Expanded Hemodialysis Versus Online Hemodiafiltration: a Pilot Study on Intradialytic Hemodynamics and Fluid Status
Phase: NA
Conditions: Dialysis Related Complication, Dialysis Hypotension, Hemodialysis-Induced Symptom
Sponsor: University of Sao Paulo

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EXPANDED HEMODIALYSIS VERSUS ONLINE HEMODIAFILTRATION: A 
PILOT STUDY ON INTRADIALYTIC HEMODYNAMICS AND FLUID STATUS  
 
 
Institution 
Department of Medicine, Renal Division, University of São Paulo, São Paulo, 
Brazil 
 
NCT ID NCT03274518   
Unique Protocol ID: 16928 
 
Document Date: 09/27/2019 
 
 
 
 
 

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Abstract 
Conventional hemodialysis (HD) is essential for the treatment of end-stage renal 
disease (ESRD) patients, by reducing serum concentration of uremic toxins and 
correcting fluid overload. 
Nevertheless, HD removes almost exclusively low-range uremic toxins. 
Therefore, medium-range molecules, such as beta-2-microglobulin might 
accumulate in tissues, leading to many clinical complications, such as 
neuropathies, tendinopathies, anemia, bone mineral disease and reduced growth 
in children.  
Convective methods might reduce incidence of these complications, by 
removing molecules of medium-range molecular weight. Online hemodiafiltration 
(olHDF) is the most extensively used method in this regard. Nevertheless, there 
are some barriers to the wider introduction of this method in clinical practice, since 
specific machines are needed for this procedure, the costs with dialysis lines are 
higher and water consumption increases. More recently, the development of new 
membranes for hemodialysis allowed removal of medium- and high-range uremic 
toxins, with albumin retention. Thus, they allow removal of a broad range of 
uremic toxins, without changing dialysis machine or increasing water 
comsumption. Such therapy is known as expanded hemodialysis (HDx). 
The aim of this present study is to compare the extraction of middle-size 
molecules, the hemodynamic behavior, fluid and nutritional status of patients 
submitted to olHDF or HDx, in a crossover study.   
 
 
 
 
 
 
 
 
 
 
 
 

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Introduction 
End-stage renal disease (ESRD) is a condition characterized by marked decline 
in renal function, usually at rates below 10 ml/min/1.73 m². In Brazil, there are 
about 110,000 patients on maintenance hemodialysis (HD) and mortality rates 
are around 19%.(1) The explanation for this high mortality rate derives from 
comorbidities such as Diabetes Mellitus, arterial hypertension and left ventricular 
hypertrophy.(2-4) Additionally, these patients are submitted to extracorporeal 
circulation, with intense body fluid variation and electrolyte composition during 
procedure. Besides, several uremic toxins are not removed during HD 
sessions.(5) 
 
Improvement of dialysis and membrane technologies has flourished in the 
last decades. They have provided better management of these patients and 
prolonged survival. 
 
Uremic syndrome 
Uremic syndrome is characterized by several clinical manifestations resulting 
from the progressive loss of renal function, with biochemical, fluid and functional 
alterations.(6, 7) 
Uremic toxins have different molecular weights. The most frequently 
reported is urea, which has molecular weight of 60 Da and is used as a marker 
of HD quality. Low molecular weight solutes are readily dialyzable by 
conventional HD. Intermediate molecular weight (IMW) solutes have a molecular 
weight between 500 and 60000 Da. Among them are beta-2-microglobulin (β2M), 
which is associated with dialysis-related amyloidosis, leptin, related to 
malnutrition, prolactin, which is associated to infertility of women in dialysis, 
hepcidin, related to the anemia of patients with CKD, among others.(8, 9) IMW 
solutes are not significantly removed by conventional HD and tend to accumulate 
in the organism of dialytic patients.(10) More recently, membranes for HD with 
high permeability to medium molecules and with selective retention of albumin 
have also emerged as an option to convective therapies. Such modality is known 
as expanded hemodialysis (HDx).(11) 
 
 
 

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Online Hemodiafiltration 
The olHDF technique combines diffusion with high convection rates in which the 
dialysis fluid, free of toxins and pyrogens, is used to prepare the replacement 
fluid.(12) 
The online module of dialysis machine prepares the replacement fluid by 
a cold sterilization process. There is a cross-flow water preparation, in order to 
avoid the accumulation of possible contaminants. The addition of bicarbonate 
and acid solutions to water follows the process. Next, the ready-for-infusion 
dialysis solution is passed through another ultrafilter prior to being infused into 
patients. The microbiological safety of these systems is demonstrated in clinical 
studies with an absence of activity-inducing cytokines and pyrogenic 
reactions.(13, 14) 
Some studies have compared olHDF with HD. The Contrast study(15) 
included 714 patients, with an average follow-up of 3 years. There were no 
differences in mortality in both modalities. However, for replacement volume 
above 21.95L, there was reduction in mortality of olHDFol group. The Turkish 
study(16) also presented similar data, without differences in general mortality, 
with the exception of the subgroup of patients with a replacement volume greater 
than 17.4L. 
The Eshol study,(17) which included 906 patients, with an average follow-
up of 1.91 years, showed a reduction in mortality using olHDF, regardless of the 
replacement volume used. In this study, mean replacement volume was 23.7L. 
 
Dialysis membranes 
Blood-dialysate interaction through semi-permeable membranes has always 
characterized dialysis methods since the first dialysis sessions in the mid-
twentieth century. 
Some physical characteristics determine the dialysis membranes: 
- KoA: determines the permissibility to the diffusion of small molecules, in 
the presence of ideal diffusion conditions (with theoretically infinite blood and 
dialysate flows); 
- Kuf: is determined by hydraulic conductance of a membrane in the 
presence of a transmembrane pressure; 

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- sieving: proportion of molecules that can cross the membrane, according 
to their molecular weight. 
 
The diffusive process depends fundamentally on the density of pores in 
the membrane. The ultrafiltration and sieving properties vary depending on the 
mean pore diameter of the membrane. 
The size of the pores determines which molecules are allowed to move 
across membranes. The molecular size at which the sieving coefficient is only 0.1 
is termed membrane’s cutoff value. That is, molecules with molecular weight 
above this value are unlikely to cross the membrane. 
However, the cutoff value is not the only one that defines the permeability 
of a membrane. Another parameter, termed “retention onset” (RO) should also 
be determined for this purpose. It describes the molecular weight/radius where 
the sieving value is 0.9. Besides, dialysis membranes can have different pore 
sizes. Membranes with a more heterogeneous distribution of pore size may 
present greater loss of albumin than a membrane with more homogeneous sizes 
of these pores, although both have the same cutoff values.(11)  
High cutoff membranes have recently been introduced into clinical 
practice, with the potential benefit of removing toxins with high molecular weight, 
typically associated with sepsis, rhabdomyolysis and hematological diseases, 
such as inflammatory cytokines, myoglobin, free light chains. Such membranes, 
however, also lead to loss of albumin, which can lead to or aggravate malnutrition. 
More recently, membranes with high cutoff values, but with tight pore size 
distribution have been developed. The main concept is to keep both cutoff and 
retention onset values close to each other, but with a cutoff value lower than of 
albumin. This should allow removal of middle-to-high weight range uremic toxins, 
with very low albumin leak. Thus, these membranes, denominated high retention 
onset (HRO) membranes, allow performing both diffusive and convective 
processes in a conventional hemodialysis machine. These new HRO membranes 
defined a new modality of HD, denominated expanded hemodialysis (HDx). 
 
 

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Hypothesis 
Our hypothesis is that HDx is noninferior to olHDF in the following parameters: 
- 
Hemodynamic stability 
- 
Nutritional and fluid status 
- 
Removal of beta-2 microglobulin 
 
Objectives 
To evaluate each patient, through a prospective, randomized and cross-over 
study, the intradialytic hemodynamic behavior, fluid and nutritional status 
assessed by electrical bioimpedance and B2M removal in two dialytic modalities: 
HDFol versus HDx. 
 
Subject and Methods 
Inclusion criteria 
Adult patients who are on maintenance HD at Hospital das Clínicas and agree to 
participate in the study by signing the informed consent form. 
 
Exclusion criteria 
Patients who cannot understand or who refuse to sign the informed consent form; 
Patients who are currently on daily HD or olHDF. 
 
Concise methods 
a) Clinical and laboratorial data 
Clinical data will be collected from the institution's chart, recorded and filled with 
all necessary precautions to keep confidentiality of patient's information. They 
are: baseline renal disease, age, history of smoking, sedentary lifestyle, presence 
of comorbidities such as hypertension and diabetes mellitus, family history of 
cardiovascular disease, history of coronary and cerebrovascular disease and 
medications. 
Laboratory tests used to determine the biochemical, hematological and 
bone mineral profile characteristics will be obtained from routinely collected 

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exams. Such exams are processed by the Central Laboratory of Hospital das 
Clínicas / FMUSP. 
 
b) Dialysis 
All dialysis procedures will be performed by the Dialog+ Admea™  machine 
(BBraun Melsungen AG, Germany). 
The olHDF will be prescribed as follows: blood flow 350 - 400 ml/min, 
dialysate flow 800 ml/min, post-dilution flow (90-100 ml/min), with high-flux 
Xevonta™ (BBraun Melsungen AG, Germany) or CAHP/DICE™ (Baxter 
Healthcare Corporation, Deutschland) dialyzers, with surface area of 1.7-2.4 
m². The duration of each session will be from 3,5h to 4h, depending on current 
dialysis prescription. Total substitution volume will be higher than 20 L per 
session. 
HDx will follow the same prescription of olHDF, regarding blood and 
dialysate flows and dialysis duration. There will be no substitution volume. 
Theranova™ dialyzers (Baxter Healthcare Corporation, Deutschland) will be 
used for each session. 
Before initiating protocol and during the washout period, patients will be 
submitted to high-flux HD, which is the standard treatment in our service.  
 
c) Hemodynamic monitoring 
Cardiac output index (CI), stroke volume (SV - integrated mean of the flow 
waveform between the current upstroke and the dichotic notch), peripheral 
arterial resistance (PAR - ratio of mean arterial pressure to stroke volume 
multiplied by heart rate) and blood pressure (BP) will be accessed by finger 
beat to-beat monitor Finometer™ (Finapress Medical Systems BV, 
Arnhem, The Netherlands), within 15 minutes after starting olHDF or HDx 
sessions (predialysis) and again, 15 minutes before its end (post-dialysis), 
according to a previous studies of our group.(18-20). 
 
d) Biolectrical impedance 
Segmental tetrapolar bioelectrical impedance (BIS) will be performed in all 
patients while recumbent, before starting study protocol and before each 
phase of the study (HDx or olHDF), by the multifrequency InBody™ S10 

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(Biospace Co., Ltd., Korea) device. It allows assessment of the following 
parameters regarding body fluids: total body water, total extracellular body 
water, lower limbs total water content, lower limbs extracellular water 
content. Additionally, α-angle, which is a marker of cellular integrity and 
nutritional status, will be noted.(21) 
 
 
e) Blood and Effluent samples 
Blood samples will be collected pre-session, mid-session and post-dialysis 
sessions, both in the first and last dialysis sessions of each of the periods 
studied (HDFol or HDx). Pre-session blood samples will be collected 
immediately after arteriovenous fistula puncture and the middle and post-
session samples will be collected from the arterial line, 2 minutes after 
reduction of blood flow to 50 ml/min and suspension of dialysate flow and/ 
or replacement. 
In addition, partial and homogeneous collection of the effluent will 
be performed by a drainage hose, with an infusion pump operating 
continuously at a rate of 1l/h, as previously validated in the literature,(22-
25) and successfully replicated by our service.(26, 27) The whole effluent 
of dialysis session will be collected. 
 
 
Description of study design and procedures are described in figure 1. 
Blood and effluent samples to be collected are depicted in table 1. 
 
 

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Figure 1. Protocol description 
 
 
Table 1. Description of Serum and effluent samples 
Blood 
First Sample 
(pre-dialysis) 
Second Sample 
(mid-dialysis) 
Third Sample 
(post-dialysis) 
Albumin 
X 
X 
X 
β2-microglobulin 
X 
X 
X 
Creatinin 
X 
X 
Phosphorus 
X 
X 
X 
Hematocrit 
X 
Hemoglobin 
X 
Total Protein 
X 
X 
X 
Urea 
X 
X 
X 
Effluent 
Albumin 
X 
β2-microglobulin 
X 
Phosphorus 
X 
Urea 
X 

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Statistical Analysis 
According to parametric distribution or not of the studied variables, paired t test 
or Wilcoxon’s test will be used, respectively. The following variables will be 
compared in the two following situations HDFol versus HDx, HDFol versus high-
flux HD and HDx versus high-flux HD: 
 
 Pre-dialysis serum samples: albumin, β2-microglobulin, creatinine, 
phosphorus, hematocrit, hemoglobin, total proteins, urea; 
 Intradialytic serum samples: albumin, β2-microglobulin, phosphorus, total 
proteins, urea; 
 Post-dialysis serum samples: albumin, β2-microglobulin, creatinine, 
phosphorus, total proteins, urea; 
 Intradialytic effluent samples: albumin, β2-microglobulin, phosphorus, total 
proteins, urea; 
 Pre-dialysis hemodynamic variables: blood pressure, cardiac index; 
 Post-dialysis hemodynamic variables: blood pressure, cardiac index, 
systolic volume, peripheral vascular resistance; 
 Pre-dialysis bioimpedance variables: extracellular water / total body water 
ratio and α-angle;  
 Post-dialysis bioimpedance variables: extracellular water / total body water 
ratio and α-angle. 
 
 
 
 
 
 
 
 
 
 
 
 

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