Physiology Exam #3. Note Packet. L#16-18
Physiology Exam #3. Note Packet. L#16-18 0800
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This 10 page Study Guide was uploaded by Denise Croote on Saturday January 23, 2016. The Study Guide belongs to 0800 at Brown University taught by John Stein in Fall 2014. Since its upload, it has received 103 views. For similar materials see Principles of Physiology in Biology at Brown University.
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Date Created: 01/23/16
Denise Croote Principles of Physiology – Unit 3 Renal System Renal Functions: • Regulating volume and concentration of solutes (Na, Cl-, K+, HCO3-, Ca++, Mg++) • The net output from cellular metabolism is an acid load (from what you eat/burn) your body must deal with this acid load appropriately • The kidneys can get rid of less acid, but it takes a hours to days (takes longer than just holding your breath and increasing the partial pressure of CO2 in the blood) • Excreting metabolic waste • Can secrete hormones and renin (renin is an enzyme that catalyzes a reaction) Anatomy • Kidneys are in the abdominal cavity back wall, connected to the bladder by ureters • Filter plasma, secrete urine into the bladder (secrete 1-3mL per hour) • Most of the urine is water – if you are dehydrated urine flow rates will be on the lower end • A slice of the kidney shows that the cortex (outside) and medulla (inside) • A nephron is mostly located in the cortex but has a loop (the loop of henle) that extends into the medulla • Individual nephrons each filter tiny quantities of plasma and empty into the renal pelvis (1 million nephrons per kidney) • Healthy kidneys have 4x the necessary amount of nephrons (which is why it is okay to donate a kidney) • Even though they are quite small, a disproportionate amount of blood (1/5) gets pumped to the kidney from the heart on every stroke • When you vasoconstrict, you shunt blood away from the kidneys because you need the blood to be sent to muscles during flight or fight situations • It is possible to cut off nearly all blood flow to the kidney and then go into renal failure (ex. = vasoconstriction after injury involving blood loss) • This is the primary reason why the kidney was the first organ that was successfully replicated in an artificial form • there were a lot of soldiers who were dying in WW2 as a result of renal failure, weren’t getting transfusions fast enough and by the time they got the transfusion their kidneys had already gone offline Anatomy of the nephron • Glomerulus – front end of the nephron, surrounds a capillary bed - filter that allows water, wastes, and small materials to pass through, but blocks larger particles like cells and proteins from passing through, filters 125mL/minute of plasma • Some of the leakiest capillary beds in the body are the glomerulary capillary beds • Afferent arteriole comes into the glomerulary capillary bed, dumps blood, and efferent arteriole leaves • Another capillary bed surrounds the entire tubule system • Filtrate from the glomerulus is collected in bowmans space, bowmans capsule is technically outside the body because it is in the lumen General Mechanism: Dump filtrate into the tubule system and then re-absorb what we want to bring back in (hormones, sugars, water, aa, ions) • Surrounding the tubules are capillary beds that aid in the re-absorption • Seems weird – why don’t you just dump the things you want to get rid of? • Body does this because it already knows how to selectively take things that are outside the body and shuttle them into the body (digestive system does this when it absorbs nutrients from the lumen of the small intestine) • Kidney excretes its waste (what is not re-absorbed) in the form of urine • Proximal tubule (still in cortex) descending loop of Henle (in medulla) ascending loop of Henle (in medulla) distal tubule (swings close to the glomerulus termed juxtagolmerular apparatus) collecting duct ureter bladder • juxtagolmerular apparatus is a monitoring systems, by swinging close to the glomerulus, the back end of the production line is telling the front end of the production line what it is doing • juxtagolmerular apparatus has a macula densa cells Detailed Mechanism: 1.) Afferent arteriole meets a capillary bed (with a large surface area) and dumps blood plasma 2.) Plasma diffuses across capillary beds to bowmans capsule a. Easy for small solutes like ions, sugars, water, and amino acids to cross, harder for proteins to filter across b. Sometimes you will see protein in the urine, like after intense exercise, but normally it is prevented from entering the urine by the juxtagolmerular apparatus, which is good because we would have no way to reabsorb protein it in the tubules further down if it got past 3.) Blood plasma that does not get filtered exits through the efferent arteriol 4.) After collecting in bowmans capsule, the filtrate enters the proximal tubule 5.) Macula densa cells are specialized cells in the wall of the distal tubule and they are sampling the fluid that zooms by, they can release paracrine signaling factors that act on the neighboring cells, telling them what to do something based on what they sense in the environment Filtration • 125 mL/minute of filtrate travels down the tubule, 124mL/minute re-absorbed (losing 1mL/minute) • There is a small ability to actively secrete waste from the blood into the urine • What is re-absorbed becomes plasma again and what is left over becomes the urine • if your kidneys did not re-absorb anything, you would excrete 125ml/minute and you bladder (with a max capacity of 500mL) would fill up in three minutes • If you drank concentrated saline solution, your urine flow rate would slow down because you would conserve as much water as you could • Why is urine yellow? • Bilirubin makes bile green and feces brown, and it also colors the urine yellow. • If you have a small amount of urine coming out the bilirubin will be more concentrated and the urine more yellow Artificial Kidney • Willem Kolff created the artificial kidney during the war • Kolff filled a big vat with isotonic saline and passed blood through a semi-permeable membrane (sausage casings). The semipermeable membrane let water and urea diffuse freely and the toxic urea diffused into the tank from high concentration to low concentration. The filtrate (with less urea) returned to the body • Today, artificial kidneys are small tubes. Blood comes in one end; dialysis fluid comes in the other direction. Effectively eliminates the waste using counter- current flow Renal Statistics • Heart pumps about 5L per minute, 1000mL of that goes to the kidneys • Since your blood is 50% plasma, 500ml/minute of plasma go to the kidneys • Glomerular Filtration Rate (GFR) describes how much blood passes through the filter in a minute = 125mL/minute • Leaves a filtration fraction of how much you filter (GFR) divided by how much could be filtered (blood plasma arriving at the kidney) which is the renal plasma flow (RPF) • Leaves us with 125/500mL GFR Regulation: • pH describes the hydrostatic pressure in the capillary bed, starts off at 55mmHg • Because many of the plasma proteins do not get filtered, there is a higher concentration of proteins in the blood plasma than in the filtrate, creating an osmotic gradient that draws the water backwards, working against the hydrostatic pressure. • Ions and sugars are permeable so they do not generate an osmotic pressure. • There is a resistance to flow in the tubule system called “backflow” – and this accounts for a pressure of 15mmHg pushing back against the 55mmHg • Ex.) Kidney stone build up of minerals, forms in the urinary track. It blocks the exit of the urine, the bladder fills, stretches, creates a pressure and that pressure backs up into the ureters and nephrons, preventing filtration in the capillary beds Renal Pressure Regulation • Plasma must travel across the epithelium cells of the capillary wall, through the extracellular space, through the cells lining Bowman’s capsule or the “podocytes” • Podocytes are not tight enough to restrict the flow of small proteins (no real physical barrier). Instead, proteins are prevented from flowing by the extracellular matrix. Extracellular matrix contains negatively charged molecules that repel proteins (because proteins are mostly negatively charged). • there is a 100 mmHg pressure in the afferent arteriole because it is receiving blood that is being pumped from the heart • Think of it as a circuit in series • Pressure is drops across a resistance, the bigger the resistance, the bigger the drop in pressure • 1/2 of the resistance is at the front end and 1/2 is at the back end , pressure in glomerulus will be 50mmHg • Overall, if you increase the resistance of the pre-capillary sphincter, the pressure in the glomerulus drops, if you increase the resistance of the post capillary sphincter, the pressure in the glomerulus builds up. Scenario One: Increase the resistance in the afferent artrdrop in pressure in the glomeruls drop in GFR drop in renal blood flow because afferent arteriol constriction shunts blood elsewhere filtration fraction? Scenario Two: Increase the resistance in the efferent artriincrease the pressure in the glomerulus rise in GFR drop in renal blood flow because constriction in the kidney is occurrin increase filtration fraction Scenario Three: Decrease resistance in the afferent arteiincrease pressure in the glomeruls increase GFR increase renal blood flwfiltration fraction? Scenario Four: ** Decrease resistance in the efferent arteiodecrease pressure in the glomeruls decrease GFR increase renal blood flw filtration fraction decreases If you want to cut off blood flow to the kidneys but still filter, increase the resistance in the efferent arteriole (after the filtration is occurring) GFR Regulation 1.) Sympathetic Stimulation • Moderate levels of stress, you constrict both the afferent and the efferent to decrease pressure but still filter • Severe sympathetic stimulation gives you mass constriction of the arteriole to totally stop filtration 2.) Autoregulation • Renal baroreceptors - sudden increase in blood pressure in the arterioles causes a reflexive increase in force. Stretching the walls of the kidney causes the walls of the kidney to squeeze back (increase in force – stress activated Ca channels) • Juxtaglomerular Apparatus – Macula Densa Cells • Sample the environment and release paracrine factors to act on the afferent arteriole • If we need more GFR, dilation of the afferent arteriole (more pressure in capillaries) • If we have more than enough GFR, constrict the afferent arteriole (less pressure andless filtration) • Release Renin • Atrial Natriuretic Peptide (ANP) Structure of tubule system • The lumen is outside the body and epithelial cells line the lumen • Next to the lumen is the cortical collecting duct. Apical side faces the lumen and the basolaterial side faces inward. • Transport is regulated at the luminal membrane by diffusion, active transport, etc. • primary ions transports into the collecting ducts is K+, Na+, water ions • Re-absorbing Na+ is easy because a concentration gradient pushes the Na+ into the cells (Na+ concentration is usually lower in the cells) and because of the electrical driving force (the membrane potential inside the cell is negative), basolateral membrane also decreases the sodium inside the cell by actively pumping it out. • Cl- is pulled along as Na+ moves, water can go across the membrane or squeeze through the gap junctions Glucose Flow Rate • 125mg/min of glucose molecules enters the tubule system • Proximal tubule: all sugar is reabsorbed, massive sodium/glucose co-transport at the apical membrane. Use concentration and electrical gradient of Na+ to pull sugar alone for the ride. • Urine: 0mg/min of glucose leave in the Urine Water Flow Rate • 125mL/min enter the tubule • Proximal tubule: massive absorption • Descending loop of Henle: massive absorption • Ascending loop of Henle: no gain or loss of water (not permeable) • Distal Tubule: range of options, keep flow high and don’t reabsorb, or reabsorb more water • Collecting Duct: also has ability to tweak • Urine: 1ml/minute (but can vary depending on state of body) Sodium Transport • Proximal: massive absorption • Descending loop of Henle: continues to absorb • Ascending loop of Henle: actively transported back into body (even though water is not moving) – urine gets more dilute because water remains but salts leave • Urine: little bit Potassium Transport • Proximal: massively re-absorbed • Descending loop of Henle: continue collecting • Ascending loop of Henle: continue collecting • Distal tubule: rise in potassium ions (meaning they must be actively secreted) Inulin Transport – inulin is filtered but is not re-absorbed or secreted. If you inject inulin in the blood stream and measure the rate at which it comes out in the urine you can access how well the kidneys are filtering. If very little inulin comes out, you know the kidneys aren’t functioning properly. PAH Transport: - is filtered, not absorbed in the proximal and loop of Henle but actively secreted along the collecting duct and distal tubule Clearance: the amount of blood plasma that is 100% cleared of solute • 500mL/minute of plasma go to the kidney and you filter 125mL/plasma every minute. • The clearance of inulin is 125mL/minute because the re-absorbed plasma has no inulin in it (all comes out in the urine) • The remaining 375 that did not get filtered still has inulin (not cleared) • The blood coming out of the kidney has a lower concentration of inulin – because the completely cleared 125 gets added to the 375 • Urine flow rate – home many mL of urine per minute Concentration of solute in plasma * clearance = concentration of x in urine * urine flow rate (mg X/mL of plasma) * (mL plasma/minute) = mg X/mL of urine * mL urine/minute • Clearance (mL/minute cleared of a solute) = (concentration of inulin in urine * urine flow rate) / concentration of inulin in the plasma • Clearance of inulin is equal to to glomerular filtration rate • Inject inulin into an animal and measure concentration in the plasma, measure the concentration of inulin in the urine, how much is the urine flowing and solve for GFR • The concentration of solutes in the urine tends to be higher than in the plasma because a lot of solutes are being forced into a small urine volume • The clearance of PAH will be even greater because you are filtering AND secreting • If we are clearing all of the PAH from the blood, and we calculate renal plasma flow. • RPF = Renal Plasma Flow = Clearance PAH / 0.91 • Some error: 91% of the plasma that goes to the kidney gets cleared of PAH, the other plasma does not flow close enough to the tubule Transport Maximum • 100-125mg/minute of glucose is being filtered, all be re-absorbed (normal) • We have more than enough transporters to re- absorb 2x and 3x the normal amount of sugar • When we rise up to 400-500mg/100 mL we can no longer transport everything and sugars are secreted in the urine (Diabetics) Water Adjustments • Positive free water clearance occurs: too much water in blood, need to dilute the urine (taking water from your blood) • If your body has the perfect balance of water and solutes your urine has the perfect balance of water and solutes • Negative free water clearance: If you have too little water in the blood, need to concentrate the urine (adding water to your blood) • Proximal Tubule: isosmotic fluid comes in • Descending Loop: water is re-absorbed (hyper- osmotic) • Ascending Loop: water is not re-absorbed, solutes are re-absorbed via active transport (hypo-osmotic fluid- more dilute than your body) • Collecting Duct: ADH changes tubule permeability to either re-absorb and create a hyper-osmotic solution or to leave it hypo-osmotic Counter Current Exchange: • How can ducks stand in ice cold water? How are they not cooling their entire body down? • Arteries delivery the warm blood to the feet are right next to veins returning the cold blood to the heart • Heat exchange occurs in a counter current flow • As the warm blood goes down the leg it warms up the cool blood coming up the leg • If you have them flowing in a counter current way the blood going up gains more and more heat and the last thing it encounters is the hottest part of the system (37d blood at the top) Application: Step one: filtrate (urine) made more dilute in the ascending limb by movement of solutes out, moving solutes into the interstitial fluid not only makes the urine more dilute, but it also makes the vasa recta (efferent arteriol) more concentrated • Combination of Na+ and Cl- used to keep this gradient high and encourage water removal from urine. Also absorb some of the urea from the urine, to give the counter current multiplier system one more solute to use to increase the concentration in the vasa recta Step Two: Vasa recta runs parallel to the collecting duct • Counter current multiplier, large gradient draws water out of the urine • The last part of the vasa recta that the collecting duct sees is the most concentrated part, resulting in the maximal absorption of water • Longer the loop the greater the multiplication, more water transport proteins, large osmotic gradient, longer distance were counter current exchange can occur • Fresh water fish - short loops of henle, don’t set up an osmotic gradient because they have an over-abundance of fresh water, always drawing water into their bodies, always making dilute urine. • Desert animal – longer and more numerous loops, greater osmotic gradient, allows them to concentrate the urine even more and conserve all of the water MODULATORS 1) Antidiuretic hormone (ADH) (retain water) Triggers: 1.) Rise in osmolarity 2.) Decreased stretch in atria 3.) Drop in bp Hypothalamic osmo-receptors respond to changes in osmolarity and modify release of ADH based on how much shrinking/swelling of the cells occurs Atrial cells can trigger the release of ADH if they sense a decrease in stretch Decrease osmolarity/large blood volume less ADH decrease in permeability @ collecting ducts and distal tubule water leaves in urine Dehydrated/Increase in osmolarity/low blood volume massive ADH increase in permeability collecting ducts and distal tubule water re-absorbed Mechanism: 1.) vasopressin in the blood binds to g protein coupled receptors in the lumen of the collecting duct, activating a cAMP second messenger signaling cascade that inserts aquaporins into the apical membrane of the collecting duct (~minutes) 2.) ADH also increases the osmotic gradient in the renal medulla by increasing the permeability of urea in the collecting duct a. Allows the ascending loop to be more concentrated that it normally Aquaporin would without ADH. effect b. Also allows the urine remaining effect in the collecting duct to be more concentrated that it would ***If your blood is too dilute your urine will be even more dilute ***If your blood is too concentrated your urine will be even more concentrated Not ideal to be dehydrated because then this counter current exchange has to be set and blood vessels must live in extreme conditions (1200mOsm/L) 2) Renin/Angiotensin/Aldosterone (retain water) • Liver angiotensinogen (inactive) + rennin (from kidney) angiotensin I + ACE (from blood vessels) angiotensin II aldosterone Triggers: 1.) Macula densa cells sense a decrease in flow volume and solute flow (Na+ and Cl-) in the distal tubule and release Renin 2.) Decreased artial pressure and blood pressure 3.) Increase in sympathetic nerves that release renin • Angiotensin II is a very potent vasoconstrictor – it causes thirst and induces the release of aldosterone from the adrenal cortex 1) Making more angiotensin II will trigger your body to increase vasoconstriction, and retain more fluid, ultimately increasing blood pressure • Aldosterone regulates how much NaCl the kidney re-absorbs, encourages your kidney to excrete potassium into the urine and retain sodium, thereby retaining water Not changing the osmolarity, re-absorping both solutes and water so the total goal is to increase volume Steroid hormone so it goes into the cytosol, binds to a receptor and regulated transcription Takes more time than the ADH hormone Effects of Aldosterone: • More channels in the apical membrane - Na goes down its concentration gradient, Cl- and water follows • More proteins that regulate these pumps and transporters making the gradient steeper • More Na/K ATPase pumps in the basolaterial membrane. Potassium is pumped into the epithelial cells by the ATPase pump, high concentration in these cells causes it to travel down its concentration gradient into the lumen, meaning that you lose K+ in the urine 3) Atrial Natriuretic Peptide (ANP) (dump water) Triggers: increase in plasma volume, distention of atria Induce water and salt loss Dilates the afferent and constricting the efferent increase in pressure in the golmerular capillary more pressure means more filtration more filtration means more fluid going into the tubule system more flow at macula densa cells less rennin release combined with less absorption in the distal and collecting tubule leads to more loss of fluids Also inhibits aldosterone and ADH SCENARIOS 1.) Drop in Blood Pressure Macula densa cells sense decrease in GFR trigger release of rennin Cardiovascular control center increases sympathetic activity which stimulates juxtaglomerular cells to release renin Angiotensin II activates the sympathetic response and constricts arterioles Aldosterone increases sodium and water re-absorption to increase volume Stimulates the release of ADH to increase water retention Stimulates thirst 2.) Handling a salt load Goal: save water in the kidneys to dilute the salt Salt in the body increases osmolarity triggering the release of ADH (~minutes) Secretion of ADH, increases renal absorption of water, and triggers thirst Increases plasma volume and blood pressure Return: Rise in blood pressure triggers a decrease in aldosterone pathway Less aldosterone means less water retention (less transport of sodium across so less water follows) (~hours), returns plasma volume to normal Common problem in society is high blood pressure – high salt diet can exaggerate the problem Chronic heart failure – ventricle loses contractility, can’t do as much work at a certain pre-load, response if to fill body with a higher blood volume, excess volume starts pooling, swelling in the ankles and feet A lot of medications to help these individuals would be to make the heart stronger, beat with more force, and pump more volume out of the body ACE inhibitors inhibit angiotensin I ↓angiotensisn II, ↓aldosterone ↑water loss
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