Fish Oil and HDL Function in Patients on Maintenance Hemodialysis

Patients receiving maintenance hemodialysis (HD) experience exceptionally high cardiovascular (CV) mortality that is not adequately addressed by conventional lipid-lowering strategies. The PISCES trial demonstrated that high-dose n-3 polyunsaturated fatty acid (n-3 PUFA) supplementation reduces CV events in HD patients, yet the underlying mechanism remains unknown.

In the uremic milieu, HDL undergoes qualitative changes-including enrichment with serum amyloid A (SAA), loss of anti-oxidative capacity, and impaired cholesterol efflux capacity (CEC)-that render it dysfunctional and may contribute to CV risk independently of HDL cholesterol concentration. Evidence from non-dialysis populations suggests that n-3 PUFA can favorably modify the HDL proteome and improve HDL function. The investigators hypothesize that n-3 PUFA supplementation favorably modulates HDL function in HD patients, which could help explain the CV benefit observed in PISCES.

EFFLUX-HD is a single-center, prospective, randomized, open-label, crossover, exploratory mechanistic study conducted at the Chronic Hemodialysis Unit of the Vienna General Hospital (Medical University of Vienna). Forty adults on maintenance HD are randomized 1:1 to one of two treatment sequences that differ in the order of an 8-week n-3 PUFA supplementation period (4 g/day fish oil; approximately 1.6 g EPA and 0.8 g DHA, matching the PISCES dose) and an 8-week off-treatment period, without a formal washout, for a total of 16 weeks per participant. The crossover design allows each participant to serve as their own control, removing the substantial between-participant variability in HDL functional measures.

Outcomes are analyzed using linear mixed-effects models. No formal sample-size calculation was performed given the exploratory, mechanistic design; the target of 40 participants is intended to estimate within-participant effects and the variability of HDL functional parameters to inform future confirmatory trials. The study was approved by the Ethics Committee of the Medical University of Vienna and is conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice.

• n-3 PUFA (fish oil) (Dietary supplement): 4g/day fish oil (four 1 g capsules) providing approximately 1.6 g EPA and 0.8 g DHA, taken for 8 weeks, matching the PISCES dose

Primary outcomes

• Cholesterol Efflux Capacity (CEC) [Weeks 1, 8, and 16]: Cholesterol efflux capacity of apolipoprotein B-depleted serum, measured with a cell-based fluorescent assay and reported as percentage cholesterol efflux (%).

Secondary outcomes

• Serum Amyloid A (SAA) [Weeks 1, 8, and 16]: Serum amyloid A concentration in serum, obtained from routine clinical laboratory measurement and reported in mg/L.
• Biologically Effective HDL [Weeks 1, 8, and 16]: Biologically effective HDL, calculated from concomitantly measured HDL cholesterol and serum amyloid A concentrations and reported in mg/dL.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* age ≥ 18 years
* receiving maintenance in-center hemodialysis
* able to provide written informed consent
* clinically stable condition (no hospitalization within 4 weeks prior to baseline)

Exclusion Criteria:

* inability or unwillingness to provide informed consent
* known hypersensitivity or intolerance to fish oil or n-3 PUFA-containing products
* use of n-3 PUFA supplements at baseline or within the preceding 8 weeks
* pregnancy
* acute infection, hospitalization or major inflammatory condition at the time of baseline assessment
* any condition that, in the investigator's opinion, would make participation unsafe or interfere with study participation or data interpretation
* inherited lipid metabolism disorders