Randomized investigation of increased dialyzer membrane hydrophilicity on hemocompatibility and performance

Background Hemodialyzers should efficiently eliminate small and middle molecular uremic toxins and possess exceptional hemocompatibility to improve well-being of patients with end-stage kidney disease. However, performance and hemocompatibility get compromised during treatment due to adsorption of plasma proteins to the dialyzer membrane. Increased membrane hydrophilicity reduces protein adsorption to the membrane and was implemented in the novel FX CorAL dialyzer. The present randomized controlled trial compares performance and hemocompatibility profiles of the FX CorAL dialyzer to other commonly used dialyzers applied in hemodiafiltration treatments. Methods This prospective, open, controlled, multicentric, interventional, crossover study randomized stable patients on post-dilution online hemodiafiltration (HDF) to FX CorAL 600, FX CorDiax 600 (both Fresenius Medical Care) and xevonta Hi 15 (B. Braun) each for 4 weeks. Primary outcome was β2-microglobulin removal rate (β2-m RR). Non-inferiority and superiority of FX CorAL versus comparators were tested. Secondary endpoints were RR and/or clearance of small and middle molecules, and intra- and interdialytic profiles of hemocompatibility markers, with regards to complement activation, cell activation/inflammation, platelet activation and oxidative stress. Further endpoints were patient reported outcomes (PROs) and clinical safety. Results 82 patients were included and 76 analyzed as intention-to-treat (ITT) population. FX CorAL showed the highest β2-m RR (76.28%), followed by FX CorDiax (75.69%) and xevonta (74.48%). Non-inferiority to both comparators and superiority to xevonta were statistically significant. Secondary endpoints related to middle molecules corroborated these results; performance for small molecules was comparable between dialyzers. Regarding intradialytic hemocompatibility, FX CorAL showed lower complement, white blood cell, and platelet activation. There were no differences in interdialytic hemocompatibility, PROs, or clinical safety. Conclusions The novel FX CorAL with increased membrane hydrophilicity showed strong performance and a favorable hemocompatibility profile as compared to other commonly used dialyzers in clinical practice. Further long-term investigations should examine whether the benefits of FX CorAL will translate into improved cardiovascular and mortality endpoints. Trial registration eMPORA III registration on 19/01/2021 at ClinicalTrials.gov (NCT04714281). Supplementary Information The online version contains supplementary material available at 10.1186/s12882-024-03644-5.


Methods for obtaining blood samples
• The pre-dialysis blood sample was obtained from the native arterial needle, before it was flushed or connected to the blood tubing.The venous blood samples were drawn slowly from the venous port -before the blood was diluted with the substitution solution -at the standard blood flow of approx.300 mL/min, at running blood and dialysate.Arterial blood samples at the later timepoints were drawn at a temporarily reduced blood flow of 100 mL/min and at running dialysate.

Clinical safety
Repeated measurements of routine lab data and vital signs showed the patterns expected in patients undergoing state-of-the-art HDF.The mean hemoglobin concentration increased during HDF sessions (+0.6 g/dL overall), blood pressure decreased (systolic: -6.1 mmHg; diastolic: -2.2 mmHg), heart rate remained stable (+0.1 bpm), and body weight decreased (-2.1 kg).There were no conspicuous differences between dialyzers.
HDF: Hemodiafiltration; MedDRA: Medical Dictionary for Regulatory Activities; PT: Preferred Term; SOC: System Organ Class.* Related to the medical procedure.All other SAEs were neither considered related to the dialyzer nor to the medical procedure.Removal rates of other molecules (secondary performance endpoints) were calculated according to the same formula, using the concentrations of the molecule at the start and after 240 min of HDF.
Bloodside clearances Kb [mL/min] were calculated using the following formula (adapted from 11 ): 1Hct denotes the arterial hematocrit as a proportion, Qb [mL/min] the effective blood flow rate at the time clearance is calculated, Qsub [mL/min] the HDF substitution rate, QUF [mL/min] the ultrafiltration rate, Cart [mg/dL] the plasma concentration before the dialyzer of the molecule whose clearance is to be calculated (arterial plasma), and Cven [mg/dL] the plasma concentration after the dialyzer (venous plasma).
Non-clearance and non-removal related secondary variables were corrected for hematocrit (Hct) according to the following two formulas: Blood cell counts: Markers of complement activation, markers of inflammation (except for blood cell counts), markers of oxidative stress, β-Thromboglobulin (β-TG), and Thromboxane (TxB2): The corrections were calculated for each collection time point (t) except pre-dialysis values (pre).
The primary analysis consisted of the four parts listed below.It used a gate-keeping procedure to prevent inflation of the Type 1 error rate. 12The first two steps, which were performed in parallel, implement the Bonferroni-Holm procedure.The overall one-sided α over all tests was 2.5%.Assuming no carry over effect, a linear mixed model was used for the statistical analysis.This model included the fixed effects "period" and "dialyzer" and the random effects "center" and "patient".The patients within each center identified the subjects with repeated measurements in the three periods.The comparison of the FX CorAL with each of the other two comparator dialyzers was done by defining contrasts or estimators of the fixed effect "dialyzer".
The non-inferiority tests were based on the per protocol (PP) population which included all subjects who entered the study in accordance with each inclusion and exclusion criterion and who finished the study in accordance with the study protocol, without any major protocol deviations occurring.
For validation purposes, this analysis was repeated on the intention to treat (ITT) population which included all patients who were randomized and for whom primary outcome data was available for at least one dialyzer.The superiority tests were performed on the ITT population and for validation on the PP population.
Analyses of secondary performance endpoints and PROs applied the same linear mixed model as described for the primary endpoint to calculate mean differences between FX CorAL and its comparators as well as the corresponding 95% confidence intervals.
Hemocompatibility markers were analyzed descriptively and compared between dialyzers, based on their concentration or activity profile over one HDF session.The analyses included intradialytic changes vs. the baseline (pre-)value at the session's start.In addition, the eMPORA III study determined interdialytic changes: these are changes of the pre-values of the marker within one treatment period, which consisted of 12 sessions with one type of dialyzer.
Blood cell counts as well as hemocompatibility and activity markers were corrected for Hct changes over an HDF session.Missing values for all safety and efficacy endpoints were not replaced and described as a distinct category in tables.Based on the 'missing at random assumption', the linear mixed model allowed the modelling of incomplete data.

Section 1 :
Formulas for calculating β2-m Removal Rate (RR) and bloodside clearance Kb; Statistical concept β2-m RR [%] was calculated using the following formula 10 : Hct240 min denotes the hematocrit as a proportion after 240 min of HDF, Hctpre the hematocrit as a proportion at the start of HDF; cβ2m,240 min denotes the β2-m concentration after 240 min of HDF, cβ2m,pre the β2-m concentration at the start of HDF.Thus, β2-m RR was corrected for concentration effects due to the dialysis treatment by considering the hematocrit.

Table S1 :
Methods for obtaining blood samples and analytical methods of investigated variables

Table S2 :
Overview of Patient Reported Outcomes (PRO; Safety population)

Table S4 :
Overview of hemocompatibility markers: intra-and interdialytic changes (ITT population) Values indicate LS mean differences to the baseline (pre) values before the start of HDF.LS mean: Least Squares mean.Intradialytic: changes within a dialysis session.Interdialytic: changes over a dialysis period (12 sessions under one allocated dialyzer type).Shaded lines indicate parameters of key clinical interest for the variable.p-values formatted in bold script mark values <0.05 and the associated parameter.p-values are descriptive and not adjusted for multiple testing.

Table S5 :
Overview of Serious Adverse Events (SAEs), Adverse Events (AEs), and clinical safety (Safety population)