Recent advances in understanding renal ammonia metabolism and transport

Abstract

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.

Figure 1. Correlation of metabolic acidosis with severity of chronic kidney disease

progressive decreases in renal function correlate with an increased risk of metabolic acidosis. Data from [5].

Figure 2. Effect of lithium therapy on urinary ammonia excretion in response to an acute acid load in humans

Top panel shows urinary ammonia excretion, expressed as mmol per mmol creatinine, at baseline, and following an acute acid load. Baseline urinary ammonia excretion was significantly higher in lithium-treated subjects than in control subjects. An acute acid load, induced by oral ammonium chloride loading, resulted in significant increases in urinary ammonia excretion in both groups at each time point. However, at each time point, urinary ammonia excretion was significantly greater in lithium-treated subjects than in control subjects. Bottom panel shows changes in urinary ammonia excretion relative to adjusted for baseline urinary ammonia excretion rates. An acute acid load resulted in significant increases in ammonia excretion relative to baseline excretion in both groups. *P < 0.05 versus baseline; #P < 0.05 versus control at same time point. Figure from [17], and used with permission.

Figure 3. Effect of proximal tubule specific glutamine synthetase deletion on urinary ammonia excretion

Left panel shows that proximal tubule-specific glutamine synthetase deletion increased basal urinary ammonia excretion significantly. Right panel shows that increased ammonia excretion occurred despite no change in urinary pH. Figure from [25] and reprinted with permission.

Figure 4. Effect of NBCe1 deletion on urinary ammonia and pH

Top: effects on urine ammonia. Despite the metabolic acidosis associated with NBCe1 gene deletion, ammonia excretion decreased with heterozygous gene deletion and was suppressed significantly further with homozygous deletion. Bottom: effects on urine pH. Urine pH was significantly more acidic (lower) in mice with heterozygous NBCe1 deletion than in wild-type mice and was decreased significantly further by homozygous NBCe1 deletion. Figure originally published in [28] and reprinted with permission.

Figure 5. Effect of NBCe1 deletion on NaDC1 expression

NaDC1 is an apical Na⁺-coupled citrate transporter present in the proximal tubule that is thought to the primary mechanism regulating urinary citrate excretion. NBCe1 deletion decreased NaDC1 mRNA (left panels) and immunolabel expression (right panels). This effect was unrelated to the associated metabolic acidosis, as experimental metabolic acidosis in the absence of NBCe1 gene deletion increased NaDC1 mRNA and immunolabel expression. Figures 2 (left panel) and 3 (right panel) from [29] were combined and are used with permission.

Figure 6. Model of collecting duct ammonia secretion

Ammonia uptake across the basolateral plasma membrane primarily involves transporter-mediated uptake by either Rhbg or Rhcg, with a component of diffusive NH₃ absorption. Cytosolic NH₃ is transported across the apical plasma membrane by a combination of Rhcg and diffusive transport. Not shown is that in the IMCD, but not the CCD, basolateral Na⁺-K⁺-ATPase also contributes to basolateral plasma membrane NH₄⁺ uptake. Cytosolic H⁺ is generated by a carbonic anhydrase-II mediated mechanism, and is secreted across the apical plasma membrane via H⁺-ATPase and H⁺-K⁺-ATPase. Luminal H⁺ titrates luminal NH₃, forming NH₄⁺ and maintaining a low luminal NH₃ concentration necessary for NH₃ secretion. Figure from [35] with permission.