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In vivo utilization of the renotropic substrate alphaketoglutarate (α-Kg) is associated with a high RQ and augments the glutamate pool. The glutamate pool influences glutaminase-I activity and NH4 production. In vitro studies show that α-Kg may contribute to titratable acid (TA) formation, and to reneal gluconeogenesis (RGP). RGP has been coupled with ammoniagenesis. The present studies in man demonstrate that these several processes may be interelated through metabolism of α-Kg. Trans-renal extractions of α-Kg, glucose, oxygen and PAH with measurementz of inulin and PAH clearances, Na, NH4 + and TA excretions were measured in 6 children with acyanotic congenital heart defects and 4 children with normal renal functions, recovering from glomerulonephritis, during an infusion of Na α-Kg. The urinary pH rose from 5.2 to 6.1. α-Kg infusion increased RGP, fract ional Na reabsorption (RNa), and TA, but decreased NH4 + excretion. Statistically significant correlations were found for renal α-Kg utilization directly with RGP, RNa, QO2 and, inversely, with NH4 + excretion. RGP also was inversely correlated with NH4 + excretion. QO2 was correlated with RNa, but could account for only 60-80% of α-Kg utilized. Increased RNa was associated with increased glucose utilization. These observations indicate that the renal concentration and metabolism of α-Kg might regulate pathways leading to urinary acidification of Na reabosrption, as well as to RGP. The latter may be a metabolic control device for Na reabsorption. (Supported by NIH grant HD 168-03,04.).

The proximal tubular uptake and utilization of aketoglutarate (αKG) has been linked to corticalblood flow, H+ secretion and anaerobic CO2 production. Oxidation of aKG at the substrate level is the first step in energy-dependent gluconeogenesis by renal cortex. Thus, renal αKG dissimilation and renal glucose production (RGP), might reflect locus and extent of altered cell function in the kidney. To explore this, Na αKG was infused, with parental consent, in 10 children with renal disease (9 acute glomerulonephritis [AGN], I nephrotic) and 12 controls under standard loading, inulin and PAH clearance conditions. Renal extractions of PAH (EPAH) and αKG as well as RGP were determined from frequent concurrent samples of renal vein and aortic blood in 3 patients with AGN, the nephrotic, and 6 controls, with ‘normal’ kidneys but congenital heart defects. The studies were repeated in the 3 AGN patients during healing. Renal uptake and utilization of αKG and RGP were calculated for body size and estimated kidney weight. In vitro RGP by human kidney slices obtained at operation from 2 intact and 2 diseased kidneys also was assayed for comparison. In AGN, significantly reduced renal uptake and utilization of the αKG load with persistently high H+ excretion and decreased reabsorption of Na accompanied the low CIN, EPAH and CPAH (CPAH/EPAH). All patterns approximated controls with healing. RGP usually was impaired, especially in the nephrotic child. RGP with αKG in vivo was similar to in vitro values for ‘normal’ human kidney slices with glycerol, fructose, pyruvate, αKG, succinate or malate as substrates. These results imply increased ‘non-cortical’ renal blood flow and impaired proximal tubule metabolism referrable to αKG in the kidney diseases studied. (APS)