Tubular Processing of the Glomerular Filtrate Dr Saima
Tubular Processing of the Glomerular Filtrate Dr. Saima Rizwan
Basic Mechanisms of Urine Formation Figure 26 -8; Guyton and Hall
Tubular Reabsorption Figure 27 -1; Guyton and Hall
Primary Active Transport of Na+ Figure 27 -2; Guyton and Hall
Mechanisms of Secondary Active Transport Figure 27 -3; Guyton and Hall
Glucose Transport Maximum Figure 27 -4; Guyton and Hall
Transport Maximum Some substances have a maximum rate of tubular transport due to saturation of carriers, limited ATP, etc. • Transport Maximum: Once the transport maximum is reached for all nephrons, further increases in tubular load are not reabsorbed and are excreted. • Threshold is the tubular load at which transport maximum is exceeded in some nephrons. This is not exactly the same as the transport maximum of the whole kidney because some nephrons have lower transport max’s than others. • Examples: glucose, amino acids, phosphate, sulphate
Reasorption of Water and Solutes is Coupled to Na+ Reabsorption Tubular Cells Interstitial Fluid - 70 m. V Na + K+ ATP Na + ATP 0 mv Copyright © 2006 by Elsevier, Inc. K+ Tubular Lumen H+ Na + glucose, amino acids Na + Urea H 20 Na + Cl- - 3 m. V
Mechanisms by which Water, Chloride, and Urea Reabsorption are Coupled with Sodium Reabsorption Figure 27 -5; Guyton and Hall
Cellular Ultrastructure and Primary Transport Characteristics of Proximal Tubule Figure 27 -6; Guyton and Hall
Changes in Concentration in Proximal Tubule Figure 27 -7; Guyton and Hall
Cellular Ultrastructure and Transport Characteristics of Thin and Thick Loop of Henle very permeable to H 2 O) not permeable to H 2 O) Figure 27 -8; Guyton and Hall
Sodium Chloride and Potassium Transport in Thick Ascending Loop of Henle Figure 27 -9; Guyton and Hall
Sodium Chloride Transport in Early Distal Tubule Figure 27 -10; Guyton and Hall
Early Distal Tubule • Functionally similar to thick ascending loop • Not permeable to water (called diluting segment) • Active reabsorption of Na+, Cl-, K+, Mg++ • Contains macula densa
Cellular Ultrastructure and Transport Characteristics of Early and Late Distal Tubules and Collecting Tubules • not permeable to H 2 O • not very Permeable to urea • permeablility to H 2 O depends on ADH • not very Permeable to urea Figure 27 -11; Guyton and Hall
Sodium Chloride Reabsorption and Potassium Secretion in Collecting Tubule Principal Cells Figure 27 -12; Guyton and Hall
Cortical Collecting Tubules Intercalated Cells Tubular Lumen H 20 (depends on ADH) K+ K+ H+ K+ ATP Na + H+ ATP ATP Cl - Copyright © 2006 by Elsevier, Inc.
Cellular Ultrastructure and Transport Characteristics of Medullary Collecting Tubules Figure 27 -13; Guyton and Hall
Normal Renal Tubular Na+ Reabsorption 7% (16, 614 m. Eq/day) 65 % (1789 m. Eq/d) 25, 560 m. Eq/d 25 % 2. 4% (6390 m. Eq/d) (617 m. Eq/day) 0. 6 % (150 m. Eq/day) Copyright © 2006 by Elsevier, Inc.
Concentrations of solutes in different parts of the tubule depend on relative reabsorption of the solutes compared to water. • if water is reabsorbed to a greater extent than the solute, the solute will become more concentrated in the tubule (e. g. , creatinine, inulin) • if water is reabsorbed to a lesser extent than the solute, the solute will become less concentrated in the tubule (e. g. , glucose, amino acids)
Concentration of Different Substances in Tubular System Figure 27 -14; Guyton and Hall
Regulation of Tubular Reabsorption • Glomerulotubular Balance • Peritubular Physical Forces • Hormones - aldosterone - angiotensin II - antidiuretic hormone (ADH) - natriuretic hormones (ANP) - parathyroid hormone • Sympathetic Nervous System • Arterial Pressure (pressure natriuresis) • Osmotic factors
Glomerulotubular Balance Tubular Reabsorption Tubular Load
Peritubular Capillary Reabsorption Figure 27 -15; Guyton and Hall
Peritubular Capillary Reabsorption Reabs = Net Reabs Pressure (NRP) x Kf = (10 mm. Hg) x (12. 4 ml/min/mm. Hg) Reabs = 124 ml/min
Determinants of Peritubular Capillary Reabsorption Kf Reabsorption Pc Reabsorption
Determinants of Peritubular Capillary Hydrostatic Pressure Glomerular Capillary Ra Peritubular Re Capillary Arterial Pressure Ra Re Pc Pc Pc
Determinants of Peritubular Capillary Colloid Osmotic Pressure c Reabsorption Plasm. Prot. Filt. Fract. a c Filt. Fract. = GFR / RPF c
Summary of Factors that Influence Peritubular Capillary Reabsorption Kf Pc c Ra Re Art. Press a Filt. Fract. Reabsorption Pc ( Reabs) Reabsorption c c
Effect of increased hydrostatic pressure or decreased colloid osmotic pressure in peritubular capillaries to reduce reabsorption Figure 27 -16; Guyton and Hall
Aldosterone Actions on Late Distal, Cortical and Medullary Collecting Tubules • Increases Na+ reabsorption - principal cells • Increases K+ secretion - principal cells • Increases H+ secretion - intercalated cells
Late Distal, Cortical and Medullary Collecting Tubules Principal Cells Tubular Lumen H 20 (+ ADH) Na + K+ ATP K+ Cl - Aldosterone Copyright © 2006 by Elsevier, Inc.
Abnormal Aldosterone Production • Excess aldosterone - Conn’s syndrome Na+ retention, hypokalemia, alkalosis, hypertension • Aldosterone deficiency - Addison’s disease Na+ wasting, hyperkalemia, hypotension
Control of Aldosterone Secretion Factors that increase aldosterone secretion • Angiotensin II • Increased K+ • adrenocorticotrophic hormone (ACTH) (permissive role ) Factors that decrease aldosterone secretion • Atrial natriuretic factor (ANF) • Increased Na+ concentration (osmolality)
Angiotensin II Increases Na+ and Water Reabsorption • Stimulates aldosterone • Directly increases Na+ reabsorption (proximal, loop, distal, collecting tubules) • Constricts efferent arterioles - decreases peritubular capillary hydrostatic pressure - increases filtration fraction, which increases peritubular colloid osmotic pressure)
Ang II Increases Tubular Na+ Transport Tubular Cells Interstitial Fluid Tubular Lumen Ang II Na + Na+ ATP + K Na+ HCO 3 - Ang II Copyright © 2006 by Elsevier, Inc. c. AMP H+
Effect of Angiotensin II on Peritubular Capillary Dynamics Glomerular Capillary Ra Peritubular Re Capillary Arterial Pressure Ang II Re Pc (peritubular cap. press. ) renal blood flow FF c
Ang II Constriction of Efferent Arterioles Causes Na+ Retention and Maintains Excretion of Waste Products Na+ depletion Ang II Resistance efferent arterioles Glom. cap. press Prevents decrease in GFR and retention of waste products Copyright © 2006 by Elsevier, Inc. Renal blood flow Peritub. Cap. Press. Filt. Fraction Na+ and H 2 O Reabs.
Angiotensin II Blockade Decreases Na+ Reabsorption and Blood Pressure • ACE inhibitors (captopril, benazipril, ramipril) • Ang II antagonists (losartan, candesartin, irbesartan) • decrease aldosterone • directly inhibit Na+ reabsorption • decrease efferent arteriolar resistance Natriuresis and Diuresis + Blood Pressure
Antidiuretic Hormone (ADH) • Secreted by posterior pituitary • Increases H 2 O permeability and reabsorption in distal and collecting tubules • Allows differential control of H 2 O and solute excretion • Important controller of extracellular fluid osmolarity
Feedback Control of Extracellular Fluid Osmolarity by ADH Extracell. Osm (osmoreceptorsposterior pituitary) ADH secretion Tubular H 2 O permeability (distal, collecting) H 2 O Reabsorption (distal, collecting) H 2 O Excretion Copyright © 2006 by Elsevier, Inc.
Late Distal and Collecting Tubules Tubular Cells Tubular Lumen H 20 (depends on ADH) Aquaporin-2 Aquaporin-3 H 2 0 ADH Aquaporins c. AMP V 2 receptor Copyright © 2006 by Elsevier, Inc. Vesicle H 2 0
Abnormalities of ADH • Inappropriate ADH syndrome (excess ADH) - decreased plasma osmolarity, hyponatremia • “Central” Diabetes insipidus (insufficient ADH) - increased plasma osmolarity, hypernatremia, excess thirst
Atrial Natriuretic Peptide + Increases Na Excretion • Secreted by cardiac atria in response to stretch (increased blood volume) • directly inhibits Na+ reabsorption • inhibits renin release and aldosterone formation • increases GFR • helps to minimize blood volume expansion
Atrial Natriuretic Peptide (ANP) Blood volume ANP Renin release aldosterone GFR Ang II Renal Na+ and H 2 O reabsorption Na+ and H 2 O excretion
Parathyroid Hormone Increases Renal Ca++ Reabsorption • Released by parathyroids in response to decreased extracellular Ca++ • Increases Ca++ reabsorption by kidneys • Increases Ca++ reabsorption by gut • Decreases phosphate reabsorption • Helps to increase extracellular Ca++
Control of Ca++ by Parathyroid Hormone Extracellular [Ca++] Vitamin D 3 Activation Ca++ Intestinal Reabsorption PTH Renal Ca++ Reabsorption Ca++ Release From Bones
Sympathetic Nervous System Increases Na+ Reabsorption • Directly stimulates Na+ reabsorption • Stimulates renin release • Decreases GFR and renal blood flow
Normal Potassium Intake, Distribution, and Output from the Body <2% Figure 29 -1; Guyton and Hall > 98 %
Effects of severe hyperkalemia • Partial depolarization of cell membranes • Cardiac toxicity ventricular fibrillation or asystole Effects of severe hypokalemia • Hyperpolarization of cell membranes • Fatigue, muscle weakness • hypoventilation • delayed ventricular repolarization
Internal Potassium Regulation K+ intake 100 m. Eq/d Extracell. K+ Insulin → Aldosterone → -adrenergic → Alkalosis → 59 mmol (< 2%) K+ output Total = 100 m. Eq/d Intracell. K + ←Cell lysis ← strenuous exercise ← - blockade ← Acidosis 3920 mmol (> 98 %)
Internal Distribution of K+ • Factors That Promote Hypokalemia - aldosterone - insulin - epinephrine ( -adrenergic) - alkalosis • Factors That Promote Hyperkalemia - cell lysis - acidosis - strenuous exercise - -blockade - increased ECF osmolarity
External K+ Balance - Role of Kidneys K+ intake 100 m. Eq/d Extracell. K+ Intracell. K + 4. 2 m. Eq/L x 14 L 140 m. Eq/L x 28 L 59 m. Eq 3920 m. Eq K+ output Urine = 92 m. Eq/d Feces = 8 m. Eq/d Total = 100 m. Eq/d
Effect of Changes in K+ Intake on Plasma K+ 4. 6 4. 4 Plasma K+ Conc. 4. 2 (m. Eq/L) 4. 0 3. 8 30 60 90 120 150 180 210 K+ Intake ( m. Eq/day)
Control of Potassium Excretion K+ K+ K+ Excretion = Filtration - Reabsorption + Secretion
Renal Tubular Sites of Potassium Reabsorption and Secretion Figure 29 -2; Guyton and Hall
Potassium Secretion by Principal Cells Figure 29 -3; Guyton and Hall
Control of Cortical Collecting Tubule (Principal Cells) K+ Secretion • Aldosterone : increases K+ secretion • Extracellular K+ concentration : increases K+ secretion • Sodium (volume) delivery : increases K+ secretion • Acid - base status: - acidosis : decreases K+ secretion - alkalosis : increases K+ secretion
Effect of Aldosterone on K+ Excretion 4 3 Urinary K+ Excretion 2 (x normal) 1 0 2 1 3 4 5 Plasma Aldosterone (x normal
K+ Intake Plasma K+ Concentration K+ Secretion Cortical Collecting Tubules K+ Excretion Copyright © 2006 by Elsevier, Inc. Aldosterone
Effect of Changes in K+ Intake on Plasma K+ After Blocking Aldosterone System 4. 6 4. 4 Plasma K+ Conc. 4. 2 (m. Eq/L) normal Aldosterone System blocked 4. 0 3. 8 30 60 90 120 150 180 210 K+ Intake ( m. Eq/day)
Effects of Increased Extracellular [K+] to Increase K+ Secretion • Increased Na+ - K+ ATPase activity • Increased K+ gradient for diffusion into tubular lumen • Increased aldosterone
Effect of Extracellular K+ on Plasma Aldosterone Figure 29 -5; Guyton and Hall
Effect of Increased Na+ Intake on Renal Excretion of K+ Figure 29 -9; Guyton and Hall
Alkalosis K+ in Cells K+ Secretion K+ Excretion K+ Depletion
Acute and Chronic Renal Pressure Natriuresis Figure 29 -11; Guyton and Hall
Integrated Responses to Heart Failure Excretion Na+ = Filtration Na+ - Reabsorption Na+ 1. Small decrease in GFR 2. Increased fractional Na+ Reabsorption - decrease in blood pressure - decreased peritubular capillary pressure - increased angiotensin II - increased aldosterone - increased sympathetic activity Net effect = Na+ retention, volume expansion
Regulation of Fluid Balance In Hypertension When there is a disturbance of kidney function that tends to cause sodium and water retention, and if local and hormonal mechanisms are unable to maintain balance, increased blood pressure (hypertension) serves to allow the kidney to “escape” from sodium and water retention.
(x normal) Urine Na+ Renal-Body Fluid-Arterial Pressure Feedback Angiotensin II Aldosterone Sympathetics Kidney damage Na+ 1 Intake 50 100 Arterial Pressure Copyright © 2006 by Elsevier, Inc. - + 150 Total Peripheral Resistance Arterial Pressure Na+ Intake X Extracellular Fluid Volume Cardiac Output
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