alpha intercalated cell

**Location:** Late distal convoluted tubule, connecting tubule, and cortical/medullary collecting duct, interspersed among principal cells. Alpha-intercalated cells are mitochondria-rich "dark" cells.

**Mechanism (acid secretion/bicarbonate generation):** - Intracellular carbonic anhydrase (CA II) converts CO2 + H2O to H2CO3, which dissociates into H+ and HCO3-. - Apical (luminal) H+-ATPase (V-type) pumps H+ into the lumen. This is aldosterone-stimulated. The apical H+/K+-ATPase also secretes H+ and reabsorbs K+ (activated in hypokalemia). - Basolateral Cl-/HCO3- exchanger (AE1/band 3, SLC4A1) moves new HCO3- into the blood. Cl- exits via basolateral channels. - Secreted H+ is buffered in the lumen by NH3 (forming NH4+, which is trapped) and by phosphate (titratable acid). This makes the cells the main site of urinary acidification (urine pH down to about 4.5).

**Regulation:** - Stimulated by acidosis, aldosterone (acts on both principal and intercalated cells), and hypokalemia. - Aldosterone increases Na+ reabsorption in principal cells via ENaC. This makes the lumen more negative, which favors H+ and K+ secretion.

**Contrast with beta-intercalated cells:** Beta cells have the opposite polarity. They secrete HCO3- via apical pendrin (Cl-/HCO3- exchanger) and have a basolateral H+-ATPase. They are active in metabolic alkalosis. Principal cells reabsorb Na+/water and secrete K+.

**Clinical correlations:** - **Distal (type 1) RTA:** Defective H+ secretion by alpha-intercalated cells. Causes include AE1 mutations, H+-ATPase mutations (ATP6V1B1 with sensorineural deafness), amphotericin B (back-leak of H+), lithium, and autoimmune disease (Sjögren, SLE). Findings are a normal anion gap (hyperchloremic) metabolic acidosis, urine pH >5.5, hypokalemia, and hypercalciuria/hypocitraturia, which lead to calcium phosphate kidney stones and nephrocalcinosis. Treatment is bicarbonate/citrate. - **Type 4 RTA (hypoaldosteronism or aldosterone resistance):** Reduced aldosterone stimulation of alpha-intercalated cell H+ secretion and of principal cell K+ secretion. This causes hyperkalemia and a normal anion gap acidosis. Hyperkalemia suppresses NH3 synthesis, which reduces urinary buffering. Urine pH is usually <5.5. - **Hyperaldosteronism:** Increased H+ secretion leads to metabolic alkalosis with hypokalemia. - **Diuretics:** Loop and thiazide diuretics increase distal Na+ delivery and aldosterone-driven H+/K+ loss, which causes contraction alkalosis. Potassium-sparing diuretics (spironolactone, amiloride) impair H+ and K+ secretion and can cause hyperkalemic acidosis.

**High-yield pearl:** Alpha = Acid secretion. Type 1 RTA (distal) is the classic cause of an inability to acidify urine (urine pH >5.5 despite systemic acidosis).