Effect of High-volume Online hemodiafiLtration on intra-diaLytic hemodynAmic (iN)sTability and cardiac function in chronic hemodialysis patients (the HOLLANT study)

Worldwide, over 2 million patients are treated with extracorporeal renal
replacement therapy (ERRT).
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 (mortality reduction of 14% [95% CI 1-25]). 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
% CI 2-38)], cardiovascular 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-dialytical 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-dialytical 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 release of extracellular vesicles.
Pathophysiologically, 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.
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-dialytical 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 is preferred.
Since IDH is reduced by HD with cool dialysate (C-HD), thermal factors seem to
play an important role in the preservation of intra-dialytical hemodynamic
stability during C-HD. Hence, patients may not only benefit from a reduction in
IDH and related symptoms, but also encounter an increase in cold sensations.
Considering patient-reported outcomes, it is currently unclear whether and to
what extent the beneficial effect of C-HD and LV-HDF on IDH is counterbalanced
by concurrent patient discomfort. Interestingly, in a recently published French
study it appeared that patient tolerance was significantly better during
treatment with HV-HDF, as compared to S-HD.
As mentioned above, 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-dialytical tissue damage.

This study aims at improving the knowledge concerning HV-HDF and thus helps to
tailor the optimal ERRT for each individual patient.
The following hypotheses will be tested:
1. Intra-dialytic hemodynamic stability is better preserved during HV-HDF as
compared to S-HD, C-HD and LV-HDF.
2. Left ventricular diastolic function is better preserved during HV-DF as
compared to S-HD, C-HD and LV-HDF. As a result of superior hemodynamic
stability, HV-HDF induces less intra-dialytic injury to the heart, blood
vessels and gut as compared to S-HD, C-HD and LV-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.
4. The above-mentioned beneficial effects of HV-HD are accompanied by a
reduction in IDH-related symptoms and not by an increase in thermal sensations,
such as shivering and the quest for blankets.

This study is designed as an open, prospective cross-over, randomized
controlled intervention trial.

Patients will be subjected to different types of ERRT. In all modalities
high-flux dialyzers are used.

Standard treatment: HD with a dialysate temperature of 36.5 °C. (S-HD)

Comparators:
- HD with a (cool) dialysate temperature of 35.5 °C (C-HD)
- HDF with a convection volume of 15 L/session and a dialysate temperature of
36.5 °C (LV-HDF)
- HDF with a convection volume of >23L/session and a dialysate temperature of
36.5 °C (HV-HDF)

HDF will be performed in the post-dilution mode with a target convection volume
(substitution volume + net UF volume) of 15L (LV-HDF) or >23L (HV-HDF).
Extracorporeal blood flow rate will be targeted at 350-400 ml/min, and
filtration fraction (blood flow rate/ convection flow rate) at 25-32%.

Run-in phase during 2 weeks followed by randomisation to treatment with C-HD,
S-HD, LV-HDF and HV-HDF during 2 weeks.

Total study duration is 2 weeks (run-in phase) + 8 weeks(study phase) = 10
weeks per patient.

As none of the study treatments is experimental, no specific adverse events
are to be expected.

Possible inconveniences for the patient:
During the study, patients will be dialyzed with several modalities.Treatment
time and all the other procedures are however similar in all modalities and
will therefore cause no extra risks or put extra mental pressure on the
patients.

Application of C-HD may induce shivering, which is uncommon in LV-HDF despite a
similar energy transfer. In theory, HV-HDF may induce an even greater loss of
heat and hence provoke cold sensations in participants.

Since the measurement of intradialytical hemodynamics is an essential part of
this study, extra BP recordings, which will be taken every 15 minutes during
the last week of every dialysis modality, may cause some discomfort.

The beat-to-beat nonivasive bloodpressure measurements will be perfomed during
a total of 4 dialysis treatments with a fingercuff and may cause some
discomfort.

The speckle tracking echocardiography assessment will be performed during 4
dialysis treatments.

In the entire study, during 4 dialysis treatments blood samples will be taken
before and after the dialysis from the ECC. Therefore no extra punctures are
needed.

The total amount of blood sampled during the study is 203 ml. If the Hemoglobin
level decreases below 6.8 mmol/L, the dosage of Erythropoietin Receptor
Agonists will be increased (according to routine clinical practice).

A modified version of the Dialysis Symptom Index (DSI) will be handed out after
each treatment period (totally 4 times) and Visual Analogue Scale Thermal
Perception (VAS-TP) will be assessed both before and after 1 and 3 hours of
every dialysis treatment. Filling in the forms will take a maximum of 1
(VAS-TP) and 5 minutes (DSI) every time.

Possible advantages for the patient:
As far as we know, however, shivering has not been reported in HV-HDF, nor are
we aware of this discomfort in clinical practice. In theory, HV-HDF may enhance
both the efficacy and the quality of dialysis treatment by lowering the
incidence of dialysis-induced IDH and thus:
* avoid the subjective symptoms of intra-dialytical low blood pressure
* alleviate the repetitive intra-dialytical organ injury of chronic ERRT [and
hence, to contribute in part to the superior survival of HV-HDF (evidence level
A1)]
* diminish or even prevent the cold sensations of C-HD
* achieve these goals within 12 hours of dialysis/week, in contrast to
schedules of extended dialysis, up to 24-48 hours/week, with similar objectives
* gain knowledge about patient perceptions during dialysis with these 4
different modalities