Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity
- 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
- Section Editors
- Paul M Palevsky, MD
Paul M Palevsky, MD
- Section Editor — Renal Failure
- Professor of Medicine
- University of Pittsburgh
- VA Pittsburgh Healthcare System
- Jeffrey S Berns, MD
Jeffrey S Berns, MD
- Editor-in-Chief — Nephrology
- Section Editor — Dialysis
- Professor of Medicine
- Perelman School of Medicine at the University of Pennsylvania
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".)
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 (PTCs), where the aminoglycoside can achieve concentrations vastly exceeding the concurrent serum concentration .
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 .
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"). Aminoglycosides may also have a deleterious effect on the developing kidney in preterm and small for gestational age infants .
Renal transport of aminoglycosides
Proximal tubule cell transport and charge — Multiple amine groups on the aminoglycoside molecule confer a cationic charge at physiologic pH [11,12]. As a result, aminoglycoside molecules readily bind to anion phospholipids within the plasma membrane of the PTC in a saturable, electrostatic manner [11-14]. The relative affinity of an aminoglycoside for the PTC plasma membrane correlates with the nephrotoxicity observed in clinical practice [4,15-17]:
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