Acid-Base Physiology
A four-step read: pH, primary driver, compensation, and the anion gap
Acid-base basics and the four-step read
Henderson-Hasselbalch. pH = 6.1 + log([HCO₃⁻] / (0.03 × PCO₂)). pH depends on the ratio of HCO₃⁻ (the metabolic component, set by the kidney) to PCO₂ (the respiratory component, set by the lungs); normally that ratio is 20:1. Normal values: pH 7.40, PCO₂ 40 mmHg, HCO₃⁻ 24 mEq/L. The lungs adjust PCO₂ within minutes, while the kidney adjusts HCO₃⁻ over hours to days.
- Check pHAcidemia (<7.35) or alkalemia (>7.45)
- Find the primary driverPCO₂ (respiratory) or HCO₃⁻ (metabolic), whichever explains the pH
- Check compensationIs the other variable moving as expected?
- If metabolic acidosis, calculate the anion gapGap vs non-gap, then delta-delta
Compensation. Compensation moves the other variable in the same direction as the primary change, pushing the ratio back toward normal without overcorrecting the pH. A value outside the expected range signals a second primary disorder.
| Disorder | pH | Primary change | Compensation | Expected size |
|---|---|---|---|---|
| Metabolic acidosis | ↓ | ↓ HCO₃⁻ | Hyperventilation (↓ PCO₂) | Winter's: PCO₂ = 1.5 × HCO₃⁻ + 8 ± 2 |
| Metabolic alkalosis | ↑ | ↑ HCO₃⁻ | Hypoventilation (↑ PCO₂) | PCO₂ ↑ ~0.7 per 1 mEq/L rise in HCO₃⁻ |
| Respiratory acidosis | ↓ | ↑ PCO₂ | ↑ HCO₃⁻ | Acute +1, chronic +3.5–4 per 10 mmHg |
| Respiratory alkalosis | ↑ | ↓ PCO₂ | ↓ HCO₃⁻ | Acute −2, chronic −4–5 per 10 mmHg |
How the kidney handles acid
Reclaiming filtered HCO₃⁻. The PCT reabsorbs most filtered HCO₃⁻: secreted H⁺ combines with it, and carbonic anhydrase converts the product to CO₂ and water, which re-enter the cell to regenerate HCO₃⁻. This recovers bicarbonate but excretes no net acid.
Making new HCO₃⁻. The distal nephron (α-intercalated cells) secretes H⁺, and every H⁺ excreted adds a new HCO₃⁻ to the blood. Secreted H⁺ leaves as titratable acid (buffered mainly by phosphate) and as ammonium (NH₄⁺), which the proximal tubule makes from glutamine. Ammonium is the main adjustable buffer, rising substantially in chronic acidosis.
Metabolic acidosis
Anion gap. AG = Na⁺ − (Cl⁻ + HCO₃⁻), normally 8–12 mEq/L; it reflects unmeasured anions, mostly albumin. Correct for hypoalbuminemia by adding ~2.5 to the gap for each 1 g/dL of albumin below 4. In a high-gap acidosis, an added acid consumes HCO₃⁻ and leaves its anion behind while chloride stays put.
High-gap causes (MUDPILES). Methanol, Uremia, DKA, Propylene glycol, Iron or Isoniazid, Lactic acidosis, Ethylene glycol, Salicylates. A high serum osmolal gap alongside the anion gap points to a toxic alcohol (methanol, ethylene glycol).
Normal-gap (hyperchloremic) causes. HCO₃⁻ is lost or not regenerated, and Cl⁻ rises in its place: diarrhea (GI HCO₃⁻ loss), renal tubular acidosis, acetazolamide, and Addison disease (aldosterone deficiency). The urine anion gap (Na⁺ + K⁺ − Cl⁻) is a proxy for urinary NH₄⁺: negative when the kidney excretes NH₄⁺ appropriately (GI loss such as diarrhea), positive when it cannot (distal type 1 or type 4 RTA).
| Type | Defect | Urine pH | Serum K⁺ | Associations |
|---|---|---|---|---|
| 1 (distal) | α-Intercalated cells cannot secrete H⁺ | >5.5 | ↓ | Calcium phosphate stones; amphotericin B, Sjögren syndrome |
| 2 (proximal) | PCT cannot reclaim HCO₃⁻ | <5.5 once serum HCO₃⁻ is low | ↓ | Fanconi syndrome, acetazolamide, multiple myeloma |
| 4 (hyperkalemic) | Low aldosterone or resistance; hyperkalemia suppresses NH₄⁺ production | <5.5 | ↑ | Diabetic hyporeninemic hypoaldosteronism, ACE inhibitors, K-sparing diuretics |
Winter's formula. Respiratory compensation for metabolic acidosis is predictable: expected PCO₂ = 1.5 × [HCO₃⁻] + 8 ± 2. With HCO₃⁻ at 12, PCO₂ should be about 26 mmHg. A measured PCO₂ above the expected range means a concurrent respiratory acidosis; below it, a concurrent respiratory alkalosis.
Metabolic alkalosis and respiratory disorders
Metabolic alkalosis. A primary rise in HCO₃⁻ (pH >7.45) from vomiting (loss of H⁺ and Cl⁻), diuretics, or hyperaldosteronism; volume contraction and hypokalemia help sustain it. Compensatory hypoventilation raises PCO₂ ~0.7 mmHg per 1 mEq/L rise in HCO₃⁻. Urine Cl⁻ sorts the causes: <20 mEq/L marks saline-responsive, chloride-depleted states (vomiting, diuretics once their effect has worn off); >20 mEq/L marks saline-resistant states such as hyperaldosteronism, or a diuretic that is still acting.
Respiratory acidosis. A primary rise in PCO₂ from hypoventilation: COPD, opioids or sedatives, obesity hypoventilation, neuromuscular disease. Acutely, cellular buffering raises HCO₃⁻ only ~1 mEq/L per 10 mmHg rise in PCO₂; after several days of renal compensation, the rise reaches ~3.5–4 per 10.
Respiratory alkalosis. A primary fall in PCO₂ from hyperventilation: anxiety or pain, high altitude, pulmonary embolism, sepsis, pregnancy, and early salicylate toxicity. HCO₃⁻ falls ~2 mEq/L per 10 mmHg acutely and ~4–5 per 10 once renal compensation is complete. Acute alkalosis increases albumin binding of Ca²⁺, lowering ionized calcium and causing perioral and fingertip tingling.
Mixed disorders
Delta-delta. In a high-gap acidosis, compare the rise in the anion gap with the fall in HCO₃⁻ (Δ gap / Δ HCO₃⁻). A ratio of 1–2 is a pure high-gap acidosis. Below 1, HCO₃⁻ has fallen more than the gap explains, revealing a concurrent normal-gap acidosis. Above 2, HCO₃⁻ is higher than the gap rise predicts, revealing a concurrent metabolic alkalosis.
Salicylate toxicity. Aspirin overdose classically produces a mixed disorder in adults: an early respiratory alkalosis from direct stimulation of the medullary respiratory center, plus a high-gap metabolic acidosis as salicylate uncouples oxidative phosphorylation and lactic acid and ketoacids accumulate. Look for tinnitus, tachypnea, and fever.
Two primary disorders can coexist, and the pH may even look near normal. Always check compensation and, in any high-gap acidosis, the delta-delta.