Distal convoluted tubule

What it normally does

• It reclaims only about 5 to 7 percent of the filtered sodium, using a carrier that brings sodium and chloride in together from the urine (the sodium-chloride cotransporter, NCC), with the basolateral sodium-potassium ATPase keeping intracellular sodium low so the carrier keeps working.

  this is the fine adjustment knob, not the main tap — blocking it gives a modest, sustainable drop in blood pressure rather than a torrential diuresis, and explains why thiazides are gentle where loop diuretics are brisk.

• The wall of the DCT proper is effectively waterproof: it has no ADH-regulated water channels, so salt is pulled out but water cannot follow and the fluid leaving is more dilute than the fluid arriving. (Only at the very end, where it merges into the connecting tubule, does the epithelium begin to respond to ADH.) The DCT, with the thick ascending limb above it, is where dilute urine gets made.

  block salt uptake here and the kidney can no longer dilute properly; water is then retained without sodium, which is exactly how thiazides drop the plasma sodium.

• Calcium is let into the cell from the urine through a channel on the surface (TRPV5), ferried across by calbindin, and moved out the back of the cell by a swap that trades three sodiums in for one calcium out (the sodium-calcium exchanger, NCX1) alongside a calcium pump (PMCA). Parathyroid hormone turns the whole process up.

  the DCT and the connecting tubule just after it are where calcium is carried across the cell under hormonal control, rather than trailing sodium and water passively as it does in the segments upstream — so this is where PTH sets the final calcium balance, and where thiazides shift urinary calcium down (helped, and possibly outweighed, by extra passive calcium reabsorption in the proximal tubule when volume contracts).

• The far end hands over to the aldosterone-sensitive principal cells, where sodium is taken back through a channel (ENaC), making the lumen electrically negative, and potassium then flows out into the urine through ROMK down that electrical gradient.

  whatever sodium the DCT fails to reabsorb lands there, so extra sodium delivered downstream is largely paid for in potassium — the more so when aldosterone is high, as it is after a diuretic — and with aldosterone driving hydrogen ion secretion alongside it, that is the origin of hypokalaemia with a metabolic alkalosis.

What goes wrong

• Primary hypertension (the salt-sensitive component)← from “It reclaims only about 5 to 7 percent of the f…”

  The DCT makes the final adjustment to sodium balance, and long-term sodium balance sets long-term blood pressure. If this segment holds back a little more sodium than the body needs — from high dietary salt, ageing, fewer nephrons than average, or an overactive WNK signalling pathway driving NCC — the retained sodium holds water, plasma volume rises, and the arterioles remodel and stiffen in response. Blood pressure sits a few millimetres higher, year after year. This is one contributor among several (sympathetic drive, the renin-angiotensin system, vascular stiffening), not the whole of primary hypertension.

  Only about 5-7% of the filtered sodium is reclaimed here, but it is the adjustable 5-7%. Around a third of Australian adults have high blood pressure. It appears younger and progresses to end-stage kidney disease far more often in Aboriginal and Torres Strait Islander communities, where dialysis rates are several times the national figure and higher again in remote areas — which is why blood pressure and urine albumin are checked early and often in those patients.

  You would find: Usually nothing at all. You find it by measuring: a raised blood pressure on repeated readings, and later the damage it has done — left ventricular hypertrophy on ECG or echo, albumin in the urine, a slowly falling eGFR.

• Idiopathic hypercalciuria and recurrent calcium stones← from “Calcium is let into the cell from the urine th…”

  If the DCT (helped by an absorptive gut) lets too much calcium slip through into the urine, calcium concentration in the tubular fluid climbs. Water is then stripped out downstream in the collecting duct, so calcium oxalate supersaturates and crystallises. Most recurrent stone formers have entirely normal parathyroids and normal serum calcium — the abnormality is in the urine.

  High URINARY calcium, not high serum calcium, is what makes stones. Roughly one in ten Australians forms a stone in their lifetime, more men than women, and more in hot northern Australia where sweat losses concentrate the urine. Fluid first — that is the measure with the best evidence; a thiazide is added when fluid and diet are not enough, and the NOSTONE trial is a reminder not to promise too much from it.

  You would find: Loin-to-groin colic, vomiting, blood in the urine, and a stone on non-contrast CT. The useful test afterwards is a 24-hour urine: high calcium, low volume (and check oxalate, citrate and urate too, since low citrate and high oxalate are just as common).

• Thiazide-induced hyponatraemia← from “The wall of the DCT proper is effectively wate…”

  The DCT is where dilute urine is finished off — salt is removed from a tube that water cannot cross. Block salt uptake there and the kidney loses much of its ability to make maximally dilute urine, while the concentrating machinery in the loop and medulla is left untouched. Add the mild volume loss, which releases ADH, and water the patient drinks is retained without its sodium. Plasma sodium falls.

  Thiazides, not loop diuretics, are the classic diuretic cause of hyponatraemia — they hit the diluting segment and spare the medullary gradient, whereas loops blunt the gradient the concentrating response depends on. Common enough in older Australians to be a routine admission diagnosis. Serum sodium is usually rechecked one to two weeks after the drug is started.

  You would find: Typically an older woman, days to a few weeks after the drug is started, with nausea, confusion, unsteadiness or a fall. Serum sodium low, urine osmolality inappropriately high, urine sodium not low.

• Gitelman syndrome← from “The far end hands over to the aldosterone-sens…”

  An autosomal recessive loss-of-function mutation in SLC12A3, the gene for NCC — the transporter a thiazide blocks. Sodium escapes the DCT; the mild volume depletion drives renin and aldosterone up, so at the aldosterone-sensitive segment that sodium is reabsorbed through ENaC, the lumen turns negative and potassium is lost through ROMK while the intercalated cells secrete hydrogen ions — hence hypokalaemia with metabolic alkalosis. TRPM6 in the remodelled DCT is downregulated, so magnesium is wasted too, and urinary calcium is low for the same reasons a thiazide lowers it.

  Gitelman is a thiazide in a bottle: low K, low Mg, alkalosis, LOW urinary calcium, normal or low BP, presenting in adolescence or adulthood. Bartter is a loop diuretic in a bottle: hypokalaemic alkalosis with HIGH urinary calcium, usually normal magnesium, presenting in infancy or childhood. Gitelman is the commonest inherited tubulopathy (about 1 in 40,000) and the reason unexplained hypokalaemia gets a urinary calcium and a magnesium.

  You would find: A teenager or young adult with muscle cramps, tetany, fatigue and salt craving, and a low-normal blood pressure. Bloods show low potassium, low magnesium and a metabolic alkalosis; the discriminators are a low urinary calcium and the hypomagnesaemia.

What we give, and how it works

Open a drug to see what it binds, what that does to the cell, and what you then see in the patient.