type 1 RTA

Pathophysiology: The distal nephron's alpha-intercalated cells normally secrete H+ via H+-ATPase and H+/K+-ATPase pumps into the tubular lumen, which is critical for generating a maximally acidic urine and excreting the daily fixed acid load. In Type 1 RTA, this H+ secretion is impaired due to a defect in the H+-ATPase pump, a backleak of secreted H+ ions, or reduced luminal membrane permeability. This impairs both titratable acid and ammonium excretion, causing systemic metabolic acidosis while urine pH remains inappropriately high (>5.5) even in the setting of acidemia.

Hypokalemia occurs because impaired H+ secretion leads to compensatory increased Na+ reabsorption via ENaC, which drives K+ secretion; additionally, the acidosis itself promotes urinary K+ wasting. This is a key distinguishing feature from Type 4 RTA (hyperkalemic).

Nephrocalcinosis and nephrolithiasis (calcium phosphate stones) are common complications because chronic acidosis increases bone mineral resorption, releasing calcium and phosphate, and low urine citrate (citrate is reabsorbed to buffer acidosis) reduces its normal role as a stone inhibitor, while alkaline urine favors calcium phosphate precipitation.

Etiologies: - Autoimmune diseases (Sjögren syndrome, SLE, rheumatoid arthritis) - Genetic mutations (autosomal dominant SLC4A1 anion exchanger defect, autosomal recessive ATP6V1B1/ATP6V0A4 defects associated with sensorineural deafness) - Amphotericin B toxicity (increases membrane permeability, causing H+ backleak) - Obstructive uropathy - Hypercalciuria states

Clinical presentation: Failure to thrive in children, chronic metabolic acidosis, hypokalemia (muscle weakness), bone disease (rickets/osteomalacia from chronic acidosis-induced bone buffering), and recurrent kidney stones/nephrocalcinosis.

Diagnosis: Confirmed via ammonium chloride loading test (failure to acidify urine below pH 5.5 despite systemic acidosis) in equivocal cases. Urine anion gap is positive (indicating impaired ammonium excretion), differentiating it from GI causes of non-anion gap acidosis (which have a negative urine anion gap).

Treatment: Oral alkali therapy (sodium bicarbonate or potassium citrate) to correct acidosis, replete potassium, and reduce stone formation/bone disease by providing citrate.

Comparison to other RTAs: Type 2 (proximal) RTA involves defective HCO3- reabsorption in the proximal tubule, often with Fanconi syndrome; Type 4 RTA involves hypoaldosteronism or aldosterone resistance, causing hyperkalemia rather than hypokalemia.