This multicenter, randomized, open-label, active-controlled, parallel-group trial will evaluate the efficacy and safety of nafamostat mesylate anticoagulation compared with regional citrate anticoagulation in adult patients with sepsis-associated acute kidney injury requiring continuous renal replacement therapy. Eligible participants will be randomized in a 1:1 ratio to receive either nafamostat mesylate or regional citrate anticoagulation during CRRT. The primary outcome is MAKE30, a composite of all-cause mortality, new or ongoing renal replacement therapy, or persistent renal dysfunction within 30 days after randomization. Secondary outcomes include filter lifespan, CRRT-free days, 30-day all-cause mortality, renal replacement therapy status, persistent renal dysfunction, ICU and hospital mortality, length of stay, CRRT duration, major bleeding, new bloodstream infection during ICU stay, SOFA score, number of filters used, and protocol-defined safety outcomes.
Age 18 to 90 years, inclusive, regardless of sex.
Meets Sepsis 3.0 diagnostic criteria and develops acute kidney injury within 7 days after the diagnosis of sepsis.
Expected duration of CRRT treatment >48 hours.
Written informed consent obtained.
Requirement for therapeutic anticoagulation, such as pulmonary embolism or deep vein thrombosis.
Contraindication to systemic anticoagulation.
Hemolytic uremic syndrome or thrombotic thrombocytopenic purpura.
Acute liver failure and/or shock with persistent severe lactic acidosis, defined as two consecutive measurements of pH <7.2 lasting for more than 2 hours, with lactate >72.1 mg/dL [8 mmol/L].
Parallel
Citrate anticoagulation
DrugCitrate (3% or 4% trisodium citrate solution) is a regional anticoagulant that chelates ionized calcium in the extracorporeal circuit, thereby inhibiting the coagulation cascade. The control product is supplied as an injection solution. It should be stored in a tightly closed container. During CRRT, citrate is infused pre-filter (before the blood pump) and requires separate systemic calcium replacement to maintain normal ionized calcium levels.
Nafamostat Mesylate
DrugNafamostat mesylate is a synthetic serine protease inhibitor with a very short half-life (approximately 8 minutes). It acts locally as an anticoagulant by inhibiting thrombin, factor Xa, and other coagulation proteases. The investigational product is supplied as a lyophilized powder for injection. It must be protected from light and stored below 25 °C. For use during continuous renal replacement therapy (CRRT), the powder is reconstituted and administered as a continuous pre-filter infusion.
Major Adverse Kidney Events at Day 30 (MAKE30)
MAKE30 is a composite endpoint defined as the occurrence of any of the following within 30 days after randomization: 1. All-cause death: the participant dies within 30 days after enrollment. If death has not occurred, proceed to the next criterion. 2. New initiation of or persistent need for renal replacement therapy: on Day 30 after enrollment, the participant still requires any form of renal replacement therapy, including CRRT, intermittent hemodialysis, sustained low-efficiency daily dialysis/continuous intermittent renal replacement therapy, peritoneal dialysis, and related modalities. Even if the participant had been temporarily weaned from therapy during the interval, the event is considered to have occurred if renal replacement therapy is still required on Day 30. If this criterion is not met, proceed to the next criterion. 3. Persistent renal dysfunction: on Day 30, the participant's serum creatinine level reaches or exceeds twice the baseline value.
Mean filter lifespan
Defined as the time from CRRT initiation to technical filter failure or nontechnical termination. Nontechnical termination events will be censored in the primary analysis. 1. Technical filter failure (meeting any of the following): a. transmembrane pressure (TMP) persistently \> 250 mmHg and not reversible after flushing or adjusting blood flow rate; b. visible circuit clotting at grade 2-3 (grade 0: no visible clotting; grade 1: mild fibrin deposition; grade 2: obvious clotting but the circuit remains functional; grade 3: severe clotting requiring immediate filter replacement); c. complete occlusion of the filter or circuit such that blood flow \> 100 mL/min cannot be maintained; or d. unplanned treatment interruption caused by circuit clotting. 2. Nontechnical termination (not counted as filter failure)
CRRT-free days through Day 30
All-cause mortality by Day 30
New or Ongoing Renal Replacement Therapy
Requirement for any form of renal replacement therapy at days 27-33 after enrollment, including CRRT, intermittent hemodialysis, slow low-efficiency daily dialysis, sustained low-efficiency dialysis, peritoneal dialysis, or any other form of renal replacement therapy.
Metabolic acidosis
Citrate toxicity
Defined as total calcium/ionized calcium ratio \> 2.5 or worsening metabolic acidosis
Metabolic alkalosis
Hypercalcemia
Defined as serum total calcium \> 2.75 mmol/L
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Jianfeng Xie
Lead sponsor
Southeast University, China
Sponsor institution
Southeast University, China
Collaborator
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