Emerging Features of Ammonia Metabolism and Transport in Acid-Base Balance

Abstract

Ammonia metabolism has a critical role in acid-base homeostasis and in other cellular functions. Kidneys have a central role in bicarbonate generation, which occurs through the process of net acid excretion; ammonia metabolism is the quantitatively greatest component of net acid excretion, both under basal conditions and in response to acid-base disturbances. Several recent studies have advanced our understanding substantially of the molecular mechanisms and regulation of ammonia metabolism. First, the previous paradigm that ammonia transport could be explained by passive NH₃ diffusion and NH₄⁺ trapping has been advanced by the recognition that specific transport of NH₃ and of NH₄⁺ by specific membrane proteins is critical to ammonia transport. Second, significant advances have been made in the understanding of the regulation of ammonia metabolism. Novel studies have shown that hyperkalemia directly inhibits ammonia metabolism, thereby leading to the metabolic acidosis present in type IV renal tubular acidosis. Other studies have shown that the proximal tubule protein NBCe1, specifically the A variant NBCe1-A, has a major role in regulating renal ammonia metabolism. Third, there are important sex differences in ammonia metabolism that involve structural and functional differences in the kidney. This review addresses these important aspects of ammonia metabolism and transport.

Keywords: Ammonia; NBCe1; chronic kidney disease; glutamine synthetase; hepatic encephalopathy; lithium.

Figure 1.. Renal vein ammonia concentration is higher than renal artery ammonia concentration, indicating systemic ammonia addition of renal origin.

Graph was constructed using measurements of arterial and renal vein ammonia concentrations in ten patients. Data from ⁽¹⁾. All patients had impaired liver function, which likely contributed to the mildly elevated arterial ammonia.

Figure 2.. Model of renal ammonia transport.

The majority of renal ammonia is generated in the kidney in the proximal tubule. There it is preferentially secreted into the luminal fluid. Ammonia is reabsorbed by the TAL, causing development of a corticomedullary ammonia gradient, and then is secreted by the collecting duct.

Figure 3.. Molecular model of NH₃ and H₂O.

NH₃ and H₂O are uncharged molecules, but because of asymmetric distributions of charged elements they have significant molecular polarity. Top panels show ball and stick models, showing asymmetric distribution of hydrogen nuclei around the central atom. Red arrow shows the molecular dipole moment. Bottom panels show space-filling models pseudocolored to show electrostatic charge distribution. Models are not drawn to scale. Models generated using Avogadro, v1.0.3 and v1.2.0.

Figure 4.. Model of primary NH₃ and NH₄^± transporters and their role in ammonia transport.

Top panel shows the proximal tubule. AQP8 may have a critical role in ammonia exit from mitochondria, and apical NHE3 may have a critical role in the preferential apical ammonia secretion. Middle panel shows the TAL. Apical NKCC2 mediates secondarily active NH₄⁺ uptake via binding and transport of NH₄⁺ at the K⁺ binding site. Cytosolic ammonia exits the cell across the basolateral plasma membrane in part via Na⁺ for NH₄⁺ exchange by NHE4. A “bicarbonate shuttle” pathway involving NBCn1 may also contribute to basolateral ammonia exit. Bottom panel shows a model of collecting duct ammonia transport. Basolateral Rhbg and Rhcg mediate peritubular NH₃ and NH₄⁺ uptake. In the IMCD, basolateral Na⁺ −K⁺ -ATPase also contributes to peritubular NH₄⁺ uptake by binding and transport of NH₄⁺ at the K⁺ binding site. Apical Rhcg enables selective apical NH₃ secretion. NH₃ that is secreted is titrated to NH₄⁺ by tightly coordinated H⁺ secretion via H⁺ -ATPase and H⁺ −K⁺ -ATPase. In the IMCD, basolateral Na⁺ −K⁺ -ATPase also contributes to peritubular NH₄⁺ uptake by binding and transport of NH₄⁺ at the K⁺ binding site.

Figure 5.. Correlation between plasma K⁺ and urine ammonia excretion.

Over a wide range of plasma K⁺ measurements, there was a very strong correlation between plasma K⁺ and urinary ammonia excretion. All measurements were made in animals with normal glomerular filtration and without altering adrenal hormone synthesis or action. Reprinted with permission from J Am Soc Nephrol 29:1141–425, 2018.

Figure 6.. NBCe1-A deletion alters the correlation between serum bicarbonate and urine ammonia excretion under basal conditions and after acid loading.

NBCe1-A deletion results in a substantial decrease in basal serum bicarbonate without a change in basal ammonia excretion, it causes a greater decrease in plasma bicarbonate after acid loading, and it decreases the change in ammonia excretion in response to acid loading. These conclusions were similar whether assessing total ammonia excretion (Panel A) or using body weight–adjusted ammonia excretion (Panel B). Reprinted with permission from J Am Soc Nephrol 29:1182–1197, 2018.