Overview

Filtered HCO₃⁻≈4300 mmol/day

Fixed acid production≈50–100 mmol/day (≈1 mmol/kg)

Minimum urine pH≈4.5

1. Reclamation of filtered HCO₃⁻ (≈4300 mmol/day). In the PCT (≈80–90%), H⁺ secreted by NHE3 (and H⁺-ATPase) combines with filtered HCO₃⁻ to form H₂CO₃, which luminal carbonic anhydrase (CA IV) splits to CO₂ + H₂O; CO₂ enters the cell, is rehydrated by CA II, and the resulting HCO₃⁻ exits basolaterally via NBCe1 (Na⁺–3HCO₃⁻). The TAL (≈10–15%) and collecting duct reclaim the rest. No net acid is excreted by this process.

2. Generation of new HCO₃⁻. Each H⁺ secreted and excreted with a urinary buffer leaves a new HCO₃⁻ in the blood. Titratable acid (mainly H₂PO₄⁻ from HPO₄²⁻; ≈10–30 mmol/day) is limited by phosphate availability. Ammonium (NH₄⁺; ≈30–50 mmol/day normally, up to ≈300 mmol/day in chronic acidosis): PCT cells metabolise glutamine → 2 NH₄⁺ + 2 HCO₃⁻ (α-ketoglutarate); NH₄⁺ is secreted, reabsorbed in the TAL, concentrated in the medullary interstitium and trapped as NH₄⁺ in the acidic collecting-duct lumen (α-intercalated H⁺ secretion). Ammoniagenesis is the main adaptive response to acidosis (and is stimulated by hypokalaemia).

Net acid excretion = titratable acid + NH₄⁺ − urinary HCO₃⁻ ≈ daily non-volatile acid production (≈1 mmol/kg/day). Factors increasing H⁺ secretion: acidosis, hypokalaemia, aldosterone, angiotensin II, volume contraction (contraction alkalosis), hypercapnia (renal compensation over 3–5 days).

Location: PCT, thick ascending limb, α- and β-intercalated cells of the collecting duct.

Function

Reclaim filtered bicarbonate
Excrete fixed acid and regenerate bicarbonate
Compensate for respiratory acid–base disorders

Clinical significance

Renal tubular acidosis (RTA)

Normal-anion-gap (hyperchloraemic) metabolic acidoses. Type 1 (distal): α-intercalated H⁺ secretion defect — urine pH >5.5, hypokalaemia, calcium phosphate stones. Type 2 (proximal): reduced HCO₃⁻ reclamation (Fanconi syndrome, acetazolamide) — urine pH <5.5 once plasma HCO₃⁻ falls, hypokalaemia, rickets/osteomalacia. Type 4: hypoaldosteronism or aldosterone resistance (diabetes, ACE inhibitors, spironolactone) — hyperkalaemia, which suppresses ammoniagenesis; urine pH <5.5.

Urine anion gap

U_Na + U_K − U_Cl estimates NH₄⁺ excretion: negative in diarrhoea (appropriate renal NH₄⁺ excretion, "neGUTive") and positive in distal RTA.

Test yourself

In chronic metabolic acidosis, the main adaptive increase in renal net acid excretion comes from:

Increased titratable acid excretion
Increased urinary bicarbonate excretion
Increased ammoniagenesis and NH₄⁺ excretion
Decreased GFR

Answer: Increased ammoniagenesis and NH₄⁺ excretion

Titratable acid is limited by the amount of filtered phosphate, whereas PCT ammoniagenesis from glutamine can increase several-fold, generating a new HCO₃⁻ for each NH₄⁺ excreted.