The Glomerulus – Tubular Reabsorption and Secretion

1. Introduction
2. The Glomerulus and the Filtration Barrier
   • The Three Layers
   • Starling Forces and Net Filtration Pressure
   • Filtration Fraction
3. General Principles of Tubular Transport
4. The Proximal Convoluted Tubule
   • Sodium and Water
   • Glucose and Amino Acids
   • Bicarbonate and Acid-Base
   • Phosphate, Calcium and Other Solutes
   • Tubular Secretion in the PCT
5. The Loop of Henle
6. The Distal Convoluted Tubule
7. The Collecting Duct
   • Principal Cells
   • Intercalated Cells
8. Quantitative Summary
9. Summary
10. Quiz

• The kidney filters around 180 L of plasma every day across the glomerulus, then reclaims more than 99% of it through coordinated reabsorption and secretion along the nephron. The output is approximately 1.5 L of final urine.
• The glomerular filtration barrier has three layers. The first is the fenestrated (pore-containing) capillary endothelium. The second is the glomerular basement membrane (GBM, a fused supporting sheet shared by the endothelium and the podocytes). The third is the podocyte slit diaphragm (the filter between the foot-like projections of podocytes, the cells that wrap around the capillary). Small molecules (under about 10 kilodaltons, kDa, a measure of molecular size) pass freely. Filtration falls progressively with increasing size. Albumin restriction depends on the combined filtration barrier rather than an isolated basement-membrane charge filter.
• Each nephron segment has a characteristic transporter set. The filtered load is the amount of a substance filtered at the glomerulus. The proximal tubule reabsorbs the bulk of it: about 65% of the Na⁺ and water, nearly all of the glucose and amino acids, and most of the bicarbonate. The thick ascending limb of the loop of Henle carries the Na⁺-K⁺-2Cl⁻ cotransporter (NKCC2). This is the target of loop diuretics (drugs that act on the loop of Henle to increase urine output). The distal convoluted tubule carries the Na⁺/Cl⁻ cotransporter (NCC), the target of thiazide and thiazide-like diuretics. The collecting duct is where aldosterone (a hormone that makes the kidney retain sodium) and antidiuretic hormone (ADH) set the final urinary composition.
• Tubular secretion is the movement of solutes from the blood into the tubule. It happens predominantly in the proximal tubule (via organic anion and organic cation transporters, which carry negatively and positively charged molecules) and in the collecting duct (potassium and protons). It allows the kidney to clear the body's own waste products and many drugs faster than glomerular filtration alone could achieve.

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. 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 glomerulus is a high-pressure tuft of capillaries suspended in Bowman's capsule, the cup-shaped capsule that surrounds it. Fluid from the plasma is filtered across the wall of these capillaries into the urinary space (the space inside Bowman's capsule). This filtrate, which contains no blood cells and almost no protein, then passes into the proximal tubule. The barrier has three layers, each contributing to its selectivity:

1. Fenestrated capillary endothelium. The endothelial cells (the cells lining the capillary) have round pores, called fenestrae, about 70-90 nanometres (nm) wide. These freely admit plasma but exclude blood cells. The endothelial surface is coated with a negatively charged glycocalyx (a sugar-rich surface coat) that helps repel negatively charged plasma proteins.
2. Glomerular basement membrane (GBM). The GBM is a fused basement membrane, about 300 nm thick, shared by the endothelium and the podocytes. Its meshwork contains type IV collagen, laminin (another structural protein) and negatively charged heparan sulphate proteoglycans (sugar-rich proteins), including agrin (the main heparan sulphate proteoglycan of the GBM). These components support barrier structure; their charge alone is not an established explanation for albumin exclusion.
3. Podocyte slit diaphragm. Podocytes are highly specialised epithelial cells that wrap around the capillary. Their foot processes interlock like fingers. 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 the nephrin gene (NPHS1) typically cause congenital nephrotic syndrome, a condition that starts in the first months of life with heavy protein loss in the urine, low blood albumin and swelling. Mutations in the podocin gene (NPHS2) more often cause nephrotic syndrome that starts later, commonly before the age of 6 years, although it can also start in adults. This form is usually steroid-resistant (it does not respond to steroid treatment). With mutations in either gene, the barrier is disrupted.

Together the three layers form a graded size filter. Small solutes (water, ions, glucose, urea, creatinine) pass freely. Filtration is increasingly restricted as molecular weight rises above approximately 10 kilodaltons (kDa, the unit of molecular weight), and is essentially abolished above 70 kDa. Albumin (~67 kDa, strongly anionic) is largely retained by the combined filtration barrier.

The contribution of electrical charge to this filter is still debated. Substantial loss of GBM anionic sites in a mouse study did not produce measurable proteinuria (protein in the urine). This does not prove that charge has no role elsewhere in the barrier.

In minimal change disease (a kidney condition with heavy protein loss in the urine), electron microscopy shows effacement (flattening and loss) of the podocyte foot processes. The proteinuria in this condition has not been shown to result from an isolated loss of GBM charge. For background, see the 2025 filtration-barrier review and a human electron microscopy study (abstract only).

Diagram: the endothelium, GBM and podocyte slit diaphragm together restrict plasma proteins while allowing water and small solutes into Bowman's space. GBM negative charge alone is not an established explanation for albumin restriction.

Starling Forces and Net Filtration Pressure

The driving force for filtration is the net Starling pressure (the balance between the pressures that push fluid out of the capillary and those that hold it in) across the capillary wall. Three pressures matter:

• Glomerular capillary hydrostatic pressure (P_GC) ≈ 55 mmHg: the physical pressure of the blood in the capillary, which 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: the pull of plasma proteins, which hold water in the capillary, so it 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 (GFR) 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 arteriole (which brings blood into the glomerulus) and the efferent arteriole (which carries it away), 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 explains the haemodynamic (blood flow and pressure) effects of ACE inhibitors and ARBs (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers). These drugs preferentially relax the efferent arteriole, so they lower P_GC and can reduce GFR.

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, a hormone that constricts blood vessels). The 80% of plasma not filtered enters the peritubular capillary network (the capillaries around the tubules). Because protein-free fluid has been filtered off, this blood has a relatively higher oncotic pressure, which is 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, the fluid-filled space between cells). This route requires distinct transporters at the two surfaces.
• Paracellular: between cells through the tight junctions (the seals between neighbouring cells). 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 (the sodium-potassium pump), which keeps intracellular Na⁺ low and extracellular Na⁺ high. This electrochemical gradient (the combined concentration and electrical difference across the membrane) is then used by secondary active transporters (carriers that use this sodium gradient as their energy source) on the apical membrane. Cotransporters (symporters) drag glucose, amino acids, phosphate or chloride into the cell along with sodium. Exchangers (antiporters) bring luminal Na⁺ into the cell in exchange for protons or other ions, which leave the cell. 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⁺ and water, and most of the other solutes, are reclaimed here. The cells of the PCT have a dense apical brush border (a layer of microvilli, tiny finger-like projections of the cell surface) 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 (segments S1 and S2) carries the high-capacity, low-affinity SGLT2, which reabsorbs about 90% of filtered glucose. The late PCT (segment 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 (passive movement through a carrier protein), principally through glucose transporter 2 (GLUT2) in the early PCT.

This system normally reabsorbs virtually all filtered glucose, but it has a limit. The tubular maximum (Tm) for glucose is about 375 mg/min. It is reached when the filtered load (the amount of glucose filtered per minute) exceeds the capacity of the transporters. With a GFR of about 120 mL/min, this corresponds to a plasma glucose of roughly 17 mmol/L. Glucose starts to appear in the urine at a lower plasma level, the renal threshold of about 10-11 mmol/L, because individual nephrons differ in their capacity (a feature called splay). Exceeding the renal threshold is the basis of glycosuria (glucose in the urine) 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 (extra sodium loss in the urine); 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 (amino acids lost in the urine). The best known is cystinuria. Here the transporter for cystine and the dibasic amino acids (ornithine, lysine and arginine) is defective, which 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. Because of this dependence on carbonic anhydrase, acetazolamide, a carbonic anhydrase inhibitor, produces a metabolic acidosis (too much acid in the blood) 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 (phosphate loss in the urine). Fibroblast growth factor 23 (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 (a slight electrical difference across the tubule wall).
• Urea: passively reabsorbed as water leaves the lumen, which concentrates the urea in the lumen; 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. This happens through the megalin-cubilin complex (receptor proteins) on the brush border. The proteins are then 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 negatively charged (anionic) compounds. These include para-aminohippurate (PAH, the classical experimental marker for renal plasma flow), urate (the salt of uric acid) and bile salts. Many drugs are secreted in the same way, including penicillins, cephalosporins, methotrexate, furosemide, thiazides and 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 positively charged (cationic) compounds. These include the body's own catecholamines (such as adrenaline) and creatinine (small but real contribution). Drugs secreted in this way include cimetidine, metformin and morphine. Trimethoprim is secreted into the tubular fluid by the multidrug and toxin extrusion (MATE) transporters, which work together with the OCTs as one organic cation secretory system.

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 (the time its blood level takes to halve) 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. First, it reabsorbs another 20-25% of filtered Na⁺, mostly in the thick ascending limb. Second, it generates the medullary osmotic gradient (a gradient of increasing solute concentration towards the inner kidney, the medulla) on which urine concentration depends. The thin descending limb, the thin ascending limb and the thick ascending limb have very different transport properties.

• Thin descending limb. Highly water-permeable (rich in aquaporin-1, a water channel), 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 renal outer-medullary potassium channel (ROMK), 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 inhibits reabsorption of up to about 25% of filtered Na⁺ and dissipates the medullary gradient, so the kidney loses concentrating ability. Loop diuretics also remove the lumen-positive voltage that drives paracellular Ca²⁺ and Mg²⁺ reabsorption, so urinary losses of both ions rise. Plasma calcium and magnesium can fall as a result (hypocalcaemia and hypomagnesaemia, meaning low blood calcium and low blood magnesium). Pharmacology is detailed in Diuretics and Renal Pharmacology.

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