AcidBase Physiology

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Acid-Base Physiology
Victor L. Schuster, MDChairmanDepartment of
Medicine
Albert Einstein College of MedicineMontefiore
Medical Center Bronx, NY
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Definitions, buffers, equations, pH, pKa
Acid- tends to donate a proton
HA ? H A-
Base- tends to accept a proton
B H ? ? BH
pH ? -logH
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HA ? H A-
Taking minus logs
pKa ? -log Ka
and pH -logH
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This is the Henderson-Hasselbalch Equation
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Common buffer systems in the body
plasma H HCO3- ? H2CO3 pKa 6.1
urine H NH3 ? NH4 pKa 9.0
urine H HPO4-- ? H2PO4- pKa 6.8
cell H protein- ? proteinH pKa 7.0
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The phosphate buffer system is important in
urinary acid excretion
H HPO4-- ? H2PO4- pKa 6.8
Thus at physiological pH, the phosphate buffer
system is in the proton-acceptor form.
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The CO2 - HCO3- buffer system is important in the
plasma
H HCO3- ? H2CO3 ? CO2 H2O
The lumped pKa 6.1
Since H2CO3 pCO2 x (0.03)
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Normal values pH 7.35-7.45 H 40
nM pCO2 35-45 mm Hg HCO3- 23-27 mEq/L
(Note sometimes HCO3- is called total CO2,
which is in millimolar, not to be confused with
pCO2, which is in mm Hg) Total CO2 is the sum
of bicarbonate plus carbonic acid (H2CO3)(both in
mM) H2CO3 dissolved CO2 (0.03 x pCO2)
At a pCO2 of 40 mm Hg, H2CO3 1.2 mM
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The Bottle Experiment-1
Vacuum
CO2 Source
Initial pCO2 40 mm Hg add 13 mEq of HCl in a
few ml
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Where the HCO3- goes after acid addition
Na Cl- H HCO3-
Na Cl- H2CO3
Na Cl- CO2 H2O
Na Cl-
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HCO3- falls by 13 mEq/l
25 - 13 12 mEq/l
H2CO3 rises by 13 mEq/l
We already had H2CO3 (0.03 x 40) 1.2 mM
So H2CO3 1.2 13 14.2 mM
6.03
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The Bottle Experiment-2
Vacuum
CO2 Source
Initial pCO2 40 mm Hg add 13 mEq of HCl in a
few ml
Use CO2 source vacuum to keep the H2CO3 constant
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Vacuum
CO2 Source
HCO3- falls by 13 mEq/l
25 - 13 12 mEq/l
but H2CO3 now stays constant
(0.03 x 40) 1.2 mM
7.10
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The Bottle Experiment-3
Vacuum
CO2 Source
Clamp
Initial pCO2 40 mm Hg add 13 mEq of HCl in a
few ml
Use vacuum to lower the H2CO3 by lowering pCO2 to
25 mm Hg
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Vacuum
CO2 Source
HCO3- falls by 13 mEq/l
25 - 13 12 mEq/l
H2CO3 now reduced
(0.03 x 25) 0.75 mM
7.30
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This is an example of a metabolic acidosis with
respiratory compensation
The system tries acutely to fix the ratio
i.e. if HCO3- falls, then pCO2 falls but pH
never returns completely to normal
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Buffering of H Added to the ECF By Intracellular
H Acceptors
70 kg person 14L ECF 14L x 25 mEq/L 350 mEq
ECF HCO3-
100 mEq H into 14L expected ? HCO3- 100
14 7 mEq/L
plasma HCO3- falls by only 3.5 mEq/L
ECF
ICF
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Time course of buffering an acid load
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We generate 15,000 mmoles of CO2 per day, yet
pCO2 and pH vary little. How?
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Primary Respiratory Disorders
CO2 H2O ? H2CO3 ? H HCO3-
Note H is in nM (nano) HCO3- is in mM
(milli) i.e. one million-fold different!
Thus x moles of CO2 addition causes a large
drop in plasma pH a small ? plasma HCO3-
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Acid-Base in Various Vertebrates
Robin et al, Yale J Biol Med 1969
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Suppose pCO2 rises from 40 to 80 mm Hg
7.12
Acidosis has been produced by adding the
volatile acid CO2
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Compensation for pCO2 rise does occur, but over
days the kidney generates new HCO3-
Suppose plasma HCO3- is raised to 45 mEq/l by
the kidney
7.37
This is respiratory acidosis with metabolic
compensation
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The ABC of Acid-Base Chemistry H.W. Davenport
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Metabolic acidosis w/respiratory compensation
Step 1 Lower HCO3 Hold pCO2
Step 2 Lower pCO2
Final Low HCO3 Low pCO2 Slightly low pH
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Respiratory acidosis w/metabolic compensation
Step 1 Raise pCO2 Hold HCO3
Step 2 Raise HCO3
Final High HCO3 High pCO2 Slightly low pH
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Metabolic alkalosis w/resp compensation
Step 1 Raise HCO3 Hold pCO2
Step 2 Raise pCO2
Final High HCO3 High pCO2 Slightly high pH
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The Four Cardinal Acid Base Disorders
M acidosis
? ? ?
M alkalosis
? ? ?
R acidosis
? ? ?
R alkalosis
? ? ?
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Chronic acid-base compensations in man
Sherpas
Chronic hypoxic environment
pCO2 20 mm Hg, HCO3 14
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Tubule Handling of Acid-Base
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Big picture tubule acid-base physiology

• All filtered HCO3 is reclaimed daily from the
  glomerular filtrate (the high capacity proximal
  tubule system)
• The daily acid load from metabolism and diet is
  excreted by the collecting duct by secreting H
  onto phosphate and NH3 (the high gradient
  distal system)
• When new HCO3 is needed, as in metabolic
  acidosis, the proximal tubule synthesizes more
  NH3, protonates it, and eliminates it in the
  urine
• Between allosteric effects on transporters and
  increased ammoniagenesis, the tubular maximum
  (Tm) of the proximal tubule is plastic

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Big picture tubule acid-base physiology

• All filtered HCO3 is reclaimed daily from the
  glomerular filtrate (the high capacity proximal
  tubule system)
• The daily acid load from metabolism and diet is
  excreted by the collecting duct by secreting H
  onto phosphate and NH3 (the high gradient
  distal system)
• When new HCO3 is needed, as in metabolic
  acidosis, the proximal tubule synthesizes more
  NH3, protonates it, and eliminates it in the
  urine
• Between allosteric effects on transporters and
  increased ammoniagenesis, the tubular maximum
  (Tm) of the proximal tubule is plastic

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Proximal tubule resorption Tm limited
X in moles/time
GFR x Xplasma filtered load of X
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Proximal tubule HCO3- resorption
HCO3- in moles/time
GFR x HCO3-plasma filtered load of HCO3-
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Proximal Tubule HCO3- Reclamation
(stoichiometry 3 HCO3- to 1 H )
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Proximal Tubule is Leaky
pHmin 6.8
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Proximal tubule HCO3- reclamation is high
capacity, low gradient
Daily proximal tubule HCO3- reclamation 180 L/d
x 25 mEq/L 4500 mEq/d !
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Big picture tubule acid-base physiology

• All filtered HCO3 is reclaimed daily from the
  glomerular filtrate (the high capacity proximal
  tubule system)
• The daily acid load from metabolism and diet is
  excreted by the collecting duct by secreting H
  onto phosphate and NH3 (the high gradient
  distal system)
• When new HCO3 is needed, as in metabolic
  acidosis, the proximal tubule synthesizes more
  NH3, protonates it, and eliminates it in the
  urine
• Between allosteric effects on transporters and
  increased ammoniagenesis, the tubular maximum
  (Tm) of the proximal tubule is plastic

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Daily acid load (omnivore) 1 mEq/kg BW/day
If the urine had no proton acceptors, how much
acid could be excreted daily?
Suppose you could put out 10 l/d urine at pH
4 (not possible, but pretend)
How many mEq/d of H could be excreted?
0.1 mEq/l x 10 l/d 1 mEq/day of H
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The daily acid load adds H The H combine with
HCO3- and reduce it New HCO3 must be
generated or else metabolic acidosis will prevail
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How to generate new HCO3- ?
Solution proton acceptors Proton Acceptor 1
NH3
Glutaminase
Glutamine NH3 CO2 H2O
This is new HCO3
Proximal tubule
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NH4 undergoes counter-current multiplication-1
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NH4 undergoes counter-current multiplication-2
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NH4 undergoes counter-current multiplication-3
Na
ATP
H
ADP Pi
a IC cell
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Proton Acceptor 2 HPO4--
Urine H HPO4-- ? H2PO4- pKa 6.8
Consider 50 millimoles of phosphate in the
glomerular filtrate
Location pH HPO4-- H2PO4- amt buffered
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Principal cell
Collecting Duct Acidification
a IC cell
pHmin 5
b IC cell
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Collecting tubule H secretion is low
capacity, high gradient
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Net acid excretion urinary NH4
urinary H2PO4- - urinary HCO3-
H
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Regulation Of Acid-Base Balance
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Principles of cell pH regulation 1.
Cytoplasmic H varies with plasma H 2. Cell
is constantly bailing out H
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Henry Louis Mencken (1880 - 1956)
Newspaperman, book reviewer, and political
commentator. Covered the Scopes Monkey Trial.
Life is a struggle, not against sin, not
against Money Power, not against malicious
animal magentism, but against hydrogen
ions. Smart Set 60138-145, 1919
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Big picture tubule acid-base physiology

• All filtered HCO3 is reclaimed daily from the
  glomerular filtrate (the high capacity proximal
  tubule system)
• The daily acid load from metabolism and diet is
  excreted by the collecting duct by secreting H
  onto phosphate and NH3 (the high gradient
  distal system)
• When new HCO3 is needed, as in metabolic
  acidosis, the proximal tubule synthesizes more
  NH3, protonates it, and eliminates it in the
  urine
• Between allosteric effects on transporters and
  increased ammoniagenesis, the tubular maximum
  (Tm) of the proximal tubule is plastic

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Regulation of Proximal Tubule HCO3-
Reclamation By Systemic Acidosis
Note No new HCO3- formed!
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In acidosis, ammoniagenesis increases
Solution proton acceptors Proton Acceptor 1
NH3
Glutaminase
Glutamine NH3 CO2 H2O
This is new HCO3
Proximal tubule
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Formation of New HCO3- by Ammoniagenesis
0.1
NH4 excretion mmol/min
0.05
5
6
7
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Urine pH
After RF Pitts, 1948
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Big picture tubule acid-base physiology

• All filtered HCO3 is reclaimed daily from the
  glomerular filtrate (the high capacity proximal
  tubule system)
• The daily acid load from metabolism and diet is
  excreted by the collecting duct by secreting H
  onto phosphate and NH3 (the high gradient
  distal system)
• When new HCO3 is needed, as in metabolic
  acidosis, the proximal tubule synthesizes more
  NH3, protonates it, and eliminates it in the
  urine
• Between allosteric effects on transporters and
  increased ammoniagenesis, the tubular maximum
  (Tm) of the proximal tubule is plastic

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Proximal tubule HCO3- Tm is Variable
UHCO3V
HCO3- in moles/time
GFR x HCO3-plasma filtered load of HCO3-
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Things That Raise the Proximal Tubule HCO3- Tm
? pCO2, angiotensin II, norepinephrine K
depletion glucocorticoids
UHCO3V
HCO3- in moles/time
GFR x HCO3-plasma filtered load of HCO3-
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Proximal tubule HCO3 resorption is driven by the
pCO2
Na
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Proximal tubule HCO3 resorption is driven by the
pCO2
HCO3 resorbed moles/time
pCO2(mm Hg)
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Total Body K Depletion Increases Proximal
Tubule Acidification via Intracellular Acidosis
2. Total body K depletion
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Principal cell
Collecting Duct Acidification
a IC cell
b IC cell
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Collecting Duct H Pump Exocytosis is Driven by
the pCO2
pCO2(mm Hg)
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End of Physiology Section (Acid-Base Part 1)