The pathophysiological mechanisms of acidoses and alkaloses - Acid-base disturbances may be of respiratory or metabolic/renal origin. - The affected organ causes the disturbance, while the other, if healthy, tries to correct (compensate) the disturbance. - Respiratory conditions may occur suddenly, while the kidney takes time to compensate; thus for respiratory diseases it is important to distinguish the acute (uncompensated) and chronic (compensated) phases; metabolic conditions are always compensated (chronic) because the respiratory adaptation is rapid. - Metabolic conditions are strongly heterogenous, and may be due to many different causes. 1. RESPIRATORY ACIDOSIS 1a. Acute phase (hours) -- A disease causes a sudden impairment of gas exchanges (e.g.: interstitial pneumonia, paralysis of respiratory muscles, etc.). -- PO2 decreases (type I respiratory failure); -- PCO2 increases (type II respiratory failure) till the gradient blood-external air is high enough to allow the elimination of the CO2 produced by metabolism; -- there is only a small increase of bicarbonate, due to the action of the other buffers of blood: X + CO2 + H2O ↔ XH+ + HCO3- -- pH drops, as dictated by Henderson and Hasselbalch law: pH = 6.1 + log ([HCO3-] / 0.03 PCO2) -- hypoxemia may cause hyperventilation; if this occurs it moderates the increase of PCO2 1b. Intermediate phase (3-5 days) -- The kidney increases elimination of acids thus moderating the pH imbalance: -- the kidney uses glutamine for ammoniagenesis and production of bicarbonate according to the reaction(s): C5H10N2O3 + 4 ½ O2 → 3 CO2 + 2HCO3- + 2 NH4+ -- ammonium is excreted in the urine, together with chloride; bicarbonate is reabsorbed in the blood -- the increased bicarbonate concentration raises the pH -- urine is strongly acidic, with increased content of ammonium 1c. Chronic phase -- A new steady-state condition is reached in which: -- PCO2 and bicarbonate are both significantly increased -- the blood pH is only moderately acidic if at all -- ammoniagenesis and ammonuria return to normal levels 2. RESPIRATORY ALKALOSIS 2a. Acute phase (hours) -- A disease stimulates a sudden increase of ventilation (e.g. anemia; neurological lesions - Kussmaul breathing); this causes the arteral PO2 and PCO2 to become closer to the values in external air. -- PO2 does not significantly increase because arterial PO2 is already quite close to the external PO2 -- PCO2 decreases significantly because the external PCO2 is much lower than the arterial PCO2 -- pH increases because of the decrease of PCO2 not coupled to a parallel decrease of bicarbonate. 2b. Intermediate phase (one-two days) -- The kidney eliminates alkaline urine and possibly some bicarbonate; reduces ammoniagenesis -- The decrease of bicarbonate lowers the blood pH 2c. Chronic phase -- A new steady-state condition is reached in which: -- PCO2 and bicarbonate are both significantly decreased -- the blood pH is only moderately alkaline -- the urine pH returns to normal values. 3. METABOLIC ACIDOSIS - Metabolic acidosis (and alkalosis) develop slowly, whereas respiratory compensation occurs rapidly; because of this reason the distinction between acute (=non-compensated) and chronic (=compensated) phases does not apply. In metabolic acidoses serum bicarbonate is low (base deficit); PCO2 is also low, because of pulmonary compensation, which tries to maintain the ratio ([HCO3-] / 0.03 PCO2) within the normal range. - Metabolic acidosis (and alkalosis) may be of renal or non-renal origin. - Metabolic acidosis (much less alkalosis) may present an increased anion gap (HAGMA) or a normal anion gap (NAGMA). 3a. Of renal origin - Chronic kidney failure -- Non-volatile acids, that the lung cannot eliminate, are introduced with the diet; e.g. the metabolism of sulfur containing aminoacids (Cys and Met) produces sulfuric acid and consumes bicarbonate: C3H7NSO2 + HCO3- + 4 ½ O2 → 4 CO2 + SO4= + NH4+ + 2 H2O -- In chronic kidney failure the GFR decreases and becomes insufficient to eliminate dietary non-volatile acids; this causes HAGMA -- This may be compounded with insufficient production and excretion of ammonia. - Renal Tubular Acidoses (RTAs) -- RTAs are inherited or acquired defects of the resorption/secretion of acid-related solutes; they cause NAGMA, because the decrease of bicarbonate is compensated by retention of chloride. -- Type 1 RTA is a defect of hydrogen ion secretion in the distal tubule -- Type 2 RTA is a defect of bicarbonate resorption in the proximal tubule -- Type 3 RTA is a combination of types 1 and 2 -- Type 4 RTA (hyperkalemic RTA) is not a tubular defect but a consequence of a deficiency of aldosterone (e.g. because of Addison disease); it causes retention of potassium, loss of sodium and insufficient secretion of ammonia. 3b. Of non-renal origin -- True metabolic imbalances that produce non-volatile acids, causing HAGMA (e.g. diabetic ketoacidosis, lactic acidosis due to sepsis, etc.) -- Loss of bicarbonate causes NAGMA (e.g. diarrhoea).