Lecture 3 - The Renal System 2 PDF

Lecture 03: The Renal System 2 Human Systems Physiology 2 – NATS3054 Dr Kayte Jenkin (Subject coordinator) [email protected] PAGE 1 Lecture Overview  Urine Analysis  Renal Clearance  Regulation of Kidney Function: GFR  Autoregulation: Myogenic mechanism an...

Lecture 03: The Renal System 2 Human Systems Physiology 2 – NATS3054 Dr Kayte Jenkin (Subject coordinator) [email protected] PAGE 1 Lecture Overview  Urine Analysis  Renal Clearance  Regulation of Kidney Function: GFR  Autoregulation: Myogenic mechanism and tubuloglomerular feedback  Central regulation: Endocrine and neural controls  Importance of GFR  Regulation of Reabsorption and Secretion  Endocrine controls  Diuretics  The Counter-current Mechanism  Urine volume and concentration  Role of the nephron loop, vasa recta and collecting ducts PAGE 2  Urine Analysis Image: From the History of Medicine – NLM. Image illustrates patients gathering around a physician PAGEholding 3 up their urine samples in glass urine jars. From a book first published in 1491 Appearance urine  Urine volume is often used as key indicator of kidney function  Urine appearance can range from almost colourless to deep amber; yellow colour due to pigment from breakdown of red blood cells  Darker urine is more concentrated; has less water  Lighter urine is less concentrated; has more water  Sometimes urine can come in unexpected colours including pink, red, green or blue. Certain food dyes, foods and medications can alter urine colour, but a change in colour can also indicate renal disease  Urine is typically translucent (light is able to pass through); cloudy or foamy urine may be sign of infection, or that too much protein is present PAGE 4 Figure: https://www.nursingtimes.net Composition and properties of urine  Composition and properties of urine includes:  Chemical composition: 95% water, 5% solutes (urea, NaCl, KCl, creatinine, uric acid etc.)  Volume: Highly variable depending on hydration status, kidney function and time since last urination (1.5L per day of urine overall).  Specific gravity: compares amount of solute in a solution to deionised water. No solutes is given a value of 1.0 and the SG of of urine ranges from 1.001 (very dilute) ‐1.035 (very concentrated)  pH range: 4.5 ‐ 8.2, usually slightly acidic ~6.0 PAGE 5 Figure: https://www.istockphoto.com/photos/urine‐dipstick Urinalysis  Analyzing urine (urinalysis) can be used a diagnostic tool for detecting diseases or specific imbalances (drug testing, pregnancy testing).  Urinalysis can be performed in many different ways:  Visual observation  Chemical analysis (dipstick)  Microscopic analysis PAGE 6 Clinical Urinalysis  Urine testing in a clinical setting can be used for a range of purposes (kidney function, monitoring a medical condition, or testing for pregnancy/ovulation/drugs)  Often, when something is in the urine that shouldn’t be there, it can be an indicate a problem with the kidneys or the presence of a medical condition  Protein: Low levels may be present, but regular presence or high levels may indicate a problem with kidneys  Glucose: Typically not present, but can be indicate diabetes mellitus  RBCs: May be present during menstruation, or can be an indicator of kidney damage  WBCs: Leukocytes present in the urine can indicate an infection is present or being cleared by the body  Crystals: Can indicate the presence of kidney stones PAGE 7 Microscopic Urinalysis  Examples of things which may be seen during microscopic analysis of urine Red and white blood cells Crystal of cholesterol, calcium oxalate dehydrate and uric acid Epithelial cells Casts of red blood cells PAGE 8 Renal Clearance PAGE 9 Renal Clearance  Renal clearance (mL/min) is the measurement of rate at which kidneys remove substance from blood and is excreted in the urine  Excretion of a substance in the urine takes into account the three processes which are needed to create urine Excretion = Filtration – Reabsorption + Secretion  The kidneys handle the filtration, reabsorption and secretion of different solutes in different ways Glucose is freely filtered, but normally 100% reabsorbed, and it is not secreted, resulting in no excretion of glucose Penicillin is freely filtered, is secreted (but not reabsorbed) in the tubules, resulting in a higher renal clearance than what gets filtered PAGE 10 Silverthorn, Figure 19.3: Solute movement through the nephron  Renal Clearance  The renal clearance of some substances can be used to estimate glomerular filtration rate (GFR), a key measure of renal function  Both renal clearance and GFR are measured in mL/min  For substance to be used as an accurate measure of renal clearance and GFR, it needs to adhere to the following:  Be completely filtered in the glomerulus  Neither reabsorbed nor secreted in the tubules  Be metabolized by the kidneys alone (and not liver or digestive tract) PAGE 11 Figure: https://cih.com.vn/en/internal‐medicine‐general‐surgery/1955‐gfr‐a‐key‐to‐understanding‐how‐well‐your‐kidneys‐are‐working.html Renal Clearance and GFR  There are a variety of substances which can be used to estimate renal clearance, including:  Creatinine  Inulin  Urea  Often, measurements of GFR and renal function take into account both urine and blood concentrations of a substance PAGE 12 Silverthorn, Figure19.14: Renal Clearance Creatinine Clearance  Creatinine is normal metabolite of the body and is produced mainly by the muscle, at a relatively constant rate. Creatinine can also come from dietary sources  Creatinine is metabolized entirely by the kidney and is freely filtered. Only minor reabsorption and secretion occurs in the tubules  Plasma creatinine is inversely proportional to creatinine clearance  Blood levels of creatinine are elevated when kidneys are impaired PAGE 13 Figure Source: https://www.researchgate.net/publication/11819543_Acute_renal_failure/figures?lo=1 Creatinine Clearance and GFR  Advantages  Estimates of GFR can be taken from a single blood sample  24 hour urine collection together with blood sample can provide a more accurate estimate of GFR  Cost effective and non-invasive  Disadvantages:  Some minor secretion and reabsorption of creatinine occurs in the tubules, often GFR is overestimated  Age, sex and body size can influence muscle mass and needs to be taken into account when calculating creatinine clearance  Diet, particularly diets high in red meat can increase circulating creatinine levels and artificially inflate GFR estimates  Pregnancy has a higher risk of inaccurate GFR estimation based on creatinine clearance PAGE 14 Other measures of GFR  Urea or Blood Urea Nitrogen (BUN) is formed by the liver and is mostly (85%) excreted by the kidneys.  Similar to creatinine clearance, blood serum levels of BUN increase, while urinary excretion decreases when kidney function is impaired  A more accurate assessment of GFR can be obtained using inulin; complex carbohydrate found in plants such as garlic and artichokes  Inulin is neither secreted or reabsorbed by the tubules, but it is not an endogenous metabolite and must be injected into the blood (invasive) PAGE 15 Figure: Renal Clearance Silverthorn Renal Threshold  Sometimes substances can be found in the urine, which are not usually present (eg. blood or glucose)  This may be due to structural damage to the kidneys, or if tubular transporters cannot maintain reabsorption of the solute  If a substance is present in very high concentrations in the blood and filtrate, transport proteins can reach a saturation point  Renal threshold: Is the plasma concentration at which a substance first appears in the urine Silverthorn, Figure 19.9: Saturation of mediated transport PAGE 16  Regulation Kidney Function: GFR Amerman. Human Anatomy & Physiology – Chapter 24 PAGE 17 Colorized scanning electron micrograph shows glomeruli, the filtering units of the kidneys. Regulatory Mechanisms of Kidney Functions  Neural, endocrine and auto‐regulatory mechanisms all contribute to renal function  Auto‐regulation: Nephron structures have inherent characteristics that can adjust GFR independently from neural and hormonal control  Myogenic mechanism  Tubuloglomerular feedback system  Blood pressure provides the hydrostatic pressure that drive glomerular filtration.  Although we experience fluctuations in blood pressure throughout the day, Glomerular Filtration Rate (GFR) remains constant over a range of blood pressure. PAGE 18 Regulation of Glomerular filtration rate  GFR is controlled by the integration of many regulatory processes: 1. Central regulation Endocrine (hormonal) mechanisms: renin – angiotensin – aldosterone system (RAAS)  Autonomic mechanism via sympathetic division 2. Autoregulation at the local level:  Internal kidney mechanisms largely responsible for maintaining consistent GFR PAGE 19 Silverthorn, Figure 19.6b: Glomerular Filtration Rate Autoregulation of GFR – Myogenic Mechanism  Myogenic mechanism ‐ This is a mechanisms which is the result of the inherent tendency for afferent arterioles to contract or dilate in response to changes in blood pressure. High BP stretches afferent arteriole stimulates contraction reduces blood flow decreases GFR Low BP afferent arteriole relaxes stimulates dilation increases blood flow increases GFR PAGE 20 How Does The Myogenic Mechanism Work?  When blood pressure increases in the afferent arteriole:  stretch receptors activated  Vascular smooth muscle cells depolarize  Calcium gated voltage channels open leading to the contraction of vascular smooth muscle  When blood pressure decreases in the afferent arteriole:  The arteriole maximally dilates (as there is no signal for contraction)  Vasodilation is not as potent at regulating GFR as vasoconstriction  Under normal conditions, the afferent arteriole’s normal state is relaxed PAGE 21 Figure 12.29: Control of smooth muscle contraction, Silverthorn textbook Autoregulation of GFR – Tubuloglomerular Feedback  Tubuloglomerular feedback ‐ mechanism by which glomerulus receives feedback on the status of the downstream tubular fluid  Juxtaglomerular apparatus: a structure where afferent arteriole makes contact with ascending limb of loop of Henle (or distal convoluted tubule)  Tubule comes into contact with the glomerular afferent and efferent arterioles PAGE 22 The Juxtaglomerular Apparatus  Specialised cells in the afferent arteriole and distal tubule  Juxtaglomerular Cells:  Found in afferent arteriole. Modified endothelial cells that act as mechanoreceptors  Secrete Renin when there is a drop in GFR  Macula Densa Cells:  Found in the distal tubule. Modified epithelial cells that act as chemoreceptors.  Release prostaglandins which act on arteriole diameter (dilate or constrict) directly altering GFR via changing the glomerular hydrostatic pressure PAGE 23 Figure 24.8: The juxtaglomerular apparatus. Tubuloglomerular Feedback High GFR ↓ High rate of flow of filtrate through the nephron ↓ When flow of filtrate is too fast, decreased reabsorption of ions in tubules ↓ Increase osmolality (NaCl) in filtrate passing through Distal Tubule ↓ Detected by Macula Densa cells of Distal tubule. Release vasoconstrictor. ↓ Afferent arteriole constricts, decreasing blood flow through glomerulus ↓ GFR returns to normal. ↓ Filtration flow rate decreases PAGE 24 Tubuloglomerular Feedback Low GFR. JG cells in arteriole release renin ↓ Low rate of flow of filtrate through the nephron ↓ When flow of filtrate is too slow, increased reabsorption of ions in tubules ↓ Decrease osmolality (NaCl) in filtrate passing through Distal Tubule ↓ Detected by Macula Densa cells of Distal tubule. Release vasodilator. ↓ Afferent arteriole dilates, increasing blood flow through glomerulus ↓ RAAS activation constricts efferent arteriole, increases water and Na+ reabsorption, increases blood volume ↓ GFR returns to normal. ↓ PAGE 25 Filtration flow rate increases Central Regulation of GFR - Endocrine  The Renin‐ Angiotensin‐ Aldosterone System (RAAS) is a system which primarily regulates blood pressure but also is important in GFR regulation.  When stimulated, RAAS initiates a hormone cascade, which helps the body retain water and increase blood pressure  It achieves BP regulation by controlling water balance, electrolyte balance, and vasoconstriction PAGE 26 Figure 18.4: Factors that determine blood pressure. The Renin Angiotensin Aldosterone System (RAAS)  The RAAS pathway is coordinated by many organ systems! PAGE 27 Renin-Angiotensin-Aldosterone System (RAAS)  RAAS is activated when: Blood pressure decreases Glomerular filtration rate (GFR) of the kidney decreases Increased activation of the sympathetic nervous system Factor Site of Origin Effect Renin Kidney Converts Angiotensinogen to Angiotensin I Angiotensinogen Liver Blood protein, travels in the blood in an inactive form. Renin + Angiotensinogen = Angiotensin I Angiotensin I Blood (Product of Travels in the blood in an inactive form until it Angiotensinogen) reaches the lungs Angiotensin I + ACE = Angiotensin II Angiotensin II Lungs (Product of Acts on multiple organs to increase blood Angiotensin I) pressure and retain water Aldosterone Adrenal Glands Acts on kidneys to increase sodium reabsorption and potassium secretion helps retain water PAGE 28 RAAS Pathway In the nephron, vasoconstriction of the efferent arteriole occurs, local factors help maintain dilation of the afferent arteriole! Figure 24.14 The renin‐angiotensin‐aldosterone system. RAAS Effects PAGE 31 Figure 24.14: The renin‐angiotensin‐aldosterone system. Neural Regulation of GFR  The effect of the sympathetic nervous system depends on how much sympathetic activation is occurring.  Mild/moderate activation: RAAS is initiated and increasing amounts of Angiotensin II will be present in the blood (No effect or  GFR)  High activation: causes vasoconstriction of most blood vessels including the afferent arterioles ( GFR, helps conserve body fluids) Sympathetic nervous system (fight or flight) innervates the kidneys. There is little/no input from parasympathetic nerve fibres (rest and digest) PAGE 32 Importance of Maintaining GFR  Fluctuations in blood pressure and hydration status can cause slight changes to the net filtration rate of the glomerulus, affecting GFR  Local and central regulatory mechanisms ensure that GFR remains stable, even with changing conditions  GFR must be precisely controlled to avoid either dehydration or waste reabsorption.  Too high: pressure placed on capillaries may cause damage, and urine output increases, electrolyte and acid base balance may be impacted  Too low: waste products don’t get excreted in the urine, can result in acidosis PAGE 33 Figure 24.13: Net filtration pressure in the glomerular capillaries.  Regulation of Reabsorption & Secretion PAGE 34 Regulation of Reabsorption and Secretion  Reabsorption and secretion are the final two steps in urine formation  These processes occur throughout the tubular system of the nephron – the proximal & distal tubules, nephron loop and collecting ducts  Reabsorption and secretion is mainly regulated by hormones  Blood pH influences acid and base tubular reabsorption and secretion  The rate of flow of the filtrate through the nephron tubules (set by GFR) can also affect reabsorption and secretion processes Silverthorn, Figure 19.3: Solute movement through the nephron PAGE 35 Recall… Tubular Reabsorption & Secretion Reabsorption of water and solutes in the ascending and descending limbs of the nephron loop will be important later! PAGE 36 Figure 24.19: The Big Picture of Tubular Reabsorption and Secretion. Anti-diuretic Hormone (ADH)  ADH is the most influential factor regulating water balance   ADH results in the insertion of aquaporins (water channels) into the membrane of the distal convoluted tubule and collecting duct of the nephron  More water gets reabsorbed from filtrate into peritubular and vasa recta capillaries Review Lecture 1 which shows where ADH is released from and why PAGE 37 Aldosterone  Aldosterone is really important in the regulation of sodium balance   aldosterone results in more sodium channels being expressed in distal convoluted tubules and collecting ducts  Na+ reabsorption  Expression of Na+/K+ pumps, Na+/H+ exchangers, ENaC (sodium channels) are altered by aldosterone  K+ and H+ secretion  Indirectly, aldosterone effects water and other electrolyte reabsorption and secretion Review Lecture 1 which shows where aldosterone is released from and why PAGE 38 Silverthorn, Figure 19.8a: Principles governing the tubular reabsorption of solutes RAAS  The Renin‐Angiotensin‐Aldosterone System affects GFR, reabsorption and secretion of both water and electrolytes   Angiotensin II affects the proximal tubule directly by:  increasing sodium reabsorption and potassium secretion via  expression of Na+/K+ pumps  Increasing water reabsorption via  expression of aquaporins  Angiotensin II can also have indirect effects on the distal convoluted tubule and collecting ducts by stimulating ADH and aldosterone release PAGE 39 Figure 24.14: The renin‐angiotensin‐aldosterone system. Atrial Natriuretic Peptide (ANP)  ANP is a hormone which is released when blood pressure is too high, and the body needs to reduce water volume   ANP will result in increased urine output, decreased blood volume and decreased blood pressure  ANP affects reabsorption, secretion and GFR by:  inhibiting the expression of Na+/K+ pumps and ENaC in the proximal tubule and nephron loop,  excretion of Na+ in urine  inhibiting the expression of aquaporins in the collecting duct,  amount of water content in urine  supresses the release of ADH, renin, and aldosterone  promotes vasodilation of the afferent arteriole directly,  GFR, flow rate through the nephron, and urine volume Review Lecture 1 which shows where ANP is released from and why PAGE 40 Blood pH  The kidneys are part of the body’s acid‐base buffering system  Reabsorption and secretion of H+ and HCO3+ ions in the tubules help with the removal or conservation of acids and bases  When blood pH decreases (becomes more acidic):  Proximal tubule cells  rate of H+ secretion and HCO3+ reabsorption  Urine will become more acidic, body will  chemical buffering capacity  When blood pH increases (becomes more alkaline):  Proximal tubule cells  rate of HCO3+ secretion and H+ reabsorption  Urine becomes more alkaline Silverthorn, Figure 20.16: Overview ofPAGE renal 41 compensation for acidosis Recap: Endocrine Regulation of Fluid Balance PAGE 42 Figure 16.25: Summary of endocrine control of fluid homeostasis. Diuretics  Diuretics are substances which increase the amount of water and salt expelled from the body as urine.  Diuretics cause the kidneys to produce higher volumes of urine  Substances which are considered diuretics include caffeine, alcohol and some medications (particularly those used for controlling blood pressure) PAGE 43 Diuretics - Hypertension Medication  Hypertension (high blood pressure) is a common medical condition which can cause damage to many different organs.  Three classes of drugs act on RAAS to reduce blood pressure: ACE inhibitors – developed from snake venom; block ACE; therefore inhibit conversion of angiotensin I to II Angiotensin‐receptor blockers – block receptors on blood vessels and proximal tubule cells; prevents vasoconstriction and reabsorption of water and sodium Aldosterone antagonists – block effects of aldosterone on distal tubule; decrease reabsorption of sodium and water; leads to diuretic effect  Beta‐blockers are a type of anti‐hypertensive that causes systemic vasodilation. This can lead to  GFR and a diuretic effect  Drugs may decrease GFR in patients with pre‐existing renal disease, so renal function must be closely monitored PAGE 44 Diuretics  Other substances which people may normally consume in the diet can also result in increased urine output:  Alcohol – inhibits ADH release  Caffeine – No one clear mechanism of action, but may work through increasing GFR, increasing sodium reabsorption in the proximal tubule, and inhibiting the tubuloglomerular feedback system PAGE 45 Figure: https://www.sportsperformancebulletin.com/nutrition‐for‐endurance‐athletes/supplements/caffeine‐alcohol‐dehydration/ The Countercurrent Mechanism PAGE 46 Urine Concentration and Volume  85% of water reabsorption is obligatory, meaning a certain volume of water needs to be reabsorbed from the filtrate, regardless of fluid intake  Obligatory water loss is required to prevent build‐up of waste products and ensure electrolyte homeostasis  The remaining 15% is facultative water reabsorption is adjusted to meet the needs of the body.  Facultative water reabsorption determines final urine concentration and volume  Facultative water reabsorption is regulated by ADH and aldosterone PAGE 47 Filtrate Osmolality and Urine concentration  Osmolality of filtrate changes through different regions of nephron:  New filtrate entering renal tubule has same osmolality (isosmotic) as blood ~ 300 mOsm  Facultative water reabsorption will determine the final urine concentration Urine concentration can be anywhere between 50 – 1200 mOsm PAGE 48 Figure 24.20: Formation of dilute urine. Production of Dilute Urine  In any condition where the body needs to remove water: dilute, or hypotonic urine can be formed by the kidneys   ADH means less aquaporins will be present in the DCT and collecting duct   water reabsorbed into the blood more water is lost in the urine  Urine volume increases, and concentration decreases PAGE 49 Production of Concentrated Urine  In any condition where the body needs to conserve water: concentrated, or hypertonic urine can be formed by the kidneys   ADH causes more aquaporins to be present in the DCT and collecting duct   water reabsorbed into the blood less water is lost in the urine  Urine volume decreases, and concentration increases PAGE 50 Countercurrent Mechanism & Urine Concentration  The Countercurrent Mechanism creates and maintains medullary osmotic gradient by exchanging materials in opposite directions between filtrate and interstitial fluids  The purpose of the countercurrent mechanism is to create an environment where urine can be concentrated in the presence of the hormone ADH.  This allows your body to hold on to more water, by claiming back water during the urine production process  ADH  ADH PAGE 51 Countercurrent Mechanism & Urine Concentration  This mechanism is established by the nephron loop of juxtamedullary nephrons, allowing facultative water reabsorption to occur by establishing a concentration gradient within the kidney  Each limb (ascending and descending) of the Loop of Henle enhance (or multiply) the other’s action. Descending limb: Ascending Reabsorbs limb: Reabsorbs water but Na+, K+, and Cl‐. not salt Impermeable to water PAGE 52 Figure 24.21: The countercurrent multiplier in the nephron loop. Osmolality of the Kidneys  In the kidneys, the osmolality in the cortex is similar to that of other body fluids (~300 mOsm), but becomes more concentrated in the medulla (~1200 mOsm) 300 1200 PAGE 53 Figure 24.22: Maintenance of the medullary osmotic gradient Role of the vasa recta  The blood vessels that surround the nephron loop of juxtamedullary nephrons flow in the opposite direction to filtrate in the nephron  This counter‐current setup helps maintain the osmotic gradient in the medulla of the kidneys The vasa recta’s ascending limb The vasa recta’s gains water and descending limb loses Na+, K+, Cl‐ gains Na+, K+, Cl‐ and loses water PAGE 54 Silverthorn, Figure 20.7c: Countercurrent mechanism: Countercurrent exchange in the vasa recta The Countercurrent Mechanism and Urine Formation  The gradient formed by the counter current mechanism is essential for the concentration of urine in the collecting duct, which runs from the cortex to the medulla of the kidneys. PAGE 55 The Countercurrent Mechanism and Urine Formation  Even if ADH is present, water can only move from the filtrate to the blood if a concentration gradient is present  In times of inadequate water intake (dehydration), the kidneys can only conserve water up to a certain amount (1200mOsm)  If the filtrate in the collecting duct reaches 1200mOsm, the concentration of the filtrate will be equal to that of the medullary interstitial fluid concentration gradient is lost The kangaroo rat can produce very concentrated urine – almost 6000 mOsm! PAGE 56 Image: https://natureofscienceib.wordpress.com/2017/02/09/11‐3‐the‐kidney‐and‐osmoregulation/ Next Week  Lecture 04: The Lymphatic and Immune Systems  Practical 1: Fluid Balance and Renal Physiology  WHS induction quiz – remember to bring a copy of your completion certificate to your practical class  PPE needs to be worn to your practical class  Quiz 1 opens next Monday and will close next Friday PAGE 57