Renal Physiology

1. Renal Physiology PART ONE Renal Physiology Overview PART TWO Renal Clearance PART THREE Renal Acid-Base Balance

2. Role of the kidney in maintaining water, electrolytes, and pH balance • Plasma leaks out of the capillaries in the glomerulus. The kidneys return the nutrients to the plasma, while removing the waste products. This also maintains the pH balance, since some of the wastes are acids and bases. • Under the direction of aldosterone, they keep the balance between electrolytes, especially sodium and potassium. • This keeps the plasma volume constant to maintain BP.

3. Role of Kidneys • The kidneys can adjust blood volume, blood pressure, and blood composition • BLOOD VOLUME • Adjusts the volume of water lost in urine by responding to ADH, aldosterone, and renin • BLOOD PRESSURE • Releasing renin and adenosine (increases blood pressure) • BLOOD COMPOSITION • Releasing erythropoietin (increases RBC production)

4. Sympathetic Nervous System Effect on Kidneys • Changes the rate of blood flow (and therefore, the pressure) to the glomerulus by telling the precapillary sphincters when to contract or relax. • Sympathetic nervous system is stimulated by renin, which is released by the kidney. • Causes changes in water and sodium reabsorption by the nephron

5. Hypothalamus • The hypothalamus monitors the concentration of water in the plasma. • If the plasma is too concentrated (high osmotic pressure), it means there are many electrolytes and not enough water inside the blood vessels (the person is dehydrated, and blood pressure will drop). • Since water goes to the area that has the most particles (particles SUCK water!), water will be drawn out of the nearby cells, which will cause them to shrink. • If the plasma is too dilute (low osmotic pressure), it means there is too much water and too few electrolytes inside the blood vessels (the person is over-hydrated, and blood pressure will rise). • Water will be drawn out of the blood vessels to enter the nearby cells (causing them to swell) or the space between them (interstitial space, causing edema).

6. Hypothalamus and Adrenal Gland • When a person is dehydrated and has low blood pressure, the hypothalamus will sense that the osmotic pressure of the plasma is too high (above homeostatic levels; plasma is too concentrated: too many electrolytes and not enough water is in the plasma), it tells the pituitary gland to release ADH (antidiuretic hormone) to cause the kidneys to retain additional water to dilute the plasma. This will make the low blood pressure go back up. • The adrenal cortex will also release aldosterone, which causes sodium ions to be reabsorbed by the kidneys, and water will follow. This will also increase the plasma volume (which will dilute it), and also help the low blood pressure to go back up. • If the osmotic pressure is too low (plasma is too dilute: too much water and not enough electrolytes in the plasma), ADH and aldosterone are not released, and excess water will pass out of the body as urine. This will make the high blood pressure go back down.

7. Quiz Yourself • What does it mean when the osmotic pressure is too high? Too low? • What are the causes of each of these situations? • How does the body compensate for each of these situations? • What does it mean when the plasma is too dilute? Too concentrated? • What are the causes of each of these situations? • How does the body compensate for each of these situations?

8. pH Imbalances • Many things can alter the pH of the blood • Beverages we drink • Acids produced by metabolism • Breathing rate • Vomiting (loss of acid) • Diarrhea (loss of base) • pH imbalances are dangerous because many enzymes only function within a narrow pH range.

9. Renal Physiology Basic Mechanisms of Urine Formation 1) Glomerular filtration 2) Tubular reabsorption 3) Tubular secretion 4) Excretion How do we determine these rates? Master formula

10. Glomerular Filtration • The capillaries in the glomerulus contain many holes, called fenestrations. As blood passes through the glomerulus, the plasma passes through the fenestrations. Proteins and other large substances do not cross through; they stay in the bloodstream. • The filtered plasma leaves the bloodstream in this way, and enters the glomerular capsule, and then enters the proximal convoluted tubule.

11. Glomerular Filtration • In a sprinkler hose, the higher the water pressure, the faster the water squirts through its holes. The same process is also true for the glomerulus. • The blood pressure inside the glomerulus affects how fast the fluid can filter through the fenestrations. Therefore, blood pressure affects the glomerular filtration rate (GFR). The higher the blood pressure, the higher the GFR. • The pre-capillary sphincters can also control how much pressure is in the glomerulus, much like the water faucet controls the pressure in a hose.

12. Glomerular Filtration Rate • GFR is used as a measure of kidney function. • Normal GFR is 125 ml per minute for both kidneys combined. • That means 7.5 liters per hour, or 180 liters per day. • That is 45 gallons of filtrate produced per day! • Of course, most of that is reabsorbed. • Average urine output is about 1.2 liters per day. • That means you need to drink 1.2 liters of fluid per day (remember that caffeine and alcohol are diuretics, so you need more than that to compensate if you drink those beverages). You need to drink more (about 2 liters per day) if you are getting a cold or flu.

13. Altering GFR • Several different mechanisms can change the diameter of the afferent and efferent arterioles to alter the GFR: • Hormonal (hormones) • Autonomic (nervous system) • Autoregulation or local (smooth muscle sphincters around the arterioles or capillaries near the glomerulus)

14. Remember the route the fluid takes: Glomerulus  Proximal convoluted tubule (PCT)  Descending limb of LOH  Ascending limb of LOH  Distal Convoluted tubule  Collecting duct

15. Tubular Reabsorption • This is the process by which substances in the renal tubules are transferred back into the bloodstream. Reabsorption is the removal of water and solute molecules from filtrate after it enters the renal tubules. • Fluid goes from the glomerulus to the proximal convoluted tubule (PCT), down the loop of Henle and back up, then into the distal convoluted tubule (DCT), and into the collecting duct. • In the PCT, the nutrients are reabsorbed. If there are more nutrients than can be reabsorbed (such as excess sugar), it will be excreted in the urine. • When the nutrients are reabsorbed (in the PCT), the inside of the tubule will have more water and less nutrients. Since water goes to the area that has a higher concentration of particles (osmosis), water will also leave the tubules; this occurs in the DCT. • By the time the fluid has reached the collecting duct, nothing but waste products are left, such as urea, ammonia, and bilirubin.

16. Tubular Reabsorption • Capillaries follow the renal tubules and wrap around them. • The straight capillaries that travel longitudinally next to the tubules are called vasa recta, and the capillaries that wrap around the tubule are called peritubular capillaries. • There is a space between the capillaries and the tube, called the peritubular space.

17. Filtrate arriving from Bowman’s Capsule Tubular Reabsorption Tubular Cells Lumen of Tubule Peritubular Capillaries • The peritubular capillaries are nearby, and the particle concentration is low inside of them. Therefore, the particles in the peritubular space (high concentration of particles) will leave that space and enter into the peritubular capillaries by osmosis. • That is how the nutrients are reabsorbed from the tubules back into the bloodstream.

18. Tubular Reabsorption • The ascending limb of the Loop of Henle and the DCT are impermeable unless hormones cause substances to be moved through their walls. • If the blood is low in sodium, (after excessive sweating), aldosterone (from the adrenal cortex) will cause more sodium to be pumped out of the tubule and into the peritubular space. The sodium will then enter the capillaries. • Since water follows where salt goes, whenever the body needs more water (such as dehydration), ADH is released (from the neurohypophysis = posterior pituitary). The synthetic form of ADH is vasopressin (a medicine). • Aldosterone and ADH will increase blood volume, increasing blood pressure. • These two hormones begin their action in the ascending limb and continue to work in the DCT.

19. Tubular Secretion • Some substances are unable to filter through the glomerulus, but are not wanted by the body. • Examples are pollutants like pesticides, and many drugs, such as penicillin and non-steroidal anti-inflammatory drugs (NSAID’s). • As blood passes through the peritubular capillaries, those substances are moved from the capillaries directly into the PCT and DCT. • This is called tubular secretion.

20. Juxtaglomerular Apparatus • The distal end of the renal tubule passes next to the glomerulus to form the juxtaglomerular apparatus (juxta means “next to”).

21. Juxtaglomerular Apparatus:Alters BP and GFR by autoregulation • Two types of cells: • 1) Macula densa cells • 2) Juxtaglomerular cells

22. Juxtaglomerular Apparatus: Macula Densa Cells • If blood pressure is too low, the macula densa releases adenosine, which causes vasoconstriction of the afferent arteriole. This will slow the GFR, so less water is lost, and blood pressure increases.

23. Juxtaglomerular Apparatus: Macula Densa Cells • If blood pressure is too high, the macula densa stops releasing adenosine, which allows the sphincters to relax. • This will increase GFR so more water is lost, and blood pressure decreases.

24. Juxtaglomerular Apparatus: Juxtaglomerular Cells • Juxtaglomerular cells secrete renin if the blood pressure is still too low after adenosine has caused vasoconstriction. • Renin causes more sodium to be reabsorbed, and water follows, so blood volume increases, so blood pressure increases.

25. Summary of Autoregulation • The nephron can alter the blood pressure and flow into the glomerulus by autoregulation. • The JGA senses the blood pressure going into the glomerulus and the flow rate of the fluid going through the renal tubule. If the GFR is too low, the JGA (macula densa) will cause the pre-capillary sphincters on the nearby arterioles to contract, increasing blood pressure, like turning up the faucet on a hose. • If that restores the desired filtration rate and flow, no further action is needed. If not, the kidneys produce the enzyme renin, which makes the lungs produce angiotensin converting enzyme (ACE), which turns A1 into A2, which constricts blood vessels, and also causes the release of aldosterone and ADH, raising the blood pressure further.

26. Hormonal Regulation • If a person sweats from activity, eats very salty food, or has diarrhea, it changes the sodium and water content of the plasma. • Two hormones that affect the ascending limb of the Loop of Henle are aldosterone and antidiuretic hormone (ADH). • Adosterone is produced by the adrenal cortex and causes additional sodium ions to be pumped out of the tubule and into the bloodstream. Water comes with it by osmosis, and the blood pressure increases. • ADH is produced by the posterior pituitary gland and causes retention of additional water from the DCT and collecting ducts. Sodium is not included in this process, so the result is to dilute the plasma during dehydration from not drinking enough water, which causes the plasma to become too concentrated with particles.

27. How Low BP is Raised:The renal-angiotensin system • When baroreceptors detect low blood pressure, the kidney releases an enzyme called renin. • In the meantime, angiotensinogen is made by the liver and released into the blood. • Renin cuts angiotensinogen into angiotensin-1 (A1), which travels through blood to the pulmonary capillary bed, where cells have angiotensin converting enzyme (ACE) that cuts A1 into A2 (the active form). • Any word that ends in –ogen means it is a longer, inactive protein, called a zymogen. • To become activated, they need to be cut by an enzyme into a smaller segment. • A2 then causes vasoconstriction of the peripheral blood vessels so the body’s blood will pool up to the core organs. • Also, these high levels of A2 stimulates the adrenal cortex to make more aldosterone, and also stimulates the posterior pituitary gland to release ADH. These events will raise the blood pressure. • When blood pressure is too high, the patient might be given an ACE inhibitor such as Captopril, or a renin inhibitor such as Aliskiren, or an A2 antagonist, such as Azilsartan.

28. ALDOSTERONE WATER RENIN ACE ADH SALT ANGIOTENSINOGEN Renin-Angiotensin Kit A2 A1

30. Erythropoietin • The kidneys also monitor the oxygen content of the blood. • If O2 levels are low, the JGA releases the hormone erythropoietin to stimulate the bone marrow to produce more red blood cells.

31. Neural Regulation • The kidneys receive about 22% of the blood pumped out of the heart, so that is a substantial quantity passing through the kidneys at any given time. • If there is a stressor and the sympathetic nervous system causes us to go into fight or flight mode, the skeletal muscles need to have a maximum amount of blood flow. • Neurons from the sympathetic nervous system innervate the kidneys to decrease renal blood flow during critical situations.

32. Urine • Urine contains ions such as sodium, chloride, and potassium, as well as suspended solids, known as sediments, such as cells, mineral crystals, mucus threads, and sometimes bacteria. • The pH of urine is normally 4.6-8 • A urinalysis can identify abnormal processes occurring in the body. • Because urine is a waste product, its contents are influenced by the foods and drinks we ingest. • We may lose fluid elsewhere, such as through sweating or diarrhea, which causes the urine to become more concentrated. • Acids produced through metabolism can also change the pH of our urine. Even changes in breathing rate can change the urine pH as excess acids or bases are excreted to maintain normal plasma pH.

33. Abnormal Urinalysis • These substances should not be in the urine. When they are, it is abnormal. • Glucose • Blood • Protein • Pus • Bilirubin • Ketones

34. Causes of abnormal UA • Glucose: diabetes mellitus • Blood: bleeding in urinary tract from infection or kidney stone • Protein: kidney disease, hypertension, excessive exercise, pregnancy • Pus: bacterial infection in urinary tract • Bilirubin: liver malfunction • Ketones: excessive breakdown of lipids

35. Micturition • Urination is technically known as micturition. • Once the volume in the urinary bladder exceeds 200 ml stretch receptors in its walls send impulses to the brain, indicating the need to eliminate. • When you make the decision to urinate, the parasympathetic nervous system stimulates the smooth muscle in the urinary bladder’s internal sphincter to relax. • Remember, the internal sphincter is smooth muscle (involuntary) and the external sphincter is skeletal muscle (voluntary). Both must relax for urine to exit.

36. Diuretics for hypertension and congestive heart failure • Diuretics decrease plasma volume. One group of these drugs are called thiazide diuretics (such as Lasix). They inhibit the reabsorption of sodium and potassium from the renal tubule, causing more water to pass out as urine. • Compared to sodium, the homeostatic range of potassium is quite narrow. You can lose or gain much sodium without causing a problem, but you need a fairly exact amount of potassium or all your neurons can die. • Lasix (Furosemide) inhibits reabsorption of potassium more than other diuretics. Low blood levels of potassium are called hypokalemia. It is important for someone on Lasix to take potassium supplements or eat fruits or vegetables that have a lot of potassium (such as cantaloupe). • However, too much potassium from excessive supplements can have fatal side effects.

37. Diuretics • Furosemide (Lasix) • Mannitol • Spironolactone • Amiloride • Hydrochorothyozide

38. Homeostasis • Maintaining the proper concentration of sodium and water is critical. • If the plasma is too concentrated with particles, nearby cells can shrink and lose their function. • If the plasma is too dilute, water can enter the nearby cells and cause them to expand, also decreasing their function. • This is especially dangerous in the brain. • Studies have shown a close link between obesity, diabetes, and kidney disease. Exercise helps maintain normal kidney function by increasing blood flow, and it decreases the incidence of high blood pressure. People receiving dialysis and those who have had kidney transplants especially need to exercise.

39. The rest of this lecture is not on the test.

40. Renal Physiology Video

41. Countercurrent exchange You Tube Animation 1 https://www.youtube.com/watch?v=XbI8eY-BeXY Counter heat current exchange: Note the gradually declining differential and that the once hot and cold streams exit at the reversed temperature difference; the hotter entering stream becomes the exiting cooler stream and vice versa. You Tube Animation 2 https://www.youtube.com/watch?v=AOqIlrQhqHQ You Tube Animation 3 https://www.youtube.com/watch?v=3THZeaMfuSw

42. Countercurrent exchange • Countercurrent exchange is a mechanism occurring in nature and mimicked in industry and engineering, in which there is a crossover of some property, usually heat or some component, between two flowing bodies flowing in opposite directions to each other. The flowing bodies can be liquids, gases, or even solid powders, or any combination of those. • The maximum amount of heat or mass transfer that can be obtained is higher with countercurrent than co-current (parallel) exchange because countercurrent maintains a slowly declining concentration difference or gradient. • Countercurrent exchange, when set up in a loop (such as the Loop of Henle), can be used for building up concentrations of solutes. When set up in a loop with a buffering liquid between the incoming and outgoing fluid, and with active transport pumps, the system is called a Countercurrent multiplier, enabling a multiplied effect of many small pumps to gradually build up a large concentration in the buffer liquid.

43. Countercurrent exchange • Countercurrent multiplication is where liquid moves in a loop followed by a long length of movement in opposite directions with an intermediate zone. The tube leading to the loop passively building up a gradient of solvent concentration while the returning tube has a constant small pumping action all along it, so that a gradual intensification of the heat or concentration is created towards the loop. Countercurrent multiplication has been found in the kidneys as well as in many other biological organs.

44. Countercurrent exchange Countercurrent exchange is used extensively in biological systems for a wide variety of purposes. For example, fish use it in their gills to transfer oxygen from the surrounding water into their blood, and birds use a countercurrent heat exchanger between blood vessels in their legs to keep heat concentrated within their bodies. Mammalian kidneys use countercurrent exchange to remove water from urine so the body can retain water used to move the nitrogenous waste products.

45. Countercurrent multiplier  A countercurrent multiplier is a system where fluid flows in a loop so that the entrance and exit are at similar low concentration of a dissolved substance but at the tip of the loop there is a very high concentration of that substance. The system allows the buildup of a high concentration gradually, with the use of many active transport pumps each pumping only against a very small gradient.

46. The incoming flow starting at a low concentration has a semipermeable membrane with water passing to the buffer liquid via osmosis at a small gradient. There is a gradual buildup of concentration inside the loop until the loop tip where it reaches its maximum.

47. In the example image, water enters at 299 mg/L (NaCL / H2O). Water passes because of a small osmotic pressure to the buffer liquid in this example at 300 mg/L (NaCL / H2O). Further up the loop there is a continued flow of water out of the tube and into the buffer, gradually raising the concentration of NaCL in the tube until it reaches 1199 mg/L at the tip. The buffer liquid between the two tubes is at a gradually rising concentration, always a bit over the incoming fluid, in our example reaching 1200 mg/L. This is regulated by the pumping action on the returning tube as explained immediately.

48. The tip of the loop has the highest concentration of salt (NaCL) in the incoming tube - in the example 1199 mg/L, and in the buffer 1200 mg/L. The returning tube has active transport pumps, pumping salt out to the buffer liquid at a low difference of concentrations of up to 200 mg/L more than in the tube. Thus when opposite the 1000 mg/L in the buffer liquid, the concentration in the tube is 800 and only 200 mg/L are needed to be pumped out. But the same is true anywhere along the line, so that at exit of the loop also only 200 mg/L need to be pumped. In effect, this can be seen as a gradually multiplying effect - hence the name of the phenomena: a 'countercurrent multiplier' or the mechanism: Countercurrent multiplication.

50. A circuit of fluid in the Loop of Henle - an important part of the kidneys allows for gradual buildup of the concentration of urine in the kidneys, by using active transport on the exiting nephrons. The active transport pumps need only to overcome a constant and low gradient of concentration, because of the countercurrent multiplier mechanism. • Various substances are passed from the liquid entering the Nephrons until exiting the loop.