The Maladaptive Renal Response to Secondary Hypocapnia during Chronic HCl Acidosis in the Dog

Nicolaos E. Madias; William B. Schwartz; Jordan J. Cohen

doi:10.1172/JCI108900

It has generally been thought that homeostatic mechanisms of renal origin are responsible for minimizing the alkalemia produced by chronic hypocapnia. Recent observations from this laboratory have demonstrated, however, that the decrement in [HCO⁻₃], which “protects” extracellular pH in normal dogs, is simply the by-product of a nonspecific effect of Paco₂ on renal hydrogen ion secretion; chronic primary hypocapnia produces virtually the same decrement in plasma [HCO⁻₃] in dogs with chronic HCl acidosis as in normal dogs (Δ[HCO⁻₃]/ΔPaco₂ = 0.5), with the result that plasma [H⁺] in animals with severe acidosis rises rather than falls during superimposed forced hyperventilation.

This observation raised the possibility that the secondary hypocapnia which normally accompanies metabolic acidosis, if persistent, might induce an analogous renal response and thereby contribute to the steady-state decrement in plasma [HCO⁻₃] observed during HCl feeding. We reasoned that if sustained secondary hypocapnia provoked the kidney to depress renal bicarbonate reabsorption, the acute salutary effect of hypocapnia on plasma acidity might be seriously undermined.

To isolate the possible effects of secondary hypocapnia from those of the hydrogen ion load, per se, animals were maintained in an atmosphere of 2.6% CO₂ during an initial 8-day period of acid feeding (7 mmol/kg per day); this maneuver allowed Paco₂ to be held constant at the control level of 36 mm Hg despite the hyperventilation induced by the acidemia. Steady-state bicarbonate concentration during the period of eucapnia fell from 20.8 to 16.0 meq/liter, while [H⁺] rose from 42 to 55 neq/liter. During the second phase of the study, acid feeding was continued but CO₂ was removed from the inspired air, permitting Paco₂ to fall by 6 mm Hg. In response to this secondary hypocapnia, bicarbonate concentration fell by an additional 3.0 meq/liter to a new steady-state level of 13.0 meq/liter. This reduction in bicarbonate was of sufficient magnitude to more than offset the acute salutary effect of the hypocapnia on plasma hydrogen ion concentration; in fact, steady-state [H⁺] rose as a function of the adaptive fall in Paco₂, Δ[H⁺]/Δ Paco₂ = −0.44. That the fall in bicarbonate observed in response to chronic secondary hypocapnia was the result of the change in Paco₂ was confirmed by the observation that plasma bicarbonate returned to its eucapnic level in a subgroup of animals re-exposed to 2.6% CO₂.

These data indicate that the decrement in plasma [HCO⁻₃] seen in chronic HCl acidosis is a composite function of (a) the acid load itself and (b) the renal response to the associated hyperventilation. We conclude that this renal response is maladaptive because it clearly diminishes the degree to which plasma acidity is protected by secondary hypocapnia acutely. Moreover, under some circumstances, this maladaptation actually results in more severe acidemia than would occur in the complete absence of secondary hypocapnia.