335.
- Smith CR, Moore RD, Lietman PS. Studies of risk factors for aminoglycoside nephrotoxicity. Am J Kidney Dis 1986; 8:308.
- Raveh D, Kopyt M, Hite Y, et al. Risk factors for nephrotoxicity in elderly patients receiving once-daily aminoglycosides. QJM 2002; 95:291.
- 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.
- Paterson DL, Robson JM, Wagener MM. Risk factors for toxicity in elderly patients given aminoglycosides once daily. J Gen Intern Med 1998; 13:735.
- Bertino JS Jr, Booker LA, Franck PA, et al. Incidence of and significant risk factors for aminoglycoside-associated nephrotoxicity in patients dosed by using individualized pharmacokinetic monitoring. J Infect Dis 1993; 167:173.
- Cabrera J, Arroyo V, Ballesta AM, et al. Aminoglycoside nephrotoxicity in cirrhosis. Value of urinary beta 2-microglobulin to discriminate functional renal failure from acute tubular damage. Gastroenterology 1982; 82:97.
- Desai TK, Tsang TK. Aminoglycoside nephrotoxicity in obstructive jaundice. Am J Med 1988; 85:47.
- 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.
- Ferriols-Lisart R, Alós-Almiñana M. Effectiveness and safety of once-daily aminoglycosides: a meta-analysis. Am J Health Syst Pharm 1996; 53:1141.
- Zager RA. Gentamicin effects on renal ischemia/reperfusion injury. Circ Res 1992; 70:20.
- Molitoris BA, Meyer C, Dahl R, Geerdes A. Mechanism of ischemia-enhanced aminoglycoside binding and uptake by proximal tubule cells. Am J Physiol 1993; 264:F907.
- Zager RA. Endotoxemia, renal hypoperfusion, and fever: interactive risk factors for aminoglycoside and sepsis-associated acute renal failure. Am J Kidney Dis 1992; 20:223.
- Wade JC, Smith CR, Petty BG, et al. Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus an aminoglycoside. Lancet 1978; 2:604.
- English J, Gilbert DN, Kohlhepp S, et al. Attenuation of experimental tobramycin nephrotoxicity by ticarcillin. Antimicrob Agents Chemother 1985; 27:897.
- Bennett WM, Wood CA, Houghton DC, Gilbert DN. Modification of experimental aminoglycoside nephrotoxicity. Am J Kidney Dis 1986; 8:292.
- 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.
- Aronson JK, Reynolds DJ. ABC of monitoring drug therapy. Aminoglycoside antibiotics. BMJ 1992; 305:1421.
- McCormack JP, Jewesson PJ. A critical reevaluation of the "therapeutic range" of aminoglycosides. Clin Infect Dis 1992; 14:320.
- Whipple JK, Ausman RK, Franson T, Quebbeman EJ. Effect of individualized pharmacokinetic dosing on patient outcome. Crit Care Med 1991; 19:1480.
- Bartal C, Danon A, Schlaeffer F, et al. Pharmacokinetic dosing of aminoglycosides: a controlled trial. Am J Med 2003; 114:194.
- Destache CJ, Meyer SK, Bittner MJ, Hermann KG. Impact of a clinical pharmacokinetic service on patients treated with aminoglycosides: a cost-benefit analysis. Ther Drug Monit 1990; 12:419.
- Burton ME, Ash CL, Hill DP Jr, et al. A controlled trial of the cost benefit of computerized bayesian aminoglycoside administration. Clin Pharmacol Ther 1991; 49:685.
- 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.
- Nonoliguric acute kidney injury
- Distal tubular dysfunction
- Electrolyte abnormalities
- RISK FACTORS
- Prolonged duration of therapy
- Advanced age
- Comorbid disease
- Reduced effective volume
- Concomitant medications
- Elevated plasma drug concentrations
- Type of aminoglycoside
- Frequency of dosing