The Glomerulus – Tubular Reabsorption and Secretion

Core

Introduction

Urine is not made in a single step. It is built by the nephron in three sequential operations: filtration at the glomerulus, reabsorption of useful filtrate back into the blood, and secretion of further substances from blood into the tubule. The final urine is therefore the small remainder of an enormous filtrate, edited along the way according to the body's homeostatic needs.

This article covers each step in order. The architecture of the nephron itself is described in The Nephron; the integrated regulation of filtration is covered in Glomerular Filtration Rate and the Measurement of Kidney Function; and the systemic responses that adjust nephron behaviour are covered in Control of Plasma Volume and Control of Plasma Osmolarity.

The Glomerulus and the Filtration Barrier

The Three Layers

The glomerular tuft is a high-pressure capillary network suspended in Bowman's capsule. Plasma is filtered across the wall of these capillaries into the urinary space, then enters the proximal tubule. The barrier has three layers, each contributing to its selectivity:

1. Fenestrated capillary endothelium. The endothelial cells have round pores ~70-90 nm wide. These freely admit plasma but exclude blood cells. The endothelial surface is coated with a negatively-charged glycocalyx that helps repel anionic plasma proteins.
2. Glomerular basement membrane (GBM). A thick fused basement membrane shared by the endothelium and the podocytes. Its meshwork of type IV collagen, laminin and the heparan sulphate proteoglycan agrin imposes a strong negative charge that excludes albumin and similarly anionic proteins.
3. Podocyte slit diaphragm. Podocytes are highly specialised epithelial cells whose foot processes interdigitate around the capillary; the gaps between adjacent foot processes are bridged by the slit diaphragm, a fine zipper-like protein lattice in which nephrin and podocin are the central components. Mutations in either protein cause congenital nephrotic syndrome by destroying barrier integrity.

Together the three layers form a graded size and charge filter. Small solutes (water, ions, glucose, urea, creatinine) pass freely. Filtration is increasingly restricted as molecular weight rises above approximately 10 kDa, and is essentially abolished above 70 kDa. Albumin (~67 kDa, strongly anionic) is held back by both its size and its negative charge, and appears in normal urine only in trace amounts. Loss of the negative charge of the GBM (e.g. in minimal change disease) allows albumin through despite no obvious structural defect, producing nephrotic-range proteinuria.

Diagram: the three layers of the glomerular filtration barrier. Combined size and charge filters exclude albumin and cells while permitting water, ions and small molecules to pass freely into Bowman's space.

Starling Forces and Net Filtration Pressure

The driving force for filtration is the net Starling pressure across the capillary wall. Three pressures matter:

• Glomerular capillary hydrostatic pressure (P_GC) ≈ 55 mmHg: pushes plasma out into Bowman's space.
• Bowman's space hydrostatic pressure (P_BS) ≈ 15 mmHg: opposes filtration.
• Glomerular capillary oncotic pressure (π_GC) ≈ 30 mmHg: opposes filtration. The oncotic pressure of Bowman's space is essentially zero because protein is excluded.

Net filtration pressure  =  P_GC − P_BS − π_GC  ≈  55 − 15 − 30  =  +10 mmHg

The glomerular filtration rate is the product of this pressure and the filtration coefficient (K_f), which captures the surface area and hydraulic permeability of the barrier. The two resistance vessels; the afferent and efferent arterioles: control P_GC. Afferent constriction reduces P_GC and GFR. Efferent constriction tends to increase P_GC and so support GFR over a moderate range, but with severe constriction renal plasma flow falls and GFR drops as well. This balance is the basis for the haemodynamic effects of ACE inhibitors and ARBs, which preferentially relax the efferent arteriole.

Filtration Fraction

Of the renal plasma flow (RPF, ≈ 600 mL/min), about 20% is filtered into Bowman's space. This proportion is the filtration fraction:

Filtration fraction  =  GFR ÷ RPF  ≈  120 ÷ 600  =  0.20

Filtration fraction increases when efferent arteriolar tone rises (the kidney's standard response to volume depletion via angiotensin II). The 80% of plasma not filtered enters the peritubular capillary network at relatively higher oncotic pressure, an important driver of subsequent proximal tubular reabsorption.

General Principles of Tubular Transport

Solute movement across a tubular cell can take two routes:

• Transcellular: across the apical membrane (facing the lumen), through the cell, and across the basolateral membrane (facing the interstitium). This route requires distinct transporters at the two surfaces.
• Paracellular: between cells through the tight junctions. Whether and how much this occurs depends on the "tightness" of the junction, which differs between segments. The proximal tubule has leaky junctions; the cortical collecting duct has very tight junctions.

The energy for almost all renal transport ultimately comes from the basolateral Na⁺/K⁺-ATPase, which keeps intracellular Na⁺ low and extracellular Na⁺ high. This electrochemical gradient is then exploited by an array of secondary active transporters on the apical membrane: cotransporters (symporters) that drag glucose, amino acids, phosphate, bicarbonate or chloride into the cell along with sodium, and exchangers (antiporters) that swap intracellular Na⁺ for protons or other ions. The principles of these transporters are explained in Membrane Transport and Intracellular Calcium Regulation.

The Proximal Convoluted Tubule

The proximal convoluted tubule (PCT) is where the bulk of reabsorption happens. Roughly 65% of filtered Na⁺, water and most other solutes are reclaimed here. The cells of the PCT have a dense apical brush border that hugely amplifies their surface area and contains most of the apical transporters.

Sodium and Water

Two-thirds of filtered Na⁺ is reabsorbed in the PCT, with water following passively because of the leakiness of the epithelium and the osmotic gradient created by Na⁺ movement. The PCT is therefore iso-osmotic: by the end of the segment, tubular fluid has the same osmolarity as plasma despite a 65% reduction in volume.

The apical Na⁺ entry routes are several in parallel:

• Na⁺/H⁺ exchanger (NHE3): brings Na⁺ in, exports H⁺. Drives bicarbonate reclamation (see below).
• Na⁺/glucose cotransporters (SGLT2 and SGLT1): couple Na⁺ entry to glucose uptake.
• Na⁺/amino-acid cotransporters: one or two Na⁺ ions per amino acid.
• Na⁺/phosphate cotransporters (NaPi-IIa, NaPi-IIc).

On the basolateral side, Na⁺/K⁺-ATPase pumps Na⁺ back into the interstitium. Reabsorbed water and solutes are then taken up by the peritubular capillaries, drawn in by the elevated oncotic pressure created by the prior glomerular filtration.

Glucose and Amino Acids

Glucose is reabsorbed almost entirely in the PCT. The early PCT (S1, S2) carries the high-capacity, low-affinity SGLT2, which reabsorbs about 90% of filtered glucose; the late PCT (S3) carries the low-capacity, high-affinity SGLT1, which reabsorbs the remaining 10%. On the basolateral side, glucose leaves down its gradient by facilitated diffusion, principally through the GLUT2 transporter in the early PCT.

This system normally clears all filtered glucose, but it has a maximum: the tubular maximum (Tm) for glucose is reached when the filtered load exceeds about 375 mg/min (corresponding to a plasma glucose of around 10-11 mmol/L). Above this renal threshold, glucose appears in the urine. This is the basis of glycosuria in diabetes mellitus: covered in Diabetes Mellitus.

Pharmacologically, the SGLT2 transporter is the target of the gliflozins (dapagliflozin, empagliflozin, canagliflozin), which produce a deliberate glycosuria and natriuresis; explained further in Pharmacology of Insulin.

Amino acids are reabsorbed by a family of Na⁺-dependent transporters specific for groups of amino acids (acidic, basic, neutral, imino). Inherited defects in these transporters cause aminoacidurias; the best-known is cystinuria, a defect in the dibasic amino-acid transporter that causes recurrent cystine kidney stones.

Bicarbonate and Acid-Base

About 80-90% of filtered bicarbonate is reabsorbed in the PCT. The mechanism is indirect:

1. Apical NHE3 secretes a proton (H⁺) into the lumen in exchange for Na⁺.
2. The luminal H⁺ combines with filtered HCO₃⁻ to form H₂CO₃, which is dehydrated to CO₂ and water by luminal carbonic anhydrase (CA-IV).
3. CO₂ diffuses into the cell, where cytoplasmic carbonic anhydrase (CA-II) regenerates HCO₃⁻.
4. HCO₃⁻ is exported across the basolateral membrane by the Na⁺/HCO₃⁻ cotransporter (NBCe1).

The net effect is reabsorption of one Na⁺ and one HCO₃⁻ per cycle, with carbonic anhydrase essential at both ends. This is why acetazolamide, a carbonic anhydrase inhibitor, produces a metabolic acidosis with bicarbonate loss in the urine. The integrated handling of acid-base balance is described in Chemical Control of Breathing and Plasma pH.

Phosphate, Calcium and Other Solutes

The PCT also handles:

• Phosphate: via Na⁺/phosphate cotransporters (NaPi-IIa, NaPi-IIc) on the apical membrane. Parathyroid hormone internalises NaPi-IIa, reducing reabsorption and producing phosphaturia. FGF23 from bone has the same effect via a different pathway. The endocrine control is set out in Calcium Metabolism.
• Calcium: about 65% reabsorbed paracellularly with sodium and water, driven by the small lumen-positive transepithelial potential.
• Urea: passively reabsorbed as water leaves the lumen, concentrating it; about 50% is reclaimed in the PCT.
• Filtered proteins: the small amount of albumin that crosses the barrier, together with truly low-molecular-weight proteins such as β₂-microglobulin, are taken up by receptor-mediated endocytosis through the megalin-cubilin complex on the brush border and degraded in lysosomes.

Tubular Secretion in the PCT

The PCT is also the principal site of tubular secretion, the active movement of solutes from blood into tubular fluid. Two major transporter families are responsible:

• The organic anion transporters (OATs): secrete anionic compounds: para-aminohippurate (PAH, the classical experimental marker for renal plasma flow), urate, bile salts, and many drugs (penicillins, cephalosporins, methotrexate, furosemide, thiazides, salicylates). The OATs are the reason these drugs achieve far higher tubular concentrations than glomerular filtration alone could deliver.
• The organic cation transporters (OCTs): secrete cationic compounds, including endogenous catecholamines, creatinine (small but real contribution), and drugs such as cimetidine, trimethoprim, metformin and morphine.

Competition between substrates at OATs and OCTs is the basis of clinically important drug interactions. The classical example is probenecid, which prolongs the half-life of penicillin by competing for OAT-mediated secretion. Conversely, accumulation of secretory substrates in renal failure (urate, creatinine, many drugs) explains why dose adjustment is so often necessary at low GFR; covered in Safe Prescribing.

The Loop of Henle

The loop of Henle does two things: it reabsorbs another 20-25% of filtered Na⁺, and it generates the medullary osmotic gradient on which urine concentration depends. The two limbs have very different transport properties.

• Thin descending limb. Highly water-permeable (rich in aquaporin-1), but largely impermeable to Na⁺. As water leaves, tubular fluid becomes progressively more concentrated as it descends into the hyperosmotic medulla.
• Thin ascending limb. Water-impermeable, with passive Na⁺ reabsorption.
• Thick ascending limb (TAL). Water-impermeable, with active Na⁺ reabsorption via the apical Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2). Potassium recycles back into the lumen via the apical ROMK channel, generating a lumen-positive transepithelial voltage that drives paracellular reabsorption of Ca²⁺ and Mg²⁺.

The thick ascending limb dilutes tubular fluid (it removes solute without water) while loading the medullary interstitium with NaCl, a process called counter-current multiplication. The full mechanism is described in Control of Plasma Osmolarity.

NKCC2 is the target of the loop diuretics (furosemide, bumetanide, torasemide). Blocking NKCC2 abolishes ~25% of filtered Na⁺ reabsorption, dissipates the medullary gradient (so the kidney loses concentrating ability), and causes secondary hypocalcaemia and hypomagnesaemia by removing the lumen-positive voltage that drives their paracellular reabsorption. Pharmacology is detailed in Diuretics and Renal Pharmacology.

The Distal Convoluted Tubule

The distal convoluted tubule (DCT) reabsorbs a further 5-10% of filtered Na⁺. The apical entry route here is the Na⁺/Cl⁻ cotransporter (NCC), which moves one Na⁺ with one Cl⁻ per cycle. NCC is the target of the thiazide diuretics (bendroflumethiazide, hydrochlorothiazide, indapamide).

The DCT is also the principal nephron site of active calcium reabsorption. Apical entry is via the TRPV5 channel, and basolateral exit via the Na⁺/Ca²⁺ exchanger (NCX1) and Ca²⁺-ATPase. Parathyroid hormone increases TRPV5 expression, raising calcium reabsorption in response to hypocalcaemia.

An apparent paradox of pre-clinical pharmacology has its explanation here: thiazides cause hypercalcaemia while loop diuretics cause hypocalcaemia. Thiazides reduce intracellular Na⁺ in the DCT, which drives basolateral NCX1 to extrude more Ca²⁺ and pull more Ca²⁺ in apically: net reabsorption rises. Loop diuretics, by contrast, abolish the lumen-positive voltage in the TAL on which paracellular Ca²⁺ reabsorption depends, so urinary Ca²⁺ losses rise.

The Collecting Duct

The collecting duct is where the kidney makes its final adjustments to the urine. It runs from the cortex through the medulla to the papilla, and its cells fall into two functional types: principal cells and intercalated cells.

Principal Cells

Principal cells handle Na⁺, K⁺ and water:

• Apical epithelial sodium channel (ENaC): allows Na⁺ entry down its gradient. Basolateral Na⁺/K⁺-ATPase exports Na⁺ in the usual fashion.
• Apical renal outer-medullary potassium channel (ROMK): provides K⁺ secretion. The Na⁺ entry through ENaC creates a lumen-negative voltage that drives K⁺ out of the cell into the lumen.
• Apical aquaporin-2 (AQP2) water channels: inserted into the apical membrane in response to antidiuretic hormone (ADH) binding to V₂ receptors on the basolateral surface. With AQP2 inserted, water leaves the lumen down the osmotic gradient created in the medulla and the urine concentrates.

The behaviour of principal cells is set by two hormones:

• Aldosterone upregulates ENaC, ROMK and the Na⁺/K⁺-ATPase, increasing Na⁺ reabsorption at the cost of K⁺ and H⁺ excretion. This is the major effector limb of the renin-angiotensin-aldosterone system; see Control of Plasma Volume.
• ADH (vasopressin) dominantly increases water permeability via AQP2; it has only a small direct effect on sodium handling at this site; see Control of Plasma Osmolarity.

Pharmacologically, ENaC and aldosterone receptors are the targets of the potassium-sparing diuretics:

• Amiloride blocks ENaC directly.
• Spironolactone and eplerenone antagonise the mineralocorticoid (aldosterone) receptor.

Both produce modest natriuresis and reduced K⁺ excretion: a useful counterbalance when combined with loop or thiazide diuretics, which would otherwise waste K⁺.

Intercalated Cells

Intercalated cells fine-tune acid-base balance:

• α-intercalated cells secrete H⁺ via apical H⁺-ATPase and H⁺/K⁺-ATPase, and reabsorb HCO₃⁻ on the basolateral side via the Cl⁻/HCO₃⁻ exchanger (anion exchanger 1, AE1). They are recruited in acidosis.
• β-intercalated cells have the polarity reversed: HCO₃⁻ secretion apically (via pendrin) and H⁺ reabsorption basolaterally. They are recruited in alkalosis.

Failure of α-intercalated cell H⁺ secretion produces type 1 (distal) renal tubular acidosis, in which urine cannot be acidified below pH 5.5 despite systemic acidosis. Type 4 RTA is mechanistically different: it reflects aldosterone deficiency or resistance at the principal cells, with hyperkalaemia and impaired ammoniagenesis rather than a primary intercalated-cell defect.

Quantitative Summary

The relative contribution of each segment to sodium reabsorption is worth committing to memory because it predicts the maximum natriuretic effect of each drug class:

• Proximal convoluted tubule: ~65% of filtered Na⁺; iso-osmotic; carbonic anhydrase, NHE3, SGLT2.
• Thick ascending limb of Henle: ~25% of filtered Na⁺; NKCC2; site of loop diuretics.
• Distal convoluted tubule: ~5-10% of filtered Na⁺; NCC; site of thiazides.
• Collecting duct: ~3% of filtered Na⁺; ENaC; site of K-sparing diuretics; final urinary composition set here.

Less than 1% of filtered Na⁺ reaches the final urine in a person on a normal diet. The same is true of water, glucose and amino acids; small variations at the collecting duct produce the urine actually voided.

Summary

• The glomerular filtration barrier is a three-layer size and charge filter (endothelium, GBM, slit diaphragm) producing a near protein-free ultrafiltrate at a rate of about 180 L/day.
• Net filtration pressure (around +10 mmHg) is set by the balance of glomerular capillary hydrostatic pressure, Bowman's space pressure and capillary oncotic pressure. The afferent and efferent arterioles are the controllers.
• The proximal tubule reabsorbs around 65% of the filtered load, in iso-osmotic fashion, through apical transporters including NHE3, SGLT2, amino-acid cotransporters and NaPi-IIa, alongside the organic anion and cation transporters that handle secretion.
• The thick ascending limb dilutes tubular fluid and concentrates the medulla via NKCC2, the loop-diuretic target. The distal convoluted tubule uses NCC, the thiazide target. The collecting duct uses the epithelial sodium channel (ENaC) and aquaporin-2 (AQP2), set by aldosterone and antidiuretic hormone (ADH) respectively.
• Tubular secretion in the proximal tubule (organic anions, organic cations) clears endogenous waste and many drugs faster than glomerular filtration alone could; competition at these transporters is the basis of important drug interactions (e.g. probenecid + penicillin).
• Less than 1% of the filtered load is excreted in the final urine; the rest is reclaimed and edited, segment by segment, in a sequence that is the basis of nearly all renal pharmacology.

Reviewed by: Dr. Marcus Judge

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