Renal Lectures 2-3 BIOM 2012 PDF

Renal Physiology II Dr Niwanthi Rajapakse [email protected] Textbook: Sherwood, 8th edition, Chapters 14, 15  BIOM2012 Renal Physiology Module Lecture 1: Basic role of the kidney, renal anatomy and physiology, filtration, secretion and reabsorptio...

Renal Physiology II Dr Niwanthi Rajapakse [email protected] Textbook: Sherwood, 8th edition, Chapters 14, 15  BIOM2012 Renal Physiology Module Lecture 1: Basic role of the kidney, renal anatomy and physiology, filtration, secretion and reabsorption Lecture 2: Renal clearance, renal blood flow, glomerular filtration rate Lecture 3: Loop of Henle and countercurrent exchange, hormonal control of salt and water balance, role of vasopressin and aldosterone For all the lectures in the renal module: videos are provided to supplement the content covered in the lectures. The content in the videos are not examinable  Lecture 2: Learning Objectives At the end of Lecture 2 you should have a solid understanding of: Glomerular filtration barrier Glomerular filtration rate (GFR), The mechanisms that govern glomerular filtration rate Autoregulation of GFR Myogenic mechanism and tubular glomerular feedback Renal clearance  Glomerular Filtration Barrier Fluid forced through filtration barrier by hydrostatic pressure Glomeruli → Mechanical Filters Glomerular Filtration Barrier – Endothelial fenestrations – Basement Membrane (-ve charged) – Podocytes & slit diaphragm Glomerular capillaries more efficient filters than other capillaries – very large fenestrations – high hydrostatic pressures driving filtration (55 vs 18 mmHg) Filterability of solutes Size & Charge small molecules (7-9nm or 70000MW essentially blocked Most proteins prevented due to negative charge they carry Filtrate inside BC is virtually identical to plasma but essentially free of protein (0.02%) Glomerular filtration barrier Filtration barrier consists of 3 layers: – Single celled capillary endothelium (fenestrated), – Non-cellular basement membrane (-ve charge), – Single celled epithelial lining of Bowmans capsule (podocytes, slit diaphram) Rate of filtration – Due to the hydrostatic pressure of the cardiac pump – fluid is filtered from the blood through fenestra in the glomerular capillaries into slit pores between the foot processes of the podocytes. Blood Flow to the Kidney Renal blood flow ~ 1.2 l/min (650ml plasma/min) – 20-25% cardiac output – Kidneys only 1-2% of total body weight → Ensures a high rate of filtration of plasma – Entire plasma volume ~ 3L – Glomerular filtration 125ml/min or 180L/day → Entire plasma volume filtered ~60 times a day Allows precise & rapid control of volume and composition of body fluids Glomerular Filtration Rate – the volume of plasma filtered per minute – Filtration Fraction: The fraction of the renal plasma flow that is filtered in the glomerulus during a single pass through the kidney = GFR/Renal Plasma flow FF = 125 ml/min / 650 ml/min= 0.2 i.e. 20% of plasma flowing through the kidneys is filtered 99% of the filtrate is taken back into the body  Forces driving glomerular filtration Starlings Law Formation of the glomerular filtrate in Bowman’s capsule is the outcome of opposing pressures: - Hydrostatic pressure from the heart favors filtration, - Plasma osmotic pressure and hydrostatic pressure of the filtrate oppose it.  Glomerular filtration rate (GFR) GFR = permeability of glomerular membrane X net filtration pressure Changes in any of the forces involved in net filtration pressure can change GFR Under normal conditions, plasma oncotic pressure and Bowman’s hydrostatic pressure remain relatively constant. However, they can be altered in pathological conditions. How would each of the following affect GFR? 1) Severe burns (loss of plasma-derived fluid and proteins through burnt skin) 2) Urinary tract obstruction (eg kidney stone, enlarged prostate) 3) Severe dehydrating diarrhea Consider how the passive physical forces that influence filtration are altered in each case  Glomerular filtration rate (GFR) Severe burns Urinary tract obstruction Dehydrating diarrhea Loss of protein- Increased downstream Loss of water in rich fluid resistance stool Reduction in Increased hydrostatic Increase in plasma plasma oncotic pressure in Bowman’s oncotic pressure pressure capsule Reduce in opposing Increase in opposing Increase in opposing force force force Increases GFR Decreases GFR Decreases GFR Summary: Glomerular filtration Passive, non-selective process Small molecules – water, glucose, amino acids pass freely Larger molecules – cannot freely cross the glomerular filtration barrier. – Proteins. Thus protein in the urine indicates a renal problem! Glomerular filtration rate (GFR) – Equals the volume of filtrate formed each minute. GFR is directly proportional to the net filtration pressure  Measuring glomerular filtration rate Creatinine Urine Glomerular filtration rate (ml/min) can be estimated using a molecule which gets filtered but does not get reabsorbed or secreted. Eg. Creatinine. Amount filtered = Amount in urine Creatinine clearance = estimate of GFR = Urine concentration of Cr x urine flow rate Plasma concentration of Cr  Renal Clearance Renal clearance: volume of plasma kidneys can clear of a particular substance in a given time Renal clearance tests are used to determine GFR – To help detect glomerular damage – To follow progress of renal disease © 2016 Pearson Education, Ltd.  Renal Clearance (cont.) Renal clearance rate is calculated as: C = UV/P – C = renal clearance rate (ml/min) – U = concentration (mg/ml) of substance in urine – V = flow rate of urine formation (ml/min) – P = concentration of same substance in plasma © 2016 Pearson Education, Ltd.  Renal Clearance (cont.) Inulin, a plant polysaccharide, is standard used – Freely filtered and neither reabsorbed nor secreted by kidneys – Its renal clearance = GFR (~125 ml/min) If C < 125 ml/min, means substance reabsorbed If C = 0, substance was completely reabsorbed, or not filtered If C = 125 ml/min, no net reabsorption or secretion If C > 125 ml/min, substance was secreted (most drug metabolites) © 2016 Pearson Education, Ltd. Control of glomerular capillary pressure Arterial Pressure and Relative resistance of Afferent vs Efferent Determine PG Cap Aff Eff 1. Arterial Pressure  AP PG GFR 2. Afferent Arteriolar  AAR PG GFR Resistance  AAR PG GFR 3. Efferent Arteriolar  EAR PG  GFR Resistance  EAR PG GFR Control of GFR GFR needs to be relatively constant: → reabsorption of H2O & other substances from filtrate partly dependent on rate of flow through tubules  GFR→inadequate reabsorption → substances lost in urine  GFR→ reabsorption increased→wastes not excreted Small changes in GFR equal large changes in the volume of filtrate that must be processed. → 10% increase in GFR equals 18L more filtrate to be processed Renal Autoregulation Autoregulation : Mechanisms within the kidney act to ensure that GFR remains relatively constant when blood pressure changes  Autoregulation of GFR Controlled regulation of GFR usually involves changes in glomerular capillary pressure. An increase in glomerular capillary pressure will increase GFR (assuming no other alterations) if there was no autoregulation. GFR is highly autoregulated; GFR remains relatively constant over a wide range of mean arterial pressures.  Regulation of GFR Why is the autoregulation of GFR so important? Consider what determines GFR, as well as the consequences if GFR is perturbed. Mean arterial pressure is a critical determinant of GFR; many daily activities change mean arterial pressure (eg exercise). Autoregulation of GFR avoids imbalances in fluid, electrolyte and waste excretion due to changes in mean arterial pressure Autoregulation of GFR also prevents damage to the filtration barriers by high blood pressures.  Regulation of GFR Glomerular capillary pressure can also be altered by the resistance of afferent and efferent arterioles Mechanisms contributing to autoregulation include the myogenic mechanism and tubuloglomerular feedback.  Myogenic mechanism Myogenic tone is a property of arteriolar smooth muscle; it involves contraction of the muscle in response to stretch. Thus, an increase in MAP will reduce the diameter of the afferent arteriole and limit the increase in glomerular capillary pressure. Glomerulus Afferent arteriole Efferent arteriole  Myogenic mechanism If there was no autoregulation then: Increase in blood pressure Increase in glomerular capillary pressure Increase in GFR However with autoregulation: Increase in blood pressure Myogenic response: Reduction in afferent arteriolar diameter keeps glomerular capillary pressure constant No change in GFR  Autoregulation of GFR – Myogenic mechanism Video https://www.youtube.com/watch?v=kM4FaSOA-G0  Tubuloglomerular feedback Autoregulation: maintain renal blood flow (RBF) and glomerular filtration rate (GFR) independent of renal perfusion pressure (RPP) Mechanisms contributing to autoregulation include the myogenic mechanism and tubuloglomerular feedback. Tubuloglomerular feedback Macula densa cells: The macula densa is a collection of specialized epithelial cells in the distal convoluted tubule that detect sodium concentration of the fluid in the tubule Eg: increase in GFR increase NaCl reaching macula densa cells macula densa sends a signal to afferent arteriole to constrict reduce GFR reduce NaCl reaching macula densa (note: an increase in GFR means more NaCl will be filtered into the tubule. Thus, an increase in GFR leads to more NaCl reaching macula densa cells). Will discuss this further in Lecture 3  Tubuloglomerular feedback video https://www.youtube.com/watch?v=CF0Ahawshzg  Lecture 2: Learning Objectives Now make sure you have a solid understanding of: Glomerular filtration barrier Glomerular filtration rate (GFR), The mechanisms that govern glomerular filtration rate Autoregulation of GFR Myogenic mechanism and tubular glomerular feedback Renal clearance  Revision Question Describe the structure and function of the glomerular filtration barrier  BIOM2012 Renal Physiology Module Lecture 1: Basic role of the kidney, renal anatomy and physiology, filtration, secretion and reabsorption Lecture 2: Renal clearance, renal blood flow, glomerular filtration rate Lecture 3: Loop of Henle and countercurrent exchange, hormonal control of salt and water balance, role of vasopressin and aldosterone For all the lectures in the renal module: videos are provided to supplement the content covered in the lectures. The content in the videos are not examinable Lecture 3: Learning objectives At the end of Lecture 3 you should have a solid understanding of: Loop of Henle and countercurrent mechanism Hormonal control of salt and water balance Renin angiotensin system Factors that regulate renin release Tubuloglomerular feedback mechanism Urine Concentration: The countercurrent multiplier system Kidneys can produce hyperosmotic urine when needed. Important to survive with limited water intake Let’s see how kidneys achieve this?  Urine Concentration: The countercurrent multiplier system NaCl Water Medullary interstitium Medullary interstitium: hyperosmotic 1. In the ascending limb, NaCl is actively 4. Water diffuses out from transported out of the tubule the descending limb of the 2. Impermeable to water Loop of Henle (simple 3. medullary interstitial fluid gets diffusion) hyperosmotic Water diffuses out from the hypoosmotic compartment into the hyperosmotic compartment Hypo-osmotic compartment Hyperosmotic compartment (descending limb of the LH) (medullary interstitium)  Urine Concentration: The countercurrent multiplier system Proximal tubules always reabsorb sodium and water in the same proportions. Thus, fluid entering the descending limb of the loop of Henle has the same osmolarity as plasma - 300 mOsm/L. Along the entire length of the ascending limb, Na+ and Cl- are reabsorbed from the tubule into the medullary interstitium. This process requires energy and therefore this is termed active transport. The ascending limb is impermeable to water. So little water follows salt. Thus, the medullary interstitial fluid becomes hyperosmotic compared to the fluid in the ascending limb.  Urine Concentration: The countercurrent multiplier system The descending limb: highly permeable to water (but not to sodium chloride). Net diffusion of water occurs out of the descending limb into the more concentrated interstitial fluid until the osmolality inside this limb and medullary interstitium is equal. This is the essence of the countercurrent multiplier system. The interstitial hyperosmolarity is maintained because the ascending limb continues to pump sodium chloride to maintain the concentration difference between it and the interstitial fluid. Urine Concentration: The countercurrent multiplier system (From Vander’s Human Physiology) Urine Concentration: The countercurrent multiplier system The fluid entering the cortical collecting duct is hypoosmotic. From here on vasopressin is crucial: In the presence of vasopressin, water reabsorption occurs by diffusion until the fluid in this segment becomes isoosmotic to the intertstitial fluid in the medulla. (From Vander’s Human Physiology) Counter current mechanism video https://www.youtube.com/watch?v=XbI8eY-BeXY  Juxtaglomerular apparatus (JGA) A – Renal corpuscle B – Proximal tubule C – Distal convoluted tubule D – Juxtaglomerular apparatus 4. Bowman's space (urinary space) 5a. Mesangium – Intraglomerular cell 5b. Mesangium – Extraglomerular cell 6. Granular cells (Juxtaglomerular cells) 7. Macula densa 8. Myocytes (smooth muscle) 9. Afferent arteriole 10. Glomerulus Capillaries 11. Efferent arteriole Intrarenal baroreceptors: The juxtaglomerular cells of the afferent arteriole act as high-pressure baroreceptors and are able to detect changes in blood pressure. An increase in renal arterial pressure inhibits renin release. Intrarenal Baroreceptors (2) (3) (1) or granular cells The granular cells of the afferent arteriole: site of synthesis and release of renin. Granular cells: are also high pressure baroreceptors and respond directly to changes in renal perfusion pressure (NB: RPP inversely proportional to rate of renin secretion). Renin is needed for production of angiotensin II which is the primary stimulant for release of aldosterone. Aldosterone stimulates Na+ reabsorption. Factors that control renin release Renin is synthesised, stored and released by the granular cells in the JGA region of the afferent arteriole (Figure on previous slide) Renin release is stimulated by – Intrarenal Baroreceptors renin secretion is inversely related to the pressure in the afferent arteriole in the juxtaglomerular region. An increase in renal arterial pressure inhibits renin release. – Macula densa control of renin secretion. Increased delivery of NaCl to macula densa results in a decreased renin secretion – Augmented activity of the renal sympathetic nerves directly (-receptor mediated) and indirectly cause increased renin secretion Increased Angiotensin II levels decrease renin secretion (negative feedback system) 40 Factors that control renin release Renal baroreceptors: Pressure sensitive juxtaglomerular cells (in afferent arterioles) which respond to decreased renal arterial pressure by secreting more renin Sympathetic nerves: Are activated reflexively via baroreceptors whenever a reduction in body sodium (and hence plasma volume) decreases arterial pressure. The renal sympathetic nerves innervate the juxtaglomerular cells. An increase in sympathetic activity can increase renin release (and vice versa). Macula densa cells: Senses the amount of sodium in the tubular fluid flowing past it. A reduction in salt delivery causes the release of paracrine factors that diffuse from macula densa to nearby juxtaglomerular cells thereby activating them and causing them to release renin. Conversely, a high salt intake will lead to a very low rate of renin release.  Factors that control renin release – Summary 1. Renal baro-receptor (The juxtaglomerular cells of the afferent arteriole act as high-pressure baroreceptors and are able to detect changes in blood pressure). An increase in renal arterial pressure inhibits renin release. 2. Sympathetic nerves 3. Macula Densa cells (2) (3) (1) Decrease in NaCl in the late TAL leads to: 1. Afferent arteriolar dilatation 42 2. Increase renin release by juxtaglomerular cells of the afferent arteriole  Effects of a reduction in tubular (macula densa) sodium chloride concentration Decrease in NaCl in the late thick ascending limb (i.e where macula densa cells are located) leads to: 1. Afferent arteriolar dilatation which in turn leads to an increase in GFR (remember the decrease in NaCl in the late thick ascending limb is due to an initial reduction in GFR which filters less NaCl into the tubule)* 2. Increase renin release by juxtaglomerular cells of the afferent arteriole leads to sodium retention Remember, the process whereby the glomerular filtration rate is modified by changes in the NaCl concentration in the tubule is termed *tubuloglomerular feedback (TGF). 43 (covered in detail in Lecture 2) Renin-angiotensin-aldosterone mechanism Main mechanism for increasing blood pressure Three pathways to renin release by granular cells 1. Direct stimulation of granular cells by sympathetic nervous system 2. Stimulation by activated macula densa cells when filtrate NaCl concentration is low 3. Reduced stretch of granular cells © 2016 Pearson Education, Ltd.  Renin-angiotensin-aldosterone system increases salt and water retention Actions of ANG II: potent vasoconstrictor activates sodium reabsorption stimulates aldosterone production Stimulates antidiuretic hormone (ADH) release 45 Summary: Renin-Angiotensin System Reduced pressure at JGA “renal baroreceptor”  Vasoconstriction Increased (TPR) renal nerve (-ve) activity Aldosterone Renin release secretion  receptors Tubular glomerular Increased tubular angiotensin I Na+ reabsorption feedback at tha macula densa Stimulates ADH angiotensin II secretion thirst 46 Figure 25.14 Regulation of glomerular filtration rate (GFR) in the kidneys. SYSTEMIC BLOOD PRESSURE Blood pressure in GFR Granular cells of Inhibits baroreceptors afferent arterioles; GFR juxtaglomerular in blood vessels of complex of kidney systemic circulation Release Stretch of smooth Filtrate flow and muscle in walls of NaCl in ascending Renin afferent arterioles limb of nephron loop Sympathetic Catalyzes cascade nervous system resulting in Acts on formation of Vasodilation of afferent arterioles Angiotensin II Macula densa Aldosterone Vasoconstriction of cells of secretion by systemic arterioles; juxtaglomerular adrenal cortex peripheral resistance complex of kidney Release of vasoactive chemicals inhibited Na+ reabsorption by kidney tubules; Vasodilation of water follows afferent arterioles Blood volume GFR Systemic blood pressure Tubuloglomerular Myogenic mechanism Hormonal (renin-angiotensin-aldosterone) mechanism of Neural controls of autoregulation autoregulation mechanism Intrinsic mechanisms directly regulate GFR despite Extrinsic mechanisms indirectly regulate GFR moderate changes in blood pressure (between 80 by maintaining systemic blood pressure, which and 180 mm Hg mean arterial pressure). drives filtration in the kidneys. © 2016 Pearson Education, Ltd. Lecture 3: Learning objectives Now make sure you have a solid understanding of: Loop of Henle and countercurrent mechanism Hormonal control of salt and water balance Renin angiotensin system Factors that regulate renin release Tubuloglomerular feedback mechanism Revision question Discuss homeostatic compensation for severe dehydration  This brings us to the end of the renal module Lecture 1: Basic role of the kidney, renal anatomy and physiology, filtration, secretion and reabsorption Lecture 2: Renal clearance, renal blood flow, glomerular filtration rate Lecture 3: Loop of Henle and countercurrent exchange, hormonal control of salt and water balance, role of vasopressin and aldosterone For all the lectures in the renal module: videos are provided to supplement the content covered in the lectures. The content in the videos are not examinable