Tubular reabsorption and secretion
Tubular reabsorption and secretion: what each nephron segment does, diuretics and Tm
The proximal tubule reabsorbs two-thirds of the filtrate, the thick ascending limb dilutes it, and the distal nephron fine-tunes salt, acid and water. Covers transporters, diuretic sites, transport maximum sums, Bartter, Gitelman, Liddle and Fanconi.
The core idea
Of 180 L filtered each day, only about 1.5 L becomes urine. Every tubular cell has the Na⁺/K⁺-ATPase on its basolateral membrane; it keeps intracellular Na⁺ low, so Na⁺ flows in from the lumen through a segment-specific transporter. Learn that luminal transporter and you know the drug that blocks it, the inherited disease that mimics the drug, and the electrolyte change that follows.
Segment by segment
| Segment | Share of filtered Na⁺ | Main luminal transporter | What else happens |
|---|---|---|---|
| Proximal convoluted tubule | About 65–70% | Na⁺/H⁺ exchanger (NHE3); SGLT2 (Na⁺–glucose); Na⁺–amino acid; Na⁺–phosphate | Reabsorbs nearly all glucose and amino acids, about 80% of HCO₃⁻, most phosphate, K⁺ and water, isosmotically. Small filtered proteins taken up by endocytosis. Secretes organic acids and bases (PAH, penicillin, uric acid, creatinine). Makes ammonia and calcitriol (1α-hydroxylase) |
| Thin descending limb | — | Aquaporin-1 | Permeable to water, not solute: fluid concentrates |
| Thin ascending limb | — | Passive NaCl exit | Permeable to NaCl, not water |
| Thick ascending limb | About 25% | Na⁺–K⁺–2Cl⁻ (NKCC2) | Impermeable to water: the diluting segment. K⁺ recycling (ROMK) makes the lumen positive, driving paracellular Ca²⁺ and Mg²⁺ reabsorption. Loop diuretics; Bartter syndrome; Tamm–Horsfall protein |
| Distal convoluted tubule | About 5% | Na⁺–Cl⁻ (NCC) | Water-impermeable (cortical diluting segment). PTH-regulated Ca²⁺ reabsorption. Thiazides; Gitelman syndrome |
| Collecting duct, principal cells | About 2–3% | ENaC Na⁺ channels; ROMK K⁺ secretion; aquaporin-2 | Aldosterone (Na⁺ in, K⁺ out) and ADH (water, urea). Spironolactone, amiloride; Liddle syndrome |
| Collecting duct, intercalated cells | — | α cells: H⁺-ATPase, H⁺/K⁺-ATPase; β cells secrete HCO₃⁻ | Acid–base fine-tuning; distal (type 1) RTA |
- Passive reabsorption: water follows solute; Cl⁻ moves passively in the late PCT; urea is reabsorbed passively (about half the filtered load), so urea clearance is below GFR.
- K⁺ in urine is set mainly by secretion in the late distal tubule and collecting duct, increased by aldosterone, high Na⁺ delivery and high flow (diuretics), and alkalosis.
- The vasa recta, straight capillary loops beside the loop of Henle, act as countercurrent exchangers that preserve the medullary gradient (see urine concentration).
Transport maximum (Tm) and glucose
A substance with a Tm is reabsorbed (or secreted) by carriers that saturate. Below Tm all the filtered load is reabsorbed; above it, the excess is excreted.
- Glucose is reabsorbed in the PCT, mainly by SGLT2 (90%) with SGLT1 later; it leaves the cell by GLUT2.
- Renal threshold for glucose is about 10 mmol/L (180 mg/dL); Tm is about 375 mg/min. Glycosuria begins before the calculated Tm because nephrons differ in capacity (splay).
- Worked example: plasma glucose 400 mg/dL = 4 mg/mL; GFR 125 mL/min; filtered load = 500 mg/min; reabsorbed = 375 mg/min; excreted = 125 mg/min.
- Unreabsorbed glucose holds water in the tubule, causing osmotic diuresis: polyuria with high urine osmolality (not diabetes insipidus). Mannitol does the same deliberately.
- SGLT2 inhibitors (dapagliflozin, empagliflozin) cause glycosuria and natriuresis. More NaCl reaching the macula densa triggers tubuloglomerular feedback, constricting the afferent arteriole: eGFR falls slightly in the first weeks then stabilises, and long-term kidney function is protected. Do not stop the drug for this small stable fall.
Diuretics by site
| Class | Site | K⁺ | Urinary Ca²⁺ | Key points |
|---|---|---|---|---|
| Carbonic anhydrase inhibitor (acetazolamide) | PCT | ↓ | — | HCO₃⁻ loss, metabolic acidosis; altitude, glaucoma |
| Osmotic (mannitol) | PCT and descending limb | ↓ | — | Raised ICP; avoid in anuria and heart failure |
| Loop (furosemide) | Thick ascending limb, NKCC2 | ↓ | ↑ | Most potent; hypercalcaemia (after fluids); ototoxicity; hypomagnesaemia |
| Thiazide and thiazide-like (bendroflumethiazide, indapamide) | DCT, NCC | ↓ | ↓ | Raise serum Ca²⁺, urate and glucose; prevent calcium stones |
| K⁺-sparing (spironolactone, eplerenone; amiloride, triamterene) | Collecting duct | ↑ | — | Spironolactone: gynaecomastia; hyperkalaemia with ACE inhibitors |
- A man with recurrent calcium oxalate stones and hypercalciuria with normal serum calcium is given a thiazide or indapamide, which lowers urinary calcium.
- Thiazide hyponatraemia: thiazides block the cortical diluting segment, so the kidney cannot dilute urine, but the medullary gradient is intact, so ADH can still concentrate urine and retain water. A thin elderly woman drinking a lot of tea can drop her sodium to 118 mmol/L with inappropriately concentrated urine within weeks. Loop diuretics abolish the medullary gradient, impairing both dilution and concentration, so severe hyponatraemia is rare with them.
Inherited mimics of diuretics
| Syndrome | Defect | Like | Findings |
|---|---|---|---|
| Bartter | NKCC2 (or ROMK, Cl⁻ channel) | Loop diuretic | Hypokalaemic metabolic alkalosis, high urinary Ca²⁺, high renin and aldosterone, normal BP; childhood |
| Gitelman | NCC | Thiazide | Hypokalaemic alkalosis, low urinary Ca²⁺, low Mg²⁺; milder, later |
| Liddle | Overactive ENaC (gain of function) | Excess aldosterone | Hypertension, hypokalaemia, alkalosis, low renin and low aldosterone; treat with amiloride, not spironolactone |
Proximal tubule failure and proteins
- Fanconi syndrome: generalised proximal failure with glycosuria at normal blood glucose, aminoaciduria, phosphaturia (rickets, osteomalacia), bicarbonate wasting and hypokalaemia. Causes: myeloma light chains, Wilson disease, cystinosis, outdated tetracyclines, tenofovir, ifosfamide, lead.
- Type 2 (proximal) RTA is failure to reabsorb bicarbonate in the PCT; type 1 (distal) is failure to secrete H⁺ in the collecting duct.
- Cystinuria: defective dibasic amino acid transporter (cystine, ornithine, lysine, arginine), giving cystine stones.
- Proteins normally stay out of the filtrate because of the size and charge barrier; the few that pass are reabsorbed in the PCT. In nephrotic syndrome, heavy proteinuria loses antithrombin III (with proteins C and S), and the liver makes more fibrinogen, so renal vein thrombosis occurs (most often in membranous nephropathy). Lipiduria leaves lipid-laden "foam cells" in tubules and oval fat bodies in urine.
- Acute tubular necrosis destroys tubular reabsorption: urine sodium and FENa rise, urine osmolality approaches plasma (isosthenuria), and muddy-brown granular casts appear.
Remember Basolateral Na⁺/K⁺-ATPase powers everything; PCT does bulk isosmotic work, the thick ascending limb dilutes, the collecting duct takes orders from aldosterone and ADH.
Exam trap Loop diuretics increase urinary calcium; thiazides and indapamide decrease it.
Exam trap Thiazides cause severe hyponatraemia because they impair dilution while leaving concentration intact.
How FCPS asks about this
- Most Na⁺ and water reabsorbed: proximal tubule (65–70%), isosmotically; glucose and amino acids almost entirely here.
- Diluting segment, impermeable to water: thick ascending limb (NKCC2, furosemide).
- Na⁺ reabsorption in the collecting duct: ENaC under aldosterone; K⁺ secretion rises with aldosterone and flow.
- Renal threshold for glucose: about 180 mg/dL (10 mmol/L); excretion = filtered load − Tm.
- Diuretic to reduce hypercalciuric stones: thiazide or indapamide.
- Bartter versus Gitelman versus Liddle: high urine Ca²⁺; low urine Ca²⁺ and Mg²⁺; hypertension with low renin and aldosterone.
- Type 2 RTA: failure of proximal bicarbonate reabsorption, often part of Fanconi syndrome.
Test yourself on this topic
5 of the 47 questions in our bank on this topic. Choose an answer to see why every option is right or wrong.
Approximately what proportion of filtered sodium and water is reabsorbed in the proximal convoluted tubule?
Answer: About 65%
The proximal tubule reabsorbs about 65% of filtered Na⁺, water and K⁺ (isosmotically), about 80–90% of bicarbonate (via carbonic anhydrase), nearly all filtered glucose and amino acids (secondary active transport with Na⁺), most phosphate (regulated by PTH) and uric acid, and it secretes organic acids and bases (penicillin, PAH, many drugs). The thick ascending limb reabsorbs about 25% of Na⁺; the distal convoluted tubule about 5%; the collecting duct the final 2–3% under aldosterone. Overall about 99% of filtered sodium is reabsorbed.
Sodium handling
- PCT: ~65% (+ all glucose, amino acids; most HCO₃⁻)
- Thick ascending limb: ~25% (NKCC2)
- DCT: ~5% (NCC)
- Collecting duct: ~2–3% (ENaC, aldosterone)
Remember Sixty-five, twenty-five, five, and the last bit.
Why the other options are wrong
- About 10% Too low.
- About 25% That is the thick ascending limb.
- About 5% That is the DCT.
- About 99% Total for the whole nephron.
A man with type 2 diabetes and a glucose of 22 mmol/L (400 mg/dL) passes large volumes of urine. What is the mechanism of his polyuria?
Answer: Glucose in tubules holding water
Filtered glucose is normally reabsorbed completely by sodium–glucose cotransporters in the proximal tubule, up to a transport maximum. When plasma glucose exceeds the renal threshold of about 10 mmol/L (180 mg/dL), glucose remains in the tubular fluid, and its osmotic effect holds water and sodium in the lumen. This osmotic diuresis causes polyuria, dehydration and thirst. Urine osmolality is normal or high, unlike the dilute urine of diabetes insipidus.
Osmotic diuresis
- Renal threshold ~10 mmol/L (180 mg/dL)
- Unabsorbed glucose holds water in tubule
- Polyuria, dehydration, thirst
- Urine osmolality not low
Remember Sugar in the urine drags water with it.
Exam trap Polyuria with high urine osmolality is osmotic diuresis, not diabetes insipidus.
Why the other options are wrong
- Glucose blocking ADH release ADH is usually high from dehydration.
- Glucose damaging the collecting ducts Not the mechanism of acute polyuria.
- High glucose stimulating thirst first Thirst follows the water loss; it does not cause it.
- Insulin deficiency blocking aquaporins Insulin has no direct effect on aquaporins.
A 2-year-old has growth failure and a normal anion gap metabolic acidosis, with bicarbonate 15 mmol/L and potassium 3.2 mmol/L. While acidotic, his urine pH is 5.2. When IV bicarbonate raises his plasma bicarbonate to 22 mmol/L, large amounts of bicarbonate appear in the urine. What is the most likely diagnosis?
Answer: Proximal (type 2) renal tubular acidosis
The proximal tubule normally reabsorbs about 80% of filtered bicarbonate. In proximal RTA its reabsorptive threshold is lowered, so bicarbonate is lost in the urine until the plasma level falls to the new, lower threshold. Distal acidification still works, so at this steady state the urine can be acidified below pH 5.5. When plasma bicarbonate is raised above the threshold, bicarbonate pours into the urine, so large doses of alkali are needed. Increased sodium delivery to the distal nephron causes potassium loss. It may occur alone or as part of Fanconi syndrome.
Proximal RTA
- Lowered bicarbonate threshold in PCT
- Urine pH can fall below 5.5 at steady state
- Bicarbonate load: bicarbonaturia
- Often part of Fanconi syndrome
Remember Proximal RTA leaks bicarbonate only when plasma levels are pushed up.
Exam trap An acid urine pH during acidosis does not exclude proximal RTA.
Why the other options are wrong
- Distal (type 1) renal tubular acidosis Urine pH would never fall below 5.5.
- Type 4 renal tubular acidosis Potassium would be high.
- Diarrhoeal bicarbonate loss No diarrhoea; bicarbonate is lost in urine.
- Diabetic ketoacidosis Anion gap would be high.
After intravenous mannitol for raised intracranial pressure, a patient's urine output rises sharply. In which nephron segments does mannitol mainly act?
Answer: Proximal tubule and thin descending limb
Mannitol is filtered but not reabsorbed. It stays in the tubular fluid and holds water osmotically in the segments that are freely permeable to water, mainly the proximal tubule and the thin descending limb of the loop of Henle. Less water is reabsorbed, more fluid reaches the distal nephron and urine volume rises. It also increases medullary blood flow, which reduces the medullary concentration gradient.
Mannitol
- Filtered, not reabsorbed
- Holds water in water-permeable segments
- Mainly PCT and descending limb
- Avoid in heart failure and anuria
Remember Mannitol works where water normally leaves the tubule.
Exam trap Mannitol first expands plasma volume, so it can precipitate pulmonary oedema in heart failure.
Why the other options are wrong
- Thick ascending limb of Henle Site of loop diuretics (NKCC2); impermeable to water.
- Early distal convoluted tubule Site of thiazides (NCC).
- Cortical collecting duct principal cells Site of aldosterone antagonists and amiloride.
- Juxtaglomerular apparatus only Not a site of diuretic action.
People who lack aquaporin-1 cannot concentrate their urine fully. In which of the following segments does tubular fluid normally become hypertonic by losing water through these channels?
Answer: Thin descending limb of the loop
Aquaporin-1 is present constitutively, without ADH, in the proximal tubule and the thin descending limb. As the descending limb dips into the hypertonic medulla, water leaves through these channels and the tubular fluid becomes progressively more concentrated, reaching its highest osmolality at the hairpin. The ascending limbs are impermeable to water and remove salt, diluting the fluid. Without aquaporin-1 this concentration step and the countercurrent mechanism are impaired. Aquaporin-2, controlled by ADH, acts in the collecting duct.
Water channels along the nephron
- AQP1: proximal tubule, thin descending limb
- Always open; no ADH needed
- Descending limb fluid becomes hypertonic
- AQP2: collecting duct, ADH-controlled
Remember Descending loses water; ascending loses salt.
Exam trap Aquaporin-1 does not respond to ADH; only aquaporin-2 is ADH-regulated.
Why the other options are wrong
- Thick ascending limb of the loop Impermeable to water; it dilutes the fluid.
- Distal convoluted tubule Largely impermeable to water regardless of ADH; fluid is diluted further.
- Cortical collecting duct Uses ADH-regulated aquaporin-2.
- Macula densa region Senses NaCl; does not concentrate fluid.
Where this sits in the CPSP syllabus
- Paper 1: Renal physiology, body fluids and acid-base, Tubular reabsorption and secretion; segment functions
- Surgery & Allied, Paper 2: Renal physiology, body fluids and acid-base, Tubular reabsorption and secretion; segment functions
- Medicine & Allied, Paper 2: Renal physiology, body fluids and acid-base, Tubular reabsorption and secretion; segment functions
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