Aminoglycoside-induced functional and biochemical defects in the renal cortex.

The first site of aminoglycoside-cell interaction occurs at the plasma membrane of renal proximal tubular cells which have been shown to selectively transport and accumulate these drugs. Depression of apical membrane transport of organic base, low-molecular-weight protein, and glucose, together with loss of brush border membrane enzymes and phospholipids in the urine which results in altered phospholipid composition of this membrane, occurs early in the course of aminoglycoside administration. Less well appreciated are the alterations which occur at the basolateral membrane. These include decreased transport of organic bases, Ca2+, Na2+, and K+; increased organic acid transport; decreased activity of Na+-K+ ATPase and adenylate cyclase; decreased calcium content; and altered phospholipid composition. Many of these changes are evident within 90 min of a single injection of drug. Lysosomal dysfunction is manifested by the accumulation of phospholipids in the form of myeloid bodies consequent to the inhibition of lysosomal phospholipases by aminoglycosides. Labilization of lysosomes in vivo has been postulated to be a mechanism of cell injury. Mitochondrial dysfunction attributed to aminoglycosides includes impaired respiration, inhibition of Mg2+ binding, inhibition of Ca2+ uptake, increased permeability to monovalent cations, decreased ammoniagenesis, and decreased gluconeogenesis. However, it remains unclear how the drug gains access to mitochondria in vivo in order to initiate the functional derangements. It is evident that aminoglycosides cause multiple metabolic derangements at multiple sites within renal proximal tubular cells. At present the available evidence does not identify which, if any, of these drug effects is responsible for initiating the injury cascade. The strong possibility exists that aminoglycoside nephrotoxicity reflects the net impact of multiple minor metabolic derangements which individually are of little significance but when added together seriously compromise the cell's ability to maintain its structural and functional integrity.