Pathogen-Reduced Red Blood Cells Are Safe in Cardiac Surgery: ReCePI Phase 3 Shows Noninferior AKI Rates

Highlights

– ReCePI, a phase 3 double-blind randomized trial, tested amustaline/glutathione pathogen-reduced red blood cells (PR-RBCs) versus conventional RBCs in patients undergoing cardiac or thoracic‑aorta surgery at elevated transfusion risk.

– The primary endpoint—acute kidney injury (AKI) within 48 hours (increase ≥0.3 mg/dL serum creatinine)—occurred in 29.3% of PR‑RBC recipients and 28.0% of conventional RBC recipients; the prespecified noninferiority criterion was met.

– Secondary safety signals were reassuring overall (similar hemoglobin nadirs; low rate of treatment‑emergent, low‑titer antibodies without hemolysis), although numerically more KDIGO stage III AKI occurred in the PR‑RBC arm (9.4% vs 4.3%; P = 0.075).

Background and clinical context

Transfusion of red blood cells (RBCs) remains lifesaving in cardiac surgery but carries low residual risks of transfusion-transmitted infection, emerging pathogens, and transfusion-associated graft-versus-host disease (TA‑GVHD). Standard mitigation strategies include donor testing, leukoreduction, and gamma irradiation for TA‑GVHD prevention, but each has limitations. Pathogen-reduction technologies aim to inactivate a broad spectrum of viruses, bacteria, parasites, and residual lymphocytes in blood components and could simplify or complement existing safeguards. For RBCs, the amustaline (also known as S‑303) plus glutathione (GSH) system chemically crosslinks and inactivates nucleic acids of contaminating organisms and leukocytes while attempting to preserve RBC integrity and function.

Cardiac surgery patients are an important population for evaluating safety of modified blood components. They frequently require transfusion, and postoperative acute kidney injury (AKI) is a common complication associated with worse outcomes. AKI after cardiac surgery has multifactorial causes (ischemia‑reperfusion, hemodynamic instability, nephrotoxins, hemolysis, transfusion‑related effects), so any novel RBC processing that could affect renal risk requires careful evaluation.

Study design and methods

ReCePI (ClinicalTrials.gov NCT03459287) was a phase 3, double‑blinded, randomized, noninferiority trial enrolling adult patients undergoing cardiac or thoracic‑aorta surgery judged to have an increased probability of RBC transfusion. Participants were randomized to receive either amustaline/GSH pathogen‑reduced red cells (PR‑RBCs) or conventional RBCs intraoperatively and for 7 days postoperatively.

The primary endpoint was the proportion of patients developing AKI within 48 hours after surgery, defined as an increase in serum creatinine of ≥0.3 mg/dL from baseline—consistent with KDIGO criteria. The noninferiority margin was set pragmatically as one half (50%) of the observed incidence in the conventional arm (that is, an upper bound of the 95% confidence interval for the treatment difference had to be <50% of the conventional arm incidence). Secondary endpoints included AKI by 7 days using KDIGO staging, hemoglobin nadir, transfusion exposures, adverse events (28 days), and development of treatment‑emergent red cell antibodies (75 days).

Between-group blinding covered clinical teams and outcome assessors; 581 subjects were randomized and 321 (55%) actually received study red cells and were analyzed as transfused recipients for the primary comparison. Baseline characteristics and surgical procedures were well balanced among transfused subjects.

Key findings

Primary outcome. Among transfused subjects, AKI within 48 hours occurred in 46 of 157 (29.3%) patients in the PR‑RBC arm and 45 of 161 (28.0%) in the conventional arm. The treatment difference was 0.7% (95% CI, −8.9% to 10.4%). The prespecified noninferiority criterion was met: the upper bound of the 95% CI (10.4%) was below the noninferiority margin (14.0%), and the noninferiority test produced P = 0.001.

Secondary renal endpoints. Using KDIGO staging through 7 days, AKI rates were similar (37.1% PR‑RBC vs 34.0% conventional; P = 0.53). However, KDIGO stage III events were numerically more frequent in the PR‑RBC arm (15 of 159 [9.4%]) versus the conventional arm (7 of 162 [4.3%]); this difference approached but did not reach conventional statistical significance (P = 0.075). The trial was not powered for comparisons of stage III events, so this signal should be interpreted cautiously.

Hematologic and transfusion-related outcomes. Hemoglobin nadir on day 3 after surgery was similar (median 8.6 g/dL [IQR 7.8–9.2] PR‑RBC vs 8.4 g/dL [IQR 7.8–9.3] conventional; P = 0.52), suggesting comparable oxygen‑carrying capacity and blood loss management between groups. Transfusion exposure overall and other perioperative variables were balanced between arms.

Immunogenicity and safety. Treatment‑emergent specific red cell antibodies developed in 5 of 159 (3.1%) PR‑RBC recipients; these were low‑titer and occurred without clinical or laboratory evidence of hemolysis. No substantial differences in adverse events were reported between groups over the 28‑day safety window reported in the study summary.

Interpretation of effect sizes and statistics

The primary analysis showed noninferiority of PR‑RBCs compared with conventional RBCs for early postoperative AKI risk in this cardiac surgery cohort. The point estimate of AKI difference was small (0.7%), and the confidence interval comfortably excluded the predefined margin. That said, the choice of a margin tied to a fraction of the observed conventional-arm incidence is unconventional and makes interpretation dependent on the actual event rate in the control group; trials with fixed absolute margins sometimes provide a clearer pretrial standard. The numeric imbalance in stage III AKI, though not statistically significant, warrants attention and further investigation because stage III events carry substantial morbidity.

Expert commentary and contextualization

Why was AKI selected as the primary endpoint? Cardiac surgery AKI is a sensitive, clinically relevant outcome potentially influenced by transfusion‑related factors (e.g., hemolysis, inflammatory mediators, storage lesion). If a processing method for RBCs adversely affected RBC integrity or provoked immune or inflammatory responses, renal complications could plausibly increase. Therefore, demonstrating noninferiority for AKI is an appropriate safety benchmark for adoption in this high‑risk population.

Strengths of the trial include randomized double‑blind design, pragmatic surgical population, clinically meaningful primary outcome, and appropriate follow‑up for antibody development. Important limitations include the fact that only 55% of randomized subjects were transfused and available for primary analysis, which could introduce imbalances related to transfusion triggers and exposure; the trial was not powered to detect small differences in severe AKI (stage III) or rare adverse events; and the noninferiority margin depended on the observed control event rate.

Mechanistically, amustaline/GSH targets nucleic acids and is expected to spare structural RBC proteins and membrane function when used according to validated manufacturing processes. The absence of clinically relevant hemolysis and comparable hemoglobin nadirs provide reassuring functional correlates. The emergence of low‑titer antibodies in a small proportion of PR‑RBC recipients is biologically plausible (exposure to processed RBC neoepitopes), but the lack of hemolysis and low titers argue against clinically meaningful alloimmunization in this setting; longer surveillance and larger exposure datasets remain important.

Regulatory and implementation considerations will go beyond safety and include manufacturing scalability, cost, compatibility with existing blood bank workflows, and potential impact on blood availability. Moreover, pathogen reduction could be an attractive strategy in regions at elevated risk of emerging transfusion‑transmitted pathogens or where rapid response to outbreaks is needed.

Conclusion and implications for practice

In the ReCePI phase 3 randomized trial, amustaline/glutathione pathogen‑reduced red blood cells were noninferior to conventional RBCs with respect to early postoperative AKI among cardiac and thoracic‑aorta surgery patients who required transfusion. Hematologic outcomes, overall adverse events, and immunogenicity were reassuring in the studied population. The suggestion of a higher rate of stage III AKI in the PR‑RBC arm, while not statistically definitive, highlights the need for continued vigilance and larger post‑marketing surveillance to exclude a small excess of severe renal events.

For clinicians and transfusion services, these data support consideration of PR‑RBCs as a viable safety‑enhancing option where available and approved. Decisions about broad implementation should integrate local epidemiology, cost‑effectiveness, supply chain logistics, and ongoing monitoring programs for rare or delayed adverse events.

Funding and trial registration

Trial registration: ClinicalTrials.gov NCT03459287. Funding and full author disclosures are reported in the published article (Sekela et al., Anesthesiology. 2025).

References

1. Sekela ME, Snyder EL, Welsby IJ, Toyoda Y, Alsammak M, Sodha NR, Beaver TM, Pelletier JPR, Gorham JD, McNeil JS, Sniecinski RM, Pearl RG, Nuttall GA, Sarode R, Reece TB, Benjamin RJ; and the ReCePI Study Collaborators. Transfusion of Amustaline/Glutathione Pathogen-reduced Red Blood Cells in Cardiac Surgery: A Randomized Phase 3 Clinical Trial. Anesthesiology. 2025 Nov 1;143(5):1196-1210. doi: 10.1097/ALN.0000000000005716. Epub 2025 Aug 12. PMID: 41085306; PMCID: PMC12513042.

2. Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney Int Suppl. 2012;2:1–138.

AI thumbnail image prompt

A high-resolution, realistic operating room scene: a cardiothoracic surgical team (surgeon and anesthesiologist) standing near a cardiac bypass machine, foreground showing two labeled blood bags—one marked ‘Pathogen‑reduced (Amustaline/GSH)’ and the other ‘Conventional’—soft focus background with monitors showing vital signs and a subtle semi‑transparent overlay of a 3D kidney icon and laboratory vials; cool clinical color palette, professional medical atmosphere, crisp detail on blood bags and labels.