Question 18

Regarding regional citrate anticoagulation for continuous renal replacement therapy (CRRT):

a)    What is the mechanism by which citrate provides anticoagulation?    (20% marks)

b)    What is the metabolic fate of the citrate?    (10% mark)

c)    What are the features of citrate toxicity?    (30% marks)

d)    What conditions may increase the risk of citrate toxicity?    (20% marks)

e)    What alternative(s) to citrate could you use in a patient with severe Heparin Induced Thrombocytopaenia (HIT)?    (20% marks)

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College answer

Not available.


This question is virtually identical to Question 22 from the first paper of 2015, except the distribution of marks in 2021 was skewed, moving 10% of the marks from the metabolic fate of citrate and putting them into citrate toxicity.  To the candidates, this is a signal that primary exam material is being de-emphasised.


What is the mechanism by which citrate provides anticoagulation?

Citrate is a calcium chelator, and by robbing the clotting cascade of its ionised calcium it disables the steps of the cascade in which calcium plays a role (many people dont realise that calcium used to be Factor IV). The following are clotting cascade proteins which require calcium to function:

  • Factor VIIa
  • Factor IXa
  • Factor X
  • Factors Xa
  • Factor II (prothrombin)

So, 2, 7 9 and 10. Same as the Vitamin K-dependent factors.

What is the metabolic fate of the citrate?

The words "metabolic fate" are music to my ears.

In brief, citrate - in the course of its metabolism via the Krebs cycle - removes 3 H+ ions from the body, which has the equivalent effect of adding 3 HCO3- molecules. Thus, it is generally said that "citrate generates three bicarbonate molecules". It is true - its metabolism is the equivalent of buffering, and in excess citrate can cause a metabolic alkalosis. Thankfully, some of the citrate ends up being removed by the dialysis circuit, as it is a very small molecule.

What are the features of citrate toxicity?

Citrate toxicity - or rather, its biochemical features - is touched upon in the answer to Question 3.3 from the second paper of 2013.

In brief, the main features of citrate toxicity are as follows:

  • High anion gap metabolic acidosis
  • Potentially, also a metabolic alkalosis
  • Low ionised calcium
  • Normal total calcium (thus, a high total to ionised calcium ratio)
  • Coagulopathy

What conditions may increase the risk of citrate toxicity?

  • Liver disease (unable to metabolise the lactate)
  • Coagulopathy (requirement for regional anticoagulation of the CRRT circuit)
  • HITTS (or any other contraindication to the use of heparin)
  • Hypocalcemia
  • Decreased hepatic blood flow (eg. in sepsis or other shock states)

Citrate is mainly metabolised in the liver.

What alternative(s) to citrate could you use in a patient with severe HITS?

  • Prostacyclin (PGI2)
  • Argatroban
  • Danaparoid
  • Bivalirudin
  • Fondaparinux
  • Lepirudin

One might also mention using higher flow rates and pre-dilution as non-pharmacological means of increasing filter lifespan. In general, a massive list of strategies used to improve filter lifespan is also available somewhere around here, and it contains many options which don't involve citrate.


Oudemans-van Straaten, Heleen M., et al. "Citrate anticoagulation for continuous venovenous hemofiltration*." Critical care medicine 37.2 (2009): 545-552.

Tolwani, Ashita J., et al. "Simplified citrate anticoagulation for continuous renal replacement therapy." Kidney international 60.1 (2001): 370-374.

Bakker, Andries J., et al. "Detection of citrate overdose in critically ill patients on citrate-anticoagulated venovenous haemofiltration: use of ionised and total/ionised calcium." Clinical Chemical Laboratory Medicine 44.8 (2006): 962-966.

Uhl, L., et al. "Unexpected citrate toxicity and severe hypocalcemia during apheresis." Transfusion 37.10 (1997): 1063-1065.

Webb, A. R., et al. "Maintaining blood flow in the extracorporeal circuit: haemostasis and anticoagulation." Intensive care medicine 21.1 (1995): 84-93.

Mikaelsson, M. E. "The Role of Calcium in Coagulation and Anticoagulation."Coagulation and Blood Transfusion. Springer US, 1991. 29-37.

Mycielska, Maria E., et al. "Citrate transport and metabolism in mammalian cells." Bioessays 31.1 (2009): 10-20.

Kramer, Ludwig, et al. "Citrate pharmacokinetics and metabolism in cirrhotic and noncirrhotic critically ill patients." Critical care medicine 31.10 (2003): 2450-2455.