Overview

The TAL runs from the inner/outer medulla boundary up through the outer medulla and a medullary ray to its own glomerulus. Its cuboidal cells take up Na⁺, K⁺ and 2Cl⁻ via the apical Na⁺–K⁺–2Cl⁻ cotransporter (NKCC2), the target of loop diuretics; K⁺ is recycled back to the lumen through ROMK channels, and Cl⁻ exits basolaterally through ClC-Kb (with barttin). The recycling of K⁺ and the basolateral exit of Cl⁻ create a lumen-positive transepithelial voltage (+5 to +10 mV) that drives paracellular reabsorption of Ca²⁺ and Mg²⁺ (via claudin-16/19 tight junctions) and of additional Na⁺.

The TAL has no aquaporins, so as NaCl is removed the tubular fluid becomes progressively more dilute (≈100 mOsm/kg at the macula densa), while the interstitium becomes hypertonic — the single effect of the countercurrent multiplier. It also secretes uromodulin (Tamm–Horsfall protein), the most abundant urinary protein and the matrix of all urinary casts, and reclaims ≈10–15% of filtered HCO₃⁻ (NHE3). The calcium-sensing receptor on its basolateral membrane reduces NKCC2/ROMK activity when plasma Ca²⁺ is high.

Location: Outer medulla and medullary rays of the cortex.

Anatomy

Histology: Simple cuboidal epithelium without a brush border; many mitochondria in basolateral infoldings; macula densa plaque at its terminal portion.

Function

Reabsorb ≈25% of filtered Na⁺/Cl⁻ (NKCC2)
Dilute tubular fluid (water-impermeable)
Generate the single effect of the countercurrent multiplier
Reabsorb ≈20–25% of filtered Ca²⁺ and ≈60–70% of Mg²⁺ paracellularly
Secrete uromodulin (Tamm–Horsfall protein)

Physiology: High O₂ consumption (Na⁺/K⁺-ATPase) in a hypoxic medulla makes the medullary TAL vulnerable to ischaemia.
Regulation: ADH (V2) increases NKCC2 activity; calcium-sensing receptor and prostaglandins inhibit it.

Clinical significance

Bartter syndrome

Autosomal recessive loss of function of NKCC2, ROMK, ClC-Kb or barttin — mimics chronic loop-diuretic use: hypokalaemic metabolic alkalosis, high renin and aldosterone with normal blood pressure, and hypercalciuria (nephrocalcinosis).

Loop diuretics

Inhibit NKCC2: potent natriuresis, loss of Ca²⁺ and Mg²⁺ (lumen-positive voltage abolished), medullary gradient washout, hypokalaemic alkalosis, ototoxicity (NKCC1 in the inner ear).

Mnemonics

Loop diuretics lose calcium

"Loops Lose Calcium" (hypercalciuria) — whereas thiazides retain calcium.

Test yourself

Which segment of the nephron is called the "diluting segment" because it reabsorbs NaCl actively but is impermeable to water?

Thin descending limb
Thick ascending limb
Inner medullary collecting duct
Proximal convoluted tubule

Answer: Thick ascending limb

The thick ascending limb lacks aquaporins; NKCC2 removes NaCl so tubular fluid leaving it is hypo-osmotic (≈100 mOsm/kg) whatever the ADH level. This also generates the single effect of the countercurrent multiplier.