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Physiology of the Kidneys Major Functions of the Kidneys 1. Regulation of: body fluid osmolarity and volume electrolyte balance acid-base balance blood pressure 2. Excretion of metabolic products foreign substances (pesticides, chemicals etc.) excess substance (water, etc) 3. Secretion of erythropoitin 1,25-dihydroxy vitamin D3 (vitamin D activation) renin prostaglandin Structure of the Kidney • Outer cortex: • Contains many capillaries. • Medulla: • Renal pyramids separated by renal columns. • Pyramid contains minor calyces which unite to form a major calyx. Major calyces form renal pelvis. Renal pelvis collects urine. Transports urine to ureters. 1. Nephron and Collecting Duct Nephron: The functional unit of the kidney Each kidney is made up of about 1 million nephrons Each nephrons has two major components: 1) A renal corpuscle 2) A renal tubule Renal corpuscle Shumlyansky-Bowman’s Glomerulus (1) Capsule (2) 3 Proximal tubule 1 8 2 convoluted section (3) 7 9 4 descending limb (5) straight section(4) Loop of Henle thick ascending loop(6) thick ascending loop(7) Distal convoluted tubule (8) 6 5 Collecting ducts 10 cortical part (9) medullary part(10) Renal Blood Vessels • Afferent arteriole: • Delivers blood into the glomeruli. • Glomeruli: • Capillary network that produces filtrate that enters the urinary tubules. • Efferent arteriole: • Delivers blood from glomeruli to peritubular capillaries. • Peritubular capillaries: • Deliver blood to vasa recta. Insert fig. 17.5 Characteristics of the renal blood flow: 1, high blood flow. 1200 ml/min, or 21 percent of the cardiac output. 94% to the cortex 2, Two capillary beds Vesa Recta High hydrostatic pressure in glomerular capillary (about 60 mmHg) and low hydrostatic pressure in peritubular capillaries (about 13 mmHg) Type of Nephrons • Cortical nephron: • Originates in outer 2/3 of cortex. • Osmolarity of 300 mOsm/l. • Involved in solute reabsorption. Cortical nephron – glomeruli in outer cortex & short loops of Henle that extend only short distance into medulla-blood flow through cortex is rapid – majority of nephrons are cortical – cortical interstitial fluid 300 mOsmolar Insert fig. 17.6 Type of Nephrons • Juxtamedullary nephron: • Originates in inner 1/3 cortex. • Important in the ability to produce a concentrated urine. • Has longer LH. Juxtamedullary nephron – glomeruli in inner part of cortex & long loops of Henle which extend deeply into medulla.– blood flow through vasa recta in medulla is slow – medullary interstitial fluid is hyperosmotic – this nephron maintains osmolality in addition to filtering blood and maintaining acid-base balance Insert fig. 17.6 The juxtaglomerular apparatus macula densa, extraglumerular mesangial cells, and juxtaglomerular (granular cells) cells Juxtaglomerular apparatus • The juxtaglomerular cells are cells that synthesize, store, and secrete the enzyme renin. • Specialized smooth muscle cells in the wall of the afferent arteriole that are in contact with distal tubule. • Have mechano-receptors for blood pressure • The macula densa is an area of closely packed specialized cells lining the distal convoluted tubule where it lies next to the juxtaglomerular apparatus. • Cells of macula densa are taller and have more prominent nuclei than surrounding cells. • Sensitive to the concentration of sodium ions in the fluid. • The specific function of Extraglomerular mesangial cells (or lacis cells) is not well understood. Although is it has been associated with the secretion of Erythropoietin. URINE FORMATION The rates at which different substances are excreted in the urine represent the sum of three renal processes, • (1) glomerular filtration, • (2) reabsorption of substances from the renal tubules into the blood, and • (3) secretion of substances from the blood into the renal tubules. Processes, ensuring the formation of urine фильтрация Glomerular filtration primary urine Tubular вторичная моча Reabsorption Secretion secondary urine – Filtration: – First step in urine formation (primary urine) – Bulk transport of fluid from blood to kidney tubule » Isosmotic filtrate » Blood cells and proteins don’t filter – Result of hydraulic pressure – GFR = 180 L/day Second step in urine formation (secondary urine) – Reabsorbtion: • Process of returning filtered material to bloodstream • 99% of what is filtered • May involve transport protein(s) • Normally glucose is totally reabsorbed – Secretion: – Material added to lumen of kidney from blood – Active transport (usually) of toxins and foreign substances » Saccharine » Penicillin Glomerular Capsule • Bowman’s capsule: • Surrounds the glomerulus. • Location where glomerular filtration occurs. • Filtrate passes into the urinary space into PCT. Insert fig. 17.6 Glomerular Filtration Membrane • Endothelial capillary pores are large fenestrae. • 100-400 times more permeable to plasma, H20, and dissolved solutes than capillaries of skeletal muscles. • Pores are small enough to prevent RBCs, platelets, and WBCs from passing through the pores. –Loss of fluid from body in form of urine Amount = Amount + Amount -- Amount of Solute Filtered Secreted Reabsorbed Excreted Glomerular Filtration Glomerular filtration Occurs as fluids move across the glomerular capillary in response to glomerular hydrostatic pressure – blood enters glomerular capillary – filters out of renal corpuscle • large proteins and cells stay behind • everything else is filtered into nephron • glomerular filtrate – plasma like fluid in glomerulus Filtration Membrane – One layer of glomerular capillary cells – Basement membrane(lamina densa) – One layer of cells in Bowman’s capsule: Podocytes have foot like projections(pedicels) with filtration slits in between C: capillary BM: basal membrane P podocytes FS: filtration slit Factors that determining the glomerular filterability 1.Molecular weight Protein filtration: influence of negative charge on glomerular wall Filterablility of plasma constituents vs. water Constituent Mol. Wt. Urea Glucose Inulin Myoglobin Hemoglobin Serum albumin 60 180 5,500 17,000 64,000 69,000 Filteration ratio 1.00 1.00 1.00 0.75 0.03 0.01 Factors that determining the glumerular filterability 1.Molecular weight 2.Charges of the molecule Dextran filterability Stanton BA & Koeppen BM: ‘The Kidney’ in Physiology, Ed. Berne & Levy, Mosby, 1998 2934 Glomerular filtration • Mechanism: Bulk flow • Direction of movement: From glomerular capillaries to capsule space • Driving force: Pressure gradient (net filtration pressure, NFP) • Types of pressure: Favoring Force: Capillary Blood Pressure (BP), Opposing Force: Blood colloid osmotic pressure(COP) and Capsule Pressure (CP) Glomerular filtration rate (GFR) • Amount of filtrate produced in the kidneys each minute. 125mL/min = 180L/day • Factors that alter filtration pressure change GFR. These include: – Increased renal blood flow -- Increased GFR – Decreased plasma protein -- Increased GFR. Causes edema. – Hemorrhage -- Decreased capillary BP -- Decreased GFR GFR regulation : Adjusting blood flow • GFR is regulated using three mechanisms 1. Renal Autoregulation 2. Neural regulation 3. Hormonal regulation All three mechanism adjust renal blood pressure and resulting blood flow a. Renal autoregulation In the autoregulatory range, renal blood flow and GFR stay relatively constant despite changes in arterial blood pressure. ERPF: experimental renal plasma flow GFR: glomerular filtration rate 1) Myogenic Mechanism of the autoregulation • This is accomplished by changes in the resistance (caliber) of preglomerular blood vessels. • The circles indicate that vessel radius (r) is smaller when blood pressure is high and larger when blood pressure is low. • Since resistance to blood flow varies as r4, changes in vessel caliber are greatly exaggerated in this figure. Blood Flow = Capillary Pressure / Flow resistance b. Tubuloglomerular feedback • When single nephron GFR is increased—for example, as a result of an increase in arterial blood pressure—more NaCl is delivered to and reabsorbed by the macula densa, leading to constriction of the nearby afferent arteriole. • This negative-feedback system plays a role in renal blood flow and GFR autoregulation. 2. Neural regulation of GFR • Sympathetic nerve fibers innervate afferent and efferent arteriole • Normally sympathetic stimulation is low but can increase during hemorrhage and exercise • Vasoconstriction occurs as a result which conserves blood volume(hemorrhage)and permits greater blood flow to other body parts(exercise) 3. Hormonal regulation of GFR • Several hormones contribute to GFR regulation • Angiotensin II. Produced by Renin, released by JGA cells is a potent vasoconstrictor. Reduces GFR • Atrial natriuretic peptide ANP (released by atria when stretched) increases GFR by increasing capillary surface area available for filtration • NO • Endothelin • Prostaglandin E2 Reabsorption in Proximal Tubule Insert fig. 17.13 Reabsorption of Salt and H20 • Return of most of the molecules and H20 from the urine filtrate back into the peritubular capillaries. • About 180 L/day of ultrafiltrate produced; however, only 1–2 L of urine excreted/24 hours. • Urine volume varies according to the needs of the body. • Minimum of 400 ml/day urine necessary to excrete metabolic wastes (obligatory water loss). •GFR 125 ml/min (180L/day) •(about 1% is excreted) PCT • Total [solute] is = 300 mOsm/L. • Reabsorption of H20 by osmosis, cannot occur without active transport: • [Na+] in glomerular ultrafiltrate is 300 mOm/L. • PCT epithelial cells have lower [Na+]. • Due to low permeability of plasma membrane to Na+. • Active transport of Na+ out of the cell by Na+/K+ pumps. • Favors [Na+] gradient: • Na+ diffusion into cell. PCT (continued) • Na+/K+ ATPase pump located in basal and lateral sides of cell membrane, creates gradient for diffusion of Na+ across the apical membrane. • Na+/K+ ATPase pump extrudes Na+. • Creates potential difference across the wall of the tubule, with lumen as –pole. • Electrical gradient causes Cl- movement towards higher [Na+]. • H20 follows by osmosis. Salt and Water Reabsorption in Proximal Tubule Insert fig. 17.14 Significance of PCT Reabsorption • 65% Na+, Cl-, and H20 reabsorbed across the PCT into the vascular system. • 90% K+ reabsorbed. • Reabsorption occurs constantly regardless of hydration state. • Not subject to hormonal regulation. • Energy expenditure is 6% of calories consumed at rest. Countercurrent Multiplier • In order for H20 to be reabsorbed, interstitial fluid must be hypertonic. • Osmotic pressure of the interstitial tissue fluid is 4 x that of plasma. • Results partly from the fact that the tubule bends permitting interaction between the descending and ascending limbs. Ascending Limb LH • (sodium chloride) is actively extruded from the ascending limb into surrounding interstitial fluid. • Na+ diffuses into tubular cell with the secondary active transport of K+ and Cl-. • Occurs at a ratio of 1 Na+ and 1 K+ to 2 Cl-. Insert fig. 17.15 Ascending Limb LH • Na+ actively transported across the basolateral membrane by Na+/ K+ ATPase pump. • Cl- passively follows Na+ down electrical gradient. • K+ passively diffuses back into filtrate. • Ascending walls are impermeable to H20. (continued) Insert fig. 17.15 Descending Limb LH • Deeper regions of medulla reach 1400 mOsm/L. • Impermeable to passive diffusion of NaCl. • Permeable to H20. • Hypertonic interstitial fluid causes H20 movement out of the descending limb via osmosis, and H20 enters capillaries. • Fluid volume decreases in tubule, causing higher [Na+] in the ascending limb. Insert fig. 17.16 Countercurrent Multiplier System • Multiplies the [interstitial fluid] and [descending limb fluid]. • Flow in opposite directions in the ascending and descending limbs. • Close proximity of the 2 limbs: • Allows interaction. • Positive feedback. Insert fig. 17.16 Vasa Recta • Countercurrent exchange. • Recycles NaCl in medulla. • Transports H20 from interstitial fluid. • Descending limb: • Urea transporters. • Aquaporin proteins (H20 channels). • Ascending limb: • Fenestrated capillaries. Insert fig. 17.17 Vasa Recta (continued) • Vasa recta maintains hypertonicity by countercurrent exchange. • NaCl and urea diffuse into descending limb and diffuse back into medullary tissue fluid. • At each level of the medulla, [solute] is higher in the ascending limb than in the interstitial fluid; and higher in the interstitial fluid than in descending vessels. • Walls are permeable to H20, NaCl and urea. • Colloid osmotic pressure in vasa recta > interstitial fluid. Osmolality of Different Regions of the Kidney Insert fig. 17.19 Collecting Duct • Medullary area impermeable to high [NaCl] that surrounds it. • The walls of the CD are permeable to H20. • H20 is drawn out of the CD by osmosis. • Rate of osmotic movement is determined by the # of aquaporins in the cell membrane. • Permeable to H20 depends upon the presence of ADH. • When ADH binds to its membrane receptors on CD, it acts via cAMP. • Stimulates fusion of vesicles with plasma membrane. • Incorporates water channels into plasma membrane. Glucose and Amino Acid Reabsorption • Filtered glucose and amino acids are normally reabsorbed by the nephrons. • In PCT occurs by secondary active transport with membrane carriers. • Carrier mediated transport displays: • Saturation. • Tm. • [Transported molecules] needed to saturate carriers and achieve maximum transport rate. • Renal transport threshold: • Minimum plasma [substance] that results in excretion of that substance in the urine. • Renal plasma threshold for glucose = 180-200 mg/dl. Secretion • Secretion of substances from the peritubular capillaries into interstitial fluid. • Then transported into lumen of tubule, and into the urine. • Allows the kidneys to rapidly eliminate certain potential toxins. Proximal Tubule Secretion Insert fig. 17.13 K+ Secretion • 90% filtered K+ is reabsorbed in early part of the nephron. • Secretion of K+ occurs in CD. • Amount of K+ secreted depends upon: • Amount of Na+ delivered to the region. • Amount of aldosterone secreted. • As Na+ is reabsorbed, lumen of tubule becomes –charged. • Potential difference drives secretion of K+ into tubule. • Transport carriers for Na+ separate from transporters for K+. K+ Secretion (continued) • Final [K+] controlled in CD by aldosterone. • When aldosterone is absent, no K+ is excreted in the urine. • High [K+] or low [Na+] stimulates the secretion of aldosterone. • Only means by which K+ is secreted. Insert fig. 17.24 Renal Acid-Base Regulation • Kidneys help regulate blood pH by excreting H+ and reabsorbing HC03-. • Most of the H+ secretion occurs across the walls of the PCT in exchange for Na+. • Antiport mechanism. • Moves Na+ and H+ in opposite directions. • Normal urine normally is slightly acidic because the kidneys reabsorb almost all HC03- and excrete H+. • Returns blood pH back to normal range. Reabsorption of HCO3• Apical membranes of tubule cells are impermeable to HCO3-. • Reabsorption is indirect. • When urine is acidic, HCO3- combines with H+ to form H2C03-, which is catalyzed by ca located in the apical cell membrane of PCT. • As [C02] increases in the filtrate, C02 diffuses into tubule cell and forms H2C03. • H2C03 dissociates to HCO3- and H+. • HCO3- generated within tubule cell diffuses into peritubular capillary. Acidification of Urine Insert fig. 17.28 Urinary Buffers • Nephron cannot produce a urine pH < 4.5. • In order to excrete more H+, the acid must be buffered. • H+ secreted into the urine tubule and combines with HPO4-2 or NH3. • HPO4-2 + H+ H2PO4• NH3 + H+ NH4+