A patient on a thiazide diuretic develops hyponatremia. The mechanism involves impaired diluting capacity due to inhibition of which transporter in which nephron segment?

• A NKCC2 in the thick ascending limb, blocking free water generation in a manner identical to loop diuretics
• B NCC (Na-Cl co-transporter, SLC12A3) in the distal convoluted tubule, preventing solute reabsorption without water to dilute urine ✓
• C ENaC in the collecting duct, reducing electrogenic Na+ reabsorption
• D NHE3 in the proximal tubule, reducing iso-osmotic reabsorption and diluting the filtrate

Explanation

Thiazides inhibit NCC (sodium-chloride co-transporter, SLC12A3) in the early distal convoluted tubule (DCT1). This segment is crucial for diluting urine: it reabsorbs NaCl without water (as DCT is impermeable to water), reducing tubular fluid osmolality. When NCC is blocked, NaCl remains in the tubule, impairing maximal dilution. Paradoxically, thiazides also increase proximal tubular reabsorption (via volume depletion), and the diluting segment impairment combined with persistent ADH effect in collecting duct causes free water retention and hyponatremia. NKCC2 is the loop diuretic target; ENaC is the amiloride/spironolactone target.

Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.

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