The Canadian physiologist PA Stewart advanced the theory that the proton concentration, and hence pH, in any compartment is dependent on the charges of fully ionized and partly ionized species, and on the prevailing CO2 tension, all of which he dubbed independent variables. Because the kidneys regulate the concentrations of the most important fully ionized species ([K+], [Na+], and [Cl-]) but neither CO2 nor weak acids, the implication is that it should be possible to ascertain the renal contribution to acid–base homeostasis based on the excretion of these ions. One further corollary of Stewart's theory is that, because pH is solely dependent on the named independent variables, transport of protons to and from a compartment by itself will not influence pH. This is apparently in great contrast to models of proton pumps and bicarbonate transporters currently being examined in great molecular detail. Failure of these pumps and cotransporters is at the root of disorders called renal tubular acidoses. The unquestionable relation between malfunction of proton transporters and renal tubular acidosis represents a problem for Stewart theory. This review shows that the dilemma for Stewart theory is only apparent because transport of acid–base equivalents is accompanied by electrolytes. We suggest that Stewart theory may lead to new questions that must be investigated experimentally. Also, recent evidence from physiology that pH may not regulate acid–base transport is in accordance with the concepts presented by Stewart.
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