Renal acid/base excretion complements pulmonary CO2 elimination to regulate body acid-base balance. Normally, there is a net acid production by the body, and urine pH is slightly acidic to keep the body in pH balance. Acids excreted in the urine include H+, ammonium, phosphate, and sulfate. When the urine pH becomes alkaline, the urinary base is predominantly HCO3–. The total urinary acid excretion has to account for all these compounds, and it is calculated as
Total urinary acid excretion = [(phosphate + sulfate) + ammonium] – bicarbonate
Plasma HCO3– levels are normally 24 mEq/L, and plasma H+ levels are 0.0006 mEq/L. This means that glomerular filtrate contains over 10,000 times as much HCO3– as H+. To produce acidic urine, the first step has to be bicarbonate reabsorption.
The primary pH function of the proximal tubule is HCO3– reabsorption, a process facilitated by the presence of the enzyme carbonic anhydrase in both the lumen and the cell. Carbonic anhydrase catalyzes the reaction H+ + HCO3– ^ CO2. An apical Na+/H+ antiport secretes H+ into the tubule lumen, where H+ combines with HCO3– to form CO2. CO2 diffuses across the apical membrane into the proximal tubule cell, where it dissociates back to H+ and HCO3–. The H+ is again pumped across the luminal membrane, and the HCO3– pumped on basolateral surface by Na+/3HCO3– symport, and is returned to the body in the renal venous blood. The H+ secretion decreases the luminal fluid pH to 7.2, acidotic relative to plasma.
The proximal tubule also produces ammonia (NH4+). In this inducible reaction, glutamine is metabolized within the cell to form NH3. NH3 is uncharged, so it diffuses into tubular lumen. Within the lumen, secreted H+ binds to NH3 to form NH4+. The charged NH4+ does not freely diffuse, and remains in lumen (ammonia trapping). This process is important because the H+ bound to NH3 does not alter the pH of the luminal fluid. The activity of the enzymes regulating glutamine metabolism into ammonia is increased in chronic acidosis. Consequently, ammonia excretion is an important mechanism allowing excess acid secretion in chronic acidosis.
HCO3– becomes concentrated in the descending limb of the loop of Henle as water is reabsorbed. In the thick ascending limb, NH4+ can substitute for K+ in the Na+/K+/2 Cl– transporter.
The distal nephron pH is regulated primarily by the intercalated cells. These cells have the same transporters as seen on proximal tubule cells. There are two populations of intercalated cells, specialized for either HCO3– or H+ secretion, determined by which transport proteins are on the cell apical surface. The pH of the plasma determines which population of cells will be activated.
In acidosis, increased entry of CO2 from the basolateral side of the cell can cause net Na+/HCO3– reabsorption from the filtrate and an increase in acidity of the urine. Na+/H+ exchange is enhanced, and the H+ secreted into the lumen is trapped in the lumen by ammonia or phosphate buffers. Na+/HCO3– is cotransported on the basolateral surface. Conversely, in alkalosis, decreased entry of CO2 from the basolateral surface can promote net HCl reabsorption. This response involves primarily a decrease in the luminal Na+/H+ exchange and an increase in the luminal HCO3–/Cl– exchange.