Exam 2 Notes - Renal Physiology PDF

Exam 2 Notes Lecture 8 - Intro to Renal Physiology Renal Physiology I - Glomerular Filtration Outline o o o Functional anatomy and blood flow Glomerular filtration - principles and determination Control of glomerular filtration o RAAS is intersection of cardiovascular and renal Functional anatomy o Cross section of kidney o Cortex o Innear layer Medulla o o More outer layer o Nephron goes into medulla MEDULLA IS HYPEROSMOTIC and this is important in OSMOREGULATION of concentrated urine production! The pelvis empties into the ureter from the collecting ducts! Blood flow into the kidney o Renal artery IN and renal vein OUT o Renal artery --> interlobar arteries/veins --> arcuate arteries/veins o If you have LESS BLOOD FLOW into kidney --> this REDUCES GFR and REDUCES urine production! Blood flow into the kidney - the nephron o Summary of blood flow and urine production in nephron o Afferent arteriuoles and arcuate artery comes into the GLOMERULUS o Glomerulus is surrounded by BOWMAN'S capsule o From capillaries, this forms the glomerulus o AFFERENT arteriole o COMES INTO the glomerulus o EFFERENT arteriole o LEAVES the glomerulus o Efferent arterioles form PERITUBULAR capillaries and surround the loop of Henle! o Helps form the HYPEROSMOTIC urine o Two capillaries in nephron o Glomerulus o Peritubular capillaries o Parts of nephron o o Bowman's capsule --> PROXIMAL convoluted tubule --> descending limb --> Loop of henle --> ascending limb --> DISTAL convoluted tubule --> collecting duct! The role of DIURETICS! Nephrons are the functional units of the kidney o Many nephrons/kidney o CANNOT be regenerated o Numbers decreased by 10% each year after 40 years old o ADAPTIVE changes in other nephrons compensate o Proximal tubule and Bowman's capsule are in CORTEX, but loop of henle is in MEDULLA! o GO OVER FIGURE! Urine formation - glomerular filtration o NORMAL GFR = 180L/day filtered into Bowman's capsule o MOST reabsorbed --> ONLY 1L/day EXCRETED! o GLOMERULAR FILTRATE contents o Plasma DOES NOT HAVE P{ROTEINS --> proteinuria is a dysfunction in kidney function! o Concentration of MOST non-protein solutes is… o So EVERYTHING goes into plasma EXCEPT for proteins! Glomerular filtration rate (GFR) o GFR is about 20% of renal plasma flow! o Have all constituents of plasma except for proteins! o GFR is determined by o The BALANCE of HYDROSTATIC and COLLOID osmotic forces acting across the capillary membrane o The capillary FILTRATION coefficient (Kf) The PRODUCT of filtering and permeability! Glomerular capillary membrane o There are THREE major layers in the capillary layer of glomerulus o Capillary endothelium o Basement membrane o Layer of epithelial cells --> PODOCYTES o Efficient o HIGH permeability due to FENESTRATIONS in endothelium and SLIT pores in PODOCYTES o All components have STRONG NEGATIVE CHARGE that HINDER passage of plasma proteins o Capillary filtration coefficient o If SURFACE area changes, this can change filtration and GFR! o If BASEMENT membrane thickness decreases, this will affect GFR Glomerular capillary membrane o Look at the basement membrane and see the PODOCYTES in epithelial barrier in Bowman's capsule o See a VERY THIN basement membrane o Barrier between endothelium and space is very thin! o There are also PODOCYTES o Fluid is PUSHED THRU Bowman's capsule very quickly and easily! Filterability of solutes is INVERSELY related to their molecular weight o The HIGHER the molecular weight, the LOWER the filterability of solute o VERY INEFFICIENT filtering for LARGE molecules o PROTEINS should NEVER be in the urine! o Proteinuria! o Why is basement membrane so effective at being not permeable to proteins? o 2 reasons on next slide! Negatively charged large molecules (i.e. plasma proteins) are NOT easily filtered o When you have NEGATIVE charge, you have LESS filterability of molecule compared to positive and neutral molecules! o This prevents proteins from getting filtered in glomerulus into the renal filtrate/renal plasma! Determinants of glomerular filtration rate (GFR) o GFR determined by o SUM of hydrostatic and colloid osmotic (ONCOTIC pressure) forces across glomerular membrane which gives the NET filtration pressure o Glomerular filtration coefficient (Kf) o No need to know individual numbers o Net filtration pressure = Glomerular hydrostatic pressure - Bowman's capsule pressure glomerular colloid osmotic pressure o Glomerular hydrostatic pressure PUSHES IN o Bowman's capsule pressure PUSHES OUT o Glomerular colloid osmotic pressure PUSHES OUT o Net filtration pressure ends up being POSITIVE to around 10! o GFR INCREASES WITH PATHOLOGIES! Determinants of glomerular filtration rate - Kf o Normal Kf = 12.5mL/min/mmHg of filtration pressure o INCREASED Kf means INCREASED GFR o DECREASED Kf means DECREASED GFR! o So GFR = Kf x net filtration pressure o 12.5 x 10 = 125! --> this is a NORMAL GFR! o In disease states, Kf ma change and adversely affect GFR o Kf may be LOWERED by INCREASES in thickness of basement membrane and this can LOWER GFR and lead to renal failure o Happens in diseases such as hypertension and diabetes mellitus! Increased bowman's capsule hydrostatic pressure DECREASES GFR o o Normal bowman's capsule pressure is 18mmHg But now imagine OBSTRUCTION of urinary tract due to KIDNEY STONES o This can INCREASE bowman's capsule pressure o This will DECREASE GFR, and eventually lead to hydronephrosis (distention and dilation…) Increased glomerular capillary colloid osmotic pressure DECREASES GFR o INCREASED glomerular colloid osmotic pressure DECREASES GFR o This is bc capillaries will RETAIN MORE blood instead of filtering it o NOT very common o If plasma protein concentration INCREASES, colloid pressure would increase! o This would DECREASE GFR o CANNOT CONTROL THIS EITHER! o If arterial colloid osmotic pressure INCREASES, GFR DECREASES! Increased glomerular capillary hydrostatic pressure INCREASES GFR o Normal pressure is 60mmHg o MAIN MODE OF CONTROL in body o Glomerular hydrostatic pressure is determined by 3 variable o Systemic ARTERIAL pressure Change in systemic BP can lead to changes in GFR! o Afferent arteriolar resistance INCREASED afferent arteriolar resistance would DECREASE the GFR! o Efferent arteriolar resistance But EFFERENT arteriole will have a BIPHASIC effect If EFFERENT arteriole resistance increases a little bit, this will INCREASE the GFR! If efferent arteriolar resistance INCREASES A LOT, this will DECREASE the GFR Has a BIPHASIC effect on GFR Increased glomerular capillary hydrostatic pressure INCREASES GFR o INCREASED arterial pressure INCREASES GFR o But this is buffered by autoregulatory… o INCREASED AFFERENT ARTERIOLAR resistance REDUCES capillary hydrostatic pressure, which DECREASES GFR o Increased EFFERENT arteriolar pressure INCREASES capillary hydrostatic pressure, which INCREASES GFR o But you can ALSO have a DECREASE in GFR if there is REDUCED blood flow o BIPHASIC effect! Biphasic effect of efferent arteriolar constriction on GFR o MODERATE constriction --> hydrostatic pressure increases, and causes MILD INCREASE in GFR o SEVERE constriction --> renal blood flow DECREASES, causing DECREASE in GFR! o Whereas in AFFERENT arteriolar resistance o o o As this INCREASES, renal blood flow DECREASES, and GFR ONLY DECREASES! INCREASE in AFFERENT arteriolar resistance ONLY DECREASES GFR But EFFERENT arteriolar resistance has a BIPHASIC effect on GFR! Determinants of GFR - summary o ANG II has a critical role in maintaining the EFFERENT arteriolar resistance! Major physiological regulators of GFR o Strong activation of SYMPATHETIC nervous sytem o Epi and norepinephrine o Causes RENAL VASOCONSTRICTION --> decreases renal blood flow --> DECREASES GFR o Sympathetic activation useful in ACUTE CRISES o I.e. SEVERE hemhorrage o Do NOT want to lose blood and reduce blood flow to kidneys to preserve blood volume! o Epi and NE are similar to sympathetic activation o ANG II --> powerful vasoconstrictor of EFFERENT arterioles that maintain GFR during changing arterial pressure by renin/angiotensin system! Autoregulation - juxtaglomerular complex or JG cells o Macula densa cells o Found in DISTAL convoluted tubule o Sense change in NaCl in distal tubule o Signal the JG cells! o Juxtaglomerular cells (JG) cells o In WALLS of efferent and afferent arterioles o RELEASE RENIN, which cause vasoconstriction of efferent arterioles! o Start the renin/angiotensin system! Renin converts Angiotensinogen --> ANG I ANG I --> ANG II by ACE Renin-angiotensin system (RAAS) o Whole system regulates the GLOMERULAR HYDROSTATIC PRESSURE! o Decreased arterial pressure leads to DECREASED glomerular hydrostatic pressure o This DECREASES GFR o This DECREASES NaCl in macula densa o Release of RENIN from JG cells Lead to angiotensin II production, and INCREASED EFFERENT arteriolar resistance! This causes GLOMERULAR HYDROSTATIC PRESSURE TO INCREASE BACK TO NORMAL! o DECREASED AFFERENT arteriolar resistance o This MAINTAINS the GFR! Effectiveness of autoregulation of GFR A note about ACE inhibitors Lecture 9 - Renal Physiology II and III (Tubular Reabsorption) Renal Physiology II - Tubular Reabsorption Outline Basic mechanisms of tubular reabsorption Reabsorption in different segments of the nephron Mechanisms of urine concentration o Countercurrent multiplier o Vasa recta o ADH o Urea Tubular reabsorption - basic principles Note that there is NO glucose in urine! o Amount filtered = 180 o Amount reabsorbed = 180 o So, 100% of the glucose is REABSORBED! o Glucose in urine = diabetes, renal pathology! Kidneys also REABSORB a LOT of Na+, Cl-, K+, and BICARBONATES! By-products of metabolism such as urea and creatinine are NOT reabsorbed very much o EXCRETED the most in urine! o Urea reabsorption 50% o Creatinine reabsorption is 0%! --> None reabsorbed! Kidneys SELECTIVELY reabsorb water and essential nutrients, but also NOT reabsorb the toxic metabolic by-products it should excrete! Tubular reabsorption - basic principles Reabsorption is primarily achieved thru primary and secondary ACTIVE transport! o PRIMARY active transport --> typical active transport Transporter uses the power of ATP hydrolysis to generate energy Helps move substance AGAINST concentration gradient! This CREATES a concentration gradient to allow substance to move INTO the cell from outside! I.e. Na+/K+ pump! o SECONDARY active transport Uses the energy from the CONCENTRATION gradient established by PRIMARY active transport to DRIVE the movement of ions Could be SYMPORT or ANTIPORT I.e. SGLT (Na/Glucose) SYMPORTER! Tubular reabsorption - primary active transport Na/K pump (or ATPase) is most important Have the tubular fluid in tissues on right, and the BLOOD in the peritubular capillaries on the left ATP hydrolysis to have --> 3Na+ OUT, and 2K+ IN Na/K ATPase is located on BASOLATERAL side of tubular epithelial cells of kidneys (facing the INTERSTITIAL FLUID side) o This moves Na+ OUT into the blood and TUBULAR lumen space! o This is what creates a SALTY concentrated medulla in the kidney! o K+ moves INTO the tubular epithelial cells! o End up with LOW Na+ and HIGH K+ in cells Consequence: this creates a CONCENTRATION gradient for Na+ to move from OUTSIDE of cell to the INSIDE --> this movement happens from tubular lumen into the cell! o Note that there is a LOT of Na+ in tubular lumen! So Na+ will rush INTO tubular epithelial cells o K+ moves OUT from inside the cell to the outside! PRIMARY ACTIVE TRANSPORTERS DIRECTLY USE THE ENERGY OF ATP to create a concentration gradient for ions! o The IONIC gradient is critical for EXCRETION purposes! Tubular reabsorption - secondary active transport SYMPORTER INDIRECTLY use the concentration gradient created by the PRIMARY active transporter to DRIVE the movement of the ions! SGLT - Na/Glucose SYMPORTER o So we have LOW Na+ in cell, and HIGH Na+ in tubular lumen due to Na/K ATPase (primary transport) o The ENTRY of glucose into tubular cells from the lumen is COUPLED with entry of Na+ DOWN its concentration gradient that was created by Na/K ATPase o Note that glucose would NOT normally be able to move into the cell because there is already LOTS of glucose in cells! Glucose then exits cell from BASOLATERAL side down its own concentration gradient o GLUT transporters --> facilitated diffusion o Passive and requires no energy Another example is Na+/Amino acid symporter o AA movement is COUPLED to downhill movement of Na+ into the cell o AA moves into the cell! o Now AA can move OUT of the cell down the concentration gradient! Note that we need Na/K pump to establish the concentration gradient of LOW Na+ in cell and HIGH K+, so that Na+ can be moved IN by secondary active transporters! Tubular reabsorption - secondary active transport ANTIPORTER Also uses the concentration gradient created by Na/K pump HOWEVER, this time the DOWNHILL movement of Na+ ions is COUPLED to the UPHILL movement of H+ (protons) in the OPPOSITE direction! o Example of antiporter is Na/H exchange (NHE) antiporter! This allows for protons to get EXCRETED --> important in acid-base regulation! o Pump protons AGAINST concentration gradient! Summary SYMPORTER (CO-transporter) = movement of substance coupled in the SAME direction as the concentration gradient of the ions from primary active transport o I.e. SGLT (Na/Glucose), Na/AA symporters ANTIPORTER (COUNTER-transporter) = movement of substance coupled in the OPPOSITE direction as the concentration gradient of the ions from primary active transport o NHE (Na+/H+) exchange antiporter Note that secondary active transport ONLY works due to concentration gradient established by the primary active transporter (i.e. Na/K ATPase) Reabsorption in different parts of the nephron - proximal tubule Take-away: Urine is CONCENTRATED at LOWER parts of the nephron (LOOP of Henle and cortical collecting ducts), but is DILUTE at UPPER parts of the nephron (cortical part of nephron) Why is upper part of nephron dilute urine, but lower part concentrated? o Because this allows kidney interstitium to also be concentrated --> creates a SALTY medulla! o This is essential for us to be able to REABSORB water in lower part of nephron and make CONCENTRATED urine! o The lower parts of nephron such as LOOP of henle and collecting ducts have CONCENTRATED urine because we want to create a CONCENTRATED MEDULLARY INTERSTITIAL FLUID to help in reabsorption of water! Proximal tubule - creates an ISOSMOTIC urine! o Very efficient in reabsorption --> 65% of filtered Na+ and water, and slightly lower percentage of filtered Cl- are reabsorbed by proximal tubule o The proximal tubule is also an important site for SECRETION of ORGANIC ACIDS, and bases such as bile salts, oxalate, urate and catecholamines! o This creates an ISOSMOTIC urine --> concentration of urine is NOT changing Summary o Many ions are reabsorbed --> Na+, Cl-, HCO3-, K+, water, glucose, AA o Organic acids and bases are SECRETED --> H+, organic aids, bases o Creates an ISOSMOTIC urine in proximal tubule! Reabsorption in different parts of the nephron - DESCENDING limb of loop of Henle Loop of henle has 3 parts o THIN descending limb o THIN ascending limb o THICK ascending lumb The DESCENDING limb is HIGHLY PERMEABLE to WATER, but NOT so permeable to NaCl and urea! o Water is MOSTLY REABSORBED from urine in the DESCENDING limb and diffuses out! o Abut 20% of H20 is reabsorbed in the DESCENDING segment o This makes the tubular fluid CONCENTRATED --> HYPEROSMOTIC urine is created! Reabsorption in different parts of the nephron - THIN ASCENDING limb of loop of Henle The THIN ASCENDING limb is IMPERMEABLE to water, but reabsorbs SOME sodium chloride (NaCl) o Na+, Cl-, K+, Ca2+, HCO3-, Mg2+ and many ions are reabsorbed, but H+ is SECRETED INTO the urine! This makes the tubular fluid DILUTE --> HYPOSMOTIC urine is created! Reabsorption in different parts of the nephron - THICK ASCENDING limb of loop of Henle The THICK ASCENDING limb is ALSO IMPERMEABLE to water, but reabsorbs LARGE AMOUNTS of Na+, Cl-, K+, and other ions via active transport! o Note that H+ is SECRETED INTO the urine in tubular fluid! This makes the urine EVEN MORE DILUTE by the time it reaches the DISTAL tubule --> HYPOSMOTIC urine created! o This feature is important in allowing kidneys to DILUTE or CONCENTRATE the urine under different conditions! LOOP diuretics In the THICK ASCENDING LIMB of loop of Henle, the movement of Na+ across the LUMINAL membrane is mediated by 1Na+, 2Cl-, and 1K+ CO-TRANSPORTER! Loop diuretics act to INHIBIT the 1Na+/2Cl-/1K+ co-transporter in LOOP of HENLE o I.e. furosemide, ethacrynic acid, bumetanide o This prevents ENTRY of Na+, K+, and Cl- from lumen into the cells o This causes Na+ to be RETAINED in the lumen and the urine o Water follows salt (Na+), so this causes WATER RETENTION o Consequence: DIURESIS! Reabsorption of Na+ and water is INHIBITED! Reabsorption in different parts of nephron - EARLY distal tubule The EARLY part of distal tubule has re-absorptive properties similar to THICK ASCENDING limb of loop of Henle! o Reabsorb Na+, Cl-, Ca2+, Mg2+ Urine gets EVEN MORE DILUTED --> more HYPOSMOTIC! So LOTS of SOLUTES are reabsorbed but NOT water, which dilutes the urine! THIAZIDE diuretics 5% of the filtered load of NaCl is normally reabsorbed in the early DISTAL tubule The Na+/Cl- CO-transporter (symporter) moves BOTH ions from the lumen into the cells! THIAZIDE diuretics INHIBIT the Na+/Cl- CO-transporter in the DISTAL tubules! o Causes RETENTION of Na+ and WATER --> leads to increased DIURESIS! Reabsorption in different parts of the nephron - LATE distal tubule and cortical COLLECTING duct The second half of the DISTAL tubule and the subsequent cortical collecting duct have SIMILAR functional characteristics Anatomically, composed of TWO distinct cell types o PRINCIPAL cells o INTERCALATED cells Principal cells --> REABSORB Na+ and water from the lumen, and SECRETE K+ ions into the lumen! Intercalated cells --> aid in maintenance of ACID/BASE balance! Permeability to WATER is controlled by ADH levels (anti diuretic hormone) o In the COLLECTING duct! Reabsorption in different parts of the nephron - LATE distal tubule and cortical COLLECTING duct Water reabsorption and permeability to water depends on levels of ADH! Two cell types --> principal cells and intercalated cells Principal cells o Reabsorb Na+ and water o SECRETE K+ into the lumen Intercalated cells o MAINTAIN acid/base balance! Principal cells - REABSORB Na+, but SECRETE K+ How does this work? Na+/K+ ATPase is located on BASOLATERAL membrane pumps Na+ OUT to interstitial space o LUMINAL Na+ now ENTERS INTO cells by special channels! ATPase activity INCREASES intracellular K+ o K+ is SECRETED to lumen by specialized channels Overall, a gradient is created with HIGH Na+ OUTSIDE of cell, and HIGH K+ INSIDE of cell thanks to Na/K ATPase o Na+ can be REABSORBED from the tubular lumen into the cells now due to conc gradient o K+ can be SECRETED from cells into the tubular lumen due to conc gradient! Examples of K+ sparing diuretics - MOA (mechanisms of action) o ALDOSTERONE antagonists Spironolactone Eplerenone o Na+ channel BLOCKERS Amiloride Triamterene Principal cells are the primary site of action of POTASSIUM sparing diuretics - ALDOSTERONE antagonists The Na/K pump is SENSITIVE to ALDOSTERONE levels! o Aldosterone INCREASES Na+ and WATER retention to INCREASE blood VOLUME (ECF) in the RAAS (throwback to cardio) Aldosterone INCREASES Na+ REABSORPTION, and also WATER reabsorption Aldosterone also INCREASES K+ SECRETION! o So aldosterone INCREASES the activity of Na/K pump, leading to MORE Na+ and WATER RETENTION Aldosterone ANTAGONISTS --> SPIRONOLACTONE and EPLERENONE o Are MINERALOCORTICOID receptor antagonists that COMPETE with aldosterone for receptor sites in the PRINCIPAL cells o This INHIBTS the stimulatory effects of ALDOSTERONE on Na/K ATPase and INHIBITS Na+ reabsorption and K+ secretion! o BLOCKING Na+ reabsorption means [Na+] will now INCREASE in tubular LUMEN, which will TRAP WATER in TUBULAR LUMEN --> DIURESIS! o Aldosterone antagonists act as K+ sparing DIURETICS by BLOCKING the Na/K pump and INHIBITING the reabsorption of Na+ and the Na+ concentration gradient to move from the tubular lumen into the cell and out to the interstitial fluid! Basically LESS Na+ is reabsorbed Increased [Na+] levels increase water in tubular lumen Diuresis! Summary: Na+ reabsorption and K+ secretion are INHIBITED o Remember that BOTH Na+ reabsorption AND K+ EXCRETION/SECRETION are INHIBITED! K+ sparing diuretics have their name because they PRESERVE and PREVENT the loss of K+ ions This is commonly used in patients who are HYPOKALEMIC! If you have a patient who do NOT have steady K+ levels or you want to MAINTAIN K+ levels, you would give them an ALDOSTERONE antagonist K+ sparing diuretic! Principal cells are the primary site of action of POTASSIUM sparing diuretics - Na+ channel blockers This is another MOA for K+ sparing diuretics Na+ channel blockers --> AMILORIDE and TRIAMTERENE o Directly INHIBIT the entry of Na+ INTO the sodium channels of the LUMINAL membranes o Basically INHIBIT Na+ reabsorption directly! --> leads to DIURESIS o Because Na+ reabsorption is INHIBITED, the Na/K pump CANNOT work anymore since it NEEDS Na+ INSIDE the cell to pump it OUT to the interstitial space! o This leads to INHIBITION of K+ secretion and excretion --> leads to K+ sparing effect! This means Na+ channel blockers have the SAME END EFFECT as the ALDOSTERONE antagonists o They are BOTH K+ SPARING diuretics! Reabsorption in different parts of the nephron - medullary COLLECTING duct Reabsorb LESS than 10% of water and solutes, but as the final site for processing urine, are very important for water/solute OUTPUT o Na+, Cl-, and HCO3- are SOLUTES that are reabsorbed o H20 is water that is reabsorbed (ADH dependent) PERMEABILITY to H20 is controlled by ADH levels o HIGH ADH --> HIGH permeability to water --> INCREASED water reabsorption --> REDUCED urine volume, CONCENTRATED urine! o LOW ADH --> LOW permeability to water --> DECREASED water reabsorption --> INCREASED urine volume, DILUTE urine! o Therefore, urine concentration is regulated via water reabsorption! Can also REABSORB urea, and SECRETE H+ In LATE distal tubule, early cortical tubule, and medullary collecting duct are sensitive to ADH levels for controlling water permeability! Changes in osmolarity of tubular fluid - review As fluid flows thru the PROXIMAL tubule, solutes and water are reabsorbed in EQUAL proportions o Proximal tubule fluid is ISOSMOTIC with plasma! o Osmolarity of blood plasma = 300 mOsm/L, so anything LOWER than this is HYPOSMOTIC, but anything HIGHER is HYPEROSMOTIC! As fluid flows thru DESCENDING limb of loop of Henle, water is REABSORBED o The MEDULLARY RENAL INTERSTITIAL fluid is very HYPERTONIC and CONCENTRATED (salty medulla), so the fluid here becomes VERY CONCENTRATED o HYPEROSMOTIC with plasma! o The VASA RECTA here MAINTAINS the HYPEROSMOLARITY of the RENAL MEDULLA! Removes water quickly! Talking about the HYPERTONIC and SALTY MEDULLARY INTERSTITIAL FLUID! In the ASCENDING limb of loop of Henle, especially in THICK segment, Na+ and other solutes are REABSORBED, but water is NOT o Tubular fluid becomes DILUTE by the time it reaches DISTAL tubule o HYPOSMOTIC with plasma! The whole point of having dilute urine later on in the DISTAL tubule and ASCENDING limb, but concentrated urine down in DESCENDING limb is to MAINTAIN a HYPERTONIC MEDULLARY INTERSTITIUM! o The ANATOMY of the kidney (concentrated medulla, diluted cortex) explains why urine is concentrated as it goes down into medulla, but DILUTED as it comes back UP to the cortical regions in distal tubules! PERMEABILITY of LATE distal tubule and COLLECTING DUCT to water is dependent on ADH levels o When ADH levels are LOW --> water is NOT reabsorbed but other solutes are, DILUTE urine produced Fluid may become as DILUTE as 50 mOsm/L But the most concentrated it becomes is 600 mOsm/L at loop of Henle o When ADH levels are HIGH --> water is AVIDLY REABSORBED, so CONCENTRATED urine produced! Fluid may become as CONCENTRATED as 1200 mOsm/L! Concentrating urine TWO requirements for CONCENTRATING urine: o HIGH ADH levels o INCREASES water reabsorption in distal tubules and collecting ducts HIGH osmolarity (HYPERTONICITY) of renal medullary INTERSTITIUM Provides the osmotic GRADIENT necessary for water reabsorption to occur in the presence of HIGH ADH! Medullary interstitium MUST be concentrated AT LEAST as much as or MORE than the tubular fluid in the collecting duct Otherwise, if OSMOLARITY of medullary interstitium is NOT MORE concentrated than tubular fluid, no matter how much ADH you have, water will NOT be reabsorbed! So you need a HIGHLY HYPEROSMOTIC medullary interstitium to have water reabsorption thru nephron into the blood vessels! Cortical and juxtamedullary nephrons - nephron anatomy CORTICAL nephrons o SHORT loops of Henle that penetrate only a SHORT way into the medulla! MOST of the nephron is in the superficial CORTEX of kidney! o ENTIRE tubular structure is surrounded by extensive network of PERITUBULAR capillaries o These nephrons do NOT play a role in concentrating urine since do NOT extend much into medulla! JUXTAMEDULLARY nephrons o 20-30% of all nephrons with glomeruli located at the junction of cortex and medulla o LONG loops of Henle that penetrate DEEP into the MEDULLA! o Blood vessels that run PARALLEL to loops of Henle --> called VASA RECTA! Vasa recta helps in MAINTAINING and forming the HYPEROSMOTIC renal medullary interstitium! o These play role in OSMOREGULATION and concentrating urine! Vasa recta Surround JUXTAMEDULLARY nephrons LONG EFFERENT arterioles that forms a capillary network extending into MEDULLA from the glomeruli and run beside the loops of Henle! Like the loops of Henle, the vasa recta RETURN towards the cortex and EMPTY into CORTICAL veins! Important in creating and maintaining a HYPEROSMOTIC renal medullary interstitium! Countercurrent multiplier mechanism produces a hyperosmotic renal medullary interstitium Countercurrent multiplier mechanism produces the HYPEROSMOTIC medullary interstitium! The countercurrent mechanism depends on o ANATOMICAL arrangement of loops of Henle o VASA RECTA How does the countercurrent multiplier mechanism work? Steps 1. Assume loop of Henle is filled with fluid that has SAME OSMOLARITY as that of proximal tubule (300 mOsm/L, which is isosmotic) i. Urine is being excreted for first time and 300 mOsm/L has filled up entire loop of Henle 2. The ACTIVE ion pump of the THICK ASCENDING limb of loop of Henle REDUCES the concentration INSIDE the tubule, but RAISES the interstitial concentration when SOLUTES MOVE OUT! i. Remember that ASCENDING limb is IMPERMEABLE to water, so tubular fluid (urine) becomes DILUTED! ii. This pump establishes a 200 mOsm/L concentration gradient between tubular fluid and interstitial fluid iii. Tubular = 200 mOsm iv. Interstitial = 400 mOsm 2. The TUBULAR fluid in the DESCENDING LIMB of loop of Henle and the interstitial fluid quickly reach OSMOTIC equilibrium. Water moves OUT by OSMOSIS from the descending limb! i. The INTERSTITIAL osmoalarity is maintained at 400 mOsm/L because of CONTINUED transport of ions OUT of the THICK ASCENDING loop of Henle! ii. The tubular fluid in DESCENDING limb is now 400 mOsm/L! i. VASA RECTA HERE REMOVES the WATER that diffused out and MAINTAINS the HYPEROSMOTIC MEDULLARY INTERSTITIUM at 400 mOsm/L! 1. This is why the medullary interstitium concentration STAYS at 400 and is HYPEROSMOTIC! 2. Additional flow of fluid into the loop of Henle from the proximal tubule causes the HYPEROSMOTIC fluid previously formed in the DESCENDING LIMB to FLOW and SHIFT into the ASCENDING LIMB now! 3. In ASCENDING limb, a FURTHER 200 mOsm/L gradient is GENERATED i. The ion pump is AGAIN activated in the ASCENDING limb with transport of SOLUTES OUT into the interstitial fluid ii. This RAISES the INTERSTITIAL fluid osmolarity to 500 mOsm/L iii. This is a REPETITION of step 2! 2. Following this, step 3 REPEATS, as water AGAIN moves OUT by osmosis i. Vasa recta removes the water to MAINTAIN the hyperosmotic concentration at 500 in the medullary interstitium! 2. Steps 4-6 are REPEATED OVER and OVER. Net effect is to ADD MORE AND MORE SOLUTE to the MEDULLA in EXCESS of water! i. Water is REMOVED by vasa recta to maintain the countercurrent mechanism and the hyperosmotic medullary interstitium! ii. Consequence: With sufficient time, the INTERSTITIAL FLUID OSMOALARITY RISES to 1200-1400 mOsm/L iii. VERY concentrated! iv. Note that the CONCENTRATION of tubular fluid (urine) in the DESCENDING loop of Henle has the SAME concentration as the MEDULLARY INTERSTITIUM 1. This is what CONCENTRATES the urine at the DESCENDING limb of loop of Henle! The HYPEROSMOTIC medullary interstitium provides the necessary OSMOTIC gradient for water to move out of the tubular fluid and into the vasa recta! ADH-dependent permeability of collecting tubules When the tubular fluid leaves the loop of Henle and flows into the DISTAL tubule in renal CORTEX, the fluid is DILUTE and HYPOSMOTIC at about 100 mOsm/L o When ADH levels are HIGH --> water is AVIDLY REABSORBED in DISTAL and early CORTICAL COLLECTING tubules, urine is CONCENTRATED o FURTHER reabsorption occurs in MEDULLARY collecting ducts Note: in order for water reabsorption to occur and urine to become really concentrated at HIGH ADH levels, we NEED to MAINTAIN the HYPEROSMOLARITY of the medullary interstitium o Water will ONLY flow from low to HIGH solute concentration, so the medullary interstitium MUST BE MORE CONCENTRATED than the collecting duct at all costs! Countercurrent exchange in the vasa recta preserves the hyperosmolarity of the renal medulla Two special features of the renal medullary blood flow contribute to PRESERVATION of the HYPEROSMOLARITY and HIGH solute concentration in the medullary interstitium o LOW medullary blood flow o VASA RECTA Serves as countercurrent EXCHANGERS, MINIMIZING washout of solutes from the medullary intersititium by REMOVING excess water that diffused out of descending limb (via osmosis) Countercurrent exchange in vasa recta Vasa recta = countercurrent EXCHANGE! Steps 1. Blood enters and leaves the medulla by way of vasa recta at the boundary of cortex and renal medulla --> vasa recta surrounds the juxtamedullary nephrons and loops of Henle! 2. As blood DESCENDS into the medulla toward the papillae, it becomes progressively MORE CONCENTRATED i. Due to SOLUTE ENTRY from medullary interstitium ii. Due to LOSS of water into the interstitium iii. So we have SOLUTE and WATER exchange AT THE LEVEL of the blood vessel but NOT across the blood vessel! Important notes o BOTH the blood plasma in vasa recta AND the renal medullary interstitium get CONCENTRATED TOGETHER as the loop of Henle descends DEEPER into the medulla! i. So the blood in vasa recta PARALLELS the concentration of renal medullary interstitium and the loop of Henle! ii. This ensures that water will NOT flow from a region of low to high osmolarity! iii. This allows excess water to be REMOVED once it diffuses out of the DESCENDING limb to the interstitial fluid ▪ MAINTAINS the hyperosmolarity of the medullary interstitium! Countercurrent exchange in vasa recta U SHAPE of the vasa recta capillaries allows for LARGE EXCHANGE of solute and fluids, but LITTLE CHANGE in concentration The vasa recta does NOT CREATE the medullary hyperosmolarity, but rather MAINTAINS IT and PREVENTS it from dissipating o By removing excess water that diffuses out! o If we did NOT have vasa recta, the excess water would WASH OUT the solutes and the hyperosmolarity of the medullary interstitium we established! o Vasa recta ALLOWS for PRESERVING the concentration gradient of solutes in a way that is NOT affected by water! Quick summary Countercurrent MULTIPLIER --> CREATES the hyperosmolarity of medullary interstitium! Countercurrent EXCHANGE --> MAINTAINS the hyperosmolarity of medullary interstitium! Summary of urine-concentration mechanism and changes in osmolarity in different segments of the tubules Check out the graph on powerpoint! This is a review! Note the effect of ADH at the end o See how INCREASED water reabsorption has led to CONCENTRATED urine and has REDUCED the volume of urine from 125mL to 0.2mL!!! o But ADH ONLY WORKS if you have a HYPEROSMOTIC medullary interstitium, which is why countercurrent multiplier and exchange are important! Renal pathology: NEPHROGENIC DIABETIC INSIPIDUS o The renal medullary HYPEROSMOTICITY is DISSIPATED and washed out, NOT maintained! o Patient then becomes UNRESPONSIVE TO ADH LEVELS and CANNOT reabsorb water! Renal Physiology III - Control of Tubular Reabsorption Outline Regulation of tubular reabsorption - GLOMERULOTUBULAR feedback and hormonal control Urinary CLEARANCE measurements Regulation of tubular reabsorption - GLOMERULOTUBULAR balance GLOMERULOTUBULAR feedback --> basic mechanism of controlling tubular reabsorption o Tubules INCREASE reabsorption rate in response to INCREASED tubular load I.e. if the GFR INCREASES from 125mL/min to 150mL/min o o Absolute rate of PROXIMAL tubular REABSORPTION also INCREASES from about 81mL/min (65% of GFR) --> 97.5mL/min (65% of GFR). So the HIGHER the GFR, the HIGHER the tubular REABSORPTION rate! Regulation of tubular reabsorption - HORMONAL control What we will focus on! Summary of hormonal effects on reabsorption o Aldosterone - collecting tubule and duct INCREASE Na+ and water REABSORPTION! INCREASE K+ and H+ SECRETION! ▪ Recall the effect of aldosterone on principal cells and the Na/K pump! o ANG II (angiotensin II) - proximal tubule, THICK ascending loop of Henle, distal tubule, collecting tubule INCREASE Na+ and water reabsorption INCREASE H+ secretion! o ADH (antidiuretic hormone) - distal tubule, collecting tubule, and collecting duct INCREASE water reabsorption! o ANP (atrial natriuretic peptide) - distal tubule, collecting tubule, and collecting duct DECREASE NaCl reabsorption Hence INCREASE water EXCRETION! o Parathyroid hormone - proximal tubule, THICK ascending loop of Henle, distal tubule DECREASE phosphate reabsorption INCREASE Ca2+ reabsorption! Important notes o BOTH aldosterone and ANG II are Na+ and WATER RETENTION hormones in the RAAS pathway! o This helps INCREASE blood ECF VOLUME o ANG II also helps MAINTAIN GFR! o Why maintain GFR? Bc certain TOXIC metabolites like creatinine and urea MUST be FILTERED and CLEARED OUT of the blood even though we need to retain fluid and NaCl o So ANG II --> fluid and Na+ retention + MAINTENANCE of GFR! Review - Autoregulation of GFR and renal blood flow (RAAS) Steps 1. 2. 3. 4. DECREASED arterial pressure DECREASED glomerular HYDROSTATIC pressure DECREASED GFR Increased proximal NaCl reabsorption --> DECREASED macula densa NaCl (sense changes in NaCl in the DISTAL tubule) i. JG CELLS in walls of efferent/afferent arterioles --> INCREASED renin --> ANG II --> INCREASED EFFERENT arteriolar resistance i. DECREASED AFFERENT arteriolar resistance 2. NET effect of INCREASED EFFERENT arteriolar resistance and DECREASED AFFERENT arteriolar resistance is to BLOCK the DECREASE in glomerular hydrostatic pressure to RAISE it back to normal! The whole point is to MAINTAIN GFR to maintain essential EXCRETION function of kidney while trying to restore ECF blood VOLUME back to normal! Note: o Recall that glomerular hydrostatic pressure is determined by i. ARTERIAL pressure ii. AFFERENT arteriolar resistance iii. EFFERENT arteriolar resistance! o An INCREASE in glomerular HYDROSTATIC pressure INCREASES GFR o A DECREASE in glomerular HYDROSTATIC pressure DECREASES GFR Aldosterone Aldosterone has NO EFFECT on maintaining GFR and the afferent/efferent arterioles unlike ANG II! Secreted by zona glomerulosa cells of adrenal cortex Important in Na+/water REABSORPTION, and K+/H+ SECRETION Site of aldosterone action is on the PRINCIPAL cells of the CORTICAL COLLECTING tubules! Act by STIMULATING activity of Na/K ATPase pump on BASOLTATERAL side of CORTICAL COLLECTING tubule membrane Review - principal cells: reabsorb Na+, but secrete K+ Aldosterone stimulates activity of Na/K ATPase, which pumps Na+ out, and K+ into cells o Allows for Na+/water reabsorption and K+ secretion! Aldosterone antagonists and Na+ channel blockers are K+ sparing diuretics o INHIBIT the Na/K ATPase --> INHIBIT Na+/water reabsorption, and K+ secretion o Leads to K+ sparing effect, while also INCREASING DIURESIS --> less Na+ reabsorption, means MORE water is excreted (water follows salt, more Na+ in tubular fluid due to less reabsorption, so this will increase water excretion/diuresis)! Aldosterone The most important stimuli for aldosterone secretion: o INCREASED extracellular [K+] o INCREASED ANG II levels --> occur in conditions associated with Na+ and blood VOLUME DEPLETION or LOW BLOOD PRESSURE (BP)! RAAS! The INCREASED secretion of aldosterone leads to --> INCREASED renal Na+ and water RETENTION, helping to INCREASE ECF blood volume, and restore BP to normal! o Think back to RAAS! Aldosterone deficiency and excess ADDISON'S disease o ABSENCE/DEFICIENCY of aldosterone --> due to destruction or malfunction of adrenal gland o There is marked LOSS of Na+ from body (DECREASED Na+ reabsorption) and ACCUMULATION of K+ (DECREASED K+ secretion) CONN'S disease o EXCESS aldosterone --> due to adrenal tumors o Leads to INCREASED sodium/water retention and DECREASED plasma K+ concentration Due to INCREASED Na+ reabsorption, and INCREASED K+ secretion by kidneys! Aldosterone deficiency and excess Day to day regulation of Na+ balance can be maintained as long as MINIMAL levels of aldosterone are present INABILITY to appropriately adjust aldosterone secretion IMPAIRS regulation of RENAL K+ EXCRETION, and [K+] blood plasma concentrations! Aldosterone is even more important as regulator of K+ CONCENTRATION than it is for Na+ concentration! o Aldosterone MORE important for POTASSIUM rather than SODIUM! o This is because we have OTHER hormones such as ANG II that ALSO regulate Na+ concentration, but ALDOSTERONE IS THE ONLY AND PRIMARY WAY OF REGULATING POTASSIUM, so MORE IMPORTANT FOR POTASSIUM! Angiotensin (ANG II) Body's MOST powerful Na+ RETAINING hormone! Stimulated by: o LOW blood pressure (BP) or LOW ECF blood VOLUME o I.e. during HEMORRHAGE or LOSS of salt and water from body fluids during excessive SWEATING, or severe DIARRHEA! o Also during DEHYDRATION/THIRST! 3 main effects of ANG II that restore BP and ECF volume: o Stimulate ALDOSTERONE secretion o CONSTRICT EFFERENT arterioles --> maintains GFR! o DIRECTLY stimulates Na+ REABSORPTION in the proximal tubules, loops of Henle, distal tubules, and collecting tubules! Effect 1: Review - principal cells: reabsorb Na+, secrete K+ Already reviewed! When ANG II stimulates release of aldosterone, it acts on PRINCIPAL cells (in collecting tubule and duct) --> Increased Na+/water reabsorption, and K+ secretion Effect 2: Review - juxtaglomerular complex (RAAS) This shows the effects of ANG II on EFFERENT arteriolar resistance! Macula densa cells sense changes in NaCl in wall of DISTAL tubule JG cells in walls of afferent/efferent arterioles --> secrete RENIN and cause VASOCONSTRICTION of EFFERENT arterioles! This RESTORES GFR back to NORMAL levels! --> helps excrete TOXIC metabolites from body! Need to have this excretion functionality, cuz decreased GFR NOT good! Effect 3: ANG II directly stimulates sodium reabsorption Seen in PROXIMAL tubules, loops of Henle, DISTAL tubules, and collecting tubules! INCREASED Na+ reabsorption due to STIMULATION of: o Na/K ATPase in BASOLATERAL membrane o Na/H exchanger in LUMINAL membrane (NHE) o Na/HCO3 co-transporter in BASOLATERAL membrane! Net effect is Na+ and WATER RETENTION --> INCREASED blood VOLUME (ECF) and restores BP to normal! Note about the vasoconstrictor effect of ANG II Vasoconstrictor effect on EFFERENT arterioles aids in MAINTENANCE of normal EXCRETION of metabolic waste products such as urea and creatinine that depend mainly on an ADEQUATE GFR for their excretion o So this is why it's important to MAINTAIN GFR! Thus, increased ANG II permits kidneys to RETAIN Na+ and water WITHOUT causing retention of metabolic waste products! o Via maintaining GFR! Another note about ANG II and Aldosterone Note that ANG II and aldosterone INCREASE the amount of Na+ in EXTRACELLULAR FLUID (ECF) o AND they also INCREASE the ECF blood volume by increasing WATER reabsorption along with Na+ o Remember, water follows salt! Therefore, ANG II and aldosterone have LITTLE effect on INTRACELLULAR [Na+], except under extreme conditions! o So we are NOT changing the CONCENTRATION of Na+, but the AMOUNT of Na+ and water reabsorbed, to INCREASE the ECF blood volume! Side-note: Aldosterone also INCREASES K+ secretion/excretion! ADH increases water reabsorption Effect of ADH is to INCREASE the water permeability of DISTAL tubule, COLLECTING tubule, and collecting duct epithelia! ADH release Steps to ADH release 1. Water deficit/DEHYDRATION 1. INCREASED ECF osmolarity! 2. OSMORECEPTORS stimulate ADH secretion in posterior pituitary 1. Increased plasma ADH levels 2. INCREASED WATER permeability in distal tubules, collecting ducts 3. INCREASED water reabsorption 4. LESS water is excreted in urine --> CONCENTRATED urine! An INCREASE in ECF OSMOLARITY causes special nerve cells called OSMORECEPTORS in ANTERIOR HYPOTHALAMUS to shrink! Osmoreceptors relay signals to POSTERIOR pituitary, which releases ADH! ADH enhances renal water reabsorption ADH also released due to o DECREASED BP and blood FLUID volume due to signals from carotid sinus/aortic arches via vagus/glossopharyngeal nerves (parasympathetic) o ADH is a VASOCONSTRICTOR hormone, similar to ANG II! So ADH can be released due to TWO things: o DEHYDRATION (increased ECF osmolarity) o LOSS of blood volume (i.e. HEMORRHAGE) Disorders of urine concentrating ability Impairment to concentrate or dilute the urine appropriately can occur due to defects in: o INAPPROPRIATE secretion of ADH --> CENTRAL diabetes insipidus o Inability of nephron to RESPOND to ADH --> NEPHROGENIC diabetes insipidus o Impairment of COUNTERCURRENT mechanism! --> NEPHROGENIC diabetes insipidus! Inability to produce ADH - CENTRAL diabetes insipidus Caused by HEAD INJURIES (i.e. trauma), infections, or CONGENITAL The DISTAL tubular segments CANNOT reabsorb water! LARGE volume of DILUTE URINE produced due to LACK of ADH --> urine volumes that EXCEED 15L/day! AS LONG AS the person DRINKS enough water, large decreased in body fluid water do NOT occur --> MUST DRINK LOTS OF WATER! Treatment o Administration of SYNTHETIC ADH --> DESMOPRESSIN! o Can be given via injection, nasal spray, orally o Rapidly restores urine output to normal! CENTRAL diabetes insipidus --> LACK of ADH, nothing wrong with kidneys! Inability to respond to ADH - NEPHROGENIC diabetes insipidus Normal ADH levels in blood, but the renal tubular segments CANNOT respond appropriately! Nephrogenic diabetes insipidus due to: o FAILURE of COUNTERCURRENT mechanism to form a HYPEROSMOTIC renal medullary interstitium --> no hyperosmotic interstitium means no water reabsorbed! o FAILURE of distal and collecting tubules and ducts to respond to ADH Consequence --> produce lots of DILUTE urine! Water NOT reabsorbed! Does NOT respond to desmopressin --> this treatment will NOT work! Treatment --> CORRECT the underlying RENAL disorder! Inability to respond to ADH - NEPHROGENIC diabetes insipidus What kind of renal disorders lead to nephrogenic diabetes insipidus? o Many types of renal DISEASES can IMPAIR the urine CONCENTRATING mechanism, especially those that DAMAGE the renal medulla! Impairment of function of loop of Henle --> occurs with LOOP DIURETICS that INHIBIT electrolyte reabsorption by this segment, such as furosemide o Compromise urine-concentrating ability! Certain drugs such as LITHIUM (for manic depressive disorder) and TETRACYCLINES (antibiotics) can impair DISTAL nephron segments to respond to ADH! Some other factors that alter ADH release Primary factors are plasma osmolarity (DEHYDRATION) and blood volume/BP (HEMORRHAGE): o INCREASED plasma osmolarity --> INCREASED ADH o DECREASED plasma osmolarity --> DECREASED ADH o DECREASED blood volume/BP --> INCREASED ADH o INCREASED blood volume/BP --> DECREASED ADH Nausea, hypoxia --> INCREASE ADH levels Drugs o Morphine, nicotine, cyclophosphamide --> INCREASE ADH o Alcohol, clonidine, haloperidol --> DECREASE ADH! This is why you pee more when you drink alcohol! Alcohol is a DIURETIC! Urinary clearance Rates at which different substances are CLEARED from the plasma provide a useful way of QUANTIFYING the EFFECTIVENESS with which kidneys EXCRETE various substances! Renal clearance = the VOLUME of plasma that is completely cleared of the SUBSTANCE BY THE KIDNEYS per UNIT OF TIME! GFR provides an estimate of how well kidneys perform excretion and do urinary clearance! Estimation of GFR using INULIN clearance For estimating GFR o A substance must be filtered FREELY (filtered as freely as water) by glomerulus and NOT reabsorbed or secreted by renal tubules! o Must be EXCRETED completely by GFR! INULIN fits this criteria o It is NOT reabsorbed or secreted once filtered by kidneys! INULIN, which is NOT produced in body, is found in roots of certain plains, and MUST be administered IV (intravenously) to patient to measure GFR! o Inulin clearance helps us estimate GFR! CREATININE clearance and plasma creatinine concentration can ALSO be used to estimate GFR CREATININE clearance also helps us measure GFR Creatinine is by-product of muscle metabolism and is CLEARED from body fluids almost entirely by GLOMERULAR filtration! o Therefore, clearance of creatinine can ALSO be used to assess GFR! Plasma [creatinine] levels provide estimation of GFR o 2x INCREASE in plasma [creatinine] suggests a 50% DECREASE in GFR Summary 2 ways to measure GFR o INULIN clearance --> given via IV o CREATININE clearance --> look at plasma [creatinine] levels or creatinine clearance in urine! PAH clearance can be used to estimate renal plasma flow (RPF) PAH clearance = RENAL PLASMA FLOW (RPF) measure! Theoretically, if a substance is COMPLETELY cleared from the plasma, the CLEARANCE rate of the substance is EQUAL to the total RPF o 100% clearance = total RPF! GFR is only about 20% of TOTAL renal plasma flow o A substance that is COMPLETELY cleared from plasma must be EXCRETED by tubular SECRETION, as well as glomerular FILTRATION! There is NO KNOWN SUBSTANCE that is 100% cleared by the kidneys o PAH is about 90% CLEARANCE from plasma o Therefore, clearance of PAH can be used to estimate RPF! Filtration fraction (FF) is calculated by DIVIDING GFR by renal plasma flow (RPF) FF = GFR/RPF o Filtration fraction = fraction of plasma that is FILTERED through the glomerular membrane or HOW MUCH IS GETTING FILTERED! o GFR = INULIN or CREATININE clearance o RPF = PAH clearance! I.e. if the RPF = 650mL/min, and GFR = 125mL/min, the FF (filtration fraction) is: o FF = GFR/RPF --> 125/650 = 0.2! o This tells us that GFR is 20% of total RENAL plasma flow, which makes sense! o This tells us whether FF has decreased or increased across the glomerular membrane! Renal Pathology Outline GLOMERULAR diseases o Definitions and principles of glomerular injury o Nephrotic syndrome o Nephritic syndrome o Rapidly progressive glomerulonephritis TUBULOINTERSTITIAL nephritis o ACUTE pyelonephritis o CHRONIC pyelonephritis o Drug-induced interstitial nephritis Malignant hypertension Cystic diseases Stones Some definitions AZOTEMIA o ELEVATION of BLOOD UREA NITROGEN (BUN), and CREATININE levels o o o Reflects a DECREASED GFR! Can be PRE or POST renal! This is TOXIC and NOT GOOD! PRE-renal azotemia o Happens when there is HYPOPERFUSION of kidneys --> DECREASES GFR in absence of parenchymal damage! DECREASED blood flow to kidneys leads to DECREASED GFR INCREASED BUN and CREATININE levels! POST-renal azotemia o Happens when URINE FLOW is OBSTRUCTED BELOW the level of kidney (from kidneys) o Relief of obstruction is followed by correction of azotemia! CORRECT azotemia first, and THEN the obstruction resolves! I.e. KIDNEY STONES! Leads to DECREASED GFR --> INCREASED BUN and creatinine levels! UREMIA o When AZOTEMIA gives rise to CLINICAL manifestations and SYSTEMIC biochemical abnormalities --> UREMIA results! Waste products are NOT filtered effectively, leading to BODY-WIDE damage in other organ systems! o CHARACTERIZED by: FAILURE of renal excretory function, and many METABOLIC and ENDOCRINE ABNORMALITIES due to RENAL damage I.e. uremia can result ▪ Secondary GI problems --> uremic GASTROENTERITIS ▪ NEUROMUSCULAR problems --> peripheral neuropathy ▪ CARDIOVASCULAR problems --> uremic fibrinous pericarditis! Other important definitions NEPHRITIC syndrome o Results from GLOMERULAR injury o Due to ACUTE onset of HEMATURIA --> blood in urine Mild to moderate PROTEINURIA --> protein in urine AZOTEMIA EDEMA HYPERTENSION! NEPHROTIC syndrome o GLOMERULAR syndrome characterized by Heavy PROTEINURIA --> LOTS of protein in urine HYPOALBUMINEMIA--> LOW albumin levels in blood Severe EDEMA HYPERLIPIDEMIA LIPIDURIA --> LIPIDS in urine BOTH of these occur due to GLOMERULAR injury, but the CLINICAL PRESENTATION and symptoms are DIFFERENT o NEPHRITIC --> HEMATURIA! o NEPHROTIC --> HEAVY PROTEINURIA Principles of glomerular injury GLOMERULAR injuries usually happen due to IMMUNE reactions and immune-mediated responses! 3 IMMUNE mechanisms underlie most types of primary glomerular diseases: o Antibody response to ENDOGENOUS GLOMERULAR ANTIGENS in the BASEMENT membrane --> AUTOIMMUNE disorder! Antibodies formed against glomerular antigens in basement membrane! Formation of AUTOANTIBODIES! Basically it's an ANTIBODY response to ENDOGENOUS glomerular ANTIGENS! o Antibody response to EXOGENOUS antigens --> DRUGS I.e. DRUGS that leading to immune responses! o IMMUNE antigen-antibody complexes formed in OTHER organs that get DEPOSITED in glomerulus! Antigen-antibody complex can be deposited in glomerulus! Immune reaction --> leads to kidney damage! The antigen-antibody response leads to INFLAMMATION and then KIDNEY damage o Could be NEPHROTIC or NEPHRITIC syndrome --> clinical manifestations of glomerular DAMAGE! Lecture 10 - Renal Pathology and Acid/Base Regulation Renal pathology Outline GLOMERULAR diseases o Definitions and principles of glomerular injury o Nephrotic syndrome o Nephritic syndrome o Rapidly progressive glomerulonephritis TUBULOINTERSTITIAL nephritis o ACUTE pyelonephritis o CHRONIC pyelonephritis o Drug-induced interstitial nephritis Malignant hypertension Cystic diseases Stones NEPHROTIC syndrome Refers to a GLOMERULAR injury syndrome and series of clinical issues that include: o MASSIVE proteinuria --> LOTS of protein lost in urine o HYPOALBUMINEMIA --> LOW plasma albumin levels o Generalized EDEMA --> most OBVIOUS clinical manifestation o HYPERLIDIPEMIA and LIPIDURIA --> Excess lipids in blood and urine Nephrotic syndrome Think of these as a SERIES of CONNECTED events and diseases! Proteinuria o Damage to capillary walls of GLOMERULI, leading to INCREASED permeability to proteins! o Proteins in urine! --> there should NOT normally be proteins in urine! HYPOalbuminemia o SECONDARY to LONG-TERM PROTEINURIA --> serum albumin levels DECREASED o Result in HYPOalbuminemia, and DECREASE in PLASMA COLLOID osmotic pressure! This also affects GFR! Edema o LOW COLLOID OSMOTIC PRESSURE due to HYPOALBUMINEMIA --> REDUCES intravascular volume and RENAL BLOOD FLOW This ACTIVATES RAAS --> INCREASED Na+ and water RETENTION! End result is edema! Hyperlipidemia o Reason UNKNOWN --> INCREASED lipids in blood! o HYPOalbuminemia may trigger INCREASED synthesis of lipoproteins o MASSIVE proteinuria causes LOSS of an INHIBITOR of their synthesis o Hypoalbuminemia and proteinuria --> can lead to HYPERlipidemia! Lipiduria o INCREASED permeability of glomerular membrane to LIPOPROTEINS! o Lipids in urine! Summary of events in NEPHROTIC syndrome: o LOSS of proteins due to proteinuria --> HYPOALBUMINEMIA and DECREASED colloid osmotic pressure --> REDUCED renal blood flow --> RAAS activated --> INCREASED Na+ and water retention --> EDEMA! Causes of nephrotic syndrome PRIMARY GLOMERULAR diseases o Membranous nephropathy o Minimal-change disease o Focal segmental glomerulosclerosis o Membranoproliferative glomerulonephritis o IgA nephropathy SYSTEMIC diseases with renal manifestations o Diabetes mellitus o o o o o o Amyloidosis Systemic lupus Drugs --> such as gold, penicillamine, street heroin Infections --> malaria, syphilis, Hep B, HIV Malignancy Miscellaneous --> bee sting allergy, hereditary nephritis We will focus on PRIMARY GLOMERULAR diseases as the causes! Nephrotic syndrome causes - MINIMAL-CHANGE disease Minimal-change disease o Relatively BENIGN disorder with MINIMAL histological change! Histological changes: o See that PODOCYTES have EFFACED foot processes! --> FAULTY PODOCYTES! o Basement membrane LOOKS NORMAL! MOST frequent cause of nephrotic syndrome in children! GOOD PROGNOSIS --> VERY responsive to CORTICOSTEROID therapy! o Bc it's IMMUNE mediated response! Nephrotic syndrome causes - FOCAL segmental glomerulosclerosis (FSG) Sclerosis --> THICKENING and NARROWING! FOCAL SEGMENTAL glomerulosclerosis --> means certain segments of GLOMERULI are THICKENED and NARROWED (focal sclerosis) o Sclerosis affects SOME but NOT all glomeruli and SOME segments of each affected glomerulus! o See the NARROWED blood vessels! May be PRIMARY or SECONDARY to HIV infections or heroin abuse o Primary form accounts for 20-30% of all cases of nephrotic syndrome! o HIV and HEROIN abuse --> lead to FOCAL segmental glomerulosclerosis! POOR PROGNOSIS --> 50% develop END STAGE RENAL DISEASE in 10 years! o NOT good! WORSE outcome than minimal-change disease! Nephrotic syndrome causes - MEMBRANOUS nephropathy (MN) MEMBRANOUS nephropathy --> SLOWLY PROGRESSIVE disease! Occurs due to o AUTOANTIBODIES against podocytes o SECONDARY to INFECTIONS, exposure to TOXIC metals, or DRUGS (NSAIDS) HISTOLOGICAL changes: o Subepithelial immune complex DEPOSITS o THICKENED basement membranes and podocytes with EFFACED foot processes! o SPIKE and DOME PATTERN SPIKES of BASEMENT membrane between DOMES of SUBEPITHELIAL deposits! VARIABLE prognosis --> COULD be good or bad! o 40% develop renal failure o 10-30% have a BENIGN course with partial or COMPLETE remission of proteinuria! Nephrotic syndrome causes - MEMBRANOPROLIFERATIVE glomerulonephritis (MPGN) MPGN CHARACTERIZED by o ALTERATIONS in glomerular BASEMENT MEMBRANE (GBM) and mesangium o PROLIFERATION of glomerular cells in GBM! Accounts for 5-10% of cases of IDIOPATHIC nephrotic syndrome in children and adults o POOR PROGNOSIS! TYPE I MPGN o Caused by IMMUNE complexes deposited in, or REACTION to ANTIGENS in glomerulus --> AUTOANTIBODY response! TYPE II MPGN o DENSE deposit disease! o Caused by EXCESSIVE COMPLEMENT ACTIVATION! HISTOLOGICAL changes o Type I --> SUBENDOTHELIAL deposits o Type II --> INTRAMEMBRANOUS deposits (more DENSE deposit) o INTERPOSED mesangial cell processes (BOTH types) THICKENED GBM with TRAM-TRACK due to EXTENSION of processes of mesangial and inflammatory cells! NEPHRITIC syndrome Nephritic syndrome is a series of clinical complex, usually of ACUTE ONSET, characterized by: o HEMATURIA --> RBCs and blood in urine! o Some degree of OLIGURIA and AZOTEMIA o HYPERTENSION Although PROTEINURIA, and EDEMA are ALSO present, they are NOT as SEVERE as in NEPHROTIC syndrome! Nephritic syndrome - features INFLAMMATION o Lesions that cause NEPHRITIC syndrome have in common PROLIFERATION of the cells within GLOMERULI (MPGN) o Accompanied by INFLAMMATORY leukocytic infiltrate! Hematuria and REDUCED GFR o INFLAMMATORY reaction --> DAMAGES glomerular capillary walls, allowing BLOOD to pass into urine, and DECREASES blood volume that lead to REDUCED GFR! Consequences of REDUCED GFR o REDUCED GFR/HYPOPERFUSED kidney --> activates RAAS --> leads to OLIGURIA, Na+ and fluid RETENTION, and AZOTEMIA Recall that DECREASED GFR means LESS RENAL BLOOD FLOW to kidney (OLIGURIA), so RAAS will be activated! REDUCED GFR --> OLIGURIA and AZOTEMIA --> RAAS activated --> Na+/fluid RETENTION HYPERTENSION o HTN is a RESULT of FLUID retention and RENIN release from HYPOPERFUSED kidneys! Activated RAAS! HTN is a consequence of REDUCED GFR! Summary: o o Inflammation --> HEMATURIA and REDUCED GFR --> OLIGURIA and AZOTEMIA --> RAAS activated --> Na+ and fluid RETENTION --> HYPERTENSION (HTN) from HYPOPERFUSED kidneys! So the TRIGGER is INFLAMMATORY responses, which lead to ACUTE HEMATURIA and REDUCED GFR! Reduced GFR leads to --> OLIGURIA, fluid retention, and AZOTEMIA ▪ Azotemia because reduced GFR means we are NOT clearing the TOXIC metabolites such as BUN and CREATININE! NOT good! ▪ HYPERTENSION is another consequence of REDUCED GFR due to ACTIVATED RAAS and fluid retention (hypoperfused kidneys) Side-note: DECREASE in GFR in NEPHROTIC syndrome is NOT severe enough with proteinuria to lead to oliguria and azotemia! Acute postinfectious (poststreptococcal) glomerulonephritis (GN) Acute postinfectious/poststreptococcal GN is a COMMON glomerular NEPHRITIC disorder Caused by GLOMERULAR DEPOSITION of IMMUNE complexes resulting in proliferation of and damage to glomerular cells and INFILTRATION of LEUKOCYTES, such as neutrophils o IMMUNE-mediated cause! Common PROTOTYPIC agent --> STREPTOCOCCUS! o This typically CAUSES the INFLAMMATORY response that leads to NEPHRITIC syndrome! Other agents include o Pneumococcus, staphylococcus, mumps, measles, chicken pox, and Hep B and C! Acute postinfectious GN Histological changes o INCREASED CELLULARITY of GLOMERULAR membrane due to PROLIFERATION and SWELLING of endothelial and mesangial cells and by infiltrating neutrophils and monocytes! o Red casts in tubules --> HEMATURIA!! Normally glomerulus should be HOLLOW and EMPTY! Acute poststreptococcal GN - CLASSIC presentation In a CHILD 1-4 weeks after recovery from a group A streptococcal infection o ONLY CERTAIN NEPHRITOGENIC strains of STREPTOCOCCI cause glomerular disease! INITIAL infection usually LOCALIZED to PHARYNX or SKIN! o Starts off as STREP throat! The ONSET of this kidney disease is ACUTE and ABRUPT o Characterized by malaise, fever, nausea, and NEPHRITIC SYNDROME! o Usually a few weeks after child recovers from strep throat, nephritic syndrome results! Acute poststreptococcal GN - CLASSIC presentation Usually, this results in common NEPHRITIC syndrome features such as o OLIGURIA, AZOTEMIA, and HYPERTENSION Characteristically, there is lots of HEMATURIA, and the urine appears smoky BROWN rather than bright red! Some degree of proteinuria and edema may happen o If SEVERE, it can lead to NEPHROTIC syndrome! Acute postinfectious GN FAST RECOVERY occurs in most CHILDREN! NOT so much in adults! SOME children develop RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (GN) from acute postinfectious GN! o Due to severe INJURY with formation of CRESCENTS, or CHRONIC renal disease from secondary scarring! Could be CHRONIC condition and secondary complication! o NOT common! Prognosis in sporadic cases is LESS clear! VARIABLE prognosis! o In ADULTS, 15-50% develop END STAGE RENAL DISEASE over 1-2 decades depending on severity CHRONIC in adults! o In CHILDREN, prevalence of CHRONICITY after sporadic cases of ACUTE POSTINFECTIOUS GN is LOWER! NOT usually chronic in children! ACUTE in children! --> children QUICKLY recover! BETTER prognosis in children! Take-away: CHILDREN will usually RECOVER much FASTER from ACUTE POSTINFECTIOUS GN than ADULTS! Rapidly progressive GN (RPGN) A CLINICAL syndrome, does NOT have a specific ETIOLOGY! Characterized by PROGRESSIVE LOSS of renal FUNCTION o Typically shows NEPHRITIC syndrome with severe OLIGURIA and HEMATURIA! If UNTREATED, leads to death from renal FAILURE within weeks to months! o FATAL! RPGN Characteristic histological finding: o Formation of CRESCENTS in BOWMAN'S CAPSULE --> CRESCENTIC GN, due to RUPTURE of glomerular capillaries! Crescents o Crescents are HYPERPLASTIC lesions in Bowman's capsule due to RUPTURE of GLOMERULAR capillaries that allow BLOOD and other INFLAMMATORY mediators to ENTER Bowman's capsule and cause cell PROLIFERATION! Summary: o Glomerular capillaries are RUPTURED by crescents, which leads to passing of blood and INFLAMMATORY molecules to enter BOWMAN'S CAPSULE leading to cell PROLIFERATION! o Areas of NECROSIS with RUPTURE of capillary loops and adjacent crescent-shaped mass of proliferating cells and leukocytes filling the urinary space! Arrows Take-away: o The MAIN feature of RPGN is RUPTURE of GLOMERULAR CAPILLARIES due to CRESCENTS in BOWMAN'S capsule! Rapidly progressive GN (RPGN) - causes May be caused by many different diseases, some restricted to kidney, and some systemic Most cases are IMMUNOLOGICALLY MEDIATED! There are 3 types of RPGN: o ANTI-GBM ANTIBODY-mediated crescentic RPGN With or without LUNG involvement! o IMMUNE COMPLEX mediated crescentic RPGN Deposited in glomerular endothelial regions! o PAUCI-IMMUNE crescentic RPGN NO immune complexes present! PAUCI = LACK of immune complexes! ALL are CRESCENTIC --> have crescents! ALL cases have SEVERE glomerular injury! ANTI-GBM antibody mediated RPGN Some patients will have GOODPASTURE syndrome o ANTI-GBM antibodies --> lead to RPGN! o Some ANTI-GBM antibodies may bind to PULMONARY ALVEOLAR capillary basement membranes! o Leads to PULMONARY hemorrhages associated with renal failure! o Involves the LUNG! o GOODPASTURE syndrome = LUNG HEMORRHAGES + RENAL FAILURE! o This is a SPECIFIC kind of kidney disease associated with DISORDER of LUNGS! Diagnosis: o Look for ANTI-GBM ANTIBODIES in blood serum! Treatment o PLASMAPHERESIS --> REMOVAL of PATHOGENIC antibodies from circulation! IMMUNE COMPLEX mediated crescentic RPGN IMMUNE complexes formed ANYWHERE in the body DEPOSIT in the glomerulus o Leads to NEPHRITIC or NEPHROTIC syndrome INITIALLY that PROGRESSES to formation of CRESCENTIC RPGN when INFLAMMATORY reaction worsens! CRESCENTS can be complication of any IMMUNE COMPLEX nephritic or nephrotic disorder o IMMUNE complex mediated crescentic RPGN can be a SECONDARY complication of ACUTE POSTSTREPTOCOCCAL/POSTINFECTIOUS GN! Was discussed in acute postinfectious GN slide! Treatment o Does NOT usually respond to PLASMAPHERESIS! o PLASMAPHERESIS does NOT work bc it's an IMMUNE COMPLEX and NOT just an antibody! PAUCI-immune crescentic RPGN PAUCI-immune = LACK of immune complexes or ANTI-GBM ANTIBODIES! o NO immune complex deposition, or anti-GBM antibodies! o Due to ANOTHER type of immune mediated response! Have ANTINEUTROPHIL cytoplasmic antibodies - ANCA o Typically found in blood SERUM for PAUCI-immune crescentic RPGN! o Antibodies have ETIOPATHOGENIC role in VASCULITIS (vascular inflammations) May be due to: o SYSTEMIC VASCULITIS disorders Systemic vasculitis --> an umbrella term for group of disorders that cause INFLAMMATION in blood vessel walls with resulting ISCHEMIC tissue damage. Basically vascular INFLAMMATION! I.e. Microscopic POLYANGITIS --> inflammation of SMALL blood vessels! I.e. WEGENER GRANULOMATOSIS --> granulomas and vasculitis in RESPIRATORY tract and kidneys! o LIMITED to ONLY the KIDNEYS! Note: Even though we CANNOT find any ANTI-GBM antibodies, we can find AUTOANTIBODIES that still lead to this disorder! Tubulointerstitial Nephritis ACUTE pyelonephritis CHRONIC pyelonephritis DRUG-induced INTERSTITIAL nephritis Tubulointerstitial nephritis A group of INFLAMMATORY diseases of the kidneys that primarily affect the RENAL INTERSTITIUM and TUBULES! The glomeruli may be SPARED COMPLETELY, or affected only LATE in the course! BACTERIAL causes --> PYELONEPHRITIS o Due to BACTERIAL INFECTIONS! o Pyelo = RENAL PELVIS is prominently involved! NON-bacterial causes --> INTERSTITIAL NEPHRITIS! o May be due to INJURY caused by DRUGS --> DRUG-induced INTERSTITIAL nephritis! o o o o Metabolic disorders --> HYPOKALEMIA PHYSICAL injury --> IRRADIATION VIRAL infections IMMUNE reactions! IRRESPECTIVE of cause, divided into ACUTE and CHRONIC categories! ACUTE Pyelonephritis Caused by BACTERIAL infection! o Usually as ASCENDING INFECTION, UTI progresses UP towards the kidneys! Presents as URINARY TRACT INFECTION (UTI) o Can involve LOWER urinary tract (LOWER UTI) --> cystitis, prostatitis, urethritis ASCENDING infection --> between urinary BLADDER and URETER! o Can involve UPPER urinary tract (UPPER UTI) --> PYELONEPHRITIS! HEMATOGENOUS infection! Usually SYSTEMIC infection! Main bacterial organisms involved: o GRAM-NEGATIVE bacteria --> I.e. E.coli is MOST common! Other important organisms o Proteus, klebsiella, enterobacter, pseudomonas o Usually associated with RECURRENT infections! o STAHPYLOCOCCI and STREPTOCCUS may ALSO cause pyelonephritis but NOT common! ACUTE Pyelonephritis - presentation SUDDEN/ACUTE onset with PAIN at costoverterbral angle o Pain at the BACK, near your PELVIS/HIP! o SYSTEMIC infection --> i.e. chills, fever, malaise! URINARY TRACT INFECTION (UTI) symptoms such as --> DYSURIA, frequency, and URGENCY to urinate! Urine appears TURGID o Contains PUS --> PYURIA! Even WITHOUT antibiotic treatment, disease is BENIGN and SELF-limited! o It is a SEVERE bacterial infection, but the OUTCOME is SELF-LIMITED, resolves quickly and is BENIGN! Symptomatic phase lasts NO LONGER than a week o BACTERIURIA (bacteria in urine) may PERSIST much LONGER! CHRONIC pyelonephritis Chronic --> RECURRENT bacterial INFECTIONS o Lead to REPEATED RENAL INFLAMMATION and SCARRING, which causes CHRONIC pyelonephritis! o REPEATED ACUTE pyelonephritis leads to --> CHRONIC pyelonephritis! HALLMARK symptom o SCARRING involving PELVIS or CALYCES! o Note the CORTICAL SCARS! o SCARRING of kidneys --> leads to CHRONIC PYELONEPHRITIS! Disease can be BILATERAL --> BOTH kidneys affected o Congenital anomalies of URETHRA (posterior urethral valves) o Results in FATAL renal INSUFFICIENCY, unless anomaly is corrected Disease can be UNILATERAL --> ONE kidney affected! o Seen with renal CALCULI --> kidney STONES! o UNILATERAL obstructive lesions of ureter! Drug-induced INTERSTITIAL nephritis NON-bacterial cause of TUBULOINTERSTITIAL nephritis --> so INTERSTITIAL nephritis! DRUGS are an important CAUSE of renal injury! ACUTE drug-induced tubulointerstitial nephritis (TIN) o Occurs as an ADVERSE reaction to certain drugs! o Synthetic PENICILLINS --> methicillin, ampicillin o Synthetic ANTIBIOTICS --> rifampin o DIURETICS --> i.e. thiazides o NSAIDS o Other --> phenindione, cimetidine Drug-induced INTERSTITIAL nephritis Mechanism is IMMUNE-mediated! Drugs act as HAPTENS (INCOMPLETE antigens) o During SECRETION by tubules, COVALENTLY BIND to cytoplasmic or extracellular component of TUBULAR cells and become IMMUNOGENIC! o Drug is IMMUNOGENIC ONLY when it binds to tubular cells! Does NOT elicit immune response by ITSELF --> definition of HAPTEN! Causes TUBULOINTERSTITIAL INJURY o Due to IgE and CELL-mediated IMMUNE reactions to TUBULAR CELLS and their basement membranes! Drug-induced INTERSTITIAL nephritis - presentation Disease begins 15 days after exposure to drug! CHARACTERIZED by: o Fever o EOSINOPHILIA o RASH o RENAL abnormalities! Urinary symptoms o HEMATURIA o Minimal or NO proteinuria o LEUKOCYTURIA --> eosinophils INCREASED plasma CREATININE levels or ACUTE kidney injury with OLIGURIA o In older patients! o TUBULAR function compromised --> GFR is REDUCED! Treatment o Clinical RECOGNITION is key WITHDRAWAL of injury-causing drug is followed by RECOVERY! MUST stop GIVING the drug! May take several MONTHS for renal function to return to normal! Vascular diseases of the kidney - MALIGNANT hypertension Defined as BP>200/120mmHg --> VERY HIGH BP! o Must be treated immediately! Far LESS common in USA than BENIGN hypertension and occurs in ONLY about 5% of persons with HYPERTENSION (HTN) o RARE form of HTN! May arise DE NOVO --> WITHOUT pre-existing hypertension! May appear SUDDENLY in a person who had MILD hypertension! PREVALENCE of MALIGNANT hypertension is HIGHER in LESS developed countries! o Probably because treatment is NOT widely available! Vascular diseases of the kidney - MALIGNANT hypertension INITIATION/TRIGGERING cause o VASCULAR damage to KIDNEYS --> REDUCED GFR and BLOOD flow to kidneys! o Due to LONG-TERM HYPERTENSION, with EVENTUAL INJURY to arteriolar walls! o Recall that LONG-term HTN can cause end-organ damage, and also ANEURYSMS, or vessel damage! Leads to RENAL ISCHEMIA and REDUCED GFR --> HYPERACTIVATED RAAS! o HYPOPERFUSED kidneys with REDUCED renal blood flow to them! o VICIOUS CYCLE in which ANG II causes INCREAED INTRARENAL VASOCONSTRICTION, which FURTHER causes ISCHEMIA, which FURTHER increases RENIN SECRETION POSITIVE feedback loop! INSTEAD of maintaining the GFR, ANG II vasoconstriction on efferent arterioles will REDUCE GFR, and cause MORE ischemia! ALDOSTERONE levels are ELEVATED o INCREASED Na+ and WATER retention --> further INCREASES BP! o Makes it WORSE! Cystic diseases of the kidney Normally does NOT cause any issues! Genetically HETEROGENEOUS disorders o HEREDITARY o DEVELOPMENTAL o ACQUIRED disorders! COMMON and often present DIAGNOSTIC problems! Some such as ADULT POLYCYSTIC disease --> lead to CHRONIC renal failure! Simple cysts are frequently confused with MALIGNANT tumors! Autosomal DOMINANT polycystic disease - ADULT Autosomal DOMINANT --> ADULT polycystic disease! Autosomal DOMINANT --> means only ONE copy of the gene has to be mutated to develop the cyst! Kidneys reach an ENORMOUS size! MULTIPLE expanding cysts affect BOTH kidneys that DESTROY the intervening parenchyma! Incidence --> 1 in 500/1000 persons o Accounts for 10% of cases of CHRONIC kidney disease! o Pretty COMMON! Causes o Genetically HETEROGENEOUS --> MORE than ONE gene is involved! Caused by INHERITANCE of ONE of at least TWO autosomal dominant genes of very HIGH PENETRANCE! ▪ This means MOST people who have the mutation WILL DEVELOP the disease! Penetrance --> means just because an individual has the autosomal DOMINANT mutation does NOT mean they will develop the disease ▪ 100% penetrance = EVERY person who has the gene develops the disease! ▪ Penetrance is the % of individuals with a given GENOTYPE who EXHIBIT the PHENOTYPE associated with that genotype! So penetrance is the PROBABILITY of a gene or trait being EXPRESSED! ▪ o HIGH penetrance means MOST individuals who have the autosomal dominant gene will probably EXPRESS the mutation in their phenotype and develop the CYST! Most common mutation --> PKD1 gene in CHROMOSOME 16 is DEFECTIVE! PKD1 --> encodes a LARGE and COMPLEX cell-membrane associated protein called POLYCYSTIN-1! PKD1 mutation responsible for ONSET of adult polycystic disease! Summary: o Mutations in PKD1 are autosomal DOMINANT and associated with onset of autosomal DOMINANT polycystic disease! Autosomal DOMINANT (ADULT) polycystic disease - presentation Symptoms VARIABLE --> develop between 30-40 years o CHRONIC! Renal FUNCTION changes o REDUCED GFR, INCREASED creatinine levels! Secondary complications o HYPERTENSION, and urinary INFECTION! Ultimately FATAL, but OUTCOME is generally BETTER than most chronic kidney diseases! Condition tends to be STABLE and SLOWLY PROGRESSIVE --> CHRONIC! END-stage kidney disease occurs at about 50 years --> ULTIMATELY FATAL! o But there is VARIABLE prognosis for disorder! o Nearly NORMAL life-spans reported!! Treatment o CRISPR and gene therapy? --> fix the mutation! Autosomal RECESSIVE polycystic disease - CHILDHOOD Autosomal RECESSIVE --> CHILDHOOD form of POLYCYSTIC kidney disease! RARE autosomal RECESSIVE disorder --> BOTH copies of the gene HAVE to be mutated! Due to mutation in PKHD1 gene in chromosome 6 o PKHD1 --> codes for membrane receptor protein FIBROCYSTIN! Occurs in 1/20000 births --> CONGENITAL! Summary: PKD1 mutation --> POLYCYSTIN, autosomal DOMINANT (ADULT) polycystic disease PKHD1 mutation --> FIBROCYSTIN, autosomal RECESSIVE (CHILDHOOD) polycystic disease Autosomal DOMINANT --> ONE copy of gene mutated, BETTER prognosis and survival rate! Autosomal RECESSIVE --> BOTH copies of gene mutation, WORSE prognosis, LOW survival rates! Autosomal RECESSIVE (CHILDHOOD) polycystic disease - presentation Numerous SMALL CYSTS in CORTEX and MEDULLA Affects BOTH kidneys! Cysts also seen in liver and bile ducts! Usually present at BIRTH YOUNG infants may die quickly from HEPATIC or RENAL failure --> because BOTH copies of gene are MUTATED! o So the prognosis is WORSE and MUCH MORE LETHAL and serious than ADULT polycystic kidney disease! Patients who survive infancy develop LIVER CIRRHOSIS --> CONGENITAL hepatic FIBROSIS! Renal stones - kidney stones UROLITHIASIS or KIDNEY STONES --> CALCULUS formation at ANY level in the urinary system! o Renal calculi = kidney stones o Most often, calculi arise in KIDNEY --> hence RENAL stones! Incidence rate o MORE common in MEN than WOMEN --> men>women! GENETIC origins and causes o FAMILIAL tendency and family history of stone formation! Types of renal stones 3 types of stones o CALCIUM stones o o MAGNESIUM stones URIC acid or CYSTINE stones! In all cases, an ORGANIC matrix of PROTEIN is present to allow stone to form! Main factor --> INCREASE in the urinary concentration of constituents of stone BEYOND their solubility in urine! o This is the case for ALL the stones --> must be HIGHER than solubility in urine! Formation of renal stones - CALCIUM Main factor --> INCREASE in the urinary concentration of constituents of stone BEYOND their solubility in urine. This is the case for ALL the stones! I.e. 50% of patients who develop CALCIUM stones have HYPERCALCIURIA but NOT associated with HYPERCALCEMIA! o So patient has HIGH calcium in URINE, but NOT high calcium in BLOOD o Hypercalciuria is NOT the same as HYPERCALCEMIA o Hypercalciuria --> excess calcium in URINE o Hypercalcemia --> excess calcium in BLOOD 2 types of HYPERCALCIURIA o ABSORPTIVE hypercalciuria ABSORB CALCIUM from gut in EXCESSIVE amounts --> ABSORPTIVE hypercalciuria Promptly excrete it! Summary: INCREASED absorption + PROMPT excretion of Ca2+! o RENAL hypercalciuria Have a primary RENAL defect in calcium REABSORPTION Kidneys do NOT reabsorb calcium well --> RENAL hypercalciuria! Summary: DECREASED renal reabsorption of Ca2+! Formation of renal stones - MAGNESIUM Main cause --> ALKALINE urine from UTIs! o Magnesium stones ALWAYS occur in persons with persistently ALKALINE urine resulting from UTIs! o This is NOT due to EXCESS magnesium in urine, but a change in the SOLUBILITY of magnesium in urine --> EXCESS magnesium salts PRECIPITATE OUT to lead to stones! UTIs and PYELONEPHRITIS o So one of the CONSEQUENCES for UTIs from pyelonephritis is MAGNESIUM RENAL STONE formation! Formation of renal stones - URIC acid Causes o Diseases of RAPID CELL TURNOVER --> INCREASED URIC ACID production in urine! GOUT and diseases involving RAPID cell turnover I.e. LEUKEMIA o Lead to HIGH uric acid levels and formation of uric acid stones! ACIDIC urine --> LOW pH favors URIC acid stone formation! URIC ACID stones are NOT associated with HYPERURICEMIA or increased urine urate Rather due to tendency to excrete persistently ACIDIC urine! COMPARE and contrast: MAGNESIUM stones --> ALKALINE urine! URIC acid stones --> ACIDIC urine! Formation of renal stones - CYSTINE Causes o Genetically DEFECTIVE RENAL TRANSPORT of amino acids such as CYSTINE o ACIDIC urine --> similar to URIC acid stones, CYSTINE stones are ALSO more likely to form when urine is relatively ACIDIC! Renal stones - presentation NO symptoms - ASYMPTOMATIC o Stones MAY be present WITHOUT producing any symptoms or any renal damage! o Usually applied to stones lodged in RENAL PELVIS RENAL COLIC - SYMPTOMATIC o SMALLER stones may PASS thru URETER and BLADDER, causing PAIN --> renal or ureteral COLIC! o Characterized by PAIN towards the GROIN o Leads to HEMATURIA! IF stones pass into the URETER and BLADDER, they become SYMPTOMATIC and cause pain called RENAL/URETERAL colic! Treatment o Medications to treat underlying causes such as ACIDIC or ALKALINE urine o Treatment of UTIs --> for treating alkaline urine! Acid/Base and Fluid Balance There are 58 slides, but some are BACKGROUND slides and will NOT go over all of them! Outline Biochemical concepts of acids, bases, pH etc. 3 forms of acid/base regulation o Bicarbonate BUFFER system o Regulation of acid-base balance by LUNGS --> RESPIRATORY acidosis/alkalosis o Regulation of acid-base balance by KIDNEYS --> METABOLIC acidosis/alkalosis! Acidosis and alkalosis Anion Gap Fluid Balance Definitions of acids and bases Acids --> proton DONORS Bases --> proton ACCEPTORS! Acids o HA H+ + A HA = acid A- = conjugate base o CH3COOH H+ + CH3COO Bases o NH4+ H+ + NH3 pH pH of a solution is a measure of its [H+] o pH = -log[H+] pH is precisely regulated in the body pH is BUFFERED at different values in body BLOOD pH --> between 7.35-7.45! pH in different parts of the body o EXTRACELLULAR fluid (ECF) ARTERIAL blood --> pH 7.40 VENOUS blood --> pH 7.35 INTERSTITIAL fluid --> pH 7.35 o INTRACELLULAR fluid (ICF) --> pH 6-7.4 (MORE variable) o URINE --> pH 4.5-8.0 o Gastric HCl (stomach) --> pH 0.8 The LOWER limit of pH of ARTERIAL blood at which a person can live MORE than a few hours is 6.8 and the UPPER limit is 8 o If blood pH falls OUTSIDE the 6.8-8.0 range, you will DIE! o pH MUST be buffered in a NARROW range! pH regulation in the body 3 major systems of acid-base regulation o CHEMICAL acid-base buffer systems --> BICARBONATE buffer system! Combine with an acid or base instantly to PREVENT EXCESSIVE changes in pH and [H+] IMMEDIATE control --> SECONDS! o RESPIRATORY center --> LUNGS Regulates the REMOVAL of CO2 and therefore H2CO3 from the ECF! RESPIRATORY acidosis and alkalosis! ACIDOSIS--> response is to REMOVE CO2 ALKALOSIS --> response is to RETAIN CO2 SHORT-TERM control --> MINUTES! o RENAL --> KIDNEYS EXCRETE either ACID or ALKALINE urine READJUST the EXTRACELLULAR fluid [H+] toward normal! METABOLIC acidosis and alkalosis! LONG-TERM control --> DAYS! Note that we need the KIDNEYS to COMPLETELY restore blood pH back to NORMAL! o INITIAL respiratory and BICARBONATE buffer systems are only SHORT term solutions! The bicarbonate buffer system is quantitatively the most important in the body - BBS BICARBONATE buffer system (BBS) helps BUFFER the pH of blood! CO2 + H2O H2CO3 H+ + HCO3-(Na+) Part 1: o H2CO3 is formed by reaction of CO2 and H2O CO2 + H2O H2CO3 o Catalyzed by CARBONIC ANHYDRASE! o SLOW reaction without carbonic anhydrase! o CARBONIC anhydrase ABUNDANT in --> ALVEOLI, epithelial cells of RENAL tubules, RBCs! Find in LUNGS, KIDNEYS, BLOOD! Part 2: o H2CO3 ionizes and WEAKLY IONIZES to form H+ and HCO3 H2CO3 H+ + HCO3o The BICARBONATE salt (HCO3-) is found as NaHCO3 in the ECF, which COMPLETELY IONIZES to form HCO3- and Na+ NaHCO3 Na+ + HCO3Response to adding ACID to bicarbonate buffer system CO2 + H2O H2CO3 H+ + HCO3 Steps 1. Add ACID --> ADD H+ to system 2. INCREASED H+ is BUFFERED by HCO3i. CHEMICAL acid-base BUFFER system compensation! 2. POE shifts to the LEFT --> MORE H2CO3 is produced! 3. This causes INCREASED CO2 and H20 production! 5. INCREASED CO2 --> STIMULATES RESPIRATION, which ELIMINATES and REMOVES CO2 from ECF i. RESPIRATORY compensation! 2. KIDNEYS will EXCRETE excess [H+] i. RENAL compensation! Overall, there are 3 levels of reaction happening in response to adding acid to BBS: o Increased H+ is BUFFERED by HCO3- --> CHEMICAL o INCREASED CO2 levels STIMULATE respiration to REDUCE CO2 --> RESPIRATORY o EXCESS [H+] is EXCRETED by KIDNEYS --> RENAL Response to adding BASE to bicarbonate buffer system CO2 + H2O H2CO3 H+ + HCO3 Steps 1. Add BASE --> ADD OH- to system! 1. H2CO3 dissociates to provide the H+ that reacts with OH- to form H2O and REDUCE a change in pH 1. INCREASED HCO3-, interacts with Na to form NaHCO3 2. As H2CO3 dissociates, its concentration DECREASES, causing MORE CO2 to combine with H2O to replace the H2CO3 1. DECREASED CO2 levels result --> which INHIBITS RESPIRATION and DECREASES rate of CO2 EXPIRATION to ADDS and RETAINS MORE CO2 i. Respiratory compensation 2. Kidneys EXCRETE MORE HCO3- to REMOVE excess as well! Summary: o Adding OH- (base) to system --> DECREASES CO2, H20, and H2CO3 levels i. HCO3- levels INCREASE! o Lungs --> DECREASE respiration to ADD CO2 o Kidneys --> EXCRETE HCO3- to REMOVE excess HCO3o This is the OPPOSITE of what happens when an ACID is added! Respiration controls acid-base balance - lungs Whenever you think of acid, think of CO2 --> acid = CO2 o The HIGHER the pCO2, the MORE acidic (LOWER pH) ACIDOSIS --> INCREASES pCO2 o Response: INCREASES respiratory rate to REDUCE acidosis (CO2 is REMOVED) INCREASED [H+], so INCREASED pCO2 --> INCREASED alveolar ventilation --> REDUCED pCO2 --> DECREASE [H+] back to normal! ALKALOSIS --> DECREASES pCO2 o Response: DECREASES respiratory rate to REDUCE alkalosis (CO2 is RETAINED) DECREASED [H+], so DECREASED pCO2 --> DECREASED alveolar ventilation --> INCREASED pCO2 --> INCREASE [H+] back to normal! Check out the graph - relationship between blood pH and alveolar VENTILATION rate o As pH DECREASES (more ACIDIC) --> alveolar ventilation INCREASES o As pH INCREASES (more BASIC) --> alveolar ventilation DECREASES! Note: o HIGHER [H+] --> means LOWER pH, ACIDIC o LOWER [H+] --> means HIGHER pH, BASIC Respiration controls acid-base balance - lungs Respiratory system CANNOT return the pH and [H+] FULLY back to normal when a disturbance OUTSIDE the respiratory system has altered pH o This means lungs are ONLY 50-75% effective within a FEW minutes o They are SHORT term, there's so much they can do in a short time! o We NEED the KIDNEYS for a COMPLETE COMPENSATORY RESPONSE! LUNGS are NOT enough for FULL restoration of pH! I.e. if the pH SUDDENLY decreased by adding ACID to ECF and pH FALLS from 7.4 to 7.0 o the RESPIRATORY system can ONLY return the pH to 7.2 or 7.3! o This response occurs within MINUTES! The OVERALL buffering power of the respiratory system is 1-2x as great as the buffering power of ALL other chemical buffers in the ECF combined! Summary: o INITIALLY, the CHEMICAL buffers will act --> bicarbonate buffer system o FOLLOWED by RESPIRATORY compensation --> LUNGS These are BOTH SHORT term, and try to get the pH as CLOSE as possible back to normal --> takes MINUTES! o The KIDNEYS FINISH up the job --> FULLY restore pH back to normal LONG-term control --> takes DAYS! Kidneys regulate acid-base balance There are 3 fundamental mechanisms by which kidneys regulate acid-base balance o SECRETION of [H+] --> PROTON secretion! o REABSORPTION of FILTERED [HCO3-] --> BICARBONATE reabsorption! o PRODUCTION/SECRETION of NEW [HCO3-] --> BICARBONATE secretion! Reabsorption of Bicarbonate (HCO3-) HCO3- is FILTERED into renal tubules H+ ions are SECRETED into tubular lumen by tubular epithelial cells IF: o [H+] secreted > [HCO3-] filtered --> NET LOSS of ACID from ECF, ACIDIC urine! o [H+] secreted < [HCO3-] filtered --> NET LOSS of BASE from ECF, ALKALINE urine! o So HCO3- is the BASE, and H+ is the ACID! The RATIO of HCO3- to H+ determines whether the urine is ACIDIC or ALKALINE! If we have: o ACIDOSIS --> kidneys will EXCRETE MORE [H+] to make urine ACIDIC, get rid of acid o ALKALOSIS --> kidneys will EXCRETE more [HCO3-] to make urine ALKALINE, get rid of base! Kidneys regulate acid-base balance Daily, kidneys filter about 4320mEq HCO3 Almost ALL HCO3- is REABSORBED from the tubules! o 99.9% of HCO3- is reabsorbed! HCO3- MUST react with SECRETED H+ to form H2CO3 before it can be REABSORBED! o Therefore, 4320mEq of H+ MUST be SECRETED each day to just REABSORB the filtered HCO3 ADDITIONALLY, each day, body produces about 80mEq nonvolatile ACIDS, mainly from metabolism of proteins! o Therefore, ADDITIONAL 80mEq of H+ MUST be secreted! If we have: o ALKALOSIS --> kidneys will EXCRETE MORE [HCO3-] to REDUCE alkalosis o ACIDOSIS --> kidneys will EXCRETE MORE [H+] to REDUCE acidosis Reabsorption of bicarbonate in proximal tubule, THICK segment of loop of Henle, and early distal tubule We have the tubular lumen, tubular cells, and renal interstitial fluid o We have BICARBONATE in the tubular LUMEN o Na/H exchanger (NHE) on the LUMINAL side o Na/K ATPase, and Na/HCO3- CO-transporter on the BASOLATERAL side On the LUMINAL side o NHE removes Na+ from HCO3- and SECRETES H+ into the LUMEN to have H+ REACT with HCO3- to form H2CO3 --> H + HCO3- --> H2CO3 o H2CO3 --> H20 + CO2, H2CO3 DISSOCIATES into CO2 and H20, since this is fast reaction! o CO2 diffuses across LUMINAL side of membrane INTO the cell! INSIDE the cell o The REVERSE reaction happens now! o The cells have CARBONIC ANHYDRASE (CA) enzyme to re-form H2CO3 o CO2 + H20 --> H2CO3, H2CO3 is re-formed! o H2CO3 now DISSOCIATES again to FORM HCO3- + H+ H2CO3 --> H+ + HCO3 On the BASOLATERAL side o Na/HCO3- CO-transporter helps transport HCO3- to the renal INTERSTITIAL fluid! o HCO3- has now been REABSORBED into the intersitial space! Consequence: Bicarbonate (HCO3-) has been REABSORBED from tubular LUMEN to the INTERSTITIAL fluid in the kidneys o One HCO3- in the lumen becomes one HCO3- in the cell that is then transported OUT thru the BASOLATERAL side to the renal interstitial fluid! o In doing so, HCO3- HAD to react with SECRETED H+ ions to form H2CO3 to be reabsorbed! Note: We need 2 things for this to work: o Na/H exchanger MUST SECRETE H+ to react with HCO3- in the LUMEN to REABSORB HCO3- as H2CO3 o Carbonic ANYDRASE MUST be present in tubular cells to re-form HCO3- in cells from H2CO3 to pump it out! Combination of H+ with ammonia and phosphate buffers When H+ is SECRETED in EXCESS of HCO3- filtered INTO the tubular fluid, ONLY a small part of the excess H+ can be excreted in the ionic form H+ in the URINE! o Minimal urine pH is 4.5! --> For each liter of urine formed, a MAXIMUM of ONLY about 0.03mEq of free H+ can be excreted! So NOT much H+ in urine! To EXCRETE the 80mEq of nonvolatile acid formed by METABOLISM each day (TOXIC metabolites), about 2667L of urine would have to be excreted if the H+ remained FREE in solution o This is a LOT of urine we need to excrete JUST to get rid of the metabolic acidic waste products! HOW do we EXCRETE H+ then? o By COMBINING H+ with PHOSPHATE and AMMONIA buffers in the tubular fluid! WHY is this a problem?? o o o Imagine a situation where we do NOT have a HCO3- (bicarbonate) ion in the lumen! Then we will have EXCESS H+ SECRETED in the lumen, and this can lead to ACIDOSIS!! We do NOT want this! Solution o Once the bicarbonate is reabsorbed, H+ will react with AMMONIA and PHOSPHATE buffers to get EXCRETED, so we don't get excess H+ in urine and acidosis! Combination of H+ with phosphate - generates a NEW additional bicarbonate When HCO3- is PRESENT in lumen o H+ in lumen will COMBINE with it to form H2CO3 When HCO3- is ABSENT in lumen o H+ in lumen will combine with OTHER buffers such as PHOSPHATE/AMMONIA to be EXCRETED! o HCO3- is STILL formed in renal cells, and is STILL absorbed into the blood! Since CO2 is coming into the cell from the blood (interstitial fluid) and NOT from the lumen! o This results in NET GAIN of ONE BICARBONATE (HCO3-)! o There is NO bicarbonate re-absorbed from the tubular LUMEN, but STILL we have a bicarbonate made by the renal epithelial cells that is re-absorbed into the blood! o INCREASED BICARBONATE REABSORPTION HELPS IN DEALING WITH ACIDOSIS, and INCREASES pCO2! Combination of H+ with phosphate buffers Under normal conditions, much of the filtered phosphate is reabsorbed and only 30-40mEq are available for buffering H+ Therefore, MOST of the BUFFERING of EXCESS H+ in the tubular fluid in ACIDOSIS occurs thru the AMMONIA buffer system! o So the AMMONIA buffer system is MORE significant! Combination of H+ with ammonia Same concept as phosphate buffers When HCO3- is not present, excess H+ combines with ammonia buffers to be excreted NET GAIN of one HCO3-, helps deal with ACIDOSIS! Formation of maximally acidic urine - LATE DISTAL tubule/collecting tubules Happens in LATE distal tubule Secretion of H+ in the LATE distal tubule and collecting tubules accounts for ONLY about 5% of total H+ secreted! o But this is VERY important in forming MAXIMALLY ACIDIC urine! In PROXIMAL tubules, H+ concentration can ONLY be increased 3-4x and tubular fluid pH can be reduced to 6.7! But H+ concentration can be INCREASED 900x in the LATE DISTAL TUBULE and collecting tubules! o This DECREASES the pH of tubular fluid and urine to about 4.5, which is the LOWER limit of pH that can be achieved in normal kidneys! Intercalated cells in LATE distal tubule and cortical collecting ducts - Types A and B Type A INTERCALATED cells o SECRETE [H+], REABSORB [HCO3-] o RESPOND to ACIDOSIS! --> Goal is to REMOVE H+, or excess ACID! o H+ is secreted by hydrogen-ATPase transporter and by H/K+ ATPase transporter o Particularly important for REMOVAL of H+! H+ transporters on LUMINAL membrane, bicarbonate transporter on BASOLATERAL membrane! Type B INTERCALATED cells o SECRETE [HCO3-], REABSORB [H+] o RESPOND to ALKALOSIS! --> Goal is to REMOVE HCO3-, or excess BASE! o This is the OPPOSITE of type A cells --> because LOCATION of transporters is OPPOSITE to that of type A cells Basolateral and luminal membranes have SWITCHED! But everything else is the SAME! Bicarbonate transporters on LUMINAL membrane, H+ transporters on BASOLATERAL membrane! Intercalated cells are the main RENAL COMPENSATORY mechanism for acidosis and alkalosis! Factors that influence acid-base balance - summary ACIDOSIS --> INCREASE [H+] secretion and [HCO3-] reabsorption (what causes this?) o Increased pCO2 o Increased [H+], decreased [HCO3-] o DECREASED ECF volume (extracellular fluid volume) o INCREASED ANG II o INCREASED ALDOSTERONE! ALKALOSIS --> DECREASE [H+] secretion and [HCO3-] reabsorption o Decreased pCO2 o Decreased [H+], increased [HCO3-] o INCREASED ECF volume o DECREASED ANG II o DECREASED ALDOSTERONE! How do aldosterone and angiotensin II INCREASE H+ secretion? Recall that Aldosterone and ANG II are important for RAAS --> increased Na+/fluid retention and maintaining GFR! ALDOSTERONE and ANG II collectively --> INCREASE [H+] SECRETION! o Response to ACIDOSIS! Mechanism o ALDOSTERONE --> directly stimulates [H+] excretion in TYPE A INTERCALATED cells! o ANG II --> directly stimulates the Na/H+ exchanger in tubular cells and RELEASES ALDOSTERONE Has an INDIRECT effect on stimulating [H+] excretion! o DECREASED ECF stimulates BOTH ANG II and aldosterone!! ACIDOSIS response! o INCREASED ANG II --> increase H+ excretion o INCREASED aldosterone --> increase H+ excretion o DECREASED ECF --> INCREASES ANG II and aldosterone levels, which increase H+ excretion! Note: If TOO much [H+] is excreted by these mechanisms, ALKALOSIS can occur! Question - is CO2 from blood always reacting to make carbonic acid (H2CO3)? YES There is NO other way to directly get H2CO3 into the tubular cells CO2 is the easiest way since it diffuses across the cell membranes! Lecture 11 - Acid-Base Regulation and Intro to Respiratory Physiology Respiratory and metabolic acidosis and alkalosis RESPIRATORY acidosis o Problem in LUNGS, CANNOT excrete enough CO2 o Caused by INCREASE in pCO2 --> REDUCES pH and INCREASES [H+] o CAUSE --> HYPOVENTILATION, increased pCO2! Disorders that REDUCE alveolar ventilation, such as pneumonia, emphysema, diseases of respiratory center of brain etc. o RESPONSE --> RENAL compensation, since the problem is in the LUNGS! KIDNEYS SECRETE [H+], REABSORB [HCO3-] KIDNEYS secrete MORE [H+] to REMOVE excess ACID! --> ACIDIC urine! KIDNEYS reabsorb MORE [HCO3-] to PLASMA! Respiratory and metabolic acidosis and alkalosis RESPIRATORY alkalosis o Problem in LUNGS, excreting and REMOVING TOO MUCH CO2 o Caused by DECREASE in pCO2 --> INCREASES pH and DECREASES [H+] o CAUSE --> HYPERVENTILATION, decreased pCO2! Not very common! No lung disorders! PHYSIOLOGICAL respiratory ALKALOSIS at HIGH altitude --> due to HYPOXIA! ▪ o LOW oxygen STIMULATES respiration! RESPONSE --> RENAL compensation, since problem is in the LUNGS! KIDNEYS SECRETE [HCO3-], REABSORB [H+] --> ALKALINE urine! OR, kidneys DECREASE [H+] secretion, which DECREASES [HCO3-] reabsorption --> same thing! Corrects alkalosis! Respiratory and metabolic acidosis and alkalosis METABOLIC acidosis o DECREASE in pH --> INCREASE in [H+], DECREASE in [HCO3-] o RESPONSES PRIMARY RESPIRATORY compensation --> HYPERVENTILATION to REDUCE pCO2! Kidneys REABSORB more [HCO3-] --> due to association of H+ ions with other buffers! Also EXCRETE more [H+] CAUSES of metabolic acidosis RENAL tubular ACIDOSIS o Defective renal secretion of [H+], reabsorption of [HCO3-] o CHRONIC renal failure --> INSUFFICIENT ALDOSTERONE secretion (ADDISON'S disease) Remember aldosterone INCREASE [H+] excretion, so LESS aldosterone means LESS [H+] excretion Severe DIARRHEA o MOST common cause! o Leads to LOSS of sodium BICARBONATE, leading to metabolic acidosis DECREASED [HCO3-] DIABETES mellitus o Compromised glucose metabolism leads to INCREASED production of acetoacetic acid!! Consumption of ACIDIC poisons CHRONIC renal failure o DECREASED excretion of WEAK ACIDS o INCREASED new BICARBONATE production --> DECREASED GFR, which reduces excretion of phosphate and ammonium buffers! So MORE [H+] will combine with buffers to produce MORE [HCO3-]! Respiratory and metabolic acidosis and alkalosis METABOLIC alkalosis o INCREASED pH --> due to INCREASED [HCO3-], decreased [H+] o RESPONSES PRIMARY RESPIRATORY compensation --> HYPOVENTILATION to IINCREASE pCO2! KIDNEYS SECRETE more [HCO3-] --> by filtering MORE [HCO3-] than [H+] secreted! CAUSES of metabolic alkalosis NOT as common as metabolic ACIDOSIS! LOOP and THIAZIDE diuretics --> STIMULATES RAAS EXCESS aldosterone secretion --> HYPERACTIVATION of RAAS o Also remember that aldosterone INCREASES [H+] excretion --> lea VOMITING of intestinal contents o Seen in neonates with pyloric stenosis! o Vomiting --> means REDUCED [H+] INGESTION of ALKALINE drugs! o I.e. sodium bicarbonate Why do diuretics cause metabolic alkalosis Diuretics INCREASE delivery of Na+ and H20 to distal tubule/collecting ducts o INCREASED Na+ and FLUID LOST to the TUBULAR lumen! Leads to INCREASED [Na+] reabsorption --> due to STIMULATION of ALDOSTERONE secretion via STIMULATED RAAS o Because net NaCl concentration in tubular lumen decreases? Sodium reabsorption in DISTAL tubules/collecting ducts is COUPLED with K+ and H+ secretion! o INCREASED [Na+] reabsorption due to STIMULATED RAAS --> INCREASED [K+] and [H+] SECRETION! o Consequently, MORE [H+] and [K+] are LOST to the urine --> ALKALOSIS and HYPOKALEMIA! o These changes leads to ALKALOSIS and HYPOKALEMIA (low K+) Aldosterone and angiotensin II increase H+ secretion - review Recall that ALDOSTERONE --> STIMULATES [H+] excretion by intercalated cells! ANG II --> STIMULATES Na/H+ exchanger and stimulates ALDOSTERONE release o Collectively, BOTH aldosterone and ANG II from RAAS --> INCREASE [H+] excretion, and [K+] excretion! o This leads to ALKALOSIS and HYPOKALEMIA! DECREASED ECF blood volume --> stimulates ANG II, aldosterone (RAAS)! Potassium sparing diuretics do NOT induce metabolic acidosis K+ sparing diuretics such as ALDOSTERONE antagonists and Na+ channel blockers do NOT induce metabolic alkalosis! When aldosterone-sensitive Na+ reabsorption is INHIBITED o LESS [K+] and [H+] are EXCRETED in exchange for the [Na+] in the lumen! o Therefore, K+ and H+ are NOT lost to the urine --> so NO alkalosis or hypokalemia! Diagnosis of acidosis and alkalosis Summary figure! Anion gap to diagnose acidosis - metabolic acidosis The ANION gap can be used to DIAGNOSE METABOLIC ACIDOSIS! The CONCENTRATIONS of ANIONS and CATIONS in plasma MUST be EQUAL to maintain electrical NEUTRALITY --> [anion-] = [cation+] for neutrality! o Therefore, there is NO real anion gap in plasma CATIONS --> Na+ ANIONS --> Cl- and HCO3The ANION gap is the DIFFERENCE between primary measured CATIONS and primary measured ANIONS o Plasma ANION gap = [Na+] - [HCO3-] - [Cl-] 144-24-108 = 12 mEq/L Anion gap to diagnose acidosis Plasma ANION gap = [Na+] - [HCO3-] - [Cl-] o 144-24-108 = 12 mEq/L o [Na+] = 144 o [HCO3-] = 24 o [Cl-] = 108 In metabolic ACIDOSIS, [HCO3-] is REDUCED and [Na+] is UNCHANGED o So, [Cl-] and the concentration of ANIONS must INCREASE to maintain NEUTRALITY! IF o [Cl-] INCREASES in proportion to DECREASED [HCO3-], the anion gap will be NORMAL --> called HYPER-CHLOREMIC metabolic acidosis! I.e. if [HCO3-] falls to 20, but [Cl-] increases to 112 --> the anion gap is STILL 12mEq/L! HYPER-chloremic means the [Cl-] INCREASED as [HCO3-] DECREASED, and the anion gap is NORMAL! o [Cl-] does NOT increase in proportion to DECREASED [HCO3-], so there MUST be INCREASED levels of UNMEASURED ANIONS, therefore an INCREASED ANION GAP! NORMO-CHLOREMIC metabolic acidosis! NORMO-chloremic means [Cl-] is UNCHANGED as [HCO3-] DECREASED, and the anion gap is INCREASED! Why do we care about this? --> because we want to know the CAUSE of metabolic acidosis! o If we have NORMO-chloremic acidosis, this means the INCREASED anion gap is caused by EXCESS NONVOLATILE metabolic acids! o Metabolic acidosis CAUSED by EXCESS nonvolatile METABOLIC ACIDS such as lactic acids and ketoacids --> associated with INCREASED ANION GAP o DECREASED [HCO3-] is NOT accompanied by an equal increase in [Cl-]! Anion gap to diagnose acidosis INCREASED anion gap --> NORMO-chloremic, due to NON-VOLATILE acids! o Diabetes --> KETOACIDOSIS o LACTIC acidosis o Chronic renal failure NORMAL anion gap --> HYPER-chloremic o Diarrhea o o Renal tubular acidosis Addison's disease Treatment of acidosis and alkalosis Best treatment is to REMOVE the CAUSE, but this is difficult or impossible! Therefore, agents tah can NEUTRALIZE the acid or base have to be used! For ACIDOSIS --> give SODIUM BICARBONATE! For ALKALOSIS --> give AMMONIUM CHLORIDE! o When NH4Cl is absorbed into blood, ammonia converted by liver into UREA! o This frees up HCl, which reacts with BUFFERS of body fluids to SHIFT [H+] in ACIDIC direction! Fluid balance Water balance Intake --> fluids INGESTED Output --> fluids EXCRETED! INTAKE has to match OUTPUT --> in NORMAL conditions! In EXERCISE, there is risk of DEHYDRATION --> depending on how severe it is! Body fluid regulation Figure shows fluid DISTRIBUTION in body! o ECF --> 14L Plasma/INTRAVASCULAR volume INTERSTITIAL fluid Plasma and interstitial fluid have SAME composition EXCEPT proteins! o ICF --> 28L COMPOSITION of ICF is SIMILAR across ALL FORMS of LIFE! o ICF is DOUBLE the volume of ECF! Total body water is 60% body weight in MEN, 50% in WOMEN, and 70-75% in newborns! o This suggests LOSS of WATER WEIGHT as you get OLDER! Composition - cations and anions in ECF vs ICF Ions in ECF vs ICF ECF --> predominantly Na+, Cl-, and HCO3 ICF --> predominantly K+, phosphates Summary: o ECF --> Na+, Cl-, HCO3o ICF --> K+ o Recall that Na+ is HIGH in ECF, K+ is HIGH in ICF! Composition No need to know the values in table! In ECF --> 80% of total osmolarity is due to Na+ and Cl- ions! In ICF --> 50% of osmolarity is due to K+ ions! TOTAL osmolarity of ICF + ECF (plasma + interstitial) = 300mOsm/L Slightly GREATER osmolarity in PLASMA due to COLLOID OSMOTIC PRESSURE effect of plasma PROTEINS! Principle of osmosis Cell membranes are SELECTIVELY permeable --> IMPERMEABLE to MOST solutes, but HIGHLY permeable to water! Osmosis --> water moves from LOW to HIGH SOLUTE concentration o So water moves to region of HIGHER solute concentration! 3 behavi

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