Kidney Function I: Filtration, Reabsorption, and Secretion PDF

Kidney Function I: Filtration, Reabsorption, and Secretion. Dr Sarah A. Thomas Reader in Physiology King's College London [email protected] LECTURE LINKS This lecture has been designed as a foundation for the following three lectures. To enhance your learning experience it is advised that you f...

Kidney Function I: Filtration, Reabsorption, and Secretion. Dr Sarah A. Thomas Reader in Physiology King's College London [email protected] LECTURE LINKS This lecture has been designed as a foundation for the following three lectures. To enhance your learning experience it is advised that you follow the lectures in the correct order. Kidney function I: Filtration, reabsorption and secretion. Kidney function II: Clearance and its use in renal physiology. Production of concentrated urine by the kidney. Kidney function III: Regulation of osmolality and blood volume. Kidney function IV: Regulation of acid-base status. KIDNEY FUNCTION I: Filtration, Reabsorption and Secretion. LECTURE OBJECTIVES After studying the topics of this lecture, students should be able to: Define the key functions and anatomy of the kidney and nephron. Understand the function of the glomerular filter and the dynamics of ultrafiltration. Describe the processes of tubular reabsorption of glucose and amino acids. Describe the processes of tubular secretion of organic anions and cations. LECTURE OBJECTIVE Define the key functions of the kidney/nephron. Functions of Kidney EXCRETION OF METABOLITES OR INGESTED SUBSTANCES – – – – – – Urea from protein catabolism Uric acid from nucleic acid breakdown Creatinine from muscle creatine Hormone metabolites e.g. growth hormone metabolites End products of haemoglobin breakdown Foreign chemicals e.g. drugs, pesticides Functions of Kidney EXCRETION OF METABOLITES AND INGESTED SUBSTANCES CONTROL OF BODY FLUID COMPOSITION – Volume Regulation i.e. linked to sodium concentration – Osmoregulation i.e. water balance – pH regulation Functions of Kidney EXCRETION OF METABOLITES AND INGESTED SUBSTANCES CONTROL OF BODY FLUID COMPOSITION – Volume Regulation i.e. linked to sodium concentration – Osmoregulation i.e. water balance – pH regulation ENDOCRINE Hormones that act on the kidney e.g. anti-diuretic hormone (ADH), aldosterone, natriuretic peptides, parathyroid hormone and fibroblast growth factor 23 (FGF23). Hormones produced by the kidney e.g. renin, activated vitamin D3 (calcitriol), erythropoietin and prostaglandins LECTURE OBJECTIVE Describes the anatomy of the kidney and nephron. Gross Structure of Kidney Cortex (outer) Medulla (inner) Microanatomy of the Kidney >1 million nephrons/kidney Each nephron: i) renal corpuscle ii) tubule 2 4 Tubule 1 4 2 1 5 5 renal corpuscle Collecting duct 3 Highly diagrammatic view - if it could be flattened out 3 Bowman’s capsule Glomerulus or Glomerular Capillaries Efferent arteriole Tubule Afferent arteriole Bowman’s space Simplified diagram of renal corpuscle Renal Corpusclefocus on filtration interface Fenestrated capillary endothelium (pores max size 15nm). Basement membrane (fixed polyanions) Tubular epithelium (podocytes) (filtration slits ~8nm) Bowman’s space Capillary lumen PODOCYTES Podocyte foot processes Filtration slit NEPHRON Important features: NEPHRON Figure same as previous slide. Enlarged for handout view. No audio. NephronTypes A. CORTICAL (85%) outer 2/3 of cortex. - short Loop of Henle B. JUXTAMEDULLARY(15%) inner 1/3 cortex – long Loop of Henle – producing concentrated urine Fig 17.6 17-17 JUXTAGLOMERULAR APPARATUS Extraglomerular mesangial cells Ascending limb of loop of Henle Juxtaglomerular cells (includes granular cells). Macula densa (Beginning of distal tubule) The nephron…blood supply Fig 17.5 2 sets of arterioles (afferent and efferent) in series. 2 sets of capillary beds (glomeruli and peritubular) in series. 17-13 LECTURE OBJECTIVE Define the basic renal processes Basic Renal Processes 1) Glomerular Filtration 2) Tubular Reabsorption 3) Tubular Secretion 1. Glomerular filtration. The movement of fluid and solutes from the glomerular capillaries into Bowman’s space. 20 percent of the plasma that enters the glomerulus is filtered and enters the Bowmans space. 1. Glomerular filtration 2. Tubular secretion The secretion of solutes from the peritubular capillaries into the tubules. 1. Glomerular filtration. 2. Tubular secretion. 3. Tubular reabsorption. The movement of materials from the filtrate in the tubules into the peritubular capillaries. Amount excreted in urine Amount filtered Amount secreted Amount reabsorbed Three hypothetical substances X, Y and Z. Three hypothetical substances X, Y and Z. Substance X is filtered and secreted but not reabsorbed. e.g. para-aminohippuric acid (PAH). Substance Y is filtered and is reabsorbed, but some escapes in the urine e.g. water and most electrolytes. Substance Z is filtered and completely reabsorbed. e.g. glucose Basic Renal Processes 1) Glomerular Filtration 2) Tubular Reabsorption 3) Tubular Secretion 4) Metabolism e.g. glutamine LECTURE OBJECTIVE The function of the glomerular filter and the dynamics of ultrafiltration. What gets through the glomerular filtration barrier? Bloom and Fawcell Textbook of Histology 12th edition (1994) (Chapman and Hall, New York, London) Most plasma constituents are freely filtered except proteins. Filtration depends on molecular size, charge and possibly shape. Molecular Size The Glomerulus.. filtration Free passage Inulin 5.5 kD Myoglobin 17 kD Albumin 69 kD 1.0 [Filtrate] / [Plasma] Total block Glucose 180D 0 0 7kDa 0.5 0 1 2 3 4 Molecular radius (nm) Freely filtered Partly filtered 5 Excluded Filtration by size in kD and molecular radius Molecular Charge of large molecules The Glomerulus.. filtration Free passage The Glomerulus.. filtration [Filtrate] / [Plasma] Free passage 1 Negatively charged dextrans Filtrate Plasma ratio Total block cationic Total 0 block 0 Uncharged dextrans Positively charged dextrans anionic radiusMass (nm) kDa Relative Molecular Molecular Freely filtered Partly filtered 70 Uncharged molecules Excluded Composition of Ultrafiltrate Cells and large proteins are not normally filtered across the filtration barrier. Certain drugs and certain ions can bind to proteins and so will also not be freely filtered. For example: -Acidic drugs can bind to the protein, albumin. -Basic drugs can bind to α1-acid glycoprotein. -Calcium is a divalent cation (Ca++). 40% of plasma Ca++ is bound to proteins therefore only 60% of plasma Ca++ can be freely filtered. Infection, damage to glomerulus or very high blood-pressure can result in: -protein in urine (proteinuria) -haemoglobin in urine (haemoglobinuria) -red cells in urine (haematuria) Glomerular fltration rate (GFR) is the volume of fluid filtered from the glomeruli per minute (ml/min). GFR depends on a combination of: 1) 2) 3) Net filtration pressure Permeability characteristics Surface area And is regulated by both neural and hormonal input. Everything else being equal, a higher GFR means greater excretion of salt and water. GFR depends on: 1) Starling’s forces involved in filtration i) Hydrostatic pressure difference ii) Colloid osmotic pressure difference Plasma will flow across a capillary wall from a high to a low hydrostatic pressure and from a low to a high colloid osmotic pressure. 1) Forces involved in filtration Starling forces (opposing) i) Hydrostatic pressures (60 mmHg -15 mmHg) ii) Colloid Osmotic/Oncotic pressures (29mmHg -0 mmHg) Net glomerular filtration pressure = (60-15)-(29-0) = 16 mmHg 60 mmHg (8.0kPa) 29 mmHg (3.9kPa) 15 mmHg (2.0KPa) 0 mmHg 16 mmHg (2.1kPa) *Note: protein concentration in Bowman’s space filtrate is so low that the oncotic pressure is considered to be zero. i) Hydrostatic pressure Decreased GFR Increased GFR N.B.: Poiseuille’s Law Flow ∝ radius4 PGC=Glomerular capillary hydrostatic pressure AA=Afferent arteriole EA=Efferent arteriole GFR depends on: 2) Permeability Characteristics of filtration interface Glomerular capillaries 15nm Majority of other capillaries including peritubular capillaries 5-12nm GFR depends on: 3) Surface Area of Filtration Interface Changeable JUXTAGLOMERULAR APPARATUS Sympathetic nerve fibers Intraglomerular mesangial cells Extraglomerular mesangial cells Juxtaglomerular cells Macula densa Glomerular filtration rate GFR: 125 ml/min of filtrate formed (180 l/day) 180 litres / day Much higher than the 4 litres/day across all other capillaries in body. Reabsorption Urine output typically 1.5 litres/day because reabsorption occurs ~99% of filtered water is reabsorbed 1.5 litres /day LECTURE OBJECTIVE Describe the processes of tubular reabsorption of glucose and amino acids. Reabsorption Proximal Convoluted Tubule Proximal Straight Tubule Luminal membrane of tubule cells faces filtrate. Basolateral membrane faces peritubular capillary. Endothelial cell Proximal Tubule Walls are a single layer of columnar cells luminal membrane microvilli mitochondria 17-16 Proximal Reabsorption of Organic Nutrients e.g. glucose and amino acids. Na+-coupled 1) co-transporter 2) A tubular maximum (Tm) system 3) Specific Transporters Glucose reabsorption Tubule lumen Peritubular capillary Primary active transporter 1. SGLT Glucose Secondary active co-transporter Filtrate Intracellular Fluid Luminal membrane 2. GLUT Basolateral membrane Facilitated diffusion transporter Diffusion Interstitial Fluid Filtered glucose normally reabsorbed. Two types of glucose transporters 1. Na+-dependent glucose co-transporter (SGLT). 2. Facilitated diffusion glucose transporter (GLUT). Glucose transport by SGLT supported by Na+-K+-ATPase pump (maintains low sodium in cell which means sodium can move into the cell down its concentration gradient from tubule lumen). Blood Renal handling of plasma glucose Vander’s Human Physiology McGraw Hill, 2016. 14th edition. Filtered load is linearly proportional to plasma concentration and matches reabsorption below 200 mg/dl = 11 mM. “Reabsorbed” line shows variation with plasma [glucose]. Excreted = Filtered – reabsorbed, and shows renal threshold at 200 mg/dl. Amino acids. Reabsorbed proximal tubule (PT) At least 8 amino acid transporters 6 Na+-dependent transporters Overlapping amino acid specificity Proteins. Vast majority of filtered PROTEIN reabsorbed in PCT by endocytosis and degraded to amino acids. Important for inactivation of small polypeptide hormones e.g. insulin and growth hormone. Summary of PCT reabsorption Na+ coupled transporters for – glucose, amino acids, phosphate, sulphate Passive reabsorption – urea, chloride, potassium, calcium Bicarbonate …related to H+ secretion, important in acidbase balance. LECTURE OBJECTIVE Describe the processes of tubular secretion of organic acids and bases. Secretion in proximal tubule Two stage process. Involves basolateral and luminal (brush border) membrane transporters. Transporters broadly selective. Only means of excretion for some plasma protein bound molecules. Secretion in proximal tubule ORGANIC ACIDS (Anions) Endogenous molecules. e.g. bile salts Exogenous molecules -Drugs. e.g. penicillin -Diagnostic agent. e.g. para-aminohippuric acid (PAH). BCRP 1. Organic anion (OA-) enters epithelial cell via organic anion counter transporters.. 2. OA- enters tubule lumen via ATP- dependent primary active transporters. Secretion in proximal tubule ORGANIC BASES (Cations) Endogenous molecules. e.g. creatinine. Exogenous molecules -Drugs. e.g. morphine The AAPS Journal, Vol. 1. Organic cations (OC) enter proximal tubule cell via facilitated diffusion transporters. 15, No. 2, April 2013 2. OC enter tubule lumen via counter-transporters. Hormone Glossary ADH peptide released by the posterior pituitary & promotes water reabsorption in collecting duct. Aldosterone: this is a steroid hormone produced by the adrenal cortex; it promotes sodium reabsorption in the collecting ducts. Natriuretic peptides: These are produced by cardiac cells and promote sodium excretion in the collecting ducts. Parathyroid hormone: This is a protein produced by the parathryoid gland; it promotes renal phosphate excretion, calcium reabsorption and vitamin D production. FGF23: This is produced by bone osteocytes and promotes renal phosphate excretion and inhibits vitamin D production. Renin: This is a protein released by the juxtaglomerular apparatus; it results in the formation of angiotensin II. Angiotensin II acts directly on the proximal tubules and via aldosterone on the distal tubules to promote sodium retention and is also a potent vasoconstrictor. Erythropoietin: This is a protein produced in the kidney; it promotes red blood cell formation in bone marrow, Prostaglandins: These are produced in the kidney; they have various effects, especially on renal vessel tone. Vitamin D3 (Calcitriol): This is the active form of vitamin D3 (1,25 dihydroxycholecalciferol), which promotes calcium and phosphate absorption from the gut as a principal action. Useful equations: Equation 1: Flow = Pressure difference / Resistance Equation 2: Resistance to flow (Poiseuille’s Law) 8𝐿h Resistance = p 𝑟4 𝐿 = vessel length, r = radius of vessel lumen, h = blood viscosity Equation 3: Pressure difference p 𝑟4 Flow = 8𝐿h Monitoring of your own learning: 1. Use the lecture objectives as questions and provide answers with or without looking at your notes. 2. a. Identify the structure in this diagram. b. Label the individual components. c. Provide a descriptive figure legend. 3. Test your understanding using the multiple-choice questions and answers: http://www.ataglanceseries.com/renalsystem/mcqs.asp Further reading to support this lecture. This is not compulsory reading. -In Vander’s Human Physiology. McGraw Hill, 2016. 14th edition. Chapter 14: The kidneys and regulation of water and inorganic ions. or -The Renal System at a Glance. O’Callaghan. 4th edition. Wiley Blackwell 2017. Physical copies available and on-line access through the King’s College London library. -Earlier editions of these text books and other human physiology textbooks (e.g. Berne and Levy, Costanzo) are also suitable. NOTE: ClinicalKey student database-has many physiology e-textbooks. On-line access available through the King’s College London library.