(Chapter 23)

1. The Urinary System (Chapter 23) Lecture # 14: Urine Formation Objectives 1- To describe the process by which the kidneys filter the blood plasma. 2- To describe how the nervous system, hormones, and the kidney itself regulate filtration. 3- To describe how renal tubules reabsorb useful solutes from the glomerular filtrate. 4- To describe how the tubules secret solutes from the blood into the tubular fluid. 5- To describe how the nephron regulates water excretion. 6- To explain how the collecting duct and antidiuretic hormone regulate the volume and concentration of urine.

2. Overview of Urine Formation The kidneys convert blood plasma to urine in 3 stages: Glomerular filtrate • It is the fluid in the capsular space. It is similar to blood plasma but without protein. Glomerular filtration Renal Corpuscle creates a plasmalike filtrate of the blood. Tubular reabsorption removes useful solutes from the filtrate, returns them to the blood. 2 3 1 Tubular fluid Peritubular capillaries and • It is the fluid in the renal tubule. It is similar to above except that tubular cells have removed and added substances. Tubular secretion Renal tubule removes additional wastes from the blood, adds them to the filtrate. Collecting duct Urine Water conservation • Once the fluid enters the collecting duct is called urine. The only remaining change is water content. H2O removes water from the urine and returns it to blood; concentrates Wastes. H2O H2O Urine

3. Urine Formation I: Glomerular Filtration Glomerular filtration It is a special case of the capillary fluid exchange process in which water and some solutes in the blood plasma pass from the capillaries of the glomerulus into the capsular space of the nephron. Filtration membrane It consists of the three barriers through which fluid passes: • 1- The fenestrated endothelium of glomerular capillaries 1 Endothelial cell of glomerular capillary • Glomerular capillaries have 70-90 nm filtration pores, which exclude blood cells but are highly permeable Basement membrane Filtration slit • 2- The basement membrane Filtration pore Foot process of Podocyte (pedicels) • It consists of a proteoglycan gel with negative charge. It excludes molecules greater than 8nm. Albumin is repelled by negative charge. Blood plasma is 7% protein, the filtrate is only 0.03% protein Bloodstream • 3- The filtration slits of podocytes • Podocyte have cell extensions called pedicels, which wrap around the capillaries to form a barrier layer with 30 nm filtration slits. Negative charge is an additional obstacle for large anions Capsular space

4. Almost any molecule smaller than 3 nm can pass freely through the filtration membrane: • 1- Water, electrolytes, glucose, fatty acids, amino acids, nitrogenous wastes, and vitamins. 2- Some substances of low molecular weight are bound to the plasma proteins and cannot get through the membrane: • 3- Most calcium, iron, and thyroid hormone. Kidney infections and trauma can damage the filtration membrane and allow albumin or blood cells to filter. Proteinuria (albuminuria): It is the presence of protein in the urine. Hematuria: It is the presence of blood in the urine.

5. Filtration Pressure Three forces determine the net filtration pressure: 1-Blood hydrostatic pressure (BHP): 60 mm Hg • Much higher than in most other capillaries (10 to 15 mm Hg ). It is because the afferent arteriole is larger than the efferent arteriole, giving the glomerulus a • larger inlet and smaller outlet. 2- Hydrostatic pressure in capsular space (CP): 18 mm Hg • It is due to high filtration rate and continual accumulation of fluid in the capsule. 3- Colloid osmotic pressure (COP) of blood • The glomerular filtrate is almost protein-free and has no significant COP 32 mm Hg • It is about the same here as elsewhere. BHP 60 mm Hg - CP 18 mm Hg - COP 32 mm Hg Net filtration pressure 10 mm Hg

6. Filtration Pressure BHP 60 out COP 32 in NFP 10 out CP 18 in Blood hydrostatic pressure (BHP) + 60 mm Hgout Colloid osmotic pressure (COP) -32 mm Hgin Capsular pressure (CP) -18 mm Hgin Net filtration pressure (NFP) 10 mm Hgout High BP in THE glomerulus makes kidneys vulnerable to hypertension. It can lead to rupture of glomerular capillaries, produce scarring of the kidneys (nephrosclerosis), and atherosclerosis of renal blood vessels, ultimately leading to renal failure.

7. Glomerular Filtration Rate (GFR) The glomerular filtration rate (GFR) is the amount of filtrate formed per minute by the 2 kidneys combined. Filtration Coefficient (Kf) It is the amount of filtrate produce per minute for every 1 mm Hg of net filtration pressure = 12.5 mL/min Net filtration pressure (NFP) = 10 mm Hg Glomerular Filtration Rate (GFR) = NFP x Kf = 10 x 12.5 = 125 mL/min The amount of filtrate formed in one day is: 125 mL/min x 1440 min = 180, 000 mL = 180 liters (about 60 times the amount of blood in the body). • In an average adult 99% of filtrate is reabsorbed since only 1 to 2 L of urine is excreted per day.

8. Regulation of Glomerular Filtration Rate (GFR) GFR must be precisely controlled: If GFR is too high: • Fluid flows through the renal tubules too rapidly for them to reabsorb the usual amount of water and solutes. Urine output rises and creates a threat of dehydration and electrolyte depletion. If GFR is too low: • Wastes are reabsorbed and azotemia may occur. GFR control is achieved by three homeostatic mechanisms: Myogenic mechanism • Increased arterial blood pressure stretches the afferent arteriole. The arteriole constricts and prevents blood flow into the glomerulus from changing much. When blood pressure falls the afferent arteriole relaxes • 1- Renal autoregulation Tubuloglomerular feedback Mechanism by which glomerulus receives feedback on the status of the down-stream tubular fluid and adjust filtration to regulate the composition of the fluid. It involves the Juxtaglomerular apparatus Sympathetic nervous system and adrenal epinephrine constrict the afferent arterioles in strenuous exercise or acute conditions like circulatory shock. • 2- Sympathetic control • This reduces GFR and urine output redirects blood from the kidneys to the heart, brain, and skeletal muscles. It depends on the Renin-Angiotensin-Aldosterone Mechanism • 3- Hormonal control

9. 1- Renal autoregulation Mesangial cells In the cleft between the afferent and efferent arterioles and among the capillaries of the glomerulus. JG cells contract which constricts afferent arteriole, reducing GFR to normal. Juxtaglomerular cells Enlarged smooth muscle cells in the afferent arteriole directly across from macula densa. Afferent arteriole Efferent arteriole Macula densa • If the flow of tubular fluid increases and more NaCl is reabsorbed, the macula densa stimulates JG cells with a paracrine messenger. Nephron loop Patch of slender, closely spaced epithelial cells at end of the nephron loop on the side of the tubules facing the arterioles. The Juxtaglomerular Apparatus

10. 3- Hormonal control The Renin-Angiotensin-Aldosterone Mechanism If BP drops dramatically, renin is secreted by juxtaglomerular cells. Angiotensin II Cardiovascular system BP Adrenal cortex Hypothalamus Aldosterone Renin Vasoconstriction Thirst and drinking BP

11. Urine Formation II: Tubular Reabsorption and Secretion Proximal convoluted tubule (PCT) Distal convoluted tubule (DCT) Glomerular Filtration Renal corpuscle 3 2 1 2 2 • It is the fluid in the capsular space. It is similar to blood plasma but without protein. Glomerular filtrate Tubular fluid 2 1 Tubular Reabsorption and Secretion Tubular Reabsorption and Secretion Glomerular filtration Collecting duct (CD) Nephron loop (loop of Henle) Water conservation Tubular Reabsorption and Secretion Conversion of glomerular filtrate to tubular fluid involves the removal and addition of chemicals by tubular reabsorption and secretion occurs through PCT to DCT.

12. Tubular Reabsorption and Secretion Proximal Convoluted Tubule The PCT reabsorbsabout 65% of glomerular filtrate, removes some substances from the blood, andsecretesthem into the tubular fluid for disposal in urine. I- Reabsorption There are two routes of reabsorption: • 1- Transcellular route • Substances pass through the cytoplasm of the PCT epithelial cells and out their base. • 2- Paracellular route • Substances pass between PCT cells. Junctions between epithelial cells are quite leaky and allow significant amounts of water to pass through. • Simple cuboidal epithelium with microvilli. • 1- Transcellular route • 2- Paracellular route

13. II- Secretion It is the process in which the renal tubule extracts chemicals from the capillary blood and secretes them into tubular fluid. Secretion has two purposes in proximal convoluted tubule and nephron loop: • 1- Waste removal • Urea, uric acid, bile acids, ammonia, catecholamines, prostaglandins and a little creatinine are secreted into the tubule. • Blood of pollutants, morphine, penicillin, aspirin, and other drugs. It explains need to take prescriptions 3 to 4 times/day to keep pace with the rate of clearance. • 2- Acid-base balance • Secretion of hydrogen and bicarbonate ions help regulate the pH of the body fluids. Secretion Reabsorption

14. The Nephron Loop Tubular Reabsorption and Secretion The primary function of nephron loop is to generate salinity gradient that enables collecting duct to concentrate the urine and conserve water. Proximal convoluted tubule (PCT) Distal convoluted tubule (DCT) Renal corpuscle Nephron loop (loop of Henle) Na+ Na+ Cl- K+ K+ It is heavily engaged in the active transport of salts and have many mitochondria. Na+ K+ Na+ H2O Cl- H2O K+ H2O H2O H2O Collecting duct (CD) • The thick segment reabsorbs 25% of Na+, K+, and Cl- . Those ions leave cells by active transport and diffusion. Water can not follow since thick segment is impermeable. • The tubular fluid is very dilute as it enters distal convoluted tubule.

15. Tubular Reabsorption and Secretion The Distal Convoluted tube and the Collecting Duct The fluid arriving in the DCT still contains about 20% of the water and 7% of the salts from glomerular filtrate. If this were all passed as urine, it would amount to 36 L/day. Proximal convoluted tubule (PCT) Distal convoluted tubule (DCT) DCT and collecting duct reabsorb variable amounts of water and salt and are regulated by several hormones: Na+ Na+ Cl- Cl- K+ K+ Na+ K+ K+ H2O Renal corpuscle Na+ H2O H2O Aldosterone H2O Atrial natriuretic peptide H2O Antidiuretic hormone Nephron loop (loop of Henle) • Parathyroid hormone Collecting duct (CD)

16. Aldosterone It is a steroid secreted by the adrenal cortex. • It stimulates the reabsorption of more Na+. The net effect is that the body retains NaCl and water and blood pressure rises. Atrial natriuretic peptide (ANP) It is secreted by atrial myocardium of the heart in response to high blood pressure. It has four actions that result in the excretion of more salt and water in the urine, thus reducing blood volume and pressure. Antidiuretic hormone (ADH) It is secreted by posterior lobe of pituitary in response to dehydration and rising blood osmolarity. It makes the collecting duct more permeable to water. Water in the tubular fluid reenters the tissue fluid and bloodstream rather than being lost in urine. Parathyroid hormone (PTH) It is secreted from parathyroid glands in response to calcium deficiency. • It acts on PCT to increase phosphate excretion, and acts on the thick segment of the ascending limb of the nephron loop, and on the DCT to increase calcium reabsorption

17. Urine Formation III: Water Conservation Proximal convoluted tubule (PCT) Distal convoluted tubule (DCT) Glomerular Filtration • It is the fluid in the capsular space. It is similar to blood plasma but without protein. Glomerular filtrate Tubular fluid Urine Renal corpuscle 3 3 1 3 2 2 3 1 Tubular Reabsorption and Secretion Glomerular filtration Water Conservation Water Conservation Collecting duct (CD) Nephron loop (loop of Henle) Water conservation Tubular Reabsorption and Secretion The kidney eliminates metabolic wastes from the body, but also prevents excessive water loss as well. As the kidney returns water to the tissue fluid and bloodstream, the fluid remaining in the renal tubules passes as urine, and becomes more concentrated.

18. The collecting duct begins in the cortex where it receives tubular fluid from several nephrons. As the collecting duct passes through the medulla, it reabsorbs water and concentrates urine up to four times. Two factors enable the collecting duct to concentrate the urine: 1- The osmolarity of the extra-cellular fluid is four times as high in the lower medulla as it is in the cortex. 2- The medullary portion of the collecting duct is more permeable to water than to solutes.

19. Countercurrent Multiplier of Nephron Loop

20. 1- Glomerular Filtration. It produces glomerular filtrate. It is a special case of the capillary fluid exchange process in which water and some solutes in the blood plasma pass from the capillaries of the glomerulus into the capsular space of the nephron. It is regulated by three mechanisms (renal autorregulation, sympathetic control, and hormonal control). Renal corpuscle 2- Tubular Reabsorption and Secretion. It produces tubular fluid. Proximal Convoluted Tubule The PCT reabsorbs about 65% of glomerular filtrate, removes some substances from the blood, and secretes them into the tubular fluid for disposal in urine. Nephron Loop The primary function of nephron loop is to generate salinity gradient that enables collecting duct to concentrate the urine and conserve water. Distal Convoluted tube DCT duct reabsorb variable amounts of water and salt and are regulated by several hormones (aldosterone, atrial natriuretic peptide, antidiuretic hormone, parathyroid hormone). 3- Water Conservation. It produces urine. As the collecting duct passes through the medulla, it reabsorbs water and concentrates urine up to four times.It is regulated by the antidiuretic hormone (ADH). Collecting Duct