Lecture notes on RenalPhysiology for MBBS Dr.Abubakkar Siddique Version:03 Compiled by Dr.Abubakkar Siddique Renal Functions and Anatomy Urinary System Homeostasis Body systems maintain homeostasis Homeostasis is essential for survival of cells Cells make up body systems Cells . If there is a deficiency of these substances. the kidneys can reduce the loss of these from the body. If the ECF has an excess of water or electrolytes.Summary of Kidney Functions They contribute to homeostasis. Other functions of the kidneys include: maintaining the proper osmolarity of body fluids maintaining proper plasma volume helping to maintain proper acid-base balance excreting wastes of body metabolism excreting many foreign compounds producing erythropoietin and renin converting vitamin D to an active form . They control electrolyte and water balance of the ECF. the kidneys eliminate the excess. plus urinary output. Kidney is bean shaped structure Measures 12 X6 X3 cm Weight 120 – 170 gram in adult male and 115 – 155 gram in adult female Kidney is contained in fibrous capsule Kidney lies retroperitoneal. in the paravertebral gutter. on the posterior abdominal wall It extends from 12th thoracic vertebra to 3rd lumbar vertebra The Rt Kidney is slightly lower . 5 – 2 cm Outer cortex 1cm (Contain Glomerular and convoluted tubules) Inner medulla Formed of 8 – 18 pyramids which are conical shaped with its base towards cortico-medullary junction with its apex projects in minor calyces as papillae On the tip of each papilla are 10 to 25 small openings that represent the distal ends of the collecting ducts (of Bellini).Kidney Parenchyma 1. The cortex may extend between pyramids forming columns of Bertini Medullary rays are striated elements which radiates from the pyramids (Strait segments of nephron) . . Nephron: functional unit of the kidney . followed by proximal convoluted tubule which also lies mainly in the renal cortex. .The Nephron Nephron is the functional unit of the kidney Each kidney contains nearly million Nephrons The first part of the Nephron is the Glomerulus (renal corpuscle) which lies mainly in the renal cortex. Collecting duct which lies partly in the cortex and partly in the medulla. This is followed by a loop of Henle which is partly in the cortex and partly extends deep into the medulla This is followed by the distal convoluted tubule which lies in the renal cortex. Renal Blood Flow . Blood supply of the kidney Renal arteries arise from the Aorta opposite the intervertebral disc Lumbar 1 – 2 The renal artery enters the hillar region and usually divides to form an anterior and a posterior branch. then they divide to form interlobar arteries. Then interlobular arteries which penetrate the cortex and form afferent arteriole Afferent arteriole invaginate the Bowman's capsule and form Glomerular tuft which is modified capillaries structure through which GFR is formed . Then arcuate arteries. Cortical and Juxtamed ullary Nephron Segments . From the glomerulus's efferent arteriole emerges Efferent arteriole of the outer and middle cortical glomeruli get down between tubules where they divide into capillary network called peritubular capillaries Efferent arteriole of the inner cortical glomeruli penetrate deeply into Medullary pyramids forming vasa recta sharing in the counter current exchange system Renal venous system and lymphatic follow same patterns of arteries Kidney receive sympathetic and parasympathetic supply from Celiac plexus . b .5a.Blood Supply to the Kidneys Figure 26. Blood Supply to the Kidneys Figure 26.5c. d . . this means that each kidney is perfused with over three times its total volume every minute. or 20% of the resting cardiac output. . A small fraction of the cortical blood flow is then directed to the medulla.Renal blood flow (RBF) is huge relative to the mass of the kidneys—about 1 L/min. Considering that the volume of each kidney is less than 150 cm3. All of this blood is delivered to the cortex. the low blood flow in the medulla permits an interstitial environment that is quite different from blood plasma. . In contrast.The significance of the quantitative differences between cortical and medullary blood flow is that the high blood flow in the cortical peritubular capillaries maintains the interstitial environment of the cortical renal tubules very close in composition to that of blood plasma throughout the body. AND BLOOD PRESSURE IN THE KIDNEYS The basic equation for blood flow through any organ is as follows: Q = ΔP/ R where Q --is organ blood flow. ΔP--the mean pressure in the artery supplying the organ minus mean pressure in the vein draining that organ R-. RESISTANCE.the total vascular resistance in that organ .FLOW. Arteriolar resistances are variable and are the sites of regulation . that is. so many glomeruli and their associated vessels The resistances of the afferent and efferent arterioles are about equal in most circumstances and account for most of the total renal vascular resistance. The resistance is low because there are so many pathways in parallel.The high RBF is accounted for by low total renal vascular resistance. their effects on RBF are additive. A change in the afferent arteriole or efferent arteriole resistance produces the same effect on RBF because these vessels are in series.Arteriolar resistances are variable and are the sites of regulation. When the two resistances both change in the same direction . When they change in different directions— one resistance increasing and the other decreasing—the changes offset each other . like a slice of Swiss cheese. . Filtered fluid must pass through a three-layered glomerular filtration barrier. It also contains small plasma peptides and a very limited amount of albumin . The middle layer. the capillary basement membrane. is a gel-like acellular meshwork of glycoproteins and proteoglycans.The glomerular filtrate contains most inorganic ions and low-molecular-weight organic solutes in virtually the same concentrations as in the plasma. the endothelial cells of the capillaries. is perforated by many large fenestrae (“windows”). which occupy about 10% of the endothelial surface area. with a structure like a kitchen sponge. The first layer. They are freely permeable to everything in the blood except cells and platelets. extend from each arm of the podocyte and are embedded in the basement membrane .The third layer consists of epithelial cells (podocytes) that surround the capillaries and rest on the basement membrane. once it has passed through the endothelial cells and basement membrane. Slit diaphragms are widened versions of the tight junctions and adhering junctions that link all contiguous epithelial cells together and are like miniature ladders. Extremely thin processes called slit diaphragms bridge the slits between the pedicels. Small “fingers. and the slit diaphragms are the rungs. Spaces between adjacent pedicels constitute the path through which the filtrate.” called pedicels (or foot processes). The pedicels form the sides of the ladder. which partially occludes the slits. The podocytes have an unusual octopus like structure. The foot processes are coated by a thick layer of extracellular material. . Pedicels from a given podocyte interdigitate with the pedicels from adjacent podocytes. travels to enter Bowman’s space. BASIC RENAL PROCESSES . Five Processes of Urinary System 1. 4. Secretion. 3. Filtration. 5. >99% reabsorbed. 1. Reabsorption. 2. Excretion Micturition Related by equation: E=F-R+S 180 L / day filtered.5 L/day excreted . Three basic processes of the nephrons are glomerular filtration. A protein-free plasma is filtered from the Glomerulus into the Bowman’s capsule. filtered substances move from the inside of the tubular part of the Nephron into the blood of the peritubular capillaries. Blood cells are not normally filtered. The reabsorption rates of most substances are very high. . Urine excretion results from these three processes. tubular reabsorption. Normally about 20 % of the plasma is filtered. and tubular secretion. By tubular reabsorption. Glomerular filtrate is produced at the rate of 125 ml per minute (180 liters per day). Tubular secretion is a selective process by which substances from the peritubular capillaries enter the lumen of the Nephron tubule. Glomerular filtration is the first process. The 80% of the plasma not filtered passes into the efferent arteriole and through the peritubular capillaries. Blood pathway Filtrate pathway Glomerular capillaries Glomerular filtration Bowman’s capsule Efferent arteriole Venous blood Peritubular capillaries Tubular reabsorption Tubular secretion Tubule (from proximal tubule to collecting duct) Urine . Once in lumen – consider it outside body Composition of filtrate? .1) Filtration = Movement of fluid from blood to lumen of Nephron. negative charge the inner layer of Bowman’s capsule Podocytes Filtration slits .Glomerular Filtration Fluid filtered from the Glomerulus into Bowman’s capsule passes through 3 layers: the Glomerular capillary wall the basement membrane Collagen Glycoproteins. . Filtration occurs throughout the length of the capillaries .What Drives Filtration? How does fluid move from the plasma across the Glomerular membrane into Bowman’s capsule? No active transport mechanisms No local energy expenditure Simple passive physical forces accomplish filtration . Forces involved in Filtration Glomerular capillary blood pressure (favors filtration) Plasma-colloid osmotic pressure (opposes filtration) Bowman’s capsule hydrostatic pressure (opposes filtration) . Glomerular Capillary Blood Pressure Fluid pressure exerted by the blood within the Glomerular capillaries Glomerular capillary pressure is significantly higher than other capillary blood pressures This is due to the larger diameter of the afferent arteriole compared with the efferent arteriole Blood pressure does not fall along the length of this capillary. ~ 55mmHg) . Cap. which pushes fluid out of the Glomerulus into Bowman’s capsule (pressure build-up in glom. Pressure opposing filtration Plasma-colloid oncotic pressure.tends to push fluid out of Bowman’s capsule (~15mmHg) .caused by the unequal distribution of plasma proteins across the glomerular membrane (~30mmHg) Bowman’s capsule hydrostatic pressurethe pressure exerted by the fluid in this initial part of the tubule. . Net Filtration Pressure Force favoring filtration (glomerular capillary blood pressure of 55 mmHg) minus forces opposing filtration (plasma colloid osmotic pressure of 30 mmHg & Bowman’s capsule pressure of 15 mmHg) =55 – (30 + 15) = 10 mmHg . . 180 mm Hg) .GFR = Glomerular Filtration Rate Describes filtration efficiency: Amount of fluid filtered per unit of time Average GFR ~ 180 L/day! Filtration Coefficient is influenced by Net filtration pressure Available surface area of Glomerular capillaries GFR is closely regulated to remain constant over range of BP (80 . Glomerular Filtration Rate Depends on The net filtration pressure How much glomerular surface area is available for penetration How permeable the glomerular membrane is GFR = Kf x net filtration pressure Where (Kf)= filtration coefficient (a product of the above two glomerular properties) .Roughly 125 ml/min in males . Filtration Fraction The Percentage of Renal Plasma Flow that is Filtered FF = GFR/RPF Roughly 20% . Filtration Pressure (BP) Hydrostatic.Regulation of GFR Several mechanisms provide close control of GFR. colloid Resistance in afferent vs. efferent arterioles Tubuloglomerular feedback JG Apparatus Hormones and ANS Angiotensin II (vasoconstrictor) Prostaglandins (vasodilator) . Mechanisms to Regulate GFR Autoregulation (prevent spontaneous changes in GFR) Involves Myogenic and Tubuloglomerular feedback mechanisms Extrinsic sympathetic control (long-term regulation of arterial BP) Mediated by the sympathetic nervous system Can override autoregulatory mechanisms . Auto regulation 1-Myogenic mechanism Response to changes in pressure within the nephron’s vascular component Arterioles contract inherently in response to the stretch accompanying ↑ pressure. Vessel automatically constricts, which helps limit blood flow into glomerulus despite increased systemic pressure Opposite reaction occurs when smooth muscles sense a drop in pressure Importance of Autoregulation of GFR Myogenic and Tubuloglomerular feedback mechanisms work in tandem to auto regulate GFR within a MAP range of 80-180 mmHg Autoregulation greatly blunts the direct effect that changes in arterial pressure might otherwise have on GFR and preserves water and solute homeostasis and allows waste excretion to carry on as usual Clinical Importance of GFR and Clearance GFR is indicator for overall kidney function Clearance → non-invasive way to measure GFR Inulin (research use) Neither secreted nor reabsorbed Creatinine (clinically useful) If a substance is filtered and reabsorbed but not secreted clearance rate < GFR If a substance is filtered and secreted but not reabsorbed clearance rate > GFR 4) Excretion = Urine Output Excretion of excess ions. Secretion E=F–R+S Direct measurement of F. toxins. H2O. Reabsorption. “foreign molecules” “nitrogenous waste” (NH4+ . S impossible infer from comparison of blood & urinalysis For any substance: (Renal) Clearance = plasma volume completely cleared of that substance per minute Typically expressed as ml/min . R. urea) Depends on Filtration. Autoregulation 2-Tubuloglomerular feedback Juxtaglomerular apparatus the combination of tubular and vascular cells where the tubule passes through the angle formed by the afferent and efferent arterioles as they join the Glomerulus Smooth muscle cells within the afferent arteriole form granular cells Specialized tubular cells in this region known as macula-densa sense changes in salt level of tubular fluid . Tubuloglomerular Feedback As GFR . flow through DCT Macula densa cells: release paracrines(ATP) juxtaglomerular cells(Granular cells) (smooth muscle fibers from afferent arteriole): contract Thus GFR . . Extrinsic Sympathetic Control GFR can be changed purposefully. conserving some water and salt. ↓ GFR causes ↓ urine output. even when MAP is within the autoregulatory range GFR is reduced by the baroreceptor reflex response to a fall in blood pressure (the SNS causes vasoconstriction in most arterioles as a compensatory mechanism to ↑ TPR) Afferent arterioles innervated with sympathetic vasoconstrictor fibers much more than are the efferent aa. helping to restore plasma volume to normal . Baroreceptor Reflex Influence on the GFR in Long-term Regulation of Arterial Blood Pressure . urea Transcytosis Proteins .2) Tubular Reabsorption (99% of filtrate) Active Na+ transport (Recall Antiports and Symports) Passive (think concentration and osmotic gradients) Paracellular eg. . . . ATPase on Basolateral membrane of PCT . . . . Thus. particularly in conditions of prolonged fasting. it would be deleterious to lose glucose in the urine. .GLUCOSE Handling in PCT Under most circumstances. the kidneys normally reabsorb all of the glucose that is filtered. a uniporter. .This involves taking up glucose from the tubular lumen along with sodium via a sodium-dependent glucose symporter (SGLUT) across the apical membrane of proximal convoluted tubule epithelial cells Followed by its exit across the basolateral membrane into the interstitium via a glucose transporter (GLUT). Saturation of Renal Transport Saturation = Maximum rate of transport (tm) Same 3 characteristics as discussed in mediated transport Transport maximum determined by Saturation Renal Threshold Specificity Competition . PROTEINS & PEPTIDES in PCT Although the glomerular filtrate is protein free.. although not in the conventional way. . it is not truly free of all protein. it just has a total protein content much lower than plasma. which are then returned to the blood. angiotensin. Peptides and smaller proteins (e.g. insulin) Normally all of these proteins and peptides are reabsorbed completely. They are enzymatically degraded into their constituent amino acids. from which they gain entry to the peritubular capillaries. This energyrequiring process is triggered by the binding of filtered protein molecules to specific receptors on the apical membrane. the initial step in recovery is endocytosis at the apical membrane.For the larger proteins. is reached. whose enzymes degrade the protein to low-molecular-weight fragments. . The pinched-off intracellular vesicles resulting from endocytosis merge with lysosomes. These end products then exit the cells across the basolateral membrane into the interstitial fluid. The rate of endocytosis is increased in proportion to the concentration of protein in the glomerular filtrate until a maximal rate of vesicle formation. and thus the Tm for protein uptake. mainly individual amino acids. These products are then reabsorbed by the same transporters that normally reabsorb filtered amino acids. . are catabolized into amino acids or dipeptides and tri-peptides within the proximal tubular lumen by peptidases located on the apical surface of the plasma membrane. such as angiotensin II.Very small peptides. . . . . . . Cl etc out of ascending limb (especially thick limb) of loop of Henle to the medullary interstitium. Passive diffusion of urea from medullary collecting ducts into the medullary interstitium. Diffusion of less amounts of water from medullary tubules into medullary interstitium . Active transport of ions from collecting duct to medullary interstitium. K.Medullary concentration gradient Active transport of Na. . . . . . . DISTAL CONVOLUTED TUBULE . so that it further dilutes the already somewhat dilute fluid entering it from the thick ascending limb. Like the ascending limb of the loop of Henle. The NaCl symporter is blocked by the thiazide diuretics. . the distal tubule is not permeable to water. The major luminal entry step being via the NaCl symporter This transporter differs significantly from the Na–K– 2Cl symporter in the thick ascending limb and is sensitive to different drugs.The distal tubule continues to reabsorb sodium and chloride. Sodium channels also permit sodium entry in the distal convoluted tubule. . . COLLECTING DUCT SYSTEM . Reabsorption of sodium and water is associated with Principal cells Reabsorption of chloride occurs partially via paracellular pathways Active reabsorption is also associated with another class of collecting duct cells. there is a division of labor among several different cell types.In the collecting ducts. the Intercalated cells . . . . It can be blocked by either Triamterene or Amiloride which are used medically to serve as diuretics. . and a protein hormone secreted by heart atrial muscle cells. In the kidney it is inhibited by Atrial Natriuretic peptide is a powerful vasodilator.The Principal cells Reabsorb sodium. the luminal entry step being via Epithelial Sodium Channels(ENaC) The activity of ENaC in colon and kidney is modulated by the Aldosterone. . . . Vasopressin) The inner medullary collecting duct has a limited water permeability even in the absence of ADH. . but the outer medullary and cortical regions have almost no water permeability without ADH. The water permeability of the principal cells in the collecting duct system—both the cortical and medullary portions—is subject to physiological control by circulating Antidiuretic hormone (ADH.Principal cells in the collecting ducts are also the crucial players in reabsorbing water. . . That is. When this fluid reaches the medullary portion of the collecting ducts. water permeability for most of the collecting duct system can vary from very low to very high.Depending on levels of ADH. there is now a huge osmotic gradient favoring reabsorption. which occurs to some extent. most of the water entering the medullary collecting duct flows on to the ureter. or water diuresis. the hypo-osmotic fluid entering the collecting duct system from the distal convoluted tubule remains hypo-osmotic as it flows along the ducts. although there is little cortical water reabsorption without ADH. The result is the excretion of a large volume of very hypo-osmotic (dilute) urine. there is still a limited medullary absorption because of the enormous osmotic gradient. As so much water is not reabsorbed in the cortex. When water permeability is very low (absence of ADH). . . the cortical collecting duct is reabsorbing the large volume of water that did not accompany solute reabsorption in the ascending limbs of Henle’s loop and distal convoluted tubule.When the collecting duct system’s water permeability is very high (High ADH) As the hypo-osmotic fluid entering the collecting duct system from the distal convoluted tubule flows through the cortical collecting ducts. which leaves the cortical collecting duct to enter the medullary collecting duct. is isosmotic with cortical plasma. . In essence. most of the water is rapidly reabsorbed. Once the osmolality of the luminal fluid approaches that of the cortical interstitial fluid. the cortical collecting duct then reabsorbs approximately equal proportions of solute (mainly sodium chloride) and water. This is because of the large difference in osmolality between the hypoosmotic luminal fluid and the isosmotic (285 mOsm/kg) interstitial fluid of the cortex. but its volume is greatly reduced compared with the amount entering from the distal tubule. The result is that the tubular fluid. Therefore. and the medullary interstitium is hyper-osmotic relative to normal plasma. solute reabsorption continues. but in the presence of ADH water reabsorption is proportionally even greater. This is because the ADH has signaled much of the medullary collecting duct epithelium to have high water permeability. the tubular fluid becomes more and more hyper-osmotic.In the medullary collecting duct. and reduced in volume . Formation of a Dilute Urine • Decrease water reabsorption • Continue electrolyte reabsorption Mechanism: Decreased ADH release and reduced water permeability in distal and collecting tubules Formation of a Concentrated Urine • Increase water reabsorption • Continue electrolyte reabsorption Mechanism: • Increased ADH release which increases water permeability in distal and collecting tubules • High osmolarity of renal medulla • Countercurrent flow of tubular fluid and enters into thin limbs of loop of Henle . DCT & cortical collecting duct is impermeable to urea.Urea recycling Thick ascending limb. Urea is permeable through medullary collecting duct (permeability is enhanced by ADH). Urea move out from medullary CT. . J.G Apparatus . . G APPARATUS .J. Granular cells (also called juxtaglomerular cells) Act as intrarenal baroreceptors They act entirely within the kidney. Although granular cells acting as intrarenal baroreceptors do not send signals centrally. These intrarenal baroreceptors sense renal afferent arteriolar pressure. If low response by releasing Renin the activity of the granular cells is affected both by direct sensing of pressure in the renal arterioles and by pressures sensed by neural baroreceptors elsewhere in the body vis sympathetic neves The Macula Densa cells The macula densa cells at the end of the thick ascending limb have Na–K–2Cl symporters that rapidly take up Na, Cl, and K when GFR, and hence, NaCl delivery is high. Sodium also enters the macula densa cells via a Na–H antiporter. Since the action of this antiporter causes the cells to lose a hydrogen ion for every sodium ion entering, this increases intracellular pH. increased intra-cellular chloride. which decreases GFR. Contraction of mesangial cells decreases the effective filtration area. .A combination of cellular volume change. P2 receptor stimulation increases calcium in these cells and promotes contraction. Contraction of the afferent arteriolar smooth muscle cells increases afferent resistance and decreases RBF and GFR. and higher intracellular pH initiates intracellular signaling processes that lead to the release of ATP from the basolateral surface of the cells in close proximity to the glomerular mesangial cells This ATP stimulates Purinergic P2 receptors on the mesangial cells and afferent arteriolar smooth muscle cells. In addition. it is the increased calcium in the afferent arteriolar cells that reduces Renin secretion. The ATP may also be metabolized to Adenosine. which can stimulate Adenosine receptors that produce the same result as the P2 receptors . .. volume expansion) in which the appropriate overall response is increased sodium excretion. The same signals that reduce filtration also reduce the secretion of renin.g.High salt content in the thick ascending limb of a given nephron generates signals that reduce glomerular blood flow and reduce filtration in that nephron. thus blunting (but not eliminating) the increase in sodium excretion initiated by other processes in conditions (e. . Control of Renin secretion. First. leading to the release of chemical transmitters that alter renin secretion from the granular cells: when sodium chloride delivery increases. except in cases of renal artery stenosis. the granular cells also act as intrarenal baroreceptors. renal sympathetic nerve activity activates β1-adrenergic receptors on granular cells of the afferent arteriole to stimulate renin secretion. responding to changes in pressure within the afferent arteriole. renin production increases. renin production decreases. is a reflection of changes in arterial blood pressure. Second. Deformation of the granular cells alters renin secretion: when pressure falls. . macula densa cells in the thick ascending limb sense the delivery of tubular sodium chloride. Third. Three primary mechanisms regulate renin secretion. which. . . . . . . . . Regulation of Sodium and Water Excretion . and therefore the cells throughout the body. (2) Enough pressure to drive blood flow through peripheral tissues. has the proper osmolality. Together they ensure that (1) There is enough blood volume to fill the vascular tree. All the regulatory mechanisms that control sodium and water excretion exist for the purpose of meeting these three goals. (3) The blood.The kidneys work in partnership with the cardiovascular system. . Variations in Renal blood flow (RBF) and Glomerular filtration rate (GFR) are major means of regulating sodium excretion . SODIUM EXCRETION: THE CARDIOVASCULAR CONNECTION . K+.3) Secretion 2nd route of entry (from ECF) into tubules for selected molecules Mostly transepithelial transport (analogous to reabsorption). foreign organic ions and drugs such as penicillin etc.) . Depends mostly on active membrane transport systems Provides mechanism for rapid removal of substances (most important for H+. Micturition Spinal cord integration: 2 simultaneous efferent signals In infant just simple spinal reflex Later: learned reflex under conscious control from higher brain centers Various subconscious factors affect reflex .5. Manneken Pis in Brussels .
Report "Lecture Notes on Renal Physiology for MBBS"