Dr. Saidunnisa

Professor Of BiochemistryAcid-Base regulation

Learning Objectives• At the end of the session student shall be able to:• Explain the bicarbonate and phosphate

mechanism which operates in PCT and study the action of C.A.

• Explain the ammonia mechanism which operates in DCT with neat diagram in regulating the acid base balance.

• Explain the role of respiration in pH regulation.• Define and explain Isohydric transport of CO2.• Explain chloride shift.

Renal Regulation

• The renal mechanism tries to provide a permanent solution to the acid base disturbances.

• This in contrast to the temporary buffering system and a short term respiratory mechanism.

• Important function of the kidney is to regulate the pH of the ECF.

• Kidney excretes urine pH approx.6 with a pH lower than that of ECF pH approx.7.4.

• This is called acidification of urine.

Major Renal Mechanisms

1. Excretion of H+ ions and generation of HCO3-.

2. Reabsorption of HCO3- or (reclamation of

HCO3-).

3. Excretion of titratable acid.4. Excretion of ammonium ions.

Excretion of H+ ions and

generation of HCO3-.

1. This process occurs in PCT.2. Carbonic anhydrase catalyses the production

of H2CO3 from CO2 and H2O in the Proximal renal tubular cells. [CO2 + H2O H2CO3 ]

3. H2CO3 than dissociates to H+ and HCO3- .

[H2CO3 H+ + HCO3- ]

4. The H+ ions are secreted into the tubular lumen in exchange for Na+.

Excretion of H+ ions and

generation of HCO3-.

5. The Na+ in association with HCO3

- is reabsorbed into the blood.

6. There is net excretion of H+ ions and net generation of HCO3

-

which adds upto the alkali reserve of the body.

Reabsorption of HCO3-

or (Reclamation of HCO3-).

1. HCO3- filtered by the glomerulus is completely

reabsorbed by the PCT so that urine is normally HCO3

- free.

2. HCO3- freely diffuses from the plasma in to the

tubular lumen.

3. Here HCO3- combines with H+ ions secreted by the

tubular cells to form H2CO3.

[H+ + HCO3- H2CO3]

4. HCO3- is the only buffering anion that can be

regenerated by the kidney and returned to body fluids to replenish the base deficit.

5. H2CO3 cleaved by CA of tubular cell membrane to form CO2 +H20

[H2CO3 CO2 + H2O]

6. As the CO2 concentration builds up on the lumen it diffuses into the tubular cells along the concentration gradient.

7. In the tubular cell C02 again combines with H20 to form H2CO3 which then dissociates into H+ and HCO3

-.

8. The H+ is secreted into the lumen in exchange for Na+.

9. HC03- is reabsorbed into

plasma in association with Na+.

Excretion of titratable acid

• Titratable acidity is a measure of acid excreted into urine by the kidney.

• It reflects the H+ ions excreted into urine which resulted in a fall of pH from 7.4.

• The excreted H+ ions are actually buffered in the urine by phosphate buffer.

• H+ ion is secreted into tubular lumen in exchange for Na+ ion.

• This is obtained from the base Na2HPO4.

• The Na2HPO4 in turn combines with H+ to produce the acid NaH2PO4.

• In which form the major quantity of titratable acid in urine is present.

• As the tubular fluid moves down the renal tubules more and more H+ ions are added resulting in the acidification of urine, this causes a fall in the pH of urine to as low as 4.5.

Net acid Excretion(NAE)

• In quantitative terms titratable acidity refers to the number of milliliters of N/10 NaOH required to titrate 1liter of urine to pH 7.4.

• This is a measure of net acid excretion by the kidney.

• Major titratable acid present in the urine is NaH2PO4.

Excretion of ammonium ions.

• This predominantly occurs at the DCT.• The glutaminase present in the tubular cells

can hydrolyze glutamine to ammonia and glutamic acid.

• The NH3 diffuses into the tubular lumen and combines with H+ to form NH4+.

• Ammonium ions (NH4+) cannot diffuse back

into tubular cells and therefore excreted into urine.

• NH4+ is major urine acid .

• In about 1 / 2 to 2 / 3rd of body acid load is eliminated in form of NH4+ ions.

• For this reason renal regulation via NH4+ excretion is very effective to eliminate large quantities of acids produced in the body.

• This mechanism becomes predominant particularly in acidosis.

Anion Gap (A-)

• The body exists in a state of electro neutrality in which sum of the cations is equal to the anions.

• A- is the difference between the total concentration of measured cations (sodium and potassium) and measured anions (chloride and bicarbonate).

• A- = [Na+ + K+] - [Cl- + HCO3-]

• Normal range: 10-20mmol/ L (mean-16)

• Not all the cations and anions are measured.• Unmeasured cations: Ca++ Mg++.• Unmeasured anions: PO4-- SO4-- , protein, organic acids.• An increased anion gap is found when there is an

increased unmeasured anions.• Causes:1. Lactic acidosis2. Aspirin toxicity3. Methanol toxicity4. Diabetic ketoacidosis5. Starvation

• An decreased anion gap is found when there is an increased unmeasured cations. (Ca++ Mg++.)

• Causes:1. Lithium toxicity2. Multiple Myeloma

Generation of HCO3- by RBC

• Due to lack of aerobic metabolic pathways RBC produce very little CO2.

• The plasma CO2 diffuses into the RBC along the concentration gradient where it combines with H2O to form H2CO3.

• In the RBC, H2CO3 dissociates to produce H+ and HCO3

-.• The H+ ions are trapped and buffered by Hb.

Chloride shift

• As the concentration of HCO3

- increases in the RBC it diffuses into plasma along with the concentration gradient in exchange for CL- ions to maintain electrical neutrality.

• This phenomenon referred to as “chloride shift’’ helps to generate HC03

-.

RESPIRATORY MECHANISM

• The rate of respiration is controlled by the respiratory centre located in medulla of the brain and is highly sensitive to the changes in the pH of the blood.

• In the Lungs: • Formation of Hbo2 from HHb must release H+ ions

which will react with HCO3- to form H2CO3.

• Because of low CO2 tension in the lungs , equilibrium then shifts towards the production of CO2 which is continually eliminated in the expired air.

In the tissues

• Due to decrease O2 tension, HbO2 dissociates delivering O2 to the cells and HHb is formed.

• At the same time CO2 produced as result of metabolism in the cells is hydrated to form H2CO3 which ionizes to form H+ and HCO3

- .

ISOHYDRIC TRANSPORT OF CO2• H+ ions are accepted by Hb

to form HHb, very little change in pH occurs because of the arrival of new H+ ions.

• It allows only 0.6 H+ ions to be buffered.

• At the tissue level Hb bind to H+ ions and helps to transport CO2 as HCO3

- with minimum change in pH. This is referred to as ‘’ISOHYDRIC TRANSPORT OF CO2’’.