Week+9_Renal+Physiology_P1.pdf

Renal Physiology Copyright Notice • All materials found on Geisinger Commonwealth School of Medicine’s course and project sites may be subjecttocopyright protection,and mayberestricted from further dissemination, retention orcopying. • Disclosure • I have no financial relationship with a commerci...

Renal Physiology Copyright Notice • All materials found on Geisinger Commonwealth School of Medicine’s course and project sites may be subjecttocopyright protection,and mayberestricted from further dissemination, retention orcopying. • Disclosure • I have no financial relationship with a commercial entity producing health-care related products and/orservices. • Class material and recording will be posted every Monday by 9.00 AM. House Keeping • Office hours are Tuesdays 8-9 PM. I will be meeting you individually by appointment to answer any questions you may have • I will be holding live case study sessions on Tuesdays and Thursdays 78 PM. Attendance is not mandatory, but highly recommended. These sessions will be recorded. Learning Objectives 1. Describe functions of the kidneys and urinary system 2. Describe in sequence the tubular structure through which ultrafiltrate flows after it is formed at Bowman’s capsule to when it enters the renal pelvis. 3. Describe in sequence the blood vessels through which blood flows when passing from the renal artery to the renal vein. 4. Explain the concept of clearance and how it is used to estimate glomerular filtration rate. 5. Given the plasma and urine concentrations and the urine flow rate, calculate the filtered load, tubular transport, excretion rate, and clearance of inulin, creatinine, para-amino hippuric acid (PAH) and glucose. Readings for this session: 1. Text Book; Chapter 6 (Pages; 245 - 269) 2. Class notes Functions of the kidneys and urinary system 1. Excretory Organ: Kidneys (through filtration) remove substances in excess, harmful material and metabolism waste products 2. Regulatory Organ: The kidneys maintain a constant volume and composition of the body fluids by regulating the excretion of solutes and water, to maintain blood pH, regulate blood pressure and blood osmolarity. Clinical relevance: Patients with Chronic Kidney Disease (CKD) suffer from electrolyte imbalance, accumulation of waste products → toxicity 3. Endocrine Function of the kidneys i. Active Vitamin D3 (1,25-(OH)2 or Calcitriol) 25-hydroxyvitamin D3 ii. Renal prostaglandins Phospholipids 1α-hydroxylase Cyclooxygenase 1,25-dihydroxyvitamin D3 Clinical relevance: Osteoporosis is a common complication of CKD Prostaglandin PGE2 Prostacyclin PGI2 → Local vasodilators Clinical relevance: NSAIDs inhibit cyclooxygenase and hence can be dangerous for patients with CKD iii. Erythropoietin: EPO is a hormone produced by interstitial cells in the renal cortex in response to hypoxia. It stimulates production, maturation, and release of RBCs from bone marrow. Clinical relevance: Anemia is a common complication of Chronic Kidney Disease (CKD) iv. Renin (RAAS) Granular cells and some mesangial cells sense decreased blood pressure and release renin. Clinical relevance: RAAS inhibitors are important anti-hypertensive drug class = granular cells It is also released by increased renal sympathetic activity (via ß1 receptors ) Clinical relevance: ß1 blockers not only act in the heart, but also in the kidneys Structure of the kidney Structure of the kidney Renal Hilum The nephron as functional unit of the kidneys Outer Medulla Inner Medulla About 1 million nephrons per kidney: Medullary nephrons (1/8), Cortical nephrons (7/8) Types of Nephrons Superficial Cortical Nephrons: • Glomeruli located in outer cortex • Smaller glomeruli • Short loops of Henle Juxtamedullary Nephrons: • Glomeruli located near corticomedullary border • Larger glomeruli → higher glomerular filtration rates (GFR) • Long loops of Henle → essential for concentration of urine • A dedicated blood vessel “vasa recta” Renal Corpuscle Histology → Function: • Bowman’s capsule: Continuous with remainder of the renal tubule. Includes a ball of capillary loops (the glomerulus) → Filtration of plasma into tubular lumen Bowman’s capsule Glomerulus • Mesangium: Contains contractile cells between loops → Regulation of filtration by controlling total filtration area The kidneys filter the plasma more than 50x in a day, or the entire ECF volume about 13x in a day. Renal tubule Renal Tubule Proximal Tubule: • Proximal convoluted tubule winds randomly • Proximal straight (=recta) tubule enters the medulla Main Function: Early Proximal Convoluted Tubule: - Reabsorption of most solutes - Secretion of organics Late Proximal Convoluted Tubule: Reabsorption of NaCl Renal Tubule Loop of Henle: Normal osmolality • Thin descending limb • Thin ascending limb • Thick ascending limb Main Function: Descending limb: Water absorption Ascending limb: Reabsorption of NaCl without water → creation of interstitial osmotic gradient High osmolality Renal Tubule Distal Nephron: • Distal convoluted tubule • Connecting tubule • Collecting duct Main Function: Early distale tubule: Reabsorption of NaCl without water Late distale tubule: Reabsorption of NaCl with water, regulated by aldosterone and ADH → from tubular fluid to urine Renal Tubule Each segment of the nephron is functionally distinct, and the epithelial cells lining each segment have different ultrastructure that correlates to its function. Renal Arteries • The renal artery is a branch of the abdominal aorta • The renal artery branches into about 8 divisions called segmental arteries • Segmental arteries enter renal sinus and become interlobar arteries • Interlobar arteries curve over the renal pyramids to form arcuate arteries • Arcuate arteries give rise to several afferent arterioles → glomerular capillaries Renal Arterioles, Glomerular Capillaries and Peritubular Capillaries Afferent arteriole Glomerular capillaries: ~ 20% of the plasma in the afferent arterioles is filtered by the glomerulus Efferent arteriole: ~80% of liquid that had been in afferent arterioles, but 100% of blood cells and unfiltered large substances Peritubular Capillaries and Vasa Recta Function in cortical nephrons: delivery of nutrients to epithelial cells and serve as blood supply for reabsorption and secretion Function in medullary nephrons: “vasa recta” They follow the loop of Henle and serve as osmotic exchanger for the production of urine Review Body Fluid Composition • Water accounts for an average 60% of body weight, which varies depending on gender and the amount of adipose tissue in the body. • Total body water is distributed between two major body fluid compartments: intracellular fluid (ICF) and extracellular fluid (ECF), which are separated by the “cell membrane”. • The ICF (2/3 of body water): contained within the cells • The ECF (1/3 of body water): outside the cells and is further divided into two compartments: plasma and interstitial fluid. • Interstitial fluid is an ultrafiltrate of plasma; it has nearly the same composition as plasma, excluding plasma proteins and blood cells. • The compositions of ICF and ECF are different. • Despite the difference in the concentration of the different solutes, the osmolarity and electric charges are equal on both sides of the cell membrane (between ICF and ECF) • The difference in solute concentrations across cell membranes are created and maintained by energy consuming transport mechanisms Body Fluid Compartments • Osmolarity is the concentration of osmotically active particles, mainly can be estimated from the plasma Na+ concentration, plasma glucose concentration, and blood urea nitrogen (BUN). • In the steady state, intracellular osmolarity is equal to extracellular osmolarity. • The volume of a body fluid compartment depends on the amount of solute it contains. • Conditions that cause a disturbance/ change in the ECF osmolarity, will cause water shift across cell membranes to return to the steady state of equal osmolarity. Renal Plasma Clearance (C) Plasma volume in renal artery X X X XX X Plasma volume in renal vein Definition of Cx: Volume of plasma that is completely cleared of a substance X by the kidneys per unit time, or in other words, the ratio of urinary excretion to plasma concentration • UxV Cx = Px Cx = clearance of substance x Ux = urine concentration of substance x • V = urine flow rate Px = plasma concentration of substance x Inulin Clearance equals GFR Inulin infusion Freely filtered Neither reabsorbed nor secreted Reabsorption Secretion Amount = Concentration x Flow Creatinine Clearance estimates GFR Creatine is primarily synthesized in the liver and transported primarily to skeletal muscle, where it is stored as high energy compound phosphocreatine Creatine is also eaten, primarily in the form of meat About 1-2% of the total muscle creatine pool is converted daily to creatinine. Creatinine is freely filtered across the glomerular capillaries. However 10-20% is secreted by the proximal tubule → overestimating GFR Plasma creatinine levels approximate GFR As an approximation, plasma creatinine levels can be used to assess severity of renal damage and to monitor progression of renal disease. Demographics Aging Female African American Hispanic Asian Muscular body Malnutrition, amputation Obesity Vegetarian Cooked meat Serum creatinine Decreased Decreased Increased Decreased Decreased Increased Decreased No change Decreased Increased Explanation Decline in muscle mass Reduced muscle mass Higher muscle mass Decreased muscle mass Less creatinine generation Transient increase in creatinine generation To accurately estimate GFR from serum creatinine in an individual, various equations are used that incorporate demographic and anthropometric variables Estimation of Tubular Transport Filtered load: Px x GRF Excreted load: Ux Filtered load – Excretion: If positive: substance was reabsorbed If negative: substance was secreted xV Renal Blood Flow (RBF) Kidneys have a high blood flow • Higher than the metabolic needs • ~20‐25% of COP at rest, or ~1,200 ml/min Renal arteries are at high pressure • The arrangement of the renal arteries being close to the abdominal aorta results in high pressure blood input into the kidneys. This favors filtration in the glomerular capillaries Glomerular and peritubular capillary resistances are low • The arrangement of a million of capillary beds in parallel makes the total capillary resistance low → Both, blood flow and glomerular filtration are favored RBF and GFR are Regulated by Afferent and/or Efferent Arteriolar Resistances RBF PGc↓ P GFR Gc↑ GFR Constrict afferent   Dilate afferent   Constrict efferent   Dilate efferent   PGC, Glomerular hydrostatic pressure Renal Blood Flow Autoregulation • Autoregulation between 80 and 180 mmHg MAP, which results in constant GFR There are two general mechanisms a. Myogenic b. Tubuloglomerular feedback (see next slide) → Physiologic changes in blood pressure do not significantly alter GFR NOTE: Autonomic Nervous System (ANS) has no role in autoregulation! RBF Autoregulation: Tubuloglomerular Feedback • An increase in BP → Increased RBF & GFR, so that more Na is filtered → Higher pressure in peritubular capillaries, so that less Na is reabsorbed → More Na is delivered to the distal tubules • At the JGA, macula densa sense high Na levels • A complex mechanism occurs that involves vasoactive substances, causes afferent arteriolar vasoconstriction • This reduces RBF and GFR back to normal • The reverse of this situation leads to similar sequence of events The structural arrangement between the proximal and distal parts of the nephron is called juxtaglomerular apparatus (JGA). Contains “macula densa” Renal Plasma Flow (RPF) Measurement Clearance of Para-aminohippurate is an indicator of effective Renal Plasma Flow (Within 10% of true RPF) PAH synthesis in liver PAH excretion is the sum of filtered + secreted load, which is close to 100% clearance from plasma (with 10% error) 10-20% PAH is filtered 80-90% protein-bound PAH bypasses glomerulus and is almost fully secreted by renal tubules → Amount entering the kidney “~ equals” the amount showing up in urine → Essential drug test (e.g. ACE-inhibitors are associated with an increase in RPF) From RPF to RBF If RPF = 660 ml plasma/min and hematocrit = 0.45, then: 660 ml plasma/min RBF = 0.55 ml plasma/ml blood = 1,200 ml blood/min Filtration Fraction • Filtration Fraction is the fraction of the RPF that is filtered across the glomerular capillaries. • The filtration fraction is normally about 20% of RPF. • The remaining 80% of RPF that is not filtered leaves the glomerular capillaries via the efferent arterioles and becomes the peritubular capillary blood flow. The relationship between the GFR and RPF, the filtration fraction, is given by the following equation: 𝑮𝑭𝑹 Filtration Fraction = 𝑹𝑷𝑭