Tubular hypermetabolism as a factor in the progression of chronic renal failure

Thus, in summary, we hypothesize that nephron loss by a time-limited insult (eg, an acute immunological insult, surgical removal of five sixths of normal nephrons) may cause events in the tubules of the remaining nephrons that contribute substantially, though not exclusively, to the inexorable progression to ESRD. Specifically, hypermetabolism in the remaining tubules as assessed by oxygen consumption and ATP synthesis rates has been found to occur. This hypermetabolism in residual nephrons appears to be due to the known increased sodium transport per nephron, but nonsodium transport events also appear to be involved. With respect to the latter phenomenon, we propose that an increase in growth factor response per tubule, as a mechanism of renal hypertrophy, activates the DAG----protein kinase C----Na/H antiporter system. We have evidence in support of this sequence of events by the demonstration of a two-fold increase in membrane (particulate) protein kinase C within 24 hours after removal of the contralateral kidney and an increase in intracellular pH as assessed by NMR spectroscopy. Activation of the Na/H antiporter not only leads to proton extrusion and cellular alkalinization, which may activate cellular alkalinization, which may activate cellular enzymes such as phospholipases, but also increases intracellular Na concentration, thereby further increasing Na/K-ATPase, ATP use, and enhancing ATP synthesis. The increase in mitochondrial oxygen consumption, which accompanies the enhanced ATP synthesis, would be expected to be associated with increased oxygen radicle generation. If the tissue scavengers of oxygen radicles are not sufficient to scavenge the increase in oxygen radicles, then lipid peroxidation and tissue damage will occur.(ABSTRACT TRUNCATED AT 250 WORDS)