Acid/Base Physiology 2 (Gunn)

Question 1

Describe the respiratory regulation due to acid-base balance

Answer 1

Under normal circumstances, CO₂ and H₂CO₃ produced by increase in aerobic metabolism will be rapidly buffered by respiratory system, transported to lungs and eliminated.

Similarly, increase in non-volatile acid production will be buffered by bicarbonate system, which produce dissolved CO₂ and H₂CO_3. This will then be rapidly cleared by lungs. A_lthough to maintain acid-base balance, kidney must excrete acid equivalent to non-volatile acid produced by body and replace bicarbonate that is los_t.

Peripheral and Central Chemoreceptors

Normal lungs have the capacity to respond swiftly and very effectively to change in volatile/nonvolatile acid production. This is driven by respiratory control mechanisms, which ensure that alveolar ventilation is precisely matched to CO₂ levels in blood. The alveolar gas equation indicates that P_ACO₂ in alveoli (and therefore P_aCO₂ in arterial blood) reflects this balance.

• Peripheral chemoreceptors (in aortic and carotid bodies) are most affected by altered P_aO₂, central chemoreceptors (in brain stem) are most sensitive to altered P_aCO₂ and pH. They affect respiratory drive via negative feedback.
• Increased P_aCO₂, r_educed pH,_ reduced P_aO₂ all lead to increased respiratory drive.

Question 2

Describe the renal regulation of acid-base

Answer 2

Although maintenance of normal plasma pH depends on interaction of many buffer systems, _isohydric principl_e infers that pH change is determined by bicarbonate buffer system, as a result of acid and base at steady state. It follows that regulating ratio of [HCO₃^-]/[H₂CO₃] (or P_CO2) in plasma will tend to regulate pH.

To regulate plasma component of bicarbonate buffer system, it is achieved by:

• Maintenance and control of weak acid (CO₂) is regulated through alveolar ventilation as outlined above.
• Maintenance and control of conjugate base (HCO₃^-) is regulated through kidneys, which involves:
• Reabsorption of all [HCO₃^-] that is filtered by kidneys;
• Regeneration of all [HCO₃^-] lost in buffering of non-volatile acids by bicarbonate system;
• Excretion of all [H+] incorporated into other non-bicarbonate buffer systems

Question 3

Describe the Na/K pump in the renal system.

Answer 3

Na-K ATPase

• Basolateral ATPase
• 3 Na to 2K
• Cell: low Na, high K, -70mV potentia
• Luminal facilitated diffusion

Question 4

Describe Renal Excretion of H+ and Reabsorption of HCO₃^- (Figure 6)

Answer 4

(Step 1)

HCO₃^- are freely filtered by renal glomeruli. HCO₃^- reabsorption occurs mostly in proximal convoluted tubule (80-90%), also some in loop of Henlé and distal tubule (10-15%). Filtered HCO₃^- is exchanged for H⁺ in a process that involves vector transport of Na⁺ from tubular lumen into peritubular space.

• In tubular lumen, HCO₃^- combines with secreted H⁺ to form H₂CO₃. H₂CO₃ dissociates to form CO₂ and H₂O via carbonic anhydrase (CA present in brush border of renal tubular cells).
• CO₂ readily crosses into tubular cell down a concentration gradient.
• Inside tubular cell, _CO₂ recombines with H₂O via CA t_o form H₂CO₃. H₂CO₃ further dissociates to HCO₃^- and H⁺.
  
  • HCO₃^- passes back into blood stream.
  • H⁺ passes back into tubular fluid in exchange for Na⁺ via NKA.
• In this way, virtually all filtered HCO₃^- is reabsorbed in healthy individual.

In kidneys, HCO₃^- reabsorption rate is:

• Directly related to changes in P_aCO₂ and plasma level of [adrenal corticosteroid] (e.g. increased reabsorption in Cushing’s disease due to increased corticosteroid).
• Inversely related to changes in plasma [K+] and [Cl-].

Question 5

Describe the (overall) renal excretion of H+ and regneration of HCO3-

Answer 5

HCO3- regeneration occurs in proximal, distal tubules and collecting duct. It is associated with active transport of H+ into tubular lumen, where they combine with phosphate ions (HPO42-) and ammonia (NH3) to form titratable acid.

• There is small and fairly fixed [sodium monophosphate (Na+H2PO4-)] in filtrate.
• However, there can be substantially increased [ammonium (NH4+)] in filtrate. This is because ammonia (NH3) is produced from tubular cell glutamine, but maximum production rate require several days to develop.

In kidneys, titratable acid secretion rate is influenced by (1) availability of urinary buffers; (2) dissociation constants for those buffers; and (3) degree of acidosis.

Question 6

Describe Renal Excretion of H+ and Regeneration of HCO₃^- and glucose

Answer 6

• Glutamine (one of the AA) is transformed into glutamate can be transformed into a-keto-glutarate. A-keto-glutarate is transformed into Glucose and Bicarbonate (gluconeogenesis)
• Glutamine also produces ammonium which bidns to hydrogen-sodium antiporter, and Ammonium binds to filtered Cl- to get NH4Cl
  
  • H+ comes from the process of producing HCO3-

Question 7

Describe the excretion of H+, regeneration of HCO3-…acidify ammonia to ammonium chloride

Answer 7

In distal Convoluted Tubule (e.g. collecting duct)

• If there’s excess ammonia in the ECF, it can diffuse through the cells
• H+ ( via active transport) is pumped out into the tubular lumen
  
  • Comes from production of HCO3-
• NH3+ H+ = NH4+
• Ammonium binds to filtered Cl-
• Form ammonium chloride (secreted)

Question 8

What ist he Bicarbonate resorbption rate by the kidney influenced by?

Answer 8

• HCO3- is inversely related to plasma [Cl-]
  
  • [Cl-[ needed to maintain electroneutrality
  • E.g. volume depletiond ue to diuretics or vomiting
• HCO3- is inversely related to plasma [K+]
• Increased by increased plasma levels of adrenal corticosteroids, e.g. Cushing’s disease
• High levels of aldosterone -> high eCF HCO3-
  
  • High Aldo : high Na+ reabsorption + high K+ and H+ losses (NA/H antiporter)
  • H+ loss matched by less HCO3- reabsorption: metabolic alkalosis with hypochloraemia and hypoka;aemia, often with expanded ECF volume.

Question 9

Describe the Compensatory Responses To Sustained/Chronic Acid Base Disturbances

Answer 9

Body response to simple acid base disturbances that are sustained for some time can also be approximated using [HCO₃^-]-pH plot.

• In metabolic acidosis (e.g. lactic acid accumulation), there is ¯[HCO₃^-], thus ¯pH leads to ­respiratory drive and ­alveolar ventilation.
  
  • Therefore, ¯P_aCO₂ to return pH(­) toward normal levels, thus respiratory compensation (compensatory respiratory alkalosis).
  • The opposite response occurs with metabolic alkalosis.
• In respiratory alkalosis (hyperventilation), there is ¯P_aCO₂, thus ­pH elicits renal responses that correct imbalance.
  
  • Therefore, ¯net acid (H⁺) secretion by nephron, in exchange for ¯[HCO₃^-] reabsorption to return pH(¯) toward normal levels, thus metabolic compensation (compensatory metabolic acidosis).
  • The opposite responses occur with respiratory alkalosis.

These compensations minimise pH variation, but cannot restore normal acid base status. In order to do this, initial disturbance must be reversed.

Question 10

Describe the responses to repiratory alkalosis

Answer 10

• In respiratory alkalosis (hyperventilation), there is reduction in P_aCO₂, thus ­pH elicits renal responses that correct imbalance.
  
  • Therefore, ¯net acid (H⁺) secretion by nephron, in exchange for ¯[HCO₃^-] reabsorption to return pH(¯) toward normal levels, thus metabolic compensation (compensatory metabolic acidosis).
  • The opposite responses occur with respiratory acidosis.
• Hyperventilation reduces PCo2 and pH
• Reduces renal net acid excretion restores pH but reduces HCo3-

Question 11

Describe the responses to metabolic acidosis

Answer 11

• In metabolic acidosis (e.g. lactic acid accumulation), there is ¯[HCO₃^-], thus ¯pH leads to ­respiratory drive and ­alveolar ventilation.
  
  • Therefore, reduces P_aCO₂ to return pH(­) toward normal levels, thus respiratory compensation (compensatory respiratory alkalosis).
  • The opposite response occurs with metabolic alkalosis.

Question 12

Describe the Time Courses Of Compensatory Responses To Sudden Acid/Base Load

Answer 12

Respiratory Compensation

Respiratory compensations occur rapidly because of sensitivity of peripheral chemoreceptors to change in blood pH. It immediately responds by initiating appropriate change in ventilation rate to alter rate of CO₂ elimination.

• However, consequent change in P_CO2 alters firing of central chemoreceptors and partially inhibits ventilation response to peripheral chemoreceptor input. Until sensitivity of central chemoreceptors is reset, full compensation is not reached.
• In addition, consequent change in P_O2 alters firing of peripheral chemoreceptors (especially in hypoxia), which further limit ventilation response.

Therefore, complex interactions account for 12-24hour time course required for full respiratory compensation to develop.

Metabolic Compensation

Base Excretion in Respiratory Alkalosis

Renal base excretion is slightly slower than respiratory compensation because it occurs via reduced HCO₃^- reabsorption from filtrate. There is also some distal nephron HCO₃^- excretion to facilitate base excretion. This process is inherently slower than ventilation, particularly when there is less HCO₃^- present in filtrate (e.g. due to decreased plasma [HCO₃^-])

Acid Excretion in Respiratory Acidosis

Renal acid excretion is limited by buffer capacity of tubular fluid, once all filtered HCO₃^- has been reabsorbed. It requires much longer period to attain maximum acid excretion rate due to:

• There is small and fairly fixed [sodium monophosphate (Na⁺H₂PO₄^-)] in filtrate.
• However, there can be substantially increased [ammonium (NH₄⁺)] in filtrate. This is because ammonia (NH₃) is produced from tubular cell glutamine, but maximum production rate requires several days to develop.

Furthermore, 100% cardiac output passes through lungs and transfer of CO₂ by diffusion is rapid. Only 25% cardiac output goes to kidney and H⁺ secretion is a slower process than diffusion.

Question 13

Normal blood pH is: 7.36-7.44

Normal PCO2 = 36-44

HCO3- = 20-27

BE(ECF) = +/- 2

Answer 13

I = C

II = A

III = B

IV = E

V = D

1. metabolic alkalosis with respiratory compensation
2. no acid-base disorder
3. metabolic acidosis with respiratory compensation
4. mixed respiratory acidosis and metabolic acidosis
5. chronic respiratory alkalosis (with metabolic compensation)