Differential susceptibility to gentamicin toxicity within the proximal convoluted tubule

The proximal convoluted tubule (PCT) is the major target for injury in gentamicin nephrotoxicity but the necrosis is often patchy and focal. The PCT is structurally, functionally, and metabolically heterogeneous, and the possibility of differential vulnerability to gentamicin-induced necrosis based on this heterogeneity has not been examined. A quantitative analysis comparing the extent of necrosis in the initial portion of the PCT (S1) to that in the more distal PCT (S2) and comparing necrosis in the PCT of superficial nephrons to that in juxtamedullary nephrons was done in rats after eight daily intraperitoneal doses of 100 mg gentamicin/kg rat weight. The results indicate that the PCT of superficial nephrons are more susceptible to necrosis than the PCT of juxtamedullary nephrons and that the initial S1 segment even in the superficial nephrons is remarkably resistant to injury. These findings suggest that some aspects of the functional or metabolic heterogeneity within the PCT may be related to either differential rates of uptake of the drug or to differences in intrinsic susceptibility to its toxic effects.