Regional citrate anticoagulation combined with nafamostat mesylate for continuous kidney replacement therapy in septic acute kidney injury patients: protocol for a prospective, three-arm, randomised controlled study (RCNM-CKRT)

Abstract

Introduction

Extracorporeal circuit (EC) clotting remains a major challenge in continuous kidney replacement therapy (CKRT). While regional citrate anticoagulation (RCA) is recommended first-line, nafamostat mesylate (NM) offers an alternative with potential anti-inflammatory benefits. This trial aims to compare the effects of RCA, NM and their combination on EC lifespan during CKRT in critically ill acute kidney injury (AKI) patients with sepsis.

Methods and analysis

This is a single-centre, prospective, three-arm, open-label, randomised controlled trial. Critically ill adult patients with AKI with sepsis requiring CKRT will be enrolled. Participants will be randomly assigned (1:1:1) to receive RCA, NM or combined RCA+NM anticoagulation. The primary outcome is EC lifespan. Secondary outcomes include EC survival rates, patient mortality, inflammatory biomarker levels and safety events (eg, bleeding, citrate accumulation). The sample size of 258 patients (86 per group) was calculated to detect a significant difference in the primary outcome with 90% power. Analysis will follow the intention-to-treat principle, using Kaplan-Meier survival analysis and Cox regression for the primary outcome.

Ethics and dissemination

The RCNM-CKRT trial has been approved by the Biomedical Ethics Review Committee of West China Hospital, Sichuan University. We plan to present the results of our research at an international conference and publish in a peer-reviewed journal. The study data will be available on request, ensuring transparency and accessibility.

Trial registration number:

ChiCTR2600121436; Pre-results.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• This is an open-label three-arm randomised controlled trial that will compare three anticoagulation strategies (regional citrate anticoagulation (RCA), nafamostat mesylate (NM) and RCA+NM) during continuous kidney replacement therapy in sepsis patients with acute kidney injury.

• The primary outcome is the lifespan of the EC. Secondary outcomes include circuit survival rates at 24hours, 48 hours and 72 hours, safety events, as well as long-term patients’ outcomes, providing a comprehensive assessment of how different anticoagulation methods affect extracorporeal circuit (EC) lifespan and patient outcomes.

• The follow-up period for the primary outcome is 72 hours, ensuring high data integrity and a low risk of loss to follow-up.

• The lifespan of the EC is an objective, continuous and easily recordable endpoint that is less susceptible to subjective judgement by observers.

• A limitation of this open-label study is that blinding could not be implemented due to the different anticoagulants, drug dosages and monitoring methods required for each anticoagulation strategy, as well as for safety considerations.

Introduction

Continuous kidney replacement therapy (CKRT) serves as a cornerstone therapy for critically ill patients with acute kidney injury (AKI), playing a vital role in managing conditions such as severe acute pancreatitis and sepsis.¹ During CKRT, patient blood is circulated through an extracorporeal circuit (EC) for purification. However, contact with the foreign surfaces of the circuit and filter membrane inevitably activates the intrinsic coagulation pathway, extrinsic coagulation pathway, as well as platelets. These three are not isolated pathways but rather promote and amplify each other, triggering the coagulation cascade.^{2 3} Ultimately, this leads to premature EC failure, reduced treatment efficiency, increased resource utilisation and higher costs. Hence, establishing an effective anticoagulation protocol is a cornerstone of successful CKRT, crucial for ensuring treatment continuity and improving clinical outcomes.⁴

Regional citrate anticoagulation (RCA) is recommended as the first-line anticoagulation strategy for CKRT due to its efficacy and safety.^5–7 Ionised calcium (iCa²⁺), also known as coagulation factor IV, is essential for multiple steps in the coagulation process and platelet interactions. Citrate achieves efficient regional anticoagulation within the EC by reversibly chelating iCa²⁺. Crucially, the safety of RCA relies on a physiological closed-loop: the calcium-citrate complex (CCC) formed is rapidly metabolised by the liver. The CCC is fully metabolised in the tricarboxylic acid cycle, releasing the bound iCa²⁺, thereby restoring systemic calcium homeostasis and underpinning the regimen’s favourable safety profile.⁸

Nafamostat mesylate (NM) is a broad-spectrum serine protease inhibitor that provides anticoagulation by targeting multiple points in the coagulation cascade. It inhibits several key coagulation factors, including thrombin, factor VIIa, factor Xa and factor XIIa, demonstrating potent anticoagulant efficacy. NM is primarily metabolised by the liver and has a short half-life of approximately 8–10 minutes,^{9 10} exerting minimal effect on systemic coagulation.^{11 12} The favourable pharmacokinetic property makes it an ideal anticoagulant for ECs, and it is widely used in Japan and Korea.¹³

Beyond its anticoagulant effects, NM can also inhibit kallikrein, thereby preventing the generation of bradykinin. Recent studies further indicate that NM can suppress the formation of neutrophil extracellular traps and the release of various inflammatory mediators.^{14 15} Collectively, these actions suggest that NM may potentially offer additional benefit for critically ill sepsis patients in a systemic inflammatory state.^{16 17} Furthermore, recent studies indicate that circuits anticoagulated with NM achieve a lifespan comparable to those with RCA, demonstrate superior metabolic safety^18–20 and can reduce levels of inflammatory mediators in patients.¹⁶

In critically ill patients with sepsis, systemic inflammatory response is a common pathophysiological feature. Inflammatory mediators can directly activate endothelial cells and platelets, downregulate natural physiological anticoagulant pathways and upregulate tissue factor expression. Collectively, these actions shift the blood towards a procoagulant and hypercoagulable state, which may compromise the efficacy of a single anticoagulation strategy. Consequently, combining a standard anticoagulant (RCA) with an agent possessing anti-inflammatory potential (NM) leverages distinct anticoagulant mechanisms, which may further extend EC lifespan. RCA and NM act through distinct and potentially complementary mechanisms: citrate provides regional anticoagulation by chelating ionised calcium within the extracorporeal circuit, whereas NM inhibits multiple coagulation-related serine proteases. Previous retrospective studies in other hypercoagulable populations undergoing CKRT have suggested that adding a systemic anticoagulant to RCA may prolong circuit or filter lifespan.^{21 22} However, these studies evaluated heparin-based combinations rather than RCA+NM and no prospective studies have directly compared the effects of RCA, NM and their combination on EC lifespan. Therefore, this study aims to conduct a parallel-group, three-arm, randomised controlled trial (RCT) in critically ill patients with AKI with sepsis. The primary objective is to evaluate the EC lifespan of three anticoagulation strategies—RCA, NM and their combination (RCA+NM). Secondary objectives include assessing their effects on systemic inflammation levels and patient outcomes. This trial seeks to provide evidence for optimising clinical anticoagulation strategies in this population.

Objectives and aims

Primary objective

To compare the EC lifespan of RCA, NM and RCA+NM in critically ill patients with AKI with sepsis undergoing CKRT. EC lifespan is defined as the duration (hours) from the initiation of CKRT to the time when therapy is mandatorily discontinued and the entire EC set (including the filter, tubing and venous chamber/drip chamber) is replaced due to circuit clotting.

Secondary objective 1

To compare 24 hours, 48 hours and 72 hours EC survival rates among different anticoagulants.

Secondary objective 2

To assess the safety profiles of the different anticoagulation modalities during CKRT.

Secondary objective 3

To evaluate the effects of different anticoagulation modalities on clinical outcomes in patients with CKRT .

Secondary objective 4

To examine the effects of different anticoagulation modalities on systemic inflammatory levels in patients CKRT .

Methods and analysis

Design and setting

The ‘Regional Citrate Anticoagulation Combined with Nafamostat Mesylate for Continuous Kidney Replacement Therapy in Septic Acute Kidney Injury Patients: A Prospective, Open-Label, Three-Arm, Randomized Controlled Study (RCNM-CKRT)’ trial is an open-label randomised, three-arm, parallel-group trial conducted at West China Hospital of Sichuan University. This protocol has been prepared in accordance with the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) guidelines²³ (online supplemental file 1).

Participants

Eligible patients need to fulfil all inclusion and none of the exclusion criteria. Inclusion criteria include (1) indication for CKRT (meeting Kidney Disease Improving Global Outcomes 2012 (KDIGO 2012) AKI Stage 2–3, pH<7.20, serum potassium (K⁺)> 6.0 mmol/L, or diuretic-resistant fluid overload),²⁴ (2) 18–90 years old, (3) meeting the Sepsis-3 diagnostic criteria (a suspected or confirmed infection accompanied by an acute increase in the Sequential Organ Failure Assessment (SOFA) score of ≥2 points from baseline),²⁵ (4) anticipated intensive care unit (ICU) care>72 hours and projected CKRT treatment duration>48 hours and (5) written informed consent. Patients were excluded if they had contraindications to RCA or NM, such as severe hepatic insufficiency,²⁶ hyperlactatemia. Other key exclusion criteria comprised severe coagulopathy (defined as Plt count<30×10⁹/L, INR>2.5 or activated partial thromboplastin time (APTT)>60 s), pre-existing end-stage kidney disease (ESKD) and the concurrent use of other anticoagulants. Detailed criteria with specific parameters are presented in Box 1.

Box 1. Inclusion and exclusion criteria.

Inclusion

• Indication for CKRT (meeting KDIGO AKI Stage 2–3 (Stage 2 AKI: 2.0–2.9 fold increase of Scr from baseline or urine output<0.5 mL/kg/h for ≥12 hours; Stage 3 AKI: urine output<0.3 mL/kg for>24 hours and/or threefold increase of serum creatinine (Scr) from baseline or Scr>4 mg/dL with acute increase of>0.5 mg/dL), pH<7.20, serum K⁺>6.0 mmol/L, or diuretic-resistant fluid overload).

• 18-90 years old, regardless of gender.

• Meeting the Sepsis-3 diagnostic criteria.

• Anticipated ICU stay>72 hours and projected CKRT treatment duration>48 hours.

• Written informed consent.

Exclusion

• Contraindications to either RCA or NM use (eg, severe hepatic insufficiency: Child-Pugh score≥10, lactate>4 mmol/L, or allergy to either anticoagulant).

• Patient with ESKD with previous dialysis dependence.

• Severe coagulopathy: Plt<30 × 10⁹/L, or INR>2.5, or APTT>60 s.

• Active bleeding.

• Concurrent use of another anticoagulant.

• Pregnancy or lactation.

• History of solid organ transplantation within the past 12 months or scheduled for transplantation within the next 3 months.

• Uncorrectable critical organ dysfunction prior to enrolment: Refractory hypotension (systolic blood pressure<90 mmHg for>2 hours despite vasopressor support), or severe hypoxemia (PaO₂<60 mmHg), or hypercalcemia.

• Concurrent use of other extracorporeal blood purification therapies during the study period (eg, endotoxin/cytokine adsorption, haemoperfusion, plasma exchange or extracorporeal membrane oxygenation.

• AKI primarily attributed to specific renal pathologies such as bilateral renal artery stenosis/occlusion, acute interstitial nephritis, urinary tract obstruction or acute glomerulonephritis.

• Participation in another interventional clinical trial within the past 3 months.

• Any other condition that, in the opinion of the investigator, poses an unacceptable risk to the patient or could confound the trial results.

Consent process

After initial screening confirms a patient’s potential eligibility, the attending physician or a designated sub-investigator will approach the patient or their Legally Authorised Representative to discuss the study. This discussion will take place prior to the initiation of the study’s CKRT protocol, ensuring a decision can be made without delaying clinically indicated care. Process of informed consent: The investigator will provide a thorough explanation of the study using the approved patient information sheet. This explanation will cover, in lay language: the study’s purpose, design (three-arm randomised trial) and duration. The procedures involved, including random assignment to one of three anticoagulation methods and any specific blood draws for research. Potential benefits and risks (eg, specific risks of hypocalcemia, bleeding or allergic reaction related to RCA or NM). Written informed consent will be obtained by the investigator using the ethics committee-approved consent form. A copy of the signed form will be provided to the participant or legally authorized representative (LAR), and the original will be kept in the study site file.

Randomisation process

Eligible patients who have provided written informed consent will be randomised in a 1:1:1 ratio to one of the three study groups: the RCA group, the NM group or the RCA+NM combination group. Randomisation will be performed using a computer-generated randomisation sequence prepared by an independent researcher who is not involved in patient enrolment or clinical management. CKRT will commence immediately following randomisation. The study procedure is summarised as shown in figure 1.

Figure 1. The flow diagram of the study. CKRT, continuous kidney replacement therapy; EC, extracorporeal circuit; ICU, intensive care unit; NM, nafamostat mesylate; RCA, regional citrate anticoagulation; SOFA.Sequential Organ Failure Assessment.

Management of CKRT

To ensure uniformity of treatment among sites and between both treatment groups, the following are the standardised baseline prescriptions and monitoring plans. All patients will be treated using the continuous veno-venous haemodiafiltration mode. The prescribed dose was 30–35 mL/kg/h to achieve a delivered dose of 25mL/kg/h^{27 28}.

All replacement fluid is administered in post-dilution mode. The initial anticoagulant doses are as follows:

• NM group: loading dose: 0.1–0.5 mg/kg; maintenance dose: 0.1–0.5 mg/kg/h. Subsequently titrated within this range to maintain the post-filter APTT at 1.5–2.0 times the baseline value or at an absolute value of 45–60 s.

• RCA group: 180–200 mL/h (of 4% trisodium citrate). Subsequently titrated to maintain the post-filter ionised calcium concentration at 0.25–0.35 mmol/L.

• NM+RCA group: loading dose: 0.1–0.5 mg/kg; maintenance dose: 0.1–0.5 mg/kg/h+RCA 180–200 mL/h. The two anticoagulants will be titrated independently to maintain both the post-filter APTT target of 1.5–2.0 times the baseline value or 45–60 s and the post-filter ionised calcium target of 0.25–0.35 mmol/L.

During the CKRT, the dosage of RCA and NM will be adjusted independently according to their corresponding pharmacodynamic targets. Although the same starting dose ranges are used in the monotherapy and combination groups, the subsequent infusion rates are not fixed. In the combination group, NM and RCA will be titrated independently according to the post-filter APTT and ionised calcium targets, respectively.

Four types of CKRT machines (PrismafleX (Baxter International, USA), MultiFiltrate (Fresenius Medical Care, Germany), Aquarius (Nikkiso, Japan) and Plasauto (Asahi Kasei Medical, Japan)) will be randomly selected based on availability and proximity. In our institution, calcium-containing dialysis fluid (Chengdu Qingshanlikang, China) and calcium-containing replacement fluid (Chengdu Qingshanlikang, China) will be used among all groups to simplify the calcium supplementation process.²⁹ Additionally, 5% calcium gluconate will be administered as needed to maintain the systemic iCa² level above 1.0 mmol/L.

The blood flow rates are set at 180–200 mL/min for the NM group and 130–150 mL/min for the RCA and combination groups. Serum electrolyte concentrations and acid-base status will be monitored systematically at CKRT initiation, 2 hours, 6 hours post-initiation and subsequently at 6-hour intervals. Blood gas analysis will be performed using a Roche cobas b 123 POC system. For patients receiving RCA anticoagulation, circuit iCa²⁺ will be additionally monitored at 2 hours and 6 hours post-initiation, and subsequently at six hourly intervals. For patients receiving NM anticoagulation, systemic and post-hemofilter APTT will be additionally monitored at 6 hours post-initiation and then every 12 hours thereafter. In the combined anticoagulation group, both iCa²⁺ and APTT will be monitored. Treatment parameters will be individualised and titrated as needed to achieve the best therapeutic response, according to the physician’s clinical evaluation.

The decision to discontinue the EC because of coagulation will be made collaboratively by nurses and physicians, based on integrated evaluation of transmembrane pressure, as well as the extent and number of visible clots in the venous chamber and filter. EC will change every 72 hours (according to the recommendations of the manufacturer). Due to the differences in anticoagulant agents, dosages and monitoring methods across the various anticoagulation modalities, blinding cannot be implemented; therefore, this study is designed as an open-label trial.

Patient and public involvement

Neither participants nor the public will be involved in the study’s design, conduct or dissemination.

Outcomes

The primary outcome of the study is EC lifespan. EC lifespan is defined as the duration (in hours) from CKRT initiation until therapy is mandatorily discontinued due to clotting within the EC (including the filter, tubing and venous chamber), requiring a full circuit exchange. (*Note: According to the manufacturer’s instructions, the maximum use time for the EC is 72 hours.)

Secondary outcomes include:

• 24-hour, 48-hour, 72-hour EC survival rate.

• ICU mortality, in-hospital mortality, 28-day mortality and 90-day mortality.

• ICU and hospital length of stay.

• 28-day dialysis liberation rate (defined as freedom from any RRT for 7 consecutive days after CKRT cessation).

• Total duration of CKRT therapy.

• Levels of inflammatory biomarkers (eg, C-reactive protein (CRP), procalcitonin (PCT)) within 72 hours after initiation of CKRT.

• Patient’s SOFA score at 72 hours after the initiation of CKRT.

• New thrombotic events in the patient throughout the functional period of this CKRT circuit.

• Adverse events such as citrate accumulation, bleeding.

To monitor patient status, coagulation parameters (APTT, prothrombin time (PT)), full blood count (FBC), inflammatory markers (interleukin-6 (IL-6), CRP, PCT), kidney function (Scr, blood urea nitrogen (BUN)), Acute Physiology and Chronic Health Evaluation (APACHE) II score, SOFA score, etc, will be measured at baseline (48 hours pre-CKRT initiation) and 72 hours post-CKRT initiation.

All blood samples will be sent to the hospital’s clinical laboratory for testing. IL-6 and PCT will be measured using electrochemiluminescence immunoassay on the cobas e 801 analyzer, and CRP will be measured using immunoturbidimetry on the Beckman Coulter AU5800 chemistry analyzer.

Trial safety management and adverse event monitoring

Throughout the study period, any untoward medical occurrence in a participant will be documented as an adverse event (AE). For each AE, a complete record will be made. This includes a detailed description of the event with its date and time of onset, symptomatology, clinical course, and the outcome or resolution status (eg, resolved, resolving, ongoing, with sequelae, or fatal). The relationship to the study intervention (RCA and/or NM) will be estimated by the investigator as related, possibly related or unrelated. Safety will be actively assessed using pre-specified endpoints, which are considered AE with a potential causal relationship to the study interventions (table 1).

Table 1. Definitions and safety endpoints.

Safety endpoint	Operational definition
Citrate accumulation	Presence of any of the following: 1. iCa<0.9 mmol/L despite ongoing calcium infusion; 2. total Ca/iCa>2.5; 3. metabolic acidosis (pH<7.2 and/or BE < −5 mmol/L); 4. elevated anion gap>11 mmol/L.
Metabolic acidosis	pH<7.2 and HCO₃⁻ <20 mmol/L (excluding lactic acidosis).
Metabolic alkalosis	pH>7.5 and HCO₃⁻ >30 mmol/L.
Hypocalcemia	Systemic iCa level<0.9 mmol/L.
Bleeding event	Any clinically overt bleeding (eg, gastrointestinal). The need for transfusion will be specifically recorded.
Abnormally prolonged APTT	APTT>160 s.
Other CKRT-related AEs	Events such as dizziness/hypotension, myalgia/cramps, nausea/vomiting attributed to the extracorporeal therapy.

AE, adverse event; APTT, activated partial thromboplastin time; BE, base excess; CKRT, continuous kidney replacement therapy; iCa, ionised calcium; tCa, total calcium.

Statistical analysis

For baseline characteristics, continuous variables (eg, age, weight, BMI (body mass index), RBC count, plt count, APTT): data will be presented as mean±SD (SD) or median (IQR). For comparisons across the three groups, a one-way analysis of variance (ANOVA) will be used if the data are normally distributed and exhibit homogeneity of variances. Otherwise, the non-parametric Kruskal-Wallis H test will be employed. Categorical variables (eg, use of vasoactive drugs, mechanical ventilation, comorbidities): data will be presented as n/%. Group comparisons will be performed using the Pearson’s chi-square test or Fisher’s exact test.

The analysis of primary outcome (EC lifespan) will use both the intention-to-treat (ITT) and per-protocol (PP) analysis sets to comprehensively evaluate the effects of the different anticoagulation strategies. The primary analysis will be based on the ITT set to preserve the between-group balance achieved by randomisation, with its results reflecting effectiveness in clinical practice. The PP set analysis will serve as a key sensitivity analysis to assess the theoretical efficacy under ideal protocol adherence.

Circuits that were electively changed at 72 hours without prior clotting were treated as censored observations at the time of change. Similarly, circuits discontinued for non-coagulation reasons (eg, patient off-unit procedures, death or withdrawal) were also censored at the time of termination. Given that EC lifespan data may be ‘censored’ due to non-clotting reasons, Kaplan-Meier survival curves and the Log-rank test will be used to compare differences among the three groups, to directly display the unadjusted differences in circuit survival time among the different anticoagulation strategies.

To adjust the influence of baseline confounding factors (eg, blood flow rate (BFR), SOFA score, APACHE II score, coagulation function, haemotocrit, plt count) and more accurately assess the independent impact of different anticoagulation strategies on EC lifespan, univariate Cox regression analyses will be conducted to screen candidate variables.

A multivariable Cox proportional hazards regression model will be constructed to calculate the HR and its 95% CI. We will prioritise the inclusion of those with p<0.1 in univariate Cox regression and those considered clinically important (eg, BFR, platelet counts) to ensure that each covariate is supported by at least 10 events (the 10 Events Per Variable rule).³⁰ Prior to fitting the multivariable Cox model, Schoenfeld residual plots will be used to assess whether the model meets the proportional hazards assumption. For the analysis of the primary endpoint, missing data will not be imputed.

For outcomes such as 24-hour, 48-hour and 72-hour EC survival rates, bleeding events, incidence of citrate accumulation, ICU mortality and in-hospital mortality, descriptive statistics will be primarily used, reporting the number of events and incidence rate (n, %) for each group. The chi-square test or Fisher’s exact test will be applied for three-group comparisons. If the total number of events for a particular outcome is fewer than 10 events, only descriptive reporting will be provided, and formal between-group hypothesis testing will be omitted to avoid unreliable conclusions due to sparse data. For continuous measures such as length of ICU stay, total hospital stays, total duration of CKRT and levels of CRP, PCT and IL-6: If data meet the assumptions of normality and homogeneity of variance, one-way ANOVA will be used for three-group comparison, followed by Tukey’s HSD post-hoc test if indicated. If parametric assumptions are not satisfied, the non-parametric Kruskal-Wallis H test will be employed. For inflammatory biomarkers (CRP, PCT, IL-6), a pre-specified subgroup analysis will be performed according to the actual duration of CKRT (≤24 h vs >24 h), with descriptive and comparative analyses conducted separately within each subgroup. We hypothesise that a sufficient treatment duration is a prerequisite for observing potential anti-inflammatory effects of the anticoagulation regimens. Secondary outcome analyses will be performed on both the ITT and PP sets, with the ITT set serving as the primary basis for reporting. Safety analyses will be conducted on the Safety Set, which includes all randomised patients who received at least one dose of the assigned study anticoagulant. Unless otherwise specified, analyses will be based on available case data without statistical imputation of missing values. All safety events will be thoroughly documented and reported.

All statistical analyses in this study will be performed using the professional statistical software R (V.4.5.1). Two-sided tests will be employed, and statistical significance is defined as a p value<0.05.

Sample size

The sample size calculation was based on the primary outcome of EC lifespan. According to a preliminary retrospective study conducted at this centre (West China Hospital of Sichuan University), the mean EC lifespans were 44.23±24.77 hours for the RCA group, 34.87±22.35 hours for the NM group and 45.48±24.01 hours for the RCA+NM combination group. The observed circuit lifespan in the RCA group was consistent with published articles.^{31 32} In contrast, published data on NM anticoagulation are limited and heterogeneous, with reported lifespans ranging from 23.4 to 41 hours¹⁹.²⁰ To ensure our sample size calculation accurately reflects the situation at this centre, we ultimately used data from our centre’s retrospective study for estimation. With a two-sided type I error (α) of 0.05, a power (1−β) of 90%, an assumed attrition rate of 10% and a balanced three-arm (1:1:1) design, the calculation was performed in PASS 15.0.5. The analysis yielded a requirement of 86 patients per group. Thus, a total of 258 participants will be enrolled in the trial.

Ethics and dissemination

The study is conducted in compliance with the Declaration of Helsinki and has received ethical approval from the Institutional Review Board of West China Hospital (Approval No: 2026-138). It has been registered at https://www.chictr.org.cn (ChiCTR2600121436) on 31 March 2026. It is important to note that neither participants nor the public will be involved in the study’s design, conduct or dissemination. We will publish the results of our research after the study. The study data will be available on request, ensuring transparency and accessibility. The enrolment of patients is scheduled to commence at a university-affiliated medical centre in April 2026. The participant recruitment will be completed in April 2028. An individual researcher will monitor and review the randomisation process during the entire enrolment of the study.

Discussion

The RCNM-CKRT trial is a prospective, randomised, three-arm, clinical trial with the aim to investigate whether the addition of NM to RCA anticoagulation can further extend EC lifespan and reduce circuit clotting compared with either agent alone. For critically ill patients requiring CKRT, regional citrate anticoagulation is recommended as the first-line anticoagulant strategy by the KDIGO guidelines due to its favourable efficacy and safety profile.^{24 33} A central challenge in managing critically ill sepsis patients is the inflammation-associated coagulopathy, wherein inflammatory mediators directly tip the haemostatic balance towards a hypercoagulable state. This background may compromise the effectiveness of conventional anticoagulants. As a serine protease inhibitor, NM mesylate possesses dual properties of anticoagulation and anti-inflammation conferred by its mechanism of action. In addition to its anticoagulant effect, previous studies have indicated that NM can mitigate oxidative stress and reduce inflammatory mediators’ levels in septic patients undergoing CKRT, which contributes to improved clinical outcomes.^{16 17} Moreover, some recent studies have suggested that EC lifespan with NM anticoagulation is comparable to that with RCA.^{18 34}

This study has several limitations. First, as a single-centre trial, the findings may be influenced by local clinical practices, patient demographics, and nursing expertise, which could affect the generalisability of the results to other intensive care settings. Second, despite a standardised protocol, variations in the practical execution of anticoagulant administration and circuit management between clinicians are inevitable and constitute a potential source of performance bias. Finally, the definition of EC lifespan, though objective, requires clinical judgement to confirm clotting, which introduces a degree of assessment bias that was not formally blinded due to the nature of the interventions. These limitations highlight the need for future multi-centre studies with larger sample sizes and serial biomarker assessments to confirm and extend our findings.

In summary, this three-arm RCT aims to provide prospective evidence comparing the effects of RCA, NM, and their combination on circuit lifespan during CKRT in critically ill patients with systemic inflammation. As well as, to elucidate the potential immunomodulatory effects of NM beyond anticoagulation and to validate its additional benefits in critically ill patients with AKI and sepsis, by comparing differences in post-CKRT inflammatory biomarker levels among the three groups: RCA, NM and their combination. The results of this trial will guide the selection of anticoagulation regimens and establish a foundation for future multicentre investigations and refined protocols in patient with systemic inflammation.

Data availability statement

Data are available upon reasonable request.