AcidBase Physiology

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Acid-Base Physiology
Victor L. Schuster, MDChairmanDepartment of
Medicine
Albert Einstein College of MedicineMontefiore
Medical Center Bronx, NY
2
What you will understand after todays lectures

• How H is buffered by blood and cells
• The four acid-base disorders
• The compensations for these disorders
• How filtered HCO3 is reclaimed by the proximal
  tubule
• How the daily acid load is excreted primarily
  by the collecting duct using phosphate and NH3
• How new HCO3 is generated after metabolic
  acidosis
• How various factors modulate tubular acid-base
  handling

3
What you will understand after todays lectures

• How H is buffered by blood and cells
• The four acid-base disorders
• The compensations for these disorders
• How filtered HCO3 is reclaimed by the proximal
  tubule
• How the daily acid load is excreted primarily
  by the collecting duct using phosphate and NH3
• How new HCO3 is generated after metabolic
  acidosis
• How various factors modulate tubular acid-base
  handling

4
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
5
HA ? H A-
Taking minus logs
pKa ? -log Ka
and pH -logH
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This is the Henderson-Hasselbalch Equation
7
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
bone H CO3-- ? HCO3- pKa 6.4
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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.
9
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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Lets see if youre following it
Acid-Base in Various Vertebrates
Robin et al, Yale J Biol Med 1969
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Lets see if youre following it
Acid-Base in Various Vertebrates
Robin et al, Yale J Biol Med 1969
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pCO2
H2CO3
Logratio
pH
Vertebrate
7.50
0.6
25.0
1.40
frog
20
25.0
1.40
7.50
lungfish
20
0.6
1.55
7.65
30
0.9
35.5
turtle
7.42
1.2
20.8
1.32
man
40
20.3
1.31
7.41
46
1.4
seal
13
Lets see if youre following it
Acid-Base in Various Vertebrates
Robin et al, Yale J Biol Med 1969
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pCO2
H2CO3
Logratio
pH
Vertebrate
1.82
7.92
.06
66.6
teleost
2
7.99
77.7
1.89
elasmobr
3
.09
2.00
8.10
2
.06
100
tadpole
7.50
0.6
25.0
1.40
frog
20
25.0
1.40
7.50
lungfish
20
0.6
1.55
7.65
30
0.9
35.5
turtle
7.42
1.2
20.8
1.32
man
40
20.3
1.31
7.41
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1.4
seal
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Normal values pH 7.35-7.45 H 40
nM pCO2 35-45 mm Hg HCO3- 23-27 mEq/L
Instead of HCO3-, some labs report Total CO2
which is the sum of bicarbonate plus dissolved
CO2 (very small) plus carbonic acid (H2CO3)(all
in mM). This should not be confused with the
partial pressure of CO2, i.e. pCO2, which is in
mm Hg. If the normal pCO2 40 mm Hg, then the
normal H2CO3 0.03 x 40 1.2 mM
16
What you will understand after todays lectures

• How H is buffered by blood and cells
• The four acid-base disorders
• The compensations for these disorders
• How filtered HCO3 is reclaimed by the proximal
  tubule
• How the daily acid load is excreted primarily
  by the collecting duct using phosphate and NH3
• How new HCO3 is generated after metabolic
  acidosis
• How various factors modulate tubular acid-base
  handling

17
The Four Cardinal Acid Base Disorders
M acidosis
? ? ?
M alkalosis
? ? ?
R acidosis
? ? ?
R alkalosis
? ? ?
18
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
21
Low plasma pH reduces cardiac contraction via
number of cardiac adrenergic receptors
Isoproterenol-induced contraction vs pH
Cardiac contraction vs pH
Marsh, Margoli, Kim 1988
22
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
23
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
25
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
26
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
27
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
29
We generate 15,000 mmoles of CO2 per day, yet
pCO2 and pH vary little. How?
30
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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Suppose pCO2 rises from 40 to 80 mm Hg
7.12
Acidosis has been produced by adding the
volatile acid CO2
32
Compensation for pCO2 rise does occur, but over
days the kidney generates new HCO3-
Suppose plasma HCO3- is raised to 40 mEq/l by
the kidney
7.32
This is respiratory acidosis with metabolic
compensation
33
Chronic acid-base compensations in man
Sherpas
Chronic hypoxic environment
pCO2 20 mm Hg, HCO3 15, pH 7.5
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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
? ? ?
42
Questions?
43
What you will understand after todays lectures

• How H is buffered by blood and cells
• The four acid-base disorders
• The compensations for these disorders
• How filtered HCO3 is reclaimed by the proximal
  tubule
• How the daily acid load is excreted primarily
  by the collecting duct using phosphate and NH3
• How new HCO3 is generated after metabolic
  acidosis
• How various factors modulate tubular acid-base
  handling

44
Tubule Handling of Acid-Base
An important principle
tubule
tubule
cell
cell
H
HCO3-
H
HCO3-
45
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

46
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

47
Robert F. Pitts 1908 - 1977
Organization of the respiratory center Mechanism
of renal phosphate transport Mechanism of renal
amino acid transport Regulation of sodium
chloride transport Mechanism regulation of
ammonium transport Mechanism regulation of
bicarbonate transport Mechanism of action of
diuretics
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Proximal tubule resorption Tm limited
X in moles/time
GFR x Xplasma filtered load of X
49
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 Na )
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Proximal Tubule is Leaky
pHmin 6.8
52
Proximal tubule HCO3- reclamation is high
capacity, low gradient
Daily proximal tubule HCO3- reclamation 180 L/d
x 25 mEq/L 4500 mEq/d !
53
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

54
The daily acid load from diet metabolism adds
H to the plasma The H combine with HCO3- and
reduces it New HCO3 must be generated or else
metabolic acidosis will prevail New HCO3 is
generated by secreting H into the urine
55
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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Proton acceptors are key to this process
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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Proton acceptor 1
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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
60
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
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Google Map exit 170, I-90, Montana
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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- renal protonation
filtrate 7.4 40 10 0
end prox 6.8 25 25 15
urine 4.8 0.5 49.5 39.5
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Principal cell
Collecting Duct Acidification
a IC cell
pHmin 4.5
b IC cell
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Collecting tubule H secretion is low
capacity, high gradient
69
Net acid excretion urinary NH4
urinary H2PO4- - urinary HCO3-
H
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Questions?
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Regulation Of Acid-Base Balance
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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

73
Cell pH senses plasma pH 1. Cytoplasmic H
varies with plasma H 2. Cell is constantly
bailing out H
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Regulation of Proximal Tubule HCO3-
Reclamation By Systemic Acidosis
Note No new HCO3- formed!
75
In acidosis, ammoniagenesis increases
Solution proton acceptors Proton Acceptor 1
NH3
Glutaminase
Glutamine NH3 CO2 H2O
This is new HCO3
Proximal tubule
76
Formation of New HCO3- by Ammoniagenesis
0.1
NH4 excretion mmol/min
0.05
5
6
7
8
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

78
Proximal tubule HCO3- Tm is Variable
UHCO3V
HCO3- in moles/time
GFR x HCO3-plasma filtered load of HCO3-
79
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-
80
Proximal tubule HCO3 resorption is driven by the
pCO2
Na
81
Proximal tubule HCO3 resorption is driven by the
pCO2
HCO3 resorbed moles/time
pCO2(mm Hg)
82
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
85
Collecting Duct H Pump Exocytosis is Driven by
the pCO2
pCO2(mm Hg)
86
Na
Na
K
K
Principal cell
Aldosterone
ATP
K Depletion Induces H /K Exchangers in CCD
H
HCO3-
ADP Pi
Cl-
Cl-
a IC cell
Cl-
Cl-
HCO3-
ATP
H
ADP Pi
b IC cell
87
What you will understand after todays lectures

• How H is buffered by blood and cells
• The four acid-base disorders
• The compensations for these disorders
• How filtered HCO3 is reclaimed by the proximal
  tubule
• How the daily acid load is excreted primarily
  by the collecting duct using phosphate and NH3
• How new HCO3 is generated after metabolic
  acidosis
• How various factors modulate tubular acid-base
  handling

88
Questions?
89
End of Acid-Base Physiology Section (Part 1)