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Association between longer duration of citrate accumulation and 90-day mortality of acute-on-chronic liver failure

Regional citrate anticoagulation (RCA) is an optional anticoagulant for plasma adsorption (PA) plus plasma exchange (PE) therapy in patients with acute-on-chronic liver failure (ACLF), but with risk of transient citrate accumulation due to plasma and citrate [1]. Regardless of the anticoagulants: heparin or citrate, some patients would suffer from longer duration of citrate accumulation (LDCA), defined as the presence of citrate accumulation 2 h after PA plus PE therapy with RCA [1, 2]. However, whether citrate accumulation itself would lead to poor prognosis remains uncertain.

We conducted a retrospective study based on medical records to assess the association between LDCA and prognosis of hepatitis B virus (HBV)-related ACLF. Methods and some data from this cohort have been published already [2]. We kept to follow-up these patients for another 90 days after acquiring further ethical approval and registered this study with ChiCTR-OON-17013631. HBV-ACLF was diagnosed according to COSSH ACLF criteria [3]. Citrate accumulation was defined as the ratio of total calcium (Catot) to ionized calcium (Caion), (Catot/Caion), over or equal to 2.5 (Catot/Caion ≥ 2.5) [1, 2]. Cox proportional hazards models were applied to evaluate the association of LDCA with outcome.

From January 2018 to December 2019, we reviewed the data of 258 patients who fulfilled the HBV-ACLF criteria and received PA plus PE therapy with RCA. LDCA patients (N = 76) were more often female and older and had worse severity of disease condition than non-LDCA patients (N = 182) (Table 1). There was no significant difference in indicators, such as intracorporeal and extracorporeal Catot and Caion, representing patients receiving similar RCA during and after the first session of PA plus PE therapy with RCA.

Table 1 Characteristics of ACLF patients with or without LDCA

The 90-day mortality of LDCA patients was much higher than that of non-LDCA patients (63.2% vs. 32.4%, log-rank p < 0.001). Compared with non-LDCA patients, LDCA patients had much higher 90-day mortality risk (crude hazard ratio (HR) (95% confidence interval (CI)), 2.62 (1.79–3.84)) (Table 2). However, no significant differences in 90-day mortality risk were observed with the Cox proportional hazards models established with LDCA, age, gender, liver cirrhosis, HBV DNA, other co-existing liver diseases, comorbidities, and disease severity (Model 1, COSSH ACLF score; Model 2, CLIF-C ACLF score; Model 3, AARC ACLF score; Model 4, MELD score): Model 1 adjusted HR (95% CI), 1.07 (0.66–1.73); Model 2, 1.49 (0.95–2.36); Model 3, 1.41 (0.90–2.22); Model 4, 1.05 (0.65–1.72) (Table 2). Similarly, no significant differences in 90-day mortality risk were observed with similar Cox models established with citrate level indicators (Model 5, Catot/Caion ≥ 2.25; Model 6, Catot/Caion; Model 7, anion gap), disease severity (COSSH ACLF score), and the others mentioned above: Model 5, 1.28 (0.78–2.08); Model 6, 1.56 (0.74–3.27); Model 7, 1.06 (0.97–1.16). The disease severity was the independent risk factor of 90-day mortality (Model 1–7, all adjusted HR > 1, all p < 0.001).

Table 2 LDCA and other factors associated with risk of 90-day mortality in ACLF patients

Our study proved that ACLF patients with LDCA would suffer higher 90-day mortality. This finding was in accordance with the results in critically ill patients undergoing continuous renal replacement therapy with RCA [4]. However, no significant differences in 90-day mortality risk were found in ACLF patients with or without LDCA. As RCA brings no alteration of pro- and anti-coagulation function and ACLF patients have re-balanced but fragile coagulation function [1, 5], our new results would support the use of RCA with caution in ACLF patients. Adequate training, experienced operation, and well-developed safety protocols would further expand indications of RCA [6].

Our study for the first time assessed the association between LDCA and prognosis in ACLF patients treated with PA plus PE therapy with RCA. There were limitations: monocentric retrospective design, only HBV-ALCF cases, and applying Catot/Caion instead of directly measuring plasma citrate concentration to reflect citrate accumulation.

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.



Asian Pacific Association for the Study of the Liver—ACLF Research Consortium


Acute-on-chronic liver failure

Catot :

Total calcium

Caion :

Ionized calcium


Confidence interval


European Association for the Study of the Liver—Chronic Liver Failure-Consortium


Chinese Group on the Study of Severe Hepatitis B


Hepatitis B virus


Hazard ratio


Longer duration of citrate accumulation


Model for end-stage liver disease


Plasma adsorption


Plasma exchange


Regional citrate anticoagulation


  1. 1.

    Ma Y, Chen F, Xu Y, Wang M, Zhou T, Lu J, et al. Safety and efficacy of regional citrate anticoagulation during plasma adsorption plus plasma exchange therapy for patients with acute-on-chronic liver failure: a pilot study. Blood Purif. 2019;48:223–32.

    CAS  Article  Google Scholar 

  2. 2.

    Ma Y, Chen F, Liu C, Xu Y, Wang M, Zhou T, et al. A novel predictive score for citrate accumulation among patients receiving artificial liver support system therapy with regional citrate anticoagulation. Sci Rep. 2020;10:12861.

    CAS  Article  Google Scholar 

  3. 3.

    Wu T, Li J, Shao L, Xin J, Jiang L, Zhou Q, et al. Development of diagnostic criteria and a prognostic score for hepatitis B virus-related acute-on-chronic liver failure. Gut. 2018;67:2181–91.

    CAS  Article  Google Scholar 

  4. 4.

    Khadzhynov D, Schelter C, Lieker I, Mika A, Staeck O, Neumayer HH, et al. Incidence and outcome of metabolic disarrangements consistent with citrate accumulation in critically ill patients undergoing continuous venovenous hemodialysis with regional citrate anticoagulation. J Crit Care. 2014;29:265–71.

    CAS  Article  Google Scholar 

  5. 5.

    Wiegele M, Adelmann D, Dibiasi C, Pausch A, Baierl A, Schaden E. Monitoring of enoxaparin during hemodialysis covered by regional citrate anticoagulation in acute kidney injury: a prospective cohort study. J Clin Med. 2021;1010:4491.

    Article  Google Scholar 

  6. 6.

    Schneider AG, Joannes-Boyau O. Regional citrate anticoagulation for CRRT: still hesitating. Anaesth Crit Care Pain Med. 2021;40:100855.

    Article  Google Scholar 

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We thank all patients participating in this study for their understanding and recognition of our work.


This work was supported by grants from the 1·3·5 project for disciplines of excellence–Clinical Research Incubation Project, West China Hospital, Sichuan University (ZYJC21014), the Beijing iGandan Foundation (RGGJJ-2021-037), and the National Science and Technology Major Project for major infectious diseases such as AIDS and viral hepatitis prevention and control (2018ZX10715-003).

Author information




WM, MYJ and DLY contributed to statistical analysis, drafting of the manuscript, and interpretation of data. MYJ and BL had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. BL and TH contributed to study concept and design, and critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Hong Tang or Lang Bai.

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Approval for this study was obtained from the Biomedical Research Ethics Committee of West China Hospital of Sichuan University (No. 2020-650). All study components were performed according to the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Informed consent was not obtained because of retrospective design.

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The authors declare to have no competing interests.

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Wang, M., Ma, Y., Du, L. et al. Association between longer duration of citrate accumulation and 90-day mortality of acute-on-chronic liver failure. Crit Care 25, 387 (2021).

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