Drugs are a common source of acute kidney injury 1. They cause approximately 20 percent of community and hospital acquired episodes of acute renal insufficiency 1. In older population, the incidence of drug-induced causes of acute renal dysfunction is reported as high as 66 percent 1. Compared with 30 years ago, today the average patient is older, has more comorbidities, on many medications, and has higher chance of developing diabetes and cardiovascular conditions 1. Many drugs are known to cause acute renal injury by one or more common pathogenic mechanisms and some of them can cause by more than one pattern of injury 1. Drug-induced nephrotoxicity tends to be common in certain patients and in certain clinical situations 1. Although drug-induced acute renal dysfunction is reversible after discontinuation of the offending agent, the condition can be costly and may require hospitalization 1. Therefore, to successfully prevent drug-induced nephrotoxicity, one needs knowledge of pathogenic mechanism of renal injury, pharmacokinetic profile of the medication, clinical manifestation of the offending drug, patient-related risk factors, and strategies for preventing renal injury. This report provides a summary of aminoglycoside-induced nephrotoxicity, and suggests strategies for treatment and prevention.
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Aminoglycoside antibiotics are the most commonly used antibiotics worldwide for the treatment of gram-negative bacterial infections 2. Aminoglycoside induced nephrotoxicity is a well-known area of medical community as nephrotoxicity is one of most important side effects of this class of drug. Aminoglycoside induced nephrotoxicity ranges from mild renal insufficiency to severe renal failure 3. The incidence of nephrotoxicity from aminoglycosides is dose-dependent and appears in 10% to 25% of therapeutic courses, despite rigorous monitoring of serum drug concentration and adequate fluid volume control 2; 3; 4. Despite their undesirable side effects, aminoglycosides are continually being used in clinical practice, as they are effective against germs that are insensitive to other antibiotics 4. The reason is primarily due to their chemical stability, fast bactericidal effect, synergism with betalactamic antibiotics, limited bacterial resistance, post-antibiotic effect and low cost 4.
Pharmacokinetics of aminoglycosides:
Aminoglycosides are polar compounds due to their cationic structure 4. This property of aminoglycosides is responsible for their poor gastrointestinal absorption and rapid renal clearance 4; 5. Also, aminoglycosides are minimally bound to plasma proteins (~10 %) and are accumulated in proximal tubular cells to concentrations that exceed in plasma 5. In addition, aminoglycosides are rapidly eliminated by glomerulus filtration, resulting in few hours of serum half-life as compared to 100 hours in proximal renal tubule 5; 6. Nephrotoxicity related to aminoglycosides is probably due to polycationic charge and time-dependent accumulation of drug within proximal tubular cells 4; 5.
Clinical manifestations of aminoglycoside-induced nephrotoxicity:
Aminoglycoside related nephrotoxicity is primarily presented as nonoliguric renal failure accompanied by an increase in renal tubular proteinuria, brush border enzymuria, serum creatinine, blood urea nitrogen, decreased urine output, and electrolyte alterations (hypercalciuria, hypermagnesuria, hypocalcemia, and hypomagnesemia) 4. Renal failure is usually seen in patients 5 to 10 days after starting aminoglycoside therapy 7. In more than half of the patients, the decline in renal function is seen after the therapy has been completed 8. After discontinuation of aminoglycoside therapy, recovery from nephrotoxicity is seen in 4-6 weeks, especially in elderly patients 8. However, in patients with other underlying renal insufficiency, recovery is incomplete and may progress to chronic interstitial nephritis 8.
The mechanisms of aminoglycoside-induced nephrotoxicity are complex and involve alteration of the plasma, mitochondrial and lysosomal membranes 3. Aminoglycoside induced nephrotoxicity is caused by proximal tubular injury that then leads to cell necrosis 5. Proximal tubular cells are susceptible to the toxic effects of aminoglycosides because they are involved in concentrating and reabsorbing glomerular filtrate that exposes them to high levels of circulating aminoglycosides 1. Aminoglycosides disrupt membrane structure and permeability, which leads to inhibition of lysosomal phospholipases, lysosomal rupture, and cytoplasmic release of lysosomal acid hydrolases 3. Aminoglycosides also causes nephrotoxicity by oxidative stress and forming free radicals 1.
The nephrotoxic potential of aminoglycosides depends upon the binding of amino group present in each aminoglycosidic agent to proximal tubule 7. Gentamycin is the most nephrotoxic aminoglycoside followed by tobramycin, amikacin, netilmicin, and streptomycin in decreasing order 7; 9. Various risk factors predisposing patients to aminoglycoside-induced nephrotoxicity are depicted in Table 1.
The initial therapy for aminoglycoside-induced nephrotoxicity is basically supportive, i.e., discontinuation of the causative agent, maintaining fluid and electrolytes, and controlling sepsis 7. Renal dysfunction is usually reversible after discontinuation of aminoglycoside therapy 1; 4; 7. In some cases, however, hemodialysis may be required 7. Recent research has explored the use of antioxidants in both the experimental animal models and human studies of aminoglycoside-induced nephrotoxicity and suggests their potential use in human 10. Clinical trials are underway that will lead us to improved outcomes through the prophylactic or early therapeutic use of antioxidant therapy 10.
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Prevention strategies include use of extended-interval dosing, administration of aminoglycosidic agent during active period of day (7:30 AM to midnight), limit duration of therapy, monitor serum drug levels and renal function two to three times per week, and maintain trough levels 1 mcg/ml 1; 6. Evidence suggests treating patient with single high-dose aminoglycoside therapy (an infusion of 5-7mg/kg/24 hours for 2-3 weeks or more depending on the site of infection) as it seems to have same effectiveness compare to daily divided dose and is less nephrotoxic 7. This dosing regimen work based on the unique pharmacodynamic property of aminoglycosides: post-antibiotic effect (continuous bactericidal effect after removal of drug) and concentration-dependent killing 6; 7. It is not clear as to why this dosing regimen is less nephrotoxic, but it is believed that it may be due to less accumulation of aminoglycosides in proximal tubular cells 7. Since the reabsorption of aminoglycosides at the proximal tubular cells is saturable and energy dependent, single large dose decreases accumulation of aminoglycosides 7. Thus, single daily dosing is less nephrotoxic compared to daily divided dosing. Critically ill patients are not candidate for aminoglycoside therapy; however, clinicians may need to use it in patients with life-threatening sepsis 4; 7. Recent research suggests that individualized pharmacodynamic monitoring in critically ill patients minimizes the toxicity and the clinical failure of aminoglycoside therapy 11.
Other preventative measures include avoiding co-administration of other nephrotoxic medications and volume depletion 1. Also, it is highly recommended that renal function should be monitored frequently while patient is on aminoglycoside therapy and dose must be adjusted or drug therapy must be stopped if serum creatinine increases 3.
Aminoglycoside-induced nephrotoxicity is an important cause of renal injury, which can be reversible if detected early. Pharmacists are an essential resource in safe medication use and have a huge role to play. Two reports from Institute of medicine showed that pharmacist-physician-patient collaboration is important 1. The clinical and economic impact of pharmacists has been extensively researched and reviewed in the literature 1.
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Table 1: Risk factors for aminoglycoside-induced nephrotoxicity 1; 7.
Long duration of treatment (10 days)
Trough concentrations (2 mcg/ml)
Decreased renal blood flow
Repeated courses of aminoglycoside therapy within few months
Age (60 years)
Intracellular volume depletion
Concomitant liver disease
Underlying renal insufficiency
Electrolyte imbalances (potassium and magnesium depletion)
Concomitant exposure to other nephrotoxic drugs