Renal Physiology PDF

1 RENAL PHYSIOLOGY Dr. Samantha Solecki, DC, MS Instructor, Biology Thinker. Learner. Motivator. Lover of Anatomy & Physiology [email protected] © 2019 Pearson Education, Inc. ...

1 RENAL PHYSIOLOGY Dr. Samantha Solecki, DC, MS Instructor, Biology Thinker. Learner. Motivator. Lover of Anatomy & Physiology [email protected] © 2019 Pearson Education, Inc.  2 Learning Objectives *Acquired from the Human Anatomy and Physiology Society (HAPS) with personal additions Describe the major functions of the urinary system. List the three major processes in urine formation and where each occurs in the nephron and collecting system. With respect to filtration: Describe the structure of the filtration membrane Explain the anatomical features that create high glomerular capillary blood pressure and explain why this blood pressure is significant for urine formation. Describe the hydrostatic and colloid osmotic forces that favor and oppose filtration. Describe glomerular filtration rate (GFR), state the average value of GFR, and explain how clearance rate can be used to measure GFR. Predict specific factors that will increase or decrease GFR. With respect to reabsorption: List specific transport mechanisms occurring in different parts of the nephron, including active transport, osmosis, facilitated diffusion, passive electrochemical gradients, receptor-mediated endocytosis and transcytosis. List the different membrane proteins of the nephron, including aquaporins, channels transporters, and ATPase pumps. Compare and contrast passive and active tubular reabsorption. Describe how and where water, organic compounds, and ions are reabsorbed in the nephron. Explain why the differential permeability or impermeability of specific sections of the nephron tubules is necessary for urine formation. Explain the role of the loop of Henle, the vasa recta, and the countercurrent multiplication mechanism in the concentration of urine. State the percent of filtrate that is normally reabsorbed and explain why the process of reabsorption is so important.  3 Learning Objectives *Acquired from the Human Anatomy and Physiology Society (HAPS) with personal additions With respect to tubular secretion: List the location(s) in the nephron where tubular secretion occurs. Describe the physiological processes involved in eliminating drugs, wastes and excess ions. Compare and contrast reabsorption and tubular secretion, with respect to direction of solute movement, strength of concentration gradients, and energy required. Explain how the three processes in urine formation determine the rate of excretion of any solute. Compare and contrast blood plasma, glomerular filtrate, and urine and the relate their differences to function of the nephron. Determine the physical and chemical properties of a urine sample and relate these properties to normal urine composition. With respect to autoregulation: Describe the myogenic and tubuloglomerular feedback mechanisms and explain how they affect urine volume and composition. Describe the function of the juxtaglomerular apparatus. Describe how each of the following functions in the extrinsic control of GFR: renin-angiotensin- aldosterone, naturietic peptides, and sympathetic adrenergic activity. Predict specific factors involved in creating dilute versus concentrated urine. Explain the mechanism of action of diuretics. Describe the function of the ureters, urinary bladder and urethra. Describe the micturition reflex. Describe voluntary and involuntary neural control of micturition Provide specific examples ot demonstrate how the urinary system responds to maintain homeostasis in the body.  4 Blood Vessels of the Kidney Figure 25.5a Blood vessels of the kidney.  5 Location and Structure of Nephrons Figure 25.6 Location and structure of nephrons.  6 Function of Kidneys Kidneys, a major excretory organ, maintain the body’s internal environment by: Regulating total water volume and total solute concentration in water Regulating ion concentrations in extracellular fluid (ECF) Ensuring long-term acid-base balance Excreting metabolic wastes, toxins, drugs Producing erythropoietin (regulates blood pressure and renin (regulates RBC production) Activating vitamin D Carrying out gluconeogenesis, if needed  7 Kidney Physiology: Mechanisms of Urine Formation only 1.5 L  urine Three processes in urine formation and adjustment of blood composition Glomerular filtration Tubular reabsorption Tubular secretion  8 Kidney Physiology: Mechanisms of Urine Formation 1. Glomerular filtration – produces cell- and protein-free filtrate ; occurs in the renal corpuscle 2. Tubular reabsorption Selectively returns 99% of substances from filtrate to blood ; occurs in renal tubules and collecting ducts 3. Tubular secretion Selectively moves substances from blood to filtrate in renal tubules and collecting ducts  9 Kidney Physiology: Mechanisms of Urine Formation Kidneys filter body's entire plasma volume 60 times each day; consume 20-25% oxygen used by body at rest; produce urine from filtrate Filtrate (produced by glomerular filtration) Blood plasma minus proteins, minus cells Urine 180 mm Hg  22 Regulation of Glomerular Filtration Controlled via glomerular hydrostatic pressure If rises  NFP rises  GFR rises If falls only 18% GFR = 0 Hydrostatic pressure in the glomerulus must be tightly regulated!  23 Intrinsic Controls Maintains nearly constant GFR when MAP in range of 80–180 mm Hg Autoregulation ceases if out of that range Two types of renal autoregulation Myogenic mechanism Tubuloglomerular feedback mechanism  24 Intrinsic Controls: Myogenic Mechanism Smooth muscle contracts when stretched  BP muscle stretch  constriction of afferent arterioles  restricts blood flow into glomerulus Protects glomeruli from damaging high BP  BP dilation of afferent arterioles Both help maintain normal GFR despite normal fluctuations in blood pressure  25 Intrinsic Controls: Tubuloglomerular Feedback Mechanism Flow-dependent mechanism directed by macula densa cells; respond to filtrate NaCl concentration If GFR  filtrate flow rate   reabsorption time  high filtrate NaCl levels  constriction of afferent arteriole   NFP & GFR  more time for NaCl reabsorption Opposite for  GFR  26 Extrinsic Controls Neural and hormonal mechanisms Purpose is to maintain the GFR to maintain systemic BP Sympathetic Nervous System Renin-angiotensin-aldosterone Mechanism  27 Extrinsic Controls: Sympathetic Nervous System Under normal conditions at rest Renal blood vessels dilated Renal autoregulation mechanisms prevail If extracellular fluid volume extremely low (blood pressure low) Norepinephrine released by sympathetic nervous system; epinephrine released by adrenal medulla  Systemic vasoconstriction  increased blood pressure Constriction of afferent arterioles   GFR  increased blood volume and pressure  28 Extrinsic Controls: Renin- Angiotensin- Aldosterone Mechanism Main mechanism for increasing blood pressure – see Chapters 16 and 19 Low BP (+) granular cells of JG apparatus  release renin Three pathways to renin release by granular cells Direct stimulation of granular cells by sympathetic nervous system Stimulation by activated macula densa cells when filtrate NaCl concentration low Reduced stretch of granular cells Regulation of Glomerular 29 Filtration Rate (GFR) in the Kidneys Figure 25.14 Regulation of glomerular filtration rate (GFR) in the kidneys.  30 Table 25.1 Summary of Regulation of GFR Table 25.1 Summary of Regulation of GFR  31 Review... List the steps in urine formation and adjustment of blood fluid. Explain the filtration membrane. What is its significance? Analyze the different pressures that influence filtration. How is NFP figured?  32 2. TUBULAR REABSORPTION  33 Tubular Reabsorption Most of tubular contents reabsorbed to blood Selective transepithelial process which begins as soon as filtrate enters into the proximal tubules All organic nutrients reabsorbed Water and ion reabsorption hormonally regulated and adjusted Includes active and passive tubular reabsorption Two routes Transcellular or paracellular  34 Tubular Reabsorption Figure 25.13 Transcellular and paracellular routes of tubular reabsorption. 35 Slide 1 The transcellular route 3 Transport across the The paracellular route involves: basolateral membrane. (Often involves: involves the lateral intercellular Movement through leaky 1 Transport across the spaces because membrane tight junctions, particularly in apical membrane. transporters transport ions into the PCT. 2 Diffusion through the these spaces.) Movement through the inter- cytosol. 4 Movement through the inter- stitial fluid and into the stitial fluid and into the capillary. capillary. Filtrate Tubule cell Interstitial fluid in tubule Peri- lumen Tight junction Lateral tubular intercellular capillary space 3 4 H2O and 1 2 3 4 solutes Capillary Transcellular route endothelial cell Apical membrane Paracellular route H2O and solutes Basolateral membranes  36 Tubular Reabsorption of Sodium Na+ - most abundant cation in filtrate Transport across basolateral membrane Primary active transport out of tubule cell by Na+-K+ ATPase pump  peritubular capillaries Rapid due to the low hydrostatic pressure and high osmotic pressure Transport across apical membrane Na+ passes through apical membrane by secondary active transport or facilitated diffusion mechanisms  37 Reabsorption of Nutrients, Water, and Ions Na+ reabsorption by primary active transport provides energy and means for reabsorbing most other substances Creates electrical gradient  passive reabsorption of anions Organic nutrients reabsorbed by secondary active transport; cotransported with Na+ Glucose, amino acids, some ions, vitamins Apical carrier moves Na+ down its concentration gradient as it symports another solute  38 Passive Tubular Reabsorption of Water Movement of Na+ and other solutes creates osmotic gradient for water Water reabsorbed by osmosis, aided by water- filled pores called aquaporins Aquaporins always present in PCT  obligatory water reabsorption Aquaporins inserted in collecting ducts only if ADH present  facultative water reabsorption  39 Transport Maximum Transcellular transport systems specific and limited Transport maximum (Tm) for every reabsorbed substance; reflects number of carriers in renal tubules available When carriers saturated, excess excreted in urine E.g., hyperglycemia  high blood glucose levels exceed Tm  glucose in urine  40 Reabsorptive Capabilities of Renal Tubules and Collecting Ducts PCT Site of most reabsorption All glucose and amino acids 65% of Na+ and water Many ions All uric acid; ½ urea (later secreted back into filtrate) Reabsorption in the PCT & Nephron Loop does NOT vary with the body’s needs!!!  41 Reabsorptive Capabilities of Renal Tubules and Collecting Ducts Nephron loop Beginning here, H2O reabsorption is NOT coupled to solute reabsorption!!! Descending limb - H2O can leave; solutes cannot Ascending limb – H2O cannot leave; solutes can Thin segment – passive Na+ movement Thick segment – Na+-K+-2Cl- symporter and Na+-H+ antiporter; some passes by paracellular route Permeability differences beginning here play a critical role in the kidney ability to form concentrated or dilute urine.  42 Reabsorptive Capabilities of Renal Tubules and Collecting Ducts DCT and collecting duct Reabsorption hormonally regulated Antidiuretic hormone (ADH) – Water Aldosterone – Na+ (therefore water) Atrial natriuretic peptide (ANP) – Na+ PTH – Ca2+ Reabsorption in the DCT & Collecting Duct DOES vary with the body’s needs; fine-tuned by hormones.  43 Reabsorptive Capabilities of Renal Tubules and Collecting Ducts Antidiuretic hormone (ADH) Released by posterior pituitary gland Causes principal cells of collecting ducts to insert aquaporins in apical membranes  water reabsorption As ADH levels increase  increased water reabsorption  44 Reabsorptive Capabilities of Renal Tubules and Collecting Ducts Aldosterone Targets collecting ducts (principal cells) and distal DCT Promotes synthesis of apical Na+ and K+ channels, and basolateral Na+-K+ ATPases for Na+ reabsorption; water follows  little Na+ leaves body; aldosterone absence  loss of 2% filtered Na+ daily - incompatible with life Functions – increase blood pressure; decrease K + levels  45 Reabsorptive Capabilities of Renal Tubules and Collecting Ducts Atrial natriuretic peptide Reduces blood Na+  decreased blood volume and blood pressure Released by cardiac atrial cells if blood volume or pressure elevated Parathyroid hormone acts on DCT to increase Ca2+ reabsorption  46 Summary of Tubular Reabsorption and Secretion Figure 25.17 Summary of tubular reabsorption and secretion.  47 Table 25.2-1 Reabsorption Capabilities of Different Segments of the Renal Tubules and Collecting Ducts Table 25.2 Reabsorption Capabilities of Different Segments of the Renal Tubules and Collecting Ducts  48 Table 25.2-2 Reabsorption Capabilities of Different Segments of the Renal Tubules and Collecting Ducts 2 Table 25.2 Reabsorption Capabilities of Different Segments of the Renal Tubules and Collecting Ducts  49 3. TUBULAR SECRETION  50 Tubular Secretion Reabsorption in reverse; almost all in PCT Selected substances K+, H+, NH4+, creatinine, organic acids and bases move from peritubular capillaries through tubule cells into filtrate Substances synthesized in tubule cells also secreted – e.g., HCO3-  51 Tubular Secretion  52 Tubular Secretion Disposes of substances (e.g., drugs) bound to plasma proteins Eliminates undesirable substances passively reabsorbed (e.g., urea and uric acid) Rids body of excess K+ (aldosterone effect) Controls blood pH by altering amounts of H+ or HCO3– in urine Figure 25.15 Summary of tubular reabsorption and secretion. 53 Cortex 65% of filtrate volume Regulated reabsorption reabsorbed Na+ (by aldosterone; H2O Cl− follows) Na+, HCO3−, and Ca2+ (by parathyroid many other ions hormone) Glucose, amino acids, and other nutrients H+ and NH4+ Regulated Some drugs secretion K+ (by aldosterone) Outer Regulated medulla reabsorption H2O (by ADH) Na+ (by aldosterone; Cl− follows) Urea (increased by ADH) Urea Regulated secretion Inner K+ (by medulla aldosterone) Reabsorption or secretion to maintain blood pH described in Chapter 26; involves H+, HCO3−, and NH4+ Reabsorption Secretion  54 Reivew... List the substances reabsorbed in the PCT. Which hormone alters urine concentration for concentrated urine? Analyze the differences between the descending nephron loop and the ascending nephron loop.  55 REGULATION OF URINE CONCENTRATION AND VOLUME  56 Regulation of Urine Concentration and Volume Osmolality Number of solute particles in 1 kg of H2O Reflects ability to cause osmosis Osmolality of body fluids Expressed in milliosmols (mOsm) Kidneys maintain osmolality of plasma at 300 mOsm by regulating urine concentration and volume 1 osmol = 1 mole of particle per kg H2O Body fluids have much smaller amounts, so expressed in milliosmols (mOsm) = 0.001 osmol Kidneys regulate with countercurrent mechanism  57 Countercurrent Mechanism Occurs when fluid flows in opposite directions in two adjacent segments of same tube with hair pin turn Countercurrent multiplier – interaction of filtrate flow in ascending/descending limbs of nephron loops of juxtamedullary nephrons Countercurrent exchanger - Blood flow in ascending/descending limbs of vasa recta Role of countercurrent mechanisms Establish and maintain osmotic gradient (300 mOsm to 1200 mOsm) from renal cortex through medulla Allow kidneys to vary urine concentration  58 Osmotic Gradient in the Renal Medulla Figure 25.18 Osmotic gradient in the renal medulla. Figure 25.16a Juxtamedullary nephrons create an osmotic gradient within the renal medulla that allows 59 the kidney to produce urine of varying concentration. (1 of 4) The three key players and their orientation in the osmotic gradient: (c) The collecting ducts of all nephrons use the gradient to adjust urine osmolality. 300 300 400 (a) The long nephron loops of juxtamedullary nephrons create the gradient. They act as 600 countercurrent multipliers. The osmolality of the medullary 900 interstitial fluid progressively increases from the 300 mOsm of (b) The vasa recta preserve the normal body fluid to 1200 mOsm gradient. They act as at the deepest part of the medulla. countercurrent exchangers. 1200  60 The Countercurrent Multiplier Depends on actively transporting solutes out of the ascending limb Represents one of the ways the kidneys keep the solute load of body fluids constant Regulating urine concentration & volume Constant 200 mOsm difference between two limbs of nephron loop and between ascending limb and interstitial fluid Difference "multiplied" along length of loop to ~ 900 mOsm  61 The Countercurrent Multiplier Depends on 3 Properties of the nephron loop 1. Fluid flows in the opposite direction (countercurrent) through two adjacent parallel sections of a nephron loop 2. Descending limb is permeable to water, NOT NaCl 3. Ascending limb is impermeable to water & pumps out NaCl Properties establish a positive feedback loop to use the flow of fluid to multiply the power of the salt pumps Figure 25.16a Juxtamedullary nephrons create an osmotic gradient within the renal medulla that allows 62 the kidney to produce urine of varying concentration. (3 of 4) Long nephron loops of juxtamedullary nephrons create the gradient. These properties establish a positive feedback cycle that uses the flow of fluid to multiply the power of the salt pumps. Interstitial fluid osmolality Start here Water leaves the descending limb Salt is pumped out of the ascending limb Osmolality of filtrate Osmolality of filtrate in descending limb entering the ascending limb  63 The Countercurrent Exchanger Vasa recta Preserve medullary gradient Prevent rapid removal of salt from interstitial space Remove reabsorbed water Water entering ascending vasa recta either from descending vasa recta or reabsorbed from nephron loop and collecting duct  Volume of blood at end of vasa recta greater than at beginning Blood inside vasa recta remains isosmotic with surrounding interstitial fluid Vasa recta is able to reabsorb water and solutes without undoing osmotic gradient created by countercurrent multiplier Figure 25.16a Juxtamedullary nephrons create an osmotic gradient within the renal medulla that allows 64 the kidney to produce urine of varying concentration. (4 of 4) (continued) As water and solutes are reabsorbed, the loop first concentrates the filtrate, then dilutes it. Active transport Passive transport Water impermeable 300 300 100 Cortex 100 300 300 1 Filtrate entering the 5 Filtrate is at its most dilute as it nephron loop is isosmotic to leaves the nephron loop. At both blood plasma and 100 mOsm, it is hypo-osmotic Osmolality of interstitial fluid (mOsm) cortical interstitial fluid. to the interstitial fluid. 400 400 200 4 Na+ and Cl- are pumped out Outer of the filtrate. This increases the medulla interstitial fluid osmolality. 600 600 400 2 Water moves out of the filtrate in the descending limb down its osmotic gradient. This concentrates the filtrate. 900 900 700 3 Filtrate reaches its highest concentration at the bend of the Inner loop. medulla Nephron loop 1200 1200 Figure 25.16b Juxtamedullary nephrons create an osmotic gradient within the renal medulla that allows 65 the kidney to produce urine of varying concentration. Vasa recta preserve the gradient. The entire length of the vasa recta is highly permeable to water and solutes. Due to countercurrent exchanges between each section of the vasa recta and its surrounding interstitial fluid, the blood within the vasa recta remains nearly isosmotic to the surrounding fluid. As a result, the vasa recta do not undo the osmotic gradient as they remove reabsorbed water and solutes. Blood from efferent To vein arteriole 300 325 300 400 The countercurrent flow of fluid moves 400 through two adjacent parallel sections of the vasa recta. 600 600 900 900 1200 Vasa recta  66 Formation of Dilute or Concentrated Urine Osmotic gradient used to raise urine concentration > 300 mOsm to conserve water Overhydration  large volume dilute urine ADH production ; urine ~ 100 mOsm If aldosterone present, additional ions removed  ~ 50 mOsm Dehydration  small volume concentrated urine Maximal ADH released; urine ~ 1200 mOsm Severe dehydration – 99% water reabsorbed Figure 25.17 Mechanism for forming dilute or concentrated urine. 67 If we were so overhydrated we had no ADH... If we were so dehydrated we had maximal ADH... Osmolality of extracellular fluids Osmolality of extracellular fluids ADH release from posterior pituitary ADH release from posterior pituitary Number of aquaporins (H2O channels) in collecting duct Number of aquaporins (H2O channels) in collecting duct H2O reabsorption from collecting duct H2O reabsorption from collecting duct Large volume of dilute urine Small volume of concentrated urine Collecting Collecting duct duct Descending limb 300 Descending limb 300 of nephron loop of nephron loop 100 100 150 DCT 100 DCT 300 Osmolality of interstitial fluid (mOsm) Osmolality of interstitial fluid (mOsm) Cortex Cortex 300 100 300 300 100 300 300 400 600 400 600 600 400 600 600 100 Outer Outer medulla medulla Urea 900 700 900 900 700 900 900 Urea Urea Inner Inner medulla medulla 1200 100 1200 1200 1200 1200 Large volume Small volume of of dilute urine Urea contributes to concentrated urine Active transport the osmotic gradient. Passive transport ADH increases its recycling.  68 Urea Recycling and the Medullary Osmotic Gradient Urea helps form medullary gradient 1. Urea enters filtrate in ascending thin limb of nephron loop by facilitated diffusion 2. Cortical collecting duct reabsorbs water, leaving urea behind 3. In deep medullary region, now highly concentrated urea leaves collecting duct and enters interstitial fluid of medulla Urea then moves back into ascending thin limb Contributes to high osmolality in medulla  69 CLINICAL EVALUATION OF KIDNEY FUNCTION  70 Clinical Evaluation of Kidney Function Urine examined for signs of disease Assessing renal function requires both blood and urine examination  71 Physical Characteristics of Urine Color and transparency Clear Cloudy may indicate urinary tract infection Pale to deep yellow from urochrome Pigment from hemoglobin breakdown; more concentrated urine  deeper color Abnormal color (pink, brown, smoky) Food ingestion, bile pigments, blood, drugs Odor Slightly aromatic when fresh Develops ammonia odor upon standing As bacteria metabolize solutes May be altered by some drugs and vegetables  72 Physical Characteristics of Urine pH Slightly acidic (~pH 6, with range of 4.5 to 8.0) Acidic diet (protein, whole wheat)   pH Alkaline diet (vegetarian), prolonged vomiting, or urinary tract infections  pH Specific gravity 1.001 to 1.035; dependent on solute concentration Other normal solutes Na+, K+, PO43–, and SO42–, Ca2+, Mg2+ and HCO3– Abnormally high concentrations of any constituent, or abnormal components, e.g., blood proteins, WBCs, bile pigments, may indicate pathology  73 Chemical Composition of Urine 95% water and 5% solutes Nitrogenous wastes Urea (from amino acid breakdown) – largest solute component Uric acid (from nucleic acid metabolism) Creatinine (metabolite of creatine phosphate)  74 Table 25.3 Abnormal Urinary Constituents Table 25.3 Abnormal Urinary Constituents  75 Renal Clearance Volume of plasma kidneys clear of particular substance in given time Renal clearance tests used to determine GFR To detect glomerular damage To follow progress of renal disease  76 Renal Clearance C = UV/P C = renal clearance rate (ml/min) U = concentration (mg/ml) of substance in urine V = flow rate of urine formation (ml/min) P = concentration of same substance in plasma  77 Renal Clearance Inulin (plant polysaccharide) is standard used Freely filtered; neither reabsorbed nor secreted by kidneys; its renal clearance = GFR = 125 ml/min If C < 125 ml/min, substance reabsorbed If C = 0, substance completely reabsorbed, or not filtered If C = 125 ml/min, no net reabsorption or secretion If C > 125 ml/min, substance secreted (most drug metabolites)