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• W2612075840 abstract "There is a strong biological plausibility for benefit from removal of larger uremic toxins and increasing positive clinical experience with hemodiafiltration. However, evidence supporting hemodiafiltration is not definitive with studies that are often limited by serious methodological shortcomings. Morena et al. show that hemodiafiltration may prevent intradialytic hypotension, albeit in a study that also has some shortcomings. Ongoing research for hemodiafiltration is still needed through high-quality clinical trials that adhere to standards for clinical trial conduct and reporting. There is a strong biological plausibility for benefit from removal of larger uremic toxins and increasing positive clinical experience with hemodiafiltration. However, evidence supporting hemodiafiltration is not definitive with studies that are often limited by serious methodological shortcomings. Morena et al. show that hemodiafiltration may prevent intradialytic hypotension, albeit in a study that also has some shortcomings. Ongoing research for hemodiafiltration is still needed through high-quality clinical trials that adhere to standards for clinical trial conduct and reporting. “Knowledge is the small part of ignorance that we arrange and classify.”—Ambrose Bierce In this issue of Kidney International, Morena et al.1Morena M. Jaussent A. Chalabi L. et al.Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.Kidney Int. 2017; 91: 1495-1509Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar (2017) extend our knowledge of hemodiafiltration (HDF). The authors are to be congratulated on providing further evidence in an area in which there is still equipoise. The bottom-line insight from the French Convective versus Hemodialysis In Elderly (FRENCHIE) study is that HDF may prevent intradialytic hypotension (IDH) in vulnerable populations. The study provides a rich dataset, but at the same time illustrates important gaps in our knowledge that should drive further evidence generation around the safety and efficacy of HDF. HDF is a priority for research, not least because it is the fastest growing submodality of dialysis. Worldwide, 10% or more of patients on hemodialysis (HD) are treated with this submodality, a figure that reflects a changing clinical culture led mainly by European interests.2Sichart J.M. Moeller S. Utilization of hemodiafiltration as treatment modality in renal replacement therapy for end-stage renal disease patients—a global perspective.Contrib Nephrol. 2011; 175: 163-169Crossref PubMed Scopus (25) Google Scholar The main motivation for its adoption is the hope of improved survival for our patients and a better experience for them on dialysis. The quest to improve outcomes on dialysis has taken several paths: reduction of uremic toxicity by greater blood purification for larger and protein-bound solutes, improvements in management of extracellular fluid status, modulation of inflammatory and neurohormonal imbalances, reduction of HD procedural complications, and improvement of life experience for patient living with dialysis. In terms of dialysis therapy, the submodality with the greatest theoretical likelihood of achieving these deliverables is intensive HD, in the form of frequent ± prolonged in-center or home hemodialysis. However, it is clear that this submodality will only be available to a minority of patients, in settings with sufficient resources and capability to accommodate such treatment schedules. Directionally, HDF has been regarded as an opportunity to provide some or all of the deliverables mentioned above, yet within the constraints of the short dialysis schedule. The medical literature does indeed suggest a range of plausible improvements with HDF, including the possibility of better blood pressure control, improved quality of life, delay in the development of dialysis-related amyloidosis, better anemia control, lower calcium × phosphate product, and even improved survival. So, is there any need for further research into HDF, or is it a case of accepting its superiority over standard HD and focusing on wider and better implementation? In the literature, that there are a range of answers to this question. At one extreme, there are those who consider the evidence for HDF to be overwhelming, and the call for more to be an exercise in purism.3Gatti E. Ronco C. Seeking an optimal renal replacement therapy for the chronic kidney disease epidemic: the case for on-line hemodiafiltration.Contrib Nephrol. 2011; 175: 170-185Crossref PubMed Scopus (9) Google Scholar At the other, there are those who feel that no meaningful conclusion is possible, due to significant shortcomings in the methods and reporting of clinical trials that explore the effect and effectiveness of HDF.4Nistor I. Palmer S.C. Craig J.C. et al.Haemodiafiltration, haemofiltration and haemodialysis for end-stage kidney disease.Cochrane Database Syst Rev. 2015; 5: CD006258Google Scholar The situation has not been helped by seemingly contradictory systematic reviews of trials that compare convective with diffusive modalities (see Table 1). In theory at least, this apparent disparity can be reconciled by different degrees of separation between the pooled arms of the respective reviews. For instance, high-flux HD is sometimes included in the diffusive arm, despite the 5 to 10 L of convective exchange per treatment that occurs via internal backfiltration within the dialyzer. On the other hand, modalities with lower convective clearances (e.g., off-line and other forms of low-volume HDF) are sometimes included along with high-volume HDF in the convective arm. Either case effectively results in contamination between arms, and attenuation of effect. Historically, there has been a lack of standardization around what constitutes a primarily convective modality as opposed to a primarily diffusive one. In future trials of HDF versus HD, definitions such as the one from the European Dialysis Working Group will help trialists achieve separation between convective and diffusive arms and improve evidence synthesis by more consistent and appropriate categorization of study interventions in systematic reviews.5Tattersall J.E. Ward R.A. EUDIAL Group. Online haemodiafiltration: definition, dose quantification and safety revisited.Nephrol Dial Transplant. 2013; 28: 542-550Crossref PubMed Scopus (174) Google ScholarTable 1Comparison of published SRs comparing standard HD with HDF ± HF ± acid-free biofiltrationArticleHDF submodalities of studies included in SRStandard HD submodalities studies included in SREstimated treatment effect on overall mortality riskEstimated treatment effect on cardiovascular mortality riskEstimated treatment effect on intradialytic hypotensionMostovaya IM, Blankestijn PJ, Bots ML, et al. Clinical evidence on henodiafiltration: a systematic review and a meta-analysis. Semin Dial. 2014;27:119–127.On-line HF, on-line HDFLow- and high-flux HD0.84 (0.73–0.96)0.73 (0.57–0.92)Not availableNistor et al.4Nistor I. Palmer S.C. Craig J.C. et al.Haemodiafiltration, haemofiltration and haemodialysis for end-stage kidney disease.Cochrane Database Syst Rev. 2015; 5: CD006258Google ScholarOn-line and off-line HF, on-line and off-line HDF, acetate-free biofiltrationLow- and high-flux HD0.87 (0.72–1.05)0.75 (0.61–0.92)0.72 (0.66–0.80)aEstimates derived from only 1 study, that of Maduell et al.6Peters SA, Bots ML, Canaud B, et al. Haemodiafiltration and mortality in end-stage kidney disease patients: a pooled individualy participant data analysis from four randomized controlled trials. Nephrol Dial Transplant. 2016;31:978–984bEstimates derived from pooled individual patient data from 4 trials, including preliminary data from Morena et al.1 that may be inconsistent with the final article as published.On-line HDFLow- and high-flux HD0.86 (0.75–0.99)0.77 (0.61–0.97)Not availableSusantitaphong P, Siribamrungwong M, Jaber BL. Convective therapies versus low-flux hemodialysis for chronic kidney failure: a meta-analysis of randomized controlled traisl. Nephrol Dial Transplant. 2013;28:2859–2874High-flux HD, on-line hemofiltration, on-line HDF, acetate-free biofiltrationLow-flux HD0.88 (0.7–1.02)0.84 (0.71–0.98)0.55 (0.35–0.87)Wang AY, Ninomiya T, Al-Kahwa A, et al. Effect of hemodiafiltration or hemofiltration compared with hemodialysis on mortality and cardiovascular disease in chronic kidney failure: a systematic review and meta-analysis of randomized trials. Am J Kidney Dis. 2014;63:968–978.On-line HF, on-line HDF, acetate-free biofiltrationLow- and high-flux HD0.83 (0.65–1.05)0.85 (0.66–1.10)0.49 (0.30–0.81)HD, hemodialysis; HDF, hemodiafiltration; HF, hemofiltration; SRs, systematic reviews.Values are hazard ratios (95% confidence intervals).a Estimates derived from only 1 study, that of Maduell et al.6Maduell F. Moreso F. Pons M. et al.High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients.J Am Soc Nephrol. 2013; 24: 487-497Crossref PubMed Scopus (493) Google Scholarb Estimates derived from pooled individual patient data from 4 trials, including preliminary data from Morena et al.1Morena M. Jaussent A. Chalabi L. et al.Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.Kidney Int. 2017; 91: 1495-1509Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar that may be inconsistent with the final article as published. Open table in a new tab HD, hemodialysis; HDF, hemodiafiltration; HF, hemofiltration; SRs, systematic reviews. Values are hazard ratios (95% confidence intervals). From the ongoing dialogue, what can be distilled about the status and future of HDF? First, it must be emphasized that there is strong biological plausibility for benefit from removal of larger uremic toxins. Second, it is obvious that there is an increasing positive cumulative clinical experience with HDF. Third, there are undeniable and serious technical limitations in many of the trials testing the efficacy and effectiveness of HDF. Finally, the observed association between higher achieved convection volumes and lower mortality risk is observational and therefore potentially confounded and requires verification before dosing guidelines around convective clearance are accepted. Through this lens, what can we say about the trial of Morena et al.1Morena M. Jaussent A. Chalabi L. et al.Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.Kidney Int. 2017; 91: 1495-1509Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar? The positives are obvious. The FRENCHIE study deals with an important patient-centered and clinical outcome, and it is a reasonably large, randomized, multicenter, and controlled clinical trial that went a fair way toward completion. The negatives of the FRENCHIE study are not so obvious, but they are in the form of several potential biases and omissions, some of which are frequently found in other HDF trials. These are discussed below. The first negative concerns possible selection bias in the FRENCHIE study, resulting in exaggerated benefit in the HDF arm. This is suggested by the higher prevalence of robust vascular access (VA) in the HDF arm, compared with that in the HD arm. Although the proportion of fistulae were similar at baseline (Table 1 in Morena et al.1Morena M. Jaussent A. Chalabi L. et al.Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.Kidney Int. 2017; 91: 1495-1509Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar), there were only about one-half the number of hospitalizations for VA dysfunction in the HDF arm, suggesting more enduring and functional angioaccess in this group (Table 6 in Morena et al.1Morena M. Jaussent A. Chalabi L. et al.Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.Kidney Int. 2017; 91: 1495-1509Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). VA is likely to be a strong confounder on the causal pathway to cardiovascular disease, not only due to direct effects but also through associated characteristics that act as mediating variables (Figure 1). Randomization imbalance by VA is frequently observed in comparative trials of HDF, due to the high blood flow required during HDF to allow higher achieved convective clearances. Using the recent Estudio de Supervivencia de Hemodiafiltración On-Line (ESHOL) study as an example,6Maduell F. Moreso F. Pons M. et al.High-efficiency postdilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients.J Am Soc Nephrol. 2013; 24: 487-497Crossref PubMed Scopus (493) Google Scholar 13.1% of the HD arm had central venous catheters at baseline, and 7.5% of the HDF arm, an allocation that would have a P value of 0.000099 due to chance alone (Stata/MP 14.2 code: bitesti 906 59 0.103; StataCorp, College Station, TX). This occurred despite measures aiming to prevent such imbalance, such as allocation concealment and the requirement for all patients to achieve high exchange volumes prior to study entry (i.e., irrespective of their VA). Once imbalance such as this occurs, however, post hoc statistical adjustment can only reduce direct confounding effects and not the associated indirect effects: in other words, seemingly identical groups that differ by the type and quality of their VA are likely to also differ in other respects that are not measured or even appreciated. Some of these differences will involve important prognostic factors, affecting outcomes independently of the intervention. It is possible that the effect attributed to HDF in the ESHOL study might conceivably be explained by a single unmeasured confounder, and one with only a relatively modest effect on outcomes at that (modeled using a bias formula from Arah et al.7Arah O.A. Chiba Y. Greenland S. Bias formulas for external adjustment and sensitivity analysis of unmeasured confounders.Ann Epidemiol. 2008; 18: 637-646Abstract Full Text Full Text PDF PubMed Scopus (72) Google Scholar in Figure 1). Although randomization imbalance by VA is not as apparent in the FRENCHIE study as it was in ESHOL, it appears to be present and should be kept in mind. Second, there is a strong possibility of ascertainment bias in the FRENCHIE study. The study analysis was (correctly) performed within an intention-to-treat framework, which was essential because prominent differential dropout in the HDF arm compared with the HD arm (Supplementary Table S3 in Morena et al.1Morena M. Jaussent A. Chalabi L. et al.Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.Kidney Int. 2017; 91: 1495-1509Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). However, in their approach, the investigators chose to ignore missing data, which excluded 20% of randomized patients from analysis (Table 1 in Morena et al.1Morena M. Jaussent A. Chalabi L. et al.Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.Kidney Int. 2017; 91: 1495-1509Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar). Guidelines such as the Consolidated Standards of Reporting Trials (http://www.consort-statement.org) are very clear about the treatment of missing data, unless they are proven to be missing completely at random—to avoid bias, these data should not be omitted, but instead estimated by multiple imputation. The problem of poor handling of missing data is by no means unique to the FRENCHIE study: although there is no formal analysis of this problem in the literature, adherence to standards for analysis and reporting of missing data would appear to be poor in much of the dialysis medicine clinical trial literature. In the FRENCHIE study, the effect of this missing data on their analysis is unknown, but it should have been minimized by imputation or at least tested for in sensitivity analyses. The FRENCHIE study raises another issue that affects all clinical trials with IDH as an endpoint. The investigators chose to define this endpoint using the Kidney Disease Outcomes Quality Initiative (KQODI) criteria. There is in fact no consensus on how to grade or define IDH, despite the syndrome being a leading indicator of hemodialysis toxicity and quality of health service delivery. If the study in question is taking a patient-centered perspective, then any symptomatic hypotension is bad and can be measured as such. If the study in question is looking at IDH as a marker or mechanism of cardiovascular morbidity and mortality, then there are better definitions of IDH that predict mortality more strongly; the most potent is an absolute nadir intradialytic systolic blood pressure <90 mm Hg.8Flythe J.E. Xue H. Lynch K.E. et al.Association of mortality risk with various definitions of intradialytic hypotension.J Am Soc Nephrol. 2015; 26: 724-734Crossref PubMed Scopus (251) Google Scholar This may seem pedantic, but it is a critical issue: after all, given the inexact clinical consequences of IDH as defined by the KDOQI criteria, how can we gauge the clinical value of something that prevents it? The sources of uncertainty discussed here are generally the “known unknowns” to a large degree. The FRENCHIE study gives us a glimpse of another (perhaps larger) area of uncertainty, namely the “unknown unknowns.” A peripheral but notable finding in the FRENCHIE study was the several-fold higher rate of (albeit supraventricular) arrhythmias in the HDF group compared with the HD group. The investigators could not identify any particular cause for this finding. This does, however, raise the possibility of unappreciated intervention-related side effects, possibly from components in the infused substitution fluid. Possible culprits include electrolytes and also acetate: acetic acid is still present in most online dialysates at concentrations no less than 3 mmol/l to prevent precipitation of calcium and magnesium. During on-line HDF, exposure to acetate is known to be high due to the infusion of dialysate.9Pizzarelli F. Cerrai T. Dattolo P. Ferro G. On-line haemodiafiltration with and without acetate.Nephrol Dial Transplant. 2006; 21: 1648-1651Crossref PubMed Scopus (46) Google Scholar This apparently increased arrhythmia risk with HDF should be explored further, although it is difficult to reconcile the relevant findings in the FRENCHIE study with those of other HDF trials—none of them have evaluated serious adverse events according to international definitions, which is another serious limitation of this body of literature. In summary, what more is there to learn about HDF? Much, it seems. The technical issues of delivering HDF appear to be ironed out, although the machinery and systems required to safely deliver higher volume HDF are not always discussed or factored into economic evaluations. More importantly, however, there is still a lot to know about the patient response to the therapy. Further clinical trials are necessary to confirm the findings of previous trials around the “known unknowns” and explore the “unknown unknowns.” Critically, these should be done through definitive patient- or cluster-randomized clinical trials that adhere to standards for clinical trial conduct and reporting, avoiding the problems of selection bias and ascertainment bias that affect much of the current body of literature. MRM is a Director of Medical Affairs, Therapeutic Area, Baxter Healthcare (Asia) Pty. Ltd. Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderlyKidney InternationalVol. 91Issue 6PreviewLarge cohort studies suggest that high convective volumes associated with online hemodiafiltration may reduce the risk of mortality/morbidity compared to optimal high-flux hemodialysis. By contrast, intradialytic tolerance is not well studied. The aim of the FRENCHIE (French Convective versus Hemodialysis in Elderly) study was to compare high-flux hemodialysis and online hemodiafiltration in terms of intradialytic tolerance. In this prospective, open-label randomized controlled trial, 381 elderly chronic hemodialysis patients (over age 65) were randomly assigned in a one-to-one ratio to either high-flux hemodialysis or online hemodiafiltration. Full-Text PDF Open Archive" @default.
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• W2612075840 title "Measuring the patient response to dialysis therapy: hemodiafiltration and clinical trials" @default.
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