Yr1 CR1 Wk2 - Renal structure and function 1 - Dr Christian Saliba Lecture Slides (2022).pdf

Renal* Structure & Function 1 *concerning or pertaining to the kidney Dr. Christian Saliba Learning Objectives • Outline the general organisation - kidney, ureter, bladder & urethra • Identify the parts of the nephron & describe the role of each component (in urine production) • Describe vasculat...

Renal* Structure & Function 1 *concerning or pertaining to the kidney Dr. Christian Saliba Learning Objectives • Outline the general organisation - kidney, ureter, bladder & urethra • Identify the parts of the nephron & describe the role of each component (in urine production) • Describe vasculature of kidney (+ relating to urine production & nourishment of the nephron) • Identify components of juxtaglomerular apparatus & describe role in blood & urine volume regulation, & renal homeostasis • Explain the ‘clearance concept’ & how this is used to measure GFR + State the properties of suitable marker substances & show how clearance, hence GFR, are calculated General Anatomy • Renal arteries are branches of abdominal aorta • Tube carrying urine from kidney to bladder is URETER • URETHRA carrying urine from bladder to outside world Parts of the Kidney • Capsule - strong connective tissue membrane around the outside of the kidney • Homogenous looking cortex and underneath medulla • Medullary pyramids will lead to the calyx, where blood comes in and urine goes out, passing through the pelvis and hilum Vasculature of the Kidney The renal arteries pass into interlobular vessels and then divide into small arcuate (arch shaped) arteries in the renal cortex The Glomerulus • The arteries terminate in a little clump of capillaries in the renal cortex - glomerulus (pl. glomeruli) • There are approx. 1 million glomeruli per kidney, which filter blood (continuously) Bowman’s Capsule • Blood enters the glomerulus of each nephron in the afferent arteriole and leaves in the efferent arteriole • Each capillary glomerulus is enclosed inside a bag of tissue called Bowman’s capsule • The first stage of urine formation is the filtering of plasma from the glomerular capillaries into the space of the capsule, which empties into the proximal tubule Renal corpuscle • Diameter: afferent > efferent arteriole = considerable change in pressure between afferent & efferent arteriole • This is the filtration pressure forcing fluid through endothelium of the capillaries into capsular space • The proportion of plasma filtered into Bowman’s capsule is the filtration fraction (normally ~20%) • A ↑ filtration fraction would render blood in efferent arteriole too viscous (↑ haematocrit) Podocytes • Capillaries in the glomerulus are fenestrated and are covered on the outside with an extra layer of cells called podocytes • Podocytes have slits between them; these slits form the filtration mechanism • Slits can become inflamed & enlarged, enabling ↑ solutes (mainly proteins) to enter the urine proteinuria is thus a sign of glomerular inflammation The Nephron • Fluid leaves Bowman’s capsule, enters a long tube (proximal convoluted tubule), passes through the Loop of Henle and makes it to the distal convoluted tubule, which joins the collecting duct to drain into the ureter. • The complete set of tubes, from capsule to duct, is the nephron. • The nephron is the unit of kidney function. Each kidney contains tens of thousands of nephrons! Nephron: Location & Variants • The glomerulus & its capsule, the proximal & distal convoluted tubule are all in the renal cortex, while the loop of Henle and collecting duct are found in the medulla • Some nephrons have relatively short loops of Henle, others have long loops that project down deep into the medulla. This variation correlates with the ability to make less or more concentrated urine Nephron: Excretion Mechanism 1. Fluid filtered from Bowman’s capsule into proximal tubule 2. Filtered materials can be reabsorbed into peritubular capillaries 3. Material can also be transported out of capillaries & secreted into tubular fluid 4. Amount of material excreted is amount filtered + amount secreted - amount reabsorbed Excretion = Filtration (Mechanism) • Filtration of H2O into capsule is controlled by a balance between constriction of afferent & efferent arterioles - adjusted to a physical pressure of 55 mmHg in capillaries • Net filtration pressure in capillaries = physical (hydrostatic) pressure of 55 mmHg – osmotic pressure of 30 mmHg • Net filtration pressure in capsule = physical pressure of fluid of 15 mmHg – osmotic pressure (zero) • Total net filtration pressure 10mmHg Filtration Rate, Plasma & Urine Flow • ¼ of cardiac output flows through the kidneys/minute. If CO = 5 L/min, kidney blood flow is about 1.25 L/min • Total amount of fluid filtered through ALL glomeruli in BOTH kidneys is ~125 mL/min - Glomerular Filtration Rate (GFR) • Useful to consider also RPF (renal plasma flow), which (if we assume haematocrit of 45%) will be 1.25 x 0.55 = 680 mL/min • If GFR is 120 mL/min, suppose all this fluid appeared in urine. You would need to void 1.2 L of urine every 10 minutes!! • This does NOT happen: Urine flow is ~1 mL/min (~1.5 L/day). Almost ALL fluid filtered must therefore be REABSORBED; less than 1% appears as urine Excretion = Filtration - Reabsorption • 2⁄3 of all the water filtered in the glomerulus is reabsorbed in proximal tubule; which is lined with epithelial cells • Water is reabsorbed down an osmotic gradient from lumen into cells & out into interstitial fluid Basal membrane • Na+ passes out of lumen into cells down its concentration gradient; carrying glucose with it Luminal membrane • Basal membrane of cells contain Na+ pumps which extrude Na+ into interstitial fluid Clearance • GFR is a vitally important measure of kidney function; we need to know what it is, so we need to measure it • GFR is measured by the CLEARANCE of a selected material, measured in units of volume/time (L/min). It is the effective volume of plasma completely ‘cleared’ of a substance / minute Scenario 1 • Suppose that 100% of a blood component is filtered through glomerulus. This means that the material goes into proximal tubule at exactly the same rate as water in plasma. Suppose also that all of this filtered material appears in the urine (NONE is reabsorbed) • Then the clearance of this substance will be the same as the glomerular filtration rate (125 mL/min) Clearance Scenario 2 • Suppose that 100% of a blood component is filtered through glomerulus and all of this filtered material is REABSORBED • Then NO blood will be ‘cleared’ of this material as it is all reabsorbed - the clearance of this substance will be ZERO Scenario 3 • Suppose that 100% of the material is filtered and in addition all of the material in efferent arteriolar blood is SECRETED into the urine • Then renal venous blood will have NO material in it; all blood passing through kidney will have been cleared of the material - the clearance will then equal the renal plasma flow Summary Substance in blood can be: 1. Removed at same rate as water passes through glomeruli Clearance = Glomerular Filtration Rate (GFR) 2. Not removed at all by kidney Clearance = Zero 3. Completely removed from blood passing through kidney Clearance = Renal Plasma Flow (RPF) If kidneys are damaged, generally GFR will decrease although RPF may be normal - so measurement of GFR is an essential test of kidney health How is clearance measured? Clearance = urine concentration x urine flow plasma concentration C = [U] x V [P] So to measure the clearance of a substance you have to: 1. measure the concentration of the substance in the plasma, 2. collect urine for a fixed period to get the urine flow (mL/min), 3. measure the concentration of the substance in the collected urine Inulin • The ‘gold standard’ for measuring GFR is clearance of INULIN - a polysaccharide derived from jerusalem artichokes. It is completely filtered from the plasma and not reabsorbed • BUT inulin does not occur naturally in plasma! So to measure inulin clearance you have to infuse inulin i.v. over a period of hours, to reach a steady plasma concentration • This makes measurement of GFR by inulin clearance impractical except in specialised kidney units Creatinine • Creatinine clearance used to measure GFR in clinical practice • Produced naturally by body (product of creatine metabolism) • Filtered by glomerulus but also actively secreted (small amount) • Secretion = creatinine clearance overestimates GFR by 10-20% • It is normally already at a steady-state concentration in blood • 24h urine collection with blood test for creatinine is usually taken Do NOT confuse creatinine with creatine! Creatinine Estimate of creatinine clearance • If measurement of urinary excretion of creatinine is not possible a number of approximate methods to estimate creatinine clearance have been developed, based on blood levels only: * 𝑒𝐶 𝐶𝑟 140 − 𝐴𝑔𝑒 × 𝑊𝑒𝑖𝑔ℎ𝑡 𝑘𝑔 × 𝐶𝑜𝑛𝑠𝑡𝑎𝑛𝑡 = 𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝜇𝑚𝑜𝑙/𝐿) • The constant varies depending if patient is a female or male *you don’t need to remember the formula, just that you can get an approximation of kidney function simply from blood creatinine concentration Clearance to measure Renal Plasma Flow • If all of a particular substance is filtered along with water and in addition all of the material in the efferent arteriolar blood is secreted into the urine, then the renal venous blood will have NO material in it. Clearance will then equal renal plasma flow • Para-amino-hippuric acid used to measure renal plasma flow • PAH is infused until a steady concentration in (arterial) blood • 24h urine collecting – measure [PAH] & calculate urine flow CPAH = [PAH] urine x urine flow = RPF (mL/min) [PAH] plasma Summary - Clearance • Clearance of a substance Cs = [Us]V/[Ps] = mL or L/min • Inulin ‘gold standard’ for GFR; only used in special cases • Clearance of creatinine normally used clinically as creatinine already present in blood; slightly overestimates GFR Normal GFR (both kidneys) is 120-125 mL/min* • Clearance of PAH measures RPF because it is all secreted in blood, so all blood passing through kidney is ‘cleared’ of PAH Normal RPF (both kidneys) is 600-700 mL/min *Normal creatinine clearance: women 88-128 mL/min men 97-137 mL/min Severity of Chronic Kidney Disease (CKD) Autoregulation of GFR • GFR in a healthy kidney is ‘autoregulated’ - it does not change over a wide range of blood pressures; as is renal blood flow • As renal blood flow is constant, and metabolic rate of kidney (its oxygen consumption) is constant, the pO2 in kidney interstitium is a measure of oxygen delivery to the kidney and thus the oxygen carrying capacity of blood • Probably why erythropoietin releasing cells are in the kidney Autoregulation range How is GFR (auto)regulated? • GFR is (auto) regulated by the balance of constriction in the smooth muscle of afferent and efferent arterioles • Normally efferent arterioles are slightly narrower, producing a net filtration pressure of 10 mmHg • GFR will be increased if the afferents relax and dilate, as this will increase filtration pressure • Conversely if afferents constrict, this lowers filtration pressure and thus GFR Efferent arteriole Juxtaglomerular apparatus (JGA) • Autoregulation of GFR is controlled by the juxtaglomerular apparatus - this is where the distal tubule folds back and contacts the glomerulus at the point where the afferent and efferent arterioles enter Macula densa cells • They release local chemicals to modulate the contraction of the smooth muscle around the afferent arteriole Efferent arteriole • Lining the wall of the distal tubule are the macula densa cells - sodium sensors Distal tubule Afferent arteriole • Juxtaglomerular apparatus consists of 3 structures: distal tubule, afferent & efferent arteriole Macula densa cells Autoregulation - Tubuloglomerular feedback • Cells in the macula densa of the JGA detect the concentration of sodium in the distal tubular fluid. If sodium levels are low, this indicates that GFR is too low. Why?