Theranova vs High-flux HD Comparison

Study Overview
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Brief Summary
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This research proposal of an investigator-initiated clinical study aims to examine the impact of uremic toxin removal afforded by middle cut-off (MCO) dialysis on clinical parameters and surrogate biomarkers pertinent to nutritional, systemic and vascular complications in dialysis patients. The primary research goal is to evaluate the outcomes indicative of nutritional status (as measured by body mass index, body composition monitoring, albumin, clinical assessments such as subjective global assessment, etc.) and parameters relevant to pathophysiological processes in uremia focusing on inflammation and cardiovascular risks. The secondary research aims are to examine dialysis efficacy between MCO dialysis and conventional hemodialysis (CHD). Specifically, dialysis efficacy will be determined by within and between subject differences in baseline versus short term (6 months) and long term (12 months) effects of MCO dialysis and CHD in: Removal of small molecules (e.g. urea), middle molecules (Beta-2 microglobulin, Phosphate and Creatinine) and protein bound solutes Markers of inflammation, ossification and fibrosis Uremia associated epigenetic modification The investigators hypothesize superiority of nutritional parameters in patients undergoing MCO dialysis compared with patients on CHD. The investigators plan to randomize 60 patients to either MCO dialysis or CHD at two hemodialysis units in Hong Kong.

Detailed Description
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Accumulation of uremic toxins is associated morbidity and mortality in patients with end-stage renal disease, but the pathogenic mechanisms how they lead to various clinical complications remain elusive. Conventional hemodialysis is effective in removing small molecular solutes (in the range of 50-15,000 Da), but the removal of protein-bound and middle to larger molecular toxins (up to 50,000 Da) remains unsatisfactory even with augmented hemodialysis frequency or duration. The notion that dialysis adequacy is no longer a simple quantitative measure of small molecular removal has led to the clinical application of intensive hemodialysis and the search for novel strategies to reduce uremic toxin burden. Recently, a new class of membrane with molecular weight cut off (MWCO) close to the molecular weight of albumin was introduced. The focus of this new therapy, known as expanded dialysis using the medium cut off (MCO) dialysis membrane, is to provide the potential for more efficient removal of middle molecules and protein bound uremic toxins without excessive loss of albumin. To date, MCO dialysis has been associated with a reduction in transcription of pro-inflammatory cytokines (i.e. interleukin 6 and tumor necrosis factor-α) and middle molecules especially free lambda light chains. Protein-energy wasting and cardiovascular diseases are prevalent in chronic kidney disease and is related to inflammation and increased mortality. Despite growing data on the clearance of individual uremic toxins and biochemical parameters, the impact of MCO dialysis on clinical outcomes and mechanistic parameters related to nutrition and inflammation remains to be investigated. The objective of the study is to compare MCO dialysis with conventional high-flux HD, on nutritional parameters, inflammation and cardiovascular biomarkers and related clinical outcomes. Since twice-weekly HD is commonly practiced in Hong Kong, this study provides a distinct opportunity to investigate whether MCO dialysis might be particularly advantageous in patients receiving a relatively lower dialysis dose through the removal of a broader spectrum of uremic toxins. The investigators hypothesize that MCO dialysis with Theranova Dialyzer (HDx) improves parameters related to nutrition and inflammation compared with high-flux HD. This will be a prospective single-blinded, randomized, controlled trial with stable HD patients randomized at 1:1 ratio to either one of the following - A. to continue with HD using the same high-flux dialyzer as in the previous 6 weeks (high-flux HD arm) B. change to HDx using Theranova Dialyzer (MCO dialysis arm)

Official Title
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The Comparison of Expanded Dialysis With Theranova Dialyzer With Conventional High-flux Hemodialysis

Conditions
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End Stage Renal Failure on Dialysis

Intervention / Treatment
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* Device: High-flux dialyzer
* Device: Theranova dialyzer


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: adult patients age greater than 18 years old end-stage renal failure on two- or three-times per week high-flux HD for more than 90 days mean spKt/Vurea >1.2 per session (for 3 dialysis sessions per week) or spKt/Vurea >1.8 per session (for 2 dialysis sessions per week) Exclusion Criteria: active malignancy unable to give informed consent or complete questionnaires unstable clinical condition defined as significant clinical event requiring hospitalization in the past 90 days unreliable vascular access unable to achieve HD blood flow >150ml/min

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Theranova<br>Patients will be receiving hemodialysis using Theranova dialyzer. The other hemodialysis parameters are kept the same. | Device: Theranova dialyzer<br>* a middle cut-off dialyzer<br>|
| Active Comparator: High-flux<br>Patients will be receiving hemodialysis using a high-flux dialyzer. The other hemodialysis parameters are kept the same | Device: High-flux dialyzer<br>* a dialyzer meeting the definition of high-flux<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| lean tissue index | measured by Body Composition Monitor | 12 months | 
| Body Mass Index | measured by weight (in kilograms) divided by the square of heights (in meters) | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| asymmetrical dimethylarginine | endogenous inhibitor of nitric oxide synthase, one of the cardiovascular biomarkers | 12 months | 
| fibroblast growth factor 23 | biomarker for bone turnover | 12 months | 
| Klotho | biomarker for atherosclerosis and bone turnover | 12 months | 
| Kt/V urea | measurement of clearance of urea by hemodialysis therapy, a marker for adequacy of dialysis | 12 months | 
| beta-2 microglobulin | middle size uremic toxin | 12 months | 
| Pentraxin-3 | middle to large molecular size uremic toxin | 12 months | 
| soluble endothelial protein C receptor | a marker for endothelial dysfunction | 12 months | 
| soluble thrombomodulin | a marker for endothelial dysfunction | 12 months | 
| hemoglobulin | indication of anemia | 12 months | 
| high-sensitive C reactive protein | marker for inflammation | 12 months | 
| interleukin 6 | marker for inflammation | 12 months | 
| tumor necrosis factor alpha | marker for inflammation | 12 months | 
| albumin | marker for nutritional status | 12 months | 
| Leptin | marker for nutritional status and appetite | 12 months | 
| adiponectin | nutritional marker | 12 months | 
| phosphate | small size uremic waste produce | 12 months | 
| low-density lipoprotein | reflects lipid control | 12 months | 
| high-density lipoprotein | reflects lipid control | 12 months | 
| triglyceride | reflects lipid control | 12 months | 
| Malnutrition-Inflammation Score | a measurement scale reflecting nutritional status | 12 months | 
| Subjective Global Assesment questionnaire | a measurement scale reflecting nutritional status | 12 months | 
| fat tissue index | nutritional marker measured by Body Composition Monitor | 12 months | 
| admission rate due to cardiovascular events | number of admisisons due to cardiovascular events during the follow-up period | 12 months | 
| admission rate due to infection | number of admissions due to infection during the follow-up period | 12 months | 
| mortality rate | number of deaths during the follow-up period | 12 months | 
| 5-D itch scale | Symptomatology scale to measure itchiness | 12 months | 
| Numeric rating scale for itchiness | Symptomatology scale to measure itchiness | 12 months | 
| The Functional Assessment of Anorexia/Cachexia Therapy (FAACT) score | measurement scale for appetite | 12 months | 
| Visual analogue scale for appetite | measurement scale for appetite | 12 months | 
| Postdialysis recovery time | number of time required to feel well after receiving a hemodialysis session | 12 months | 
| Self-reported sleep quality | scale to rate the quality of sleep | 12 months | 
| Hong Kong Montreal Cognitive Assessment | measurement of cognitive function | 12 months | 
| KDQOLSFTMv1.3 questionnaire | quality of life assessment | 12 months | 
| DNA methylation analysis of TRPV1 gene | epigenetics modification | 12 months | 
| DNA methylation analysis of LY96 gene | epigenetics modificaiton | 12 months | 
| DNA methylation analysis of IFNGR1 gene | epigenetics modifications | 12 months |