Renal System Lecture 9 PDF

Dr Yasser Abdel-Wahab (Module Coordinator WEEK 9 Introduction to Anatomy and Physiology of the Renal System Aims: To give an overview of the Anatomy and Physiology of the Renal System Lecture Outlines: 1. The organisation of the renal system 2. Overview of the anatomy of the kidney, neph...

Dr Yasser Abdel-Wahab (Module Coordinator WEEK 9 Introduction to Anatomy and Physiology of the Renal System Aims: To give an overview of the Anatomy and Physiology of the Renal System Lecture Outlines: 1. The organisation of the renal system 2. Overview of the anatomy of the kidney, nephrons, ureters, bladder and urethra 3. Functions of the kidneys 4. Urination and urine formation 5. Overview of glomerular filtration 6. Tubular reabsorption in the nephron 7. Reabsorption of sodium (Na+) 8. Reabsorption of water 9. Actions of anti-diuretic hormone 10. Tubular secretions 11. K+ secretion at distal and collecting tubules 12. Renal responses to changes in plasma pH Intended Learning outcomes are: Know the general organisation of the renal system and the anatomy of the kidneys, ureters, bladder and urethra. Sketch and label a typical nephron and appreciate the structural and functional role of the nephrons. Outline the basic functions of the kidneys. Appreciate the basic physiology of proximal convoluted tubule cells. Outline the three main steps involved in urine formation Discuss glomerular filtration and factors regulating the glomerular filtration rate. Describe tubular reabsorption and the difference in reabsorption between the proximal convoluted tubules, loop of henle, and the distal convoluted tubules and collecting ducts. Outline the reabsorption of Na+ ions and the role of aldosterone in this process. Give an overview of water reabsorption and the role of ADH in water reabsorption. Discuss the importance of tubular secretions and the secretion of K+ ions. Summarise the alteration in secretion and absorption involved in maintenance of blood/plasma pH. 1  Dr Yasser Abdel-Wahab (Module Coordinator MAIN ORGANS OF THE RENAL SYSTEM The primary function of the urinary system is to help maintain body homeostasis by controlling the composition, volume and pressure of blood. The urinary system comprises of two kidneys (which produce urine), two ureters (which transport urine to the bladder), one urinary bladder (temporarily stores urine prior to elimination) and a single urethra (conducts urine to the exterior). Divisions of the Renal system Kidneys: The paired kidneys are reddish organs, shaped like kidney beans They are located above the waist between parietal peritoneum and posterior wall of the abdomen (they are retroperitoneal organs). The external anatomy of the kidney  An average adult kidney measures about 10 - 12 cm long, 5 - 7.5 cm wide and 2.5 cm thick  Hilus – this is a prominent medial indentation which is the point at which renal artery and nerves enter the kidneys and renal vein and ureter exit the kidneys  Renal Sinus – internal cavity within the kidney at the hilus were urine collects before draining to bladder Tissue layers surrounding the kidney There are 3 tissue layers surrounding and supporting the kidney:  Renal capsule – layer of collagen fiber covering entire outer surface of kidneys and continuous with outer coat of ureters at the hilus  Adipose capsule – thick layer of adipose tissue surrounding renal capsule  Renal Fascia – dense, fibrous outer layer anchoring kidneys to posterior body wall and anterior peritoneum Collagen fibers extend from the renal capsule through the adipose layer to the renal fascia Internal anatomy of the kidney As shown in the diagram a cross section of the kidney reveals the internal anatomy of the kidney which includes:  Cortex – the outer region of the kidney in contact with the renal capsule and is granular and reddish-brown in colour  Medulla – the inner region of the kidney and is made up of between 6 – 18 renal pyramids  Renal (medullary) pyramids/Renal papillae – renal pyramids are conical or triangular in shape. The base of each faces the cortex and the tip (renal papillae) 2  Dr Yasser Abdel-Wahab (Module Coordinator project into the renal sinus. Fine grooves running down the pyramid converge at the papillae.  Outer cortical region/ Juxtamedullary zone – the functional nephrons can start in the outer cortical region (cortical nephrons) or in the region of cortex close to the medulla know as the juxtamedullary zone (juxtamedullary nephrons).  Renal columns – these are bands of cortical tissue separating each of the renal pyramids  Together the cortex and renal pyramids constitute the parenchyma (functional) portion of the kidney The Nephron Nephrons are the functional units of the kidney, involved in filtration, secretion and absorption. Each kidney contains around 1 million nephrons. A diagram of the nephron, tubules and collecting ducts is shown below The main components of nephron are:  Renal corpuscle (150-250 m diameter) o Where fluid is filtered o Contains the glomerulus (capillary network), contained in the glomerular (Bowman’s) capsule  Renal tubules: o Into which filtered fluid passes o Blood enters through afferent arteriole and exits through an efferent arteriole The renal tubule consists of:  Proximal convoluted (coiled) tubule (PCT)  Loop of Henle (U-shaped nephron loop) which separates the PCT and DCT  Distal convoluted tubule (DCT) There are short connecting tubules linking the DCT of several nephrons to a single collecting duct. These collecting ducts descend through the medulla to papillary ducts at the base of the medulla. The fluid then drains into the minor calyx, then 4-5 minor calyces merge into a major calyx. A number of major calyces (2-3) merge to form the renal pelvis which fills into the renal sinus. The nephrons can start in the outer cortical region or close to the medulla in the juxtamedullary zone and these Cortical nephron and Juxtamedullary nephrons are shown in this diagram The loops of Henle connect the PCT and DCT; the first portion of the loop dips into the medulla, known as descending loop of Henle, then bends in a U-shaped known as the ascending loop of Henle, and returns to the cortex. 3  Dr Yasser Abdel-Wahab (Module Coordinator Histology of the Nephron Histology of the filter (Glomerulus): - Endothelium of glomerulus(capillaries) – fenestrated to allow passage of fluid but not blood cells - Basement membrane of the glomerulus (lamina densa) surrounds the glomerular endothelium Filtration slits in podocytes (epithelial cells wrapping around lamina densa) prevent loss of all but smallest plasma proteins from filtrate Histology of renal tubules - cuboidal epithelial cells with microvilli in PCT; cuboidal epithelial cells in thick section of Loop of Henle and squamous epithelial cells in thin segment; DCT has cuboidal epithielial cells without microvilli Histology of juxtamedullary apparatus: Macula densa – epithelial cells of DCT near renal corpuscle which are taller with cluster nuclei Juxtaglomerular cells (JG)- unusual smooth muscle fibers in wall of afferent arteriole close to the macula densa These macula densa and juxtaglomerular cells form the endocrine juxtaglomerular complex which secretes erythropoiten and rennin Blood and nerve supply of the kidney: Right and Left renal arteries splits into large anterior branch and small posterior branch. Segmental arteries, interlobular arteries which divide into afferent arteriole enters the cortex. The nerve supply is renal plexus which is the sympathetic division of the autonomic nervous system. Vasomotor nerves regulate arteriole diameter. Ureters, Urinary bladder and urethra The ureters: are muscular tubes (approx 30 cm long) which extend from the renal pelvis of the kidneys to the urinary bladder and consist of three layers:  inner mucosa of epithelial cells and lamina propia  middle muscle layer (longitudinal and circular smooth muscle)  outer connective tissue layer (continuous with renal capsule and peritoneum) Urine is forced down along the ureters by peristaltic contraction running from kidney to bladder approx every 30 seconds. The diagram to the right shows the anatomy of the male urinary bladder Urinary bladder: is a hollow muscular organ which can temporarily store up to 1 litre of urine. It is anterior to the rectum in males and anterior to the vagina and inferior to the uterus in females.  The internal mucosa lining the bladder is in folds known as rugae which disappear as bladder is extended by urine. 4  Dr Yasser Abdel-Wahab (Module Coordinator  The triangular area between the entering ureters and exiting urethra is called trigone and has smooth and thick mucosa  Trigone funnels urine into urethra upon bladder contraction. The bladder histology:  Internal mucosa  Submucosa  Muscularis consisting of: o inner and outer longitudinal smooth muscle layers o middle circular smooth muscle layer These muscles form the detrusor muscle which contract to expel urine from the bladder. The Urethra: extends from base of bladder to exterior of body (3-5 cm long in females and 18- 20cm long in males). In males the urethra is divided in three segments:  prostatic urethra – passes through centre of prostate gland  membranous urethra – short segment passing through urogenital diaphragm  spongy urethra – extends from border of urogenital diaphragm to end of penis At urogenital diaphragm, circular band of skeletal muscle acts as external urethral sphincter controlling release of urine. This sphincter is under voluntary control (pudendal nerve) and must be relaxed to allow micturition Urerthra histology:  inner mucosa (folded longitudinally) made up of: o transitional epithelium (stratified at neck of bladder to columnar at midpoint to stratified squamous near external opening) o and lamina propria - o mucin secreting cells in pockets of mucosa  smooth muscle layer in females  outer connective tissue layer of lamina propia – anchors urthera to surrounding structures Renal physiology Functions of the kidney The kidneys have three major functions  excretion of organic waste products from plasma (e.g. urea, creatinine and uric acid)  elimination of this water and waste into the external environment  homeostatic regulation of plasma volume, plasma osmolarity, plasma pH and plasma electrolyte levels This is carried out by the 2 kidneys, which produce urine. 5  Dr Yasser Abdel-Wahab (Module Coordinator Urine contains water, ions, soluble organic metabolic waste compounds, and other foreign compounds. A minimum of 500 ml of urine is produced and excreted each day. Urination (Micturition)  Urine is formed by filtration of plasma at the nephrons in the kidneys (approx 1 million nephrons/kidney).  The urine flowing through the collecting ducts from all nephrons collects at the kidneys renal pelvis.  The urine then flows through the ureters by peristaltic contraction of the ureters until entering the the bladder where it is stored until elimination from the body.  As the bladder fills stretch receptors in the bladder wall are stimulated and send impulses to the spinal cord and brain via the pelvic nerve.  The body becomes aware of the sensation of a full bladder and the response is voluntary relaxation of the external smooth muscle sphincter at the opening of the bladder, which causes relaxation of the internal urethral sphincter.  The micturition reflex also send a parasympathetic signal stimulating contraction of the detrusor muscle of the bladder.  This causes increased fluid pressure in the bladder, and if both the internal and external urethral sphincter muscles are relaxed, then urine flows out of the bladder into the urethra.  Urine flows along the urethra into the external environment, and less than 10 ml of urine will remain in the bladder. The Nephron  Each kidney has approximately 1 million nephrons.  Nephrons start with a Bowmans capsule (renal corpuscle) in the renal cortex were filtration occurs.  Nephrons then have epithelial tubules with specialized cells which allow filtration and reabsorption of water, ions and organic waste. These are the proximal convoluted tubules, loop of Henle and distal convoluted tubules.  The tubules from nephrons meet and drain into collecting ducts  Collecting ducts merge into minor calyx, which merge into major calyx and ultimately to the renal pelvis  The urine collected at the renal pelvis then flows to the bladder along the ureters. 6  Dr Yasser Abdel-Wahab (Module Coordinator This diagram summarizes the functions of the various sections of the nephron including filtration, secretion and reabsorption which will be discussed below Proximal tubular cells  The epithelial cells lining the proximal convoluted tubules are specialized for reabsorption of water, ions and organic products from the filtrate produced at the Bowmans capsule.  They have microvilli on the mucosal side to maximize surface area for reabsorption.  The products which are reabsorbed by these proximal tubular cells enters the peritubular fluid on the serosal side on the outside of the tubules. Steps involved in urine formation There are three main steps involved in urine formation. 1. Glomerular filtration – blood pressure (hydrostatic pressure) forces water, ions and organic solutes to pass through the wall of glomerular capillaries in the Bowmans capsule. About 200 litres of filtrate is produced each day at the Bowmans capsule, with approx 1800 g of NaCl being filtered. Filtration is based on size of solutes. 2. Tubular reabsorption – The large volume of filtrate generated has water, ions and organic nutrients reabsorbed back into the peritubular fluid at the proximal and distal convoluted tubules, loop of Henle and also at the collecting ducts. Reabsorption involves either simple diffusion or activity of carrier proteins 7  Dr Yasser Abdel-Wahab (Module Coordinator 3. Tubular secretion – this is the transport of solutes from the peritubular fluid back into the tubular fluid inside the tubules. It is a backup to filtration and can further low plasma levels of waste products. Secretion is the main route of excretion of many compounds such as drugs. Following these steps the volume of urine produced is about 1.5 litre each day (compared to 200 litres of filtrate) and contains ~ 10g NaCl (compared to the 1800 g filtered). These steps will be discussed in more detail below. 1. Glomerular filtration The glomerular filtration rate – is the amount of filtrate produced per minute by the kidneys. The glomerular filtration rate is approximately 125 ml/min Glomerular filtration involves passage of filtrate through three layers: 1. glomerular capillary endothelium (has pores of 60 – 100 nm diameter) 2. the dense layer (lamina densa) 3. the filtration slits (between pedicels of podocytes, 6 – 9 nm wide gaps) The pores of the glomerular capillary endothelium are large enough to allow passage of all but blood cells. Large plasma proteins are unable to cross the lamina densa, and finally the filtration slits prevent the loss of most plasma proteins. The filtrate is essentially the same as plasma apart from the presence of plasma proteins. What factors affect the rate of glomerular filtration into the Bowmans capsule?  Filtration is driven by high glomerular hydrostatic pressure (blood pressure). The pressure is high due to blood flowing away from the glomerular capillaries into arterioles with narrow diameters than the afferent arterioles which supply the glomerular capillaries. The pressure is around 50 mmHg compared to 35 mmHg in other capillaries.  Filtration is opposed by capsular hydrostatic pressure, which is pressure of the fluid in the capsule caused by resistance to flow through the nephrons along the tubules and collecting tubules and is about 15 mmHg.  Filtration is also opposed by blood colloid osmotic pressure, which is caused by proteins in the plasma. Since there are none in the filtrate the protein solution tends to draw in water out of the filtrate to reduce protein concentration in plasma. This pressure is about 25 mmHg. The net hydrostatic pressure (35 mmHg) = glomerular hydrostatic pressure (50 mmHg) – capsular hydrostatic pressure (15 mmHg) The filtration pressure (10 mmHg) = net hydrostatic pressure (35 mmHg) – blood colloid osmotic pressure (25 mmHg) 8  Dr Yasser Abdel-Wahab (Module Coordinator It is the filtration pressure which maintains the transport of water, ions and organic compounds out of the glomerular capillaries and into the fitrate. The table below summarises substances filtered at the glomerulus, their relative size (MW) and the ratio of their concentration in filtrate compared to blood 2. Tubular reabsorption Reabsorption is essential as the filtrate produced each day is ~70 times the total volume of plasma. Without reabsorption the body would become fatally dehydrated. Reabsorption at the proximal convoluted tubule PCT  Filtrate first enters the PCT where reabsorption occurs from filtrate across the epithelial cells of the PCT into the peritubular fluid were substances can re- enter the blood stream in the peritubular capillaries  Water (60-70% of total filtered) is reabsorbed by osmosis  Na+ ions (60 – 75%) and other ions are reabsorbed by both diffusion, cotransport, countertransport and active transport  Cl- ions are reabsorbed by passive diffusion.  Organic substances (99 – 100%) are also reabsorbed by facilitated transport and cotransport.  The osmotic concentration of tubular fluid and peritubular fluid in the PCT remain iso- osmotic (i.e. the same at 300 mOs). 9  Dr Yasser Abdel-Wahab (Module Coordinator Tubular reabsorption at the loop of Henle  Most tubular fluid (60-70%) has been reabsorbed at from the proximal convoluted tubule.  Approx 30 ml of fluid/min enters the descending limb of the loops.  The osmotic concentration of fluid entering the descending limb is 300 mOs (same as that at glomerular capsule and peritubular fluid of renal cortex).  Descending limb is permeable to water but not solutes.  Water passively diffuses out into the peritubular fluid from the descending limb causing an increase in osmotic concentration of the tubular fluid to around 1200 mOs.  At the bottom of the loop the volume is reduced to about 6 ml/min  The ascending limb is thicker and is impermeable to water and solutes, but actively pumps Na+ and Cl- ions out into the peritubular fluid of the surrounding medulla.  The distance between descending and ascending limbs of the loop is small and is filled with peritubular fluid.  The active transport of Na+ and Cl- out of the ascending limb into the peritubular fluid raises the osmotic concentration of the peritubular fluid around the descending limb, which encourages water movement out of the descending limb. This lowers the osmotic concentration and encourage solute movement out of the ascending limb in a countercurrent mechanism (fluid flowing in opposite directions in these sections of loop).  By the time the tubular fluid reaches the start of the distal convoluted tubule the osmotic concentration is 100 mOs, about 1/3 of that of the peritubular fluid in the surrounding renal cortex. Tubular reabsorption at the distal convoluted tubule (DCT) and collecting ducts  The cells of the DCT actively transport Na+ and Cl- ions out of the tubular fluid into the peritubular fluid.  Cells of the distal region of the DCT contain ion pumps which exchange (reabsorb) Na+ usually for K+ ions.  DCT is the main site for reabsorption of Ca2+ and this is regulated by parathyroid hormone and calcitrol.  By the time the tubular fluid reaches the collecting ducts the osmolarity is 300 mOs and the volume is 4ml/min.  Water is further reabsorbed along the collecting ducts passing through the renal medulla to give a volume of about 1ml/min with osmolarity of 1200 mOs  This reabsorption of water is controlled by hormones as discussed in detail below.  The reabsorption of Na+ will also be discussed in more detail below. 10  Dr Yasser Abdel-Wahab (Module Coordinator Tubular Na+ reabsorption  In the DCT the sodium channels and ion pumps are controlled by aldosterone.  Aldosterone stimulates synthesis and insertion of sodium channels and ions pumps into the tubular cell membrane of the DCT and collecting ducts.  Na+ can then be reabsorbed from the lumen containing the tubular fluid.  The transport of Na+ from the tubular cells into the peritubular fluid (or interstitial fluid) occurs by active (ATP-dependent) pumping through sodium-potassium exchange pumps, with K+ ions entering the cells from the peritubular fluid.  The Na+ ions can then diffuse back into the blood through the capillaries surrounding the tubules.  Other mechanisms of Na+ reabsorption along the tubules include co-transport with glucose and amino acids or urea and Cl- ions (i.e. cotransported along with one of these bound to carrier protein with one moving by following concentration gradient).  The Na+-K+/2Cl- transporter also actively pumps 1 Na+, 1 K+ and 2 Cl- ions from the tubular fluid into the tubular cells. Water reabsorption  The reabsorption of water is always by passive osmosis  A higher Na+ concentration in the peritubular fluid causes water to move from the tubular fluid into the peritubular fluid in attempt to maintain an iso-osmotic concentration between the tubular and peritubular fluid.  The volume of water excreted and reabsorbed in the DCT and collecting ducts is controlled by antidiuretic hormone (ADH) and natriuretic peptides  About 108 litres of water are reabsorbed daily Action of antidiuretic hormone ADH (Vasopressin)  ADH is secreted by the hypothalamus to control plasma volume  ADH controls the precise amount of water reabsorbed in the DCT and collecting ducts by a process known as facultative water reabsorption  ADH binds to receptors on the tubular epithelial cells of the DCT and collecting ducts and causes aquaporins (water channels) to become incorporated into the 11  Dr Yasser Abdel-Wahab (Module Coordinator cell membrane to increase water permeability and increase water reabsorption.  At basal levels of ADH low levels of aquaporins are still found in the cell membranes and less water is reabsorbed.  Thus lower ADH levels lead to large volumes of dilute urine.  Higher the ADH levels the smaller the volume and more concentrated the urine. The table below summarizes the mechanisms of reabsorption of ions and solutes Tubular secretions  Blood entering the peritubular capillaries still contain substances which need to be eliminated that were not filtered at the glomerulus.  These compounds diffuse out of the capillaries into the peritubular fluid and can be secreted into the tubular fluid of the DCT  Most important is levels of K+ ions  Raised levels of K+ in peritubular fluid are lowered by exchange for Na+ from the tubular fluid  K+ enters the tubular cells and then diffuses into the tubular fluid for secretion.  Control of H+ levels also important for maintaining pH of plasma.  H+ ions are also secreted into tubular fluid in exchange for Na+ ions  Within the tubular cells carbonic acid formed by reaction of CO2 and H2O dissociates into H+ ions and HCO3- (bicarbonate). The H+ is transported across the membrane into tubular fluid in exchange for Na+.  HCO3- diffuses into the peritubular fluid in exchange for Cl- ions and into the capillaries to prevent changes in blood pH  When pH of blood falls the H+ ions diffuse into the peritubular fluid from the capillaries, then enter the tubular cells in exchange to Na+. 12  Dr Yasser Abdel-Wahab (Module Coordinator  The PCT and DCT are also sights for deamination of amino acids, generating ammonium ions (NH4+) and HCO3-.  Ammonium ions are pumped into tubular fluid by exchange for Na+ ions and the HCO3- diffuses into the peritubular fluid as mentioned above. Tubular secretion is important for maintenance of normal homeostasis by elimination of substances from the body, such as excess H+ ions, K+ ions, and also foreign substances such as drugs. The kidneys are one of the main routes of clearance of many drugs. K+ secretion at distal / collecting tubules As mentioned above, tubular secretion of K+ is essential to prevent hyperkalaemia (excess plasma K+ levels which can be fatal).  An elevation of plasma K+ stimulates the release of aldosterone from the suprarenal cortex.  The K+ ions diffuse out of the capillaries into the peritubular fluid.  Aldosterone stimulates the production and insertion of Na-K exchange pumps into the membrane of the tubular cells as discussed earlier.  Thus K+ enters the tubular cells in exchange for intracellular Na+.  K+ then diffuses through potassium channels into the tubular fluid. Renal responses to plasma pH change When plasma pH increases (alkalosis) or decreases (acidosis) renal secretion and reabsorption rapidly alter to help normalise plasma pH. This is summarised in the table below. 13  Dr Yasser Abdel-Wahab (Module Coordinator Reading Lists:  Martini FH & Nath JL, Fundamentals of Anatomy and Physiology, San Francisco, Pearson Benjamin Cummings. Martini’s Fundamentals of Anatomy and Physiology was specially selected for this module on the basis of the quality of the textbook, the inclusion of the valuable Fundamentals of Anatomy and Physiology. It comes with Interactive CD-ROM and supporting WWW site (freely accessible to students purchasing this text). 14