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Renal Tubular Acidosis (RTA)
Renal tubular acidosis (RTA) is a group of disorders characterized by hyperchloremic (normal anion gap) metabolic acidosis with a normal or near-normal GFR, caused by defects in the kidney's ability to reabsorb bicarbonate or excrete acid - not by a reduction in GFR itself.
Pathophysiology Overview
The kidney maintains acid-base balance via two main tubular mechanisms:
- Proximal tubule: reabsorbs ~85% of filtered HCO3-
- Distal nephron (collecting duct): secretes H+ via H+-ATPase on alpha-intercalated cells and generates new HCO3-
Defects in either process - or in aldosterone signaling - lead to the distinct RTA subtypes.
Classification of RTA
| Feature | Type I (Distal) | Type II (Proximal) | Type III (Mixed) | Type IV (Hyperkalemic) |
|---|---|---|---|---|
| Defect | Impaired H+ secretion in distal nephron | Reduced HCO3- reabsorption in proximal tubule | Both proximal + distal failure | Aldosterone deficiency or resistance |
| Serum K+ | Low (or normal) | Low (or normal) | Low | High |
| Urine pH | >5.5 (cannot acidify) | <5.5 (when not treated) | Variable | Low |
| Serum HCO3- | Very low | Moderate reduction (~15-18 mEq/L) | Low | Mild reduction |
| Anion gap | Normal | Normal | Normal | Normal |
| Stone/nephrocalcinosis | Yes | Rarely | No | No |
Type I - Distal RTA (Most Common)
Mechanism: Failure of alpha-intercalated cells in the collecting duct to secrete H+ (reduced H+-ATPase activity), so urine cannot be acidified below pH 5.5 even under maximal acid load.
Clinical features:
- Hypercalciuria, hypocitraturia
- Nephrolithiasis and nephrocalcinosis
- Failure to thrive, bone demineralization, rickets in children
- Hypokalemia (from loss of electrogenic H+ secretion, forcing K+ secretion to maintain electronegativity, plus increased aldosterone)
Genetic causes:
- ATP6V1B1 mutations (AR): nephrocalcinosis + sensorineural hearing loss
- ATP6V0A4 mutations (AR): nephrocalcinosis + late-onset hearing loss
- SLC4A1 (AE1 Cl-/HCO3- exchanger) mutations (AD, rarely AR): milder phenotype; may present in teens/adults; AR form can be associated with hemolytic anemia
Acquired causes: Sjogren syndrome (most common cause in adults), amphotericin B, autoimmune hepatitis, hypergammaglobulinemia, obstructive uropathy
Key test: Urine cannot acidify below pH 5.3 even after furosemide/fludrocortisone challenge or ammonium chloride load.
Type II - Proximal RTA
Mechanism: Reduced HCO3- reabsorption in the proximal tubule. Isolated proximal RTA is rare (genetic: SLC4A4 mutation causing loss of basolateral Na+-HCO3- cotransporter). More commonly it is part of Fanconi syndrome.
Fanconi syndrome features (generalized proximal tubule dysfunction):
- Glycosuria (with normal blood glucose)
- Hyperaminoaciduria
- Phosphate wasting (hypophosphatemia)
- Low-molecular-weight proteinuria
- Hypouricemia, hypercalciuria, hypokalemia, salt wasting
- Proximal RTA
Causes of Fanconi syndrome: tenofovir, cidofovir, adefovir, ifosfamide, aristolochic acid, multiple myeloma (light chains), Wilson disease, galactosemia, cystinosis
Key feature: Urine pH is <5.5 when off treatment (can still acidify distally), but becomes alkaline when given alkali (bicarbonate spills into urine once threshold is exceeded). Fractional excretion of HCO3- rises >15% with alkali loading.
Treatment requires large doses of alkali (up to 10 mEq/kg/day), because the proximal leak is severe. Use potassium citrate to avoid worsening hypokalemia. Also vitamin D and phosphate supplementation.
Type III - Mixed RTA (Rare)
Mechanism: Mutations in carbonic anhydrase II (CA2), required for both proximal HCO3- reabsorption and distal H+ secretion.
Features: AR inheritance; associated with osteopetrosis, cerebral calcifications, mental retardation, facial dysmorphism, conductive hearing loss, blindness.
Type IV - Hyperkalemic RTA
Mechanism: Aldosterone deficiency or resistance in the distal nephron. Aldosterone normally stimulates Na+ reabsorption and H+/K+ excretion; without it, both H+ and K+ accumulate.
Causes:
- NSAIDs, ACE inhibitors/ARBs, calcineurin inhibitors, K+-sparing diuretics
- Diabetic nephropathy (hyporeninemic hypoaldosteronism - most common acquired cause)
- Obstructive uropathy
- Chronic interstitial nephritis, sickle cell disease
- Pseudohypoaldosteronism (PHA) - genetic resistance to aldosterone
Key feature: Hyperkalemia + mild metabolic acidosis (less severe than Types I or II). Low urine pH (aldosterone absence reduces ammoniagenesis, not H+ pump function directly).
Treatment: Loop diuretics (furosemide) enhance distal Na+ delivery and acid excretion; fludrocortisone for mineralocorticoid deficiency; correct the hyperkalemia.
Diagnosis: Urine Anion Gap
A useful bedside tool for nonanion gap metabolic acidosis:
Urine Anion Gap = Urine Na+ + Urine K+ - Urine Cl-
- Negative UAG (Cl- > Na+ + K+): Appropriate ammonium (NH4+) excretion - suggests extra-renal cause (e.g., diarrhea) or Type II RTA (can still acidify)
- Positive UAG: Failure to excrete NH4+ - suggests distal (Type I) or Type IV RTA
Treatment Summary
| Type | Primary Treatment |
|---|---|
| Type I (Distal) | Potassium citrate (1-2 mEq/kg/day); thiazides + fluids to reduce stone risk |
| Type II (Proximal) | High-dose oral alkali (up to 10 mEq/kg/day); K+ citrate; phosphate + vitamin D for Fanconi |
| Type IV (Hyperkalemic) | Furosemide + fludrocortisone; stop offending drugs; treat hyperkalemia |
For all types: alkali therapy (bicarbonate or citrate) to normalize pH, and regular monitoring of serum potassium.
Sources: Brenner and Rector's The Kidney (9780323532655), Campbell-Walsh-Wein Urology (9780323546423), Tintinalli's Emergency Medicine (9781260019933)
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