American Physiological Society Renal Physiology Refresher Course The Kidney and AcidBase Regulation

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American Physiological Society Renal Physiology
Refresher Course-The Kidney and Acid-Base
Regulation-

• Bruce M. Koeppen, M.D., Ph.D.
• University of Connecticut
• School of Medicine

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Outline

• Review renal acidification from the perspective
  of what should be taught to first year medical
  students
• Overview role of the kidneys
• HCO3- reabsorption along the nephron
• Generation of New HCO3-
• Regulation of renal acid excretion

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Overview
Acid/Alkali Intake Production Acid/Alkali
Excretion
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Overview

• FoodAcid/Alkali Impact
• Fruit Alkali
• Vegetables Alkali
• Meat Acid
• Grains Acid
• Dairy Products Acid

Typical American Diet results in Net Endogenous
Acid Production (NEAP)
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Fat Carbohydrate
H2O CO2
HA NaHCO3
Not shown is daily loss of HCO3- in feces same
as adding acid to body
HA NEAP 1 mEq/kg/day
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Role of the Kidney
NEAP
New HCO3-
NAE
NAE UNH4 V UTA V UHCO3- V
For definitions, see Notes
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HCO3-Reabsorption
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Proximal Tubule HCO3- Reabsorption
(2/3)
NHE-3
(1/3)
NBCe1
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Similar but Different

• Proximal TALH
• Apical Transporters
• Na-H antiporter NHE-3 NHE-3
• H-ATPase
• Basolateral Transporters
• Na-HCO3-symporter NBCe1 NBCn1
• Cl-HCO3-antiporter AE-2
• K-HCO3- symporter
• Carbonic Anhydrase
• Intracellular II II
• Membrane Bound IV IV

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Collecting Duct HCO3- Transport
H Secreting Intercalated cell
HCO3- Secreting Intercalated cell
Basolateral Cl--HCO3-antiporter AE-1
Apical Cl--HCO3-antiporter Pendrin
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Generation of New HCO3-
NEA UNH4 V UTA V UHCO3- V
NEA UNH4 V UTA V
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Generation of New HCO3-
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RhGlycoproteins
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RhGlycoproteins

• RhAG
• Red bloods cells
• Transports NH3 or functions as NH4-Hantiporter
• RhBG
• Kidney, liver, GI Tract
• Basolateral membrane of distal nephron segments
  (IC gt PC)
• Electroneurtal versus electrogenic
• RhCG
• Kidney, CNS, liver, muscle, testes, GI tract
• Apical, basolateral and intracellular
  localization of distal nephron segments (IC gt PC)
• Electroneutral versus electrogenic

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RhGlycoproteins

• Metabolic acidosis
• Does not alter expression of RhBG
• Increases expression of RhCG
• RhCG expression
• Translocation to apical
• membrane from intracellular
• pool

Figure showing percentage of relative apical RhCG
in intercalated and principal cells during
acidosis vs. control. (Fig. 3C, from Weiner and
Hamm. Ann. Rev. Physiol. 69 317, 2007)
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Regulation

• Acidosis
• ??NEA ?UNH4 V ?UTA V ?UHCO3- V
• Alkalosis
• ??NEA ?UNH4 V ?UTA V ?UHCO3- V

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Response to Acidosis

• Acute response
• ?cell pH results in more favorable kinetics of
  transporters
• Allosteric activation of transporters (e.g.,
  NHE-3)
• Insertion of transporters into membrane from
  intracellular stores (e.g., NHE-3 and H-ATPAse)
• Chronic response
• Transcription and/or translation of transporter
  genes and/or mRNA

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Hormonal Regulation

• Endothelin-1
• Increased ET-1 expression by proximal tubule and
  endothelial cells with acidosis
• ETB activation leads to phosphorylation of NHE-3
  and insertion into apical membrane (Ca and
  tyrosine kinase dependent) also NBCe1 in
  basolateral membrane
• ET-1 may also be involved in distal nephron
  regulation
• Glucocorticoid
• Secretion stimulated by acidosis
• Increased transcription, translation and
  expression of NHE-3 and NBCe1
• Stimulation of ammoniagenesis

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Hormonal Regulation

• Parathyroid Hormone (PTH)
• Secretion stimulated by acidosis
• PTH inhibits proximal Pi reabsorption
• Pi delivered distally results in an increase in
  titratable acid excretion

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Response to Acidosis
?H secretion Cellular Acidosis
ET-1 Glucocorticoid
?H secretion Cellular Acidosis
ET-1 Glucocorticoid
?Ammoniagenesis Cellular Acidosis Glucocorticoid
?New HCO3- Titratable Acid NH4 Secretion (RhCG)
?Pi Reabsorption PTH
??NEA ?UNH4 V ?UTA V ?UHCO3- V
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Response to Acidosis

• Urinary Net Charge
• UNC Na K Cl-
• UNC is negative if NH4 is excreted

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Alterations in Renal Acid Excretion

• Increased Acid Excretion
• ConditionSite
• ECF Volume Contraction
• A-II Proximal and Distal
• Aldosterone Distal and Collecting Duct
• Hypokalemia Proximal and ICs
• Decreased Acid Excretion
• ECF Volume Expansion Proximal, Distal
  Collecting Duct
• Hypoaldosteronism Distal and Collecting Duct
• Hyperkalemia Proximal

For definitions, see Notes
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Summary

• Renal NAE must equal NEAP
• NAE UNH4 V UTA V UHCO3- V
• NAE is altered in response to acid-base disorders
• Alterations in numbers and activities of
  acid-base transporters (H, HCO3- NH4)
• Mediators include pHi, ET-1 Glucocorticoid