Question 19

College Answer

This question required candidates to understand the renal response to an acid load. It was expected that candidates would answer with regard to recycling of bicarbonate in the proximal tubule, excretion of titratable acid via the phosphate buffer system and generation of ammonium and its role in acid secretion. Many candidates had a good understanding of the bicarbonate system but used this to explain the secretion of new acid.

Discussion

Production and elimination of acid

• Normal metabolism acidifies the body fluids
• Elimination of this acid load by the kidneys is accomplished by the acidification of urine (i.e. secretion of acid) and the retention of filtered alkali (i.e of bicarbonate)

Reabsorption of filtered 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)

Excretion of ammonium is the most important mechanism of acid excretion

• Ammonia (NH₃) is produced in the kidney from the metabolism of glutamine, which also produces bicarbonate
• In the proximal tubule, NH₃ binds H⁺ in the lumen and becomes ammonium (NH₄⁺)
• Ammonium is then concentrated in the inner medulla by reabsorption in the thick ascending limb
• Concentrated ammonium is then secreted in the collecting duct
• This is quantitatively the most important mechanism of acid elimination 
• Metabolism of glutamine can increase tenfold in response to metabolic acidosis

Excretion of titratable acid also contributes to eliminating acid

• Non-volatile acids produced in the course of metabolism are lactate, ketones, phosphate, sulfate, citrate urate and hippurate.
• These are filtered freely in the proximal tubule
• A large fraction is then reabsorbed in the pars recta, as many of these are essential metabolic substrates
• The remaining fraction allows urine pH to be buffered
• Phosphate is the most important of these buffers quantitatively
  • pKa of phosphate is 6.8
  • In the tubule it is present in two main forms, H₂PO₄^- and HPO₄^2-
  • With increased tubule acidity, HPO₄^2- buffers H⁺ and produces H₂PO₄^-, which is poorly absorbed
  • H₂PO₄^- is then eliminated, taking  H⁺ with it. 
• Other buffers include creatinine and citrate, which have a higher buffering capacity at low urine pH (around 5.0)

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McNamara, J., and L. Worthley. "Acid-base balance: part I. Physiology." Critical Care and Resuscitation 3 (2001): 181-187.

Atherton, John C. "Role of the kidney in acid–base balance." Anaesthesia & Intensive Care Medicine 16.6 (2015): 275-277.

Weiner, I. David, Jill W. Verlander, and Charles S. Wingo. "Renal acidification mechanisms." Core Concepts in the Disorders of Fluid, Electrolytes and Acid-Base Balance. Springer, Boston, MA, 2013. 203-233.

Madias, Nicolaos E., and Horacio J. Adrogué. "Cross-talk between two organs: how the kidney responds to disruption of acid-base balance by the lung." Nephron Physiology 93.3 (2003): p61-p66.