Dose and modality of cytokine-adsorbing hemofilters for continuous renal replacement therapy: insights from study on the relationship between the adsorption effect and the filtration flow rate

Dear editor,

I read with great interest the recent study by Kudo et al. [1], in which the investigators explored the relationship between the adsorption effect and the filtration flow rate in a cytokine-adsorbing hemofilter (CAH) during continuous renal replacement therapy (CRRT), by systematically analyzing polymethyl methacrylate (PMMA) and polyethylenimine-coated polyacrylonitrile (AN69ST) membrane performance across varying dialysate (QD) and filtration (QF) flow rates (< 600 mL/h convection volume), the study reveals two key phenomena: (1) membrane-independent enhancement of small solute (creatinine) clearance with increasing QD and QF and (2) stable cytokine (IL-6/IL-8) adsorption clearance across all tested flow configurations.

I would like to congratulate the authors, their exploratory work merits recognition for advancing our understanding of adsorption kinetics in CAH-CRRT, prompting insights on possible prescription optimization, warranting elaboration to contextualize its clinical implications:

the study revealed that in CAH-CRRT, the optimal target dose should be for the primary removal of small-molecular-weight substances since large-molecular-weight substances can be adequately removed under these conditions. This finding reinforces current CRRT dosing recommendations (20–25 mL/kg/h) for small solute management. This perspective is particularly relevant when considering the documented risks associated with high-volume hemofiltration strategies, including antimicrobial underdosing owing to altered pharmacokinetics and essential nutrient depletion, which are factors contributing to therapeutic failure and antimicrobial resistance development [2, 3].

The observed independence of cytokine adsorption from flow parameters challenges conventional modality selection rationales. While convective clearance theoretically enhances middle-molecule removal, clinical comparisons of continuous veno-venous hemofiltration (CVVH) versus continuous veno-venous hemodialysis (CVVHD) show no differences in mortality or renal recovery [4]. This study provides a novel explanation: adsorption-mediated cytokine clearance may achieve therapeutic thresholds regardless of modality, potentially explaining the historical importance of clinical outcomes.

Notably, compared with the PMMA filter, the AN69ST membrane exhibited superior adsorption clearance for IL-8 (46.2 versus 17.1 mL/min), with analogous differential performance in terms of IL-6 clearance (42.5 versus 32.4 mL/min). These experimental findings correlate with real-world evidence from Japanese insurance claims analysis, where AN69ST-based CRRT demonstrated improved intensive care unit (ICU) outcomes (mortality and length of stay) compared with those of composite controls (including PMMA/polysulfone membranes) [5]. Given the inclusion of PMMA in the comparator groups, these observational data may underestimate the true clinical benefit of AN69ST.

Furthermore, the remarkable adsorption persistence at 0/0 (QD/QF) settings in both PMMA and AN69ST suggests dominant hemoperfusion mechanisms. This phenomenon was confirmed in the SIRAKI02 trial [6], where slow continuous ultrafiltration (SCUF) mode using oXiris filters (enhanced polyethylenelmine coating and heparin-grafted AN69ST membranes) during cardiopulmonary bypass achieved cytokine adsorption with positive clinical outcomes. These findings imply that the SCUF mode without fluid removal could serve as a viable hemoperfusion strategy for reducing cytokine levels in specific clinical scenarios.

In conclusion, Kudo et al. provided valuable mechanistic data possibly informing CAH-CRRT optimization; however, the study’s in vitro design and limited convection parameters warrant cautious clinical extrapolation. Future in vivo investigations should validate these findings and explore their therapeutic implications.