Q7 Renal St George 2002
What is the mechanism of aminoglycoside renal toxicity?
Acute tubular necrosis (ATN) 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 µmol/L) occurring in 10 to 20 percent of patients. The renal injury induced by these drugs is related to the preferential accumulation in the renal cortex. The aminoglycosides are filtered and then partially taken up by, stored in, and induce damage to the proximal tubular cells. This prolonged storage (as long as 28 days after a single dose) accounts for the observation that renal failure may become clinically apparent as late as several days after the drug has been discontinued.
The more distal nephron segments also can be affected in aminoglycoside nephrotoxicity. The two major manifestations of distal dysfunction are polyuria due to decreased concentrating ability and hypomagnesaemia due to enhanced urinary losses.Magnesium depletion can then lead to secondary hypokalaemia and hypocalcaemia.
The development of renal insufficiency generally requires at least seven days of treatment. In the presence of concurrent renal ischemia (due to volume depletion or hypotension), however, the combined insults can lead to renal failure within one to two days.
Studies in experimental animals suggest that the incidence of acute renal failure is diminished with high-dose, once-daily drug administration, when compared to the more traditional divided dose regimens. This protective effect is associated with diminished aminoglycoside accumulation in the renal cortex, suggesting that drug uptake by the proximal tubule is most efficient at low doses; at higher doses, more of the drug is excreted without undergoing tubular reabsorption and therefore without accumulating in the tubular cells.
Liver disease, particularly advanced cirrhosis (in which renal perfusion is often reduced) and obstructive jaundice with a plasma bilirubin concentration above 5 mg/dL (85 µmol/L), are associated with an increased risk of aminoglycoside nephrotoxicity. How obstructive jaundice increases the sensitivity to aminoglycoside toxicity is not known.
COURSE – Most patients with aminoglycoside-induced ATN are non-oliguric, perhaps reflecting the concurrent impairment in concentrating ability. The diagnosis of this disorder is made from the history of acute renal failure beginning more than 5 days after the onset of aminoglycoside therapy, a urine sediment that is either benign or shows granular and epithelial cell casts, and a fractional excretion of sodium above 1 percent. Initial therapy is supportive, and consists of discontinuing the aminoglycoside and of maintaining fluid and electrolyte balance. The plasma creatinine concentration usually returns to the prior baseline level within 21 days after cessation of therapy. However, resolution of the acute episode may be delayed if the patient remains hypovolaemic, septic, or catabolic; in these settings, tubular regeneration cannot occur.