Effect of Increased Convective Clearance by On-Line Hemodiafiltration on All Cause Mortality in Chronic Hemodialysis Patients

Study Overview
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Brief Summary
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The purpose of this study is to compare the effect of low flux hemodialysis with online hemodiafiltration on all cause mortality and a combination of cardiovascular morbidity and mortality in chronic hemodialysis patients.

Detailed Description
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Today, an increasing number of patients with chronic renal failure (CRF) is treated with (on-line) hemodiafiltration (HDF). This practice is based on the assumption that the high incidence of cardiovascular (CV) disease, as observed in patients with CRF, is at least partially related to the retention of uremic toxins in the middle and large-middle molecular (MM) range. As HDF lowers these molecules more effectively than HD, it has been suggested that this treatment improves CV outcome, if compared to standard HD. Thus far, no definite data on the effects of HDF on CV parameters and/or clinical end-points are available. Promising data include a reduction of left ventricular mass index (LVMi) after one year of treatment with acetate free bio-filtration (AFB). Furthermore, relatively high survival rates were reported in a single center non-experimental study on patients who were treated with HDF, if compared to the EDTA registry data on HD-treated patients. Yet, these data are of observational nature, with the possibility of being biased by confounding by indication. As the accumulation of MMW substances has been implicated in increased oxidative stress and endothelial dysfunction, a reduction of these compounds might improve these derangements. In addition, cardiac dysfunction, atherosclerosis (as measured by left ventricular mass index [LVMi], carotid intima media thickness [CIMT]) and vascular stiffness (as measured by pulse wave velocity [PWV]) might be reduced during HDF, as compared to low-flux HD. Therefore, we propose a prospective, randomized multicenter trial, comparing (on-line) HDF with HD. After a stabilization period, an expected number of 700 chronic HD patients will be randomized to either HDF or low-flux HD and followed during 1-6 years. Primary end points are all cause mortality and combined CV events and mortality. In addition, LVMi, PWV, CIMT and various parameters of oxidative stress, acute phase reaction (APR) and endothelial function will be assessed and compared between treatment groups. This study will provide strong evidence on the efficacy of HDF compared to low flux HD on CV morbidity and mortality, which is currently lacking but urgently needed. It is highly likely that the outcome of this study will affect current clinical practice considerably, in the Netherlands as well as internationally. Moreover, the study will point towards the mechanisms underlying the effects of HDF. The following hypotheses will be tested: All-cause mortality and combined CV morbidity and mortality in patients treated with (on-line) HDF is lower than in patients treated with standard low-flux HD. A reduction in MMW uremic toxins by HDF leads to an improvement of the 'uremic profile' (as measured by AGE-levels, homocysteine levels, oxidative stress, and endothelial dysfunction), if compared to standard low-flux HD. The improvement of the 'uremic profile' in HDF-treated patients results in an improvement of endothelial function with a reduction in the progression of vascular injury (as measured by CIMT and PWV) and a reduction in LVMi, if compared to standard low-flux HD.

Official Title
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Effect of Increased Convective Clearance by On-line Hemodiafiltration on All Cause and Cardiovascular Mortality in Chronic Hemodialysis Patients: The Dutch Convective Transport Study (CONTRAST)

Conditions
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End-stage Renal Disease, Cardiovascular Disease

Intervention / Treatment
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* Procedure: on-line hemodiafiltration
* Procedure: low flux hemodialysis


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients treated by HD 2 or 3 times a week, for at least 2 months Patients able to understand the study procedures Patients willing to provide written informed consent Exclusion Criteria: Current age < 18 years Treatment by HDF or high flux HD in the preceding 6 months Severe incompliance (severe non-adherence to the dialysis procedure and accompanying prescriptions, especially frequency and duration of dialysis treatment and fluid restriction) Life expectancy < 3 months due to non renal disease Participation in other clinical intervention trials evaluating cardiovascular outcome

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: 1: low flux hemodialysis<br>standard treatment | Procedure: low flux hemodialysis<br>* standard treatment<br>|
| Active Comparator: 2 on-line hemodiafiltration<br> | Procedure: on-line hemodiafiltration<br>* addition of convective transport to regular dialysis treatment by using on-line hemodiafiltration<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| all cause mortality |  | entire follow up (until dead or end of study, 1-7 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| fatal and non-fatal cardiovascular events |  | entire follow up (until death or end of study, 1-7 years) | 
| Left ventricular mass index (LVMi), carotid IMT (intima media thickness), aortic pulse wave velocity (PWV) |  | first 3 years | 
| laboratory markers of endothelial dysfunction, micro-inflammation, oxidative stress |  | first three years of follow up | 
| lipid profiles, uremic toxins |  | first three years | 
| quality of life |  | entire follow up (until death or end of study, 1-7 years) | 
| nutritional state |  | entire follow up (until death or end of study 1-7 years) | 
| anemia management | hemoglobin levels, erythropoietin use / resistance iron saturation / ferritin levels, prescription of iron medication | first 12 months of follow up | 
| cost utility analysis |  | entire follow up (until death or end of study, 1-7 years) | 
| hospital admissions | hospitalization days hospital admission for infections hospital admission for any cause | entire follow up (until death or end of study, 1-7 years) | 
| blood pressure and antihypertensive medication |  | entire follow up (until death or end of study, 1-7 years) | 
| residual kidney function |  | entire follow up (until death or end of study, 1-7 years) | 
| mineral bone disease | laboratory parameters of mineral bone disease and medication (phosphate binders, vitamin D (or analogues), cinacalet) | entire follow up (until death or end of study, 1-7 years) | 
| parameters of treatment / treatment delivery | dialysis efficiency (Kt/V urea); bloodflow, dialysate flow, ultrafiltration volume, (HDF:) convection volume | entire follow up (until death or end of study, 1-7 years) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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online hemodiafiltration, low flux hemodialysis, cardiovascular disease, endothelial dysfunction, uremic toxicity, quality of life, nutritional status