Anticoagulation

Selecting an anticoagulation strategy

Although the 2012 KDIGO guidelines for acute kidney injury (AKI) recommend anticoagulation to prolong filter life, a substantial proportion of centres, estimated at approximately 33%–50%, start CKRT without anticoagulation and add it later if early filter clotting occurs.

Heparin and citrate are the anticoagulants most commonly used in CKRT.

KDIGO recommends citrate rather than heparin in suitable circumstances when there are no contraindications to its use, with a specific protocol and monitoring being essential [1].

Heparin

Heparin is inexpensive and familiar in clinical practice. It can be administered either through a separate intravenous pump or within the CKRT circuit before the filter. Administration into the circuit before the filter is preferred because it increases the heparin concentration within the filter.

However, heparin is not removed by dialysis. Prefilter administration therefore still produces systemic anticoagulation unless a reversal agent or antidote is used with it.

Less commonly, heparin is used with its reversal agent, protamine, to achieve anticoagulation confined to the dialysis circuit. As expected, heparin use without reversal is associated with an increased bleeding risk.

Regional citrate anticoagulation (RCA)

Unlike heparin, RCA does not produce systemic anticoagulation. Citrate is administered before the filter, usually aiming for a citrate concentration within the circuit of 3–6 mmol/L.

Citrate doses, infusion sites and laboratory targets differ according to the solution, device and protocol; numerical targets must therefore not be transferred between protocols without verification [1,3].

Citrate chelates calcium, binding and inactivating it. This lowers the ionised calcium concentration within the filter, usually to below 0.4 mmol/L, thereby inhibiting the coagulation cascade within the filter.

Calcium is usually replaced through a separate infusion, or, more commonly, immediately before the filtered blood is returned to the patient, to maintain systemic ionised calcium.

The RICH trial compared regional citrate with systemic heparin in critically ill patients. Median filter life was 46.5 hours with citrate and 26 hours with heparin. Bleeding complications were less frequent in the citrate group (5.1% versus 16.9%), whereas new infections were more frequent (68.0% versus 55.4%). The trial found no significant difference in 90-day mortality; its ability to determine the effect of the strategy on mortality was limited because it was stopped early [2].

Citrate disposition during CKRT

Most citrate is usually removed in the CKRT effluent. Nevertheless, a variable but important proportion reaches the patient’s body, where it is metabolised mainly in the liver.

To reverse citrate’s effect, replace calcium lost as calcium–citrate complexes, and prevent life-threatening hypocalcaemia, calcium must be administered continuously intravenously.

As noted previously, it can be administered:

— Into the patient-return limb of the CKRT circuit.

— Or through a separate calcium pump.

Calcium and citrate monitoring

Usual RCA protocols include serial monitoring of ionised calcium within the filter and systemic ionised calcium in the patient’s blood, allowing citrate and calcium infusion rates to be adjusted.

If ionised calcium within the filter is above target, the citrate infusion rate is increased, and vice versa.

If systemic ionised calcium is low, the calcium infusion rate is increased, and vice versa.

Finally, as explained later, total calcium should be monitored at least once daily to detect possible citrate accumulation.

Several different citrate formulations are available for anticoagulation, each requiring its own protocol for use.

RCA in patients with liver disease

Historically, liver disease was considered a contraindication to RCA because citrate is metabolised in the liver. Recent data, however, indicate that RCA can be used in patients with liver disease with careful monitoring.

Coagulation disturbances associated with liver disease are accompanied by both increased bleeding risk and increased thrombosis risk. Liver disease is therefore also associated with shorter CKRT filter life.

Specific protocols have been developed to reduce the risk of citrate accumulation when citrate is used in situations where citrate metabolism is absent or severely impaired.

Distinguishing excess base (metabolic alkalosis) from citrate accumulation

Citrate may be metabolised to bicarbonate, so citrate loading may be associated with increased bicarbonate and metabolic alkalosis. Citrate accumulation, in contrast, occurs when the body’s capacity to metabolise citrate decreases, and may present with reduced ionised calcium or an increased total-to-ionised calcium ratio. These findings are interpreted in the clinical context and alongside serial trends; no single marker is relied upon [1,3].

For details, see Complications.

Lactate as an indicator of citrate-accumulation risk

Lactate levels may be more useful than conventional liver-function tests for assessing citrate-accumulation risk. Like citrate, lactate is an organic anion normally metabolised mainly in the liver.

An elevated lactate level, regardless of its cause, such as shock or liver disease, therefore indicates impaired lactate metabolism and may also suggest a risk of impaired citrate metabolism.

The following levels can be used as an approximate estimate of citrate-accumulation risk:

— Lactate below 4 mmol/L: low risk.

— Lactate 4–8 mmol/L: intermediate risk.

— Lactate above 8 mmol/L: high risk.

RCA compared with systemic heparin

RCA increases treatment complexity and requires more frequent laboratory monitoring.

Nevertheless, trials have repeatedly shown RCA to be superior to systemic heparin with respect to:

— Prolonging filter life.

— And reducing bleeding complications.

The most recent and largest of these studies was the multicentre RICH trial, which randomised approximately 600 patients to:

— Systemic heparin.

— Or regional citrate anticoagulation.

Compared with systemic heparin, the study showed that RCA resulted in:

— A substantial prolongation of filter life by approximately 15 hours.

— Fewer bleeding events.

— No important difference in mortality.

Monitoring and safety

RCA protocols require training and ongoing monitoring. These points do not constitute a treatment prescription or define numerical laboratory targets; the operational reference is the institution’s protocol and the device instructions [1,3].

Heparin and other anticoagulants

Systemic heparin is used in some circumstances, with assessment of bleeding risk and contraindications and coagulation monitoring according to protocol [1]. The comparative evidence from RICH concerns citrate and heparin under that trial’s conditions, and is not automatically generalised to every anticoagulant or every patient [2].

Other anticoagulation options in CKRT

Less frequently used options for anticoagulation within the CKRT circuit include:

— Direct thrombin inhibitors.

— Nafamostat mesylate.

This is a serine-protease inhibitor that has been used for decades in East Asia.

However, to date, large randomised controlled trials adequately evaluating these options are not available.

References

[1] KDIGO. Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1–138. https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf.

[2] Zarbock A, Küllmar M, Kindgen-Milles D, et al. Regional citrate versus systemic heparin anticoagulation during continuous kidney replacement therapy: the RICH randomized clinical trial. JAMA. 2020;324(16):1629–1639. doi:10.1001/jama.2020.18618.

[3] Kovvuru K, et al. Complications associated with continuous renal replacement therapy. Semin Dial. 2021. doi:10.1111/sdi.12970.