Renal-Chemistry Elizabeth Kim, MSN, ARNP, SRNA

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Renal-Chemistry Elizabeth Kim, MSN, ARNP, SRNA

  1. 1. Renal-Chemistry Elizabeth Kim, MSN, ARNP, SRNA March 2006 Anesthesiology Nursing Program Florida International University
  2. 2. THE OUTLINE <ul><li>Brief Review of Nephrology A&P </li></ul><ul><li>Renal and Acid/Base Balance </li></ul><ul><li>Review of Diuretics </li></ul>
  3. 3. <ul><li>Rapid Renal Blood Circulation </li></ul><ul><li>Weight of Kidneys = 0.5% body weight </li></ul><ul><li>20-25% of CO goes to Kidneys </li></ul><ul><li>CO = 6 L/min </li></ul><ul><li>Renal blood flow = 1.2-1.5 L/min </li></ul><ul><li>O2 consumption = 18 ml/min </li></ul>
  4. 4. <ul><li>1300 ml blood/min  Renal Arteries </li></ul><ul><li>1298-1299 ml  Renal Veins </li></ul><ul><li>All that work for: 1-2 ml  Ureter </li></ul>Urine Formation
  5. 5. Renal Blood Flow Afferent Arteriole=>Glomerulus=>Efferent Arteriole =>Peritubular Capillaries=> Renal Vein
  6. 6. Phospholipid-Bilayer Membranes Not permeable to polar molecules (interior lipid region/nonpolar) Large hydrophilic molecules and ions do not diffuse through the lipid bilayer and need special channels to allow entrance and passage of polar species.
  7. 7. Definitions <ul><li>Polar molecules </li></ul><ul><ul><li>Have no net charge. </li></ul></ul><ul><ul><li>Have a region with a cluster of positive charges and a region with a cluster of negative charges. </li></ul></ul><ul><ul><li>Polar molecules are hydrophilic. </li></ul></ul><ul><li>Nonpolar molecules: </li></ul><ul><ul><li>Have a positive and negative charges uniformly distributed throughout the molecule. </li></ul></ul><ul><ul><li>Nonpolar are hydrophobic. </li></ul></ul>
  8. 8. <ul><li>Kidneys important in: </li></ul><ul><li>Regulation of ECF/ BP </li></ul><ul><ul><li>When extracellular fluid volume ↓, BP ↓ </li></ul></ul><ul><ul><li>If ↓ ↓ blood volume and pressure=> ↓ flow to brain and other organs </li></ul></ul><ul><ul><li>Kidneys work with CV system to maintain pressure in acceptable range </li></ul></ul><ul><ul><li>ADH and aldosterone cause active reabsorption of more sodium and water = concentrate urine </li></ul></ul><ul><li>Regulation of ionic composition </li></ul><ul><li>Electrolyte balance: Na+, K+, Ca++, Mg++, Cl- </li></ul><ul><li>Acid-base balance H+ and HCO3- </li></ul>Kidney Function
  9. 9. <ul><li>Na+: major cation (+) of ECF </li></ul><ul><li>Cl-: major anion (-) of ECF </li></ul><ul><li>Regulators of fluid balance </li></ul><ul><li>Hormonal regulation of Na+ balance: </li></ul><ul><ul><li>Mediated by aldosterone </li></ul></ul><ul><ul><li>Secreted when Na+ levels low </li></ul></ul><ul><ul><li> reabsorption in distal tubules </li></ul></ul>ECF Intravascular & Interstitial compartments ~20% of total body weight
  10. 10. Basic Nephron Processes Glomerular Filtration Tubular Reabsorption Tubular Secretion
  11. 11. Renal Water Handling <ul><li>3 Important Components: </li></ul><ul><li>Delivery of tubular fluid to diluting segments of the nephron. </li></ul><ul><li>Separation of solutes and water in the diluting segment. </li></ul><ul><li>Variable reabsorption of water in collecting ducts (CDs) </li></ul>
  12. 12. Na+ Regulation <ul><li>Defend against Na+ overload </li></ul><ul><li>Natriuretic peptides </li></ul><ul><li>ANP (atria) </li></ul><ul><li>BNP (brain) </li></ul><ul><li>C-type natriuretic peptide </li></ul><ul><li>Defends against Na+ depletion & Hypovolemia </li></ul><ul><li>RAAS axis </li></ul><ul><li>Aldosterone:  Na+ excretion </li></ul><ul><ul><li>Baroreceptors (Ao Arch & Carotid Body) </li></ul></ul><ul><ul><li>Stretch receptors (Great veins, pulmonary vasculature & atria) </li></ul></ul><ul><li> Stretch:  Sympathetic tone,  Renal perfusion=>  Renin. </li></ul>
  13. 13. The Kidney Has an Osmotic Gradient From Cortex to Medulla <ul><li>Cortex - Isotonic with the blood: ~300 mOsm/L </li></ul><ul><li>Medulla - very Hypertonic: ~1200 mOsm /L </li></ul><ul><li>Regulating osmolality = Regulating Na+ concentration (sodium salts represent 90% of total osmolality of ECF). </li></ul>
  14. 14. Loop of Henle (LOH) <ul><li>Descending LOH </li></ul><ul><li>Water reabsorbed </li></ul><ul><li>Solute retained </li></ul><ul><li>Osmolarity: ~1,200 mOsm/kg </li></ul><ul><li>Ascending LOH & Distal Tubule (DT) </li></ul><ul><li>Dilution of concentrated fluid </li></ul><ul><li>Relatively impermeable to water </li></ul><ul><li>Osmolarity leaving DT: ~ 50mOsm/kg </li></ul>
  15. 15. Where Sodium goes, Water follows Sodium Out Dilution Water: ADH Sodium: Aldosterone Water Out Concentration
  16. 16. <ul><li>DT </li></ul><ul><li>Aldosterone (adrenal cortex): Na+ Reabsorption </li></ul><ul><li>CD </li></ul><ul><li>Water Reabsorption: </li></ul><ul><li>Mediated by ADH (Vasopressin) </li></ul><ul><li>Stimulate aquaporin 2 water channels in CD </li></ul>
  17. 17. Segments of the Renal Tubule <ul><li>Proximal tubule:Reabsorbs the bulk of filtered fluid </li></ul><ul><li>Loop of Henle: Establishes and maintains an osmotic gradient in the medulla of the kidney. </li></ul><ul><li>Distal tubule and collecting duct: Final adjustments on urine pH, osmolality and ionic composition. </li></ul><ul><li>Reabsorption of water => ADH </li></ul><ul><li>Reabsorption of Na+ and secretion of K+ => Aldosterone </li></ul>
  18. 18. Homeostasis <ul><li>H+ ions are created and destroyed at all times. </li></ul><ul><li>H+ is controlled through: </li></ul><ul><ul><li>1. Buffers </li></ul></ul><ul><ul><li>2. The Lungs </li></ul></ul><ul><ul><li>3. The Kidneys </li></ul></ul>
  19. 19. Acid-Base Balance 3 Mechanisms for the regulation of acid-base balance: <ul><ul><li>The Buffer system (secs) </li></ul></ul><ul><ul><li>Respiratory system (mins) </li></ul></ul><ul><ul><li>Renal system (hrs-day) </li></ul></ul><ul><ul><ul><li>Renal H+ excretion, which controls plasma HCO 3 - </li></ul></ul></ul><ul><ul><ul><ul><li>For each HCO 3 - reabsorbed or regenerated a H+ is secreted into the renal tubular fluid. </li></ul></ul></ul></ul><ul><ul><ul><li>Predominate buffers: phosphate (HPO4 2 ) & ammonia (NH3) </li></ul></ul></ul>
  20. 20. Acid-Base Review <ul><li>Henderson-Hanselbalch Equation </li></ul><ul><li>Relationship bt </li></ul><ul><ul><li>pH </li></ul></ul><ul><ul><li>PaCO2 </li></ul></ul><ul><ul><li>NaHCO3- </li></ul></ul><ul><li>Defines the above relationship but substitutes H+ concentrations for pH </li></ul>
  21. 21. Renal Acid-Base Balance HCO 3 - /H 2 CO 3 Buffering System Major extracellular buffering system <ul><li>To maintain normal pH, the kidneys must perform 2 physiological functions: </li></ul><ul><ul><li>1 st : Reabsorb all the filtered HCO3 (~85% at PT) </li></ul></ul><ul><ul><li>2 nd : Excrete the daily H+ load (CD) </li></ul></ul>
  22. 22. Hydrogen H 2 O + CO 2  H 2 CO 3  H + + HCO 3 - <ul><li>Adding acid load to the body fluids results in consumption of HCO 3 - by H+ added and the formation of carbonic acid, forms H2O & CO 2 </li></ul><ul><li>Only the urinary system can eliminate excess hydrogen ions, permanently and restore the bicarbonate buffering ions to the blood. </li></ul>
  23. 23. Hydrogen Ions <ul><li>Continuously produced as substrates are oxidized in the production of ATP </li></ul><ul><li>Largest contribution of metabolic acids arises from the oxidation of carbohydrates, principally glucose. </li></ul><ul><li>Net production of hydrogen ions: ~60 mEq/day. </li></ul>
  24. 24. Hydrogen Ion Regulation <ul><li>Metabolic reactions in the body are highly sensitive to pH or H+ ion concentration. </li></ul><ul><li>H+ ions change shapes of proteins, including enzymes (H+ changes can greatly effect the chemical reactions in your body. </li></ul>
  25. 25. Hydrogen Gains Losses <ul><li>CO 2 + H 2 0  H 2 CO 3  HCO 3 - + H + </li></ul><ul><li>Protein breakdown. </li></ul><ul><li>Loss of HCO 3 - in GI tract.  </li></ul><ul><li>Loss of HCO 3 - in kidney.  </li></ul><ul><li>(3) and (4) result in a gain of plasma H + because HCO 3 - is no longer available to bind H + . </li></ul><ul><li>Loss of H + from stomach in vomiting. </li></ul><ul><li>Loss of H + in urine. </li></ul><ul><li>Hypoventilation. </li></ul>
  26. 26. Buffers <ul><li>Buffer: Any substance that can reversibly bind H + . </li></ul><ul><li>HCO 3 - : Important buffer.  </li></ul><ul><li>Buffer - + H +  Hbuffer </li></ul><ul><li>When H + increases, the reaction is forced to the right and more H + is bound to buffer. </li></ul><ul><li>CO 2 + H 2 0  H 2 CO 3  HCO 3 - + H + </li></ul>
  27. 27. Homeostasis of H + by the Kidneys <ul><li>HCO3- Excretion  Free H+ in plasma.  </li></ul><ul><li>Alkalosis: Kidney excretes HCO 3 - to free up H + in the plasma. </li></ul><ul><li>Acidosis: Kidney tubules produce HCO 3 - </li></ul>
  28. 28. Bicarbonate Filtration and Reabsorption <ul><li>HCO 3 - </li></ul><ul><li>Easily filtered </li></ul><ul><li>Undergoes marked tubular reabsorption in the proximal tubule and collecting ducts </li></ul><ul><li>CO 2 + H 2 0  H 2 CO 3 (CA)  HCO 3 - + H + </li></ul><ul><li>HCO3- diffuses down its concentration gradient into the plasma. </li></ul><ul><li>H + : secreted into the tubule. This combines with filtered HCO 3 - to form CO 2 and H 2 0. </li></ul>
  29. 29. Bicarbonate filtration and reabsorption <ul><li>If plasma HCO 3 - is low, the H + combines with other buffers. </li></ul><ul><li>HCO 3 - is still produced in the renal tubules and diffuses into the plasma, raising plasma HCO 3 - . </li></ul>
  30. 30. Kidney Response to Acidosis <ul><li>H + is secreted to reabsorb all the filtered bicarbonate. </li></ul><ul><li>More H + is secreted to bind to other buffers in the urine. </li></ul><ul><li>More HCO 3 - is created and diffuses into the plasma, to bind H + and make the plasma more alkaline. </li></ul><ul><li>Glutamine metabolism and ammonium (NH 4 +) excretion increase. Ammonium grabs H + and HCO 3 - goes into the plasma, making it more alkaline. </li></ul>
  31. 31. Kidney responses to Alkalosis <ul><li>H + secretion is down, so H + cannot reabsorb all the bicarbonate. A significant amount of bicarbonate is excreted in the urine. </li></ul><ul><li>Glutamine metabolism and ammonium excretion are down, so little bicarbonate goes into the plasma. </li></ul>
  32. 32. Renal Mechanisms Acid-Base Balance CO 2 + H 2 O H 2 CO 3 HCO 3 - + H + Carbonic anhydrase <ul><li>Kidneys alter/replenish H + by altering plasma [HCO 3 - ] </li></ul><ul><li> [H + ] plasma (alkalosis)  kidneys excrete lots of HCO 3 - </li></ul><ul><li> [H + ] plasma (acidosis)  kidneys produce new HCO 3 - </li></ul>
  33. 33. HCO 3 - Reabsorption H 2 O + CO 2  H 2 CO 3  HCO 3 - + H + Lumen Blood HCO3- + Na+ H+ Na+ H+ H 2 CO 3 H20 + CO2 CA CO2 + H20 CA HCO3- HCO3- Na+ K+ <ul><li>Daily glomerular ultrafiltrate 180L (contains 4300 mEq of HCO 3 - ) </li></ul><ul><li>H+ in the tubular lumen combines w/ filtered HCO 3 - </li></ul><ul><li>Body produces excess acids during normal metabolism </li></ul><ul><li>To maintain balance: the kidneys excrete more H+ ions and the urine becomes more acidic. </li></ul>Na+ H2CO3 <ul><li>Na+-H+ exchange </li></ul><ul><li>Permits HCO3- reabsorption/acid excretion </li></ul>CA combines CO2 and water to form HCO 3 - and H + CA: Accelerates the dissociation of H 2 CO 3 into H 2 O + CO 2 HCO 3 - reabsorption: relies on tubular secretion of H + ,
  34. 34. Carbonic Anhydrase H 2 O + CO 2  H 2 CO 3  HCO 3 - + H + Lumen Blood HCO3- + Na+ H+ Na+ H+ H2CO3 H20 + CO2 CA CO2 + H20 CA HCO3- HCO3- Na+ K+ <ul><li>Brush border </li></ul><ul><li>Keeps the luminal H+ low </li></ul><ul><li>Lumen: Filtered HCO 3 - is converted to CO 2 . </li></ul><ul><li>Intracellular: Converted back to HCO 3 - to be returned to the systemic circulation, thus reclaiming the filtered HCO 3 - . </li></ul>Na+ H2CO3 <ul><li>1. Na+-H+ exchange </li></ul><ul><li>Permits HCO3- reabsorption/acid excretion </li></ul>Rehydration CA combines CO2 and water to form HCO 3 - and H + CA Dehydration CA: Accelerates the dissociation of H 2 CO 3 into H 2 O + CO 2
  35. 35. HPO4 2- + H => H2PO4 - <ul><ul><li>Recombine H + with another buffer e.g. HPO 4 2- </li></ul></ul><ul><ul><li>Excreted as H 2 PO 4 2- </li></ul></ul><ul><ul><li>Net gain of HCO 3 - by plasma </li></ul></ul><ul><li>In the normal kidney about 1 mg/kg of acid must be cleared each day.  This is done by reclaiming filtered bicarb and excreting hydrogen ions with phosphate buffers and ammonium.  Bicarb then diffuses into the blood and hydrogen into the urine, buffered by ammonium and phosphates. </li></ul>
  36. 36. NH3 = produced in renal tubular cell by glutaminase on amino acid glutamine. Unionized, rapidly crosses into the renal tubule down its concentration gradient. <ul><li>Renal production and secretion of ammonium (NH 4 + ) </li></ul><ul><li>Urinary H + excretion = renal addition of new HCO 3 - to plasma </li></ul>NH3 + H+ =>NH4 Lumen Blood Glutamine Glutaminase NH3 + Glutamate Na+ Na+ NH3 Glutamate NH3 + H + H+ NH4+ ATPase Na+ Na+ K+ K+
  37. 37. Diuretics Weak Organic Acids <ul><li>Most diuretics inhibit sodium transport </li></ul><ul><li>Interfere with the normal regulatory activity of the kidney. </li></ul><ul><li>Block the entry of Na+ from the urine into the cell. </li></ul>
  38. 38. <ul><ul><li>The Glomerulus </li></ul></ul><ul><ul><ul><li>Glomerular filtration rate (GFR) can be changed by drugs affecting renal blood flow (RBF) </li></ul></ul></ul><ul><ul><ul><ul><li>Xanthine alkaloids (caffeine, theophylline, aminophylline) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>weak diuretic effect </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Increased cardiac output and vasodilation resulting in increased RBF, which increases GFR </li></ul></ul></ul></ul>
  39. 39. <ul><ul><li>The Proximal Convoluted Tubule </li></ul></ul><ul><li>Majority 2/3 of filtered Na+ is reabsorbed at proximal tubules. </li></ul>Lumen Blood HCO3- + Na+ Na+ H+ H2CO3 H20 + CO2 CA CO2 + H20 CA HCO3 - HCO3 - Na+ K+ <ul><li>Carbonic anhydrase inhibitors </li></ul><ul><ul><li>Blocks NaHCO 3 reabsorption in the luminal membranes of the proximal tubule cells </li></ul></ul><ul><ul><ul><li>Causes sodium bicarbonate to be excreted in urine </li></ul></ul></ul><ul><ul><li>-SO 2 NH 2 (sulfonamide) group is essential for activity </li></ul></ul><ul><ul><li>Will increase urine pH within 30 minutes. Maximal increase in 2 hours. </li></ul></ul>Na+ H2CO3 H+ Increase Urine pH CAI
  40. 40. Osmotic Diuretics Proximal Convoluted Tubule Thin descending limb (Does not participate in salt reabsorption Water reabsorption only) <ul><li>2 main mechanisms of action </li></ul><ul><ul><li>Increase osmolarity in renal filtrate: Result: less water reabsorbed and more water excreted. </li></ul></ul><ul><ul><li>Increase in plasma osmolarity. Extracts water from intracellular compartment to the blood compartment. Decreases blood viscosity and increases renal blood flow. </li></ul></ul>
  41. 41. <ul><li>Osmotic Diuretics </li></ul><ul><ul><li>Mannitol (Osmitrol ®) </li></ul></ul><ul><li>Monosaccharide not normally found in mammals </li></ul><ul><li>Nonreabsorbable solute – primarily undergoes glomerular filtration </li></ul><ul><li>Reduces Na+ reabsorption due to ↑ urine flow rates </li></ul><ul><li>Mannitol’s large size and its several hydroxyl groups give it a low membrane permeability </li></ul><ul><li>No specialized transporters for this solute. </li></ul>
  42. 42. Na+-K+-2Cl- Cotransport TAL Actively reabsorbs NaCl and KCl via the Na+-K+-2Cl-symport (35% salt absorption). TAL: not permeable to water 2Cl- K+ Na+ 2Cl- K+ Na+ K+ Na+ K+ K+ 2Cl- K+ 2Cl- Blood Urine
  43. 43. LASIX <ul><ul><li>Inhibition of this transporter system leads to accumulation of K+ in the cell because of Na+/K+ ATPase bringing K+ into the cell also. This results in back diffusion of K+ into the tubular lumen which reduces the lumen positive potential and causes an increase in Mg++ and Ca++ excretion </li></ul></ul><ul><li>Thick Ascending Limb </li></ul><ul><li>Major site of salt absorption and action of an important group of diuretics </li></ul><ul><li>~ 25 % of filtered Na+ is reabsorbed by these cells. </li></ul><ul><li>Loop diuretics </li></ul><ul><ul><li>Most effective diuretics available </li></ul></ul><ul><ul><li>Inhibits Na+/K+/2Cl- transport system to reduce the reabsorption of NaCl in the thick ascending limb of the loop of Henle </li></ul></ul>
  44. 44. <ul><ul><li>Increase renal excretion of K+, Mg+ </li></ul></ul><ul><ul><li>Not effective at low GFR </li></ul></ul>Early Distal Tubule Thiazides: Inhibit Na+-Cl- symport
  45. 45. <ul><li>Late Distal Tubule </li></ul><ul><li>Spironolactone: </li></ul><ul><ul><li>Competitively inhibits aldosterone </li></ul></ul><ul><ul><li>Inhibits Na+ reabsorption in the late distal tubule and collecting duct. </li></ul></ul><ul><ul><li>Decreases K+ secretion </li></ul></ul>
  46. 47. References <ul><li>Craig, C.R & Stitzel, R.E. (1997). Modern pharmacology with clinical applications. 5 th edition. Brown and Company Inc. </li></ul><ul><li>Devlin,T. M. (1997). Textbook of biochemistry. 4 th edition.Wioley-Libss, Inc. New York, NY </li></ul><ul><li>Johnson, L.R. (1998). Essential medical physiology. 2 nd edition. Lippincott-Raven </li></ul><ul><li>Lingappa, V.R. & Farey, K. (2000). Physiological medicine: a clinical approach to basic medical medical physiology. McGraw-Hill </li></ul><ul><li>Weldy, N.J. (1996). Body fluids and electrolytes. 7 th edition. Mosby </li></ul>

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