Expanded Hemodialysis Versus Online Hemodiafiltration

• Sponsor: University of Sao Paulo (Other)
• Overall Status: Completed
• CT.gov ID: NCT03274518
• Collaborator: (none)
• Enrollment: 16
• Location: 1
• Arms: 2
• Actual Duration (Months): 15.9
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

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 consumption. 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.

Condition or Disease	Intervention/Treatment	Phase
Dialysis Related Complication; Dialysis Hypotension; Hemodialysis-Induced Symptom	Device: Expanded Hemodialysis; Device: Online Hemodiafiltration	N/A

Detailed Description

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.

Concise methods

1. 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 exams. Such exams are processed by the Central Laboratory of Hospital das Clínicas / FMUSP.

1. 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, Germany) 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, Germany) 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.

1. 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).

2. Bioelectrical 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 (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.

3. 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. The whole effluent of dialysis session will be collected.

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Investigator)
• Masking Description: Investigator who collects laboratorial, hemodynamics and bioimpedance data will be blinded for intervention (online hemodiafiltration or expanded hemodialysis)
• Primary Purpose: Treatment
• Official Title: Expanded Hemodialysis Versus Online Hemodiafiltration: a Pilot Study on Intradialytic Hemodynamics and Fluid Status
• Actual Study Start Date: Nov 13, 2017
• Actual Primary Completion Date: Oct 18, 2018
• Actual Study Completion Date: Mar 11, 2019

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 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. 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.	Device: Online Hemodiafiltration; Intervention: Conversion from conventional HD to online Hemodiafiltration por 1 month. Online hemodiafiltration has been associated with lower incidence of intradialytic hypotension in comparison to conventional hemodialysis.
Experimental: Expanded Hemodialysis 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.	Device: Expanded Hemodialysis; Intervention: Conversion from conventional HD to expanded hemodialysis por 1 month. High cutoff with high retention onset dialyzers allow clearance of middle molecules, without reducing significantly serum concentration of albumin. It allows higher convective clearance in comparison to conventional hemodialysis, but it is unknown if such clearance is similar to online hemodiafiltration. Therefore, the aim of the present intervention is to compare this dialyzer with online hemodiafiltration; Other Names: Theranova Dialyzer

Outcome Measures

Primary Outcome Measures

1. Medium Molecule Clearance [One month after starting protocol]

   Beta-2-Microglobulin clearance

2. Medium Molecule Removal [One month after starting protocol]

   Beta-2-Microglobulin extraction

Secondary Outcome Measures

1. Intradialytic Hemodynamics [Cardiac output (liters per minute) one month after starting protocol]

   noninvasive cardiac output assessment

Other Outcome Measures

1. Fluid Status [One month after starting protocol]

   noninvasive assessment of extracellular and total body water

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Adult patients who are on maintenance hemodialysis 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 hemodialysis or online hemodiafiltration.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Hospital das Clínicas	São Paulo		Brazil	05403-000

Sponsors and Collaborators

• University of Sao Paulo

Investigators

• Principal Investigator: Bruno C Silva, PhD, Renal Division, Unversity of São Paulo

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Sep 27, 2019
• Informed Consent Form - Oct 17, 2018

More Information

Publications

None provided.

• Responsible Party: Bruno Caldin da Silva, Principal Investigator, University of Sao Paulo
• ClinicalTrials.gov Identifier: NCT03274518
• Other Study ID Numbers: 16928
• First Posted: Sep 7, 2017
• Last Update Posted: Sep 30, 2019
• Last Verified: Sep 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Bruno Caldin da Silva, Principal Investigator, University of Sao Paulo: Hemodialysis; Hemodiafiltration; fluid status; hemodynamics
• Additional relevant MeSH terms: Hypotension

Study Results

Participant Flow

Arm/Group Title	Online Hemodiafiltration	Expanded Hemodialysis
Arm/Group Description	Arm description: Online Hemodiafiltration first, then expanded hemodialysis. First, patients changed fom conventional HD to online hemodiafiltration for 1 month. Then, patients returned to conventional HD for 2 weeks (washout period). Then, patients underwent the second intervention (expanded hemodialysis) for 1 month, in a cross-over design.	Arm description: expanded hemodialysis first, then online hemodiafiltration. Intervention: Conversion from conventional HD to expanded hemodialysis for 1 month. Then, patients returned to conventional HD for 2 weeks (washout period). Then, they underwent the second intervention (online hemodiafiltration), for 1 month, in a cross-over design.
Period Title: First Intervention
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0
Period Title: First Intervention
STARTED	8	8
COMPLETED	8	8
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Online Hemodiafiltration	Expanded Hemodialysis	Total
Arm/Group Description	Patients were included in this study group per sequence: Online hemodiafiltration (olHDF) first for 1 month, then expanded hemodialysis (HDx) for 1 month. Baseline characteristics assessed: Age Gender Ethnicity Region of Enrollment Serum Beta-2 Microglobulin	Patients were included in this study group per sequence: Expanded hemodialysis (HDx) first for 1 month, then online hemodiafiltration (olHDF) for 1 month. Baseline characteristics assessed: Age Gender Ethnicity Region of Enrollment Serum Beta-2 Microglobulin	Total of all reporting groups
Overall Participants	8	8	16
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	7 87.5%	8 100%	15 93.8%
>=65 years	1 12.5%	0 0%	1 6.3%
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	39.5	46	39.5
Sex: Female, Male (Count of Participants)
Female	3 37.5%	2 25%	5 31.3%
Male	5 62.5%	6 75%	11 68.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	8 100%	7 87.5%	15 93.8%
Not Hispanic or Latino	0 0%	1 12.5%	1 6.3%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Brazil	8 100%	8 100%	16 100%
Serum Beta-2 Microglobulin (mcg/ml) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mcg/ml]	23.2 (6.9)	27.8 (5.5)	25.2 (6.1)

Outcome Measures

1. Primary Outcome

Title	Medium Molecule Clearance
Description	Beta-2-Microglobulin clearance
Time Frame	One month after starting protocol

Outcome Measure Data

Analysis Population Description

Beta-2 Microglobulin clearance (ml/min)

Arm/Group Title	Online Hemodiafiltration	Expanded Hemodialysis
Arm/Group Description	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. 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.	High cutoff with high retention onset dialyzers allow clearance of middle molecules, without reducing significantly serum concentration of albumin.
Measure Participants	16	16
Median (Inter-Quartile Range) [ml/min]	53	59.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Online Hemodiafiltration, Expanded Hemodialysis
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin was defined as difference within 20% in comparison to reference method (olHDF)
Statistical Test of Hypothesis	p-Value	0.4534
	Comments
	Method	t-test, 2 sided
	Comments

2. Primary Outcome

Title	Medium Molecule Removal
Description	Beta-2-Microglobulin extraction
Time Frame	One month after starting protocol

Outcome Measure Data

Analysis Population Description

Beta-2-microglobulin mass extraction (mg)

Arm/Group Title	Online Hemodiafiltration	Expanded Hemodialysis
Arm/Group Description	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. 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.	High cutoff with high retention onset dialyzers allow clearance of middle molecules, without reducing significantly serum concentration of albumin.
Measure Participants	16	16
Mean (Standard Deviation) [mg]	198 (81)	239 (86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Online Hemodiafiltration, Expanded Hemodialysis
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin was defined as difference within 20% in comparison to reference method (olHDF)
Statistical Test of Hypothesis	p-Value	0.1179
	Comments
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

Title	Intradialytic Hemodynamics
Description	noninvasive cardiac output assessment
Time Frame	Cardiac output (liters per minute) one month after starting protocol

Outcome Measure Data

Analysis Population Description

Intradialytic cardiac output variation (post-pre dialysis), l/min

Arm/Group Title	Online Hemodiafiltration	Expanded Hemodialysis
Arm/Group Description	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. 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.	High cutoff with high retention onset dialyzers allow clearance of middle molecules, without reducing significantly serum concentration of albumin.
Measure Participants	16	16
Median (Inter-Quartile Range) [l/min]	-1.3	-1.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Online Hemodiafiltration, Expanded Hemodialysis
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The non-inferiority margin was defined as difference within 20% in comparison to reference method (olHDF)
Statistical Test of Hypothesis	p-Value	0.3054
	Comments
	Method	t-test, 2 sided
	Comments

4. Other Pre-specified Outcome

Title	Fluid Status
Description	noninvasive assessment of extracellular and total body water
Time Frame	One month after starting protocol

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Online Hemodiafiltration	Expanded Hemodialysis
Arm/Group Description	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. 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.	High cutoff with high retention onset dialyzers allow clearance of middle molecules, without reducing significantly serum concentration of albumin.
Measure Participants	16	16
Mean (Standard Deviation) [liter/liter]	0.39 (0.01)	0.385 (0.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Online Hemodiafiltration, Expanded Hemodialysis
	Comments
	Type of Statistical Test	Non-Inferiority
	Comments	The lower the ECW/TBW ratio, the lower pre-dialysis excess fluid. A non-inferiority margin was defined as difference within 10% from reference method (olHDF)
Statistical Test of Hypothesis	p-Value	0.045
	Comments
	Method	t-test, 2 sided
	Comments

Adverse Events

Time Frame	3 months
Adverse Event Reporting Description	No adverse events noted
Arm/Group Title	Online Hemodiafiltration		Expanded Hemodialysis
Arm/Group Description	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. 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. Online Hemodiafiltration: Intervention: Conversion from conventional HD to online Hemodiafiltration por 1 month. Online hemodiafiltration has been associated with lower incidence of intradialytic hypotension in comparison to conventional hemodialysis.		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. Expanded Hemodialysis: Intervention: Conversion from conventional HD to expanded hemodialysis por 1 month. High cutoff with high retention onset dialyzers allow clearance of middle molecules, without reducing serum concentration of albumin. It allows higher convective clearance in comparison to conventional hemodialysis, but it is unknown if such clearance is similar to online hemodiafiltration. Therefore, the aim of the present intervention is to compare this dialy
All Cause Mortality
	Online Hemodiafiltration		Expanded Hemodialysis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Serious Adverse Events
	Online Hemodiafiltration		Expanded Hemodialysis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)
Other (Not Including Serious) Adverse Events
	Online Hemodiafiltration		Expanded Hemodialysis
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/8 (0%)		0/8 (0%)

Limitations/Caveats

The sample size was small and trial length was relatively short. We did not directly assessed albumin extraction. Besides, the relatively low ultrafiltration coefficient of both dialyzers limited dialysis performance in all treatment groups.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.