Uremic Toxin Removal and Hemodynamics in Long-Hour Hemodialysis and Hemodiafiltration; A Randomized Cross-Over Study

Overall survival of patients on renal replacement treatment (RRT) remains low,
although many efforts have been made in the past decades to improve the outcome
of the dialysis population e.g. by increasing the removal of uremic toxins.
Especially protein-bound solutes and peptides are difficult to remove by
conventional dialysis treatments, and exactly these particular uremic toxins
(mainly p-cresol and indoxyl sulphate) are associated with cardiovascular
morbidity and mortality in patients with chronic kidney disease (CKD) and in
dialysis patients. Also at the cellular level, multiple adverse effects of
(protein-bound) uremic toxins have been described.
Intensive haemodialysis (HD) [short-daily haemodialysis, in-centre nocturnal
haemodialysis (NHD) and nocturnal home haemodialysis] is associated with
significant improvement of several clinical (e.g. blood pressure, left
ventricular hypertrophy, coronary calcification, sleep apnoea, quality of life,
fertility), biochemical (e.g. phosphate control, anemia) and biological (e.g.
endothelial function, inflammation) parameters . A potential explanation for
these observed results is the increased clearance of uremic toxins due to the
increased duration and/or frequency of haemodialysis. The kinetics of
(protein-bound) uremic toxins in nocturnal haemodialysis has not been studied
yet extensively.
Convective strategies, especially online haemodiafiltration (HDF), may further
increase uremic toxin removal. This has especially been shown for small uremic
retention solutes, phosphate, beta2-microglobulin and cytokines, but it is
uncertain whether online HDF also increases the removal of protein-bound uremic
toxins.
We hypothesize that increasing the duration of haemodialysis together with
augmentation of convection leads to further increase of (especially
protein-bound) uremic toxin removal, which may ultimately lead to improvement
of cell biology and eventually of clinical parameters.
Next to the possible improvements in uremic toxin removal, long dialysis also
was shown to result in better hemodynamic stability. This is likely due to a
more physiologic fluid removal due to long treatment times. This may reduce
myocardial stunning which is associated with increased cardiovascular morbidity
and mortality. However, also beneficial effects of long dialysis on the
functioning of the autonomic nervous system, which is often disturbed during
dialysis, might be involved and may lead to improved hemodynamic stability.
There is circumstantial evidence that also HDF has beneficial effects on the
autonomic nervous system, even in short term, such as during a single dialysis
session. The effects of a combination of increasing the dialysis duration and
adding convection on hemodynamic stability and autonomous nervous system
function have not been studied yet.

The primary aim of this study is to compare the removal of (especially
protein-bound) uremic toxins between 4-hour and 8-hour HD and HDF in order to
evaluate the influence of dialysis duration and of convection on the removal of
uremic toxins.
A secondary aim is to compare the haemodynamic response and autonomic nervous
system functioning [blood pressure (BP), heart rate, heart rate variability,
cardiac output, relative (RBV) and central blood volume (CBV), and peripheral
microcirculation with capillaroscopy] between 4-hour and 8-hour HD and HDF.

Twenty prevalent conventional hemodialysis (CHD) patients (dialysing 3 days a
week during 4 hours per dialysis session) will undergo, in random order, a
mid-week 4-hour HD session, a mid-week 4-hour HDF session, a mid-week 8-hour HD
session, and a mid-week 8-hour HDF session with a 2-week interval between every
session to assess the influence of treatment duration and of convection on the
removal of uremic toxins and on the haemodynamic responses and autonomic
nervous regulation. In between the study dialysis sessions these patients will
receive routine CHD treatments. Ten non-participating hemodialysis patients
with significant residual urine production (and therefore the absence of
significant ultrafiltration during hemodialysis) will undergo the same
measurement during one conventional 4-hour hemodialysis session to study the
effects of hemodialysis without ultrafiltration on microcirculation and
endothelial function. Fifteen other non-participating patients without
significant residual urine output and therefore the need for ultrafiltration
during hemodialysis will also undergo the same measurement during one standard
dialysis treatment. In this last patient group, bio-impedance will also be
performed with the BCM (Body Composition Monitor) before and after the study
session. Also, twenty non-participating hemodialysis patients will undergo
capillaroscopy at times 0, 30, 60, 120, (150) and 240 minutes when blood
samples will be drawn to check the levels of several inflammatory and
endothelial markers, in an attempt to correlate observed glycocalyx changes
with inflammation. These patients will be studied twice, the first time when
Low Molecular Weight Heparin (LMWH) is given at the start of the treatment and
the second time when LMWH is given 120 minutes after the start of the
treatment, in order to evaluate the potential effect of LMWH on the endothelial
glycocalyx.

Prevalent conventional hemodialysis patients will undergo a conventional
hemodialysis session to study the baseline kinetics and hemodynamics and will
subsequently undergo, in a random way, a 4-hour hemodiafiltration session and
an 8-hour hemodialysis and hemodiafiltration session, each session separated
from the other by a 2-week interval.

In this study, only non-invasive techniques which pose a minimal burden to the
patient will be used. Blood sampling will coincide with the dialysis sessions.
The study will not have direct benefit for the participants. The study can only
be performed with this specific patient group.