acid base physiology 2010 by 26hw29

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									      Acid-Base Physiology

     Victor L. Schuster, MD
            Chairman
     Department of Medicine

Albert Einstein College of Medicine
    Montefiore Medical Center
             Bronx, NY
   What you will understand after today’s lectures:
1. How H+ is buffered by blood and cells

2. The four acid-base disorders

3. The compensations for these disorders

4. How filtered HCO3 is reclaimed by the proximal tubule

5. How the “daily acid load” is excreted primarily by the collecting duct
   using phosphate and NH3

6. How new HCO3 is generated after metabolic acidosis

7. How various factors modulate tubular acid-base handling
   What you will understand after today’s lectures:
1. How H+ is buffered by blood and cells

2. The four acid-base disorders

3. The compensations for these disorders

4. How filtered HCO3 is reclaimed by the proximal tubule

5. How the “daily acid load” is excreted primarily by the collecting duct
   using phosphate and NH3

6. How new HCO3 is generated after metabolic acidosis

7. How various factors modulate tubular acid-base handling
Definitions, buffers, equations, pH, pKa


    “Acid”- tends to donate a proton


                  HA  H+ + A-


   “Base”- tends to accept a proton


                  B + H+  BH+

               pH  -log[H+]
              HA  H+ + A-
                     [H+][A-]
             Ka 
                       [HA]

                                  [HA]
    Rearrange:       [H+] = Ka
                                  [A-]
            Taking minus logs:

                                    [HA]
-log[H+] = -log[Ka] - log
                                     [A-]
              pKa  -log Ka

              and pH = -log[H+]
                                    [HA]
 -log[H+] = -log[Ka] - log
                                    [A-]


                             [A-]
        pH = pKa + log
                             [HA]


This is the Henderson-Hasselbalch Equation
       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-  protein•H   pKa = 7.0


bone     H+ + CO3--  HCO3-          pKa = 6.4
      The phosphate buffer system
  is important in urinary acid excretion


H+ + HPO4--  H2PO4-            pKa = 6.8

                              [HPO4--]
     if 7.4 = 6.8 + log
                              [H2PO4-]

      then        [HPO4--]
                              =4
                  [H2PO4-]


          Thus at physiological pH,
    the phosphate buffer system is in the
           proton-acceptor form.
     The CO2 - HCO3- buffer system
       is important in the plasma

H+ + HCO3-  H2CO3           CO2 + H2O

     The “lumped” pKa = 6.1

                        [HCO3-]
   pH = 6.1 + log
                        [H2CO3]


      Since H2CO3 = pCO2 x (0.03)

                          [HCO3-]
   pH = 6.1 + log
                       [.03 x pCO2]
 Let’s see if you’re following it:


Acid-Base in Various Vertebrates




    Robin et al, Yale J Biol Med 1969
 Let’s see if you’re following it:


Acid-Base in Various Vertebrates




    Robin et al, Yale J Biol Med 1969
                            HCO3    Log
Vertebrate   pCO2   H2CO3                    pH
                            H2CO3   ratio




   frog       20     0.6    25.0    1.40    7.50

 lungfish     20     0.6    25.0    1.40    7.50

  turtle      30     0.9    35.5    1.55    7.65

  man         40     1.2    20.8    1.32    7.42

   seal       46     1.4    20.3    1.31    7.41
 Let’s see if you’re following it:


Acid-Base in Various Vertebrates




    Robin et al, Yale J Biol Med 1969
                            HCO3    Log
Vertebrate   pCO2   H2CO3                    pH
                            H2CO3   ratio

 teleost      2      .06    66.6    1.82    7.92

elasmobr      3      .09    77.7    1.89    7.99

 tadpole      2      .06    100     2.00    8.10

   frog       20     0.6    25.0    1.40    7.50

 lungfish     20     0.6    25.0    1.40    7.50

  turtle      30     0.9    35.5    1.55    7.65

  man         40     1.2    20.8    1.32    7.42

   seal       46     1.4    20.3    1.31    7.41
  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
   What you will understand after today’s lectures:
1. How H+ is buffered by blood and cells

2. The four acid-base disorders

3. The compensations for these disorders

4. How filtered HCO3 is reclaimed by the proximal tubule

5. How the “daily acid load” is excreted primarily by the collecting duct
   using phosphate and NH3

6. How new HCO3 is generated after metabolic acidosis

7. How various factors modulate tubular acid-base handling
       The Four Cardinal Acid Base Disorders



Disorder           pH         pCO2 [HCO3-]


M acidosis                           

M alkalosis                          

R acidosis                           

R alkalosis                          
        “The Bottle Experiment”-1
                  Vacuum       CO2 Source

                   Clamp       Clamp




     1 liter of
      25 mM
     NaHCO3




Initial pCO2 = 40 mm Hg; add 13 mEq of HCl in a few ml


 H+ + HCO3-       H2CO3        CO2 + H2O
Where the [HCO3-] goes after acid addition:


Na+ + Cl- + H+ + HCO3-



Na+ + Cl-     + H2CO3



Na+ + Cl-     + CO2 + H2O



Na+ + Cl-
             H+ + HCO3-     H2CO3          CO2 + H2O

             Vacuum       CO2 Source
                                        HCO3- falls by 13 mEq/l
              Clamp       Clamp
                                          25 - 13 = 12 mEq/l


                                       H2CO3 rises by 13 mEq/l

1 liter of                              We already had H2CO3:
 25 mM                                  (0.03 x 40) = 1.2 mM
NaHCO3


                          So H2CO3 = 1.2 + 13 = 14.2 mM

                                        [12]
               pH = 6.1 + log                    = 6.03
                                       [14.2]
Low plasma pH reduces cardiac contraction via number of
            cardiac adrenergic receptors




Cardiac contraction vs pH                          Isoproterenol-induced
                                                     contraction vs pH




                      Marsh, Margoli, & Kim 1988
           “The Bottle Experiment”-2
                     Vacuum      CO2 Source

                     Clamp       Clamp




        1 liter of
         25 mM
        NaHCO3



  Initial pCO2 = 40 mm Hg; add 13 mEq of HCl in a few ml
Use CO2 source & vacuum to keep the H2CO3 constant

   H+ + HCO3-        H2CO3       CO2 + H2O
             H+ + HCO3-     H2CO3          CO2 + H2O

             Vacuum       CO2 Source

                                       HCO3- falls by 13 mEq/l

                                        25 - 13 = 12 mEq/l

                                                    but
1 liter of                                H2CO3 now stays constant
 25 mM
NaHCO3                                  (0.03 x 40) = 1.2 mM



                                        [12]
               pH = 6.1 + log                    = 7.10
                                       [1.2]
             “The Bottle Experiment”-3
                       Vacuum      CO2 Source

                       Clamp       Clamp




          1 liter of
           25 mM
          NaHCO3



    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
     H+ + HCO3-        H2CO3       CO2 + H2O
             H+ + HCO3-     H2CO3          CO2 + H2O

             Vacuum       CO2 Source


                                       HCO3- falls by 13 mEq/l

                                        25 - 13 = 12 mEq/l
                                          H2CO3 now reduced
1 liter of                             (0.03 x 25) = 0.75 mM
 25 mM
NaHCO3




                                        [12]
               pH = 6.1 + log                     = 7.30
                                       [0.75]
This is an example of a “metabolic acidosis with
           respiratory compensation”

                                [HCO3-]
    pH = 6.1 + log
                            [.03 x pCO2]


    The system tries acutely to fix the ratio


       i.e. if HCO3- falls, then pCO2 falls

  but pH never returns completely to normal
              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- =
Add 100 mEq H+        100 ÷ 14 = 7 mEq/L


 plasma                          50% (50 mEq)
  HCO3-                            must be
   falls                            titrated
by only 3.5                           intra-
  mEq/L                            cellularly

                     EC              ICF
       Time course of buffering an acid load:


 Plasma HCO3- system
Seconds/
minutes

           Drop in pCO2
           minutes/
            hours
                      Intracellular & bone
                          2-4 hrs

                                    Renal generation of de
                                        novo HCO3-

                                           Hrs to days
      We generate ~15,000 mmoles of
CO2 per day, yet pCO2 and pH vary little. How?

CO2 + H2O  H2CO3  H+ + HCO3-




H+ + HCO3-    H2CO3       CO2 + H2O
            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-]
Suppose pCO2 rises from 40 to 80 mm Hg:

                                  [HCO3-]
       pH = 6.1 + log
                              [.03 x pCO2]

                                  [25]
       pH = 6.1 + log
                              [.03 x 80]

             = 7.12

Acidosis has been produced
by adding the volatile acid CO2
       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:

                                     [HCO3-]
        pH = 6.1 + log
                                [.03 x pCO2]
                                     [40]
        pH = 6.1 + log
                                [.03 x 80]

              = 7.32

This is “respiratory acidosis with
       metabolic compensation”
Chronic acid-base compensations in man


Sherpas




          Chronic hypoxic environment

   pCO2 = 20 mm Hg, [HCO3] = 15, pH 7.5
The ABC of Acid-Base Chemistry
        H.W. Davenport
               pCO2 isobars
            60     40       20




HCO3   25
-




              7.4
              pH
Metabolic acidosis w/respiratory compensation
 Step 1:
 Lower HCO3                       pCO2 isobars
 Hold pCO2                     60     40       20
  Step 2:
  Lower pCO2



    HCO3          25
    -


Final:
Low HCO3
Low pCO2
Slightly low pH
                                 7.4
                                  pH
Respiratory acidosis w/metabolic compensation
  Step 1:
  Raise pCO2                     pCO2 isobars
  Hold HCO3                   60     40       20
   Step 2:
   Raise HCO3



     HCO3          25
     -


 Final:
 High HCO3
 High pCO2
 Slightly low pH
                                 7.4
                                  pH
  Metabolic alkalosis w/resp compensation
 Step 1:
 Raise HCO3                     pCO2 isobars
 Hold pCO2                   60     40       20
  Step 2:
  Raise pCO2



    HCO3           25
    -


Final:
High HCO3
High pCO2
Slightly high pH
                                7.4
                                 pH
       The Four Cardinal Acid Base Disorders



Disorder           pH         pCO2 [HCO3-]


M acidosis                           

M alkalosis                          

R acidosis                           

R alkalosis                          
Questions?
   What you will understand after today’s lectures:
1. How H+ is buffered by blood and cells

2. The four acid-base disorders

3. The compensations for these disorders

4. How filtered HCO3 is reclaimed by the proximal tubule

5. How the “daily acid load” is excreted primarily by the collecting duct
   using phosphate and NH3

6. How new HCO3 is generated after metabolic acidosis

7. How various factors modulate tubular acid-base handling
                Tubule Handling of
                   Acid-Base
                 An important principle:


tubule                           tubule
         cell                              cell


 H+                 HCO3-       HCO3-             H+
“Big picture”: tubule acid-base physiology

1. All filtered HCO3 is reclaimed daily from the glomerular filtrate (the
   “high capacity” proximal tubule system)

2. 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)

3. When new HCO3 is needed, as in metabolic acidosis, the proximal
   tubule synthesizes more NH3, protonates it, and eliminates it in the
   urine

4. Between allosteric effects on transporters and increased
   ammoniagenesis, the “tubular maximum” (“Tm”) of the proximal
   tubule is plastic
“Big picture”: tubule acid-base physiology

1. All filtered HCO3 is reclaimed daily from the glomerular filtrate (the
   “high capacity” proximal tubule system)

2. 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)

3. When new HCO3 is needed, as in metabolic acidosis, the proximal
   tubule synthesizes more NH3, protonates it, and eliminates it in the
   urine

4. Between allosteric effects on transporters and increased
   ammoniagenesis, the “tubular maximum” (“Tm”) of the proximal
   tubule is plastic
  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
 Proximal tubule resorption: “Tm limited”




                                             filtered

   X in
                                             UxV
moles/time


                                               resorbed



    GFR x [X]plasma = “filtered load of X”
             Proximal tubule HCO3- resorption




                                              filtered

 HCO3- in
                                              UHCO3V
moles/time


                                                  HCO3- Tm



 GFR x [HCO3-]plasma = “filtered load of HCO3-”
Proximal Tubule HCO3- Reclamation




                      Na+
     HCO3   -               Na+
                H+   H+
                            HCO3-
      CO2 + H2O

                                    (stoichiometry =
                                    3 HCO3- to 1 Na+ )
Proximal Tubule is “Leaky”




                   Na+
  HCO3   -               Na+
             H+   H+
                         HCO3-
  CO2 + H2O



     H+
                   Na+


   pHmin = 6.8
Proximal tubule HCO3- reclamation is
   “high capacity, low gradient”
Daily proximal tubule HCO3- reclamation ~180 L/d x 25 mEq/L
                       = 4500 mEq/d !




            =
“Big picture”: tubule acid-base physiology

1. All filtered HCO3 is reclaimed daily from the glomerular filtrate (the
   “high capacity” proximal tubule system)

2. 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)

3. When new HCO3 is needed, as in metabolic acidosis, the proximal
   tubule synthesizes more NH3, protonates it, and eliminates it in the
   urine

4. Between allosteric effects on transporters and increased
   ammoniagenesis, the “tubular maximum” (“Tm”) of the proximal
   tubule is plastic
The daily acid load from diet & metabolism adds H+ to
the plasma

The H+ combine with HCO3- and reduce it

 H+ + HCO3-     H2CO3        CO2 + H2O


New HCO3 must be generated or else metabolic
acidosis will prevail

New HCO3 is generated by secreting H+ into the urine
     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 60:138-145, 1919
 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+
Proton acceptor #1
            How to generate new HCO3- ?

               Solution: “proton acceptors”
                Proton Acceptor #1: NH3
                    Glutaminase
Glutamine                                   NH3 + CO2 + H2O



                                  Na+
                     H+          H+
            NH4+
                     NH3          NH3
                                            HCO3-

                                Na+                      This is
                               NH4+                     new HCO3
                   NH4+


                          Proximal tubule
NH4+ undergoes counter-current multiplication-1




               NH4+
NH4+ undergoes counter-current multiplication-2




           H+
                           H+
                 NH4+     NH3
                          NH4+        NH3
                                      NH4+
NH4+ undergoes counter-current multiplication-3




                    NH3
                              NH3
                                                   NH3
              Na+            H+         ATP
     NH3
                NH4   +                       H+
                               ADP + Pi



                            a IC cell          NH4+
Proton acceptor #2
Google Map: exit 170, I-90, Montana
                  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
                                                        Na+
                              Na+
                                                            K+
                              K+

                               Principal cell

                              ATP
 Collecting             H+
                               ADP + Pi                 HCO3-
   Duct
Acidification                                               Cl-

                                                       Cl-
                                     a IC cell

                               Cl-
                    HCO3-                              Cl-
                                                 ATP
                                                       H+
                pHmin = 4.5            ADP + Pi
                                     b IC cell
Collecting tubule
  H+ secretion
        is
 “low capacity,
 high gradient”
         Net acid excretion =

                      urinary NH4+
                             +
                      urinary H2PO4-
                             -
                      urinary HCO3-
                                            NH4+

                                     NH3
                                +
H2PO4-        HPO4-- +    H+ +
                                    HCO3-
                                             H2CO3
                     “Not present”
Questions?
 Regulation
Of Acid-Base
  Balance
“Big picture”: tubule acid-base physiology

1. All filtered HCO3 is reclaimed daily from the glomerular filtrate (the
   “high capacity” proximal tubule system)

2. 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)

3. When new HCO3 is needed, as in metabolic acidosis, the proximal
   tubule synthesizes more NH3, protonates it, and eliminates it in the
   urine

4. Between allosteric effects on transporters and increased
   ammoniagenesis, the “tubular maximum” (“Tm”) of the proximal
   tubule is plastic
      Cell pH senses plasma pH:

1. Cytoplasmic [H+] varies with plasma [H+]
2. Cell is constantly bailing out H+




                                                     H+
                                      ~-60 mV
pHi   7
                                   metabolism
                                                H+

                7
                pHo
Regulation of Proximal Tubule HCO3- Reclamation
              By Systemic Acidosis

                 Acute allosteric pHi effect;
                 and a transcriptional effect




                 Na+
HCO3   -                Na+
           H+   H+
                       HCO3-
CO2 + H2O
                                        Note:
                                        No new HCO3- formed!
  In acidosis, ammoniagenesis increases

               Solution: “proton acceptors”
                Proton Acceptor #1: NH3
                    Glutaminase
Glutamine                                   NH3 + CO2 + H2O



                                  Na+
                     H+          H+
            NH4+
                     NH3          NH3
                                            HCO3-

                                Na+                      This is
                               NH4+                     new HCO3
                   NH4+


                          Proximal tubule
 Formation of New HCO3- by Ammoniagenesis


            0.1


  NH4+                               Acidosis
excretion
            0.05
mmol/min
                              Control


                    5           6         7     8

                                  Urine pH

                  After RF Pitts, 1948
“Big picture”: tubule acid-base physiology

1. All filtered HCO3 is reclaimed daily from the glomerular filtrate (the
   “high capacity” proximal tubule system)

2. 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)

3. When new HCO3 is needed, as in metabolic acidosis, the proximal
   tubule synthesizes more NH3, protonates it, and eliminates it in the
   urine

4. Between allosteric effects on transporters and increased
   ammoniagenesis, the “tubular maximum” (“Tm”) of the proximal
   tubule is plastic
         Proximal tubule HCO3- Tm is Variable




                                              filtered

 HCO3- in                                    UHCO3V
                                                         New
moles/time
                                                         HCO3
                                                          Tm
                                                  HCO3
                                                   Tm

 GFR x [HCO3-]plasma = “filtered load of HCO3-”
   “Things That Raise the Proximal Tubule HCO3- Tm”

              pCO2, angiotensin II, norepinephrine;
                 K+ depletion; glucocorticoids



                                               filtered

 HCO3- in                                     UHCO3V
                                                          New
moles/time
                                                          HCO3
                                                           Tm




 GFR x [HCO3-]plasma = “filtered load of HCO3-”
Proximal tubule HCO3 resorption
     is driven by the pCO2




                                   CO2

                Na+
        H+     H+      H2O + CO2


                      HCO3-
             Proximal tubule HCO3 resorption
                  is driven by the pCO2




   HCO3                     Maladaptive decrease
 resorbed                   in proximal tubule
moles/time                  acidification with
                            the compensatory drop in
                            pCO2



                      pCO2(mm Hg)
              Total Body K+ Depletion
       Increases Proximal Tubule Acidification
              via Intracellular Acidosis


                                         Na+
                        HCO3   -                (1) Na+
                                   H+   H+
                                               (3) HCO3-
                        CO2 + H2O

1. CCD K+ secretion
                                                  K+
2. Total body                                     H+
       K+ depletion
3. K+ depletion            4. Acidification of
       of proximal                prox tubule cell
       tubule cells               by K+/H+ exchange
                                                  Na+
                        Na+
                                                      K+
                        K+

                         Principal cell           Aldosterone
                        ATP
 Collecting        H+
                         ADP + Pi                 HCO3-
   Duct
Acidification                                         Cl-

                                                 Cl-
                               a IC cell

                         Cl-
                HCO3-                            Cl-
                                           ATP
                                                 H+
                                 ADP + Pi
                               b IC cell
          Collecting Duct H+ Pump Exocytosis
                  is Driven by the pCO2




H+ secreted
 moles/time




                   pCO2(mm Hg)
                                                  Na+
                        Na+
                                                      K+
                        K+

                         Principal cell           Aldosterone
                        ATP
 K+ Depletion      H+
                                                  HCO3-
                         ADP + Pi
   Induces
                         K+                           Cl-
    H +/K+
                 H+                              Cl-
Exchangers in                  a IC cell
     CCD
                         Cl-
                HCO3-                            Cl-
                                           ATP
                                                 H+
                                 ADP + Pi
                               b IC cell
   What you will understand after today’s lectures:
1. How H+ is buffered by blood and cells

2. The four acid-base disorders

3. The compensations for these disorders

4. How filtered HCO3 is reclaimed by the proximal tubule

5. How the “daily acid load” is excreted primarily by the collecting duct
   using phosphate and NH3

6. How new HCO3 is generated after metabolic acidosis

7. How various factors modulate tubular acid-base handling
Questions?
End of Acid-Base Physiology Section
              (Part 1)

								
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