Prevalence and Risk Factors for Aminoglycoside Nephrotoxicity in Intensive Care Units

Aminoglycosides are potent bactericidal antibiotics that are highly effective against gram-negative bacterial infections. They have increasingly been used as gram-negative organisms have become progressively more resistant to beta-lactam antibiotics and fluoroquinolones (8). In fact, they were recently found to be prescribed in 12.1% of the cases in which an antibiotic was necessary in the intensive care unit (ICU) (10). Aminoglycosides are administered by the parenteral route, have low albumin plasma binding levels, and are freely eliminated by glomerular filtration and reabsorbed by the proximal tubule (26). A fraction of the filtered load of the antibiotic binds to megalin, a receptor from the brush border of proximal tubule segments S1 and S2, which then transports it to the interior of the tubule cells (25). Their half-life in the renal cortex is estimated to range from 30 to 700 h (1). The most important adverse effects of aminoglycosides are nephrotoxicity, ototoxicity, and, more rarely, neuromuscular blockade. Renal injury can occur in a substantial number of patients receiving an aminoglycoside, and whether it occurs depends on the patient's clinical condition and interactions with other nephrotoxic drugs (26). The most usual clinical presentation for aminoglycoside-associated nephrotoxicity is nonoliguric acute kidney injury (AKI), which occurs following 7 to 10 days of therapy (1, 26). Aminoglycoside-associated kidney injury may manifest as a decrease in the glomerular filtration rate (GFR), enzymuria, aminoaciduria, glycosuria, hypomagnesemia, hypocalcemia, and hypokalemia. Fanconi-like and Bartter-like syndromes, as well as impaired renal concentrating mechanisms, have also been described (15, 19, 26). Several risk factors for aminoglycoside-associated nephrotoxicity have been identified, including the presence of comorbidities, volume depletion, liver dysfunction, sepsis, renal dysfunction, hypokalemia, hypomagnesemia, advanced age, prolonged therapy, the type of aminoglycoside, the frequency of aminoglycoside dosing, an elevated serum aminoglycoside concentration, the timing of aminoglycoside administration, the simultaneous consumption of other medications, and interactions with other nephrotoxic drugs (5, 34). However, the majority of published studies (2, 5, 24, 27, 29, 30, 32) did not evaluate several of the most important risk factors simultaneously, had small sample sizes, or did not use appropriate statistical methods for risk factor assessment. In addition, few studies analyzed ICU patients. Therefore, the aim of the present study was to assess the prevalence of aminoglycoside-associated nephrotoxicity in a large cohort of ICU patients and identify the independent risk factors associated with the development of renal injury. (Part of this work was presented at the American Society of Nephrology meeting in 2005 and published as an abstract [26a]).