Renal1_2_3Sp10 - NPB101 Renal 1 ­1 Renal Topic#1...

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Unformatted text preview: NPB101 Renal 1 ­1 Renal Topic #1 Topic #1 •  •  •  Func6ons of the Renal System Func6onal Anatomy of Kidney – anatomy of the nephron – the func6onal unit of the kidney Modes of Renal Nephron’s Processing of the Plasma 1.  2.  3.  Filtra6on Filtra6on with Reabsorp6on Filtra6on with Secre6on •  Rela6onship between the Plasma Concentra6on of a Substance & its Excre6on Rate into the Urine 1.  2.  3.  Only Filtered and then excreted Filtered and Reabsorbed Filtered and Secreted •  Volume/min of Plasma Processed by the Kidney –  –  –  Volume filtered at the Glomeruli Volume reabsorbed Proximal Tubule, Loop of Henle, and Distal Tubules/Collec6ng Ducts Volume Excreted •  Fluid Compartments 1 May 11, 2010 NPB101 Renal 1 ­2 Renal Topic #1 Topic #1 (Con6nued) •  •  Renal Regula6on of Plasma Osmolality and Plasma Volume Glomerular Filtra6on –  –  –  –  –  Review Starling Filtra6on Equa6on Comparison of Glomerular Filtra6on with Filtra6on in Skeletal Muscle Structure – Func6on of the Glomerular Capillaries and Bowman’s Capsule, the segment of the proximal tubules that cup the glomerular capillaries. Autoregula6on of GFR Intrinsic Mechanism for Autoregula6on of GFR •  Myogenic Mechanism •  Tubuloglomerular Feedback May 11, 2010 2 NPB101 Renal 1 ­3 Func%ons of the Renal System: 1.  Excretory System removes products of metabolism (urea, + others), H+ ions, drugs, etc. 2.  Conserves Essen%al Nutrients Delivered To The Kidneys –  –  sugars  ­ glucose, galactose amino acids 3.  Regulates Body Water And Electrolytes –  –  –  regula6on of plasma osmolality through Vasopressin (An6diurec6c Hormone – ADH) volume regula6on through conserving or excre6ng Na through Renin ­Angiotensin ­ Aldosterone System – water & therefore, plasma volume, follows Na electrolytes –Na, K, Ca, and others. 4.  Cri%cal Role In Acid  ­ Base Balance Within The Body –  –  Kidney is the only organ system in the body that excretes H+, and conserves buffer exis%ng buffer base (HCO3 ­) & synthesizes new HCO3 ­. Returns pH and buffer base concentra6ons, par6cularly HCO3 ­, to normal levels. 5.  Endocrine Func%on –  –  Renin – Angiotensin – Aldosterone System for conserving plasma volume Synthesis & Secre6on of Erythropoie6n – synthesis of new red blood cells May 11, 2010 3 NPB101 Renal 1 ­4 Anatomy of the Kidney & Nephron Fig. 14 ­1 Fig. 14 ­5 Fig. 14 ­3 May 11, 2010 4 NPB101 Renal1 ­ 5 Renal Processing of the Plasma and the Tubular Fluid 1.  2.  3.  4.  Glomerular Filtra%on Tubular Reabsorp%on Tubular Secre%on Urinary Excre%on Fig. 14 ­6 May 11, 2010 5 NPB101 Renal 1 ­6 Rela6onship between Filtra6on and Excre6on, Filtra6on + Reabsorp6on & Excre6on, and Filtra6on + Secre6on & Excre6on: Concept of Transport Maximum Excre6on Rate = GFR ([P]) mg/min + Secre6on Rate mg/min – Reabsorp6on Rate mg/min Secretion & Reabsorption have Transport Maximums: GFR ([P]) + Secre6on Rate GFR ([Pl]) Secretion and Reabsorption depend upon membrane carriers and transporters. There is a finite number of these within the nephrons of the kidney and each has a transport capacity. Once the transport capacity is exceeded, the reabsorption and secrete rates remain constant. Filtration does not have a transport maximum. Example for Reabsorption: Glucose (renal threshold about 200 mg/dl or 2 mg/ml) May 11, 2010 6 NPB101 Renal 1 ­7 Volume & Modes of Plasma Processed by the Kidney •  •  ~ 25% of the Cardiac Output ~ 125 ml/min or 20% of the Renal Plasma Flow Filtered at the Glomerulus – Glomerular Filtra%on Rate (GFR) ~ 650 ml/min or 80% Flows into Efferent Arterioles & into Peritubular Capillaries and Vasa Recta Urine Flow ~ 1 ml/min •  •  Therefore, over 99% of the Glomerular Filtrate is reabsorbed. May 11, 2010 Fig. 14 ­6 7 NPB101 Renal 1 ­8 Fluid Compartments within the body (60 ­40 ­20 Rule) 60% body mass is water. This 60% body water par66oned into 1.  2.  40% in the intracellular compartment 20% in the extracellular compartment •  •  ~ 12% is inters66al (this includes about 1% as synovial fluid in joints, aqueous humor in the eyes, pericardial fluid, fluid between the visceral and parietal pleura) ~ 8% is in vascular compartment. Kidney regulates plasma volume & body water through 1.  ADH (An6diure6c Hormone) regulates plasma osmolality, and to a lesser extent vascular volume through affec%ng water reabsorp%on (ADH present) & excre%on. 2.  •  Regula%on of Na reabsorp%on and excre%on conserves or excretes fluid volume within the body since water follows Na. Na excre6on and reabsorp6on regulated through Constant Frac%on Na Reabsorp%on and Renin ­ Angiotensin II–Aldosterone system (R ­A ­A System). Note: If the body is hypovolemic and/or hyperosmo%c, compensa%on will only occur through intake of water (orally or through an IV). May 11, 2010 8 NPB101 Renal 1 ­9 Glomerular Filtra6on Table 14 ­1 Comparison of Glomerular Filtra%on to Capillary Filtra%on in Skeletal Muscle Capillaries •  125 ml/min versus 100 – 200 ml/hour for all other vascular systems in body. Pc = 55 mmHg (favors filtra6on) Pbc = 15 mm Hg (opposes filtra6on) (Note the very high pressure compared to inters66al fluid pressure in other vascular beds) Πc = 30 mm Hg (opposes filtra6on) Πbc = 0 (glomerular capillaries very impermeable proteins) Kf much greater than in skeletal muscle •  Much greater surface area – 100X/ gm 6ssue greater than in skeletal muscle. •  Much greater permeability to water •  Much greater Permeability  ­ electrolytes, sugars, and amino acids much greater than in skeletal muscle. (Generate liple osmo6c force opposing filtra6on) +10 mm Hg Net force favoring filtra6on (10 mm Hg) greater than for other systemic vascular beds (2 – 4 mm Hg). May 11, 2010 Glomeruli NOT PERMEABLE large protein & cells •  Therefore, πbc = 0 9 NPB101 Renal 1 ­10 Glomerular Capillary Structure & Capillary Filtra6on •  •  •  Space between endothelial cells in capillary wall much greater than in skeletal muscle. Basement Membrane – discon6nuous and very permeable Filtra%on Slits between foot processes of Podocytes (outer surface of capillaries), Podocytes with their foot processes form barrier to filtra6on of proteins. •  Podocytes contrac6le: contrac6on flapens podocytes decreasing permeability; relaxa6on increases permeability (See Fig. 14 ­13). •  [Mesangial cells (Fig 14 ­11) are cells between capillaries within the glomerular bundle. 1.  2.  contrac6le (sympathe6c) & decrease capillary permeability by narrowing filtra6on slit phagocy6c ac6vity and clear protein from the filtra6on slits between the podocytes.] Fig. 14 ­7 Capillary Permeability (Kf) can change 1.  Contrac6on and Relaxa6on Mesangial Cells 2.  Contrac6on and Relaxa6on of Podocytes May 11, 2010 10 NPB101 Renal 1 ­11 Glomerular Filtra6on Autoregulated Defini%on of Autoregula%on: Intrinsic (does not depend upon innerva6on) regula6on that maintains rela6vely constant blood flow with changes in arterial blood pressure. Ques%on: For autoregula6on what must happen to afferent arteriole resistance with changes in arterial pressure? Mechanisms of Autoregula%on GFR: 1.  Myogenic Mechanism – stretch induced contrac6on. Tubuloglomerular Feedback  ­ JGA •  Release of Adenosine and ATP from macular densa cells in response to increase GFR and Na delivery. Adenosine and ATP constrict afferent arterioles reducing GFR. 11 2.  Fig 14 ­12 May 11, 2010 •  NPB101 Renal 2 ­1 Renal Topic #2 Topic #2 •  Overview of Renal Handling Glomerular Filtrate •  Concept of Filtered Load •  Epithelial Transport  ­ Reabsorp6on of the Glomerular Filtrate & Secre6on into Tubular fluid Concept: The basolateral membrane Na/K ATPase pumps generates the electrochemical gradients across the apical (luminal) membrane and across the basolateral membrane for both the reabsorp6on and secre6on of solute. •  Reabsorp6on of Water Concept: Always down an osmo%c gradient – never ac%ve transport •  Proximal Tubule Handling of the Tubular Fluid – Reabsorp6on and Secre6on May 11, 2010 12 NPB101 – Renal 2-2 Renal Topic #2, Continued Topic #2, Con6nued •  Processing of the filtrate by the Loop of Henle –  Countercurrent Mul%plier System – genera6on of the medullary osmo6c gradient using NaCl for reabsorp6on of water from the distal tubules/collec6ng ducts –  Countercurrent Exchange in the Vasa Recta Capillary Network – balancing maintaining the medullary osmo6c gradient and the reabsorp6on of solute and water in the medullary inters66um into the vascular compartment. •  Processing of the Tubular Fluid by the Distal Tubules and Collec6ng Ducts May 11, 2010 13 NPB101 Renal 2 ­3 Concept of Filtered Load Filtered Load (mg/min) = GFR(ml/min) (Psubstance (mg/ml)) Defini%on: Rate at which a substance is delivered to the tubular fluid and to the epithelial cells of the tubule for processing. •  determines rate of reabsorp6on and excre6on. •  Note: Na does not exhibit a transport maximum for reabsorp6on because solvent drag through the paracellular pathway for Na reabsorp6on does not depend on membrane transporters. –  Filtered load will change with changes in plasma concentra6on of a filtered substance. –  Filtered load will change with short ­term changes in GFR •  Reflex responses to changes in blood pressure determines glomerular capillary pressure primarily through changes in afferent arteriolar resistance. •  and changes in protein onco6c pressure determined by rela6onship between fluid intake and loss of body water. Ques%on: With short ­term increases & decreases in arterial blood pressure, what will happen to GFR and protein onco6c pressure of the plasma entering the peritubular capillaries? May 11, 2010 14 NPB101 Renal 2 ­3 Transport between Tubular Fluid and Peritubular Capillaries 1.  Transcellular Route –  –  Membrane transporters on apical (luminal) and basolateral membranes of epithelial cells Water Channels (Aquaporins) apical and basolateral membranes. 2.  Paracellular Route –  –  –  –  –  movement of water through spaces between epithelial. Water always moves down a hydrosta6c and/or osmo6c gradient. It is never ac6vely transported. Bulk flow of water between cells down a hydrosta6c and/or osmo6c gradient. This bulk flow of water can drag or carry dissolved solute with it – Solvent Drag. Responsible for reabsorp6on of Na (along with membrane transporters) – •  Solvent drag (and Na Reabsorp6on) does not have a transport maximum. 113 Renal 04 May 11, 2010 15 NPB101 Renal 2 ­4 Reabsorp6on of the Glomerular Filtrate by the Proximal Convoluted Tubule & Secre%on into the Proximal Tubule Overview •  85% of the total Glomerular Filtrate volume reabsorbed in the proximal tubule 66% of the filtered load of Na is reabsorbed (Constant Frac%onal Na Reabsorp%on) –  Regardless of the filtered load of Na, 66% will be reabsorbed and 33% will be excreted. •  •  100% filtered glucose and amino acids are reabsorbed in proximal tubule. 85% of the filtered HCO3 ­ (over 99.9% of the total filtered load of HCO3 ­ reabsorbed by the nephrons) (~ 50% of the filtered load of urea is reabsorbed – follows reabsorp6on of water.) In addi6on to Filtra6on, secre%on of H+ (and H+ as NH4+) •  •  •  Ques%on: What will happen to the tubular fluid concentra6on of a substance as it moves along the proximal tubule (and nephron) if the substance is filtered but not reabsorbed and not secreted? May 11, 2010 16 NPB101 Renal 2 ­5 Details of Reabsorp%on & Secre%on in the Proximal Tubule Points: •  Basolateral membrane Na/K ATPase pump generates the electrochemical gradient for reabsorp6on of substances from tubular fluid into epithelial cells and then movement into the peritubular capillaries. Glucose, AA + other molecules reabsorbed by Secondary Ac6ve Transport – co transport ­ with Na. Na also reasorbed by paracellular solvent drag of water. Other molecules and ions also reabsorbed by paracellular solvent drag. Water reabsorp6on occurs through the paracellular and transcellular pathways. Water is always reabsorbed down a hydrosta6c and/or osmo6c gradient. It is NEVER ac6vely reabsorbed. 85% of filtered load of HCO3 ­ reabsorbed across the apical membrane as CO2. HCO3 ­ regenerated within cell reabsorbed across basolateral membrane by facilitated diffusion (uses membrane transporter) H+ (& NH4+) secreted in exchange for Na – Na electrochemical gradient drives the secre6on of H+ (& NH4+) (50% of filtered urea reabsorbed.) 17 •  •  •  •  •  •  85% total filtrate reabsorbed 85% of filtered HCO3 ­ reabsorbed 66% of the filtered load Na reabsorbed 100% of normal filtered load Glucose and AA reabsorbed. H+ (&NH4+) secreted. •  •  May 11, 2010 NPB101 Renal 2-6 Reabsorption in Loop of Henle Fig. 14 ­24 May 11, 2010 18 NPB101 Renal 2-7 Reabsorption in Loop of Henle (See also Fig. 14-25 in your textbook) •  •  •  20% filtered water reabsorbed thin descending limbs. 25% of the filtered Na reabsorbed in the Loop Henle Countercurrent Mul%plier system generates the medullary osmo6c gradient for the reabsorp6on of water in the late distal tubules and collec6ng ducts. (you do not need to know the details of how the mul6plier works.) •  Countercurrent Exchange through Vasa Recta Capillary network (not shown in this figure – see next slide) reabsorbs water and solute into the blood from medullary inters66um. Concepts: Countercurrent Mul%plier reabsorbs Na for genera6ng medullary osmo6c gradient for reabsorp6on of water. Countercurrent Exchange through the Vasa Recta returns the reabsorbed Na and water to the vascular compartment May 11, 2010 19 NPB101 Renal 2 ­8 Countercurrent Exchange by the Vasa Recta Return of the reabsorbed Na and Water to the Vascular Compartment – Vasa Recta Capillary Network Flow Through (a) Countercurrent Exchange (b) Opposing Needs: 1.  2.  Keep solute in the medullary region for the reabsorption of water. Return the solute and reabsorbed water in the medullary region to the vascular compartment. Need for a balance between generation of the medullary osmotic gradient by the countercurrent multiplier system and the removal of the gradient by the vasa recta. Fig. 14 ­28 Increases in blood flow washout medullary osmotic gradient. Decreases in blood flow will conserve medullary osmotic gradient. 20 Countercurrent flow through vasa recta both preserves medullary osmo%c gradient and returns solute and water to the vascular compartment. May 11, 2010 NPB101 Renal 2 ­9 Ques6ons about Rela6onship between Blood Flow through the Vasa Recta & the Medullary Osmo6c Gradient For these ques6ons, assume there is no change in the ac6vity of the countercurrent mul6plier system. Ques%on #1: What would you predict will happen to vasa recta blood flow under condi6ons where addi6onal water volume (plasma volume) is conserved – i.e. dehydra6on with an increase in plasma osmolality? Ques%on #2: What would you predict will happen to vasa recta blood flow under condi6ons where water is not conserved – well hydrated with a decrease in plasma osmolality? May 11, 2010 21 NPB101 Renal 2 ­10 Distal Tubules and Collec%ng Ducts •  •  •  5% of the filtered load of Na reabsorbed in the distal tubule and early collec6ng duct. Secre%on of addi%onal H+ by cells in the Distal Tubule & Collec6ng Ducts Impermeable to water UNLESS ADH (An6diure6c Hormone, Vasopressin) is secreted from the Posterior Pituitary Gland. •  S%mula%on of ADH secre%on from posterior pituitary gland with 1.  Increases in plasma osmolality •  S6mula6on of osmorectors in the hypothalamus •  Ac6va6on of osmoreceptors ac6vates neurons which release ADH from the posterior pituitary gland 2.  Decreases in plasma volume – decrease in stretch of the volume receptors in pulmonary veins ­lew atrium decrease in reflex inhibi%on of ADH secre6on (disinhibi%on of ADH secre6on) May 11, 2010 22 NPB101 Renal 2 ­11 Distal Tubules and Collec%ng Ducts •  Ac%on of ADH: ADH s6mulates inser6on of water channels (aquaporins) in distal tubules & collec6ng ducts, and increases permeability of the collec6ng ducts to urea, and decreases vasa recta blood flow 1.  Water reabsorbed down the osmo6c gradient generated by countercurrent mul6plier system in the Loops of Henle into the medullary inters66um. 2.  Urea diffuses into the medullary inters66um and takes water with it (water follows down the osmo6c gradient generated with the reabsorp6on of urea). 3.  Water (and solute) picked up by vasa recta and returned to vascular system. Note: Increases in plasma osmolality are only corrected by increasing fluid intake. May 11, 2010 23 NPB101 Renal 3 ­1 Renal Topic #3 1.  Regulation of Vascular Volume & Control of Blood Pressure •  •  •  Renin-Angiotensin-Aldosterone (Dominant Role) ADH (Minor Role) Atrial and Brain Natiuretic Peptides (Minor Role) 2.  Regulation of Body pH and Acid-Base Balance •  •  Dilution and Blood Buffers Respiratory Compensation to Disturbance in Acid-Base Status through changes in ventilation Renal Correction to Acidosis – elimination of H+ and returning buffer base (HCO3-) to normal levels. •  •  •  May 11, 2010 •  Excretion of H+ Conserving of existing HCO3- (buffer base) Synthesis of new HCO3- to return [HCO3-] to normal 24 NPB101 Renal 3 ­2 Regula6on of Vascular Volume – ADH & Renin ­Angiotensin ­Aldosterone (R ­A ­A System) and Atrial and Brain Na6ure6c Pep6des Volume Regula%on occurs through 1.  ADH – minor role •  •  Increases volume inhibit ADH secre6on through afferent input from volume receptors pulmonary veins and lew atrium decrease water reabsorp6on distal tubules and collec6ng ducts Decreases volume reduce inhibi6on ADH secre6on from volume receptors (disinhibi6on) increase ADH secre6on •  •  ADH s6mulates inser6on of water channels (Aquaporins) in distal tubule and collec6ng ducts water reabsorbed osmo6cally into medullary inters66um. S6mulates Renin Secre6on from JGA 2.  Atrial and Brain Na%ure%c Pep%des (Both synthesized and released from heart)  ­ minor role •  •  Secreted with increases plasma volume Decreases Na transporters in apical membrane of distal tubule decrease Na reabsorp6on and increase Na and water excre6on. 3.  Regula6on of Na reabsorp6on with water following through Renin ­Angiotensin ­ Aldosterone System  ­ Dominant Role •  •  May 11, 2010 Decreases in plasma volume and/or decreases in blood pressure ac6vate R ­A ­A System increase Na and water reabsorp6on. Conserves exis6ng plasma volume 25 NPB101 Renal 3 ­3 Renin ­Angiotensin ­Aldosterone System (R ­A ­A System) and Water Reabsorp6on Renin (an enzyme secreted by granular cells within the Juxtaglomerular Apparatus – see Fig. 14 ­11))   Plasma globulin, Angiotensinogen, conver6ng it to the inac%ve Angiotensin I converted in the lungs and other 6ssues by Angiotensin Conver6ng Enzyme (ACE) to ac6ve Angiotensin II. Angiotensin II Adrenal Cortex (Zona Glomerulosa region) s6mula6ng the synthesis and secre6on of Aldosterone – a steroid hormone. Aldosterone – acts on thick ascending segments of the Loops of Henle, Distal Tubules and Collec6ng Ducts. 1.  2.  Increases Na transporters in the epithelial cell membranes of the Loops of Henle, Distal Tubules and Collec6ng Ducts increase Na and Water reabsorp6on. Increases ATPase ac%vity increase transport capacity for Na in basolateral membranes of Loops of Henle, Distal Tubules and Collec6ng Ducts increasing reabsorp6on of Na into the medullary inters66um and the reabsorp6on of water (requires ADH at distal tubules & collec6ng ducts). May 11, 2010 26 NPB101 Renal 3 ­6 Regula6on of Body pH and Acid ­Base Balance Metabolism generates H+ through produc%on of CO2, acid salts such as lactate, and acid salts from sulfates from metabolism of sulfur containing amino acids H+ buffered by 1.  2.  Dilu6on in body water Buffering through blood and cellular buffers −  Plasma Proteins −  Plasma HCO3 ­ dominant buffer because •  •  large [HCO3 ­ respiratory elimina6on of co2 (&, therefore H+) from H+ + HCO3 ­ ↔ H2CO3 ↔ co2 + H2O −  Intracellular Proteins May 11, 2010 27 NPB101 Renal 3 ­7 Regula6on of Body pH and Acid ­Base Balance Respiratory Compensa%on to Increases and decreases [H+] –  Increases [H+] can be eliminated from body by both H+ and co2 s6mula6on of ven6la6on However, with increase ven6la6on & removal of CO2 (&H+) also decreases [HCO3 ­ removing [HCO3 ­ buffer –  With decreases [H+] decreases in ven6la6on & removal of CO2 increase [HCO3 ­ While respiratory system can compensate for increases and decreases in [H+] and pH, it cannot eliminate all acid and return buffer base concentra%on of HCO3 ­ to normal. May 11, 2010 28 NPB101 Renal 3 ­8 Acid ­Base Balance – Kidney’s Role in Excre6on H+ & Restoring [HCO3 ­ (Buffer Base) Under condi%ons of acid produc%on by the body, Kidney’s role 1.  2.  3.  Secrete and excrete acid (H+), independent of buffer bases, conserve exis6ng HCO3 ­ (reabsorp6on of all filtered HCO3 ­) and regenerate new HCO3 ­ to replace HCO3 ­ lost through respiratory compensa6on to acidosis Secre%on, Excre%on H+ & Regenera%on of New HCO3 ­ 1.  Proximal Tubule cells and Distal Tubule Cells secrete H+ across the apical (luminal) membrane into the tubular fluid in exchange for Na (Na+  ­ H+ an%porter). Distal Tubule cells can also secrete H+ independent of Na. Proximal tubular cells synthesize NH3 from the metabolism of glutamine. •  4.  NH3 diffuses into the tubular fluid where it combines with H+ NH4+. NH4+ excreted into the urine. 2.  3.  Tubule cells SYNTHESIZE NEW HCO3 ­ from increases intracellular CO2 replacing HCO3 ­ lost to the plasma by respiratory compensa6on to acidosis. (co2 + H2O HCO3 ­ + H+) (H+ secreted and excreted)) 29 May 11, 2010 ...
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