Question 12

College Answer

This question sought knowledge of an important and basic area of physiology that applies to many
circumstances encountered in daily intensive care practice. For a good answer candidates were
expected to mention that bicarbonate is freely filtered, it’s fate along the nephron and that it is not
normally found in the urine. Mechanisms by how it is reabsorbed and generated along the different
segments of the nephron were expected to be described in some detail. The last part of this
question relating to hypoventilation was poorly answered. For a good answer candidates were
expected to mention that Hypoventilation results in an increase in arterial PCO2 that readily
diffuses into tubular cells resulting in increased intracellular H2CO3 and subsequently bicarbonate,
that is reabsorbed, and H+ that is secreted.
Syllabus: D1 Renal Physiology, 2e, 2k
References: Ganong, Review of Medical Physiology, Ch 39 and 40

Discussion

What the examiners here say about the mechanism of renal compensation for chronic hypercapnia is interesting, because it is derived from the official college textbook, but not especially well supported in the nephrology literature. Moreover it is not clear what the college mean by "hypoventilation"  - do they mean acute or chronic? Surely chronic, as acute (minute by minute) changes in respiratory CO₂ handling basically go unnoticed by the kidneys. Certain changes do take place with longer exposure, and that's what is included in the answer, 

Renal handling of bicarbonate

• All filtered bicarbonate is reabsorbed by the nephron
• 80% of filtered bicarbonate is reabsorbed in the proximal tubule
  • It is converted to lipid-soluble CO₂ by apical carbonic anhydrase, allowing it to be reabsorbed into the proximal tubule cells
• 20% more is reabsorbed in the thick ascending limb of the loop of Henle
• Regulation of bicarbonate reabsorption regulates responses to alkalosis and respiratory acid-base disturbances, but cannot compensate for metabolic acidosis, as the maximum effect is a maintenance of the status quo (when 100% of bicarbonate is reabsorbed)

Changes in pH along the nephron

• Beginning of proximal tubule: same pH as plasma (eg. 7.4)
• End of proximal tubule: pH 6.8
• Hairpin turn of the loop of Henle: pH ~ 7.4
• End of the thick ascending limb: pH 6.8
• End of the distal convoluted tubule: pH 6.7
• End of the collecting duct: pH 6.0-5.5

Response to hypoventilation

• The following changes are triggered by the delivery of CO₂ to the basolateral membrane of proximal tubule cells:
  • Initial changes:
    • Increased acidification of tubule fluid, even acutely, by unclear mechanisms (potentially due to CO₂ entry and subsequent acidification of tubule cells producing increased apical H⁺ export)
    • NHE3 Na⁺/H⁺ transporter expression increases over the next 1-2 days
    • Renal ammonia synthesis and ammonium secretion is rapidly increased 
    • ATP-powered H⁺ pumps are distributed to the apical membrane 
  • Later:
    • Bicarbonate reabsorption in the proximal tubule is increased
      (by 50% over 3-5 days, at PaCO₂ of 80%)
    • At the end of the process of adaptation, the increased bicarbonate reabsorption maintains a stable status quo and the renal acid excretion decreases back to a more normal level, similar to what it was before the onset of the chronic respiratory acidosis
    • In this status quo, ammonia excretion remains elevated while the excretion of other titratable acids is reduced

Barker, E. S., et al. "The renal response in man to acute experimental respiratory alkalosis and acidosis." The Journal of clinical investigation 36.4 (1957): 515-529.

Adrogué, Horacio J., and Nicolaos E. Madias. "Renal acification during chronic hypercapnia in the conscious dog." Pflügers Archiv 406.5 (1986): 520-528.

Cogan, Martin G. "Chronic hypercapnia stimulates proximal bicarbonate reabsorption in the rat." The Journal of clinical investigation 74.6 (1984): 1942-1947.

Madias, Nicolaos E., Charles J. Wolf, and Jordan J. Cohen. "Regulation of acid-base equilibrium in chronic hypercapnia." Kidney international 27.3 (1985): 538-543.

Boron, Walter F. "Acid-base transport by the renal proximal tubule." Journal of the American Society of Nephrology 17.9 (2006): 2368-2382.