Toxins Removal and Inflammatory State modulAtion During Online Hemodiafiltration: Comparison of Two Different Dialyzers (TRIAD2)

March 16, 2021 updated by: Gabriele Donati, IRCCS Azienda Ospedaliero-Universitaria di Bologna
The primary goal of the study is to evaluate in patients on three times a week on-line HDF the efficacy, in terms of toxin removal and modulation of the inflammatory state, of two different dialyzers: Helixone versus Asimmetric cellulose triacetate (ATA).

Study Overview

Status

Not yet recruiting

Conditions

Intervention / Treatment

Detailed Description

Patients with end-stage renal disease (ESRD) have a significantly increased cardiovascular mortality rate compared to the general population.

According to the USRDS (United States Renal Data System), in 2017 the prevalence of cardiovascular disease in the United States was 65.8% in patients with chronic kidney disease (CKD), compared to 31.9% of the subjects with stable renal function (https://www.usrds.org/2017/view/v1_04.aspx).

In the natural history of nephropathy, besides the traditional cardiovascular risk factors, an increasingly important role is played by the nontraditional factors related to uremia and dialysis treatment, namely anemia, hyperhomocysteinemia, malnutrition, hyperparathyroidism, electrolyte imbalance, and above all chronic inflammatory state and oxidative stress. The main components of dialysis-related inflammatory response include neutrophil and monocyte activation, cytokine release, oxidative stress with production of free radicals, lipid and protein oxidation, and alterations in blood redox state.

There is much evidence to indicate that ESRD patients, especially those on dialysis, are exposed to increased oxidative and carbonyl stress, that cause chemical modifications of proteins and accumulation of AGEs (advanced glycation end products).

The formation of AGEs occurs through Maillard reaction, a non-enzymatic glycation of peptide amino groups, resulting in protein structural and functional alteration and production of reactive carbonyl species .

Several studies have demonstrated a correlation between the levels of tissue AGEs and the development of various complications, since the accumulation of AGEs constitutes an index of hyperglycemia, oxidative stress and inflammation. The activation and up-regulation of the AGE receptors, including the main one RAGE (AGE Receptor), leads to the initiation of inflammatory cascades involved in the formation of atherosclerotic plaques and endothelial dysfunction, and lastly in the pathogenesis of cardiovascular disease. AGEs are also related to the thickening of the intima-media tunica of the carotid arteries, considered a marker of arteriosclerosis, as clinically confirmed by the close relationship between coronary artery disease and atherosclerotic complications in diabetes and renal failure.

Besides AGEs, a huge pattern of protein-bound toxins and of middle molecular weight uremic toxins are known to contribute to the uremic syndrome in terms of cardiovascular complications, inflammation and fibrosis . Concerning protein-bound uremic toxins, p-cresyl sulfate and indoxyl sulfate have received considerable attention recently. Among middle molecules, B2M, free light chains and FGF23 have been identified as markers of disease progression and mortality in CKD and hemodialysis.

Furthermore, the activation of leukocytes, both in response to the exposure to dialysis membranes and as a consequence of the retrotransportation of substances that promote the expression of cytokines from the dialysate, increases the release of proinflammatory cytokines, such as IL-1β, TNF-α and IL-6.

The biocompatibility and flow properties of the different filters can influence the inflammatory and oxidative response to dialysis and the levels of oxidized molecules. In general, short-term dialysis with high-flow membranes has been shown to decrease plasma levels of oxidized low-density lipoproteins, regardless of the filter material.

Nonetheless, the introduction of high-flux membranes, which increased clearance of middle molecules, appears to be inadequate to improve patient survival, as reported by two major randomized trials, the HEMO study [24] and the MPO study.

The use of on-line HDF, that combines convective and diffusive solute removal, can counterbalance the rapid decrease of middle molecule diffusion obtained with high flux hemodialysis. The integration of diffusion with convection allows a more modest sieving coefficient decrease for middle molecular weight solutes. To date, evidence from four randomized controlled trials on HDF suggests, although not definitely, that HDF with convection volumes >20 L results in better patient outcomes .

Moreover, a correlation of the membrane typology with inflammation and oxidative stress in the medium-long term was found in patients undergoing chronic dialysis treatment. A prospective study in a cohort of 50 patients who started hemodialysis with a high-flux polysulfone membrane (HF80 series, Fresenius Medical Care, St. Wendel, Germany) evaluated the variation of the inflammation and oxidative stress biomarkers. The results showed significantly increased circulating levels of IL-6, C-reactive protein (CRP) and higher carbonylation rate in dialysis patients compared to healthy controls in the first year of observation, and this trend was maintained in the following 12 months.

Successive studies investigated the long-term effects on inflammation and oxidative stress of dialysis with Helixone (Fresenius Medical Care), another type of high-flux polysulfone membrane designed to maximize the clearance of uremic toxins of average molecular weight (> 500 Daltons, Da) compared to conventional high-flux membranes. The introduction of changes as reduced hollow fiber wall thickness (≈35 μm), smaller inner diameter (≈185 μm) and higher average pore size (≈3.3 nm) has improved the clearance of medium molecular weight molecules, including β2-microglobulin (B2M), limiting the passage of larger molecules like albumin, without significant effects on inflammatory parameters .

The features of synthetic membranes related their chemical composition and the asymmetric structure of the fibers make them preferable for new highly-convective therapies, such as high-volume hemodiafiltration (HDF), only partially allowed with cellulose.

However, cellulose triacetate (CTA) and modified cellulose membranes remain the best option for the patients with hypersensitivity reactions to synthetic fibers. Although synthetic membranes, including those based on polysulfone, have a lower risk of hypersensitization than non-biocompatible ones (such as Cuprophane), in some cases adverse reactions have been reported, plausibly due to the contact between the dialyzer itself with plasma proteins and platelets.

Moreover, the choice of polysulfone membranes has been proven to affect the intracellular and serum levels of bisphenol A (BPA, molecular weight 228.3 kDa), a ubiquitous environmental toxicant found in plastic food and beverage containers, as well as in some dialyzers, with several detrimental effects. BPA is considered an endocrine-disrupting chemical that acts mainly as a female hormone: it is associated with reproductive dysfunction, immune abnormality and increased incidence of cancer. Patients on hemodialysis are a high-risk population for BPA overload, because the normal urinary elimination of the conjugated molecule decreases with low renal function. For these reasons, BPA can be thought as a uremic toxin, similarly to p-cresol, and a particular attention should be given to BPA-containing medical devices, including dialysis membranes.

Mas et al. compared BPA-free and BPA-containing dialyzers in 72 patients under on-line HDF, using a prospective 9-month, crossover study design. BPA-free dialyzers determined a greater long-term decrease in BPA levels compared to BPA-containing dialyzers, although at three months the difference was not significant. This may be due to the use of the on-line HDF technique that has been related to lower BPA levels than conventional hemodialysis.

Recently, a new generation filter in asymmetric triacetate (ATA) has been introduced, born from a technology that combines the requirements of synthetic membranes for the possibility of being used with high-volume HDF and the advantages of natural fibers (cellulose) in terms of reduced allergic reactions.

These novel ATA membranes have been demonstrated to achieve satisfactory Kt and convection volume, with good biocompatibility and inflammatory profiles, indicating them as a valuable option for patients allergic to synthetic membranes under HDF treatment.

Study Type

Interventional

Enrollment (Anticipated)

16

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

  • Italy
      • Bologna, Italy, 40138
        • Nephrology Dialysis and Renal Transplantatio Unit, StOrsola University Hospital
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Patients with chronic renal failure under periodic standard bicarbonate hemodialysis;
  • Three times a week dialysis session;
  • Residual diuresis <200 mL/day;
  • Age >18 years;
  • Vascular access for hemodialysis with blood flow >250 mL/minute;
  • Need of on-line hemodiafiltration (HDF) for signs of middle molecules intoxication (e.g. B2M >30 mg/L, peripheral neuropathy, cardiovascular comorbidities) or for intradialytic hypotension.

Exclusion Criteria:

  • Acute coronary syndrome;
  • Acute hemorrage;
  • Enrollment in another study protocol;
  • Active infection;
  • Malignancy;
  • Inability to provide written signed consent to participate in the study.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Non-Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Hemodiafiltration with ATA filter
patients with clinical history of hypersensitivity to polisulfone/poliethersulfone dialysis filters or hypersensitivity to drugs or generic allergens.
Device: 1) high flux hemodiafiltration thrice -weekly during a 24 month follow-up
  1. the comparison of the effects of the two membranes on the serum levels of albumin, B2M, CRP, myoglobin, light chains, retinol binding protein, homocysteine, p-cresol, indoxyl sulfate, BPA, alpha-1-microglobulin (A1M), FGF23 (fibroblast growth factor 23), and inflammatory cytokines;
  2. the evaluation of the changes induced by the two filters on lymphocyte subsets, monocyte activation and senescence, and apoptosis rate;
  3. the definition of the impact of the two membranes on the accumulation of AGEs as an index of metabolic and oxidative stress, determined by a non-invasive method based on the measurement of skin autofluorescence through a dedicated device (AGE Reader, DiagnOptics Technologies BV, Groningen, Netherlands).
Other Names:
  • 2) assessment of uremic toxins, inflammation and effects of patients sera in culture of endothelial cells
  • 3) Body impedance analysis by means of Electro fluid graph (EFG®, Akern, Pontassieve, Italia)
  • 4) Measurement of AGEs accumulation through skin autofluorescence. (AGE Reader, DiagnOptics Technologies BV)
Active Comparator: Hemodiafiltration with Helixone filter
no history of hypersensitivity to polisulfone/poliethersulfone dialysis filters is assessed; no history of hypersensitivity to drugs or generic allergens is assessed.
Device: 1) high flux hemodiafiltration thrice -weekly during a 24 month follow-up
  1. the comparison of the effects of the two membranes on the serum levels of albumin, B2M, CRP, myoglobin, light chains, retinol binding protein, homocysteine, p-cresol, indoxyl sulfate, BPA, alpha-1-microglobulin (A1M), FGF23 (fibroblast growth factor 23), and inflammatory cytokines;
  2. the evaluation of the changes induced by the two filters on lymphocyte subsets, monocyte activation and senescence, and apoptosis rate;
  3. the definition of the impact of the two membranes on the accumulation of AGEs as an index of metabolic and oxidative stress, determined by a non-invasive method based on the measurement of skin autofluorescence through a dedicated device (AGE Reader, DiagnOptics Technologies BV, Groningen, Netherlands).
Other Names:
  • 2) assessment of uremic toxins, inflammation and effects of patients sera in culture of endothelial cells
  • 3) Body impedance analysis by means of Electro fluid graph (EFG®, Akern, Pontassieve, Italia)
  • 4) Measurement of AGEs accumulation through skin autofluorescence. (AGE Reader, DiagnOptics Technologies BV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Measurement of uremic toxins
Time Frame: 24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Beta 2 microglobulin (B2M), C-reactive protein (CRP), albumin, myoglobin, light chains, retinol binding protein, homocysteine, p-cresol, indoxyl sulfate, BPA, alpha-2-macroglobulin (A2M), FGF23 (fibroblast growth factor 23)
24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Measurement of endothelial cells metabolism
Time Frame: 24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
The patients' sera will be incubated with Human Coronary Artery Endothelial Cells (HCAECs), a human cell line isolated from normal coronary arteries. HCAECs are the ideal candidates for the study of endothelial cell functions and metabolism, proving an excellent model system to study all aspects of cardiovascular function and disease
24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Patients survival
Time Frame: 24 months
the mortality rate of the patients will be recorded
24 months
Body impedance analysis
Time Frame: 24 months.
Body impedance analysis will be carried out monthly through Electro fluid graph machine
24 months.
AGEs measurements
Time Frame: 24 months
AGEs measurements will be carried out monthly through skin autofluorescence
24 months
Measurement of inflammatory cytokines
Time Frame: 24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
measurement of interleukin 1 beta (IL-1 β), interleukin 6 (IL-6), interleukin 10 (IL-10),interleukin 12 p 70 (IL-12 (p70)), interleukin 17 (IL -17), tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ)
24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Measurement of inflammatory cell activation
Time Frame: 24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Measurement of lymphocyte subsets, monocyte activation and senescence, and apoptosis rate
24 months. Blood samples will be drawn at Time 0 (on starting the study when the patients starts HDF treatment), after 1 month, after 3 months, after 6 months, after 12 months, and after 24 months (study end)
Infection rate
Time Frame: 24 months
The number of infections that affected the patients and the rate of hospitalization for infections will be recorded
24 months
Cardiovascular diseases
Time Frame: 24 months
The number of cardiovascular disease that affected the patients and the rate of hospitalization for cardiovascular disease will be recorded
24 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS Azienda Ospedaliero-Universitaria di Bologna

Collaborators

University of Bologna

Investigators

  • Study Director: Gaetano La Manna, Prof, StOrsola University Hospital, Bologna, Italy

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

January 1, 2022

Primary Completion (Anticipated)

May 1, 2023

Study Completion (Anticipated)

May 1, 2024

Study Registration Dates

First Submitted

September 5, 2020

First Submitted That Met QC Criteria

September 12, 2020

First Posted (Actual)

September 18, 2020

Study Record Updates

Last Update Posted (Actual)

March 17, 2021

Last Update Submitted That Met QC Criteria

March 16, 2021

Last Verified

March 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 596/2019/Oss/AOUBo

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

Clinical Trials on Inflammation

Clinical Trials on 1) high flux hemodiafiltration thrice -weekly during a 24 month follow-up

Search Similar Trials

Sponsors and Collaborators

Medical Conditions

Drug Interventions

CROs by country

CROs in Malta

Conditions

Rare Diseases

Drug Interventions

Dietary Supplements

Sponsor/Collaborators

Locations

Subscribe