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

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.