Post-Dilution Online Hemodiafiltration - Is This Standard Care For ESRD Patients?
Renewed interest in convective renal replacement therapy is fueled by the desire to reduce high mortality of maintenance dialysis patients. Is online hemodiafiltration the answer?
Author:Suleman ShahReviewer:Han JuAug 09, 202418K Shares333.3K Views
Although encouraging data have been obtained from retrospective analyses or prospective cohort studies, widespread implementation of online hemodiafiltrationhas been hampered by lack of conclusive evidence of improved survival compared to hemodialysis.
This review discusses standard care for end-stage renal disease patients (ESRD).
Current maintenance dialysis practice patterns (three times per week, single-pool Kt/Vurea of 1.2) effectively prevent death of ESRD patients from uremia.
Numerous advancements in dialysis technologyand improvements in patient care have helped ESRD patients to live better with their disease and allowed elderly frail patients to be treated.
However, mortality remains an important issue.
b. approximately 8 years- for a dialysis patient aged 40 to 44 years
c. 4.5 years- for those aged 60 to 64 years
d. 3 years- for those aged 75 years or more
Survival of aged dialysis patients is slightly better when compared to survival in patients with lung cancer or colorectal cancer.
Conventional hemodialysis procedures do not perfectly reproduce normal excretory renal function.
Low-flux hemodialysis membranes clear small water-soluble solutes from the body efficiently by diffusion.
Removal of other compounds is, however, limited due to:
- middle or large molecular size
- protein binding
- sequestration within body compartments
In patients undergoing conventional dialysis (low-flux membrane, commercial dialysis fluid), these three contribute to high morbidity and mortality of standard dialysis patients:
- retention of middle-sized to large-sized organic solutes
- incompletely corrected inorganic ion disturbances
- aggravation of low-grade systemic inflammation(so-called residual uremic syndrome)
Partial removal of toxic substances by high-flux membranes has been shown to improve outcomes, at least in:
- patients with hypoalbuminemia or diabetes
- patients who have been on hemodialysis for a long period (3.7 years)
The desire to further improve outcomes of dialysis patients by enhanced removal of middle-sized to large-sized uremic toxins promoted renewed interest in combining convective and diffusive therapies (hemodiafiltration).
The aim of this review is to discuss if high-efficiency post-dilution online hemodiafiltration improves all-cause mortality.
Definition Of High-Efficiency Post-Dilution OL-HDF
Online hemodiafiltration (OL-HDF) is the currently available most advanced convective technique. It represents a safe and cost-effective mode of RRT.
In Europe, 18% of patients receiving extracorporeal RRT in 2011 were treated with OL-HDF.
In selected countries such as Switzerland, Slovenia and Slovakia, over 60% of patients were treated with OL-HDF.
The growth in the prescription of online hemodiafiltration is attributable to a number of clinical benefits, such as:
(a) enhanced removal of uraemic toxins;
(b) reduced inflammation and oxidative stress;
(c) lower incidence of intradialytic hypotensive episodes; and
(d) better patient well-being and quality of life.
The widespread implementation of this technique, however, has been hampered by lack of conclusive evidence of lower mortality from randomized trials or by lack of approval of online creation of substitution fluid by the U.S. regulatory agency.
EUDIAL’s Definition Of HDF
This section discusses the definition of hemodiafiltration (HDF) by the European Dialysis Working Group (EUDIAL) of the European Renal Association - European Dialysis Transplantation Association (ERA-EDTA).
Hemodiafiltration is a blood purification therapy combing diffusive and convective solute transport using high-flux membranes characterized by:
- an ultrafiltration coefficient >20 ml/h/mmHg/m2
- a sieving coefficient β2-microglobulin >0.6
Convective transport is achieved by an effective convection volume of at least 20% of the total blood volume processed.
Appropriate fluid balance is maintained by external infusion of an ultrapure, non-pyrogenic solution into the patient’s blood.
Various modes of hemodiafiltration, which differ by the site of replacement fluid infusion, are used worldwide. They are:
- post-dilution HDF
- pre-dilution HDF
- mid-dilution HDF
- mixed-dilution HDF
Post-dilution hemodiafiltration represents the most efficient mode of HDF for clearing middle and large molecular-weight uremic substances.
However, successful post-dilution online hemodiafiltration depends on:
- high extracorporeal blood flow rates (>350 ml/min)
- reliable vascular access (an arteriovenous fistulawith a flow rate of >600 ml/min)
- the ability to achieve adequate anticoagulation throughout the session
- absence of increased blood viscosity (high hematocrit, cryoglobulinemia, and gammopathies)
The EUDIAL group recommends quantification of hemodiafiltration by using the effective convection volume normalized to a body size-related factor as a surrogate for the convective dose.
In post-dilution hemodiafiltration, the effective convection volume is equal to the total volume that is ultra-filtered, including weight loss.
The Dialysis Outcomes and Practice Patterns Study (DOPPS) defined high-volume or high-efficiency post-dilution online hemodiafiltration as a treatment with substitution volumes over 15 l/session.
Today, it may be more appropriate to assume that the threshold of total convective volume should be in the range of 22 to 24 liters/session to reduce mortality of ESRD patients significantly.
Reduction Of Mortality In ESRD Patients With High-Efficiency Post-Dilution OL-HDF
The results came from recent randomized controlled trials (RCTs).
The collective body of evidence obtained from prospective observational studies or retrospective analyses points towards a survival benefit for ESRD patients undergoing online hemodiafiltration compared to patients maintained either on low-flux or high-flux dialysis.
However, early prospective RCTs were inconclusive.
These mostly small studies were either not designed to investigate mortality as an endpoint or did not reach statistical significance.
Recently, three large-scale trials analyzed the potential impact of high-substitution volume on reduction of mortality of ESRD patients, namely:
- Convective Transport Study (CONTRAST)
- Turkish HDF study
- ESHOL (Evaluation of Systems for Higher Order Logic) study
The investigators of the CONTRAST trial randomly assigned 714 prevalent (>2 years) hemodialysis patients to online post-dilution hemodiafiltration or to continued low-flux hemodialysis.
The arbitrary planned target volume was 24 l/treatment (6 L/h). The average convection volume, which included weight loss, was only 20.7 L/HDF treatment session.
After a mean follow-up of 3 years, the investigators did not detect any beneficial effect of online hemodiafiltration on all-cause mortality (primary outcome) or on fatal or non-fatal cardiovascular events (secondary endpoints).
The post hoc analysis found that mortality of hemodiafiltration patients with the highest delivered convection volume (upper tertile >21. 95 L/session) was considerably lower than in patients who were randomized to low-flux hemodialysis.
In the Turkish online hemodiafiltration study, 782 prevalent hemodialysis patients were randomly assigned to either post-dilution hemodiafiltration or high-flux hemodialysis.
The follow-up period was 2 years, and the mean substitution volume was 17.2 L (13.5–20.0 L)/session.
Neither the all-cause mortality rate nor the non-fatal cardiovascular rate was found to be different in the online hemodiafiltration group and in the high-flux group.
In a post hoc analysis, online hemodiafiltration with substitution volume >17.4 L/session was associated with better cardiovascular and overall survival.
The Catalonian investigators assigned 906 chronic hemodialysis patients either to continuous high-flux hemodialysis or to switch to high-efficiency post-dilution online hemodiafiltration.
The mean follow-up was 1.9 years.
The median replacement volume and the convective volume in online hemodiafiltration patients ranged from 20.8 to 21.8 L/session and 22.9–23.9 L/session, respectively.
Compared with patients who continued high-flux hemodialysis, patients assigned to online hemodiafiltration had a:
- 30% lower risk of all-cause mortality
- 33% lower risk of cardiovascular mortality
- 55% lower risk of infection-related mortality
Intradialytic hypotension complicating sessions and all-cause hospitalizations were observed less frequently in patients who had received hemodiafiltration.
Limitations Of Recently Published Trials
Although the CONTRAST, the Turkish online hemodiafiltration, and the ESHOL studies were RCTs, all three studies present some significant pitfalls that reduce the strength of evidence of the conclusions.
The important concern is whether high-convection volumes can be achieved in the majority of patients in everyday clinical practice.
In ESHOL study, in order to consider the general applicability, it would be interesting to know the number of patients screened in order to select the 939 participants.
Astonishingly, more than 90% of the participating online hemodiafiltration patients achieved the targeted convection volume.
However, almost 30% of the participating patients terminated the study prematurely.
Fifty patients who were on online hemodiafiltration, but no patients on high-flux HD dropped out because of vascular access problems.
In the Turkish HDF study, 40 patients of the online hemodiafiltration group terminated the study early due to vascular access problems, mainly the insufficient blood flow rate.
In the CONTRAST study, ultrafiltration volumes of 20 to 24 L/session were achieved only in one-third of the patients.
There were large variations of ultrafiltration volumes from center to center underscoring the gap between hemodiafiltration prescription and delivery (13 to 22 L/session).
In theory, both patient-related and technique-associated factors may reduce the prescribed ultrafiltration rate.
For a fixed treatment duration time, ultrafiltration volumes rely on:
- poor blood flow
- high albumin
- high hematocrit
In the Turkish study, the substitution volume ranged from 13.5 to 20 L, but 96.7% of the patients were treated with more than 15 liters of replacement volume per session (target volume).
There is no doubt that inadequate achievement of target ultrafiltration volume represents a severe protocol violation that may invalidate primary objectives of the CONTRAST study.
It is not clear why some patients who were randomized to high-volume post-dilution online hemodiafiltration were able to achieve target convection volumes, but otherswere not.
Confounding factors for patient selection may have been differences in vascular access or cardiac function, determining whether patients could achieve high convection volumes rather than the prescribed protocol.
Thus, it is plausible that better survival rates in those with better vascular access simply reflect “healthier” patients.
Unfortunately, in the ESHOL study, patients who were randomized to online hemodiafiltration were younger - and more often - men. Also:
- very few patients had diabetes mellitus
- a higher percentage of patients were using a fistula
- a few were using catheters
Moreover, they had a lower comorbidity index than patients who were assigned randomly to high-flux HD.
Of clinical relevance, more patients in the online hemodiafiltration group underwent renal transplantation. They were censored at transplantation and, by definition, they were survivors until transplantation.
Blood flow and dialysate flow rates were significantly lower in the high-flux group of the ESHOL trial, and these patients had significantly lower Kt/Vurea values.
These differences in baseline characteristics may have influenced group differences with respect to survival.
High-Efficiency Post-Dilution HDF Improves Survival: Putative Mechanisms
Recent randomized controlled trials suggest that high-convection volumes confer a survival benefit for hemodiafiltration patients over hemodialysis patients.
A trial reached this conclusion based on the primary analysis of the endpoints and two trials concluded based on post hoc analyses.
They reinforced the concept of a convective dose–survival relationship as proposed by the DOPPS investigators.
The threshold total convective volume remains unknown to bring a significant survival effect to ESRD patients, but it should be at least 22 to 24 L/session.
It is not clear whether the convective volume dose should be tailored to individual patients’ needs and expressed as liters per kilogram or per body surface area.
The mechanisms through which high convection volumes reduce mortality from cardiovascular or infectious disorders remain elusive.
It is not clearly understood whether the benefits of high-efficiency hemodiafiltration on patient survival partly depend on:
- higher clearance of toxic uremic molecules,
- less systemic inflammation; and/or
- lower episodes of intradialytic hypotension
β2-microglobulin seems to be one of the most representative and clinically relevant uremic toxins and it is strongly implicated in morbidity and mortality of ESRD patients.
Our prospective randomized crossover investigations have clearly shown that high-efficiency online hemodiafiltration is associated with lower time averaged concentrations of β2-microglobulin.
In the ESHOL study, the plasma levels of β2-microglobulin increased significantly, probably due to the loss of residual renal function.
In comparison, the β2-microglobulin levels in the Turkish online hemodiafiltration were unchanged in both the treatment groups.
Whereas in the CONTRAST study, β2-microglobulin level decreased through hemodiafiltration as expected because prior dialysis treatment in this study was performed with impermeable low-flux membranes.
Threshold concentration of β2-microglobulin cannot be established as a risk reference indicator without measuring residual renal function during hemodiafiltration for ESRD patients receiving renal replacement therapy.
Conclusion
Current renal replacement therapies of ESRD should not be considered as competing therapeutic options, rather as complementary methods of dealing with uremia.
Each modality has its own unique advantages and disadvantages; and at the same time, all modalities share problems.
Neither one is the best suited for all patients.
Ideally, patients treated with high-volume convective modalities, such as high-efficiency online hemodiafiltration, require a vascular access capable of delivering a blood flow rate between 350 and 400 ml/min or higher consistently.
Vascular access flow rate plays a fundamental role in removing middle molecules and the advantages of higher convective volumes are strongly limited by inadequate vascular access.
As the number of older patients and patients with diabetes mellitus or hypertensive nephrosclerosis is increasing both in the incident or prevalent dialysis populations, it is anticipated that not all ESRD patients may have an ideal vascular access for high-efficiency online hemodiafiltration.
Recently conducted RCTs provided encouraging data that high-efficiency post-dilution online hemodiafiltration results in higher survival, less morbidity and better quality of life in ESRD patients.
These results may vary in clinical practice. High-efficiency online hemodiafiltration will be used more often.
The volume of ultrafiltration seems to be the key performance factor of the best clinical hemodiafiltration practice.
To confirm and add more details to the results of published RCTs, properly designed trials relating various levels of convective volumes to clinical endpoints seem to be the only appropriate way to define the minimal and/or optimal convective dose of online hemodiafiltration.
Suleman Shah
Author
Suleman Shah is a researcher and freelance writer. As a researcher, he has worked with MNS University of Agriculture, Multan (Pakistan) and Texas A & M University (USA). He regularly writes science articles and blogs for science news website immersse.com and open access publishers OA Publishing London and Scientific Times. He loves to keep himself updated on scientific developments and convert these developments into everyday language to update the readers about the developments in the scientific era. His primary research focus is Plant sciences, and he contributed to this field by publishing his research in scientific journals and presenting his work at many Conferences.
Shah graduated from the University of Agriculture Faisalabad (Pakistan) and started his professional carrier with Jaffer Agro Services and later with the Agriculture Department of the Government of Pakistan. His research interest compelled and attracted him to proceed with his carrier in Plant sciences research. So, he started his Ph.D. in Soil Science at MNS University of Agriculture Multan (Pakistan). Later, he started working as a visiting scholar with Texas A&M University (USA).
Shah’s experience with big Open Excess publishers like Springers, Frontiers, MDPI, etc., testified to his belief in Open Access as a barrier-removing mechanism between researchers and the readers of their research. Shah believes that Open Access is revolutionizing the publication process and benefitting research in all fields.
Han Ju
Reviewer
Hello! I'm Han Ju, the heart behind World Wide Journals. My life is a unique tapestry woven from the threads of news, spirituality, and science, enriched by melodies from my guitar. Raised amidst tales of the ancient and the arcane, I developed a keen eye for the stories that truly matter. Through my work, I seek to bridge the seen with the unseen, marrying the rigor of science with the depth of spirituality.
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