Adequacy of Haemodiafiltration: Middle Molecules Clearance, Patients Reported Outcomes and Sodium Balance

The goal of this observational study is to understand the differences in terms of middle molecules clearance and patient outcomes in High (>23Litres (L)) vs Low (<23 L) convection volume (CV) Hemodiafiltration (HDF) and to understand the effect of dialysate fluid sodium concentration (137 vs 140 mmol/L) on overhydration volume in patients on HD and HDF.

Study Overview

• Status: Recruiting
• Conditions: Nutrition; Haemodialysis; Malnutrition (Calorie); Patient Reported Outcome Measurements; Haemodiafiltration; Fluid Balance Outcomes

Detailed Description

Background and Rationale The concept of normalised urea clearance (Kt/V) to determine the efficiency of dialysis emerged over four decades ago. This is based on evidence that Kt/V below a certain threshold is associated with poor outcomes , although the survival benefit appears to be capped beyond a threshold of around 1.2 . Dialysis techniques have evolved significantly since this evidence emerged. Routine use of high-flux membranes and convective treatments/Haemodiafiltration (HDF), increase removal of toxins of larger molecular weight such as middle molecules. Some of these have direct toxic potential unlike urea. Nevertheless, the metric of dialysis efficiency is still based on conventional small molecule clearance which doesn't correlate with removal of more clinically relevant middle molecules removed during HDF. Moreover, the relationship of small molecules clearance with patient reported symptoms and their nutritional status remains inconsistent. Most recent dialysis prescription guidelines highlight the limitations of Kt/V and suggest using this parameter as only one aspect of dialysis efficiency amongst others including nutrition, bone and mineral metabolism, salt and fluid homeostasis and anaemia management. Updating measure of dialysis quality to align more with current dialysis practice (HDF) seems a logical step. There are multiple aspects of quality of dialysis including toxins clearance, dialysis related symptoms burden, quality of life, fluid status and nutrition. This study aims to develop a metric of HDF adequacy which encompass these aspects comprehensively.

1.1 Toxins clearance and dialysis symptoms burden

One of the recent advances in dialysis is increasing use of haemodiafiltration (HDF) which appears to improve survival when large convection volumes are delivered. There is no agreed definition for high-volume HDF but it is generally accepted that ≥23 liters convection volume per session is high volume HDF since this volume has been associated with a beneficial survival outcome in most recent HDF trial (CONVINCE Trial). It is unclear though, what drives the benefit of high volume HDF. Convective treatment removes more middle molecules (such as β2-Microglobulin (β2M)) compared to conventional diffusive treatments, and enhanced middle molecules clearance is considered a plausible mechanism of survival benefit . Direct evidence for this though, is lacking. In the absence of an instrument to measure dialysis efficiency in HDF, currently the HDF prescription relies on achieving the same small molecule clearance as conventional HD and additionally achieving a certain convection volume. Interestingly by achieving the desirable convection volume, the delivered small molecules clearance exceeds the threshold at which survival benefit was reported to be capped in HEMO study. This method of HDF prescription needs to be rationalised. Measuring middle molecules clearance - as β2M clearance - could reflect the convection volume as well as small molecules clearance. Such a strategy may have a role in assessment of HDF adequacy. However, given the strong correlation between serum β2M and RKF, the impacts of RKF on β2M clearance need to be taken into consideration before using this tool to assess the HDF adequacy. This study intends to explore the relationship between HDF convection volume and β2M clearance and the change in this relationship with declining kidney function.

Whilst survival is considered the outcome of primary importance in clinical trials, there are other outcomes which may be of similar or greater importance to patients and carers. The Standardised outcomes in Nephrology (SONG) is a global initiative to establish set of core outcomes for research across the spectrum of kidney disease. These outcomes are developed based on the shared priorities of all relevant stakeholders. While high volume HDF has been shown to be related to better survival, there is little data on the relationship between HDF convection volume and important patient reported outcomes such a Fatigue, Recovery time after dialysis and cognitive function. It is important to understand the impact of HDF volume or its potential surrogate middle molecules clearance on these important outcomes. Similarly, it is unclear if HDF volume or Middle molecules clearance is related to other important aspects of dialysis efficiency such as bone and mineral metabolism, cumulative phosphate binder use and nutritional status. Many of these patient reported outcomes and biochemical and nutritional markers are important components of SONG-HD outcomes. Understanding these relationships could lead to development of more comprehensive and clinically relevant dialysis efficiency marker in HDF.

1.2 Dialysate sodium and fluid status

Sodium and fluid handling are the fundamental aspects of dialysis in end stage kidney disease (ESKD). There is wealth of evidence to relate fluid and sodium dysregulation with poor outcomes in dialysis patients. Despite this the optimal dialysate sodium concentration remains controversial. Different dialysis units use different standard dialysate sodium concentration. Fluid and sodium handling could potentially be more important in HDF compared to HD due to exposure to large convection volume and sodium retention due to Gibbs-Donnan effect in HDF. In-fact one plausible mechanism of benefit in HDF is better haemodynamic stability possibly as a result of fluid and salt retention. Although there is no evidence of bioimpedance measured fluid retention in high volume HDF compared to HD, the fluid status in HDF has not been assessed with varying dialysate sodium and with varying delivered convection volume. Optimum dialysate sodium or Dialysate - plasma sodium gradient in HDF remains an important but uncertain aspect of HDF prescription. This study aims to explore the effect of different dialysate sodium levels on patients' volume status in HD and HDF and also with varying HDF convection volume.

• Study Type: Observational
• Enrollment (Estimated): 300

Contacts and Locations

• Study Contact: Name: Usama Afzal Butt, MBBS, MRCP (UK); Phone Number: +441438284340; Email: usama.butt1@nhs.net

Study Locations

• United Kingdom
  • Hertfordshire
    • Stevenage, Hertfordshire, United Kingdom, SG1 4AB
      • Recruiting
      • Lister Hospital, East and North Hertfordshire NHS Trust
      • Contact: Usama Afzal Butt, MBBS, MRCP; Phone Number: +441438284340; Email: usama.butt1@nhs.net
      • Principal Investigator: Enric Vilar, MBChB, MRCP, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Non-Probability Sample

Study Population

Adult patients with ESKD receiving hemodialysis accross 5 dialysis units in East and North Hertfordshire NHS Trust , UK.

Description

Inclusion Criteria:

• Age 18 years or above.
• Ability to give informed consent.
• End stage kidney disease (ESKD) treated by haemodialysis for at least 3 months.
• Prognosis > 6 months as assessed by principal investigator (PI)

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort
HDF group; Particiapants receiving hemodiafiltration
HD group; Participants receiving high flux hemodialysis
Low dialysate sodium group; Participants dialysing with dialysate sodium concentration 137 mmol/L
High dialysate sodium group; Participants dialysing with dialysate sodium concentration 137 mmol/L

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of high (≥23L) versus low volume HDF (<23L) on middle molecules clearance and on clinical and patients reported outcomes.	Effect of high (≥23L) versus low volume HDF (<23L) on β2M clearance.; Effect of high (≥23L) versus low volume HDF (<23L) on dialysis related symptom score (measured using IPOS-Renal questionnaire).; Effect of high (≥23L) versus low volume HDF (<23L) on cognitive function (Assessed using PROMIS cognitive function short form).; Effect of high (≥23L) versus low volume HDF (<23L) on malnutrition score (Measured using modified subjective global assessment tool).; Effect of high (≥23L) versus low volume HDF (<23L) on serum phosphate level (mmol/L).; Effect of high (≥23L) versus low volume HDF (<23L) on phosphate binder dose (mg/day). This will be measured cross-sectionally at 0,6 and 12 month time points and longitudinally over time correcting for variables including residual renal function.	12 months
Effect of dialysis fluid sodium concentration of (137 vs 140 mmol/L) on overhydration volume in patients on HD and HDF.	Effect of dialysis fluid sodium concentration of (137 vs 140 mmol/L) on overhydration volume (measured with Bioimpedance) in patients on HD and HDF. This will be assessed cross-sectionally at 0,6 and 12 months and also longitudinally over time correcting for confounding variables such as RKF.	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Correlation between middle molecule clearance (β2M clearance) with rate of major adverse cardiovascular events (non-fatal MI, Non-fatal stroke, cardiovascular death) and all cause hospitalizations.	Correlation between middle molecule clearance (β2M clearance) with rate of major adverse cardiovascular events (non-fatal MI, Non-fatal stroke, cardiovascular death) and all cause hospitalizations.	5 years

Collaborators and Investigators

• Sponsor: East and North Hertfordshire NHS Trust
• Investigators: Principal Investigator: Usama Afzal Butt, MBBS, MRCP, East and North Hertfordshire NHS Trust

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2025
• Primary Completion (Estimated): November 1, 2030
• Study Completion (Estimated): November 1, 2030

Study Registration Dates

• First Submitted: July 2, 2026
• First Submitted That Met QC Criteria: July 16, 2026
• First Posted (Actual): July 21, 2026

Study Record Updates

• Last Update Posted (Actual): July 21, 2026
• Last Update Submitted That Met QC Criteria: July 16, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: Middle molecules clearance in haemodiafiltraion; Effect of dialysis clearance on nutritional status; Effect of dialysis clearance on patient reported outcome measure; Effect of dialysate sodium on fluid status
• Additional Relevant MeSH Terms: Nutrition Disorders; Nutritional and Metabolic Diseases; Malnutrition
• Other Study ID Numbers: RD2024-52; IRAS (Other Identifier: 348018); REC (Other Identifier: 24/PR/1131)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No