Alpha ketoglutarate, ornithine and growth hormone displace glutamine dependent ammoniagenesis and enhance renal base generation and function

Abstract

Renal base generation requires accelerated interorgan glutamine fluxes during chronic acidosis (1). Decreased ureagenesis and muscle erosion are reflections of nitrogen mobilized and addressed as glutamine for renal extraction and ammoniagenesis. Since glutamine is shared with other homeostatic systems, renal base demands may jeopardize patient recovery. Therefore attempts to substitute other potential base generating fuels have been undertaken. Alpha ketoglutarate decreases renal glutamine uptake and ammoniagenesis (2, 3). Omithine may also be base generating, as well as ammoniagenic (4) especially during acute acidosis when proton gradients are at their zenith. More interesting, both alpha ketoglutarate and omithine reduce protein turnover in catabolic (acidotic) conditions (5.6). However, despite the documented alpha ketoglutarate sparing glutamine action, the positive effect of alpha ketoglutarate on base generation remains to be seen. Theoretically. 1 mole of = KG’ should, upon oxidation or conversion to glucose, yield 2 moles of HCO-, regardless as to whether glutamine, omithine or alpha ketoglutarate was the nutrient delivered. It was to test this hypothesis as well as the cellular mechanisms underlying these effects that the following studies were performed. In addition, since growth hormone spares glutamine nitrogen (7). its effect on base generation was also included. Experiments were performed on kidneys isolated from chronically acidotic rats (fed 110 mM HCl in a liquid elemental diet for 4 days; acid intake 2896 f 91 prnol/day/lOO g BW, arterial plasma HCO-, 15.6 + 1.6 mM, and NH,’ excretion 2256 f 361 pmol/day/ 100 g BW). The isolated kidney (7) was perfused with a recycling artificial plasma solution containing albumin (5 g%), glucose (5 mM) and HCO-, (19 mM). Changes in perfusate HCO-, content were compared to accurately measured urinary loss: base production was obtained from the incremental rise in perfusate bicarbonate after subtracting excreted HCO-,. Ammonia dependent HCO-, production was assessed from the rate of ammonium production (urine plus perfusate accumulation). The kidneys were perfused for 45 min (equilibration) and then. infusions of gln (500 nmol/min).