Fish Oil and HDL Function in Patients on Maintenance Hemodialysis

Official title

Mechanistic Effects of n-3 Polyunsaturated Fatty Acid Supplementation on HDL Function in Patients Receiving Maintenance Hemodialysis (EFFLUX-HD): Study Protocol for a Randomized, Open-label, Crossover Trial

Overview

Patients who receive maintenance hemodialysis have a very high risk of cardiovascular disease, and standard cholesterol-lowering treatments such as statins have not been shown to reduce cardiovascular events in this group. A recent clinical trial (PISCES) found that high-dose omega-3 fatty acids (fish oil) reduced cardiovascular events in hemodialysis patients, but the reason for this benefit is not understood. One possible explanation is that, in kidney failure, high-density lipoprotein (HDL) no longer works normally. This study investigates whether omega-3 fatty acid supplementation improves the function of HDL in people on maintenance hemodialysis. Forty adults on maintenance hemodialysis will take part. Each participant receives fish oil (4 g per day) for 8 weeks and also has an 8-week period without supplementation; participants are randomly assigned to the order of these two periods (crossover design), for a total of 16 weeks each. The main measure is cholesterol efflux capacity, a laboratory test of how well HDL removes cholesterol from cells. The study also examines other markers of HDL quality. This is an exploratory, mechanistic study. Its aim is to determine whether omega-3 fatty acids change HDL function and to inform the design of larger future trials.

Detailed description

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.

Interventions

• Dietary supplement n-3 PUFA (fish oil)
  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 outcome measures

• Cholesterol Efflux Capacity (CEC) [Time frame: Weeks 1, 8, and 16]

Secondary outcome measures (2)

• Serum Amyloid A (SAA) [Time frame: Weeks 1, 8, and 16]
• Biologically Effective HDL [Time frame: Weeks 1, 8, and 16]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Crossover

Masking

Open label

Primary purpose

Prevention

Study locations

Austria · 1 center

• Chronic Hemodialysis Unit, Division of Nephrology and Dialysis, Department of Medicine III — Vienna

Identifiers

NCT: NCT07730385 · EK Nr: 1072/202 (EFFLUX-HD)

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗