Question

Question 1: Why do you think that the adding of sodium acetoacetate resulted in a 50% decrease in renal ammonia production?

Question 2: Explain how ketone bodies depress renal ammoniogenesis by preventing the transformation of glutamine and glutamate into α-ketoglutarate in the mitochondria of the renal tubular cell.

Excerpt:

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-β-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 β-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 β-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 α-ketoglutarate in the mitochondria of the renal tubular cell.

Answer 1

1. Sodium acetoacetate act as ketone bodies. Ketone bodies are predominantly fromed by the metabolism of glutamine. Ketone bodies serve as a substrate replacing glucose for the brain during prolonged starvation. It also act as a signal to muscle, resulting in diminution of alanine and glutamine production. Since less glutamine and alanine are produced in the presence of sodium acetoacetate (ketone bodies), the level of glutamine decereases and thus the substrate (glutamine) for ammonia production is no longer available and thats why renal ammonia production is decreased.

2. Glutamine and glutamete are converted into alpha ketoglutarate and ammonia during its metabolism. In the presence of ketone bodies the level of glutamine is decreased and consequently its metabollic product alpha ketoglutarate and ammonia production is also decreased. Decreased level of glutamine and alanine causes a reduction in gluconeogenesis from protein which favours sparing of nitrogen during prolonged starvation.