Chapter 57 - Renal Ammonium Ion Production and Excretion

Abstract

The maintenance of systemic acid-base balance within relatively narrow limits is essential for life. However, the development of metabolic acidosis, which is characterized by a significant decrease in plasma pH and bicarbonate ions, is a common clinical condition. Metabolic acidosis is caused by the overproduction of acid due to a high protein diet, increased catabolism of endogenous proteins during prolonged fasting, sepsis or cachexia, and various alterations in metabolism such as diabetic ketoacidosis, lactic acidosis, or genetically determined acidurias. It also results from loss of base due to excessive diarrhea or renal defects in bicarbonate reabsorption. The onset of metabolic acidosis triggers an essential adaptive response in the kidney that is characterized by a pronounced increase in catabolism of plasma glutamine and an increased synthesis of bicarbonate and ammonium ions that occur predominantly within the proximal convoluted tubule. These adaptations are sustained, in part, by increased expression of the genes that encode a basolateral glutamine transporter, the mitochondrial glutaminase and glutamate dehydrogenase, and the cytoplasmic phospho enol pyruvatecarboxykinase and by activation of the mitochondrial glutamine transporter, the apical Na + /H + exchanger, and the basolateral Na + -3HCO 3 – co-transporter. The resulting increases in the corresponding activities facilitate the basolateral uptake of glutamine, an increased reabsorption of bicarbonate ions, the increased synthesis of ammonium and bicarbonate ions, and their vectoral transport across the apical and basolateral membranes, respectively. Nearly 80% of the generated ammonium ions are subsequently reabsorbed within the medullary thick ascending limb to produce a high interstitial concentration of ammonium ions within the renal medulla. This gradient provides the driving force for the final transport of ammonium ions into the urine that occurs via specific ammonia channels located within the basolateral and apical membranes of the collecting ducts. All of these steps are finely regulated to ensure that the levels of renal ammonium ion production and excretion are appropriate to sustain normal acid–base balance.