Renal Physiology Lecture 1 - Kidney Function 1 PDF

IMED3112: Integrated Medical Systems 2 Renal Physiology Lecture 1 Kidney Function 1 Rob White Physiology [email protected] Lecture Outcomes • Outline the functions of the kidney in maintaining homeostasis • Describe the nephron’s role in filtration, reabsorption and secretion • Describe the...

IMED3112: Integrated Medical Systems 2 Renal Physiology Lecture 1 Kidney Function 1 Rob White Physiology [email protected] Lecture Outcomes • Outline the functions of the kidney in maintaining homeostasis • Describe the nephron’s role in filtration, reabsorption and secretion • Describe the physiological control of renal blood flow and glomerular filtration • Describe the regulation of tubular filtrate modification Read: Guyton & Hall Chapters 26 -29 What have my kidneys done for me lately? • Regulation of: – – – • Excretion of: – – – • body fluid osmolarity and volume blood pressure Electrolyte/acid-base balance metabolic products - urea, uric acid, creatinine, bilirubin foreign substances (pesticides, chemicals etc.) excess substance (water, etc) Endocrine function et al.: – – – EPO, renin, vitamin D activation Excretion of hormones (clearance) Gluconeogenesis Urinary system The Nephron Nephrons • Renal corpuscle (glomerulus and Bowman’s capsule) and both convoluted tubules in cortex, loop of Henle extend into medulla • Multiple nephrons empty into single collecting duct • 2 types: – Cortical nephrons – 80% of nephrons • Renal corpuscle in outer portion of cortex and short loops of Henle extend only into outer region of medulla – Juxtamedullary nephrons – other 20% • Renal corpuscle deep in cortex and long loops of Henle extend deep into medulla • Peritubular capillaries and vasa recta • Ascending limb has defined thick and thin regions • Enable kidney to secrete very dilute or very concentrated urine Nephrons and blood vessel structure Cortical nephrons Juxtamedullary nephrons Nephron: vascular component Glomerulus: ball-like tuft of glomerular capillaries  filter blood plasma. Renal artery: Afferent arteriole •Supplies the glomerulus capillaries. Efferent arteriole • Drains glomerulus •Forms (subdivides) the peritubular capillaries (which later rejoin to form venules & renal vein). Nephron: tubular component Distal . tubule Proximal tubule Efferent arteriole Afferent arteriole Cortex Medulla Juxtaglomerular region Bowman’s capsule Cups glomerulus & collects filtered fluid, which passes into tubule Collecting duct Loop of Henle U shaped loop that dips into renal medulla Input from up to 8 distal tubules. Drains into the renal pelvis. Functions of the Nephron Reabsorption Secretion Excretion Filtration Urine Formation Blood in Filtration GFR Peritubular space Filtrate Crude  refined Reabsorption (osmosis) Secretion Blood out Urine out Overview of renal physiology 1. Glomerular filtration – Water + most solutes in plasma filter out of glomerular capillaries into Bowman’s capsule  renal tubule 2. Tubular reabsorption – As filtered fluid moves along tubule and through collecting duct, about 99% of water and many useful solutes reabsorbed  peritubular space  returned to blood 3. Tubular secretion – Material is secreted into tubular fluid (such as wastes, drugs, and excess ions) – removes substances from blood • Solutes in tubular fluid  renal pelvis  excreted (urine) Solute excretion = glomerular filtration + secretion - reabsorption Filtration and Reabsorption of Some Compounds Nephron Function Renal Blood Flow 2 Functions • Provides blood to be filtered • Reclaims reabsorbed substances Blood supply of the kidneys • Immense blood supply – <0.5% of body mass, receive 2025% of cardiac output at rest – ~95% to cortex – Renal art  segmental, interlobar, arcuate, interlobular arts –  afferent arteriole (1 per nephron)  glomerulus –  Efferent arteriole (1 per nephron)  peritubular capillaries (vasa recta)  peritubular venule  renal vein 2 capillary beds in series 1. Glomerular High hydrostatic pressure (~55 mmHg) 2. Peritubular Low hydrostatic pressure (~13 mmHg) Vasa Recta Pglom.cap. vs Pperitub.cap. Starling’s Law: NFP = (CHP + IFOP) – (PCOP + IFHP) • Net filtration pressure (NFP) balance of 2 pressures 1. Pressures that promote filtration 2. – – – – Capillary hydrostatic pressure (CHP) Interstitial fluid osmotic pressure (IFOP) Pressures that promote reabsorption Plasma colloid osmotic pressure (PCOP) Interstitial fluid hydrostatic pressure (IFHP) • Glomerular capillary: – CHP > PCOP, drives filtration • Peritubular capillary: – PCOP > CHP, net reabsorption from peritubular space. Not just P, PCOP increases • Glomerular filtration concentrates proteins in capillaries  increase PCOP • Thus low P, high PCOP create a strong absorptive environment in peritubular capillaries/vasa recta Glomerular filtration Fluids move across the glomerular capillary in response to net glomerular hydrostatic pressure  glomerular filtrate (plasma-like) • Prevents filtration of large things – Cells, platelets – Protein complexes – Large/medium-sized (>50kDa) proteins • GFR – Depends on • Permeability of membrane • surface area of membrane • filtration pressure 3 barriers to cross Glomerular capillary wall (pores between endothelial cells). Basement membrane - mix of collagen (structural) & glycoproteins (repel plasma proteins). Podocytes: filtration slits between cellular foot processes. Filtration slit Pedicel Fenestration (pore) of glomerular 1 endothelial cell: prevents filtration of blood cells but allows all components of blood plasma to pass through 2 3 Basal lamina of glomerulus: prevents filtration of larger proteins Slit membrane between pedicels: prevents filtration of medium-sized proteins Podocyte of visceral layer of glomerular (Bowman’s) capsule Factors that determining glomerular filterability 1. Molecular weight • Size-exclusion 2. Charges of the molecule • Negative charges of the basement membrane/podocytes repel anions Glomerular filtration rate (GFR) – amount of filtrate formed in all the renal corpuscles of both kidneys each minute – For a young healthy 70kg adult, GFR=125ml/min or 180 L/day (36x blood volume) – Homeostasis requires kidneys maintain a relatively constant GFR • Too high –too quick for reabsorption • Too low – excessive reabsorption, some waste products not adequately excreted - Renal hypoxia – GFR directly related to net filtration pressure Net filtration pressure (NFP) • The total pressure that promotes filtration NFP = GBHP – CHP – BCOP GBHP: Glomerular blood hydrostatic pressure The blood pressure of the glomerular capillaries forcing water and solutes through filtration slits CHP: Capsular hydrostatic pressure the hydrostatic pressure exerted against the filtration membrane by fluid already in the capsular space and represents “back pressure” BCOP: Blood colloid osmotic pressure due to presence of proteins in blood plasma and also opposes filtration 1 GLOMERULAR BLOOD HYDROSTATIC PRESSURE (GBHP) = 55 mmHg 2 CAPSULAR HYDROSTATIC PRESSURE (CHP) = 15 mmHg 3 BLOOD COLLOID OSMOTIC PRESSURE (BCOP) = 30 mmHg Afferent arteriole (larger diameter) Proximal convoluted tubule Sites of regulation Efferent arteriole (smaller diameter) Glomerular (Bowman's) capsule NET FILTRATION PRESSURE (NFP) =GBHP – CHP – BCOP = 55 mmHg 15 mmHg 30 mmHg = 10 mmHg Capsular space Controlling filtration pressure Renal arteriolar resistance • • • • • • Efferent arteriole constriction Reduces renal blood flow Increases GFR Afferent arteriole constriction Reduces renal blood flow Reduces GFR Aff. art. Eff. art. ↓ RBF/GFR ↑ RBF/GFR ↓RBF/↑GFR Three Mechanisms regulating GFR 1. Renal autoregulation 2. Neural regulation 3. Hormonal regulation 1. Renal autoregulation • Kidneys themselves maintain constant renal blood flow and GFR using – – Myogenic mechanism – occurs when stretching triggers contraction of smooth muscle cells in afferent arterioles – reduces GFR Tubuloglomerular mechanism – macula densa provides feedback to glomerulus, inhibits release of NO causing afferent arterioles to constrict and decreasing GFR Autoregulation of GFR and RBF The kidneys are able to maintain a fairly constant RBF and GFR over a large range of arterial pressures. This is a local effect intrinsic to the kidneys Rhoades & Tanner, 2003 If there was no autoregulation At normal MAP (100 mmHg) - GFR = 125 mL/min or 180 L/day - results in 1.5 L/day of urine production. Increasing MAP to 125 mmHg would -↑ GFR to 225 L/day - urine flow = 46.5 L/day.  Extreme FLUID and SALT LOSS! Myogenic Autoregulation • Automatic regulation of RBF + GFR • In response to slight changes in BP • Control at the local level (e.g. smooth muscle cells) (a) ↑ MAP automatically induces vasoconstriction of afferent arteriole  ↓ flow  ↓ GFR and bringing it back to normal (b) ↓ MAP induces afferent arteriole vasodilation  ↑ flow and GFR, and bringing GFR back to normal levels. Tubuloglomerular feedback ↑ GFR = ↑ amount of solutes (NaCl) [NaCl] sensors ↑ GFR = ↑ NaCl load, ↓ time to reabsorb it ↓ GFR = ↓ NaCl load, ↑time to reabsorb it NaCl reabsorption Is time dependent – ↑time ↓[NaCl] The Juxtaglomerular Apparatus Sherwood, 1997 Tubuloglomerular feedback • Juxtaglomerular apparatus - Macula densa (MD) – a collection of densely packed epithelial cells at the TAL/DCT junction. – Juxtaposed to its own glomerulus, between the afferent and efferent arterioles. – Position enables it to rapidly alter glomerular resistance in response to changes in the flow rate through the distal nephron. • MD monitors tubular fluid composition (an indicator of GFR). – ↑ DCT [NaCl]  ↓ time spent in tubules  elevated GFR – ↓ DCT [NaCl]  ↑ time spent in tubules  reduced GFR • MD NaCl sensor: Na-K-2Cl cotransporter (NKCC2). – Decreased NaCl stimulates the release of NO from the macula densa  aff. art. dilation  ↑ GFR. – ↓ DCT [NaCl]  aff. art dilation  ↑ GFR – ↑DCT [NaCl]  aff. art. constriction  ↓ GFR Extra-Renal Factors affecting GFR 1. Sympathetic nerves  NA Moderate - ↓Aff./Eff. art. ↓ RBF/GFR  ↓ urine  ↑ Bvol/BP Maximal - ↓↓↓ Aff. art. ↓↓↓ GFR – normally minimal activity; overrides if strong • eg. after haemorrhage  “renal shut-down” 2. Circulating hormones – Atrial natriuretic peptide (ANP): • – ↑Aff.:↓Eff. ↑↑ GFR (noΔRBF) Angiotensin II: **complex and variable** • ↓Aff.:↓↓Eff.  ↓RBF: ↓/noΔ GFR (limits RBF but ‘maintains’ GFR due to greater efferent constriction) (*but massively increases BP at the same time  ↑ ↑ ↑ perfusion pressure* = it depends, sorry ) Angiotensin is also regulated by Tubuloglomerular Feedback ↓ GFR  ↓[NaCl]  renin release  AtII Fine tuning... Intraglomerular mesangial cells • Intraglomerular mesangial cells (smooth muscle-ish) regulate intraglomerular capillary blood flow. • MC contraction is coupled with contraction of the glomerular capillary endothelium basement membrane  ↓ surface area  ↓ GFR Respond to: • AtII, ANP, ADH • NO • Capillary stretch On to the tubules...