• Buffering is essential for maintaining a normal H⁺ concentration (H⁺ homeostasis).
• Buffering is defined in Chapter 1.
• It is discussed in Chapter 36 in relation to gas transport.
• This discussion emphasizes the roles of:
  • Proteins
  • Hemoglobin
  • The carbonic anhydrase system in the blood
• Carbonic anhydrase is also present in high concentrations in gastric acid-secreting cells.
• Carbonic anhydrase is also present in renal tubular cells.
• Carbonic anhydrase is a protein with a molecular weight of 30,000.
• Each carbonic anhydrase molecule contains one zinc atom.
• Carbonic anhydrase is inhibited by:
  • Cyanide
  • Azide
  • Sulfide
• In the body, buffering is not limited to the blood.
• The main buffers in the blood, interstitial fluid, and intracellular fluid are listed in Table 39–2.

Table: Table 39–2

• The main buffers in cerebrospinal fluid and urine are the bicarbonate and phosphate buffer systems.
• In metabolic acidosis, only about 15–20% of the acid load is buffered by the H₂CO₃–HCO₃⁻ system in the extracellular fluid (ECF).
• Most of the remaining acid is buffered inside the cells.
• In metabolic alkalosis, about 30–35% of the OH⁻ load is buffered inside the cells.
• In respiratory acidosis and respiratory alkalosis, almost all buffering occurs inside the cells.
• In animal cells, the main regulators of intracellular pH are HCO₃⁻ transporters.
• These transporters include:
  • The Cl⁻–HCO₃⁻ exchanger (AE1)
  • Three Na⁺–HCO₃⁻ cotransporters
  • One K⁺–HCO₃⁻ cotransporter

KEY CONCEPT

• Buffering is the body’s first defense against changes in H⁺ concentration. Although blood buffers are important, most buffering during metabolic and respiratory acid–base disorders occurs inside the cells. Carbonic anhydrase plays a key role in buffering and is abundant in blood, gastric cells, and renal tubular cells. Intracellular pH is mainly regulated by HCO₃⁻ transporters.

Conceptual Examples

• Example 1: During metabolic acidosis, only 15–20% of the excess acid is buffered by the ECF bicarbonate system, while most buffering occurs inside the cells.
• Example 2: During respiratory acidosis, almost all buffering occurs intracellularly, helping reduce changes in blood H⁺ concentration.
• Example 3: Carbonic anhydrase rapidly converts CO₂ and H₂O into H₂CO₃ and back again, helping maintain normal acid–base balance in the blood, stomach, and kidneys.

SUMMARY

• When a strong acid is added to the blood, the main buffer reactions shift to the left.
• As a result, the blood levels of the three main buffer anions decrease:
  • Hemoglobin (Hb⁻)
  • Protein (Prot⁻)
  • Bicarbonate (HCO₃⁻)
• The anions of the added acid are filtered into the renal tubules.
• These anions are accompanied mainly by sodium (Na⁺) to maintain electrical neutrality.
• The renal tubules replace Na⁺ with H⁺.
• At the same time, equal amounts of Na⁺ and HCO₃⁻ are reabsorbed into the blood.
• This process conserves Na⁺.
• It also removes acid from the body.
• It restores the normal level of buffer anions in the blood.
• When CO₂ is added to the blood, similar reactions occur.
• However, CO₂ forms carbonic acid (H₂CO₃).
• As a result, the plasma HCO₃⁻ concentration increases instead of decreasing.

KEY CONCEPT

• The kidneys help maintain acid–base balance by replacing Na⁺ with H⁺ in the renal tubules, reabsorbing Na⁺ and HCO₃⁻, and excreting acid. When a strong acid is added, buffer anions decrease and are later restored by the kidneys. When CO₂ increases, carbonic acid is formed, causing plasma HCO₃⁻ to increase.

Conceptual Examples

• Example 1: When a strong acid enters the blood, HCO₃⁻ is used as a buffer, so its level falls. The kidneys then reabsorb new HCO₃⁻ and excrete H⁺, restoring normal acid–base balance.
• Example 2: During respiratory acidosis, CO₂ increases, forming H₂CO₃. As a result, the plasma HCO₃⁻ concentration increases, helping buffer the extra acid.

RENAL COMPENSATION TO RESPIRATORY ACIDOSIS & ALKALOSIS

• An increase in arterial PCO₂ caused by decreased ventilation produces respiratory acidosis.
• A decrease in arterial PCO₂ produces respiratory alkalosis.
• The initial changes occur before any compensatory mechanism starts.
• These early changes are called uncompensated respiratory acidosis or uncompensated respiratory alkalosis.
• In both conditions, the kidneys respond to compensate.
• The kidneys help move the blood pH back toward normal.
• Renal HCO₃⁻ reabsorption depends on the amount of HCO₃⁻ filtered by the kidneys.
• The filtered amount of HCO₃⁻ depends on:
  • Glomerular filtration rate (GFR)
  • Plasma HCO₃⁻ concentration
• HCO₃⁻ reabsorption also depends on the rate of H⁺ secretion by the renal tubular cells.
• HCO₃⁻ is reabsorbed in exchange for H⁺.
• The rate of H⁺ secretion is directly proportional to the arterial PCO₂.
• Higher PCO₂ provides more CO₂ inside the tubular cells.
• More CO₂ forms more H₂CO₃ inside the cells.
• More H₂CO₃ produces more H⁺.
• As a result, more H⁺ is secreted into the tubular fluid.
• When PCO₂ is high, the inside of most cells becomes more acidic.
• During respiratory acidosis, renal H⁺ secretion increases.
• This removes more H⁺ from the body.
• Although plasma HCO₃⁻ is already increased, the kidneys reabsorb even more HCO₃⁻.
• This further increases the plasma HCO₃⁻ concentration.
• This is the renal compensation for respiratory acidosis.
• As plasma HCO₃⁻ increases, chloride (Cl⁻) excretion also increases.
• Therefore, the plasma Cl⁻ concentration decreases.
• During respiratory alkalosis, arterial PCO₂ is low.
• Low PCO₂ decreases renal H⁺ secretion.
• As a result, HCO₃⁻ reabsorption decreases.
• More HCO₃⁻ is excreted in the urine.
• This further lowers the already reduced plasma HCO₃⁻ concentration.
• These changes help return the blood pH toward normal.

KEY CONCEPT

• The kidneys compensate for respiratory acid–base disorders by changing H⁺ secretion and HCO₃⁻ reabsorption. In respiratory acidosis (high PCO₂), the kidneys secrete more H⁺ and reabsorb more HCO₃⁻, increasing plasma bicarbonate. In respiratory alkalosis (low PCO₂), the kidneys secrete less H⁺ and excrete more HCO₃⁻, lowering plasma bicarbonate and helping restore normal pH.

Conceptual Examples

• Example 1: A patient with chronic hypoventilation develops respiratory acidosis. The kidneys increase H⁺ secretion and reabsorb more HCO₃⁻, helping raise the blood pH toward normal.
• Example 2: A patient with hyperventilation develops respiratory alkalosis. The kidneys decrease H⁺ secretion and excrete more HCO₃⁻, helping lower the blood pH back toward normal.

METABOLIC ACIDOSIS

• Metabolic acidosis occurs when acids stronger than hemoglobin (Hb) and other buffer acids are added to the blood.
• Metabolic alkalosis occurs when the H⁺ concentration decreases because alkali is added or acid is lost from the body.
• For example, when sulfuric acid (H₂SO₄) is added to the blood, the released H⁺ is buffered.
• As a result, the levels of the following plasma buffer anions decrease:
  • Hemoglobin (Hb⁻)
  • Protein (Prot⁻)
  • Bicarbonate (HCO₃⁻)
• The H₂CO₃ formed is converted into H₂O and CO₂.
• The CO₂ is rapidly excreted by the lungs.
• This is the state of uncompensated metabolic acidosis.
• In reality, the increase in plasma H⁺ stimulates respiration.
• As respiration increases, the arterial PCO₂ decreases instead of increasing or remaining constant.
• This decrease in PCO₂ is the respiratory compensation for metabolic acidosis.
• Respiratory compensation raises the blood pH toward normal.
• The kidneys then begin renal compensation.
• The kidneys excrete the excess H⁺ from the body.
• The kidneys also restore the body’s buffer systems to normal.

KEY CONCEPT

• Metabolic acidosis occurs when excess acid is added or bicarbonate is lost. The added H⁺ is first buffered, lowering Hb⁻, Prot⁻, and HCO₃⁻ levels. The lungs then compensate by increasing ventilation and lowering PCO₂. Finally, the kidneys excrete excess H⁺ and restore the body’s bicarbonate and buffer systems.

Conceptual Examples

• Example 1: A patient with lactic acidosis develops metabolic acidosis. The lungs increase breathing to remove CO₂, and later the kidneys excrete more H⁺ to restore normal pH.
• Example 2: When H₂SO₄ enters the blood, the released H⁺ is buffered by HCO₃⁻, causing the plasma bicarbonate level to decrease. Later, the lungs remove CO₂ and the kidneys regenerate HCO₃⁻, helping return acid–base balance to normal.

RENAL COMPENSATION

• In metabolic acidosis, the anions that replace HCO₃⁻ in the blood are filtered by the kidneys.
• These anions are filtered together with cations, mainly sodium (Na⁺), to maintain electrical neutrality.
• The renal tubular cells secrete H⁺ into the tubular fluid in exchange for Na⁺.
• For every H⁺ secreted:
  • One Na⁺ is reabsorbed into the blood.
  • One HCO₃⁻ is added back to the blood.
• Without urinary buffers, the urine would quickly reach its lowest possible pH (4.5).
• In that case, only a small amount of H⁺ could be secreted.
• Urinary buffers bind (tie up) secreted H⁺, allowing much more H⁺ to be excreted.
• Secreted H⁺ reacts with HCO₃⁻ to form CO₂ and H₂O.
• This process allows bicarbonate (HCO₃⁻) to be reabsorbed.
• Secreted H⁺ also reacts with HPO₄²⁻ to form H₂PO₄⁻.
• Secreted H⁺ also reacts with NH₃ to form NH₄⁺.
• These buffering reactions allow large amounts of H⁺ to be secreted safely.
• As more H⁺ is excreted, larger amounts of HCO₃⁻ are returned to or added back to the body’s depleted bicarbonate stores.
• These processes also allow more Na⁺ and other cations to be reabsorbed.
• Only when the acid load becomes extremely large are cations lost in the urine together with the acid anions.
• This can cause increased urine output (diuresis).
• It can also reduce the body’s cation stores.
• During chronic acidosis, the liver increases glutamine synthesis.
• This process uses some NH₄⁺ that would normally be converted into urea.

Figure: Figure 39–5

• The newly formed glutamine is transported to the kidneys.
• In the kidneys, glutamine provides an additional source of NH₄⁺.
• Over several days, NH₃ secretion increases.
• This is called adaptation of NH₃ secretion.
• This adaptation improves renal compensation during chronic acidosis.
• The metabolism of glutamine in the kidneys also produces α-ketoglutarate.
• α-Ketoglutarate is further metabolized to produce HCO₃⁻.
• The newly formed HCO₃⁻ enters the bloodstream.
• This bicarbonate helps buffer the excess acid.

Figure: Figure 39–5

• When a strong acid such as H₂SO₄ is added to the blood, the overall reaction is:

$$\mathbf{2NaHCO_3 + H_2SO_4 \rightarrow Na_2SO_4 + 2H_2CO_3}$$2NaHCO3​+H2​SO4​→Na2​SO4​+2H2​CO3​

• For every 1 mole of H⁺ added, 1 mole of NaHCO₃ is consumed.
• The kidneys effectively reverse this reaction by regenerating bicarbonate:

$$\mathbf{Na_2SO_4 + 2H_2CO_3 \rightarrow 2NaHCO_3 + 2H^+ + SO_4^{2-}}$$Na2​SO4​+2H2​CO3​→2NaHCO3​+2H++SO42−​

• The regenerated HCO₃⁻ is returned to the blood.
• The H⁺ and SO₄²⁻ are excreted in the urine.
• H₂SO₄ itself is not excreted directly.
• Instead, H⁺ leaves the body as:
  • Titratable acid
  • NH₄⁺ (ammonium)
• During metabolic acidosis, the lungs increase ventilation, causing PCO₂ to decrease.
• The lower PCO₂ reduces renal H⁺ secretion.
• Therefore, respiratory compensation slightly inhibits the kidney’s acid-secreting response.
• However, the lower PCO₂ also decreases the filtered load of HCO₃⁻.
• Because of this, the overall inhibitory effect on renal compensation is small.

KEY CONCEPT

• In metabolic acidosis, the kidneys restore acid–base balance by secreting H⁺, reabsorbing Na⁺, and regenerating HCO₃⁻. Urinary buffers (bicarbonate, phosphate, and ammonia) allow large amounts of H⁺ to be excreted without making the urine excessively acidic. During chronic acidosis, increased glutamine metabolism produces more NH₃ and new HCO₃⁻, making renal compensation much more effective. Although respiratory compensation lowers PCO₂ and slightly reduces H⁺ secretion, its overall effect on kidney compensation is minimal.

Conceptual Examples

• Example 1: A patient with chronic metabolic acidosis increases glutamine production. The kidneys convert glutamine into NH₃ and new HCO₃⁻, allowing more H⁺ to be excreted as NH₄⁺ while replenishing bicarbonate stores.
• Example 2: Phosphate (HPO₄²⁻) and ammonia (NH₃) act as urinary buffers. They bind secreted H⁺ to form H₂PO₄⁻ and NH₄⁺, enabling the kidneys to excrete large amounts of acid without the urine pH falling below its minimum limit.
• Example 3: When H₂SO₄ is added to the body, bicarbonate is consumed to buffer the acid. The kidneys then regenerate bicarbonate and excrete H⁺ and sulfate, restoring normal acid–base balance.

METABOLIC ALKALOSIS

• In metabolic alkalosis, the plasma HCO₃⁻ concentration increases.
• The blood pH also increases.
• The respiratory compensation is a decrease in ventilation (hypoventilation).
• This decrease in ventilation occurs because the H⁺ concentration falls.
• Slower breathing causes arterial PCO₂ to increase.
• The increased PCO₂ helps lower the blood pH toward normal.
• At the same time, the plasma HCO₃⁻ concentration increases even further.
• The amount of respiratory compensation is limited.
• The carotid and aortic chemoreceptors monitor arterial PO₂.
• If arterial PO₂ falls significantly, these chemoreceptors stimulate the respiratory center.
• As a result, breathing increases, preventing excessive hypoventilation.
• Therefore, respiratory compensation in metabolic alkalosis cannot continue indefinitely.
• In metabolic alkalosis, the kidneys receive a larger filtered load of HCO₃⁻.
• More renal H⁺ secretion is used to reabsorb this increased amount of filtered HCO₃⁻.
• If the plasma HCO₃⁻ concentration rises above 26–28 mEq/L, not all HCO₃⁻ can be reabsorbed.
• Excess HCO₃⁻ is then excreted in the urine.
• This urinary loss of HCO₃⁻ helps reduce alkalosis.
• The increased PCO₂ slightly promotes renal H⁺ secretion.
• This tends to oppose (inhibit) the kidney’s compensatory response.
• However, this inhibitory effect is relatively small.

KEY CONCEPT

• Metabolic alkalosis is characterized by increased plasma HCO₃⁻ and elevated blood pH. The lungs compensate by reducing ventilation, increasing PCO₂, and bringing the pH closer to normal. This compensation is limited because low arterial PO₂ stimulates the carotid and aortic chemoreceptors to increase breathing. The kidneys further compensate by excreting excess HCO₃⁻ once the plasma HCO₃⁻ level exceeds 26–28 mEq/L. Although the rise in PCO₂ slightly increases renal H⁺ secretion, its effect on renal compensation is minimal.

Conceptual Examples

• Example 1: A patient with persistent vomiting loses large amounts of HCl, causing metabolic alkalosis. The lungs slow breathing, increasing PCO₂, while the kidneys excrete excess HCO₃⁻ to help restore normal pH.
• Example 2: A patient taking large amounts of sodium bicarbonate (NaHCO₃) develops metabolic alkalosis. If the plasma HCO₃⁻ rises above 26–28 mEq/L, the kidneys begin excreting bicarbonate in the urine, helping reduce the alkalosis.
• Example 3: During metabolic alkalosis, hypoventilation cannot continue indefinitely because a fall in arterial PO₂ activates the carotid and aortic chemoreceptors, which stimulate breathing and limit respiratory compensation.

MADE BY EASIEST AND SELF LEARNING DR SHEEN.