proximal renal tubular acidosis

Pathophysiology: The proximal tubule normally reabsorbs ~85-90% of filtered bicarbonate via the Na+/H+ exchanger (NHE3) and carbonic anhydrase-dependent processes. In proximal RTA, this reabsorptive capacity is reduced, causing bicarbonate wasting in the urine until plasma bicarbonate falls to a new, lower steady-state threshold (~15-18 mEq/L), at which point the reduced filtered load can be reabsorbed and the urine can be acidified appropriately (urine pH <5.5 once acidotic). This distinguishes it from distal (Type 1) RTA, where the urine cannot be acidified regardless of systemic pH.

Hypokalemia occurs due to increased distal Na+ delivery, which stimulates aldosterone-mediated Na+ reabsorption in exchange for K+ secretion, exacerbated by bicarbonaturia carrying Na+ into the distal nephron.

Etiologies: Often occurs as part of Fanconi syndrome, characterized by generalized proximal tubular dysfunction with glucosuria, phosphaturia, aminoaciduria, and uricosuria. Causes include: - Genetic: cystinosis (most common cause in children), Wilson disease, Lowe syndrome - Multiple myeloma (light chain nephrotoxicity) - Drugs/toxins: acetazolamide, ifosfamide, tenofovir, expired tetracyclines, heavy metals (lead, cadmium) - Vitamin D deficiency (secondary)

Clinical features: Normal anion gap (hyperchloremic) metabolic acidosis, hypokalemia, and features of Fanconi syndrome if present (rickets/osteomalacia due to phosphate wasting and impaired vitamin D activation, growth failure in children). Nephrolithiasis and nephrocalcinosis are less common than in distal RTA because urinary citrate excretion is not markedly reduced.

Diagnosis: Suspect in a patient with normal anion gap metabolic acidosis, hypokalemia, and evidence of proximal tubular dysfunction. Fractional excretion of bicarbonate (FEHCO3) >15% after an IV bicarbonate load confirms proximal RTA. Urine anion gap is typically negative (unlike in distal RTA/GI bicarbonate loss differentiation, this test is more useful for distal RTA).

Treatment: Correcting the acidosis is difficult because bicarbonate therapy increases urinary bicarbonate loss and can worsen hypokalemia; large doses of alkali (10-15 mEq/kg/day) are often required. Thiazide diuretics can help by causing mild volume depletion, which enhances proximal bicarbonate reabsorption. Potassium supplementation is often necessary. Treat underlying cause when identifiable (e.g., cysteamine for cystinosis, discontinue offending drug).

Comparison with Type 1 (distal) RTA: Type 1 has more severe acidosis, higher risk of nephrolithiasis/nephrocalcinosis due to low urine citrate and high urine pH, and cannot acidify urine even when acidotic. Type 4 RTA is associated with hyperkalemia due to hypoaldosteronism.