Countercurrent mechanism

The core idea

Concentrated urine needs two things: a very hypertonic medullary interstitium (up to about 1,200 mOsm/kg) and a collecting duct that water can cross. The loop of Henle creates the first; ADH provides the second. Without ADH, urine stays dilute however salty the medulla is. Note that in absolute terms the proximal tubule still reabsorbs the most water (about 65%) with or without ADH; ADH controls the final 10–15% in the distal nephron.

The countercurrent multiplier (loop of Henle)

• The thick ascending limb pumps NaCl out (NKCC2) but is impermeable to water: tubular fluid becomes dilute (about 100 mOsm/kg at the top) while the interstitium becomes salty.
• The descending limb is permeable to water but not solute, so water leaves into the salty interstitium and the fluid concentrates as it descends.
• Flow in opposite directions multiplies a small horizontal difference (about 200 mOsm/kg) at each level into a large vertical gradient: its function is to create a hyperosmotic medulla, from about 300 in the cortex to about 1,200 mOsm/kg at the papilla.
• Juxtamedullary nephrons with long loops make the gradient; desert animals have very long loops.

Urea recycling

With ADH, urea leaves the inner medullary collecting duct (UT-A1 transporters) and supplies about half of the inner medullary osmolality. Low-protein diets and malnutrition reduce urea and concentrating ability.

The countercurrent exchanger (vasa recta)

The hairpin vasa recta carry slow blood down and up the medulla. Solutes diffuse in on the way down and out on the way up, so blood leaves without washing away the gradient. Increased medullary flow (osmotic diuresis, loop diuretics) washes it out.

ADH (vasopressin)

• A neurosecretory hormone: made in the supraoptic (mainly) and paraventricular nuclei of the hypothalamus, carried down axons bound to its carrier neurophysin II, stored and released from the posterior pituitary. The precursor also yields copeptin, released in equal amounts. Copeptin is stable in blood, so it is measured instead of ADH in diagnosing DI. (Oxytocin's carrier is neurophysin I.)
• Osmoreceptors sit in the anterior hypothalamus, in the organum vasculosum of the lamina terminalis (OVLT) and subfornical organ, outside the blood–brain barrier.
• Released by: a rise in plasma osmolality (about 1–2%; the most sensitive stimulus), a fall in blood volume or pressure of about 10% or more (less sensitive but more powerful once triggered, and able to override low osmolality), angiotensin II, nausea, pain, stress, surgery, nicotine, morphine, carbamazepine.
• Inhibited by: low osmolality, alcohol, cold, ANP.
• V2 receptors (collecting duct principal cells): Gs, cAMP, protein kinase A; aquaporin-2 inserted into the luminal membrane; water reabsorbed into the hypertonic medulla. ADH also raises urea permeability. V1 receptors on vessels use Gq and IP₃, causing vasoconstriction.
• Net effect: concentrated urine and a fall in plasma osmolality.

Thirst

Thirst centres lie in the anterior hypothalamus with the osmoreceptors. Thirst is increased by raised osmolality, hypovolaemia and angiotensin II; it is reduced quickly by the act of drinking and by gastric distension, before the water is absorbed. Thirst protects against hypernatraemia whenever water is available, so hypernatraemia occurs mostly in infants, the elderly and the unconscious. In severe dehydration ADH, renin, angiotensin II, aldosterone and thirst all rise; a thirsty person's next response is more ADH and concentrated urine.

Physiological ADH states

• After major surgery (first 24–48 hours): stress raises ADH and aldosterone, so urine output and urine sodium fall despite adequate fluids. Excess hypotonic fluid at this time causes dangerous hyponatraemia.
• Pregnancy: the osmotic thresholds for thirst and ADH reset about 10 mOsm/kg lower, so sodium of about 134 mmol/L is normal.
• Heart failure and cirrhosis: low effective arterial filling causes non-osmotic ADH release via baroreceptors, so water is retained and sodium falls even though total body sodium is high (oedema).

Urine osmolality limits

• Maximum about 1,200 mOsm/kg (high ADH); minimum about 50 mOsm/kg (no ADH).
• The daily solute load is about 600–800 mOsm; at maximum concentration this needs at least 0.5 L (the obligatory urine volume).
• Water excretion depends on solute: with a minimum urine osmolality of 50, 300 mOsm of solute allows only 6 L of urine. A beer drinker eating almost nothing (beer potomania, tea and toast) has so little solute that he cannot excrete his water intake, despite suppressed ADH and urine osmolality of 60 mOsm/kg.

Diabetes insipidus and related polyuria

• Losing the supraoptic nucleus means loss of ADH, so more water is lost in urine, with thirst.
• Water deprivation test: in DI urine stays dilute despite deprivation; desmopressin then concentrates it in central but not nephrogenic DI.
• Chronic hypokalaemia (for example laxative abuse) and hypercalcaemia down-regulate aquaporin-2 and reduce medullary tonicity; correct the electrolyte before diagnosing primary nephrogenic DI.
• Acute tubular necrosis gives urine osmolality near plasma (about 300), urine Na⁺ above 40 and FENa above 2% because damaged tubules cannot concentrate.

SIADH

• Low plasma osmolality (< 275 mOsm/kg) with inappropriately concentrated urine (> 100 mOsm/kg), euvolaemia, urine Na⁺ above 30 mmol/L, and normal thyroid, adrenal and renal function.
• Causes: small cell lung cancer, CNS disease, pneumonia, drugs (carbamazepine, SSRIs, cyclophosphamide, vincristine), surgery.
• Why urine sodium is high: water retention mildly expands volume, which suppresses renin and aldosterone and raises ANP, causing natriuresis. Therefore isotonic saline can lower sodium further when urine osmolality exceeds that of the saline.
• Treatment: fluid restriction; then tolvaptan, a V2 receptor antagonist that causes aquaresis (water loss without solute), started in hospital because sodium can rise too fast.

Correcting sodium safely

• Severe symptomatic hyponatraemia (seizures, drowsiness, sodium 116): give a bolus of 3% hypertonic saline (about 150 mL), repeated if needed, to raise sodium a few mmol/L quickly.
• Then limit the total rise to about 8–10 mmol/L in 24 hours; faster correction of chronic hyponatraemia causes osmotic demyelination days later. Correcting hypernatraemia too fast causes cerebral oedema.

Remember Loop multiplies, vasa recta exchange, ADH opens aquaporin-2: no ADH, no concentrated urine.

Exam trap ADH is made in the hypothalamus (supraoptic nucleus) and released from the posterior pituitary; its stable surrogate is copeptin, not neurophysin I.

Exam trap SIADH has low plasma osmolality with inappropriately concentrated urine and high urine sodium in a euvolaemic patient.

How FCPS asks about this

• Function of the countercurrent multiplier: creates a hyperosmotic medulla; the vasa recta preserve it as exchangers.
• Most sensitive stimulus for ADH: a 1–2% rise in plasma osmolality sensed in the anterior hypothalamus (OVLT); hypovolaemia is more powerful.
• ADH mechanisms: V2, cAMP, aquaporin-2 for water; V1, IP₃ for vasoconstriction.
• Damage to the supraoptic nucleus: loss of ADH, polyuria with dilute urine (central DI).
• Polyuria in pregnancy resolving after delivery: placental vasopressinase; treat with desmopressin.
• SIADH: serum osmolality below 275 with urine above 100 mOsm/kg; tolvaptan blocks V2 receptors.
• Urine osmolality 1,200 with serum 350: water deprivation, a normal kidney response.