The effect of ketone bodies on renal ammoniogenesis

Abstract

A B S T R A C T Infusion of ketone bodies to ammonium chloride-loaded acidotic dogs was found to induce significant reduction in urinary excretion of ammonia. This effect could not be attributed to urinary pH variations. Total ammonia production by the left kidney was measured in 25 animals infused during 90 min with the sodium salt of D,L-f-hydroxybutyric acid adjusted to pH 6.0 or 4.2. Ketonemia averaged 4.5 mM/ liter. In all experiments the ammonia content of both urine and renal venous blood fell markedly so that ammoniogenesis was depressed by 60% or more within 60 min after the onset of infusion. Administration of equimolar quantities of sodium -acetoacetate adjusted to pH 6.0 resulted in a 50% decrease in renal ammonia production. Infusion of ketone bodies adjusted to pH 6.0 is usually accompanied by a small increase in extracellular bicarbonate (3.7 mM/liter). However infusion of D,L-sodium lactate or sodium bicarbonate in amounts sufficient to induce a similar rise in plasma bicarbonate resulted in only a slight decrement in ammonia production (15%). The continuous infusion of 5% mannitol alone during 90-150 min failed to influence renal ammoniogenesis. Infusion of pure sodium-free P-hydroxybutyric acid prepared by ion exchange (pH 2.2) resulted in a 50% decrease in renal ammoniogenesis in spite of the fact that both urinary pH and plasma bicarbonate fell significantly. During all experiments where ketones were infused, the renal extraction of glutamine became negligible as the renal glutamine arteriovenous difference was abolished. Renal hemodynamics did not vary significantly. Infusion of P-hydroxybutyrate into the left renal artery resulted in a rapid decrease in ammoniogenesis by the perfused kidney. The present study indicates that ketone bodies exert their inhibitory influence within the renal tubular cell. Since their effect is independent of urinary or systemic acid-base changes, it is suggested that they depress renal ammoniogenesis by preventing the transformation of glutamine and glutamate into a-ketoglutarate in the mitochondria of the renal tubular cell. INTRODUCTIONIt is well-known that diabetic subjects suffering from ketoacidosis excrete large amounts of ammonia in their urine (1). The major stimulus for increased renal production and excretion of ammonia is believed to be the severe metabolic acidosis caused by progressive accumulation of ketones in the body fluids (2). A similar mechanism is thought to be operative during prolonged fasting in obese human subjects (3). It is not known however, whether ketone bodies influence renal ammoniogenesis solely by their acidifying effect or by some other mechanism. During studies designed to investigate the effect of ketone bodies on uric excretion in the dog, a significant decrease in urinary ammonia excretion was persistently noted during ketone infusion. This paradoxical observation prompted the undertaking of the present study. The data reveal that ketone bodies markedly depress renal ammoniogenesis in the dog. This effect does not appear to...

Effect of ketone bodies on glucose production and utilization in the miniature pig.

“…On the other hand alkali-treatment reduces urinary N-excretion in prolonged fasted subjects (50,51). Contrary to our data, it was reported that the infusion of sodium free ,B-OHB provoked a 50% decrease in renal ammoniogenesis in dogs (52). Yet, it should be mentioned that the ketosis here (4.5 mM) differed from our experimental conditions (0.5-1 mM) and that NH' only contributes up to -10% of total N-excretion (compare with Fig.…”

Differential Effects of Sodium Acetoacetate and Acetoacetic Acid Infusions on Alanine and Glutamine Metabolism in Man

“…Indeed, it has been shown in dogs that ketone bodies inhibit the uptake of GLN by the kidney (23), an important site of removal of this amino acid (24). However, since this effect has been observed with the sodium salt as well as with the acid form of ketone bodies (23), it cannot account for our observation that Na AcAc and AcAc acid have opposite effects on GLN concentration.…”

Renal Hemodynamics and Ammoniagenesis

“…Total renal blood flow was calculated using the corresponding hematocrit value. All analytical methods used in this study has been previously reported (7). The partial pressure of ammonia (,NH3) in arterial and renal venous blood was calculated from total ammonia concentration and pH by the method of Denis, Preuss, and Pitts (8) using the equation of Jacquez, Poppell, and Jeltsch (9).…”