Potassium balance influences secretion of H+ by the proximal tubule. Hypokalemia stimulates and hyperkalemia inhibits H+ secretion. It is thought that K+-induced changes in intracellular pH are responsible at least in part for this effect, with hypokalemia acidifying and hyperkalemia alkalinizing the cells. Hypokalemia also stimulates H+ secretion by the collecting duct. This occurs as a result of increased expression of the H+,K+-ATPase in intercalated cells.
Formation of New HCO3 −
As discussed previously, reabsorption of the filtered load of HCO3 − is important for maximizing RNAE. However, HCO3 − reabsorption alone does not replenish the HCO3 − lost during neutralization of the nonvolatile acids produced during metabolism. To maintain acid-base balance, the kidneys must replace this lost HCO3 − with new HCO3 − . Generation of new HCO3 − occurs by excretion of titratable acid and by synthesis and excretion of NH4 + .
Production of new HCO3 − as a result of titratable acid excretion is depicted in
Fig. 37.6 . Because of HCO3 − reabsorption by the proximal tubule and loop of Henle, fluid reaching the distal tubule and collecting duct normally contains little HCO3 − . Thus when H+ is secreted it will combine with non-HCO3 − buffers (primarily Pi) and be excreted as titratable acid. Because the H+ was produced inside the cell from hydration of CO2, a HCO3 − is also produced. This HCO3 − is returned to the ECF as new HCO3 − . As noted, Pi excretion increases with acidosis. However, even with increased Pi available for titratable acid formation, this response is insufficient to generate the required amount of new HCO3 − . The remainder of new HCO3 − generation occurs as a result of NH4 + generation and excretion.
NH4 + is produced by the kidneys, and its synthesis and subsequent excretion adds HCO3 − to ECF. Importantly, this process is regulated in response to the acid-base requirements of the body.
NH4 + is produced in the kidneys via metabolism of glutamine. Essentially the kidneys metabolize glutamine, excrete NH4 + , and add HCO3 − to the body. However, formation of new HCO3 − via this process depends on the kidneys’ ability to excrete NH4 + in urine. If NH4 + is not excreted in urine but instead enters the systemic circulation, it is converted into urea by the liver. This conversion process generates H+ , which is then buffered by HCO3 − . Thus production of urea from renal-generated NH4 + consumes HCO3 − and negates formation of HCO3 − through synthesis and excretion of NH4 + by the kidneys. However, normally the kidneys excrete NH4 + in urine and thereby produce new HCO3 − .
The process by which the kidneys excrete NH4 + is complex.
Fig. 37.7 illustrates the essential features of this process. NH4 + is produced from glutamine in the cells of the proximal tubule, a process termed ammoniagenesis. Each glutamine molecule produces two molecules of NH4 + and the divalent anion 2-oxoglutarate2− . Metabolism of this anion ultimately provides two molecules of HCO3 − . HCO3 − exits the cell across the basolateral membrane and enters the peritubular blood as new HCO3 − . NH4 + exits the cell across the apical membrane and enters the tubular fluid. The primary mechanism for NH4 + secretion into the tubular fluid involves the Na+/H+ antiporter, with NH4 + substituting for H+ . In addition, some NH3 can diffuse out of the cell into the tubular fluid, where it is protonated to NH4 + .