Key Facts

RTA is an important cause of normal anion gap metabolic acidosis. The type determines the potassium level and specific management.

Epidemiology

• Type 4 is most common (often associated with diabetes and CKD)
• Type 1 and 2 are rarer; more often seen in paediatric or specialist nephrology practice
• Type 3 (mixed): extremely rare, mainly described historically

Pathophysiology

Type 1 (Distal):

• Collecting duct alpha-intercalated cells cannot secrete H+ (defective H+-ATPase or back-leak of H+)
• Cannot acidify urine below pH 5.3 despite systemic acidosis
• Alkaline urine → calcium phosphate precipitation → nephrocalcinosis and renal stones
• K+ wasting → hypokalaemia (compensatory K+ secretion for impaired H+ secretion)

Type 2 (Proximal):

• Defective bicarbonate reabsorption in proximal tubule (reduced threshold from normal ~24 to ~15 mmol/L)
• Massive bicarbonaturia at normal serum HCO3; once serum HCO3 drops below threshold, urine can be acidified
• Often part of generalised proximal tubular dysfunction (Fanconi syndrome)
• K+ wasting → hypokalaemia

Type 4 (Hyperkalaemic):

• Aldosterone deficiency or resistance → reduced H+ and K+ secretion in collecting duct
• Hyperkalaemia → reduced renal ammoniagenesis → further impaired acid excretion
• Low urine pH (can acidify urine, but not enough ammonium production)

Type 1 (Distal)

• Recurrent nephrocalcinosis and renal stones (calcium phosphate)
• Growth failure in children
• Muscle weakness (hypokalaemia)
• Bone disease (osteomalacia – chronic buffering of acid by bone)
• Polyuria and polydipsia

Type 2 (Proximal)

• Fanconi syndrome features: glycosuria, aminoaciduria, phosphaturia, uricosuria, bicarbonate wasting
• Rickets/osteomalacia (phosphate wasting)
• Growth failure in children
• Muscle weakness (hypokalaemia)

Type 4 (Hyperkalaemic)

• Often asymptomatic or mild symptoms
• Found in context of diabetes + CKD or aldosterone deficiency
• Hyperkalaemia symptoms: weakness, cardiac arrhythmia risk
• Mild metabolic acidosis

Red Flags

• Severe hypokalaemia (types 1/2) → cardiac arrhythmia risk
• Recurrent renal stones in young patients → investigate for type 1 RTA
• Unexplained normal anion gap acidosis → consider RTA

Bloods

• ABG/VBG: metabolic acidosis with normal anion gap
• U&Es: potassium (low in types 1/2, high in type 4), bicarbonate (low)
• Chloride: elevated (hyperchloraemic acidosis)
• Anion gap: normal (8-12 mmol/L)
• Calcium: may be high-normal or elevated in type 1

Urine

• Urine pH: >5.3 in type 1 (despite acidosis); variable in type 2; <5.3 in type 4
• Urine anion gap: positive (impaired ammonium excretion) in all RTA types; negative in GI bicarbonate loss (normal NH4+ excretion)
• Fractional excretion of bicarbonate: >15% in type 2 during bicarbonate loading

Special Tests

• Ammonium chloride loading test: confirms type 1 RTA (urine pH remains >5.3)
• Renal USS: nephrocalcinosis in type 1
• Short Synacthen test/aldosterone levels: if type 4 suspected
• Urinary amino acids, glucose, phosphate: Fanconi syndrome screen (type 2)

Type 1 (Distal)

• Sodium bicarbonate 1-2 mmol/kg/day (or potassium citrate if stones/nephrocalcinosis)
• Potassium supplementation if hypokalaemic
• Adequate hydration to prevent stones
• Treat underlying cause (e.g., immunosuppression for Sjogren)

Type 2 (Proximal)

• Sodium bicarbonate 5-15 mmol/kg/day (higher doses needed as most is excreted)
• Potassium supplementation (bicarbonate therapy worsens hypokalaemia)
• Phosphate replacement and vitamin D if Fanconi syndrome
• Thiazide diuretics: paradoxically increase proximal bicarbonate reabsorption by reducing ECF volume

Type 4 (Hyperkalaemic)

• Fludrocortisone 50-200mcg OD: if aldosterone deficiency
• Sodium bicarbonate: to correct acidosis
• Dietary potassium restriction
• Stop offending drugs: spironolactone, amiloride, trimethoprim, ACEi/ARBs if possible
• Potassium binders: sodium zirconium cyclosilicate or patiromer if hyperkalaemia persistent

Referral

• All types → nephrology for investigation and management
• Children with growth failure → paediatric nephrology

• Type 1: good prognosis with treatment; untreated → progressive nephrocalcinosis and CKD
• Type 2: prognosis depends on underlying cause; Fanconi syndrome from myeloma = poor; drug-induced = reversible
• Type 4: generally good; usually controlled by treating hyperkalaemia and acidosis
• Nephrocalcinosis (type 1) can lead to progressive CKD if not treated early

RTA Types Comparison