The Kidneys Generate New Bicarbonate and Excrete Ammonium Ion

Renal generation and excretion of ammonium ion (NH₄⁺) is a major component in the maintenance of acid-base balance; renal NH₄⁺ excretion is illustrated in Figure 44-2.

FIGURE 44-1 Schematic illustration of buffer mechanisms at work in tubule fluid. In the proximal tubule, buffering by filtered bicarbonate (HCO₃ ) predominates because of the relatively high concentration of HCO₃. In the cortical collecting duct, buffering by filtered, nonbicarbonate buffers, such as HPO₄², predominates.

FIGURE 44-2 Schematic illustration of the roles of various nephron segments in ammonium excretion. In the proximal tubule, glutamine is Catabolized to generate ammonium ion (NH₄*) and bicarbonate (HCO₃ ). NH₄* is secreted into the lumen by substitution for H* on the Na*∕H* exchanger in the apical plasma membrane. Ammonium ion recycles in the loop of Henle by reabsorption by the thick ascending limb, in which NH₄* is reabsorbed by substitution for K* on the Na*∕K*,2CΓ co-transporter in the apical plasma membrane, which is followed by some form of facilitated transport across the basolateral plasma membrane.The elevation of the interstitial NH₄* concentration results in movement into the descending thin limbs of Henle's loop and subsequent return to the thick ascending limb.This medullary recycling results in a high concentration of ammonia (NH₃) and NH₄* in the medullary interstitium and prevents its return to the cortex, where it would be reabsorbed into the blood.

intracellular NH₄⁺ enters the tubule fluid through secondary active transport by substitution for H' on the Na⁺∕H⁺ exchanger. Glutamine metabolism also produces new bicar­bonate anions. Thus the net result of the renal generation and excretion of NH₄* is acid excretion and bicarbonate produc­tion. Renal ammoniagenesis is enhanced by acidosis and is an important renal response to an increase in the acid load.

In the thick ascending limb of Henle’s loop, luminal NH₄⁺ is reabsorbed by substitution for K^, on the Na⁺>K^,>2CΓ co­transporter. The NH₄⁺ reabsorption in this segment reduces the amount of ammonia species delivered to the late distal tubule and increases ammonia (NH₅) in the medullary inter­stitium.

High NH₅∕NH₄⁺ concentrations are enhanced and main­tained in the medullary interstitium by a countercurrent multi­plication system in the loops of Henle, similar to that described in Chapter 43. This creates a steep concentration gradient for NH₅, which favors its movement into the medullary collecting duct. The established paradigm is that ammonia diffuses across plasma membranes and into the luminal fluid, where it acts as a buffer and combines with H' to form NH₄⁴. Because NH₄ ^f is lipid insoluble, it cannot diffuse back across the apical plasma membrane and is trapped within the tubule fluid.

The formation of NH₄' from intraluminal NH₅ and H⁺ lowers the concentration of both NH₅ and H⁺ in the tubule fluid. This contributes to the maintenance of a favorable gra­dient for the diffusion of NH₃ into the tubule fluid and reduces the electrochemical gradient for H^, that is created by active proton secretion in the collecting duct.

Until recently, NH₅ diffusion and trapping in the collecting duct was believed to be the only significant mechanism of NH₄* excretion. However, several studies have demonstrated transporter-mediated NH√ secretion in the collecting duct. Recently, members of the Rh glycoprotein family, which trans­port ammonium in other systems, have been found in the mam­malian collecting duct. Although it remains to be proven that these transporters mediate ammonium secretion in the native collecting duct, in vitro studies suggest such a role for them.

Finally, the comparative aspects of ammonia excretion are intriguing. It is known that ammoniagenesis and ammonia excretion is an important mechanism controlling acid-base homeostasis in mice, rats, dogs, chickens, and humans. In these species, ammonia excretion accounts for up to 60% of net acid excretion in basal conditions and can increase to 90% of net acid excretion in models of metabolic acidosis. How­ever, the findings in these animals cannot be applied generally to other species. Rabbits have low urinary ammonia excretion rates and do not increase ammonia excretion during meta­bolic acidosis. Some might not consider this surprising because rabbits normally excrete neutral or alkaline urine and might not be expected to have a full complement of mechanisms to excrete acid urine. However, domestic cats, which usually excrete acid urine, also do not increase renal ammonium excretion in response to a model of metabolic acidosis.

the filtered HCO₅, it cannot maintain a large pH gradient across the apical plasma membrane. The net secretion of H⁺ in this segment is particularly dependent on the intraluminal buffers discussed earlier, which combine with secreted H⁴ and prevent the concentration of H^, in the tubule fluid from rising significantly. As a result, although the majority of renal acid secretion (HCO₃ reabsorption) occurs in the proximal tubule, the pH of the tubule fluid when it leaves this segment is similar to that of the glomerular filtrate.