Tubular Reabsorption & Secretion

The renal tubule converts the ~180 L/day of plasma ultrafiltrate into ~1.5 L of final urine by selectively reabsorbing what the body needs and secreting what it must dump. This segment-by-segment handling of Na⁺, glucose, amino acids, K⁺, H⁺, urea and organic ions is the physiological backbone for understanding diuretics, RTA, and electrolyte disorders — a perennially high-yield, conceptually demanding area for NEET PG.

Core definitions

• Reabsorption = movement of a substance from tubular lumen → peritubular capillary blood (filtrate back to body).
• Secretion = movement from peritubular blood/tubular cell → lumen (added to urine).
• Excretion = Filtration − Reabsorption + Secretion.
• Transport maximum (Tm) = the maximal rate at which a carrier-mediated substance can be transported (saturation of carriers); applies to glucose, amino acids, phosphate, sulphate.
• Renal threshold = plasma concentration at which the substance first appears in urine (lower than the Tm-predicted value because of splay).
• Splay = the rounding of the titration curve due to heterogeneity of nephrons (different Tm/GFR ratios) and the low affinity (high Km) of the SGLT carrier.

High-yield: Glucosuria appears at a renal threshold of ~180 mg/dL (≈10 mmol/L), but the true average glucose Tm is ~375 mg/min in men (~300 in women). The gap between threshold and Tm is splay.

Driving force: the basolateral Na⁺-K⁺-ATPase

Nearly all tubular transport is ultimately powered by the basolateral Na⁺-K⁺-ATPase, which pumps 3 Na⁺ out and 2 K⁺ in, keeping intracellular Na⁺ low and the cell interior negative. This electrochemical gradient drives apical Na⁺ entry, and Na⁺ entry is coupled (co-/counter-transport) to almost everything else — glucose, amino acids, phosphate, H⁺, Cl⁻. Block the pump (e.g. digoxin-like agents, hypoxia) and tubular reabsorption collapses.

Flow of glucose reabsorption: Lumen → apical SGLT (secondary active, Na⁺-coupled) → cytosol → basolateral GLUT2/GLUT1 (facilitated) → blood.

Feature	SGLT2	SGLT1
Location	Early PCT (S1, S2)	Late PCT (S3)
Na⁺ : glucose stoichiometry	1 : 1	2 : 1
Affinity / capacity	Low affinity, high capacity (~90% reabsorbed)	High affinity, low capacity (~10%)
Basolateral exit	GLUT2	GLUT1
Drug target	Gliflozins (dapagliflozin, empagliflozin)	—

High-yield: SGLT2 inhibitors lower the renal threshold for glucose → therapeutic glucosuria, mild osmotic diuresis, weight loss, and cardio-renal protection. Familial renal glucosuria = SGLT2 (SLC5A2) mutation; glucose-galactose malabsorption = SGLT1 mutation.

Proximal convoluted tubule (PCT) — the bulk reabsorber

The PCT reabsorbs ~65–67% of filtered Na⁺ and water, and is isosmotic (water follows solute, tubular fluid stays ~300 mOsm). It reclaims essentially 100% of glucose and amino acids, 80–90% of filtered HCO₃⁻, and most phosphate.

Two phases of PCT Na⁺ handling:

1. Early PCT (S1): Na⁺ reabsorbed with HCO₃⁻ (via NHE3 apical Na⁺/H⁺ exchanger driving HCO₃⁻ reclamation via carbonic anhydrase), glucose, amino acids, phosphate, lactate, citrate.
2. Late PCT (S2/S3): Na⁺ reabsorbed with Cl⁻ (luminal Cl⁻ now high after HCO₃⁻/organic solutes removed); paracellular and transcellular Cl⁻ movement dominates.

Bicarbonate reclamation flow: Filtered HCO₃⁻ + secreted H⁺ (via NHE3) → H₂CO₃ → (luminal carbonic anhydrase IV) → CO₂ + H₂O → CO₂ diffuses into cell → (cytosolic CA II) reforms HCO₃⁻ → exits basolaterally via Na⁺-HCO₃⁻ cotransporter (NBC1).

High-yield: Acetazolamide (CA inhibitor) blocks PCT HCO₃⁻ reabsorption → bicarbonaturia, mild diuresis, type 2 (proximal) RTA-like picture and metabolic acidosis. Used in glaucoma, altitude sickness, alkalosis.

Glomerulotubular balance: the PCT reabsorbs a constant fraction (~65%) of whatever is filtered, so if GFR rises, absolute reabsorption rises proportionally — preventing massive solute loss. Mediated by peritubular Starling forces (oncotic pressure) and luminal solute load.

High-yield: PAH (para-aminohippurate) is both filtered and avidly secreted by the PCT organic anion transporters, so at low plasma levels its clearance ≈ renal plasma flow (RPF). Probenecid blocks this OAT-mediated secretion (and that of penicillin, methotrexate, urate).

PCT secretion of organic ions

• Organic anions (OAT): PAH, urate, penicillins, cephalosporins, methotrexate, furosemide/thiazides (must be secreted to reach their luminal site), NSAIDs.
• Organic cations (OCT/MATE): creatinine, dopamine, cimetidine, metformin, morphine.

High-yield: Loop diuretics and thiazides are highly protein-bound, so they are not filtered well — they reach their luminal targets by OAT-mediated secretion. In renal failure or with probenecid, less drug reaches the lumen → diuretic resistance.

Loop of Henle — countercurrent multiplication

The loop establishes the medullary osmotic gradient (300 mOsm at cortex → ~1200 mOsm at papilla) that allows the collecting duct to concentrate urine.

Limb	Permeability	Net effect
Thin descending	Permeable to water, impermeable to solute	Water leaves → fluid becomes hyperosmotic
Thin ascending	Impermeable to water, permeable to NaCl (passive)	NaCl leaves passively
Thick ascending (TAL)	Impermeable to water, active NaCl reabsorption	Dilutes lumen → "diluting segment"

• The TAL uses the apical Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2 / SLC12A1) — the target of furosemide, bumetanide, torsemide.
• K⁺ recycles back into the lumen via ROMK channels, generating a lumen-positive transepithelial potential that drives paracellular reabsorption of Ca²⁺ and Mg²⁺.

High-yield: Loop diuretics inhibit NKCC2 → abolish the medullary gradient and the lumen-positive potential → increased urinary Ca²⁺ (used in hypercalcaemia). Bartter syndrome = genetic loss of NKCC2/ROMK/ClC-Kb → "diuretic-like" salt wasting, hypokalaemic metabolic alkalosis, hypercalciuria, normal/low BP.

Countercurrent multiplication (single-effect, stepwise):

1. TAL actively pumps NaCl out → ~200 mOsm gradient between lumen and interstitium (the "single effect").
2. Descending limb equilibrates with the now-hypertonic interstitium (water leaves).
3. Axial flow shifts hyperosmotic fluid into the bend.
4. Repetition multiplies the modest 200 mOsm single effect into a steep 900 mOsm cortico-papillary gradient.
5. The vasa recta act as countercurrent exchangers, preserving the gradient; urea recycling contributes ~50% of papillary osmolality.

Distal convoluted tubule (DCT)

• Apical Na⁺-Cl⁻ cotransporter (NCC / SLC12A3) — target of thiazides.
• Impermeable to water → continues diluting the fluid ("cortical diluting segment").
• Ca²⁺ reabsorption here is active and PTH-regulated via apical TRPV5 channels; thiazides paradoxically increase Ca²⁺ reabsorption (useful in calcium stones, hypocalciuria).

High-yield: Thiazides → hypocalciuria (good for recurrent Ca oxalate stones) but cause hypercalcaemia, hyponatraemia, hypokalaemia, hyperuricaemia, hyperglycaemia, hyperlipidaemia (the "hyper-hypo" profile). Gitelman syndrome = NCC loss → thiazide-like picture: hypokalaemic alkalosis + hypomagnesaemia + hypocalciuria.

Aldosterone-sensitive distal nephron (late DCT + collecting duct)

This is the fine-tuning segment (reabsorbs final ~3–5% of Na⁺) and the chief site of K⁺ and H⁺ secretion.

Principal cells:

• Apical ENaC (epithelial Na⁺ channel) reabsorbs Na⁺ → blocked by amiloride, triamterene.
• Na⁺ entry makes lumen electronegative → drives K⁺ secretion via ROMK.
• Aldosterone ↑ ENaC, ↑ Na⁺-K⁺-ATPase, ↑ ROMK → Na⁺ retention + K⁺/H⁺ loss.
• ADH (vasopressin) inserts aquaporin-2 into the apical membrane → water reabsorption.

Intercalated cells:

• α (type A): secrete H⁺ via apical H⁺-ATPase and H⁺/K⁺-ATPase; reabsorb HCO₃⁻ basolaterally (via Cl⁻/HCO₃⁻ exchanger, AE1) — important in acidosis.
• β (type B): secrete HCO₃⁻, reabsorb H⁺ — important in alkalosis.

High-yield: Spironolactone/eplerenone = mineralocorticoid-receptor antagonists; amiloride/triamterene = direct ENaC blockers. All four are K⁺-sparing. Liddle syndrome = gain-of-function ENaC → hypertension, hypokalaemia, low renin/aldosterone → treat with amiloride, NOT spironolactone.

Potassium handling summary

• ~65% reabsorbed in PCT (paracellular, solvent drag), ~25% in TAL (NKCC2).
• Net secretion occurs in the principal cells of the distal nephron — this is the regulated step.
• Secretion ↑ by: high plasma K⁺, aldosterone, high distal flow/Na⁺ delivery, alkalosis.
• Secretion ↓ by: acidosis (acute), low flow, K⁺-sparing diuretics.

Urea handling

• ~50% reabsorbed passively in PCT.
• TAL, DCT, cortical CD are urea-impermeable → urea concentrates.
• Inner medullary collecting duct has ADH-stimulated UT-A1/A3 transporters → urea enters interstitium → contributes to medullary hyperosmolarity (urea recycling). High protein intake and ADH enhance maximal concentrating ability.

Diuretic site map (the integrating table)

Diuretic class	Site	Target	Key effect on electrolytes
Carbonic anhydrase inhibitor (acetazolamide)	PCT	CA	↑HCO₃⁻ loss, metabolic acidosis, mild hypokalaemia
Osmotic (mannitol)	PCT, descending limb	—	↑Na⁺ & water loss, risk of pulmonary oedema
Loop (furosemide)	TAL	NKCC2	↓K⁺, ↑Ca²⁺ excretion, alkalosis, ototoxic
Thiazide (HCTZ)	DCT	NCC	↓K⁺, ↓Ca²⁺ excretion, alkalosis, hyperglycaemia
K⁺-sparing (amiloride/spironolactone)	CD	ENaC / MR	↑K⁺ retention, mild acidosis
ADH antagonist (tolvaptan)	CD	V2 receptor	Free-water loss (aquaresis), ↑Na⁺

High-yield: Loop + thiazide cause hypokalaemic metabolic alkalosis; CA inhibitors and K⁺-sparing agents cause metabolic acidosis (with hyperkalaemia for the latter). This single fact is repeatedly tested.

Phosphate, calcium and magnesium quick notes

• Phosphate: PCT, via NaPi-IIa/IIc; inhibited by PTH and FGF23 → phosphaturia. Tm-limited.
• Calcium: 65% PCT (paracellular), 20% TAL (paracellular, lumen-positive), DCT active/PTH-controlled.
• Magnesium: chiefly TAL paracellular via claudin-16/19 (paracellin-1); hence loop diuretics → hypomagnesaemia; Gitelman → hypomagnesaemia.

Clinical correlates & differentials

Disorder	Defective transporter/segment	Picture
Type 2 (proximal) RTA	PCT HCO₃⁻ reabsorption (CA, NBC1)	Failure to reclaim HCO₃⁻, urine pH variable, Fanconi if generalised
Type 1 (distal) RTA	α-intercalated H⁺-ATPase	Cannot acidify urine; urine pH >5.5, hypokalaemia, stones
Type 4 RTA	Aldosterone deficiency/resistance	Hyperkalaemic acidosis
Bartter	TAL (NKCC2/ROMK/ClC-Kb)	Loop-diuretic phenotype, hypercalciuria
Gitelman	DCT (NCC)	Thiazide phenotype, hypocalciuria + hypomagnesaemia
Liddle	ENaC gain-of-function	HTN, hypokalaemia, low renin/aldosterone
Fanconi syndrome	Global PCT failure	Glucosuria, aminoaciduria, phosphaturia, proximal RTA, uricosuria

High-yield: Distinguish Bartter vs Gitelman by calcium: Bartter = hypercalciuria (loop-like); Gitelman = hypocalciuria + hypomagnesaemia (thiazide-like). And Liddle vs hyperaldosteronism: both hypertensive + hypokalaemic, but Liddle has low aldosterone and responds to amiloride.

Recently asked / exam angle

• SGLT2 inhibitor mechanism and which transporter handles 90% of glucose (SGLT2, early PCT) — frequent in physiology + pharmacology overlap.
• Glucose Tm vs threshold vs splay — favourite conceptual MCQ; threshold (~180 mg/dL) < Tm (~375 mg/min) because of splay.
• NKCC2 and the lumen-positive potential driving Ca²⁺/Mg²⁺ reabsorption — and why loop diuretics cause hypercalciuria but thiazides cause hypocalciuria.
• Bartter vs Gitelman vs Liddle matching with transporters and serum/urine calcium.
• Site of action matching of diuretics with their acid-base side effects.
• PAH clearance = RPF and the role of OAT secretion; probenecid interactions.
• Urea recycling and ADH-dependent UT-A transporters in the concentrating mechanism.
• α vs β intercalated cells and the RTA classification.

Mnemonics:

• Diuretic order, lumen → end: "CALD-K" — Carbonic anhydrase (PCT) → Aqueous/osmotic → Loop (TAL) → Distal thiazide (DCT) → K⁺-sparing (CD).
• PCT reabsorbs "Glucose, Amino acids, Bicarb, Phosphate, Na, Water" — "Good All-rounders Build Pretty Nice Wells."
• "Gitelman = low calcium, low magnesium" (both "low" like the lowercase distal tubule).

Rapid revision

1. PCT reabsorbs ~65% of Na⁺/water isosmotically and 100% of glucose & amino acids.
2. Basolateral Na⁺-K⁺-ATPase powers virtually all tubular transport.
3. Glucose: SGLT2 (early PCT, 90%) + SGLT1 (late PCT, 10%) apically; GLUT2 exit; Tm ~375 mg/min, threshold ~180 mg/dL, gap = splay.
4. NHE3 + carbonic anhydrase reclaim HCO₃⁻ in PCT; acetazolamide blocks this → proximal RTA-like acidosis.
5. PAH clearance ≈ RPF; PAH and many drugs are secreted by OAT in PCT (blocked by probenecid).
6. TAL = NKCC2 (loop diuretic target), water-impermeable diluting segment, generates lumen-positive potential → Ca²⁺/Mg²⁺ paracellular reabsorption.
7. Loop diuretics → hypercalciuria; thiazides (NCC, DCT) → hypocalciuria.
8. Countercurrent multiplication builds the 300→1200 mOsm medullary gradient; urea recycling (ADH-driven UT-A) supplies ~50%.
9. Principal cells: ENaC + ROMK, aldosterone- and ADH-sensitive; amiloride/spironolactone act here and are K⁺-sparing.
10. α-intercalated cells secrete H⁺ (H⁺-ATPase) — defect = distal (type 1) RTA with urine pH >5.5.
11. Bartter = hypercalciuria (loop-like); Gitelman = hypocalciuria + hypomagnesaemia (thiazide-like); Liddle = ENaC gain, low aldosterone, treat with amiloride.
12. Loop & thiazide → hypokalaemic alkalosis; CA inhibitors & K⁺-sparing → metabolic acidosis (latter with hyperkalaemia).