Recent Advances in Understanding Renal Ammonia Metabolism and Transport

I. David Weiner; Jill W. Verlander


Curr Opin Nephrol Hypertens. 2016;25(5):436-443. 

In This Article

Abstract and Introduction


Purpose of review The purpose of this review is to provide a succinct description of the recent findings that advance our understanding of the fundamental renal process of ammonia metabolism and transport in conditions relevant to the clinician.

Recent findings Recent studies advance our understanding of renal ammonia metabolism. Mechanisms through which chronic kidney disease and altered dietary protein intake alter ammonia excretion have been identified. Lithium, although it can acutely cause distal renal tubular acidosis, was shown with long-term use to increase urinary ammonia excretion, and this appeared to be mediated, at least in part, by increased Rhcg expression. Gene deletion studies showed that the ammonia recycling enzyme, glutamine synthetase, has a critical role in normal-stimulated and acidosis-stimulated ammonia metabolism and that the proximal tubule basolateral bicarbonate transporter, NBCe1, is necessary for normal ammonia metabolism. Finally, our understanding of the molecular ammonia species, NH3 versus NH4 +, transported by Rh glycoproteins continues to be advanced.

Summary Fundamental studies have been recently published that advance our understanding of the regulation of ammonia metabolism in clinically important circumstances, and our understanding of the mechanisms and regulation of proximal tubule ammonia generation, and the mechanisms through which Rh glycoproteins contribute to ammonia secretion.


Normal acid–base balance is critical for normal health, and failure to achieve this leads to a wide variety of clinical disorders, including growth retardation, nausea and vomiting, electrolyte disturbances, cardiac arrhythmias, impaired cardiovascular catecholamine sensitivity, osteoporosis and osteomalacia, nephrolithiasis, skeletal muscle atrophy, and accelerated progression of chronic kidney disease (CKD).[1,2] Recent studies also show an important correlation between abnormal acid–base homeostasis and increased mortality.[3]

The kidneys contribute to acid–base homeostasis by net acid excretion, which is achieved by ammonia (ammonia exists in two molecular forms, NH3 and NH4+, that are in equilibrium with each other. We use the term 'ammonia' to refer to the combination of these two molecular forms. When referring to a specific molecular form, we state specifically either 'NH3' or 'NH4+') and titratable acid excretion, and is decreased by bicarbonate excretion. Ammonia excretion is the greatest component of basal net acid excretion and changes in ammonia excretion are the predominant component of changes in net acid excretion in response to acid–base disturbances.[1,4]