The nephron and how diuretics work

How the kidney filters blood and takes back salt and water segment by segment, and how each diuretic blocks one of those steps.

Updated Nov 12, 2026

The kidneys filter a large volume of plasma every day and reabsorb almost all of the salt and water. Each part of the nephron uses a different transporter, so each diuretic class acts at one site with a predictable strength and set of side effects. This page explains the segments, the general rules of diuretic action, how oedema forms, how diuretics are chosen in heart, liver and kidney disease, and how vasopressin controls water.

Key points

Each kidney has about a million nephrons: a glomerulus that filters and a tubule that reabsorbs and secretes.
The proximal tubule reabsorbs the most sodium; the thick ascending limb (NKCC2) is the target of loop diuretics; the distal tubule (NCC) of thiazides; the collecting duct (ENaC, aldosterone) of potassium-sparing agents.
Most diuretics must reach the tubular lumen, mainly by secretion in the proximal tubule, to work.
After the first doses the effect fades (braking) as the body defends its volume, and distal segments grow and take up more sodium.
Diuretic resistance is handled by checking salt intake and adherence, adjusting dose and route, and blocking two segments at once (sequential nephron blockade).
Vasopressin acts on V2 receptors to insert aquaporin-2 channels in the collecting duct; vaptans block it and raise serum sodium.

Segment by segment

Glomerulus: filters water and small solutes; proteins and cells stay in the blood.
Proximal tubule: reabsorbs the largest share of filtered sodium, plus bicarbonate (via carbonic anhydrase), glucose (via SGLT2), amino acids and water. Organic acid and base transporters here secrete most diuretics into the lumen. Sites of carbonic anhydrase inhibitors and SGLT2 inhibitors; osmotic diuretics act here and in the loop.
Thin descending limb: permeable to water, not salt; water leaves into the concentrated medulla.
Thick ascending limb: impermeable to water; the Na+–K+–2Cl− cotransporter (NKCC2) takes up a large share of filtered salt and builds the medullary gradient. Loop diuretics block it, which makes them the strongest and also blunts concentrating ability.
Distal convoluted tubule: the Na+–Cl− cotransporter (NCC), blocked by thiazides; also a main site of calcium reabsorption, which thiazides enhance.
Collecting duct: principal cells reabsorb sodium through ENaC and secrete potassium under aldosterone's control; amiloride and triamterene block ENaC, spironolactone and eplerenone block the aldosterone receptor. Vasopressin controls water permeability here.

General principles of diuretic action

The more sodium a segment normally reabsorbs, and the less a later segment can make up for, the stronger the diuretic acting there; this is why loop diuretics are more powerful than thiazides, and potassium-sparing drugs are weak. Diuretics that act before the collecting duct deliver more sodium and fluid there, which increases potassium and hydrogen loss: hence hypokalaemia and metabolic alkalosis with loop and thiazide diuretics. Loop diuretics have a threshold and a ceiling: below a certain luminal concentration little happens, and above the ceiling more drug adds little. Because furosemide is highly bound to albumin and is secreted into the tubule, low albumin, heavy proteinuria (drug bound in the urine) and kidney failure (competing organic acids) all reduce the amount reaching its site.

Braking and diuretic resistance

With repeated doses, natriuresis falls even though the drug is still present. Volume loss activates the renin–angiotensin–aldosterone and sympathetic systems, and salt retention between short-acting doses (post-diuretic rebound) cancels part of the gain. Over weeks, the distal tubule hypertrophies and reabsorbs more of the extra sodium delivered to it. When a patient stays congested despite diuretics, common causes are high salt intake, NSAIDs, poor absorption of oral furosemide in a swollen gut, low kidney perfusion or not taking the drug. Responses include restricting salt, giving the loop diuretic intravenously or more often, switching to a loop diuretic with more reliable absorption such as torasemide or bumetanide, and adding a thiazide-type drug (for example metolazone) to block the hypertrophied distal tubule: sequential nephron blockade. That combination is powerful and needs close watch of potassium, sodium, volume and kidney function.

How oedema forms and how diuretics are chosen

Oedema forms when capillary pressure rises, plasma oncotic pressure falls or the kidney retains salt. In heart failure, cirrhosis and nephrotic syndrome the kidney senses an underfilled circulation and holds on to sodium, so diuretics treat the kidney's response, not the cause.

Heart failure: loop diuretics for congestion; a mineralocorticoid antagonist for its survival benefit; thiazide added for resistance.
Cirrhosis with ascites: spironolactone is the base, because secondary hyperaldosteronism drives the retention; a loop diuretic is often added. Over-diuresis can trigger kidney failure and encephalopathy.
Nephrotic syndrome: loop diuretics, often at higher doses because of low albumin and urinary drug binding, with treatment of the kidney disease itself.
Kidney failure: loop diuretics remain useful while there is residual function; thiazides work less well alone but help in combination.
Not every swelling needs a diuretic: oedema from calcium channel blockers or venous insufficiency does not respond well.

Vasopressin and water balance

Plasma osmolality is kept in a narrow range by thirst and by vasopressin (antidiuretic hormone), released from the posterior pituitary when osmolality rises or when blood volume falls sharply. On V2 receptors in the collecting duct, vasopressin raises cAMP and inserts aquaporin-2 water channels, so water returns to the blood and urine becomes concentrated; V1 receptors on blood vessels cause vasoconstriction. Too little vasopressin action causes diabetes insipidus (central, treated with the V2 agonist desmopressin, or nephrogenic, as with lithium). Too much causes water retention and hyponatraemia, as in SIADH or heart failure. Tolvaptan, a V2 antagonist, increases free-water excretion and raises serum sodium; it is started in hospital because correcting sodium too fast can cause osmotic demyelination, and it can injure the liver.

Test yourself

Think of the answer, then tap the question to see it.

Why are loop diuretics stronger than thiazides?

The thick ascending limb reabsorbs a much larger share of filtered sodium than the distal tubule, and later segments cannot make up for it.

Why do loop and thiazide diuretics cause hypokalaemia?

They deliver more sodium and fluid to the collecting duct, where sodium uptake through ENaC drives potassium secretion, helped by aldosterone.

What is sequential nephron blockade?

Adding a thiazide-type diuretic to a loop diuretic so the hypertrophied distal tubule cannot reclaim the extra sodium; strong, but electrolytes need close watch.

Why is spironolactone the base diuretic in cirrhotic ascites?

Salt retention in cirrhosis is driven largely by secondary hyperaldosteronism, which spironolactone blocks.

How does vasopressin concentrate urine, and how does tolvaptan oppose it?

Through V2 receptors it inserts aquaporin-2 channels in the collecting duct; tolvaptan blocks V2, so more free water is excreted and sodium rises.

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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Your Kidneys & How They Work (National Institute of Diabetes and Digestive and Kidney Diseases, 2026); DailyMed - FUROSEMIDE injection, solution (DailyMed (U.S. National Library of Medicine), 2026); DailyMed - TOLVAPTAN tablet (DailyMed (U.S. National Library of Medicine), 2026).

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