25 RENAL TRANSPORT

👩‍⚕️ MRCS Tip: Renal transport is one of the most reliably examined physiology topics in Part A. If you can map each nephron segment to (a) what it absorbs, (b) which transporter does the work, and (c) which diuretic blocks it, you will pick up easy marks every sitting.

How the nephron processes filtrate

Around 180 L of plasma is filtered into Bowman's space each day. Less than 1% leaves as urine. The nephron achieves this through five functionally distinct segments arranged in series, each with characteristic transporters on the apical (luminal) membrane and a universal Na+/K+ ATPase on the basolateral side. The basolateral pump is the engine — it keeps intracellular Na+ low so that Na+ flows down its electrochemical gradient from lumen into cell, dragging glucose, amino acids, bicarbonate, water and other solutes with it.

Everything that follows is a variation on that theme: different apical transporters, different permeabilities, different hormonal control.

Master table — nephron segments at a glance

Segment	% Na+ reabsorbed	Key apical transporter	Other handled	Water permeable?	Hormone control	Diuretic site
PCT	65–70%	NHE3 (Na+/H+); SGLT2 (glucose); Na+/amino acid	HCO3- reclaimed; glucose; amino acids; PO4	Yes (isotonic)	PTH (inhibits PO4); AngII	Acetazolamide; mannitol (osmotic)
Thin descending LoH	—	None (passive)	Water out	Yes (AQP1)	—	None
Thin ascending LoH	Small	Passive NaCl	NaCl out	No	—	None
Thick ascending LoH	25%	NKCC2 (Na+/K+/2Cl-)	Ca2+, Mg2+ (paracellular)	No	—	Loop diuretics (furosemide, bumetanide)
DCT	5–8%	NCC (Na+/Cl-)	Ca2+ (PTH-stimulated via TRPV5)	No	PTH	Thiazides
Collecting duct — principal cell	2–3%	ENaC (Na+); AQP2 (water)	K+ secreted	Variable (ADH-controlled)	Aldosterone (ENaC); ADH (AQP2)	Amiloride; spironolactone
Collecting duct — α-intercalated	—	H+-ATPase; H+/K+ ATPase	H+ secreted; HCO3- reabsorbed	No	Aldosterone (mildly)	—

Memorise this table. Almost every renal physiology SBA can be answered from it.

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Proximal convoluted tubule — bulk reabsorption

The PCT reabsorbs roughly two-thirds of everything filtered. It is isotonic reabsorption: water follows solutes so the fluid leaving the PCT has the same osmolality as plasma, just smaller in volume.

Glucose is reabsorbed by SGLT2 in the early PCT (≈90%) and SGLT1 in the late PCT (≈10%). Both use the Na+ gradient. Glucose appears in urine only when plasma glucose exceeds the transport maximum (~11 mmol/L) — this is why glycosuria suggests diabetes mellitus. SGLT2 inhibitors (dapagliflozin, empagliflozin) are now standard in diabetes and heart failure; they deliberately cause glycosuria.

Bicarbonate is reclaimed via NHE3. The H+ secreted into the lumen combines with filtered HCO3- to form H2CO3, which carbonic anhydrase (in the brush border) splits into CO2 and water. CO2 diffuses into the cell, is rehydrated by intracellular carbonic anhydrase back to HCO3-, and exported basolaterally. Acetazolamide inhibits carbonic anhydrase here, causing bicarbonate loss and a mild metabolic acidosis — useful in glaucoma, altitude sickness, and as a weak diuretic.

Amino acids, phosphate, citrate and other organic solutes all hitch a ride on the Na+ gradient. PTH inhibits phosphate reabsorption, which is why hyperparathyroidism causes phosphaturia.

Loop of Henle — the counter-current multiplier

The loop's job is to build a hypertonic medullary interstitium so that the collecting duct can later concentrate urine.

Thin descending limb is permeable to water (AQP1) but not solute. As filtrate descends into the hypertonic medulla, water leaves and tubular fluid becomes progressively concentrated — peaking at ~1200 mOsm/kg at the hairpin.

Thick ascending limb (TAL) is the engine of the counter-current multiplier. It is impermeable to water but actively pumps NaCl out via NKCC2. This dilutes tubular fluid (down to ~100 mOsm/kg) while loading the interstitium with NaCl — hence its nickname the diluting segment.

NKCC2 also drives a lumen-positive voltage, which forces Ca2+ and Mg2+ out paracellularly. Loop diuretics (furosemide, bumetanide) block NKCC2 and therefore cause:

➡ Massive natriuresis and diuresis (most powerful diuretic class)

➡ Hypokalaemia (more Na+ delivered to CD → more Na+/K+ exchange)

➡ Hypocalcaemia and hypomagnesaemia (lost paracellular gradient)

➡ Metabolic alkalosis (volume contraction + H+ loss in CD)

➡ Ototoxicity (NKCC2 also exists in the inner ear)

Bartter syndrome is essentially a genetic furosemide — loss-of-function in NKCC2.

Vasa recta — the counter-current exchanger

The medullary gradient built by the loop would be washed out by blood flow if the vasa recta ran straight through. Instead they form hairpin loops parallel to the loop of Henle. Solutes diffuse out of the ascending vasa recta back into the descending vasa recta, while water does the opposite. This passive counter-current exchange preserves the gradient.

> Pearl: The loop of Henle is the counter-current multiplier (active, energy-using, makes the gradient). The vasa recta is the counter-current exchanger (passive, blood vessel, preserves the gradient). Examiners love this distinction.

Distal convoluted tubule — fine-tuning sodium and calcium

The DCT reabsorbs ~5–8% of Na+ through the NCC (Na+/Cl- cotransporter), blocked by thiazides (bendroflumethiazide, hydrochlorothiazide). Thiazides are weaker than loop diuretics but useful in hypertension and mild oedema.

A useful exam trap: thiazides cause hypercalcaemia, whereas loops cause hypocalcaemia. The mechanism is that blocking NCC lowers intracellular Na+, which stimulates basolateral Na+/Ca2+ exchange and thereby increases Ca2+ reabsorption. Loop diuretics increase calcium excretion — useful in acute hypercalcaemia.

Gitelman syndrome is the genetic equivalent of thiazide therapy — loss-of-function in NCC, presenting with hypokalaemia, metabolic alkalosis, and hypocalciuria.

PTH binds DCT receptors to activate the TRPV5 calcium channel, increasing calcium reabsorption — the basis of PTH's hypercalcaemic action on the kidney.

Collecting duct — hormonal control of final urine

The CD has two cell populations:

Principal cells carry ENaC (epithelial Na+ channel) on the apical membrane. Aldosterone (from adrenal zona glomerulosa) increases ENaC number and activity, driving Na+ reabsorption and K+ secretion. Spironolactone and eplerenone competitively antagonise the mineralocorticoid receptor; amiloride and triamterene block ENaC directly. Both classes are potassium-sparing.

Principal cells also carry aquaporin-2 (AQP2), the only water channel under hormonal control. ADH (vasopressin) binds V2 receptors → cAMP → AQP2 insertion into the apical membrane → water reabsorption. No ADH = dilute urine (diabetes insipidus). Lots of ADH = concentrated urine (SIADH, hypovolaemia).

α-intercalated cells secrete H+ via apical H+-ATPase and H+/K+ ATPase, with basolateral HCO3- export. This is where the kidney makes new bicarbonate and excretes the daily acid load (≈70 mmol/day, as NH4+ and titratable acid).

β-intercalated cells do the opposite — they secrete HCO3- and reabsorb H+ during alkalosis.

Acid-base summary

➡ PCT reclaims filtered HCO3- (≈4,500 mmol/day) via NHE3 and brush-border carbonic anhydrase.

➡ Collecting duct excretes the daily H+ load and generates new HCO3- via α-intercalated cells.

➡ NH4+ is the principal urinary buffer — synthesised from glutamine in the PCT and trapped in the lumen of the CD.

Renal tubular acidosis (RTA) — the three types you must know

Type	Defect	Urine pH	Serum K+	Classic cause
Type 1 (distal)	α-intercalated cell can't secrete H+	>5.5 (inappropriately high)	Low	Sjögren's, SLE, amphotericin; kidney stones (calcium phosphate)
Type 2 (proximal)	PCT can't reabsorb HCO3-	Low (initially), variable	Low	Fanconi syndrome, multiple myeloma, acetazolamide
Type 4	Aldosterone deficiency or resistance	<5.5	High	Diabetic nephropathy, Addison's, ACE inhibitors, K+-sparing diuretics

All three give a normal anion gap (hyperchloraemic) metabolic acidosis. Type 4 is the only one with hyperkalaemia — the easiest discriminator in an SBA.

Diuretic summary

Class	Site	Target	Key adverse effect
Carbonic anhydrase inhibitor (acetazolamide)	PCT	Carbonic anhydrase	Metabolic acidosis, hypokalaemia
Osmotic (mannitol)	PCT + descending limb	None (osmotic effect)	Pulmonary oedema if overdosed
Loop (furosemide, bumetanide)	TAL	NKCC2	↓K+, ↓Ca2+, ↓Mg2+, alkalosis, ototoxicity
Thiazide (bendroflumethiazide)	DCT	NCC	↓K+, ↑Ca2+, ↑uric acid, ↑glucose
K+-sparing — aldosterone antagonist (spironolactone)	CD	Mineralocorticoid receptor	↑K+, gynaecomastia
K+-sparing — ENaC blocker (amiloride)	CD	ENaC	↑K+

> Pearl: "Loops Lose Calcium, Thiazides Take it back." A single mnemonic that has rescued countless candidates.

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Test yourself

What is the mechanism when thiazide and loop diuretics are used together?

• ((Antagonism::Both reduce Na+ reabsorption — they do not oppose each other.))
• ((Potentiation::Implies one enhances the other's mechanism — not the precise term.))
• ((Synergism::☑️ Blocking Na+ at two sites (NKCC2 in TAL + NCC in DCT) gives a greater combined effect.))
• ((Tachyphylaxis::Refers to rapid tolerance with repeated dosing — not relevant.))
• ((Competitive inhibition::They act at different transporters, not the same one.))

👩‍⚕️ Sequential nephron blockade is potent but dangerous — severe hypokalaemia, hyponatraemia and dehydration. Reserved for resistant oedema.

What is the primary mechanism of Na+ reabsorption in the nephron?

• ((Simple diffusion::Na+ moves against its concentration gradient — diffusion alone cannot achieve this.))
• ((Osmosis::Describes water movement, not ion transport.))
• ((Active transport::☑️ Basolateral Na+/K+ ATPase drives Na+ reabsorption throughout the nephron.))
• ((Facilitated diffusion::Carrier-mediated but ATP-independent — insufficient for Na+ reabsorption.))
• ((Solvent drag::Paracellular assist mechanism, not the primary driver.))

👩‍⚕️ The Na+/K+ ATPase is the engine — every apical transporter ultimately depends on the gradient it sets up.

What mainly mediates the counter-current multiplier?

• ((Active transport out of the thin ascending limb::The thin ascending limb is passive, not active.))
• ((Water impermeability of the thick ascending limb::☑️ NaCl is pumped out via NKCC2 but water cannot follow — this generates the medullary gradient.))
• ((Solute permeability of the descending limb::The descending limb is permeable to water, not solute.))
• ((Solute permeability of the thick ascending limb::Solute IS transported here, but the defining feature is water impermeability.))
• ((Water permeability of the thin ascending limb::The ascending limb is impermeable to water — that's the whole point.))

👩‍⚕️ The TAL is the "diluting segment". It removes solute but retains water — tubular fluid leaves dilute, interstitium becomes concentrated.

Where are SGLT2 transporters located?

• ((Proximal convoluted tubule::☑️ SGLT2 reabsorbs ~90% of filtered glucose. SGLT2 inhibitors (e.g. dapagliflozin) cause therapeutic glycosuria.))
• ((Distal convoluted tubule::NCC lives here, not SGLT2.))
• ((Thick ascending limb::NKCC2 is the dominant transporter here.))
• ((Collecting duct::ENaC and aquaporin-2 — no glucose handling.))
• ((Descending loop of Henle::Aquaporin-1 only — water reabsorption.))

Where are mannitol and glucose normally handled in the nephron?

• ((Distal convoluted tubule::Glucose is fully reabsorbed before reaching the DCT.))
• ((Ascending loop of Henle::Site of NKCC2 — no glucose handling.))
• ((Descending loop of Henle::Water reabsorption only.))
• ((Collecting tubule::Site of Na+/water fine-tuning, not glucose.))
• ((Proximal convoluted tubule::☑️ Glucose reabsorbed via SGLT2/SGLT1. Mannitol is filtered but NOT reabsorbed — it traps water osmotically here.))

👩‍⚕️ Glucose IS reabsorbed (unless plasma glucose > Tm ~11 mmol/L). Mannitol is NOT — that is exactly how it works as an osmotic diuretic.

What is the site of action of furosemide?

• ((Proximal convoluted tubule::Site of acetazolamide, not furosemide.))
• ((Distal convoluted tubule::Site of thiazides.))
• ((Thick ascending limb of the loop of Henle::☑️ Furosemide inhibits the NKCC2 cotransporter.))
• ((Descending limb::No diuretic acts here.))
• ((Collecting duct::Site of spironolactone and amiloride.))

What is the site of action of bendroflumethiazide?

• ((Proximal convoluted tubule::Acetazolamide acts here.))
• ((Distal convoluted tubule::☑️ Bendroflumethiazide inhibits the NCC (Na+/Cl-) cotransporter.))
• ((Thick ascending limb::Loop diuretics act here.))
• ((Descending limb::No major diuretic target.))
• ((Collecting duct::K+-sparing diuretics act here.))

A patient on long-term lithium develops polyuria. Which transporter is most likely impaired?

• ((NKCC2 in the thick ascending limb::Lithium does not block NKCC2.))
• ((NCC in the DCT::Genetic loss causes Gitelman syndrome — not the lithium mechanism.))
• ((ENaC in the collecting duct::Amiloride blocks this; can paradoxically treat lithium-induced DI.))
• ((Aquaporin-2 in the collecting duct::☑️ Lithium causes nephrogenic diabetes insipidus by reducing AQP2 expression and response to ADH.))
• ((SGLT2 in the PCT::Causes glycosuria, not polyuria from water handling failure.))

👩‍⚕️ Nephrogenic DI = the kidney can't respond to ADH. Lithium and demeclocycline are classic causes.

A patient has hyperchloraemic metabolic acidosis with hypokalaemia and urine pH of 6.5. Which is most likely?

• ((Type 1 (distal) RTA::☑️ α-intercalated cells fail to secrete H+ — urine stays inappropriately alkaline despite systemic acidosis.))
• ((Type 2 (proximal) RTA::Urine pH can acidify normally once HCO3- is depleted — pH usually <5.5.))
• ((Type 4 RTA::Aldosterone deficiency causes hyperkalaemia, not hypokalaemia.))
• ((Diabetic ketoacidosis::Raised anion gap, not normal anion gap.))
• ((Diarrhoea::Causes hyperchloraemic acidosis but urine acidifies normally (pH <5.5).))

👩‍⚕️ Inappropriately alkaline urine in the face of acidosis = distal RTA. Calcium phosphate stones are a classic complication.

Which diuretic is most likely to cause gynaecomastia?

• ((Furosemide::Causes hypokalaemia and ototoxicity — not gynaecomastia.))
• ((Bendroflumethiazide::Causes hyperglycaemia, hyperuricaemia and hypercalcaemia.))
• ((Amiloride::K+-sparing but no anti-androgen activity.))
• ((Spironolactone::☑️ Cross-reacts with androgen and progesterone receptors → gynaecomastia, impotence, menstrual irregularity.))
• ((Acetazolamide::Causes metabolic acidosis and renal stones.))

Revision summary

➡ PCT reabsorbs 65–70%: SGLT2 (glucose), NHE3 (Na+/H+, drives HCO3- reclaim), amino acids. Acetazolamide and mannitol act here.

➡ Thin descending LoH — water out only (AQP1).

➡ Thick ascending LoH — NKCC2; the diluting segment; loop diuretic target; impermeable to water = engine of the counter-current multiplier.

➡ DCT — NCC (thiazide target); Ca2+ reabsorbed under PTH control.

➡ Collecting duct principal cells — ENaC (aldosterone, blocked by amiloride and spironolactone) and AQP2 (ADH).

➡ α-intercalated cells — secrete H+ and generate new HCO3-.

➡ Counter-current multiplier = loop of Henle (active). Counter-current exchanger = vasa recta (passive).

➡ Loops lose calcium; thiazides take it back.

➡ RTA type 1 = distal, urine pH >5.5, hypokalaemia, stones.

➡ RTA type 2 = proximal, Fanconi, hypokalaemia.

➡ RTA type 4 = aldosterone deficient, hyperkalaemia (the only hyperkalaemic RTA).

➡ Spironolactone = gynaecomastia. Furosemide = ototoxicity. Thiazide = hyperCa2+, hyperglycaemia, hyperuricaemia.