PPA Renal Lecture Notes PDF

Lecture 1 Anatomy of the Kidney and Nephron with Emphasis on Glomerular Filtration Lihui Yuan, PharmD, PhD PHA5561 Pathophysiology and Patient Assessment II [email protected]  Renal Lecture Series Lecture 1. Anatomy of Kidney and Nephron with emphasis...

Lecture 1 Anatomy of the Kidney and Nephron with Emphasis on Glomerular Filtration Lihui Yuan, PharmD, PhD PHA5561 Pathophysiology and Patient Assessment II [email protected]  Renal Lecture Series Lecture 1. Anatomy of Kidney and Nephron with emphasis on Glomerular Filtration Lecture 2. Nephron Segments: Mechanisms of Water and Sodium Reabsorption Lecture 3. Assessment of Renal Function, Osmotic Pressure, and Body Water Distribution Lecture 4. Endocrine Systems Regulating Water and Sodium Homeostasis Lecture 5. Disorders of Water and Sodium Homeostasis: Hyponatremia, Hypernatremia, and Polyuria Lecture 6. Renal Regulation of Potassium Lecture 7. Renal Regulation of Acid-Base Physiology: emphasis on Metabolic Alkalosis and Metabolic Acidosis Lecture 8. Renal Pathophysiology: Acute and Chronic Kidney Failure 2  Learning Objectives  List the basic renal functions  Describe the gross anatomy of the kidney  Naming the nephron segments  Describe the three basic renal processes  Discuss the glomerulus components and their role in filtration  Describe autoregulation and explain the mechanism 3 Renal Functions: Removal of metabolic waste products urea, uric acid, creatinine, urobilin Removal of foreign chemicals and bioactive substances Foreign chemicals, drugs (dose adjustment for renal impairment) Regulation of water and electrolyte balance (osmolarity, blood pressure, pH) How kidney regulate blood pressure? Volume and resistance Blood pressure = ??? CO × TPR 4 Renal Functions: continue Gluconeogenesis Synthesis of glucose from non-carbohydrate sources (amino acids and glycerol). Most occurs in liver, but substantial amount in kidney, e.g. during fasting. Production of hormones and enzymes Erythropoietin: Red blood cell production constrictor Why patient with chronic renal guaso Renin: Rate limiting enzyme for AngII production disease tend to have anemia? Hint: Erythropoietin 1,25-dihydroxyvitamin D (Calcitriol): active form of VitD for absorption of Ca2+ 5  Basic Anatomy of the Kidney -Paired bean shaped structures that are positioned behind the peritoneum on each side of the vertebral column. The kidney runs from the 12th thoracic vertebrae to the 3rd lumbar vertebrae. -Combined weight of both kidneys is less than 0.5% of the total body weight. In males each kidney weighs 125 to 170 g; females 115 to 155 g.  Basic Anatomy of the Kidney: Continue  Each kidney is covered by a fibrous non-distensible capsule. In the middle of the concave surface is a small slit in the capsule, which is called the hilus. -  The hilus serves as the point of Hilus entry for the renal artery and nerves and as the exit point for the renal vein, lymphatics, and the ureter.  The renal hilus opens up into the renal sinus, which is the space holding the calices, pelvis, blood vessel, nerves and fat. 7 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed.  Basic Anatomy of the Kidney: Continue  Cortex  Medulla (Pyramids) -  Minor calices Hilus  Major calices  Renal pelvis  Ureter 8 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed.  Kidney two basic layers: Cortex Granularity due to the presence of glomeruli (microscopic capillaries) and a large number of tubules. Medulla The darker inner region, subdivided into 8 to 18 cone-like shaped renal pyramids. -At the tip of each pyramid contains tiny perforations through which urine escapes into the minor calices of the renal sinus. 9 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed.  Comparison between Cortex and Medulla Cortex: Medulla: Glomeruli Tubules Filtration (What is this?) Reabsorption (What is this?) High pressure (favors Low pressure (favors filtration) reabsorption) 66X63 9. = x0 85. = 27.9 High O2 Low O2 Lower interstitium High interstitium osmolarity osmolarity 10  Blood flow through the renal circulation: The kidneys have a very high blood flow and possess glomerular capillaries that are flanked by > - 20 % of Cardiac upstream and downstream arterioles. Output 1.) a high resistance afferent arteriole, which is followed by: 2.) a high pressure glomerular capillary network for filtration, which is followed by: 3.) a second high resistance efferent arteriole, which is followed by: 4.) a low pressure capillary network (peritubular capillaries), which takes up the absorbed fluid. 11 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed. Nephron = Functional unit of the Kidney -Nephrons: 800,000 to 1,200,000 per kidney -operate independently until merging with collecting ducts of the other nephrons -Made up of: Glomerulus (where filtrates form, how?) Tubules (convert blood filtrate into urine). The tubule and glomerulus meet at a structure called Bowman’s capsule. 12  You should be able to describe the Structure of structure of the nephron and their location in terms of cortex and medulla, the nephron 13 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed.  Test of Knowledge Which of the following statement about nephron is correct? A. Nephron segment is composed of only tubular system. B. The main function of renal cortex is reabsorption. C. The glomerular pressure needs to stay relatively high for filtration to occur. D. The peritubular vascular pressure needs to stay high for absorption to occur. 14  Basic renal processes Three primary processes: 1. Glomerular Filtration: process by which water and solutes in the blood leave the vascular system through the filtration barrier and enter Bowman’s space (~20% of plasma enters tubule) 2. Tubular Secretion: process of moving substances into the tubular lumen from the peritubular capillaries. Note: this term also applies to substances excreted from epithelial cells that line the tubules. 3. Tubular Reabsorption: process of moving substances from the tubular lumen into the peritubular capillaries. a Also called filtration, secretion, and reabsorption. ↑ Spil ary For any substance: system Amount excreted = amount filtered + amount secreted – amount reabsorbed.  Basic renal processes Not all processes apply to all substances (e.g. glucose almost completely reabsorbed, toxins almost entirely secreted). Many substances can undergo multiple processes. For a given substance, rate of each process may be subject to physiological changes. Questions to think about: H+ Na+ Glucose When will the body needs to reabsorb more Na+? Does the glucose always get reabsorbed?  Tubule segments: -the proximal tubule -the loop of Henle -the distal convoluted tubule -the cortical collecting tubule and the medullary collecting ducts. Make sure to understand: Reabsorption mechanism of each segment Mechanism and site of actions of drugs; particularly, diuretics. 17  Glomerulus The renal corpuscle is composed of two main structural components: The glomerulus (or glomerular capillaries) and a surrounding capsule called Bowman’s capsule. AA – afferent arteriole > - Blood comes in EA – efferent arteriole > - Blood comes out US - “urinary” (Bowman’s) space. 3 PO - podocytes of Bowman’s capsule filters & selectively GBM - glomerular basement membrane decides what come in what can can't JGA (juxtaglomerular apparatus) — MD - macular densa — GC - granule cells -produce renin — EGM – extraglomerular mesangial cells > - help push the filtration 18  Filtration barrier: > - negatively charged Capillary endothelium Glomerular basement membrane (GBM) Podocyte foot processes The size and charge of the particles determine if a molecule will be filtrated or not. *Prefers smaller & more positive 19 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed.  Microscopic Image of Filtration Barrier Podocytes Fenestration Filtration slits 20 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed. Test of Knowledge The urine test of JM showed positive for red blood cells and proteins, which of the follow could be the cause? A. Damage to the glomerulus B. Damage to the proximal tubule C. Damage to the macula densa D. Damage to the loop of henle. 21 Major Determinants of Glomerular Filtration Definitions: than capillaries smaller than artery but bigger > - Arteriole = small diameter blood vessel in the microcirculation that extends and branches out from an artery and leads to capillaries. The kidney comprises less than 0.5% of the total body weight, but they receive ≈ 20% of the cardiac output. The high blood flow allows for the forming of an ultra-filtrate in the glomeruli. Filtrate = portion of the blood that is filtered. Hydrostatic pressure forces a liquid against a semipermeable membrane (glomerular capillaries) -The afferent and efferent arterioles determine the hydrostatic pressure of the glomerular capillaries. -The vascular tone of the arterioles is under control of a rich sympathetic innervation 22  Efferent Cortex -Afferent Medulla H2O Hydrostatic pressure also Na+ determines filtration H2O Neuronal control of renin release: Sympathetic innervation of granular cells (JGA cells) Increased sympathetic nervous activity stimulates renin production from kidney What happens next with renin release? (think of what was discussed in the cardiovascular module) Go to next page! 24 Test of knowledge With the renin release from the granular cells in the kidney, which of the following will occur? A. Renin causes vasodilation and decreases resistance, makes it easier to form filtrates in the Bowman’s space. A. Renin causes vasoconstriction and increases blood pressure, makes it easier to form filtrate in the Bowman’s space. 25  Control of Renal Blood Flow (RBF) and Glomerular Filtration Rate (GFR) RBF and GFR must be maintained within narrow limits; however, systemic mean arterial pressure can range from 80-170 mmHg. Stable blood flow to the glomerulus is maintained by autoregulation: a property of vascular beds serving the kidney, brain and heart. Two basic mechanisms underlie autoregulation: Myogenic response: Independent of hormonal and neuronal control, depending only on the physical sheer stress, regulated through stretch induced ion channels Tubuloglomerular feeback: Hormonal and neuronal control (Where does this occur?) 26  2.0 Relative vascular 1.5 Efferent arteriolar resistance resistance 1 0.5 0 Afferent arteriolar resistance 1200 Renal blood flow 600 (ml/min) 0 150 The goal is to maintain GFR GFR (ml/min) 100 50 0 40 80 120 160 Renal arterial pressure (mmHg)  Proximal Tubule Autoregulation Side door Bowman’s Capsule Bowman’s Space A BP is high! Afferent Entrance Arteriole Efferent Arteriole Exit When pressure is high Glomerular Capillary renal blood flow glomerular filtration hydraulic pressure decreases myogenic response  Tubuloglomerular feedback 29 Source: Rennke HG, Denker BM: Renal Pathophysiology 3rd Ed. Tubuloglomerular Side door Bowman’s Capsule feedback β1 β1 β1 JGAJGAJGA Afferent Efferent Entrance Arteriole Arteriole Exit JGAJGA JGA β1 β1 β1 K+ Na+ Na+ prostaglandins 2Cl- Cl- Na+-K+-2Cl- Na+ Cl- Co-transporter Co-transporter Macula densa Macula densa responds to changes in luminal delivery of NaCl. NaCl entry into these cells is mediated by Na+-Cl- or Na+-K+-2Cl- co-transporters in the luminal membrane of the DCT or TAL, respectively. The activity of this transporter is controlled by NaCl concentration. Volume depletion decreases the amount of NaCl that is delivered to the macula densa, which increases renin release via prostaglandins.  Proximal Tubule Side door Bowman’s Capsule Bowman’s Space Afferent Entrance Arteriole Maintains GFR Efferent Arteriole Exit Glomerular Capillary glomerular filtration renal blood flow hydraulic pressure Tubuloglomerular feedback  Lecture 2 Nephron Segments: Mechanisms of Water and Sodium Reabsorption. Lihui Yuan, PharmD, PhD PHA5561 Pathophysiology and Patient Assessment II [email protected]  Renal Lecture Series Lecture 1. Anatomy of Kidney and Nephron with emphasis on Glomerular Filtration Lecture 2. Nephron Segments: Mechanisms of Water and Sodium Reabsorption Lecture 3. Assessment of Renal Function, Osmotic Pressure, and Body Water Distribution Lecture 4. Endocrine Systems Regulating Water and Sodium Homeostasis Lecture 5. Disorders of Water and Sodium Homeostasis: Hyponatremia, Hypernatremia, and Polyuria Lecture 6. Renal Regulation of Potassium Lecture 7. Renal Regulation of Acid-Base Physiology: emphasis on Metabolic Alkalosis and Metabolic Acidosis Lecture 8. Renal Pathophysiology: Acute and Chronic Kidney Failure 2  Learning Objectives  Describe the arrangements of the tubule segments and function  Discuss the mechanism of solutes transportation out of the tubule lumen  Describe the counter-current mechanism  Discuss how the counter-current mechanism and endocrine signals interact in the collecting duct to make dilute or concentrated urine 3  Basic renal processes Three primary processes: Glomerular Filtration: process by which water and solutes in the blood leave the vascular system through the filtration barrier and enter Bowman’s space. (~20% of plasma enters tubule) Tubular Secretion: process of moving substances into the tubular lumen from the peritubular capillaries. Note: this term also applies to substances excreted from epithelial cells that line the tubules. Tubular Reabsorption: process of moving substances from the tubular lumen into the peritubular capillaries. Also called filtration, secretion, and reabsorption.  Kidney receives ~20% CO as a small organ Reabsorption is vital in preserve the plasma volume Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed.  Peritubular Capillary Tubules How does reabsorption occur? What barriers does a solute need to cross? Tubule Peritubular Capillary LAB Lumen Basolateral membrane Apical membrane H2O Na+ H2O Na+ General Mechanism of Trans-tubular Sodium Reabsorption Na+ Na+ Na+ Negative (3) Na+ Na+ (2) Na+ Reabsorption of filtered sodium occurs in two steps: 1.) sodium must move from the lumen across the apical membrane L A B 2.) subsequently, sodium is moved out of the cell into the interstitium and peritubular capillary across the Epithelial salt and water reabsorption basolateral membrane. Citation: Chapter 4 Basic Transport Mechanisms, Eaton DC, Pooler JP. Vander’s Renal Physiology, 9e; 2018. Available at: https://accessmedicine.mhmedical.com/ViewLarge.aspx?figid=209143686&gbosContainerID=0&gbosid=0&groupID=0&sectionId=185663984&multimediaId=undefined Accessed: July 29, 2021 Copyright © 2021 McGraw-Hill Education. All rights reserved  General Mechanism of Trans-tubular Sodium Reabsorption Summary Transmembrane transporters or channels are required for sodium reabsorption. Active transport of sodium out of the cells is mediated by the Na+/K+ ATPase. The pump keeps the intracellular sodium concentration low and generates a negative potential inside of the luminal cell. The low sodium concentration and negative intracellular charge create favorable electrochemical gradient for sodium to enter the luminal cell from inside of the lumen. Active reabsorption or secretion of other substances (glucose or amino acids) can be done by coupling transportation of sodium. 9 Test of Knowledge Which of the following statement is correct about the Na+ reabsorption? A. Na+ needs to cross basolateral membrane, then apical member to be reabsorbed. B. Na+/K+ ATPase pumps 3 Na+ to the inside of cell for every 2 K+ pumped out of the cell. C. Na+/K+ ATPase pumps 2 K+ to the inside of cell for every 3 Na+ pumped out of the cell. solateral D. The Na+/K+ ATPase is located on the apical membrane. 10 Proximal Tubule Most of the reabsorption of fluid and solutes occurs in the PT NaCl, NaHCO3 (sodium bicarbonate), water Divalent ions: Ca2+, HPO42-, and SO42- Filtered nutrients: glucose and amino acids Functions of proximal tubule: Na+ and glucose reabsorption Acid-base balance Regulation of Ca2+ and HPO42- Excretes endogenous and exogenous solutes (Drugs) into the proximal tubule lumen. 11  Afferent arteriole H2O H2O Na+ H2O Bowman’s Capsule Na+ H2O Peritubular H2O Na+ Capillary H2O Na+ H2O Proximal Tubule Glucose H2O H2O Na+ H2O Na+ H2O H+ H2O Na+ H2O Water, Na+, glucose reabsorption Glucose Na+ H+ H+ secretion H2O  Transport of sodium out of the luminal cells is mediated by the Na+/K+ ATPase pump. Na+ Na-Glucose Co- 3Na+ Transporter Na-K- Glucose ATPase active reabsorption of other substances (glucose) can be 2K+ coupled to transport of sodium Na+ Proximal Tubular Cell Peritubular Tubular Na-H sodium reabsorption and exchanger Capillary Lumen hydrogen secretion H+ (contributes to regulation acid-base balance) H2O aquaporin H2O aquaporin Aquaporins and osmotic gradient promote water reabsorption. L Apical Membrane A B Basolateral Membrane  Test of Knowledge Which of the following substances can be reabsorbed at the PCT region? A. Na+. B. Glucose. C. Water. D. All of the above. 14 Loops of Henle The ascending limb is permeable to ions but not water The descending limb is permeable to water but not ions 15  Loops of Henle -Main function is to create hyperosmotic interstitium that allows the concentrating of urine. The descending limb is permeable to water but not ions, whereas the ascending limb is permeable to ions but not water. ≈ 25% of the filtered sodium is reabsorbed in the ascending limb of the loop of Henle. Robust active transport of sodium out of the ascending limb makes the interstitial fluid in the medulla very concentrated. This occurs via the countercurrent mechanism. 16  H2O aquaporin H2O aquaporin Aquaporins and osmotic gradient promote water reabsorption. H2O aquaporin Tubular Peritubular Thin descending Limb of Loop of Henle Cell Capillary Lumen Permeable to water H2O aquaporin H2O aquaporin L Apical Membrane A B Basolateral Membrane  Tubular Thick Ascending Limb of Loop of Henle Cell Peritubular Lumen Capillary Na-K ATPase creates low intracellular Na+ and an electronegative gradient Na+ relative to the lumen Na+-K+-2Cl- K+ Co-transporter 3Na+ major player for sodium Na-K- 2Cl- reabsorption in the loop of Henle. ATPase Filtrates Chloride is the rate limiting factor for 2K+ transporter activity. Loop diuretics work here! For sodium reabsorption to Potassium occur, K+ has to recycle back Ion Channel K+ into the lumen via ion channel Chloride Cl- Ion Channel Chloride exits through a selective basolateral ion channel Na+ Ca2+ Mg2+ Tight Junction L Apical Membrane A Positivity from K+ recycling passively drives reabsorption of cations across tight junctions B Basolateral Membrane  H2O H2O H2O H2O Na+ Cortex Na+ Na+ Na+ Na+ CT concentration Countercurrent Medulla mechanism [ More More sodium Sodium at the bottom Papilla than water of the U  20 Source: Rennke HG, Denker BM: Renal Pathophysiology 3rd Ed.  Distal Convoluted Tubule Begins at the macula densa (i.e. juxtamedullary complex) and ends at the transition to the connecting tubule Major site at which urinary calcium excretion is actively regulated. Fine control of salt and water excretion. Normally reabsorbs 5-8% of filtered NaCl and this is regulated mainly by a Na+/Cl- cotransporter. Inhibition of the Na+/Cl- transport (thiazide diuretic) will potently augment sodium excretion in the presence of a loop diuretic. 21  Distal Convoluted Tubule: continue If more fluid is delivered to the distal tubule because of the administration of a loop diuretic, then more NaCl can be reabsorbed at the distal tubule. This response of the distal tubule reduces the efficacy of loop diuretic sodium excretion. 22 Test of Knowledge Which of the following statement is correct about the diuretics? A. Thiazide diuretics works at the thick ascending loop of henle. B. Loop diuretics works at the distal convoluted tubule. C. There is no therapeutic indication of combining loop and thiazide diuretics. D. Close monitoring of blood pressure and electrolytes is needed with combined use of thiazide and loop diuretics. 23  Autoregulation Autoregulation is a broad term for a collection of mechanisms through which renal blood flow and glomerular filtration rate are kept relatively constant across a wide range of systemic arterial pressures. Why regulate GFR necessary? Remember… Excretion of salt and water is strongly regulated by GFR. GFR is heavily influenced by renal arterial pressure. 24 Tubuloglomerular feedback 25 Source: Rennke HG, Denker BM: Renal Pathophysiology 3rd Ed. Tubuloglomerular feedback Bowman’s Capsule β1 β1 β1 JGAJGAJGA Afferent Efferent Arteriole Arteriole JGAJGA JGA β1 β1 β1 prostaglandins Thick ascending Na+-K+-2Cl- Na+ Cl- Distal Convulated loop of henle Co-transporter Co-transporter Tubule K+ Na+ Decreased GFR 2Cl- Cl- Na+ Lumen Macula densa responds to changes in luminal delivery of NaCl. NaCl entry into these cells is mediated by Na+-Cl- or Na+-K+-2Cl- co-transporters in the luminal membrane of the DCT or TAL, respectively. The activity of this transporter is controlled by NaCl concentration. Volume depletion decreases the amount of NaCl that is delivery to the macula densa, which increases renin release via prostaglandins. Tubuloglomerular Feedback Proximal Tubule Bowman’s Capsule Bowman’s Space Afferent Efferent Arteriole Maintains GFR Arteriole Glomerular Capillary glomerular filtration renal blood flow hydraulic pressure  Na-K ATPase creates low intracellular Na+ and Na+ electronegative gradient Reabsorption of NaCl is regulated by Na+ Cl- relative to the lumen Na+ Cl- Co-Transporter Co-transporter 3Na+ Cl- Na-K- ATPASE 2K+ Tubular Vitamin D- Distal Tubule Peritubular Lumen dependent Capillary Ca++ Ca++ binding Ca- Protein Ca++ ATPase distal tubule regulates urinary Ca++ excretion and is under the influence of parathyroid hormone and Vitamin D. 1Ca++ Ca+-Na+ exchanger 3Na+ L Apical Membrane A B Basolateral Membrane  Test of Knowledge The Na+/Cl- and Na+/Cl-/K+ transporters at the macula densa detect which of the following signal? A. The amount of Cl- that delivered to this segment. B. The osmotic concentration at this segment. C. The amount of Na+ and Cl- delivered to this segment. D. The amount of K+ delivered to this segment. 29 Collecting Tubule Collecting tubule: joins with several tubules to collect the filtrate. Made up of the initial collecting tubule, cortical collecting ducts, and medullary collecting ducts. Intercalated cells make up ≈ 1/3 of the cells lining the collecting tubules and secrete H+ or HCO3- and reabsorb K+. This regulates acid base balance. 30  Collecting Tubule Reabsorb the final 3-4 % of filtrates. Relatively impermeable to water except with the presence of AVP. Entry of sodium in collecting ducts occurs via selective sodium channels in the apical membrane with aldosterone. The number of open sodium or water channels is under the hormonal control of: Atrial natriuretic peptide (ANP) Vasopressin (AVP; also known as antidiuretic hormone) Aldosterone. 31  Tubular 3Na+ Peritubular Collecting Tubule Lumen Na-K- Capillary ATPASE + 2K+ Na+ Na+ channel -- ALDO Aldosterone cGMP R ANP receptor ANP Gs ATP AQP2 H2O V2 receptor AVP Adenylyl Cyclase cAMP PKA H2O AQP3/4 Cl- L Apical Membrane A Tight Junction B Basolateral Membrane  AVP makes concentrated urine and decreases the [pNa+] H2O Cortex H2O H2O H2O Water reabsorption in Very Salty Na+ the collecting tubule concentration AVP Medulla Na+ Na+  Lecture 3 Assessment of Renal Function, Osmotic Pressure, and Body Water Distribution Lihui Yuan, PharmD, PhD PHA5561 Pathophysiology and Patient Assessment II [email protected]  Section Overview Lecture 1. Anatomy of Kidney and Nephron with emphasis on Glomerular Filtration Lecture 2. Nephron Segments: Mechanisms of Water and Sodium Reabsorption Lecture 3. Assessment of Renal Function, Osmotic Pressure, and Body Water Distribution Lecture 4. Endocrine Systems Regulating Water and Sodium Homeostasis Lecture 5. Disorders of Water and Sodium Homeostasis: Hyponatremia, Hypernatremia, and Polyuria Lecture 6. Renal Regulation of Potassium Lecture 7. Renal Regulation of Acid-Base Physiology: emphasis on Metabolic Alkalosis and Metabolic Acidosis Lecture 8. Renal Pathophysiology: Acute and Chronic Kidney Failure 2  Learning Objectives  Utilize the concept of clearance to estimate GFR  Explain the creatinine clearance and its relationship to GFR  Describe osmolarity, osmolality, osmotic pressure and how they influence body water distribution.  Explain how the consumption of water, sodium, or isotonic saline will affect body water distribution, plasma tonicity, urine and sodium excretion. 3  Glomerular Filtration Rate (GFR) Glomerular filtration rate = amount of fluid filtered into Bowman’s capsule per unit time. It is expressed as ml/min. Estimation of GFR is an essential part of the assessment of patients with kidney disease. The total GFR equals the sum of the filtration rate of all the functioning nephrons, can be used to evaluate the severity and course of renal disease. Decreased GFR means the disease is progressing and rise in GFR indicates recovery. 4  Assessment of Renal Function: Clearance Measurement of “renal clearance” evaluates the kidney’s ability to handle solutes and water. Allows estimation of the net amount reabsorbed or secreted by the renal tubules, thereby providing information on the three basic functions of the kidney: Glomerular filtration, tubule reabsorption, and tubule secretion. The limitation of clearance assessment is that it measures the overall nephron function and does NOT provide information about nephron segment and transporters involved. 5  All solutes excreted in urine come from the blood perfusing the kidney. The clearance of a solute is the volume of blood that is totally cleared in a given time. route of entry routes of exit routes of exit For any solute that the kidney doesn’t metabolizes or produces, the only route of entry to the kidney is the renal artery, and the only two routes of exit are the renal vein and the ureter. 6 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed.  Arterial input of “X” Venous output of “X” Urine output of “X” Px,a · RPFa = Px,v · RPFv + Ux · V Px,a = plasma concentration of X in the renal artery (mmole/ml) Px,v = plasma concentration of X in the renal vein (mmole/ml) RPFa = renal plasma flow in the renal artery (ml/min) RPFv = renal plasma flow in the renal vein (ml/min) UX = concentration of X in urine (mmole/ml) V = urine flow (ml/min) Urinary excretion rate of X is the product of Ux · V (i.e. concentration per unit time) 7 Source: Boron WF, Boulpaep EL: Medical Physiology, Updated Ed. To use clearance to estimate GFR we first must utilize a solute the kidney completely clears from an incoming volume of arterial blood (substance X ). Assume: the flow in the arterial blood is equal to that excreted in urine (Cx ). So RPFa is equal to the rate of clearance of Cx. Because all of X is filtered and excreted in urine, Px,v · RPFv , becomes zero. Arterial input of “X” Venous output of “X” Urine output of “X” Cx 0 Px,a · RPFa = Px,v · RPFv + Ux · V Px,a = plasma concentration of X in the renal artery (mmole/ml) Px,v = plasma concentration of X in the renal vein (mmole/ml) RPFa = renal plasma flow in the renal artery (ml/min) To determine the clearance need to solve for Cx RPFv = renal plasma flow in the renal vein (ml/min) Uv = concentration of X in urine (mmole/ml) V = urine flow (ml/min) Urinary excretion rate of X is the product of Ux · V (i.e. concentration per unit time) 8 To use clearance to estimate GFR we first must utilize a solute the kidney completely clears from an incoming volume of arterial blood (i.e. inulin). For inulin, the concentration in the arterial blood is equal to that excreted in urine. Therefore the clearance rate for inulin (Cinulin) is equal to: Cinulin = [Uinulin · V] / Pinulin This is the classic clearance equation. We need to know three parameters to calculate the clearance of a solute: 1.) the concentration of inulin in urine (Uinulin) Px,a = plasma concentration of X in the renal artery (mmole/ml) 2.) the urine flow (V) Px,v = plasma concentration of X in the renal vein (mmole/ml) RPFa = renal plasma flow in the renal artery (ml/min) 3.) the concentration of inulin in the blood (Pinulin). RPFv = renal plasma flow in the renal vein (ml/min) Uv = concentration of X in urine (mmole/ml) V = urine flow (ml/min) Main point: clearance gives you an index of the rate that the kidney is Urinary excretion rate of X is the product of Ux · V (i.e. filtering something out of the blood. concentration per unit time) 9 Why do we use inulin? 1.) Inulin is able to achieve a stable plasma concentration 2.) Inulin is freely filtered at the glomerulus 3.) Inulin is not reabsorbed, secreted, synthesized, or metabolized by the kidney. Is inulin the best? 10 Creatinine Clearance The creatinine can be used to estimate GFR. Creatinine: -Derived from the metabolism of creatine in skeletal muscle -Relatively stable plasma concentration -Freely filtered at the glomerulus -Not reabsorbed, synthesized or metabolized by the kidney. Creatinine clearance = [Ucr · V] / Pcr Ucr = urine concentration of creatinine V = urine flow Pcr = plasma concentration of creatinine. But Creatinine is secreted into the urine in the proximal tubule. So, creatinine excretion exceeds creatinine filtration by 10-20% in normal subjects and creatinine clearance tends to overestimate GFR by the same 10-20%. Normal creatinine clearance values (GFR) : adult women: 95 + 20 ml/min, adult men 120 + 25 ml/min 11  Test of Knowledge Patient GM’s GFR has dropped from 108 ml/min to 60 ml/min over a course of 6 months, which of the following statement can be drawn from this? A. Kidney collecting tubule damage B. Kidney medulla damage C. Kidney function deteriorating D. Na+/K+ ATPase pump is not working 12  Plasma creatinine varies inversely with GFR. Note the shape of the curve. Increase from 1.0 to 1.5 mg/dl will indicate a large fall in GFR from 120 to 80 ml/min (i.e. this is the most sensitive and important part of the curve). In adults the range for normal creatinine concentration is from 0.8 to 1.3 mg/dl in men and from 0.6 to 1.0 mg/dl in women (i.e. lower muscle mass). Confounds and limitations: creatinine production varies with muscle mass and meat intake. Plasma creatinine can fall by 15% by switching to a meat free diet, without any change in GFR. Muscle mass declines with age and from ages 50 to 90, there is a progressive decline in creatinine excretion. 13 Source: Rennke HG, Denker BM: Renal Pathophysiology 3rd Ed.  Osmotic pressure Osmolality 280 - 290 mOsm/kg (Serum) Osmolality 50 to 100 mosmol/kg in the (Urine) absence of ADH to a maximum of 900 to 1200 mosmol/kg with peak ADH 14  Explanation of osmotic pressure Osmotic Pressure Cl- Na+ H2O H2O H2O H2O H2O Cl- H2O H2O Na+ H2O H2O Na+ Na+ H2O H2O Cl- H2O H2O H2O Na+ Cl- H2O H2O H2O H2O H2O Cl- H2O Semipermeable membrane (permeable to H20, but not NaCl) Physiological Role of Osmotic Pressure: The osmotic pressure of a solute is proportional to the number of solute particles, not the size, weight, or valence of the particle. The osmotic pressure is determined by the molar concentration of the solutes that are present. The unit of measure for osmotic pressure is the osmole (Osm or mOsm). Glucose M.W. =180; so, 180 mg of glucose is equal to 1 mmol, which generates 1 mOsm of osmotic pressure. Comparison: NaCl M.W.= 58.44; so 58.44 mg of NaCl is equal to 1 mmol of NaCl; however, it will generate 2 mOsm due to its dissociation into sodium and chloride ions. Solutes generate an osomotic pressure by their inability to cross a plasma membrane. Some solutes like urea are lipid soluble and can freely cross membranes. As a result, there is no osmotic pressure generated by urea because it is not an effective osmole. 16  Test of Knowledge Which of the following substances can not generate an osmotic pressure? A. Ethanol B. HCO3- C. K+ D. Na+ 17  Osmotic Pressure and Distribution of Body Water Osmotic pressure determines the distribution of the body water. In normal adults, water comprises 55% to 60% of lean body weight in men and 45% to 50% in women. Adipose tissue contains no water. The body water is primarily located:  Inside of cells (Intracellular space, intracellular fluid)  Outside of cells (Extracellular space, extracellular fluid) The extracellular fluid includes:  Interstitial fluid that bathes the cells  Intravascular fluid that’s in the vasculature These extracellular spaces are separated by the capillary wall. 18  Distribution of Body Water 60% of the total body weight is comprised of water. A 70kg person has 42 L of water. 1: Intracellular fluid volume=2/3 of total (28L/70 kg) 2: Extracellular fluid volume=1/3 of total (14L/70 kg)  plasma volume = 25% ECF (3.5L/70 kg)  interstitial volume = 75% ECF (10.5L/70 kg)  Distribution of body water Extracellular Fluid Intracellular Fluid Capillary Plasma Endothelium Membrane Intravascular Interstitial Intracellular Space /Plasma Space Space /blood 10.5 liters 28 liters 3.5 liters [Na+] = 142 mM [Na+] = 145 mM [Na+] = 15 mM [K+] = 4.4 mM [K+] = 4.5 mM [K+] = 120 mM [Cl-] = 102 mM [Cl-] = 116 mM [Cl-] = 20 mM Protein = 1mM Protein = 0 mM Protein = 4 mM Osmolality = 290 mOsm Osmolality = 290 mOsm Osmolality = 290 mOsm Distribution of Body Water Distribution of water between these compartments is determined by osmotic pressure. The main contributor of the osmotic pressure:  Potassium inside of the cells  Sodium outside of the cells (the interstitial fluid)  Proteins (especially albumin) in the plasma Cells: sodium and potassium concentration are determined by the Na+-K+- ATPase pumps on the cell membrane. Sodium can freely move from across the capillary wall, and therefore, is an ineffective osmole at the site separating interstitial from the intravascular compartments (keep in mind interstitial and intravascular space are all part of extracellular space) 21 Distribution of body water Large plasma proteins cannot easily diffuse across the capillary, and as a result, are the primary effective solutes in plasma (i.e. hold water within the vascular space). The pressure generated is called plasma oncotic pressure. Why doesn’t water from the interstitium continually flow into the vascular space down a favorable protein concentration gradient? This does not occur because the plasma oncotic pressure is counterbalanced by the capillary hydraulic pressure (generated by cardiac contraction), tends to push water into the interstitium. Keep this in mind when we are discussing congestive heart failure and edema. 22 Pist-H = hydraulic pressure in the interstitium (Low) Pcap-H = hydraulic pressure in capillary (High) Pcap-O = oncotic pressure in capillary (High) Pist-O = oncotic pressure in the interstitium (Low) Capillary Pcap-H Pcap-O Albumin Interstitium Pist-H Pist-O  Test of Knowledge Which of the following is the same among blood plasma, interstitial fluid and the intracellular fluid? A. [Na+] B. [K+] C. Osmolality D. [Protein] 24  Relationship between plasma osmolality and sodium concentration Osmolality: The total number of solutes in a solution, unit is mOsm/Kg Osmolarity: The total number of solutes in a solution, unit is mOsm/L We can estimate the osmolality of the body water by calculating the plasma osmolality from the following formula: Plasma osmolality ≈ 2 X [PNa] + [glucose] /18 + [BUN] /2.8 Plasma sodium [PNa] is multiplied by 2 to account for the osmotic contributions of the accompanying anions (mainly chloride Cl- and bicarbonate HCO3-). Glucose is ignored, since it is present in a much lower concentration than sodium salts; Urea can be ignored, since it is an ineffective osmole. 25  Relationship between plasma osmolality and sodium concentration: continue Important to note that: Urea contributes to the plasma osmolality but not to osmotic pressure. Sodium contributes to the plasma osmolality and to the osmotic pressure at the cell membrane, but not at the capillary wall (capillary wall separates the intravascular space and interstitium, all part of the extracellular space) Plasma proteins, albumin, are the main determinants of the plasma oncotic pressure. However, albumin does not contribute to plasma osmolality since a normal plasma albumin concentration is less than 1 mmol/L. 26  Osmoregulation and Volume Regulation Table illustrating how adding NaCl, H2O, and isotonic saline to the extracellular fluid affects the [pNa], extracellular fluid (ECF) volume, urinary sodium excretion, and the intracellular fluid (ICF) volume. NaCl H20 Isotonic Saline Plasma Na ↑ ↓ ECF volume ↑ ↑ ↑ Urine Na ↑ ↑ ↑ ICF volume ↓ ↑ 27 Extracellular Fluid Intracellular Fluid Na+ H2O [Na+] = 15 mM H2O H2O H2O H2O Na+ [Na+] = 142 mM H2O H2O H2O H2O H2O Na+ H2O Na+ H2O H2O H2O H2O H2O H2O Na+ H2O H2O H2O H2O Net effects: H2O -hypernatremia H2O H2O -increased plasma osmolality -increased extracellular fluid volume -Decreased intracellular fluid volume -increased urine sodium excretion Extracellular Fluid Intracellular Fluid H2O H2O H2O [K+] = 120 mM H2O H2O H2O H2O H2O H2O Na+ H2O H2O H2O H2O [K+] = 4.4 mM H2O Na+ H2O Na+ H2O H2O H2O H2O H2O H2O Na+ H2O H2O H2O H2O Net effects: H2O -hyponatremia H2O H2O -Decreased plasma osmolality -increased extracellular fluid volume -increased intracellular fluid volume -increased urine sodium excretion Extracellular Fluid Intracellular Fluid H2O H2O H2O H2O H2O H2O H2O Na+ H2O H2O H2O H2O Na+ H2O H2O H2O H2O Na+ H2O Na+ H2O H2O H2O H2O H2O H2O H2O Na+ H2O H2O H2O H2O Net effects: H2O -No change in osmolality or plasma sodium H2O H2O -Increased extracellular fluid volume -No change in intracellular fluid volume -Increased urine sodium excretion Homework: Suppose you exercise on a hot day, leading to the loss of sweat, which is a relatively dilute fluid containing low concentrations of sodium and potassium. What will happen to the plasma sodium concentration, extracellular fluid volume, and urinary sodium excretion? 31  Lecture 4 Endocrine Systems Regulating Water and Sodium Homeostasis Lihui Yuan, PharmD, PhD PHA5561 Pathophysiology and Patient Assessment II [email protected] Homework: Suppose you exercise on a hot day, leading to the loss of sweat, which is a relatively dilute fluid containing low concentrations of sodium and potassium. What will happen to the plasma sodium concentration, extracellular fluid volume, and urinary sodium excretion? Sweat Plasma Na ↑ ECF volume ↓ Urine Na ↓ ICF volume ↓ 2  Section Overview Lecture 1. Anatomy of Kidney and Nephron with emphasis on Glomerular Filtration Lecture 2. Nephron Segments: Mechanisms of Water and Sodium Reabsorption Lecture 3. Assessment of Renal Function, Osmotic Pressure, and Body Water Distribution Lecture 4. Endocrine Systems Regulating Water and Sodium Homeostasis Lecture 5. Disorders of Water and Sodium Homeostasis: Hyponatremia, Hypernatremia, and Polyuria Lecture 6. Renal Regulation of Potassium Lecture 7. Renal Regulation of Acid-Base Physiology: emphasis on Metabolic Alkalosis and Metabolic Acidosis Lecture 8. Renal Pathophysiology: Acute and Chronic Kidney Failure 3  Learning Objectives  Describe how plasma osmolality and extracellular volume are sensed.  Explain how the endocrine and behavioral mechanisms control the plasma osmolality and blood volume.  Describe how vasopressin, angiotensin II, aldosterone and atrial natriuretic peptide affect plasma osmolality and extracellular volume. 4 Endocrine Regulation of Water and Sodium Balance Some basic concepts: Too much water = hyponatremia (low plasma sodium concentration) Too little water = hypernatremia (high plasma sodium concentration) Too much sodium can cause volume overload and edema Too little sodium can cause volume depletion 5 Hormonal Role in Water and Sodium Balance The plasma sodium concentration and extracellular fluid volume are regulated independently. Osmoregulation: osmoreceptors in the hypothalamus regulate the release of arginine vasopressin (AVP/ADH: anti-diuretic hormone) and thirst. AVP reduces water excretion while thirst increases water intake. The end result of osmoregulation is to increase the volume, thus [pNa+] is decreased. So [pNa+] is mediated by changing water balance, not by changing the sodium. 6  Volume regulation: Multiple receptors and effectors: Intrarenal: Afferent arterioles, macula densa 7 Hormonal Role in Water and Sodium Balance Major sensors and effectors of the osmoregulatory and volume regulatory pathways Osmoregulation Volume Regulation What is sensed Plasma osmolality Effective tissue perfusion Sensors Hypothalamic Cardiopulmonary osmoreceptors Atria Afferent arteriole Macula densa Effectors AVP RAAS Thirst ANP NE AVP 8 Osmoreceptors in the Initiation of AVP Release and Thirst Osmoreceptors : located in the organum vasculosum of the lamina terminalis (OVLT) which lies within the hypothalamus. The osmoreceptor senses an effective osmotic gradient between the plasma and the receptor expressing cell, leading to water movement out of the cells. -triggers AVP release from the Posterior Pituitary Plasma sodium concentration is the major determinant of AVP. The osmoreceptors are extremely sensitive and as small as a 1% change in osmolality can be sensed and will evoke AVP release and thirst. 9  OVLT (osmoreceptors) Osmoregulation PVN and SON (AVP) ME Na+ Na+ Na+ water + reabsorption V2 vasoconstriction V1 AVP Posterior Pituitary  Osmoregulation The net effect is that the urine osmolality may be As high as 1000 to 1200 mOsm/kg in the presence of AVP (concentrates urine but decreases the [pNa+] ) Or as low as 30 to 50 mOsm/kg without AVP (dilutes urine but increases the [pNa+] ). Defects in the AVP pathway increase the urine output. Nephrogenic diabetes insipidus: Inherited defects in the V2 receptor Defects in Aquaporin-2 gene Side effect of lithium therapy or hypercalcemia. 11 AVP interaction with Renal Prostaglandins. AVP stimulates the production of renal prostaglandins in a variety of cells in the kidney. The prostaglandins impair the anti-diuretic and vascular response of AVP. (i.e. short negative feedback loop). Think about what may happen if a patient is given high doses of non-steroidal anti-inflammatory drugs that suppress prostaglandins. 12 Tubular Collecting Tubule Peritubular Lumen Capillary 3Na+ Na-K- ATPASE 2K+ Gs ATP H2O AQP2 V2 receptor AVP Adenylyl Cyclase cAMP PKA H2O AQP3/4 NSAID block Prostaglandins and facilitate the effects of AVP (concentrates urine, increases plasma volume) prostaglandins Apical Tight Junction Basolateral Membrane Membrane  Test of Knowledge One patient’s urine osmolality has increased from 120 mOsm/kg to 500 mosm/kg, which of the following can cause this change? A. Increased AVP level B. Decreased AngII level C. Increased Prostaglandin level D. Decreased aquaporin channels 14 Volume depletion in the Initiation of AVP Release and Thirst Small acute changes in blood volume have no effect on AVP release. Severe volume depletion will increase secretion of AVP, which indicates the existence of non-osmol, volume sensitive receptors for AVP release. Once severe hypotension occurs, there is a marked rise in AVP resulting in circulating levels that exceed those induced by hyperosmolality. Thirst is also stimulated by volume depletion (i.e. AngII). 15  Severe hypotension/volume depletion causes a marked increase in AVP levels that exceed those induced by hyperosmolality. 16 Source: Rennke HG, Denker BM: Renal Pathophysiology 3rd Ed.  Test of Knowledge Which of the following scenario can cause more AVP release? A. A car accident that caused 15% loss of total blood volume. B. A salty lunch that caused the plasma osmolarity increased from 283 mOsm/kg to 288 mOsm/kg. 17  A Word about Thirst When [PNa+] is elevated: Thirst increases water intake AVP reduces water excretion These responses will decrease [PNa+] back to normal. The sensation for thirst is so powerful that normal individual cannot become hypernatremia if they have access to water. Example: Central diabetes insipidus: Defects in production, storage and release of AVP. Patients maintain normal plasma osmolality by drinking excessive amount of water to compensate for the inability to reabsorb water. Because the thirst mechanism is so effective it is very difficult for patients to comply with doctors’ order to reduce water intake. 18  The Renin-Angiotensin-Aldosterone-System (RAAS) The RAAS: An endocrine system that is activated in response to loss of extracellular fluid and decreases in blood pressure. Plays a major role in the regulation of systemic blood pressure, urinary sodium excretion and renal hemodynamics. Important regulators in RAAS: Renin: A proteolytic enzyme secreted by specialized cells: JGA cells in the afferent arterioles of the glomerulus. AngII: Strong vasoconstrictor 19  angiotensinogen renin Renin release angiotensin I ACE Hypovolemia Aldosterone Angiotensin II Hypotension ANGII Na+ Angiotensin reabsorption Type 1 Receptor AT1 Vasoconstriction  Actions of the RAAS AngII binding to angiotensin-type 1 receptors (AT1) on cell membranes can cause:  Vasoconstriction  Sodium retention/reabsorption These responses will expand the extracellular fluid volume, reverse hypovolemia and hypotension. Two factors contribute to Na+ retention/reabsorption: 1) AngII directly stimulates the reabsorption of Na+ in the early proximal tubule 2) AngII induces release of aldosterone Water reabsorption in the proximal tubule passively follows the sodium, AngII promotes the reabsorption of both water and sodium to increase the extracellular fluid volume. 21  Control of Renin Secretion The main determinant of renin secretion in normal subjects is salt intake. High salt intake expands the ECF and suppresses renin release. This effect is reversed by a low salt intake. Sodium intake and excretion in a normovolemic subject is roughly the same, which ranges from 80 to 250 mEq/day in a typical American diet. Sensors that lead to renin release: #1: The afferent arteriole baroreceptors (prostaglandin) #2: The cardiopulmonary baroreceptors (SNS) #3: The macula densa cells in the distal tubule 22 #1: Renin Release : Afferent Arteriole Bowman’s Capsule β1 β1 β1 JGA JGA JGA Afferent Efferent renin renin renin Arteriole Arteriole JGA JGA JGA β1 β 1 β1 prostaglandins baroreceptors Baroreceptors in the wall of the afferent arteriole are stimulated by a reduction in renal perfusion pressure. This will cause the production of prostaglandins, followed by renin release from JGA cells.  NTS #2: Renin Release: Cardiopulmonary Baroreceptors + + IML Renal sympathetic nerve cardiopulmonary NE baroreceptors Cardiopulmonary baroreceptors are also affected by a fall in perfusion pressure, leading to increased activity of the sympathetic nervous systems. This stimulates β1 receptors in the juxtaglomerular apparatus to release renin. #3: Tubuloglomerular feedback Bowman’s Capsule β1 β1 β1 JGAJGAJGA Afferent Efferent Arteriole Arteriole JGAJGA JGA β1 β1 β1 prostaglandins Thick ascending Na+-K+-2Cl- Na+ Cl- Distal Convoluted loop of henle Co-transporter Co-transporter Tubule K+ Na+ 2Cl- Cl- Na+ Lumen Macula densa responds to changes in luminal delivery of NaCl. NaCl entry into these cells is mediated by Na+-Cl- or Na+-K+-2Cl- co-transporters in the luminal membrane of the DCT or TAL, respectively. The activity of this transporter is controlled by NaCl concentration. Volume depletion decreases the amount of NaCl that is delivered to the macula densa, which increases renin release via prostaglandins.  Test of Knowledge All of the following is the function of AngII except: A. Vasoconstriction B. Sodium reabsorption C. Water reabsorption via V2 receptors D. Aldosterone production 26 Aldosterone (ALDO)  Synthesized in the adrenal zona glomerulosa.  A steroid hormone, can diffuse into the tubular cell and activates the mineralocorticoid receptor (MR) in the cytosol.  Major effects of ALDO occur in the distal nephron, the site at which the final composition of urine is determined.  Primary targets are the principle cells in the collecting ducts. Results in the synthesis of sodium channel for the reabsorption of Na+.  ALDO-induced elevations in luminal sodium permeability promotes passive sodium diffusion into the tubular cell.  Subsequently, sodium is returned back to the systemic circulation by the Na+/K+ ATPase pump. 27 Control of Aldosterone Secretion Volume depletion and elevated plasma potassium concentration are the main stimulators of aldosterone secretion. Volume depletion induces AngII release, AngII stimulates Aldo release to absorb Na+, then water follows sodium to increase the volume. Potassium triggers ALDO secretion by acting directly on the adrenal. AngII and potassium act on the zona glomerulosa to promote the synthesis of aldosterone. 28 Atrial Natriuretic Peptide (ANP) ANP is released from myocardial cells in the atria and, in heart failure, from the ventricles as well. It circulates primarily as a 28-amino acid polypeptide. Most of its actions are mediated by attachment to a specific receptor on the cell membrane of target cells. The interior domain of these receptors has guanylate cyclase activity, leading to the formation of the second messenger cyclic GMP. 29 ANP Actions ANP has two major actions that contribute to volume regulation: 1.) A direct vasodilator that lowers systemic blood pressure 2.) Increases urinary sodium and water excretion. In the medullary collecting duct ANP closes luminal membrane Na+ channels to decrease Na+ reabsorption, increase Na+ excretion and volume loss. ANP also suppresses renin release and aldosterone synthesis. 30 Tubular Collecting Tubule Peritubular Lumen Capillary 3Na+ Na-K- + ATPASE 2K+ Na+ Na+ channel - Aldosterone ALDO cGMP R ANP receptor ANP Gs ATP AQP2 AVP H2O V2 receptor Adenylyl Cyclase cAMP PKA H2O AQP3/4 Cl- Apical Tight Junction Basolateral Membrane Membrane  Control of ANP secretion ANP is released from the atria in response to volume expansion, which is sensed as an increase in atrial stretch. The release of ANP is increased with an elevation in cardiac filling pressure. For example, high salt diet, congestive heart failure, salt retention in renal failure. The rise in ANP secretion removes excess sodium and fluid. Plasma hormone concentration ANP 25 renin 20 15 10 5 6 8 10 12 14 Days on high salt diet 32  Test of Knowledge The normal K+ concentration is 3.5-5 mM, a patient’s recent test showed that the K+ level of 5.8 comparing to 4.1 before, which of the following statement could be true? A. Patient’s AngII level will increase B. Patient’s ANP level will increase C. Patient’s aldosterone level will increase D. Nothing will change 33  Lecture 5 Disorders of Water and Sodium Homeostasis: Hyponatremia, Hypernatremia, and Polyuria Lihui Yuan, PharmD, PhD PHA5561 Pathophysiology and Patient Assessment II [email protected]  Section Overview Lecture 1. Anatomy of Kidney and Nephron with emphasis on Glomerular Filtration Lecture 2. Nephron Segments: Mechanisms of Water and Sodium Reabsorption Lecture 3. Assessment of Renal Function, Osmotic Pressure, and Body Water Distribution Lecture 4. Endocrine Systems Regulating Water and Sodium Homeostasis Lecture 5. Disorders of Water and Sodium Homeostasis: Hyponatremia, Hypernatremia, and Polyuria Lecture 6. Renal Regulation of Potassium Lecture 7. Renal Regulation of Acid-Base Physiology: emphasis on Metabolic Alkalosis and Metabolic Acidosis Lecture 8. Renal Pathophysiology: Acute and Chronic Kidney Failure 2  Learning Objectives  Explain the causes of hyponatremia, hypernatremia, and polyuria  Apply the knowledge of plasma and urine measurements to differentiate the underlying causes of hyponatremia, hypernatremia, and polyuria  Discuss the mechanism of treatments for hyponatremia, hypernatremia, and polyuria 3 Hyponatremia Acute Chronic Chronic 4 Hyponatremia Symptoms and Treatments Acute hyponatremia produces neurologic symptoms (slurred speech, ataxia, seizures, coma). Chronic hyponatremia (developed over more than a few days) produces few if any symptoms. Why? The brain adapts by losing organic solutes (osmolytes, mostly amino acids; glutamine) and this decreases the osmotic gradient between the cells and the plasma which decreases the movement of water into cells, less possibility to develop cerebral edema. Treatment: Timing is important! Acute hyponatremia: Hyponatremia developed rapidly (i.e. over the course of hours). Rapid correction is safe and can be lifesaving. Chronic hyponatremia: Treatment is different when the cerebral edema has been partially corrected by the osmolytes. Rapid correction can reduce the brain volume below normal and produce osmotic demyelination. This disorder can lead to irreversible severe neurological damage. 5  Disorders of Water Balance: Hyponatremia, Hypernatremia, and Polyuria Too much water = hyponatremia (low plasma sodium concentration) Too little water = hypernatremia (high plasma sodium concentration) Too much urine production = Polyuria The ability of water to diffuse freely across virtually all cell membranes means that the maintenance of a relatively constant plasma sodium concentration and plasma osmolality is essential for the maintenance of cell volume, particularly in the brain. Changes in the plasma sodium concentration (hyponatremia and hypernatremia) generally resulted from water imbalance: AVP and thirst. 6  Hyponatremia Hyponatremia (plasma sodium concentration below 135 mEq/L) is one of the most common electrolyte disorders. Hyponatremia can be produced in two ways: 1.) Water retention 2.) Loss of sodium Water retention resulting in hyponatremia generally occurs only when there are abnormalities in renal water excretion. In normal subjects the ingestion of water reduces plasma osmolality and rapidly lowers AVP, thereby allowing the excess water to be excreted in urine. In the absence of AVP, the urine osmolality can fall to a level between 40 and 100 mOsm/kg due to the diluting effects. 7  Hyponatremia Etiology In absence of renal failure, excess of AVP most likely promotes hyponatremia. The main causes for persistent AVP release: 1.) Depletion of the effective circulating volume 2.) The syndrome of inappropriate antidiuretic hormone (SIADH) 8 #1: Depleted effective circulating volume: Congestive heart Failure (CHF) Progressive decrease in cardiac output promotes the development of hyponatremia by: 1.) Enhanced secretion of the three “hypovolemic hormones”: renin, norepinephrine, and AVP. AVP directly promotes water retention. 2.)The hypovolemic stimulus to AVP release also increases thirst. The consequent increase in fluid intake facilitates further water retention. 9  #2: SIADH SIADH is most often seen with neurological disease, malignancy, and after major surgery:  Virtually any neuropsychiatric disorder or severe pain with or without narcotic administration.  Drugs: oral hypoglycemic agent or chlorpropamide  Ectopic production by tumors: often oat cell carcinoma of the lung  Postoperative patient, a response mediated by pain  Pulmonary disease The degree of hyponatremia is related to the severity of the diluting effect and the amount of water that is consumed. The development of hyponatremia is gradual, most patients are asymptomatic. 10 Diagnosis of Hyponatremia  The history and physical examination  Laboratory tests:  Plasma creatinine concentration (rule our renal failure)  Evaluation of adrenal and thyroid function  Plasma osmolality  Urine osmolality  Urine sodium concentration 11 Plasma Osmolality Patients with true hyponatremia will have a proportional reduction in plasma osmolality. Exceptions: There are some disorders in which plasma osmolality is normal or even elevated. The most common example is hyperglycemia in uncontrolled diabetes mellitus. What about treatment? Hyponatremia or hyperglycemia? 12 Hyponatremia: Decreased Plasma Osmolality < 280 mOsm/kg Water H2O H2O H2O H2O H2O H2O Na+ Na+ H2O H2O H2O H2O H2O Na+ H2OH2O H2O H2O H2O Na+ Na+ H2O H2O Na+ H2O H2O H2O Na+ H2O H2O H2O Na+ H2O H2O H2O Na+ H2O H2O Hyponatremia: Increased Plasma Osmolality > 300 mOsm/kg of water Glucose Glucose H2O Glucose H2O H2O H2O H2O H2O Glucose Na+ Na+ H2O H2O H2O H2O H2O Glucose Na+ H2OH2O H2O H2O H2O Na