Comparison of regional citrate, systemic heparin, and no anticoagulation during continuous renal replacement therapy in critically ill adults with acute kidney injury: a prospective multicenter nonrandomized comparative study

Introduction

Acute kidney injury (AKI) is common among critically ill patients and is consistently associated with increased morbidity, mortality, and resource utilization (1-3). Continuous renal replacement therapy (CRRT) is frequently used in hemodynamically unstable patients because it allows gradual solute and fluid removal, but its effectiveness depends on maintaining extracorporeal circuit patency for clinically meaningful durations (4-9). Premature circuit clotting reduces delivered dose, increases blood loss and transfusion exposure, interrupts fluid management, and increases workload and cost (7).

Anticoagulation is therefore central to CRRT delivery, yet critically ill patients often have simultaneous competing risks of thrombosis and bleeding. Systemic unfractionated heparin remains widely used because it is inexpensive and familiar, but it increases systemic bleeding exposure and may precipitate or worsen thrombocytopenia, including heparin-induced thrombocytopenia (HIT) (10). Regional citrate anticoagulation (RCA), which chelates ionized calcium within the circuit while preserving systemic hemostasis through calcium replacement, is increasingly used and is recommended in many guidelines when monitoring resources are available (10-16). However, RCA can cause clinically important metabolic complications, including hypocalcemia, alkalosis, and citrate accumulation, particularly when citrate metabolism is impaired (17-19).

In practice, an anticoagulation-free strategy is also used for patients judged to be at high bleeding risk or when anticoagulation is contraindicated, but this approach may shorten circuit life and increase circuit replacement (7,20). Prior randomized trials have largely compared RCA with systemic heparin under protocolized conditions and rarely included a contemporaneous anticoagulation-free cohort. Prospective multicenter comparative data that evaluate all three strategies within the same contemporary intensive care setting therefore remain limited.

We therefore conducted a prospective multicenter observational study to compare RCA, systemic heparin anticoagulation (SHA), and anticoagulation-free CRRT in critically ill adults with AKI. We focused on clinically actionable outcomes: clotted-circuit burden, circuit lifespan (CLS), safety complications, treatment interruptions, and short-term direct cost. We present this article in accordance with the STROBE reporting checklist (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2026-0006/rc).

Methods

Study design and setting

This was a prospective, multicenter, observational comparative study conducted over 24 months (April 2022 to March 2024) in two tertiary intensive care units (ICUs): the Critical Care Department, Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt, and the Critical Care Department, King Fahad Military Medical Complex (KFMMC), Dhahran, Saudi Arabia.

Ethical consideration

The protocol was reviewed and approved by the local research ethics committees at both participating centers before enrollment of the first participant at each site. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of the Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt (approval No. md-195-2022), and by the Institutional Review Board of King Fahad Military Medical Complex, Dhahran, Saudi Arabia (AFHER-IRB-2022-024). Written informed consents were obtained from all participants and/or their legally authorized representatives prior to enrollment. Because this was an investigator-initiated nonrandomized observational study, no prospective trial registration was performed.

Participants and recruitment

Adults (≥18 years) admitted to the participating ICUs who developed AKI and required CRRT were prospectively identified at the time CRRT was initiated and were recruited from routine ICU care. AKI was defined using KDIGO criteria (serum creatinine increase ≥0.3 mg/dL within 48 hours, or ≥1.5 times baseline within 7 days, and/or urine output <0.5 mL/kg/hour for ≥6 hours) (9). Indications for CRRT followed routine ICU practice and included persistent AKI for 72 hours, refractory fluid overload, severe metabolic acidosis, hyperkalemia, or uremic complications. Baseline variables recorded at CRRT initiation included age, admission diagnosis, presumed cause of AKI, vasopressor use, hemoglobin, platelet count, international normalized ratio (INR), and validated illness-severity scores [Acute Physiology and Chronic Health Evaluation II (APACHE II) and Sequential Organ Failure Assessment (SOFA)].

Exclusion criteria

Exclusion criteria were end-stage kidney disease on chronic dialysis, pregnancy, severe liver failure or decompensated chronic liver disease, therapeutic systemic anticoagulation for another indication, known primary bleeding or hematologic disorders, baseline platelet count <100×10⁹/L, INR >1.4 at CRRT initiation, anticipated inability to deliver CRRT, expected survival <24 hours, and contraindications to RCA (e.g., severe hepatic dysfunction, severe lactic acidosis/hyperlactatemia, inability to monitor ionized calcium, or inability to provide protocolized calcium replacement) (18,21). To avoid misclassification of circuit performance, patients were excluded if all CRRT circuits were electively terminated by physician order for reasons unrelated to circuit function, such that clotting outcomes could not be meaningfully assessed.

Anticoagulation strategy and assignment

Participants were classified according to the anticoagulation strategy used at CRRT initiation: RCA, SHA, or no anticoagulation (n=50 each). Strategy selection was determined by the treating intensivists’ clinical judgment and routine institutional practice; no randomization was performed. In general, patients with lower perceived bleeding risk were more likely to receive systemic heparin, whereas patients with higher bleeding risk were preferentially managed with RCA; when citrate was contraindicated or unavailable, CRRT was performed without anticoagulation. Because allocation was clinician-directed and no single mandated bleeding-risk score governed treatment selection across centers, confounding by indication was anticipated.

Bias minimization and masking

To reduce bias introduced by clinician-directed strategy selection, both centers used common eligibility criteria, standardized CRRT operating parameters, the same pragmatic outcome definitions, and shared data-collection forms. Owing to the nature of bedside CRRT management, treatment allocation was not concealed and no masking was feasible.

Sample size rationale

The target sample size of 150 patients (50 per group) was prespecified in the study protocol using MedCalc 19 with a two-sided alpha of 0.05 and 80% power, based on an expected mortality proportion of 42% drawn from prior comparative CRRT literature. No interim analysis or stopping rule was used.

Systemic heparin protocol

For SHA, unfractionated heparin was administered according to institutional protocols with activated partial thromboplastin time (aPTT) monitoring. Typical regimens included an initial bolus of 10–20 units/kg followed by a continuous infusion of 5–15 units/kg/hour, targeting an aPTT of 45–60 seconds.

Regional citrate protocol

For RCA, citrate was infused pre-filter and titrated according to achieved blood flow to provide regional anticoagulation (target post-filter ionized calcium typically 0.25–0.35 mmol/L), while systemic calcium was replaced through a separate infusion to maintain systemic ionized calcium in the physiological range (typically 1.0–1.2 mmol/L). During RCA, venous blood gas analysis and electrolytes, including ionized calcium, were monitored every 6 hours. Total calcium and the total-to-ionized calcium ratio were checked regularly and whenever citrate accumulation was suspected. RCA was discontinued and an alternative strategy was chosen if clinically significant citrate toxicity or refractory metabolic disturbance developed.

No-anticoagulation protocol

In the no-anticoagulation group, CRRT was delivered without anticoagulants using optimized blood flow rates (generally ≥150 mL/minute), the same nominal blood-flow target range applied in the other strategies whenever feasible, and frequent circuit monitoring.

CRRT protocol

Continuous venovenous hemofiltration or hemodiafiltration was performed using standardized protocols on commercial CRRT platforms routinely used across the two centers. ICU and dialysis nurses at both sites were trained on the available CRRT machines and had passed local competency testing before independently managing CRRT sessions. Double- or triple-lumen central venous dialysis catheters were inserted under ultrasound guidance (internal jugular or femoral veins). Blood flow was typically maintained at 150–200 mL/minute with prescribed replacement and/or dialysate rates of 20–30 mL/kg/hour, adjusted to the clinical condition and metabolic targets. Circuits were changed when clinically indicated or at the manufacturer-recommended maximum use time (72 hours).

Outcomes

Primary outcomes were clotted circuits per patient and CLS. A clotted circuit was defined as premature circuit termination requiring circuit replacement because of visible clotting, persistent high transmembrane pressure despite troubleshooting (typically >250 mmHg), or inability to maintain extracorporeal blood flow. The number of clotted circuits per patient was analyzed in the full cohort. The prospectively coded CLS variable in the study database represented the average lifespan of circuits terminated because of malfunction, defined as clotting and/or reaching the manufacturer-recommended 72-hour filter-expiry threshold with a single circuit; therefore CLS analyses were restricted to participants with at least one such recorded event.

Safety outcomes and data collection

Secondary outcomes included bleeding events, metabolic disturbances, thrombocytopenia and HIT probability, treatment interruptions, and a short-term direct-cost estimate. Data were collected prospectively from CRRT flow sheets, laboratory records, and bedside clinical documentation using shared definitions at both sites. Only new or worsening abnormalities arising after CRRT initiation were counted as treatment-emergent complications. Bleeding was recorded when clinically evident, including overt bleeding from any site and/or hemoglobin decline prompting transfusion or procedural intervention. Because this was a pragmatic observational study, bleeding was not prospectively adjudicated using a formal major/minor scale; instead, events are reported descriptively by site and clinical consequence. No intracranial, fatal, or other life-threatening bleeding events were documented.

Cost estimation

A direct-cost estimate over the first 72 hours incorporated anticoagulant medication, monitoring requirements, including laboratory tests and calcium infusion for RCA, and circuit replacement needs with associated nursing time. Costs related to downstream consequences, such as bleeding management, were not included.

Statistical analysis

After retrieval of the original patient-level study spreadsheet and coding manual, all analyses were repeated from the raw data. Continuous variables were examined for distributional form and are reported as median [interquartile range (IQR)] when skewed. Categorical variables are reported as number (%). The principal unit of analysis was the individual patient. Between-group comparisons used Kruskal-Wallis tests for continuous variables and chi-square or Fisher exact tests for categorical variables, as appropriate. Pairwise comparisons were performed only after omnibus testing and were Bonferroni-adjusted. Analyses were based on the initial anticoagulation strategy selected at CRRT initiation, even if a later change in anticoagulation was required. Exact P values are reported according to the journal requirements. No multivariable adjustment, matching, propensity modeling, clustering adjustment, or imputation was performed; therefore, findings are interpreted as unadjusted associations rather than causal effects. Analyses were performed using IBM SPSS Statistics (version 26.0; IBM Corp., Armonk, NY, USA).

Results

Participant flow

A total of 150 critically ill adults were enrolled and classified according to the anticoagulation strategy used at CRRT initiation: 50 RCA, 50 heparin, and 50 no anticoagulation. All enrolled participants contributed to the baseline, clotted-circuit, and safety analyses; CLS and recorded-cost analyses were restricted to patients with eligible prospectively coded entries (Figure 1).

Figure 1 Participant flow through the study. A total of 150 adults with AKI requiring CRRT were enrolled and assigned by the treating team to RCA (n=50), systemic heparin (n=50), or no anticoagulation (n=50) at CRRT initiation. All enrolled participants contributed to the baseline, clotted-circuit, and safety analyses. CLS analyses included only participants with at least one recorded malfunction-related circuit-lifespan value (RCA, n=14; heparin, n=19; no anticoagulation, n=25). AKI, acute kidney injury; CLS, circuit lifespan; CRRT, continuous renal replacement therapy; RCA, regional citrate anticoagulation.

Study population

Illness-severity scores were similar across groups, but age and baseline bleeding-risk characteristics differed, consistent with clinician-directed allocation (Table 1). Median age was 73 [66.2–81.5] years in the RCA group, 70 [55–76.8] years in the heparin group, and 70 [61–80] years in the no-anticoagulation group (P=0.03). HAS-BLED score ≥3 occurred in 20/50 (40%) RCA patients and 28/50 (56%) no-anticoagulation patients, but in none of the heparin patients (P<0.001). Pre-existing gastrointestinal (GI)/retroperitoneal bleeding and pre-existing thrombocytopenia were also more common in the citrate and no-anticoagulation groups than in the heparin group.

Circuit performance

Across the cohort, 399 CRRT circuits were used over 9,490 hours of therapy (RCA: 107 circuits/2,697 hours; heparin: 131 circuits/3,012 hours; no anticoagulation: 161 circuits/3,781 hours). At least one clotted circuit occurred in 12/50 (24%) RCA patients, 18/50 (36%) heparin patients, and 24/50 (48%) no-anticoagulation patients (overall P=0.044). Median clotted circuits per patient were 0 [0–0], 0 [0–1], and 0 [0–2], respectively (overall P=0.03), and the Bonferroni-adjusted pairwise comparison identified RCA versus no anticoagulation (P=0.03) (Table 2, Figure 2).

Figure 2 Proportion of participants with at least one clotted circuit across anticoagulation strategies. Clotted circuits were recorded in 12/50 (24%) RCA patients, 18/50 (36%) heparin patients, and 24/50 (48%) no-anticoagulation patients (overall P=0.044). RCA, regional citrate anticoagulation.

CLS

The prospectively coded CLS variable was available for 14 RCA patients, 19 heparin patients, and 25 no-anticoagulation patients because it was recorded only when at least one malfunction-related circuit termination occurred. Median CLS among eligible participants was 20 [13.5–25] hours with RCA, 12 [8.5–23.5] hours with heparin, and 10 [6–16] hours with no anticoagulation (overall P=0.03). In Bonferroni-adjusted pairwise testing, RCA versus no anticoagulation yielded P=0.03 (Table 3).

Safety outcomes

Overall, complications captured during the index CRRT course occurred more frequently in the citrate group (44/50; 88%) than in the heparin group (27/50; 54%) or the no-anticoagulation group (35/50; 70%) (overall P<0.001) (Table 4). In the RCA group, ionized hypocalcemia occurred in 37/50 (74%) and citrate toxicity in 8/50 (16%). ECG changes attributed to hypocalcemia were documented in 3/50 (6%) citrate-treated patients.

Bleeding

Bleeding was observed only in the systemic heparin group (5/50; 10%) and did not occur in the citrate or no-anticoagulation groups (overall P=0.006). No intracranial, fatal, or life-threatening bleeding was recorded. Bleeding events included minor oozing around a tracheostomy site (n=3), epistaxis (n=1), and GI bleeding with hemoglobin decline (n=1); heparin was discontinued in all affected patients (Figure 3).

Figure 3 Bleeding incidence across anticoagulation strategies. Bleeding events occurred only in the systemic heparin group (5/50, 10%; overall P=0.006), and no intracranial or life-threatening bleeding was recorded. RCA, regional citrate anticoagulation.

Thrombocytopenia and HIT probability

Thrombocytopenia occurred in 13/50 (26%) in the citrate group, 16/50 (32%) in the heparin group, and 21/50 (42%) in the no-anticoagulation group (overall P=0.23). Intermediate-to-high probability HIT scores were documented in 10/50 (20%) heparin-treated patients (overall P<0.001), while low-probability HIT scores were recorded in 6/50 (12%) heparin-treated patients (overall P=0.002).

Economic and treatment interruption outcomes

Hypotension leading to interruption of dialysis occurred in 14/50 (28%) patients in the citrate group, 5/50 (10%) in the heparin group, and 14/50 (28%) in the no-anticoagulation group (overall P=0.043). Recorded 72-hour cost estimates were available only for patients with a non-zero prospectively coded cost entry (RCA n=11, heparin n=17, no anticoagulation n=24). Median recorded cost was 3,760 [2,460–3,760] SAR in the RCA group, 2,460 [2,460–3,360] SAR in the heparin group, and 2,460 [1,560–2,460] SAR in the no-anticoagulation group (overall P=0.006) (Table 5). Because this field was not applicable to patients without recorded clotted-circuit cost entries, it should not be interpreted as a whole-cohort economic comparison.

Discussion

In this prospective multicenter observational study of critically ill adults receiving CRRT, reanalysis of the recovered patient-level dataset confirmed that RCA was associated with a lower clotted-circuit burden than no anticoagulation. Median recorded CLS among eligible malfunction-related cases was also longer with RCA than with no anticoagulation. Bleeding remained confined to the heparin group, whereas citrate was accompanied by frequent biochemical complications.

These findings are broadly consistent with randomized trials and meta-analyses showing that citrate-based anticoagulation can preserve circuit patency while reducing bleeding compared with systemic heparin in many intensive care settings (12-16). In our cohort, the clearest signal remained the contrast between RCA and no anticoagulation. That comparison is clinically relevant because no-anticoagulation CRRT is often chosen for patients with perceived high bleeding risk, yet repeated circuit loss can reduce delivered therapy and increase bedside workload (7). These findings should also be interpreted within contemporary CRRT nomenclature, RCA implementation, and circuit-management literature (22-27).

Systemic heparin remains attractive because it is inexpensive, familiar, and easy to titrate, but it exposes patients to systemic anticoagulation at a time when coagulopathy, recent procedures, and thrombocytopenia are common (10). Although bleeding events in this cohort were not catastrophic, they occurred only in the heparin group and prompted discontinuation of heparin in all affected patients. Because only five bleeding events occurred, Bonferroni-adjusted pairwise Fisher tests yielded P=0.17 for RCA versus heparin and P=0.17 for heparin versus no anticoagulation, while RCA and no anticoagulation were identical (P>0.99). The clinical pattern nevertheless remained directionally consistent with prior literature favoring RCA in patients at increased bleeding risk (12-16).

The metabolic consequences of citrate were clinically prominent. Nearly three-quarters of citrate-treated patients developed ionized hypocalcemia, and 16% met criteria for citrate toxicity. Most events were manageable with protocolized calcium replacement and laboratory monitoring, but these findings reinforce that RCA should be used in centers that can reliably monitor ionized calcium and acid-base status, recognize citrate accumulation early, and adjust or discontinue citrate promptly when needed (17-19,21).

Economic and treatment interruption outcomes: Hypotension leading to interruption of dialysis occurred in 14/50 (28%) patients in the citrate group, 5/50 (10%) in the heparin group, and 14/50 (28%) in the no-anticoagulation group (overall P=0.043) (Table 4). Exploratory pairwise Fisher exact testing yielded P=0.12 for RCA versus heparin, P>0.99 for RCA versus no anticoagulation, and P=0.12 for heparin versus no anticoagulation. Recorded 72-hour direct cost among participants with a non-zero prospectively coded cost entry differed across groups (overall P=0.006), with medians of 3,760 [2,460–3,760] SAR in the RCA group, 2,460 [2,460–3,360] SAR in the heparin group, and 2460 [1,560–2,460] SAR in the no-anticoagulation group. Because this field was coded only when clotting-related direct cost was applicable, it should not be interpreted as a whole-cohort economic comparison.

This study has several strengths, including its prospective multicenter design, the inclusion of an anticoagulation-free strategy, and the use of pragmatic bedside outcomes. Important limitations should also be recognized. Treatment allocation was clinician-directed rather than randomized, introducing confounding by indication. In fact, the citrate and no-anticoagulation groups contained more patients with high HAS-BLED scores and other baseline bleeding-risk features than the heparin group. Age also differed across groups. Residual confounding is therefore likely. In addition, the recovered study spreadsheet did not contain every baseline laboratory variable used in earlier manuscript drafts, so the revised manuscript prioritizes variables that were verifiable in the recovered patient-level dataset.

In summary, our data support RCA as a reasonable strategy for CRRT in critically ill adults when monitoring resources and trained staff are available, particularly compared with an anticoagulation-free approach. Future work should prioritize standardized allocation criteria, prospective adjustment for confounding, and health-economic analyses derived directly from patient-level cost data.

Conclusions

In critically ill adults with AKI receiving CRRT, RCA was associated with lower clotted-circuit burden than no anticoagulation and with longer recorded CLS among eligible participants. Compared with systemic heparin, RCA showed numerically lower clotting burden and longer recorded CLS, but pairwise P=0.46 and P=0.43, respectively. RCA was also associated with no observed bleeding events but required close biochemical monitoring because hypocalcemia and citrate toxicity were not uncommon. Because allocation was clinician-directed and baseline age and bleeding-risk profiles differed across groups, these findings should be interpreted as associations rather than causal effects.

Acknowledgments

We thank the nursing and dialysis teams at Cairo University (Kasr Al Ainy) and King Fahad Military Medical Complex for their support in protocol implementation and bedside monitoring during CRRT.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2026-0006/rc

Data Sharing Statement: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2026-0006/dss

Peer Review File: Available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2026-0006/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jeccm.amegroups.com/article/view/10.21037/jeccm-2026-0006/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Research Ethics Committee of the Faculty of Medicine, Cairo University (Kasr Al Ainy), Cairo, Egypt (approval No. md-195-2022), and by the Institutional Review Board of King Fahad Military Medical Complex, Dhahran, Saudi Arabia (AFHER-IRB-2022-024). Written informed consents were obtained from all participants and/or their legally authorized representatives prior to enrollment.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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