The Impact of the Selective Cytopheretic Device on Neutrophil-to-Lymphocyte Ratios and Hematological Parameters in AKI: A Pooled Analysis

Background The Selective Cytopheretic Device (SCD) is an immunomodulatory cell-directed extracorporeal therapy that reprograms activated neutrophils and monocytes towards immune homeostasis in hyperinflammatory conditions such as acute kidney injury (AKI). However clinical mechanisms remain unclear.

We examined the effect of SCD treatment from prior AKI clinical studies on systemic inflammation through neutrophil-to-lymphocyte ratios (NLR) and other hematological measures to gain insights into the mechanism of the SCD. Linear-mixed effects regression was used to estimate differences in NLR and other hematological measures between SCD treated patients and controls over the first six days after initiating CKRT.

Hematological data were analyzed from 98 patients with AKI requiring continuous kidney replacement therapy (CKRT) treated with the SCD, and 32 CKRT only control patients. SCD reduced NLR across all individual studies through Day 6 of treatment, while the control group demonstrated upward trends in NLR past day 3. When analyzed as pooled groups, both cohorts displayed similar baseline NLRs (SCD = 23.6 vs. control = 21.7; p=0.636). SCD treated adult patients demonstrated a statistically significant reduction in NLR vs. control adult patients at Day 6 (SCD = 13.3 vs. control = 25.7 at day 6; ptrend = 0.011). This difference was maintained following sensitivity analysis upon exclusion of an adult ICU study due to a shorter follow-up period (SCD = 13.7 vs. control = 25.6; ptrend = 0.013). NLR reductions in the SCD group were driven by decreases in neutrophils and increases in lymphocytes. No statistically significant differences were observed between groups for monocyte-to-lymphocyte ratio (MLR) levels or platelets over the same treatment duration.

In a pooled analysis of multiple AKI clinical studies SCD treatment demonstrated reductions in NLR. This analysis provides further clinical mechanistic evidence of leukocyte immunomodulation in targeting the dysregulation of effector immune cells in hyperinflammatory conditions such as AKI and sepsis. Competing Interest Statement SPI and KKC are employees of SeaStar Medical and receive salary and company stock as compensation. HDH has financial interests in SeaStar Medical and Innovative Biotherapies. JLK and NJO are paid consultants for SeaStar Medical. Funding Statement The hematological analysis was funded by SeaStar Medical. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Yessayan LT, Neyra JA, Westover AJ, Szamosfalvi B, Humes HD: Extracorporeal Immunomodulation Treatment and Clinical Outcomes in ICU COVID-19 Patients. Crit Care Explor May 2022;4(5):e0694. doi:10.1097/CCE.0000000000000694 Ding F, Yevzlin AS, Xu ZY, Zhou Y, Xie QH, Liu JF, Zheng Y, DaSilva JR, Humes HD: The effects of a novel therapeutic device on acute kidney injury outcomes in the intensive care unit: a pilot study. ASAIO J Sep-Oct 2011;57(5):426-432. doi:10.1097/MAT.0b013e31820a1494 Tumlin JA, Galphin CM, Tolwani AJ, Chan MR, Vijayan A, Finkel K, Szamosfalvi B, Dev D, DaSilva JR, Astor BC, Yevzlin AS, Humes HD, Group SCDI: A Multi-Center, Randomized, Controlled, Pivotal Study to Assess the Safety and Efficacy of a Selective Cytopheretic Device in Patients with Acute Kidney Injury. PLoS One 2015;10(8):e0132482. doi:10.1371/journal.pone.0132482 Tumlin JA, Chawla L, Tolwani AJ, Mehta R, Dillon J, Finkel KW, DaSilva JR, Astor BC, Yevzlin AS, Humes HD: The effect of the selective cytopheretic device on acute kidney injury outcomes in the intensive care unit: a multicenter pilot study. Semin Dial Sep-Oct 2013;26(5):616-623. doi:10.1111/sdi.12032 Goldstein SL, Ollberding NJ, Askenazi DJ, Basu RK, Selewski DT, Krallman KA, Yessayan L, Humes HD: Selective Cytopheretic Device Use in Continuous Kidney Replacement Therapy in Children: A Cohort Study With a Historical Comparator. Kidney Med Apr 2024;6(4):100792. doi:10.1016/j.xkme.2024.100792 Goldstein SL, Askenazi DJ, Basu RK, Selewski DT, Paden ML, Krallman KA, Kirby CL, Mottes TA, Terrell T, Humes HD: Use of the Selective Cytopheretic Device in Critically Ill Children. Kidney Int Rep Mar 2021;6(3):775-784. doi:10.1016/j.ekir.2020.12.010 Krallman KA, French X, Humes HD: Multi-Center Study to Assess the Safety of a Selective Cytopheretic Device (SCD) for Treatment of Immunomodulatory Dysregulation due to AKI in Children ≥10 and ≤20kg: Report from the first 6 patients. presented at: American Society of Nephrology Kidney Week; November 2-7 2022 2022; San Diego, CA. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data produced in the present study are available upon reasonable request to the authors