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Renal Physiology.docx

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Western University
Physiology 3120
Tom Stavraky

Renal Physiology Renal Anatomy • Kidneys are important organs that carry out a number of functions • Kidneys remove waste products form our bodies  collected as urine o Urea o Creatinine o Ammonia • Overview of Kidney Function o Regulates ionic composition of blood o Regulates blood pH (7.3-7.4) o Regulates blood volume o Regulates blood pressure o Maintains blood osmolarity (concentration of all molecules found in blood – approx. 300 mOsm) o Produces hormones (EPO – erythropoietin & indirectly angiotensin II) o Regulates blood glucose levels (gluconeogenesis) o Excretes wastes & foreign substances Kidneys • 2 bean-shaped • Located posteriorly to abdomen – on each side of spine th th • Approx. at the level of 11 & 12 rib • Technically outside abdominal cavity – sandwiched between membranes that line the abdomen & bones/muscles of back (retroperitoneal) • Blood supply enters & exits inner (concave) side of each kidney • Exit of the ureter comes from the inner side of each kidney – carries urine from the kidney to the bladder • Cortex o Outer tissue layer o Smooth with granules (nephron glomeruli) • Medulla o Inner tissue layer o Triangular/pyramid o Striated o Organized radially • Renal Pelvis o Waste collects (filtrate) – fluid-filled o Centre of kidney • Calyces o Organized radially o Collects filtrate o Brings it to the centre of kidney like funnels • Renal artery o Blood flows into kidney • Renal vein o Blood flows out kidney • Ureter o Removes filtrate (urine once in calyces) • Kidney à ultrafiltrate or filtrate à once fluid is in calyces you can call it urine • Organ Blood Flow o Kidney makes up less than 0.5% of whole body mass - receives ~20% of total CO in a day o Blood travels to the kidney via left & right renal arteries o After blood supply is divided to provide blood to individual filtering units of the kidney: nephrons o Have about 5-6 L of blood o Filtered & processed in 20- 25 minutes Renal Blood Flow Nephron  Smallest functional unit of kidney  Each kidney has approx. 1 million nephrons  Made of 2 basic structures o Renal corpuscle  Glomerulus  Bowman’s capsule o Tubule  Divided into specific sections based on structure & function differences  Made up of single layer of epithelial cells  Can undergo cell death and the kidneys will be fine o Only if nephrons reach critical number then kidney failure occurs  Multiple nephrons converge on one collecting duct (5-10)  Renal corpuscle is near proximal & distal tubule - twisted on top  Nephrons are categorized based on their anatomical distinct locations within the kidney (lending to variations in overall function within the kidney)  Made up of 2 basic structures: o Rena l corpuscle (composed of glomerulus & Bowman’s capsule) o Tubule (subdivided into specific sections based on functional & structural differences) Renal-Corpuscle Components • Found in the cortex of the kidney – granular appearance of the cortex • Made of two structures: o Bowman’s capsule  Fluid- filled hollow ball-like structure that surrounds the glomerulus  Inside capsule: Capsular or Bowman’s space – fluid from blood can filter into  Continuous with the beginning of the first part of the tubule: proximal tubule  Cells are parietal epithelial cells o Glomerulus or glomeruli capillaries  Specialized structure of “leaky” or fenestrated capillaries  Cells are called endothelium (specialized type of epithelial cells)  Cells have many pores (fenestrae) so that basically everything in blood besides red blood cells, white blood cells & proteins can filter out  Endothelium is fused with epithelium of Bowman’s capsule • Cell layer that fuses these 2 structures: basal lamina (or basement membrane) o Composed of collagens, proteoglycans & negatively charged glycoproteins o Double basal lamina layer o Serves as rough sieve to filter & exclude most plasma proteins form entering Bowman’s capsule • Third filtering component is specialized cells that surround glomerular capillaries called podocytes o Cell portion of capsule that fuses to capillaries o Visceral layer – special type of epithelial cells o Long “foot-like” processes that interlace with each other & around the glomerular capillaries (purple) o Are also connected to basal lamina o Leaves narrow filtration slits around capillaries to provide further barrier to what is filtered into capsule (pink) – material cannot go through podocytes • Afferent arteriole – enters renal corpuscle • Efferent arteriole – leaves renal corpuscle • Not all blood is not filtered into Bowman’s Space  blood leaves via efferent arteriole • Juxtaglomerular apparatus o Tube of cells between afferent & efferent arteriole o Nephron’s tubular segment – tubule wraps back to renal corpuscle (late part of ascending limb of loop of Henle) o Purple cells – macula densa cells • Juxtaglomerular/granular cells o Beside afferent arteriole o Secrete enzymes important for kidney function o Close to juxtaglomerular apparatus – sit beside macula densa cells • Barriers to filtration o oSize of pores of capillaries o Double basal lamina o Filtration slits – podocytes Clinical Note: Urine Tests • Urine is an easily testable excretion of the body that can identify overall health • Barriers to filtration exclude protein (most), as well as red & white blood cells – should not be detected o Fenestrations can become bigger o Basal lamina changes properties o Filtration slits can enlarge • Reasons for finding proteins o Infection o Pregnanacy o Ingesting too much protein • Reason for findings RBC & WBC o Infections • Urine test strips have been generated that use a colourimetric reaction to indicate the presence of these and other substances in urine • Other substances that can be detected in urine to identify pathology or physiological differences: glucose, ketones, pH, bilirubin & hCG • Glucose should not be excreted – very important biological molecule  find it: diabetes Tubules Anatomy • Sections of tubule have distinctive function based on the cells that make up structure (cellular structure) • Tubule of nephron is made of a single layer of epithelial cells attached to a basement membrane • Tight junctions proteins seal these cells tightly to each other • However, each section of the tubule varies in the type of epithelial cell and in the level of how tight these junctions are • Generally polar – different functions at either side of membrane Proximal Tubule • Microvilli on inner (luman) side of membrane • Microvilli – increase surface area – allow for more interactions with filtrate – more ability to process filtrate Thin Limb Cells • Very flattened in nature • Simple squamous – fragile • Have absorptive function but are delicate in nature Collecting Duct Cells • Principle cells o Few microvilli – some increase in SA • Intercalated cells o Long microvilli – great increase in SA Processes of Nephron • Kidneys filter 180 L of plasma a day • We only excrete approx. 1.5 L of urine a day • Most of the filtrate must be reabsorbed back into our body • Filtration: movement of substances & solvent from blood into bowman’s capsule • Reabsorption: movement of substances from tubule back into bloodstream (glucose, amino acids, water & ions) • Secretion: rare, movement of substances from the blood (that was not originally filtered into bowman’s space) to the tubule (ex. drugs) • Excretion: anything left in tubule  leave the body as urine Glomerular Filtration • In healthy kidneys, from all blood that enters the kidneys, approx. 20% is filtered into Bowman’s space • Rate of fluid filtration is carefully regulated as to prevent filtering too much into nephrons or too little • Fluid that filters into Bowman’s space = ultrafiltrate • Consequences of filtering too much fluid into kidneys o Risk of damaging nephrons – reducing renal health (are not capable of regenerating) • Consequences of filtering too little fluid into kidneys o No balance of ions & water o Don’t excrete toxins Glomerular Filtration Rate (GFR) • Amount of fluid/solutes that are filtered per unit time into Bowman’s space from glomerular capillaries • Rate of filtration is due to forces in the nephron - combination of forces are called net filtration pressure o Hydrostatic pressure of glomeruli capillaries (P )GC  Pressure of blood flowing through glomerular capillaries  How much pressure is exerted by heart & how much blood is getting to kidney  Favors filtration  ~55 mmHg o Colloid osmotic pressure of glomeruli capillaries (π ) GC  Pressure created due to presence of proteins (blue blobs)  Most proteins stay in glomerular capillaries so higher pressure here – drawing water to proteins  Favors reabsorption  ~ - 30 mm Hg o Hydrostatic pressure of Bowman’s capsule (BC)  Pressure of fluid already in Bowman’s capsule creates back pressure (fluid that has filtered already)  Favors reabsorption  ~ - 15 mm Hg o Colloid osmotic pressure of Bowman’s capsule (πBC  Pressure created due to presence of proteins in Bowman’s capsule  But almost no protein in Bowman’s capsule, ~ 0 mm Hg Net filtration pressure = (P GC + π )-BCπ GC + P ) BC Since π BC ~ 0, then (only in healthy kidney) = P GC – π GC - P BC = 55 mm Hg – 30 mm Hg – 15 mm Hg = + 10 mm Hg < 10 mm Hg – not filtering enough > 10 mm Hg – filtering too much Filtration Coefficient • Net filtration pressure contributes the most to GFR • Filtration coefficient can also effect the rate of fluid filtration in the kidney • Determined by how much surface area is available for filtration (filtration sites are bigger or pores are bigger) – change permeability • Increasing space between podocytes – increase GFR • Increasing permeability of basal lamina or size of glomeruli pores – increase GFR GFR Regulation by Renal Blood Flow • Local constriction and dilation of the afferent & efferent arteriole regulates the blood flow to the corpuscle and therefore affects GFR • Arterioles contain smooth muscle – so they have the ability to constrict & dilate • Constriction of arterioles o Afferent arteriole constriction: decrease rate of blood flow after constriction  less blood into glomeruli  increase in GFR  less filtration (decrease hydrostatic pressure of capillaries) o Efferent arteriole constriction: build-up fluid (blood) in the glomeruli – increase in GFR • Autoregulatory mechanisms of kidney to protect kidney’s from changing blood pressures • Myogenic Response o Steps  Afferent arteriole stretches  Stretch sensitive ion channels open in response to stretch  Smooth muscle cells in arteriole depolarize  Voltage-gated calcium channels in smooth muscle to open  Smooth muscle contracts (arteriole constricts)  Blood flow decreases in glomerulus (decrease GFR) • Tubuloglomerular Feedback o High GFR increases too much: more water and salt are filtered through o Actual content of filtrate can regulate GFR locally o Tubule twists upon itself – late part of ascending limb of loop of Henle passes through afferent & efferent arteriole o Macula densa: salt-detector cells that are found at this specialized junction o Cells sense filtrate content and if Na /Cl levels are too high (GFR is too high) cells release chemical signal that stimulates afferent arteriole to constrict & reduce GFR How to Measure GFR • Cannot measure amount of fluid that filters into our nephrons without being invasive – difficult to do • We can extrapolate information because urine is the output of the kidney • Urine (& blood) is an easy fluid to analyze – most substances are filtered, those substances that are filtered can then be reabsorbed or some of that substance is secreted into the filtrate • When examining the output of kidney: Excretion [substance X] = Filtration [substance X] – Reabsorption [substance X] + Secretion [substance X] • Finding Rate of Filtration o Need to obtain substance that is filtered but Isn’t reabsorbed & isn’t secreted • Is measuring total urine produced in a day (volume) sufficient for determining how much fluid was filtered in the kidney in a day? o Need to eliminate reabsorption and secretion to get rate of filtration o Creatinine – waste product o Make in our body all the time, no problem filtering & excreting it o One problem it is secreted a little it o Plant protein insulin – in a clinic inject individual with this – so measure how fast it takes them to excrete it o The best thing to measure but more invasive [creatinineplasma 4 mg/L (measured) [creatinineurine 300 mg creatinine/L of urine (measured) Urine volume = 2.4 L of urine/day (measured) Creatinine excretion rate = [creatinineurine Urine volume GFR = creatinine excretion rate ÷ [creatinine]plasma GFR = 300 mg/L x 2.4 L/day ÷ 4 mg/L = 180 L/day = 125 mL/min Renal Handling • Output of urine & substances found in urine does not tell us how the substance was handled in kidney • Calculate GFR & know how much of substance was dissolved in plasma –can determine renal handling Filtered Load of X = [X] x GFR plasma Determined that plasma concentration of glucose is 1 mg/mL plasma Calculated that GFR is 125 mL/min Filtered load = [glucose] x GFR plasma Filtered load = 1 mg/mL x 125 mL/min Filtered load = 125 mg glucose/min Healthy kidneys absorb 100% of glucose that was filtered Ex. Filtered load of Na is 630 g per day but find no Na in the urine – Na was completely reabsorbed Tubule Transport Mechanisms • Proximal tubule o Reabsorb ions & water o Hub of reabsorption • Collecting duct o Fine tuner of the filtrate o Reabsorbs together with distal convoluted tubule (14%) o Selective to what it absorbs depending on status of body • 1% of filtrate is excreted • Tubule is made of a single cell layer of epithelial cells attached to basement membrane • Polar epithelial cells – membranes have different functions • Cells are physically linked together via tight junctions • Luminal or Apical Membrane: facing inside of tubule or lumen • Basolateral Membrane: faces the outside (interstitium of the kidney) • Paracellular: reabsorption in between cell (level varies depending on location) o Don’t need carriers – not restricted by lipid membrane • Transcellular: reabsorption through a cell o CO 2an diffuse o H2Oneeds aquaporins (channels)  need channels on both membranes • Secretion o Rare & specific o Blood  basolateral membrane  tubule cell  luminal membrane  tubule lumen Na Reabsorption + + + • Na is low inside cell ~5 mM Na as compared to interstitial (extracellular) fluid ~150 mM Na • K is high inside the cell as compared to outside • Because filtrate in the lumen is derived from the blood plasma, it has a Na concentration of ~150 mM + • Na will always want to leave filtrate into tubule cell – large concentration gradient – drives reabsorption • If there are ion channels & transporters for Na in luminal membrane – then it will move into tubule cells + • Active transporters on basolateral membrane that moves Na out of tubule cell – concentration gradient is maintained Na Channels • Properties: simple diffusion, Na moves from [high] to [low] • Locations: luminal membrane of each section of the tubule with the exception of the proximal tubule • Additional notes: some are hormonally regulated in the nephron (in response to low Na levels) + o Change location of Na channel o Change gene expression + Na Symporters • Properties: protein carriers, facilitated diffusion, Na moves from [high] to [low] but other ions can move + against their gradients, moves Na ion in the same direction across a membrane with one or more other ions/molecules • Types: Na /glucose (2 Na or 1 Na & 1 glucose), Na /amino acid, ion multiplier (Na /2 + + - chloride/potassium), Na /Cl • Location: luminal membrane of proximal tubule (most), ascending limb of the loop of Henle, & distal convoluted tubule • Additional notes: some symporters require more than one Na ions to drive the transporter (ex. Na /glucose uses 2 or 3) + Na Exchangers (Antiporters) • Properties: facilitated transport, moves Na across membrane & other ion in opposite direction + + + + • Types: Na /H , Na /Ca • Location: luminal membrane of proximal tubule, basolateral membrane of the distal convoluted tubule, basolateral membrane throughout the tubule • Additional Notes: Na /H exchanger is hormonally regulated + **reabsorb Na paracellularly Anion Transport: Chloride • Ion reabsorption must remain electroneutral • Chloride is the major anion reabsorbed • 60% of chloride is reabsorbed in proximal tubule • **bicarbonate we want to absorb • Trouble with chloride o Transport is against an electrical gradient into tubule cells – inside of tubule cells are –ve (-70) o Transport out of tubule cells must have a chemical gradient – Cl is high outside Chloride Channels • Properties: simple diffusion, chloride moves from [high] to [low] • Locations: basolateral membrane of the ascending limb of the loop of Henle & distal convoluted tubule • Additional Notes: all chloride reabsorption in the proximal tubule is paracellular Chloride Symporters • Types: ion multiplier (Na / 2 Cl/K ), Cl/K , Na /Cl - • Properties: facilitated transporters, moves at least 1 ion down concentration gradient from [high] to [low] • Locations: Ascending limb of loop of Henle & distal convoluted tubule, some on luminal, some on basolateral • Additional Notes: all ions need to be present in order for the carrier to change conformation **also reabsorbed paracellular – proximal tubule Water Reabsorption Water Channels • Types: Aquaporins (AQ) I, II, III, IV • Locations: all tubule segments (luminal & basolateral membranes) BUT not in ascending limb of loop of Henle or distal convoluted tubule • Properties: H O2moves across membrane from [high] to [low], driven by reabsorption of ions (osmosis) • Additional Notes: AQ II is hormonally regulated (only found on luminal membrane of collecting duct) by ADH (vasopressin Paracellular Water Transport • Locations: only proximal tubule • Properties: can be reabsorbed between cells with looser tight junctions Diabetes Mellitus • Glucose should never be found in urine • Identification of excreted glucose in urine suggests that an individual has diabetes mellitus • Increased levels of filtered glucose cannot be efficiently reabsorbed by SGLT (Na /glucose symporters) found in the proximal tubule • Result is inefficient glucose reabsorption and therefore greater glucose levels in urine Cl- channel on basolateral • Favorable concentration gradient because from interstitium (outside) ions are taken up by blood quickly so • there is low concentration • outside – favoring movement out of tubule celle • calcium channel – • doesn’t exist on any • Water moves by osmosis 1. Aquaporin II – nephron • Hormonally regulatedated by PTH is the hormone that regulates itor IV – not (parathryoid hormone) • Na is reabsorbed by 3 and is hormonally regulated (aldosterone) • K leak channel (secretes calcium) – hormonally regulated by aldosterone • ATPase is hormonally regulated by aldosterone + Na Balance – Hormonal Regulation • Two hormone pathways/systems to regulate sodium levels o Sodium levels are low  Renin-Angiotensin-Aldosterone System (RAAS) o Sodium levels are high Gout"  Atrial Natriuretic Peptide (ANP) • Urate is an organic anion that causes gout when plasma levels get too high • If sodium levels are too high, the ECF volume increases as does blood pressure • •Mechanisms to detect changes in blood pressure & filtrate composition to regulate sodium body content • Purines (found in beer, wine & meat) are broken down into uric acid  urate RAAS P•thwInteresting way in which urate is handled: most filtered urate is reabsorbed in the proximal tubule • Liver oakeAlthough it’s a breakdown product of purines – most is reabsorbedormone function (big) • Renin (enzyme) secreted by juxtaglomerular cells in kidney • Secretion is then controlled to obtain proper urate plasma levels – later on in the proximal tubule • Types of altered renal function that cause gout+small) – inactive protein o oRenProblems with secretion of urate (mutation or drug affecting transporter) o Problems with filtration – don’t filter (low GFR) – less chance for balance of urate o Problems with reabsorbtion – excessive reabsorption of urate • ACE (angiotensin converting enzyme) – made by capillary endothelial cells o Cleavage of angiotensin I to angiotensin II o ACE is made the most in the capillary bed of the lungs – responsible for most of the cleavage + • Rate limiting step: renin (only thing that is secreted by low Na ) • Angiotensin II go to adrenal cortex – stimulate adrenal glands to release aldosterone f Angiotensin II • Made by: Cleavage of angiotensinogen à angiotensin I à angiotensin II • Properties: Peptide hormone, released into blood • Stimulus: Renin release • Action: Increases sodium reabsorption (in proximal tubule) by: + + o Increasing activity of Na /H exchanger (makes conformation changes more efficient & turns faster) o Increasing activity of Na /K ATPase (makes conformational change more efficient)  Angiotensin II – filters  goes to tubule  Receptor on luminal membrane  Binding of angiotensin II to receptor – causes a decrease in secondary response messenger cAMP  Sig+al+cascade  changes +ct+vity of Na /H exchanger & Na /K ATPase o Decreasing GFR by constricting both afferent and efferent arteriole  Reduces blood flow into glomeruli & decreases
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