Anticoagulation for continuous kidney replacement therapy

INTRODUCTION — Kidney replacement therapy (KRT) is commonly required in patients with severe acute kidney injury (AKI). Continuous kidney replacement therapy (CKRT) is an alternative to an intermittent therapy such as standard hemodialysis.

CKRT may require anticoagulation to prevent clotting of the extracorporeal circuits, although CKRT without anticoagulation is often attempted [1].

This topic reviews strategies to prevent clotting and approaches to anticoagulation for patients on CKRT. Other issues related to CKRT are discussed elsewhere (see "Continuous kidney replacement therapy in acute kidney injury" and "Drug removal in continuous kidney replacement therapy"). Anticoagulation for patients on intermittent hemodialysis is provided elsewhere. (See "Anticoagulation for the hemodialysis procedure".)

INDICATIONS AND RATIONALE — Anticoagulation is used to prevent clotting of the extracorporeal system. Clotting of the circuit may be minor, leading to clotting in the capillary fibers and reduced solute clearances, or major, leading to loss of the hemofilter, tubing, and blood in the circuit [2,3]. Replacing the hemofilter and tubing interrupts CKRT and reduces the total therapy time. Studies have shown that interruptions from clotting may reduce the total time on CKRT from 24 to 16 hours per day [4,5]. Such reductions reduce the effectiveness of CKRT. A sufficient operating time is required to ensure that an adequate KRT dose is delivered.

However, anticoagulation increases the complexity and cost of the procedure. At our center, we perform CKRT without anticoagulation, providing filter life can be maintained for >24 hours. We use anticoagulation if the filter life cannot be maintained for >24 hours. However, some centers routinely use anticoagulation from the start in order to prevent clotting, and the Kidney Disease Improving Global Outcomes (KDIGO) guidelines suggest the use of anticoagulation [6]. However, a Cochrane systematic review concluded that the most effective anticlotting options for CKRT remain to be determined [7].

AVAILABLE ANTICOAGULANT THERAPIES — The most commonly used options for CKRT anticoagulation include regional citrate (RCA) and unfractionated heparin (UFH) [8].

Low-molecular-weight heparin (LMWH), thrombin antagonists (argatroban and bivalirudin), UFH with protamine reversal, heparinoids, platelet-inhibiting agents, and heparin surface-coated hemofilters are less common options.

Regional citrate anticoagulation — RCA decreases the rate of clotting and may be used in all CKRT modalities [9-18]. Compared with systemic heparin, RCA reduces the risks of bleeding [9,15,19-22]. (See 'Preferential use of regional citrate anticoagulation' below.)

During RCA, sodium citrate is infused into the inflow ("arterial") limb of the extracorporeal circuit, chelating calcium and inhibiting clotting. The majority of the calcium citrate complex is removed across the hemofilter. Any calcium citrate complex that remains postfilter is returned to the patient and indirectly metabolized to bicarbonate by the liver, kidney, and skeletal muscle. Regional anticoagulation is reversed by dilution of citrate in the extracellular compartment and by its rapid metabolic clearance [23].

A systemic calcium infusion is required to replace the calcium that is lost in the effluent in order to maintain a normal ionized serum calcium concentration.

The use of RCA may require modification of the composition of dialysate or replacement fluid. The concentration of buffers (eg, bicarbonate, lactate) should be reduced to prevent alkalosis since citrate provides alkali. In addition, citrate can also bind magnesium and, therefore, we prefer dialysates or replacement fluid solutions that have 0.75 mmol/L rather than 0.5 mmol/L of magnesium.

Ideally, the dialysate and replacement fluids should also be calcium free to prevent reversal of the citrate effect in the extracorporeal circuit, although this is not absolutely necessary. If calcium-containing replacement fluid is used, more citrate is required to chelate calcium in both the blood and replacement fluid, but a separate calcium reinfusion may not be required.

RCA use for CKRT is not approved by the US Food and Drug Administration (FDA). The absence of a US FDA-approved citrate regimen has been a barrier to use of citrate regimens in the United States. Some institutional pharmacies have been unwilling to permit off-label use of citrate.

Unfractionated heparin — UFH is widely used for CKRT [24], particularly in the many institutions that do not have the ability to use RCA [25-27]. UFH is effective, inexpensive, and widely available [25-27].

However, there are disadvantages associated with the use of UFH, including unpredictable and complex pharmacokinetics that result in dosing variability, the development of heparin-induced thrombocytopenia (HIT), heparin resistance due to low patient antithrombin levels, and an increased risk of bleeding [28]. (See "Clinical presentation and diagnosis of heparin-induced thrombocytopenia".)

The reported incidence of bleeding ranges from 10 to 50 percent and is related to the degree of prolongation of the activated partial thromboplastin time (aPTT) [3,29,30].

Other — Other approaches include UFH with protamine reversal, low-molecular-weight heparins, thrombin antagonists, danaparoid, nafamostat maleate, prostacyclin and other prostanoids, and platelet-inhibiting agents [31-51].

We do not routinely use these agents, because there are insufficient data that have demonstrated benefit, and their safety among CKRT patients has not been adequately studied.

OUR APPROACH

Initial approach — For most patients, we attempt CKRT without anticoagulation. We usually can achieve adequate CKRT filter survival without anticoagulation, providing the patient has a well-functioning vascular access [52-55]. (See "Prescription of continuous kidney replacement therapy in acute kidney injury in adults", section on 'Vascular access' and "Prescription of continuous kidney replacement therapy in acute kidney injury in adults", section on 'CKRT blood flow rate'.)

The following strategies may prolong hemofilter survival in the absence of anticoagulation.

●Maintain adequate blood flow ─ We try to maintain blood flow between 100 to 300 mL/min. Very low blood flows are a common cause of circuit clotting because they increase the risk of stasis and increase the filtration fraction, which causes hemoconcentration across the hemofilter [56]. (See "Prescription of continuous kidney replacement therapy in acute kidney injury in adults", section on 'Filtration fraction'.)

However a higher blood flow (ie, >300 mL/min) may also cause clotting by triggering pressure alarms that stop the blood flow and cause stasis. Even in the absence of clotting, very high blood flows limit the lifespan of the extracorporeal circuit tubing and hemofilter because they can only process a finite volume of blood before the tubing starts to degrade. (See "Prescription of continuous kidney replacement therapy in acute kidney injury in adults", section on 'CKRT blood flow rate'.)

●Minimize hemoconcentration within the hemofilter ─ Hemoconcentration refers to the increasing concentration of red blood cells, platelets, and coagulation factors in blood. The risk of clotting may be increased by hemoconcentration within the hemofilter, which occurs as a result of ultrafiltration (ie, the removal of water across the hemofilter).

We minimize hemoconcentration with the hemofilter by the following approach:

•We administer predilution rather than postdilution replacement fluid. For convective therapies, such as continuous venovenous hemofiltration (CVVH), giving fluid before the hemofilter (ie, predilution replacement) decreases hemoconcentration within the hemofilter.

•We keep the filtration fraction <20 to 25 percent. Filtration fraction is the fraction of plasma water that is removed from blood during ultrafiltration. Higher filtration fractions are associated with increased circuit clotting, presumably from hemoconcentration and blood protein-membrane interactions [57]. (See "Prescription of continuous kidney replacement therapy in acute kidney injury in adults", section on 'Filtration fraction'.)

•We also use saline flushes, although there are no data that show that this decreases clotting.

Hemoconcentration may also be decreased by the use of diffusive therapies (such as continuous venovenous hemodialysis [CVVHD]) and continuous venovenous hemodiafiltration (CVVHDF) rather than postdilutional convective therapies (such as CVVH). (See "Continuous kidney replacement therapy in acute kidney injury", section on 'Definition of CKRT modality'.)

Some studies have suggested that CVVH is associated with increased hemofilter clotting, believed to be related to the high ultrafiltration rate required for adequate CVVH [58]. In addition to clotting within the hemofilter, clotting also occurs with blood-air interfaces. As such, careful priming of the extracorporeal circuit and adding saline to the drip chamber such that there is a layer of saline above the blood level may minimize blood-air contact.

●React promptly to alarms – Alarms are triggered by increases in pressure, which are generally associated with blood stasis. Slow reaction allows the stasis to persist longer and leads to clotting [24,57,59].

●Reduce the blood-air contact in the drip chamber – Contact between blood and air increases platelet activation, which may cause clotting [60]. Blood-air contact can be minimized by adding saline to the drip chamber such that there is a layer of saline above the blood level [57].

●Avoiding overheating dialysate and replacement solutions – Cooling of replacement solution below normothermia has been shown to improve patency in animal studies [61,62]. While it is not clinically feasible to lower the temperature of replacement fluid below normal, we are careful not to overheat the solution.

●Avoiding mechanical obstruction of blood lines – When moving patients, care should be taken not to kink lines and to ensure that lines are clearly visible.

If there is repeated clotting, the first step is to ensure that the vascular access is functioning adequately.

Patients with repeated clotting of hemofilter — If the hemofilter cannot be maintained without anticoagulation for at least 24 hours, we use anticoagulation unless the clotting is due to access problems.

If regional citrate anticoagulation (RCA) is available and the patient has no contraindications, we use RCA rather than unfractionated heparin (UFH). RCA is effective and increases the hemofilter lifespan and lowers the bleeding risk and transfusion requirement compared with UFH [9,15,19-22].

For patients who have contraindications or do not tolerate RCA, or if RCA is not available, UFH may be used.

Multiple randomized trials [9,10,15,16,18-21,63-76] and meta-analyses [22,77,78] have shown that RCA is better than heparin at preserving filter patency and has a lower risk of adverse events, including bleeding. There does not appear to be a survival benefit of either heparin or RCA [9,78]. The largest meta-analysis (11 randomized trials, 992 patients) compared RCA with either systematic (nine trials) or regional (two trials) heparin [78]. The risk of circuit loss was lower with RCA compared with regional heparin (hazard ratio [HR] 0.52, 95% CI 0.35-0.77) and systemic heparin (HR 0.76, 95% CI 0.59-0.98). The risk of bleeding was lower with RCA compared with systemic heparin (relative risk [RR] 0.36, 95% CI 0.21-0.60) and similar between RCA and regional heparin. There was no difference in survival between groups. However, another meta-analysis that included different studies reported no overall advantage for citrate in terms of circuit clotting but reported a reduction in major bleeding associated with RCA as compared with unfractionated heparin (RR 0.22, 95% CI 0.08-0.62) [7]. In a subsequent large trial, compared with systemic heparin, RCA led to a prolonged filter life span but a higher frequency of new infections [9]. Consistent with prior studies, there was no difference in survival between groups. Similarly, a report from the United Kingdom found no overall difference in survival with RCA compared with UFH and only a marginal difference in bleeding events [79].

Citrate anticoagulation is not approved by the US Food and Drug Administration (FDA) for CKRT; commercial solutions for citrate anticoagulation for CKRT are not available in the United States [80,81].

Preferential use of regional citrate anticoagulation — The mechanism by which citrate works is described above [10-16,18-21,63-76,82]. (See 'Regional citrate anticoagulation' above.)

Method — We use a blood flow rate of 80 to 200 mL/min. In contrast to patients who are not receiving any anticoagulation, higher blood flows are not required to prevent clotting. In addition, higher blood flows are counterproductive since the amount of required citrate increases with higher blood flows.

A variety of methods of RCA have been described [10-16,18-21,63-76,82]. In all, citrate solution is infused into the blood at the beginning of the extracorporeal circuit. In the United States, the citrate solution that is used for anticoagulation may need to be custom made by the hospital pharmacy, although in Europe and other countries, citrate preparations and dialysates are commercially available. Commercially available replacement and dialysate solutions that have been specifically designed for CKRT include Prismocitrate 10/2, which contains 10 mm/L citrate, 2 mmol/L citric acid, and 136 mmol/L sodium; Prismocitrate 18/0, which contains 18 mmol/L citrate; and calcium-free dialysates (Ci-Ca dialysate).

Some centers may use commercially available citrate solutions that were not designed for CKRT and have high concentrations of citrate and sodium. Depending upon the concentration of citrate solution used and the corresponding sodium load, compensatory hyponatremic replacement and/or dialysate solutions with either no or reduced bicarbonate concentrations may be required to prevent the development of electrolyte abnormalities. (See "Prescription of continuous kidney replacement therapy in acute kidney injury in adults", section on 'CKRT solutions'.)

A separate calcium infusion is delivered to the patient and titrated to keep the systemic ionized calcium concentration in normal range. The citrate infusion rate is adjusted to keep the ionized calcium concentration in the extracorporeal circuit <0.35 mmol/L (measured as the postfilter ionized calcium concentration), which correlates with citrate blood concentration of 4 to 6 mmol/L. It is important that the analyzer is calibrated to measure these low ionized calcium values [83].

Calcium chloride or calcium gluconate is infused into the venous return line at an initial rate of 2 to 3 mmol/hour to replace calcium lost in the effluent when using calcium-free dialysate and replacement fluids. The rate is adjusted according to measurements of plasma calcium concentration to prevent hypocalcemia or hypercalcemia [23].

Citrate-based anticoagulation can also be used among patients receiving CVVHD (table 1) [84].

Contraindications — We do not use RCA, at least initially, in patients who are likely to have impaired metabolic clearance of citrate:

●Acute liver failure with blood transaminases values >1000 international unit/L ─ This is usually from ischemia (ie, shock liver) but could be related to hepatitis from any cause. Such patients are unlikely to metabolize citrate appropriately, resulting in severe acidosis and decreases in ionized calcium. However, we may attempt anticoagulation with RCA once liver function starts to improve.

●Cardiogenic shock with blood lactate values >8 mmol/L ─ Similar to patients with acute liver failure, such patients will not metabolize citrate. RCA may be used if there is clinical improvement and a decrease in lactate to ≤8 mmol/L.

Monitoring — We check blood electrolytes at least every six hours and include sodium, potassium, chloride, ionized calcium, magnesium, and blood gas analysis, along with calculation of the anion gap. At least once daily, total blood calcium concentration should be monitored to calculate the calcium ratio (total calcium/ionized calcium) or calcium gap (total calcium minus ionized calcium), which, if abnormal, may indicate citrate accumulation. Blood gas analyzers may need to be recalibrated to measure low-ionized calcium concentrations.

The need for monitoring anticoagulation efficacy in the circuit depends on the method of citrate delivery. If the dose of citrate is fixed in relation to the blood flow, monitoring is not necessary as long as blood flow is constant. If the citrate dose is not fixed to a constant blood flow rate, postfilter ionized calcium levels should be measured at least every six hours and the infusion of citrate titrated for an ionized calcium <0.35 mmol/L.

Once steady state is reached after 48 to 72 hours and the patient remains stable, monitoring of electrolytes can be decreased to every 12 hours.

Citrate accumulation and indications to stop RCA — Regional citrate anticoagulation (RCA) should be stopped if there is citrate accumulation. It is difficult to predict which patients will develop citrate accumulation. Patients at very high risk are those with acute liver failure who have transaminases >1000 international unit/L, those with acute on chronic liver failure [85], and also those with cardiogenic shock and lactate concentrations >8 mmol/L, although other causes of hyperlactatemia do not necessarily preclude the use of citrate [86]. As noted above, we do not use RCA in such patients. (See 'Our approach' above.)

Citrate accumulation is suggested by the following [87-90]:

●Worsening metabolic acidosis with increasing anion gap

●Decreasing ionized calcium requiring escalating calcium infusion rates

●Increasing total calcium

●A ratio of total calcium to ionized calcium >2.5

There is no absolute value or threshold that is used to stop RCA. We generally look at trends of all those criteria and stop RCA only when all criteria are met. Prior to stopping RCA, certain measures to reduce citrate accumulation can be tried, such as reducing the citrate infusion rate for patients on hemofiltration or increasing the dialysate infusion rate for patients on hemodialysis or hemodiafiltration.

In general, we will stop RCA if serum bicarbonate levels continue to fall over several measurements with increasing anion gap, if the ratio of total calcium to ionized calcium exceeds 2.5 and does not respond to the above modifications, and if the calcium infusion rates exceeds 90 mL/hour. Since the calcium infusion is titrated according to ionized calcium levels, most patients do not develop significantly low ionized calcium levels. Positive calcium balance by excessive correction of hypocalcemia should be avoided among patients with severe rhabdomyolysis. (See "Etiology of hypercalcemia", section on 'Rhabdomyolysis associated with acute renal failure'.)

Other complications — The potential complications associated with regional citrate include hypocalcemia (ie, in absence of other evidence of citrate toxicity), hypercalcemia, hypernatremia, hypomagnesemia, and acid-base disorders [15]. Either alkalosis or acidosis can occur [91]. These are rarely indications to stop CKRT, providing acidosis is not accompanied by other evidence of citrate accumulation. (See 'Citrate accumulation and indications to stop RCA' above.)

The rate of specific complications depends on the specific protocol used and on patient comorbidities. In a study of 133 patients treated with RCA, severe alkalosis (pH >7.55) was present in approximately 2 percent of patients and severe hypocalcemia (ionized calcium ≤0.9 mmol/L) in approximately 11 percent [91]. Hypercalcemia (ionized calcium ≥1.5) did not occur in this study.

Alkalosis is less common when replacement solutions and dialysate solutions contain reduced bicarbonate concentrations. Solutions commonly used for patients who are not on RCA contain bicarbonate solution of 32 to 35 mEq/L, whereas solutions for patients treated with RCA contain bicarbonate concentration of 22 to 25 mEq/L. (See "Prescription of continuous kidney replacement therapy in acute kidney injury in adults", section on 'CKRT solutions'.)

As noted above, severe acidosis may develop if citrate is not metabolized by the liver or muscle (see 'Citrate accumulation and indications to stop RCA' above). However, acidosis may also develop in the absence of citrate accumulation [91].

Unfractionated heparin — If the patient requires anticoagulation and we cannot use RCA, we use UFH. We start with a loading dose of 500 to 1000 international units followed by infusion of 500 units per hour. We adjust the heparin infusion according to activated partial thromboplastin time (aPTT) or ratio (aPTTr).

We target an aPTT of 45 seconds or aPTTr 1.5 times normal [3,28-30,54,92,93]. The heparin dose should be reduced in patients with disseminated intravascular coagulation or thrombocytopenia.

Combined RCA and unfractionated heparin — Regional citrate anticoagulation (RCA) has not been shown to reduce platelet activation or thrombin generation in critically ill patients undergoing CKRT [94]. As such, circuit clotting was increased with the first wave of coronavirus disease 2019 (COVID-19) infections, and therefore, many centers combined systemic heparin with RCA without observing an increase in bleeding complications [95].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in adults".)

SUMMARY AND RECOMMENDATIONS

●Continuous kidney replacement therapy (CKRT) may require anticoagulation to prevent clotting in the extracorporeal system and loss of the hemofilter. Clotting decreases the total therapy time and efficacy. A sufficient time on CKRT is necessary to ensure an adequate KRT dose is delivered. (See 'Indications and rationale' above.)

●For most patients, we attempt CKRT without anticoagulation, although many clinicians use anticoagulation from the outset. We usually can achieve adequate CKRT filter survival if the patient has a well-functioning vascular access. Strategies to prolong hemofilter survival in the absence of anticoagulation are discussed. (See 'Initial approach' above.)

●If the hemofilter cannot be maintained without anticoagulation for at least 24 hours, we use anticoagulation. If regional citrate anticoagulation (RCA) is available and the patient has no contraindications, we use RCA rather than unfractionated heparin (UFH). RCA is better than heparin at preserving filter patency and is less likely to cause adverse events, including bleeding. However, RCA has not been shown to provide a survival benefit compared with heparin. (See 'Patients with repeated clotting of hemofilter' above.)

●Contraindications to RCA include acute liver failure with transaminases >1000 units/L and cardiogenic shock with lactate values >8 mmol/L. (See 'Contraindications' above.)

●Patients on RCA should be closely monitored for evidence of citrate accumulation and other complications of CKRT. Our monitoring strategy is defined. (See 'Monitoring' above.)

●Prior to stopping RCA for citrate toxicity, certain measures to reduce citrate accumulation can be tried, such as reducing the citrate infusion rate for patients on hemofiltration or increasing the dialysate infusion rate for patients on hemodialysis or hemodiafiltration. RCA should be stopped if these measures fail. Citrate accumulation is suggested by worsening metabolic acidosis, decreasing ionized calcium, and increasing total calcium. We stop RCA if serum bicarbonate levels continue to fall over several measurements with increasing anion gap, if the ratio of total calcium to ionized calcium exceeds 2.5, and if the calcium infusion rates exceeds 90 mL/hour. (See 'Citrate accumulation and indications to stop RCA' above.)

●If the patient requires anticoagulation and we cannot use RCA, we use UFH. Our protocol is defined. (See 'Unfractionated heparin' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Ashita J Tolwani, MD, and Keith M Wille, MD, who contributed to earlier versions of this topic review.