Thick ascending limb of Henle (NKCC2)
Loop of Henle · 25% Na+ NKCC2 Loop diuretics
The engine of the concentrating mechanism: it reabsorbs ~25% of filtered sodium via the luminal Na+/K+/2Cl- cotransporter without water, diluting the tubular fluid and salting the medullary interstitium. It is the site of loop diuretic action.
Traced from the start
- Glomerular filtration barrier
- Proximal tubule: Na+/H+ exchange and bicarbonate reclamation
- Thick ascending limb of Henle (NKCC2)
Detail
- Reabsorbs
- ~25% of filtered Na+, K+ and Cl-; ~25% of Ca2+ and 60-70% of Mg2+ paracellularly (claudin-16/19) driven by a lumen-positive potential; ~10-15% of HCO3- via NHE3
- Transporter
- Apical NKCC2 (SLC12A1) and ROMK (K+ recycles back into the lumen, creating the ~+8 mV lumen-positive voltage); basolateral Na+/K+-ATPase and ClC-Kb chloride channel with its barttin subunit
- Water
- Impermeable: the 'diluting segment'; fluid leaves at ~100-150 mOsm/kg regardless of ADH
- Hormone
- ADH (V2, cAMP) and angiotensin II increase NKCC2 activity; the TAL also secretes uromodulin (Tamm-Horsfall protein), the matrix of urinary casts
- Diuretic
- Loop diuretics (frusemide, bumetanide, ethacrynic acid) bind the Cl- site of NKCC2 from the lumen; the strongest natriuretics, excreting up to 20-25% of filtered Na+; also venodilate acutely and abolish the medullary gradient
When it goes wrong
Loop diuretic
Hypovolaemia; hypokalaemic hypochloraemic metabolic alkalosis (more distal Na+ delivery plus secondary hyperaldosteronism); hypocalcaemia and hypomagnesaemia (lumen-positive drive lost); hyperuricaemia; ototoxicity (NKCC1 in the stria vascularis) with high IV doses, aminoglycosides or ethacrynic acid
Loop diuretic after IV saline repletion in severe hypercalcaemia
Calciuresis: an adjunct once the patient is volume-replete, never before
Bartter syndrome (loss of NKCC2 type I, ROMK type II, ClC-Kb type III, barttin type IV with sensorineural deafness)
The picture of chronic loop-diuretic use: hypokalaemic metabolic alkalosis, hypercalciuria with nephrocalcinosis, polyuria, normal or low blood pressure, high renin and aldosterone; antenatal polyhydramnios
Medullary ischaemia from hypotension, NSAIDs, contrast or rhabdomyolysis
TAL and S3 cells are the most oxygen-hungry in the worst-perfused zone, so they die first in acute tubular necrosis: muddy brown casts, FE Na over 2%, isosthenuria
Practise this structure
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