1) Metabolism produces acids. Our metabolism oxidizes reduced carbon (sugars, fats) to produce energy. Oxidized carbon compounds are acidic: they are either carboxylic acids or CO2, whose reaction in water is:
2) The principal acid produced by metabolism is CO2 which is produced at a rate of over 9 mmol/min. or 14 mol/day. The calculus is as follows: a healthy adult subject with a basal metabolism of 2,000 kcal day uses 2,000/117 = 17 mol O2/day (117 kcal/mol being the energy equivalent of O2). Assuming a respiratory quotient of 0.8 this corresponds to 17x0.8 = 13.7 mol CO2/day.
3) Transport of CO2 from the tissues to the lungs; role of blood buffers. Given that the pulmonary and systemic blood flow is 5 L/min., the gas exchange is approx. 2.2 mmol/L for O2 and 1.8 mmol/L for CO2. These quantities largely exceed the solubility of the two gases. Evolution has devised clever solutions to these problems.
- Only 2% of blood O2 is freely dissolved; the remaining 98% is reversibly bound to hemoglobin a protein that is highly soluble and reaches high concentrations in the blood (14 g/dL or 2.2 mM per tetrameric molecule).
- The blood contains buffers whose cumulative buffer capacity largely exceeds that of CO2. As a consequence, its pH is almost constant at 7.4 and forces the concersion of CO2 to bicarbonate (see eq. 1, above); bicarbonate is water soluble; total CO2 is partitioned as follows: 5% CO2; 90% bicarbonate; 5% protein-bound carbamates.
4) Sdp is constant. Eq. 1 makes clear that the sum of X and HCO3- is constant because either can only be produced at the expense of the other. We call this sum the sum of deproptonated buffer components, Sdp.
5) Other metabolic acids and bases; ammonia and H2SO4. The diet may contain acids and bases in addition to the nutrients that can be converted to CO2; notably the metabolism of aminacids produces ammonia and that of Cys also produces H2SO4. The ammonia derived from aminoacids assumes the form of ammonium ion and is accomapnied by bicarbonate; moreover it is almost entirely converted to the non-basic urea or used in the biosynthesis of glutamine.
If we take alanine as an example, and write down its overall metabolic fate (neglecting energy cofactors such as ATP and NADH), we obtain the following:
The reaction described by eq. 2 produces the conjugated acid of ammonia and the conjugated base of CO2, thus there is no net production of acids or bases. Ammonium ion can follow two pathways:
- it can be converted to urea, a compound that does neither behave as an acid nor as a base; this reaction consumes an equivalent amount of bicarbonate:
If we compare the metabolism of Cys to that of Ala, we obtain a very different picture:
6) Renal reabsorption of bicarbonate. Under physiological conditions the glomerular filtrate contains approximately 3.5 mol/day of bicarbonate, which is nearly completely reabsorbed; indeed the amount of bicarbonate in the urine, when urinary pH is lower than 6.6, is negligible. However under conditions of alkalosis and production of basic urine, some bicarbonate excretion does occur.
The principal ion exchangers involved in reabsorption of bicarbonate are SLC26A7 and AE1, a chloride/bicarbonate exchanger located in the basolateral membrane of alpha-intercalated cells. The principal exchanger involved in secretion of bicarbonate in the urine is pendrin (SLC26A4), a chloride/bicarbonate exchanger located in the apical membrane of beta-intercalated cells
7) Renal excretion of acids; ammoniagenesis.
The kidney excretes acids and the urine pH ranges between 4.5 and 7 or slightly higher. The principal acid excreted in the urine is the ammoniium ion produced by ammoniagenesis. This metabolic process uses glutamine as the donor of ammonia and is carried out by two consecutive deaminations carried our by blutaminase and glutamate dehydrogenase:
8) Acute respiratory acidosis.
9) Chronic respiratory acidosis.
10) Respiratory alkaloses.
11) Non-renal metabolic acidoses.
12) Renal metabolic acidoses.
13) Metabolic alkaloses.
14) The misleading concept of hyperchloremic acidosis. In many cases metabolic acidoses may be associated to an increase of serum chloride concentration. Since according to the now obsolete Van Slyke definition the chloride anion was considered a fixed acid, it seemed logical at the time to consider hyperchloremia and acidosis a nosological entity. However the relationship between hyperchloremia and acidosis is an indirect one, whose mechanism deserves description but does not form a nosological entity. Before discussing this point, it seems pretinent to recall that chronic respiratory acidosis is usually hypochloremic, a fact that contributes to illustrate the obsolescence of Van Slyke's definition of acids. Metabolic acidoses cause a decrease of bicarbonate concentration, because of two reasons: (i) the acidic pH causes the ratio [HCO3-]/[CO2] to decrease; and (ii) compensatory hyperventilation causes [CO2] to decrease, further decreasing [HCO3-]. A typical example is as follows: pH=7.2; PCO2=26 mmHg; [HCO3-]=10 mM; [HCO3-]/[CO2]=12.8. Since the concentration of serum cations is unaltered, and the serum has zero net electrical charge, the loss of bicarbonate must be compensated by and increase of either or both chloride and anion gap. Thus hyperchloremia is only indirectly related to metabolic acidosis. The mechanism of serum chloride increase in normal anion gap metabolic acidoses (NAGMA) is mainly linked to reduced chloride loss in the urine, because there is less bicarbonate to reabsorb in the glomerular filtrate; thus less chloride is excreted in the urine in the exchange for bicarbonate, and more is reabsorbed as a counterion of reabsorbed urinary cations. Under conditions of severe metabolic acidosis the kidney ammoniagenesis increases, and elimination of ammonium cations is coupled to elimination of chloride; but chloride lost because of this reason is much less than the chloride spared because of the reduced reabsorption of bicarbonate. Indeed maximal urinary excretion of ammonium in metabolic acidosis is 200 mmol/day; minimal reabsorption of bicarbonate under the same condition is in the order of 1,000 mmol/day. To summarize: hyperchloremia and acidosis may or may not occur in combination; but hyperchloremia is not a cause of acidosis, if anything it is its indirect consequence.