Online hemodiafiltration confers a reduced mortality risk. However, it is not clear why HDF improved survival. To gain more insight in this issue, the effect of 4 dialysis techniques (differing in dialysate temperature and the absence/presence of convective clearance) on intradialytic hemodynamic stability and cardiac function will be investigated in a prospective cross over trial.

Despite the use of high permeable dialyzers, which combine diffusive with convective clearance, the clinical outcome of hemodialysis (HD) patients remains poor. In post-dilution online hemodiafiltration (denoted further on as HDF) diffusive clearance is similar to HD, while the amount of convective transport is considerable increased. Recently, 4 randomized controlled trails have been published which compared HD with HDF. Although the results of the individual studies were inconclusive, a recent meta-analysis, using individual patient data of these studies, showed a superior outcome for patients treated with HDF. The largest mortality reduction was obtained in patients receiving the highest convection volume (high-volume HDF [HV-HDF] >23 L/1.73 m2/session): all-cause mortality [22% (95 % confidence interval [CI] 2-38)], cardiovascular disease (CVD) mortality [31% (95 % CI 0-53)].

It is far from clear, however, why (HV)HDF is associated with an improved survival. Both long term and short term effects may be involved. With respect to the latter, the intra-dialytic removal of middle molecular weight (MMW) uremic retention products and a superior bio-incompatibility (BI) profile may play a role. In addition, treatment with HDF may induce less intra-dialytic hypotension (IDH) and less tissue injury. Enhanced removal of the MMW substance FGF23 may reduce the intra-dialytic acute phase reaction (APR), which is regarded a chief element of HD-induced BI. Other key components which may contribute to IDH and are supposed to be alleviated by HDF, include dialysis-induced hypoxia and intra-dialytic extracellular vesicle release. Patho-physiologically, IDH depends both on a decline in the circulating blood volume and an impaired response to hypovolaemia. As a result, venous return, cardiac output and peripheral vascular resistance are impaired. Since IDH is reduced by HD with cool dialysate (C-HD), thermal factors may play an important role.

Microcirculatory dysfunction is a prominent feature of HD patients. Since IDH occurs in 20-30% of the sessions, any interference with an already abnormal perfusion may further deteriorate the structure and function of vital organs, such as the brain, gut and heart. HD-associated cardiomyopathy, which is considered a model of repetitive organ ischemia-reperfusion injury, is superimposed on the cardiac changes resulting from the various inflammatory and metabolic derangements of pre-dialysis kidney disease. As measured by imaging techniques and biomarkers, HD induces a fall in cardiac perfusion and elicits tissue injury. While cardiac MRI is considered the reference method for LV quantification, intra-dialytic measurements can only be obtained in stable patients who can be safely transferred to the radiology department. Echocardiography, though, can be performed in all individuals at the bed-side, including hypotension-prone patients. Because of its superiority over standard echocardiography, especially with respect to diastolic (dys)function, speckle tracking echocardiography will be used in the present study.

As mentioned, the effect on long term survival is especially prominent when HV-HDF is applied. Theoretically, HV-HDF is also the preferred treatment to circumvent dialysis-induced IDH, and hence, to alleviate the repetitive intra-dialytic tissue damage. Therefore, the following hypotheses will be tested:

1. intra-dialytic hemodynamic stability is better preserved during HV-HDF as compared to standard (S)-HD, C-HD and low volume (LV)-HDF;
2. mainly as a result of a better intra-dialytic hemodynamic stability, the severity of organ injury, especially the heart, is least evident during HV-HDF;
3. the mechanism of a better preserved intra-dialytic hemodynamic stability during HV-HDF depends on its superior thermal balance and/or bio-incompatibility, clearance of MMW substances, or a combination of these items.

Worldwide, however, (HV)HDF is only limited available. Since intradialytic hemodynamic instability may contribute substantially to the poor clinical prospects of end-stage-kidney-disease (ESKD) patients, these individuals may benefit from each maneuver that minimizes the number and severity of intradialytic hypotensive episodes. Therefore, the question which of the comparator treatments [(S)-HD, C-HD and LV-HDF] has the best intradialytic hemodynamic stability, appears relevant as well.

Inclusion Criteria:

• treatment with HD or HDF 3 x per week during at least 4 hours for at least 2 months
• ability to understand study procedures
• willingness to provide informed consent
• single pool Kt/V urea (spKt/Vurea) ≥ 1.2
• achievement of blood flow of ≥360 ml/min and/or convection volume of >23 Liter per treatment during the run-in phase

Exclusion Criteria:

• - current age < 18 years
• severe incompliance to dialysis procedure and accompanying prescriptions, especially frequency and duration of dialysis treatment
• life expectancy < 3 months
• participation in another clinical intervention trial

treatment period will not be available to the assessors of secondary outcomes.