Bicarbonate generation, renal

This mixed disorder often occurs in patients with chronic obstructive pulmonary disease and chronic respiratory acidosis who are treated with salt restriction, dinretics, and possibly glncocorticoids. When diuretics are initiated, the plasma bicarbonate may increase because of increased renal bicarbonate generation and reabsorption, providing mechanisms for both generating and maintaining metabolic alkalosis. The elevated pH diminishes respiratory drive and may therefore worsen the respiratory acidosis. 

The early compensatory response to acute respiratory acidosis is chemical buffering. If respiratory acidosis is prolonged (more than 12 to 24 hours), renal excretion of H+ increases, which generates new bicarbonate. 

Carbonic anhydrase (CA, also called carbonate dehydratase) is an enzyme found in most human tissues. As well as its renal role in regulating pH homeostasis (described below) CA is required in other tissues to generate bicarbonate needed as a co-substrate for carboxylase enzymes, for example pyruvate carboxylase and acetyl-CoA carboxylase, and some synthase enzymes such as carbamoyl phosphate synthases I and II. At least 12 isoenzymes of CA (CA I—XII) have been identified with molecular masses varying between 29 000 and 58 000 some isoenzymes are found free in the cytosol, others are membrane-bound and two are mitochondrial. 

Carbonic acid represents the respiratory component of the buffer pair because its concentration is directly proportional to the PCO2, which is determined by ventilation. Bicarbonate represents the metabolic component because the kidney may alter its concentration by reabsorption, generating new bicarbonate, or altering elimination. The bicarbonate buffer system easily adapts to changes in acid-base status by alterations in ventilatory elimination of acid (PCO2) and/or renal elimination of base (HCO3). 

Metabolic alkalosis is a simple acid-base disorder that presents as al-kalemia (increased arterial pH) with an increase in plasma bicarbonate. It is an extremely common entity in hospitalized patients with acid-base disturbances. Under normal circumstances, the kidney is readily able to excrete an alkali load. Thus evaluation of patients with metabolic alkalosis must consider two separate issues (1) the initial process that generates the metabolic alkalosis and (2) alterations in renal function that maintain the alkalemic state. °... 

Henle (e.g., furosemide, bumetanide, and torsemide) and distal convoluted tubule (thiazides), have most commonly been associated with the generation of metabolic alkalosis. These agents promote the excretion of sodium and potassium almost exclusively in association with chloride, without a proportionate increase in bicarbonate excretion. Collecting duct hydrogen ion secretion is stimulated directly by the increased luminal flow rate and sodium delivery, and indirectly by intravascular volume contraction, which results in secondary hyperaldosteronism. Renal ammoniagenesis may also be stimulated by concomitant hypokalemia, further augmenting net acid excretion. 

Mineralocorticoid excess also plays a significant role in the maintenance of metabolic alkalosis. In patients with volume-responsive metabolic alkalosis, intravascular volume depletion stimulates aldosterone secretion. As discussed earlier, excess mineralocorticoid activity may also underlie the generation of metabolic alkalosis. In either situation, the increased mineralocorticoid effect stimulates collecting duct H+ secretion. Metabolic alkalosis may also be maintained by persistent hypokalemia. Hypokalemia has a multitude of effects on renal acid-base homeostasis, enhancing proximal tubular bicarbonate reabsorption, stimulating ammoniagenesis and increasing distal tubular H secretion. ... 

Ammonium ions are major contributors to buffering urinary pH, but not blood pH. Ammonia (NH3) is a base that combines with protons to produce ammonium (NH4 ) ions (NH3 + H -> NH4 ), a reaction that occurs with a pK of 9.25. Ammonia is produced from amino acid catabolism or absorbed through the intestine, and kept at very low concentrations in the blood because it is toxic to neural tissues. Cells in the kidney generate NH4 and excrete it into the urine in proportion to the acidity (proton concentration) of the blood. As the renal tubular cells transport H into the urine, they return bicarbonate anions to the blood. 

If tubular reabsorption does not meet physiological requirements, a renal tubular mechanism for generating bicarbonate is called into play this mechanism is shown in outline in Figure 1.4B. Carbon dioxide from metabolism reacts with water to yield hydrogen ions, which are actively pumped into the tubular fluid rendering the urine acid, and bicarbonate ions, which diffuse into the renal interstitial fluid and hence into the general extracellular fluid of the body. The tubules continually add bicarbonate to the body by this mechanism. 

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