L 9

ACID-BASE PHYSIOLOGY

Renal Bicarbonate Regulation and Acid Base Balance

LEARNING OBJECTIVES

  • Describe the mechanisms for bicarbonate recovery as well as the creation of "new" bicarbonate in the pertinent segments of the nephron.

  • Explain mechanisms that modify renal hydrogen ion secretion.

  • Explain mechanisms associated with renal bicarbonate secretion.

  • Define the four categories of acid-base imbalance.

  • Explain how compensation works in acid-base imbalances using the Davenport diagram.

I. GLOBAL RENAL OVERVIEW

The following figure summarizes carbonic acid and non-carbonic acid production in the body, acid buffering, bicarbonate recovery, and "new" bicarbonate formation. This simplified figure will provide a background to assist you with mechanisms and transporters; it is not all-inclusive. Each number corresponds to the same number in the figure:

  1. Acid production: Non-aerobic metabolism will produce lactic acid, sulfuric acid, phosphoric acid, and organic acids from other metabolic processes (+60 mEq/L/day).

  2. Buffering of H+: The acid (H+) is buffered by blood (bicarbonate, hemoglobin, and plasma proteins), tissue proteins, and bone.

  3. Carbon dioxide conversion: Carbon dioxide, generated from the tissues, is converted to carbonic acid in the red blood cells by the enzyme carbonic anhydrase (CA). This acid dissociates into bicarbonate and H+, which is buffered by deoxygenated hemoglobin.

  4. Lungs' role: At the lungs, the low PCO2 shifts this equation to the left. Overall, carbonic acid leaves the body as CO2.

  5. Bicarbonate consumption: Because bicarbonate is consumed by non-carbonic acids, it must be replenished by the kidney (new bicarbonate formation). Notably, filtered bicarbonate is NOT reabsorbed but rather “recovered.”

  6. Mechanism of bicarbonate recovery: In the proximal tubule cells, carbon dioxide and water are converted to bicarbonate and H+ with the enzyme carbonic anhydrase (CA). The H+ is secreted into the lumen, and bicarbonate is “recovered” by circulation. Bicarbonate is “recovered” by its production and loss (1:1) in the proximal tubule.

  7. New bicarbonate formation mechanisms: New bicarbonate is formed by:

    • a. Proximal tubule: Glutamine is metabolized to form new bicarbonate and ammonium (NH4+). The new bicarbonate is then added into circulation.

    • b. Medullary collecting duct: Carbonic anhydrase produces “new” bicarbonate in this area. The secreted H+ is neutralized by non-bicarbonate buffers, leading to a net increase in “new” bicarbonate.

II. RENAL BICARBONATE REGULATION

  • Glomerular filtration rate: Approximately 180L/day (slightly less than 50 gallons/day). With a plasma bicarbonate concentration of 24 mEq/L, approximately 4300 mEq of HCO3- is filtered out of plasma and into the nephron per day.

  • To maintain normal pH, filtered bicarbonate must return to circulation. It is crucial to underline that filtered bicarbonate is not reabsorbed but is instead “recovered” through mechanisms across the nephron.

  • Percentage of bicarbonate recovery: Under normal acid-base conditions:

    • Approximately 80% of bicarbonate is recovered in the early proximal tubule,

    • Approximately 10% in the thick ascending limb,

    • Approximately 6% in the distal tubule,

    • Approximately 4% in the cortical collecting ducts.

    • Almost no bicarbonate is present in the urine, emphasizing that the recovery is critical for maintaining acid-base balance.

A. Bicarbonate Recovery (High Capacity, Low Gradient, 1:1)

  • The initial step in bicarbonate recovery is the conversion of carbon dioxide and water into H+ and HCO3- within the renal tubular cells via carbonic anhydrase (CA) which is widely present throughout the nephron.

  • Proximal Tubule Mechanism:

    1. Formation: H+ and HCO3- are formed by CA within renal tubular cells.

    2. **H+ secretion: **

      • Two-thirds (2/3) of H+ secretion occurs through the Na+-H+ exchanger across the apical membrane into the tubular lumen, expedited by high Na+ concentrations, contributing to the system's high capacity.

      • One-third (1/3) of H+ is transported using an ATP-dependent pump.

      • Clinical Note: The predominant mechanism for H+ secretion in the proximal tubule relies on the Na-H exchanger. A lower filtered sodium concentration could impair H+ secretion and acid-base balance.

      • Clinical Note: Angiotensin II enhances the activity of the Na-H exchanger and the Na-HCO3- co-transporter on the basolateral membrane, facilitating bicarbonate recovery and promoting alkalosis.

    3. Buffering process: The secreted H+ is rapidly buffered by filtered bicarbonate; carbonic acid thus produced converts back to CO2 and H2O because of luminal carbonic anhydrase.

      • Clinical Note: Luminal carbonic anhydrase optimizes the H+ gradient, favoring additional H+ secretion contributing to the high capacity recovery system.

    4. Bicarbonate transport: Inside proximal tubular cells, bicarbonate is transported across the basolateral membrane into the interstitial fluid via a 3HCO3- : 1Na+ co-transporter (high capacity) and by chloride ion exchange.

    5. Net Effect: 1:1 Recovery: This mechanism operates as a high capacity, low gradient system achieving bicarbonate recovery at a 1:1 ratio.

B. New Bicarbonate Formation

  • When considering a non-volatile acid, the equation shows sodium bicarbonate (NaHCO3) being consumed in buffering while lungs remove CO2.

  • Each day, approximately 50-70 mEq of acid/day is generated by metabolism necessitating an equal replenishment of bicarbonate.

  1. New Bicarbonate via Glutamine metabolism:

    • a. Start: Proximal tubular cells transport amino acid glutamine efficiently (basolateral), co-transporting sodium and glutamine into the cells (apical).

    • b. Glutamine Metabolism: Glutamine is broken down by glutaminase (GLS)—deaminated and oxidized— resulting in 2HCO3- and 2NH4+.

    • c. Retention of new bicarbonate: It is contingent on NH4+ secretion via sodium exchange. Returning NH4+ to circulation leads to its metabolism by the liver forming urea and H+. This effect can reduce the formation of new bicarbonate.

    • d. Handling ammonium: The positive charge on NH4+ inhibits its reabsorption in the proximal tubule. Filtered ammonia (NH3) may buffer H+ secreted into the tubular lumen, leading to NH4+ formation; this process is termed “diffusion trapping,” allowing substantial H+ excretion with minimal pH change in tubular fluid.

    • Clinical Note: In chronic acidosis, ammonium secretion markedly rises due to increased glutaminase activity, with NH4+ excretion potentially increasing from 30-40 mEq/day to over 300 mEq/day. Potassium balance affects glutaminase as hyperkalemia suppresses its activity.

  2. New bicarbonate via non-bicarbonate buffers (Low Capacity, High Gradient):

    • a. Start: In the medullary collecting tubule, similar to the proximal tubule, H+ and HCO3- formation occurs via carbonic anhydrase.

    • b. New HCO3- transport: This is facilitated by chloride ion exchange to reach the interstitial fluid.

    • c. H+ secretion: Mainly relies on active transport via H+-ATPase (high gradient).

    • d. Buffering: Due to minimal filtered bicarbonate remaining in the distal nephron, H+ is largely buffered by non-bicarbonate buffers—principal ones include disodium phosphate (Na2HPO4, pK = 6.8), creatinine (pK = 4.97), and uric acid (pK = 5.75). As a result, the formation of new bicarbonate through CA and neutralized H+ by non-bicarbonate buffers results in a net gain of new bicarbonate.

    • e. Availability Limitation: The supply of Na2HPO4 is regulated, balancing phosphate vs. acid-base ratios.

Quick renal bicarbonate summary:

  1. H+ and HCO3- generation inside renal tubular cells is catalyzed by carbonic anhydrase.

  2. H+ is secreted into renal tubule lumen, whereas HCO3- is transported out into systemic circulation.

  3. Recovery of filtered HCO3- occurs when secreted H+ binds to filtered HCO3-, successfully converting it to H2O and CO2 without gaining HCO3-.

  4. Generation of new HCO3- is achieved with glutamine metabolism and resultant NH4+ excretion, leading to a net gain of HCO3-.

  5. New HCO3- is generated when secreted H+ binds a non-bicarbonate buffer during tubular transit, resulting in a net gain of bicarbonate.

III. MECHANISMS ASSOCIATED WITH RENAL H+ AND HCO3- SECRETION

The recovery of bicarbonate and generation of new bicarbonate are dependent on H+ ion secretion and subsequent excretion. Understanding the regulations influencing H+ secretion and HCO3- secretion rates is essential.

A. Mechanisms Regulating H+ Secretion:

  1. Effect of PCO2: The partial pressure of CO2 in extracellular fluid influences CO2 diffusion into renal cells. Higher extracellular CO2 concentration means higher intracellular CO2 levels leading to increased H+ production by carbonic anhydrase.

    • Example: Increased plasma CO2 increases intracellular CO2, increasing H+ production and secretion. Therefore, respiratory acidosis heightens H+ excretion, while the reverse holds true when PCO2 decreases.

  2. Effect of [HCO3-]: The extracellular HCO3- concentration impacts bicarbonate transport from renal tubular cells, ultimately affecting H+ secretion.

    • Example: A reduction in HCO3- facilitates its transport out of renal cells leading to reduced intracellular HCO3- levels, thus increasing H+ production and H+ secretion. Conversely, an increase in extracellular HCO3- decreases H+ secretion.

  3. Acidosis and carbonic anhydrase: Acidosis drives changes in carbonic anhydrase expression and activity, favoring both H+ production and secretion as well as bicarbonate formation. The opposite is true for alkalosis.

    • Clinical Note: It is crucial to remember that the transcellular exchange of ions may have implications beyond simple diffusion down a concentration gradient.

  4. Limitations to H+ secretion: Ample buffer in tubular fluid is vital; as buffer concentrations drop, tubular fluids grow increasingly acidic. When pH approaches 4.4, the H+ concentration gradient may exceed the H+-ATPase's capacity to transport H+ ions.

Summary of Mechanisms Regulating H+ Secretion:

  • H+ secretion is increased when:

    • ↑ Partial pressure of CO2

    • ↓ Extracellular HCO3-

    • ↑ Activity of carbonic anhydrase

    • ↓ Lumen [H+] (↑ lumen pH)

  • H+ secretion is decreased when:

    • ↓ Partial pressure of CO2

    • ↑ Extracellular HCO3-

    • ↓ Activity of carbonic anhydrase

    • ↑ Lumen [H+] (↓ lumen pH)

B. Mechanisms Regulating Bicarbonate Ion Secretion:

  • During chronic metabolic alkalosis, specific cells in the cortical collecting duct secrete HCO3- into the tubular fluid, trading it for hydrogen ions into the interstitial fluid. Bicarbonate will associate with a cation (typically Na+) in the tubular lumen, leading to NaHCO3 elimination through urinary excretion. These cells essentially mirror others in the medullary collecting duct.

IV. VISUALIZATION OF ACID-BASE BALANCE WITH THE DAVENPORT DIAGRAM

  • While the Davenport diagram is not commonly applied clinically, it helps visualize various changes associated with mass action as well as metabolic and respiratory acidosis or alkalosis, noting their corresponding compensation.

  • **Normal values in the diagram: **

    • pH = 7.40 ± 0.05

    • HCO3- = 24 ± 2 mEq/L

    • PCO2 = 40 ± 5 mmHg

  • Uncompensated Changes = “Pure” Disturbances:

    • A “pure” acid-base disorder occurs before any other system has had a chance to correct it. For example, a pure metabolic disruption affects PCO2 (remaining 40 mmHg) while pH shifts in response without any alteration in PCO2.

    • Mass Action: Changes in PCO2 will lead to corresponding adjustments in HCO3- concentration along a mass action line.

      • An increase in PCO2 of 10 mmHg results in a 1 mEq/L increase in HCO3-

      • A decrease in PCO2 of 10 mmHg will diminish HCO3- by 2 mEq/L.

A. METABOLIC Acid-Base Imbalances & Mechanisms for Compensation:

  • A change in extracellular HCO3- concentration will reciprocally affect its concentration in cerebrospinal fluid.

    • Example: Metabolic acidosis occurs with a reduction in extracellular HCO3-, leading to increased H+ concentration, thus stimulating the chemosensitive neurons and increasing ventilation. This ventilation enhancement decreases PCO2, thus stabilizing pH but at the expense of reducing HCO3-.

    • Alkalosis from elevated HCO3- succeeds in raising cerebral HCO3-, lowering H+ concentration, reducing diffusion and, in turn, chemoreceptor signaling instrumental in ventilation, driving PCO2 up.

  1. Compensation for Metabolic Acidosis:

    • Rooted in decreased HCO3- concentration. Compensatory actions seek to reduce PCO2 to restore normal pH, ideally achieving a HCO3-:CO2 ratio nearing 20:1. Consequently, CO2 decreases, which can lead to further reductions in bicarbonate but works to bring pH back towards the normal range.

    • Uncompensated → Partial-Compensation:

      • pH = 7.25 → 7.33

      • HCO3- = 17 → 15 mEq/L

      • PCO2 = 40 → 30 mmHg

      • This highlights partial compensation in a metabolic acidosis scenario.

  2. Compensation for Metabolic Alkalosis:

    • Occurs when HCO3- levels rise. Compensatory responses aim to facilitate CO2 increase to normalize pH and HCO3-:CO2 ratio to around 20:1,

    • Consequently, an increase in CO2 occurs to slow breathing rates.

    • Uncompensated → Partial-Compensation:

      • pH = 7.50 → 7.47

      • HCO3- = 30 → 30.5 mEq/L

      • PCO2 = 40 → 46 mmHg

      • Illustrating partial compensation in metabolic alkalosis.

  3. Limitations to Respiratory Compensation:

    • Typically, respiratory compensation achieves “Partial Compensation” only. Rarely, the return to normal plasma pH values occurs exclusively by adjusting ventilation rates. In extreme cases:

      • For metabolic acidosis, respiratory compensation involves ↑ ventilation, limited by the energy required for sustained breathing and affects PCO2 signaling.

      • In situations of metabolic alkalosis, low ventilation due to hypoxemia can see limits at PCO2=60 mmHg, suggesting that severe metabolic acid-base imbalances rarely get fully corrected through respiratory avenues alone.

B. RESPIRATORY Acid-Base Imbalance & Mechanisms for Compensation:

  • A reduction in ventilation raises extracellular CO2 (respiratory acidosis). Elevated CO2 concentrations in renal tubular cells lead to compensatory mechanisms involving increased expression and activity of carbonic anhydrase, which promotes H+ secretion and HCO3- generation into the circulation.

    • In the proximal tubule, glutamine metabolism is likewise augmented by respiratory acidosis, fostering new HCO3- formation and H+ loss via NH4+ trapping. In the medullary collecting tubule, H+ secretion alongside buffering by non-bicarbonate buffers results in extra "new" bicarbonate production to elevate plasma HCO3- and counteract the increase in CO2.

  1. Compensation for Respiratory Acidosis:

    • Stemmed from high CO2 levels. The compensatory approach is to boost HCO3- levels, bringing pH closer to the normal range, maintaining a HCO3-:CO2 ratio around 20:1.

      • Note that elevated CO2 boosts plasma HCO3- simply due to mass action, which differs from what is termed true compensation. Actual compensation happens when renal efforts increase HCO3- levels beyond mass action expectations.

      • Uncompensated → Compensated:

      • pH = 7.32 → 7.4

      • HCO3- = 25 → 30.5 mEq/L

      • PCO2 = 50 → 50 mmHg.

  2. Compensation for Respiratory Alkalosis:

    • Occurs due to reduced CO2 concentration, mount compensatory responses designed to reduce HCO3- in an effort to restore pH.

    • Uncompensated → Compensated:

      • pH = 7.54 → 7.4

      • HCO3- = 22 → 15 mEq/L

      • PCO2 = 30 → 30 mmHg.

  3. Renal Compensation:

    • Adjusting plasma pH back to normal values (7.35 – 7.45) relies on modifying renal HCO3- recovery/production or excretion rate—a process that is more time-consuming as it depends on gene expression and protein synthesis changes.

    • While renal mechanisms can lead to “Complete Compensation,” this process typically necessitates time to fully implement.

Summary of Acid-Base Imbalances and Compensatory Mechanisms: