Acid–Base Physiology: Buffers & Compensation

Arterial pH is clamped at 7.40 (≈ 40 nEq/L H⁺) within a narrow 7.35–7.45 window, because enzyme kinetics, protein charge, and membrane potentials all depend on [H⁺]. Defense comes in three tiers with very different speeds: (1) chemical buffers act in seconds, (2) the lungs adjust PaCO₂ in minutes, and (3) the kidneys adjust HCO₃⁻ and excrete acid over hours–days — slow, but the only route that eliminates fixed (nonvolatile) acid and rebuilds buffer stores.

The dominant extracellular buffer is the bicarbonate system:

CO₂ + H₂O ⇌ H₂CO₃ ⇌ H⁺ + HCO₃⁻ (carbonic anhydrase catalyzes the first step).

Its pKa is 6.1 — more than a full pH unit (≈1.3) below 7.4, which would make it a weak buffer in a sealed test tube. It dominates in vivo only because it is an open system: the lungs continuously blow off CO₂ and the kidneys regenerate HCO₃⁻, so both sides of the reaction are independently controlled.

Henderson-Hasselbalch: pH = 6.1 + log([HCO₃⁻] / (0.03 × PaCO₂)). At the normal 24 / (0.03×40) = 24/1.2, the 20:1 ratio gives pH 7.4 — pH tracks the ratio, not absolute values. By the isohydric principle, every buffer pair in a solution equilibrates with the same [H⁺], so measuring one (bicarbonate) reports on all. For fast bedside math use the Henderson equation: [H⁺] = 24 × PaCO₂ / [HCO₃⁻].

The kidney does two distinct jobs: reclaim filtered HCO₃⁻ and generate new HCO₃⁻ by excreting acid.

Proximal tubule (reclamation, ~80–90% of filtered HCO₃⁻): the luminal Na⁺/H⁺ exchanger (NHE3) secretes H⁺; secreted H⁺ + filtered HCO₃⁻ → H₂CO₃ → (luminal carbonic anhydrase IV) CO₂ + H₂O. CO₂ diffuses into the cell, cytoplasmic CA II regenerates HCO₃⁻, which exits basolaterally on the Na⁺-HCO₃⁻ cotransporter (NBCe1). No net acid is excreted here — bicarbonate is merely reclaimed. (This is why acetazolamide → proximal HCO₃⁻ wasting → normal-AG metabolic acidosis.)

Distal nephron / collecting duct (new HCO₃⁻): α-intercalated cells secrete H⁺ via an apical H⁺-ATPase and H⁺/K⁺-ATPase, and export the newly made HCO₃⁻ across the basolateral membrane on the Cl⁻/HCO₃⁻ exchanger (AE1/band 3). Aldosterone stimulates distal H⁺ secretion.

Secreted H⁺ cannot be excreted free (urine floor ≈ pH 4.5); it must be buffered as titratable acid (mainly phosphate) and, more importantly, as NH₄⁺.

Net acid excretion = titratable acid + NH₄⁺ − urinary HCO₃⁻. The adjustable, high-capacity arm is ammoniagenesis: the proximal tubule metabolizes glutamine to NH₄⁺ and α-ketoglutarate, and oxidation of α-ketoglutarate generates the new HCO₃⁻ returned to blood, while NH₄⁺ is trapped in the lumen and excreted. Net: each NH₄⁺ lost in urine = one new HCO₃⁻ gained. This pathway is strongly upregulated in chronic metabolic acidosis — the main way the kidney ramps up acid excretion.