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Early distal convoluted tubule: thiazide-sensitive NaCl cotransporter

Distal tubule · 5-7% Na+ NCC Thiazides

Water-impermeable 'cortical diluting segment' that reabsorbs a further ~5-7% of filtered sodium with chloride through NCC, driving tubular fluid osmolality down to ~50-100 mOsm/kg. Thiazide diuretics act here.

Traced from the start

  1. Glomerular filtration barrier
  2. Proximal tubule: Na+/H+ exchange and bicarbonate reclamation
  3. Thick ascending limb of Henle (NKCC2)
  4. Early distal convoluted tubule: thiazide-sensitive NaCl cotransporter

Detail

Reabsorbs
~5-7% of filtered Na+ and Cl-; K+ secretion begins in the late DCT and connecting tubule
Transporter
Apical NCC (SLC12A3, electroneutral Na+/Cl- cotransport); basolateral Na+/K+-ATPase and ClC-Kb; activity set by the WNK1/WNK4-SPAK kinase cascade
Water
Impermeable even with ADH: fluid becomes hypotonic (~50-100 mOsm/kg); this is where free water for dilute urine is generated
Hormone
Aldosterone and angiotensin II (via WNK4/SPAK) increase NCC; high K+ intake dephosphorylates and inhibits NCC, shunting Na+ to the collecting duct to drive K+ secretion
Diuretic
Thiazides (hydrochlorothiazide, chlorthalidone, indapamide) block NCC from the lumen: moderate natriuresis (3-5% of filtered Na+), ineffective below GFR ~30 mL/min except metolazone; raise distal Na+ delivery so K+ and H+ are lost downstream

When it goes wrong

Thiazide diuretic

Hypokalaemia; hyponatraemia (urinary dilution impaired while ADH-driven water retention persists, classically an elderly woman within weeks of starting); hypercalcaemia, hyperuricaemia and gout, hyperglycaemia, hyperlipidaemia, metabolic alkalosis

Thiazide in nephrogenic diabetes insipidus

Paradoxical fall in urine volume: mild volume contraction raises proximal reabsorption so less fluid reaches the ADH-resistant collecting duct

Gitelman syndrome (loss-of-function NCC)

Mimics chronic thiazide use: hypokalaemic metabolic alkalosis, hypomagnesaemia, hypocalciuria, normal blood pressure; presents in adolescence or adulthood with cramps, fatigue and tetany

Gordon syndrome (pseudohypoaldosteronism type II: WNK4, WNK1, KLHL3 or CUL3 mutations overactivate NCC)

Hypertension with hyperkalaemia and hyperchloraemic acidosis, low renin; corrected by thiazides

Practise this structure

2 questions in the bank tagged Tubular Transport.

A 7-year-old boy has passed large volumes of urine and craved salty food since infancy, and he is small for his age. His blood pressure is 92/56 mmHg and he has…

Foundations · middle twist

A healthy adult receives an intravenous glucose load. Plasma glucose is 12 mmol/L (reference 3.5–7.8 mmol/L), the measured glomerular filtration rate is 120 mL/…

Mechanisms of disease · common