Premed · Premed · Anatomy Physiology 2
Lecture 19: Glomerular Filtration and Tubular Function
Anatomy and Physiology II
Learning Objectives
By the end of this lecture, students will be able to:
- Describe the three processes involved in urine formation: filtration, reabsorption, and secretion
- Explain the forces governing glomerular filtration and calculate net filtration pressure
- Define glomerular filtration rate (GFR) and explain its regulation (intrinsic and extrinsic mechanisms)
- Describe the major reabsorption and secretion processes along each segment of the renal tubule
- Explain the countercurrent multiplier and countercurrent exchange mechanisms
- Describe the role of ADH and aldosterone in regulating urine concentration and volume
Lecture Content
I. Overview of Urine Formation
Urine formation involves three fundamental processes. Glomerular filtration is the passive, non-selective filtration of plasma from the glomerular capillaries into Bowman's capsule. Tubular reabsorption is the selective transport of substances from the tubular fluid back into the peritubular capillary blood. Tubular secretion is the selective transport of substances from the peritubular capillary blood into the tubular fluid. The relationship among these processes can be expressed simply: urine equals filtered minus reabsorbed plus secreted. Approximately 180 liters of filtrate are produced per day, of which about 178.5 liters are reabsorbed, leaving only 1 to 2 liters excreted as urine, representing roughly 99% reabsorption.
II. Glomerular Filtration
The Filtrate
Glomerular filtrate is essentially plasma without proteins. It contains water, glucose, amino acids, electrolytes, urea, creatinine, and other small solutes at plasma concentrations but does not contain blood cells, platelets, or significant amounts of protein, since albumin and larger proteins are excluded by the filtration membrane.
Net Filtration Pressure (NFP)
Glomerular filtration is driven by the balance of hydrostatic and osmotic pressures, known as Starling forces. Glomerular hydrostatic pressure (GHP), approximately 55 mmHg, is the blood pressure in the glomerular capillaries and favors filtration by pushing fluid out. This pressure is higher than in other capillary beds because the efferent arteriole is narrower than the afferent arteriole. Capsular hydrostatic pressure (CHP), approximately 15 mmHg, is the pressure of filtrate already in Bowman's capsule and opposes filtration. Blood colloid osmotic pressure (BCOP), approximately 30 mmHg, is the osmotic pressure generated by plasma proteins (mainly albumin) in the glomerular capillaries and opposes filtration by pulling water back into the capillary. Capsular colloid osmotic pressure is normally negligible, approximately 0 mmHg, because proteins are not filtered. The net filtration pressure is therefore calculated as GHP minus CHP minus BCOP, which equals 55 minus 15 minus 30, yielding a net positive pressure of +10 mmHg that drives filtration continuously.
Glomerular Filtration Rate (GFR)
The GFR is the volume of filtrate formed per minute by both kidneys, normally approximately 125 mL per minute or about 180 liters per day. GFR depends on net filtration pressure, the surface area of the glomerular capillaries, and the permeability (filtration coefficient, Kf) of the filtration membrane. Clinically, GFR is measured using creatinine clearance, since creatinine is freely filtered and minimally secreted or reabsorbed. A decline in GFR indicates loss of renal function.
<image>A diagram showing the forces governing glomerular filtration. Panel A: A cross-section of the renal corpuscle showing the afferent arteriole (larger diameter) entering the glomerular capillary tuft and the efferent arteriole (smaller diameter) exiting. The three Starling pressures are indicated with arrows: glomerular hydrostatic pressure (55 mmHg, outward arrow favoring filtration), capsular hydrostatic pressure (15 mmHg, inward arrow opposing filtration), and blood colloid osmotic pressure (30 mmHg, inward arrow opposing filtration). The net filtration pressure is calculated as +10 mmHg. Panel B: A bar chart comparing the magnitudes of the three pressures, with the net filtration pressure shown as the resultant. Panel C: A schematic showing how changes in afferent and efferent arteriolar diameter affect GHP and GFR — afferent constriction decreases GHP and GFR; efferent constriction increases GHP and GFR (within limits).</image>
III. Regulation of GFR
A. Intrinsic (Autoregulation) — Maintains Stable GFR Despite BP Changes (80–180 mmHg)
The myogenic mechanism operates through the inherent contractile response of smooth muscle. When increased blood pressure stretches the afferent arteriole wall, the smooth muscle contracts (vasoconstriction), preventing an excessive increase in GFR. Conversely, decreased blood pressure allows the afferent arteriole to relax (vasodilation), maintaining GFR.
Tubuloglomerular feedback (TGF) is mediated by the juxtaglomerular apparatus, specifically the macula densa. When GFR increases, faster flow through the tubule delivers more NaCl to the macula densa, which releases paracrine signals causing afferent arteriole constriction, thereby reducing GFR back to normal. When GFR decreases, less NaCl reaches the macula densa, prompting afferent arteriole dilation and renin release to restore GFR.
B. Extrinsic Regulation
The sympathetic nervous system exerts variable effects depending on the degree of activation. Mild sympathetic stimulation has minimal effect on GFR because autoregulation overrides it. However, strong sympathetic stimulation, such as during hemorrhage or severe exercise, produces marked afferent arteriole constriction through norepinephrine acting on alpha-1 adrenergic receptors, dramatically reducing GFR to conserve blood volume and redirect blood to the heart and brain.
The renin-angiotensin-aldosterone system (RAAS) is activated when JG cells release renin in response to low blood pressure in the afferent arteriole, low NaCl at the macula densa, or sympathetic stimulation. Renin cleaves angiotensinogen (produced by the liver) to form angiotensin I, which is then converted to angiotensin II by ACE (angiotensin-converting enzyme), located mainly in the pulmonary capillaries. Angiotensin II is a potent systemic vasoconstrictor that raises blood pressure, preferentially constricts the efferent arteriole to maintain GFR even when systemic blood pressure drops, stimulates aldosterone release from the adrenal cortex to promote sodium and water reabsorption, stimulates ADH release for water reabsorption, stimulates thirst, and directly enhances sodium reabsorption in the PCT.
Atrial natriuretic peptide (ANP) is released by atrial cardiomyocytes in response to atrial stretch from high blood volume. It dilates the afferent arteriole and constricts the efferent arteriole to increase GFR, inhibits sodium reabsorption to promote natriuresis and diuresis, and functionally opposes the RAAS.
IV. Tubular Reabsorption
Approximately 99% of filtrate is reabsorbed, with most reabsorption occurring in the PCT. Transport mechanisms include transcellular transport (through the tubular cell from apical membrane through cytoplasm to basolateral membrane, then into interstitial fluid and the peritubular capillary) and paracellular transport (between tubular cells through tight junctions, which is limited). Both active transport (requiring ATP, either primary or secondary) and passive transport (osmosis, diffusion, and facilitated diffusion) are employed. The transport maximum (Tm) represents the maximum rate at which a substance can be reabsorbed when carriers become saturated. The renal threshold for glucose is approximately 180 mg/dL; above this concentration, glucose appears in the urine (glycosuria), which is the basis of diabetic glucosuria.
Proximal Convoluted Tubule (PCT) — The Workhorse
The PCT reabsorbs approximately 65% of filtrate volume. Sodium reabsorption is the primary driving force for most other reabsorption. The basolateral Na+/K+ ATPase pumps sodium out of the tubular cell, creating a low intracellular sodium concentration. Sodium then enters from the tubular fluid via apical symporters (Na+-glucose, Na+-amino acid, Na+-phosphate) and antiporters (Na+/H+ exchanger). Glucose and amino acids are 100% reabsorbed through secondary active transport coupled with sodium, unless the Tm is exceeded. Water is reabsorbed by osmosis following solute reabsorption in what is called obligatory water reabsorption, as the PCT is always permeable to water via aquaporin-1 channels. Approximately 80% of filtered bicarbonate is reabsorbed through a process linked to hydrogen ion secretion by the Na+/H+ exchanger. Chloride is reabsorbed both paracellularly and transcellularly. About 50% of urea is passively reabsorbed following water. Approximately 65% of potassium is reabsorbed paracellularly. The PCT also secretes hydrogen ions, ammonium, organic acids (drugs and toxins), and organic bases.
Loop of Henle
The descending limb (thin segment) is highly permeable to water via aquaporin-1 but impermeable to solutes. Water moves out by osmosis into the hyperosmotic medullary interstitium, so the tubular fluid becomes progressively more concentrated as it descends.
The ascending limb has two functionally distinct segments. The thin ascending limb is permeable to NaCl, which diffuses out passively, but impermeable to water. The thick ascending limb (TAL) features the Na-K-2Cl cotransporter (NKCC2) on its apical membrane, which actively transports sodium, potassium, and two chloride ions from the lumen into the cell. The basolateral Na+/K+ ATPase then pumps sodium into the interstitium. Because the TAL is impermeable to water, the tubular fluid becomes progressively more dilute (hypotonic), earning it the name "diluting segment." This segment is the site of action of loop diuretics such as furosemide, which inhibit NKCC2.
Distal Convoluted Tubule (DCT)
The early DCT continues to dilute the tubular fluid via the NaCl cotransporter (NCC), which is the site of action of thiazide diuretics. The late DCT and collecting duct are sites of regulated reabsorption. Aldosterone, released from the adrenal cortex, acts on principal cells to increase sodium reabsorption through apical ENaC channels and potassium secretion through apical ROMK channels. Aldosterone is stimulated by angiotensin II and elevated plasma potassium. Antidiuretic hormone (ADH, or vasopressin), released from the posterior pituitary, increases water permeability of the late DCT and collecting duct by inserting aquaporin-2 (AQP2) channels into the apical membrane. ADH release is stimulated by increased plasma osmolarity (detected by hypothalamic osmoreceptors) and decreased blood volume or pressure. Without ADH, the collecting duct is impermeable to water and dilute urine is produced. With ADH, water is reabsorbed and concentrated urine results. Parathyroid hormone (PTH) stimulates calcium reabsorption in the DCT, and ANP inhibits sodium reabsorption to promote excretion.
Collecting Duct
Principal cells in the collecting duct handle sodium reabsorption under aldosterone's influence and water reabsorption under ADH's control. Intercalated cells manage acid-base balance: type A intercalated cells secrete hydrogen ions via H+ ATPase and reabsorb bicarbonate, thereby acidifying the urine (stimulated in acidosis), while type B intercalated cells secrete bicarbonate and reabsorb hydrogen ions (stimulated in alkalosis). The inner medullary collecting duct is permeable to urea, a permeability facilitated by ADH, and urea recycling into the medullary interstitium contributes approximately 50% of the medullary osmotic gradient.
<image>A comprehensive diagram of tubular reabsorption and secretion along the nephron. Panel A: An overview of the entire nephron showing the percentage of water and key solutes reabsorbed at each segment — PCT (65% water, 65% Na+, 100% glucose, 100% amino acids, 80% HCO3-, 50% urea), descending limb (15% water), thick ascending limb (25% Na+, 0% water, labeled "diluting segment"), DCT (variable Na+ and water, regulated), and collecting duct (variable water and urea, regulated). Panel B: A detailed cellular diagram of PCT reabsorption showing the tubular lumen, a PCT cell with brush border microvilli, and the peritubular capillary. The basolateral Na+/K+ ATPase is shown pumping 3 Na+ out and 2 K+ in, creating the gradient. On the apical side, Na+-glucose symporter (SGLT2), Na+/H+ antiporter, and aquaporin-1 channels are labeled. Glucose exits basolaterally via GLUT2. Panel C: A cellular diagram of the thick ascending limb showing the apical NKCC2 cotransporter (Na+/K+/2Cl-), basolateral Na+/K+ ATPase, apical ROMK channel recycling K+ back to the lumen, and the absence of aquaporin channels (impermeable to water).</image>
V. Countercurrent Mechanism — Producing Concentrated Urine
Countercurrent Multiplier (Loop of Henle)
The countercurrent multiplier establishes the medullary osmotic gradient, which ranges from approximately 300 mOsm/L at the cortex to 1,200 mOsm/L at the papilla. The mechanism works as follows: the thick ascending limb actively pumps NaCl into the medullary interstitium without water following, making the interstitium hyperosmotic. This high interstitial osmolarity draws water out of the descending limb, which is permeable to water, concentrating the tubular fluid within the descending limb. The concentrated fluid rounds the bend and enters the ascending limb, where NaCl is pumped out again. This cycle progressively multiplies the osmotic gradient from cortex to papilla. The "single effect" of NaCl pumping at the TAL is thus multiplied by the countercurrent flow arrangement.
Countercurrent Exchange (Vasa Recta)
The vasa recta are hairpin-shaped capillaries that parallel the loops of Henle and carry blood in the opposite direction to the tubular fluid. Their function is to supply blood to the medulla without washing out the osmotic gradient. As blood descends into the medulla, water leaves the vasa recta and solutes enter, equilibrating with the hyperosmotic interstitium. As blood ascends back toward the cortex, water re-enters and solutes leave, equilibrating with the progressively less concentrated interstitium. The net effect is that blood leaves the medulla with approximately the same osmolarity as when it entered, thereby preserving the gradient.
Urea Recycling
ADH increases urea permeability in the inner medullary collecting duct, allowing urea to diffuse from the collecting duct into the deep medullary interstitium, where it contributes approximately 50% of the medullary osmotic gradient. Some urea is recycled back into the thin ascending limb and eventually re-enters the collecting duct, maintaining a high medullary urea concentration.
<image>A multi-panel figure illustrating the countercurrent mechanism. Panel A: The countercurrent multiplier — a schematic of the loop of Henle with numerical osmolarity values at different levels. The descending limb shows progressively increasing tubular fluid osmolarity from 300 mOsm/L at the cortex to 1200 mOsm/L at the papilla (water leaving via osmosis, depicted by outward arrows). The thick ascending limb shows decreasing osmolarity from 1200 to ~100 mOsm/L (NaCl being pumped out, depicted by outward arrows, no water movement). The interstitium shows the gradient from 300 at the corticomedullary junction to 1200 at the papilla. Panel B: The countercurrent exchange in the vasa recta — a hairpin capillary loop next to the loop of Henle showing blood descending (losing water, gaining solutes) and ascending (gaining water, losing solutes), with numerical osmolarity values matching the interstitial gradient. Panel C: The collecting duct descending through the medullary gradient. With ADH present, aquaporin-2 channels are shown on the apical membrane, water exits into the hyperosmotic interstitium, and concentrated urine (~1200 mOsm/L) exits at the papilla. Without ADH, the collecting duct is impermeable to water and dilute urine (~50–100 mOsm/L) is produced.</image>
VI. Production of Dilute vs. Concentrated Urine
Dilute Urine (Low ADH)
When plasma osmolarity is low, such as during overhydration, osmoreceptors in the hypothalamus detect the low osmolarity and ADH release is inhibited. The thick ascending limb continues to pump NaCl out of the tubular fluid, diluting it to approximately 100 mOsm/L. Without ADH, the collecting duct remains impermeable to water, so the dilute filtrate passes through without water reabsorption, resulting in a large volume of dilute urine at 50 to 100 mOsm/L, theoretically up to 20 liters per day.
Concentrated Urine (High ADH)
When plasma osmolarity is high, such as during dehydration, or blood volume is low, osmoreceptors and baroreceptors stimulate ADH release from the posterior pituitary. ADH inserts AQP2 channels in the collecting duct, allowing water to be reabsorbed into the hyperosmotic medullary interstitium. The result is a small volume of concentrated urine, up to approximately 1,200 mOsm/L, potentially as little as 500 mL per day. Aldosterone, activated via the RAAS, simultaneously enhances sodium reabsorption to further conserve water.
VII. Clinical Correlations
Diabetes insipidus results from either a deficiency of ADH (central diabetes insipidus) or renal insensitivity to ADH (nephrogenic diabetes insipidus), producing large volumes of dilute urine and extreme thirst. SIADH (syndrome of inappropriate ADH secretion) involves excess ADH, leading to water retention and dilutional hyponatremia. Diuretics act at specific nephron segments: loop diuretics (furosemide) block NKCC2 in the TAL and impair the medullary gradient, increasing water and salt excretion; thiazide diuretics (hydrochlorothiazide) block NCC in the DCT; and potassium-sparing diuretics (spironolactone) block aldosterone receptors in the collecting duct. Chronic kidney disease (CKD) is a progressive decline in GFR leading to accumulation of wastes and fluid imbalance. Acute kidney injury (AKI) is a sudden drop in GFR with causes classified as prerenal (hypovolemia), intrarenal (tubular necrosis), or postrenal (obstruction).
