1. University of Connecticut
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

2. 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

3. Overview Acid/Alkali Intake + Production = Acid/Alkali Excretion
Metabolic Production
of Acid/Alkali
Acid/Alkali
Excretion
Acid/Alkali Intake + Production = Acid/Alkali Excretion

4. 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)

5. HA = NEAP = 1 mEq/kg/day O2 Insulin Fat & Carbohydrate H2O + CO2 O2
HA + NaHCO3
NaA + H2O + CO2
Protein
Organic Anions
(e.g., citrate)
“New”
HCO3
Not shown is daily loss of HCO3- in feces – same as adding acid to body
NH4A + HA
HA = NEAP = 1 mEq/kg/day

6. Role of the Kidney NAE = UNH4+ V + UTA V – UHCO3- V NEAP New HCO3- NAE
UNH4+ V, rate of ammonia excretion; UTAV, rate of titratable acid excretion; UHCO3-V, rate of bicarbonate excretion
NAE = UNH4+ V + UTA V – UHCO3- V
For definitions, see “Notes”

7. HCO3-Reabsorption
Fig Reprinted with permission by Mosby.

8. Proximal Tubule HCO3- Reabsorption
(2/3)
NHE-3
(1/3)
NBCe1
Fig Reprinted with permission by Mosby.

9. Similar but Different Proximal TALH Apical Transporters
Na-H antiporter NHE NHE-3
H-ATPase
Basolateral Transporters
Na-HCO3-symporter NBCe NBCn1
Cl-HCO3-antiporter AE-2
K-HCO3- symporter
Carbonic Anhydrase
Intracellular II II
Membrane Bound IV IV

10. Collecting Duct HCO3- Transport
H+ Secreting Intercalated cell
HCO3- Secreting Intercalated cell
Fig Reprinted with permission by Mosby.
Basolateral Cl--HCO3-antiporter: AE-1
Apical Cl--HCO3-antiporter: Pendrin

11. Generation of New HCO3- NEA = UNH4+ V + UTA V – UHCO3- V
HCO3- Reabsorption
NEA = UNH4+ V + UTA V
Titratable Acid
HPO4= + H H2PO4-
Fig Reprinted with permission by Mosby.

12. Generation of New HCO3-
Glutamine
2 HCO3-
2 NH4+
2H+ +
urea

13. Figure 38-5. Reprinted with permission by Mosby.
RhGlycoproteins

14. RhGlycoproteins RhAG: RhBG: RhCG: Red bloods cells
Transports NH3 or functions as NH4+-H+antiporter
RhBG:
Kidney, liver, GI Tract
Basolateral membrane of distal nephron segments (IC > PC)
Electroneurtal versus electrogenic
RhCG:
Kidney, CNS, liver, muscle, testes, GI tract
Apical, basolateral and intracellular localization of distal nephron segments (IC > PC)
Electroneutral versus electrogenic

15. RhGlycoproteins Metabolic acidosis: RhCG expression
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)
Figure 3C. From David Weiner and L. Lee Hamm. Molecular Mechanisms of Renal Ammonia Transport. Ann. Rev. Physiol. 69: 317, 2007.
Available by subscription at

16. Regulation Acidosis Alkalosis NEA = UNH4+ V + UTA V – UHCO3- V

17. Response to Acidosis Acute response Chronic 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

18. Hormonal Regulation Endothelin-1 Glucocorticoid
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

19. 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

20. Response to Acidosis NEA = UNH4+ V + UTA V – UHCO3- V
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)
Fig Reprinted with permission by Mosby.
Pi Reabsorption
PTH
NEA = UNH4+ V + UTA V – UHCO3- V

21. Response to Acidosis Urinary Net Charge UNC = [Na+] + [K+] – [Cl-]
UNC is negative if NH4+ is excreted

22. 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 IC’s
Decreased Acid Excretion
ECF Volume Expansion Proximal, Distal & Collecting Duct
Hypoaldosteronism Distal and Collecting Duct
Hyperkalemia Proximal
AII, angiotensin II; ECF, extracellular fluid; IC, intercalated cell
For definitions, see “Notes”

23. 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
pHi, intracellular pH