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Renal Acid-Base Handling

Renal Acid-Base Handling. Introduction. [H+] is maintained within narrow limits Normal extracellular [H+] ≈ 40 nanomol/L (one-millionth the mmol/L concentrations of Na+, K+, Cl-, HCO3-) Regulation of [H+] at this low level is essential for normal cellular (protein) fxn

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Renal Acid-Base Handling

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  1. Renal Acid-Base Handling

  2. Introduction • [H+] is maintained within narrow limits • Normal extracellular [H+] ≈ 40 nanomol/L (one-millionth the mmol/L concentrations of Na+, K+, Cl-, HCO3-) • Regulation of [H+] at this low level is essential for normal cellular (protein) fxn • Increase in [H+] change charge, shape and function of proteins

  3. 3 Basic Steps of H+ Regulation • Chemical buffering by extracellular and intracellular buffers • Control of partial pressure of CO2 in the blood by alterations in alveolar ventilation • Control of plasma [HCO3-] by changes in renal H+ excretion

  4. Buffers • Take up or release H+ ions to maintain a stable [H+] • HPO42- (base) + H+ ⇄ H2PO4- (acid) • HCO3- (base) + H+ ⇄H2CO3 (acid)

  5. Henderson-Hasselbalch Equation • Ka (dissociation constant) = [H+] [A-] • [H+] = Ka [HA] • -log [H+] = -log Ka - log [HA] • pH = pKa+ log [A-] • pH = 6.10 + log [HCO3-]/0.03 Pco2 • H++ HCO3- ⇄ H2CO3⇄ H20 + CO2 [HA] [A-] [A-] [HA]

  6. Bicarbonate Buffer System • The major physiologic buffer system • [HCO3-] and Pco2 regulated independently • [HCO3-] regulated by renal H+ excretion • Pco2 regulated by changes in alveolar ventilation • As H+ are buffered by HCO3, elevation in Pco2 is prevented by increase in alveolar ventilation, thus enhancing effectiveness of HCO3 buffering • Capable of removing large quantity of H+ due to large amount of HCO3 in the body

  7. Buffering During Metabolism of Sulfur-Containing Amino Acids Diet ECF 2H+ 2 CO2 + 2 H2O 2 HCO3- Sulfur-AA SO42- 2 HCO3- Glutamine SO42- 2 NH4+ 2 NH4+ Kidney Urine •Acid balance is achieved when SO42- are excreted in the urine with NH4+ because HCO3- is generated in the process

  8. Buffering During Metabolism of Organic Phosphates Diet ECF HCO3- CO2 + H2O H+ RNA-P- HCO3- HPO42- CO2 + H2O H+ H2PO4- Kidney Urine

  9. Base Balance During Metabolism of Organic Anions Diet ECF HCO3- CO2 H+ liver K+ + OA- Glucose liver OA- K+ OA- Kidney Urine

  10. Acid-Base Balance Production H+ Production HCO3- Removal HCO3- Removal H+ Add “new” HCO3- Urine Excrete OA

  11. Alveolar Ventilation • Main physiologic stimuli to respiration •  Pco2 • Chemoreceptors in respiratory center in brainstem respond to CO2-induced ∆ cerebral interstitial pH •  Po2 • Peripheral chemoreceptors in the carotid bodies

  12. Sequential Response to H+ Load

  13. Renal H+ Excretion: Basic Principles • Achieved by H+ secretion • Na+/H+ exchange: proximal tubules and thick ascending limb of the LOH • H+-ATPase: collecting tubules • Acid load cannot be excreted as free H+ ions • Urinary [H+] is extremely low (< 0.05 mEq/L) in the physiologic pH range

  14. Renal H+ Excretion: Basic Principles • Acid load cannot be excreted unless virtually all of the filtered HCO3- has been reabsorbed • Secreted H+ ions bind to: • Filtered buffers (HPO42-, creatinine) • NH3 to form NH4+ • Rate of NH4+ generation in the proximal tubules varies according to physiologic needs

  15. Renal H+ Excretion: Basic Principles • Extracellular pH is the primary physiologic regulator of net acid excretion • Other factors include: • Effective circulating volume • Aldosterone • Plasma [K+]

  16. 2 Basic Steps of Renal H+ Excretion • Reabsorption of the filtered HCO3- • Excretion of 50-100 mEq of H+ produced per day (daily acid load on a typical Western diet)

  17. Reabsorption of Filtered HCO3- • Loss of filtered HCO3- = addition of H+ • Virtually all of the filtered HCO3- must be reabsorbed • Normal person reabsorbs about 4300 mEq of HCO3- per day (GFR 180 L/day x 24mEq/L HCO3- )

  18. Renal H+ Secretion • Secreted H+ ions are generated within tubular cells from dissociation of H2O • OH- ions combine with CO2 to form HCO3-, catalyzed by intracellular carbonic anhydrase • HCO3- is absorbed across basolateral membrane • Secretion of one H+ ion in the urine = generation of one HCO3- in the plasma

  19. Renal H+ Secretion • If secreted H+ combines with filtered HCO3- , the result is HCO3- reabsorption thus preventing HCO3- loss in the urine • If secreted H+ combines with HPO42- or NH3, a new HCO3- is added to the plasma (replaces the HCO3- lost in buffering the daily H+ load)

  20. Net Acid Excretion Net Acid Excretion (NAE) = titratable acid + NH4+ - urinary HCO3- excretion can be increased quantity not replenishable (HPO42-, Cr) Titratable acid represents the amount of alkali that is required to titrate the urine pH back to the plasma pH (7.4)

  21. Proximal Acidification • Proximal tubules reabsorb 90% of filtered HCO3- • Primary step is secretion of H+ by Na+-H+ exchanger in luminal membrane • Energy indirectly provided by Na+/K+ ATPase in basolateral membrane • HCO3-returned to systemic circulation by Na+/3 HCO3- cotransporter • Carbonic anhydrase plays central role

  22. Proximal Acidification UpToDate, 2009

  23. Distal Acidification • H+ secretion in distal nephron occurs in type A intercalated cells in the cortical collecting tubule and in the cells of the medullary colllecting tubule • H+ secretion is mediated by active luminal secretory pumps • H+-ATPase • H+/K+ ATPase

  24. Distal Acidification • H+ secretion by intercalated cells is indirectly influenced by Na+ reabsorption in the adjacent principal cells • Na+ absorption makes the lumen relatively electronegative, thus promoting H+ secretion • HCO3- reabsorption across basolateral membrane is mediated by Cl-/ HCO3- exchanger

  25. Type A Intercalated Cell UpToDate, 2009

  26. Type B Intercalated Cell UpToDate, 2009

  27. Type A vs B Intercalated Cells

  28. Ammonium Generation and Excretion Glutamine 2-Oxoglutarate2- + 2 NH4+ Liver 2 NH4+ Urea 2HCO3- to body 2 NH4+ in urine 2 HCO3-

  29. Ammonium Generation and Excretion Exogenous Endogenous Proteins 2HCO3- Methionine + Glutamine 2NH4+ 2H+ + SO42- 2 CO2 + 2H2O H+ NH4+ + NH3 2HCO3- 2NH4+ + SO42-

  30. Ammonium Generation and Excretion UpToDate, 2009

  31. Medullary Ammonium Recycling Fluid, Electrolyte and Acid-Base Physiology, 2010

  32. Ammonium Generation and Excretion Comprehensive Pediatric Nephrology, 2008

  33. Regulation of Renal H+ Excretion • Extracellular pH • Effective circulating volume • Renin-angiotensin-aldosterone system • Chloride depletion • Plasma potassium

  34. Extracellular pH Is Major Regulator of Renal H+ Excretion • NAE varies inversely with extracellular pH • Acidemia⇑prox and distal acidification • Proximal tubule • ⇑luminal Na+/H+ exchange • ⇑luminal H+-ATPase activity • ⇑Na+/3HCO3- activity in basolateral membrane • ⇑NH4 production from glutamine • Collecting tubule • ⇑luminal H+-ATPase activity in intercalated cells • Alkalemia⇓prox HCO3-reabsorption and ⇑HCO3- secretion in CCD

  35. Effective Circulating Volume • Hypovolemia activates RAAS system, causing HCO3-reabsorption • Angiotensin II • ⇑luminal Na+/H+ exchange in proximal tubule • ⇑basolateral Na+/3HCO3- activity in proximal tubule • Aldosterone • ⇑luminal H+-ATPase activity in collecting tubule • ⇑basolateral Cl-HCO3- activity in collecting tubule • ⇑Na+ absorption in principal cells in cortical collecting tubule, resulting in net H+ secretion

  36. Effective Circulating Volume • Hypochloremia commonly occurs in metabolic alkalosis • Low filtered [Cl-] increases H+ secretion • Cl- is passively cosecreted with H+ secretion via H+-ATPase to maintain electroneutrality thus ability to secrete H+ is enhanced with low tubular fluid [Cl-] • In setting of low tubular fluid [Cl-], Na+ reabsorption must be accompanied by H+ or K+ secretion in CCD

  37. Hypochloremia Decreases HCO3- Secretion Type B Intercalated Cell • Energy for luminal Cl-/HCO3- exchange is provided by favorable inward gradient for Cl- • Low tubular [Cl-] ⇓gradient thus less HCO3- secreted UpToDate, 2009

  38. Plasma K+ Influences Renal H+ Secretion Hypokalemia Changes in K+ balance lead to transcellular cation shifts that affect intracellular [H+] Hypokalemia leads to low intracellular pH Cell ECF K+ H+ Na+

  39. Intratubular Acidosis Increases H+ Excretion in Hypokalemia • ⇑H+ secretion in proximal tubule • ⇑luminal Na+/H+ exchange • ⇑basolateral Na+/3HCO3- activity • ⇑NH4 generation from glutamine in proximal tubule • ⇑H+ secretion in distal nephron • ⇑luminal H+/K+ATPase, resulting in H+ secretion and K+ absorption

  40. Renal Acification: Summary Molecular and Genetic Basis of Renal Disease, 2007

  41. References • Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte Disorders. New York, McGraw-Hill, 2001, pp 299-371. • Bidani A, Tuazon DM, Heming TA: Regulation of Whole Body Acid-Base Balance. In DuBose TD, Hamm LL (eds): Acid-Base and Electrolyte Disorders. Philadelphia, Saunders, 2002, pp 1-21.

  42. References • Alpern RJ, Hamm LL: Urinary Acidification. In DuBose TD, Hamm LL (eds): Acid-Base and Electrolyte Disorders. Philadelphia, Saunders, 2002, pp 23-40. • Halperin ML, Goldstein MB, Kamel KS: Fluid, Electrolyte and Acid-Base Physiology. Saunders, 2010, pp 3-29.

  43. References • UpToDate, 2009 • Mount DB, Pollak MR: Molecular and Genetic Basis of Renal Disease: A Companion to Brenner and Rector’s The Kidney. Saunders, 2007. • Geary D, Schaefer F: Comprehensive Pediatric Nephrology. Mosby, 2008.

  44. Distal Acidification Comprehensive Pediatric Nephrology, 2008

  45. Chronic Metabolic Acidosis and Respiratory Compensation

  46. Medullary Transfer of Ammonium Fluid, Electrolyte and Acid-Base Physiology, 2010

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