ACID BASE BALANCE

Buffers of Body Fluids, Role of Plasma Buffers, Renal Mechanisms & Regulation of pH

1. Definition of a Buffer

• Tietz Textbook of Laboratory Medicine, 7th Ed.

2. Normal pH of Body Fluids

3. BUFFERS OF BODY FLUIDS

A. Bicarbonate/Carbonic Acid Buffer System (Most Important Plasma Buffer)

• The lungs can rapidly dispose of or retain CO2 (open system - far greater buffering power)
• It is present at high concentrations (24 mmol/L HCO3-)
• The kidneys can increase or decrease bicarbonate reclamation
• Buffer value (β) of the bicarbonate buffer in plasma = 55.6 mmol/L

1. PCO2 - regulated by the lungs (respiratory component)
2. [HCO3-] - regulated by the kidneys (metabolic/renal component)

• Tietz Textbook of Laboratory Medicine, 7th Ed.

B. Phosphate Buffer System

• pKa = 6.8 (close to plasma pH of 7.4, making it a good buffer)
• At plasma pH 7.4, ratio HPO4²-/H2PO4- = 4:1
• Total concentration accounts for ~5% of the nonbicarbonate buffer value of plasma
• Organic phosphate (2,3-DPG in erythrocytes at ~4.5 mmol/L) accounts for ~16% of the nonbicarbonate buffer value of erythrocytes
• Most important in the titration and excretion of acids in urine (urinary buffer)

C. Plasma Protein Buffer System

• Buffer value (β) of nonbicarbonate buffers of plasma = ~7.7 mmol/L at pH 7.40
• Albumin accounts for >90% of the nonbicarbonate buffer value of plasma
• Plasma proteins have multiple titratable groups (imidazole groups of histidine residues are key)
• Reaction during CO2 equilibration: $$\text{CO}_2 + \text{H}_2\text{O} \rightarrow \text{H}_2\text{CO}_3 \rightarrow \text{HCO}_3^- + \text{H}^+$$ $$\text{HPr} \rightarrow \text{H}^+ + \text{Pr}^-$$
• For each HCO3- generated, one nonbicarbonate buffer base disappears
• In alkalosis, excess nonbicarbonate buffer base; in acidosis, negative excess (base consumed)

D. Hemoglobin Buffer System

• The most abundant nonbicarbonate buffer in blood (present in erythrocytes)
• Buffer value (β) of nonbicarbonate buffers of erythrocyte fluid = ~63 mmol/L
• Non-HCO3- buffering power of whole blood = ~25 mM/pH unit
• Non-HCO3- buffering power of plasma alone = only ~5 mM/pH unit (lacks cellular elements)
• Hemoglobin buffers the H+ generated when CO2 enters red blood cells in peripheral tissues: $$\text{CO}_2 + \text{H}_2\text{O} \xrightarrow{\text{carbonic anhydrase}} \text{H}^+ + \text{HCO}_3^-$$
• The H+ is then buffered by deoxyhemoglobin (Hb): Hb + H+ → HHb
• Isohydric shift (Hamburger phenomenon): HCO3- exits the RBC and Cl- enters to maintain electroneutrality
• Tietz Textbook of Laboratory Medicine, 7th Ed.; Medical Physiology (Boron)

4. RESPIRATORY REGULATION OF pH

• Acidosis (↓ pH or ↑ CO2) → stimulates peripheral and central chemoreceptors → hyperventilation → ↑ CO2 blown off → pH rises
• Alkalosis (↑ pH or ↓ CO2) → hypoventilation → CO2 retained → pH falls

5. RENAL MECHANISMS IN ACID-BASE REGULATION

Mechanism 1: Na+-H+ Exchange

• The Na+/H+ exchanger (NHE) exchanges luminal Na+ for intracellular H+
• Isoforms NHE-1 and NHE-3 are predominant in renal tubules
• Enhanced in acidosis, inhibited in alkalosis - both isoforms are transcriptionally upregulated by acidosis
• The proximal tubule cannot maintain >1 pH unit gradient; distal tubules can maintain up to 3 pH units
• Maximum urine acidity reached at ~pH 4.4
• Defective in Type 1 and Type 4 Renal Tubular Acidosis (RTA)
• K+ competition: Hyperkalemia → more K+ exchanged for Na+ → less H+ excreted → acidosis; Hypokalemia → more H+ exchanged → urine acidified → alkalosis

Mechanism 2: Ammonia Production and NH4+ Excretion

• Renal tubular cells deamidate glutamine → NH3 + glutamate (or alpha-ketoglutarate)
• NH3 (lipid-soluble) diffuses freely into tubular lumen
• In the lumen: NH3 + H+ → NH4+ (trapped, cannot diffuse back = ionic trapping)
• NH4+ is excreted in urine, carrying H+ out of the body
• This process is upregulated in chronic acidosis (up to 10-fold increase in glutamine deamidation)

Mechanism 3: Reclamation of HCO3-

• ~4500 mEq of HCO3- is filtered daily at the glomerulus
• 85-90% reabsorbed in the proximal tubule, remainder in distal tubule/collecting duct
• Mechanism: H+ secreted into lumen combines with filtered HCO3- → H2CO3 → CO2 + H2O (catalyzed by carbonic anhydrase on brush border)
• CO2 diffuses into tubular cell → recombines with H2O → H2CO3 → H+ + HCO3- (catalyzed by intracellular carbonic anhydrase)
• HCO3- exits to peritubular capillary via basolateral membrane; H+ is secreted again
• In acidosis: HCO3- reclamation is maximized
• In alkalosis: excess HCO3- is excreted in urine
• Tietz Textbook of Laboratory Medicine, 7th Ed.

6. NOTE ON REGULATION OF pH IN THE BODY

• pH is controlled by the ratio: HCO3- (kidney) / PCO2 (lungs)
• Acidemia = pH < 7.35 | Alkalemia = pH > 7.45
• Acidosis/alkalosis can be metabolic (primary HCO3- disturbance) or respiratory (primary PCO2 disturbance)
• Compensation always moves the pH back toward normal but rarely to exactly 7.40 by a single mechanism

• Tietz Textbook of Laboratory Medicine, 7th Edition - Sections on Buffer Systems, Acid-Base Balance, and Renal Mechanisms in Regulation of Acid-Base Balance
• Medical Physiology (Boron & Boulpaep) - Chapter on Acid-Base Physiology (Walter Boron), pp. 921-924