LABORATORIO DE URGENCIAS

Effect of Hemodiafiltration or Hemodialysis on Mortality in Kidney Failure

                                      Peter J. Blankestijn, M.D; Robin W.Vernooij, Ph.D; Carinna Hockham,
                                  Ph.D; Giovanni F.Strippoli, M.D et al.

                                                NEJM; June 2023; DOI: 10.1056/NEJMoa2304820

Kidney failure is a severe and common chronic noncommunicable disease that is increasing in incidence worldwide.^1,2 Hemodiafiltration and hemodialysis are two accepted, commonly used therapies for patients with this disease, with practice differences across continents that may favor one method over the other, although hemodialysis is more often used overall.
Several studies have suggested that patients with kidney failure may benefit from high-dose hemodiafiltration as compared with standard hemodialysis. However, given the limitations of the various published studies, additional data are needed.
Among the four randomized, controlled trials that have investigated whether hemodiafiltration offers survival benefits as compared with hemodialysis, three were inconclusive,^3-5 whereas the fourth showed a survival benefit for hemodiafiltration.⁶ However, concerns about attrition during follow-up in these trials were raised by observers in the scientific and nephrology communities.^7,8 A meta-analysis of individual participant data from the four trials suggested a survival benefit with hemodiafiltration when a convection volume was delivered at a high dose, with a putative threshold of at least 23 liters per session in postdilution mode.⁹ Analyses of dose dependency were not predefined; thus, the risk of confounding according to the medical indication for treatment exists. The results of study-level meta-analyses, including additional studies with various dialysis methods, were inconclusive as well.¹⁰ In light of such uncertainty, we initiated a pragmatic, open-label, randomized, controlled trial to investigate whether high-dose hemodiafiltration offers survival benefits as compared with conventional high-flux hemodialysis.^11,12
The trial CONVINCE aimed to assess benefits and harms of high-dose hemodiafiltration as compared with conventional high-flux hemodialysis regarding death from any cause, cause-specific mortality, cardiovascular events, hospitalizations, patient-reported outcomes, and cost-effectiveness.
Patients were treated at 61 centers in eight European countries 

PATIENTS

Adult patients (≥18 years of age) were eligible for inclusion if they had received a diagnosis of kidney failure (stage V), had been treated with hemodialysis for at least 3 months, were candidates for high-dose hemodiafiltration (a convection volume of ≥23 liters in postdilution mode per session), were willing to undergo dialysis sessions three times a week, and had an understanding of the trial procedures and an ability to adhere to the trial protocol, including completion of patient-reported outcome assessments. Written informed consent was provided by the patient or a designated guardian in accordance with local regulations.
Exclusion criteria were severe nonadherence to the dialysis procedure and accompanying prescriptions, especially the frequency and duration of dialysis treatment; a life expectancy less than 3 months; previous hemodiafiltration treatment less than 90 days before screening; anticipated kidney transplantation from a living donor within 6 months after screening; evidence of any other disease or medical condition that may interfere with the planned treatment, affect patient compliance, or place the patient at high risk for treatment-related complications; participation in any other study, as discussed with and decided by the scientific committee; or unavailability for trial visits for 3 months or more.

RANDOMIZATION,PROCEDURES and FOLLOW-UP

Patients who met the inclusion criteria were randomly assigned in a 1:1 ratio to receive either high-dose hemodiafiltration or continuation of high-flux hemodialysis. Trial-group assignments were made by means of centralized block randomization stratified according to center. The trial intervention was high-dose hemodiafiltration with on-line production of substitution fluid and ultrapure bicarbonate-based dialysis fluid at a convection volume of at least 23 liters per session in postdilution mode. Convection volume (i.e., total ultrafiltration volume) is the sum of the substitution volume and the net ultrafiltration volume (i.e., the treatment-induced weight loss as calculated to estimate dry weight). 
Convection volumes and reasons why high-dose targets could not be reached were recorded on the electronic case record form. The comparison group received conventional hemodialysis by means of high-flux dialysis membranes and ultrapure bicarbonate-based dialysis fluid. All the participating centers had experience with hemodiafiltration, so continuous delivery of hemodiafiltration in compliance with local quality regulations could be expected.
Our trial was pragmatic, meaning that all data were collected as part of routine clinical practice. For patients who were receiving high-dose hemodiafiltration, we collected data at each follow-up visit regarding achieved convection volume and the number of treatment sessions not performed as high-dose hemodiafiltration in the previous 3 months.¹¹

OUTCOMES

The primary outcome of the trial was death from any cause. Key secondary outcomes were cause-specific mortality, composite fatal and nonfatal cardiovascular events, kidney transplantation, and recurrent hospitalizations for any cause and for causes related to infection.¹¹ Cardiovascular events were defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, therapeutic coronary procedure (coronary-artery bypass graft, percutaneous transluminal coronary angioplasty, or stenting), therapeutic carotid procedure (endarterectomy or stenting), and vascular intervention (revascularization, percutaneous transluminal angioplasty, or stenting), or peripheral limb amputation.
Reasons for hospitalization (e.g., infection-related or cardiovascular) were recorded during the trial period. Since all the patients had stage V disease, the trial population had a wide variety of frequent adverse events. Thus, the ethics committee approved our request to restrict the reporting of adverse events only to serious events regarding the primary and secondary outcomes. Findings with respect to patient-reported outcomes and cost-effectiveness are not reported here.

RESULTS
* PATIENTS
From November 2018 through April 2021, a total of 1360 patients underwent randomization (with 683 patients assigned to receive high-dose hemodiafiltration and 677 to receive high-flux hemodialysis).
The characteristics of the patients, including demographic features, coexisting illnesses, laboratory values, and medications — were well balanced at baseline. The median follow-up was 30 months (interquartile range, 27 to 38) for the patients in the two treatment groups. Loss to follow-up occurred in 18 patients (2.6%) in the hemodiafiltration group and in 12 (1.8%) in the hemodialysis group. The target volume of at least 23±1 liters per session for high-dose convection was achieved in 92% of delivered hemodiafiltration sessions, whereas the mean convection volume among the patients was stable over the course of the trial (Table S2 and Fig. S1).
The Kt/V value (in which K represents the urea clearance by the dialyzer, t represents the treatment time, and V represents the urea distribution volume) was higher in the hemodiafiltration group than in the hemodialysis group and remained so during the course of the trial
* PRIMARY OUTCOME
Death from any cause occurred in 118 patients (17.3%) in the hemodiafiltration group (7.13 events per 100 patient-years) and in 148 patients (21.9%) in the hemodialysis group (9.19 events per 100 patient-years) (hazard ratio, 0.77; 95% confidence interval [CI], 0.65 to 0.93; P=0.005). Of the 266 total deaths, 68 (25.6%) were attributed to cardiovascular disease, 26 (9.8%) to Covid-19, and 56 (21.1%) to other infections .
Treatment effects differed according to whether patients had a history of cardiovascular disease at baseline. Among the patients with such a history, the risk of death was similar in the two groups (hazard ratio, 0.99; 95% CI, 0.76 to 1.28). However, among those without such a history, the risk of death was lower in the hemodiafiltration group (hazard ratio, 0.58; 95% CI, 0.42 to 0.79).
Treatment effects also differed according to the history of diabetes mellitus, with a lower risk of death in the hemodiafiltration group among those without diabetes mellitus (hazard ratio, 0.65; 95% CI, 0.48 to 0.87) but a similar risk among those with diabetes mellitus (hazard ratio, 0.97; 95% CI, 0.72 to 1.31).
In sensitivity analyses, competing risks of kidney transplantation or treatment switches were included, along with the exclusion of the recruiting site as a random effect. In these analyses, the results were similar to those in the primary analysis (Section S6).
* SECONDARY OUTCOMES
The risk of death from cardiovascular causes (hazard ratio, 0.81; 95% CI, 0.49 to 1.33) and the composite outcome of fatal or nonfatal cardiovascular outcomes (hazard ratio, 1.07; 95% CI, 0.86 to 1.33) were similar in the hemodiafiltration group and the hemodialysis group. An apparent reduction in favor of the high-dose hemodiafiltration group with respect to infection-related death, including from Covid-19, was found (hazard ratio, 0.69; 95% CI, 0.49 to 0.96).
The risk of recurrent hospitalization was similar in the two groups, including for nonfatal hospitalization (hazard ratio, 1.11; 95% CI, 0.98 to 1.25) and for infection-related hospitalization that included Covid-19 (hazard ratio, 1.06; 95% CI, 0.86 to 1.30) and that excluded Covid-19 (hazard ratio, 0.97; 95% CI, 0.74 to 1.26).

DISCUSSION

In our trial, we found a lower risk of death from any cause among patients with kidney failure who were receiving high-dose hemodiafiltration than among those receiving conventional high-flux hemodialysis. A previous meta-analysis of 11 studies (involving 3396 patients) that compared various convective dialysis therapies (hemofiltration, hemodiafiltration, and acetate-free biofiltration) with hemodialysis showed a reduction in cardiovascular mortality but no effect on death from any cause, nonfatal cardiovascular events, or hospitalization.¹⁰ An individual-participant data analysis of four randomized, controlled trials involving 2793 patients^3-6 showed a significant reduction in death from any cause and from cardiovascular causes that favored hemodiafiltration, especially among patients receiving high-dose hemodiafiltration.⁹ This beneficial effect of hemodiafiltration has been attributed to confounding according to indication (i.e., a high convection volume was predominantly reached in healthier patients with lower event risks).
Our trial differs from previous studies in that we enrolled patients who were likely candidates for high-dose hemodiafiltration nearly all the time. We did not identify an association between failure to achieve the high-dose target and any particular patient characteristic or vascular access type.^15-20 Thus, our trial results support the evidence that high-dose hemodiafiltration can result in a clinically important survival benefit. Furthermore, since our trial was both randomized and controlled, our finding does not appear to be due to confounding according to indication.
The results of previous pharmacologic intervention studies involving patients with kidney failure have often been neutral. Possibly, such results have to do with the fact that an intervention that is targeted to modify a single mechanism or intervention late in the patient-treatment pathway is not sufficiently powerful or protective to mitigate risk and to change clinical outcome in patients with multiple coexisting illnesses.²¹ Hemodiafiltration is a general and nonselective intervention that potentially involves multiple mechanisms, including increased removal of uremic toxins and other physiologic processes.²²
Analyses of both infection-related and cardiovascular deaths showed a suggestion of benefit for hemodiafiltration, although drawing such conclusions is complicated because Covid-19 as a diagnosis was added during the course of the trial. We cannot make the distinction between death from Covid-19 and death from other causes (e.g., cardiovascular) in a patient with Covid-19. Thus, these subanalyses should be interpreted with some caution.
We increased the likelihood of an unbiased effect estimate through the trial design, which included complete follow-up of mortality, no data censoring after certain key events (e.g., renal transplantation) ²³ and competing-risk statistical analyses. However, some limitations exist. Our achieved sample size was lower than we originally calculated because of the Covid-19 pandemic and difficulties in recruitment during lockdowns. Furthermore, we found an overall risk of death that was lower than what has been generally reported and lower than what we used for determining the sample size.^1,2,9,24 The lower mortality can be partly attributed to selection by the treating physician to enroll patients who were likely to reach a convection volume of at least 23 liters during each session, an indication that these patients had relatively good vascular access. Furthermore, patients were expected to complete outcome assessments.¹¹ An overall lower risk of death among the trial patients as such does not invalidate our findings of an association between hemodiafiltration and a reduction in death from any cause.
For our trial to have an effect on clinical practice, the question of the applicability of the findings to clinical practice is important. Features to support generalizability include a pragmatic trial design without numerous exclusion criteria. However, our inclusion criteria may have resulted in a trial population that was healthier than the general hemodialysis population in Europe¹ and in the United States²⁴ (Section S8). Also, we did not collect data regarding race or ethnic group among our European patients, so our findings may not be generalizable to non-White patients with kidney failure.
Moreover, among the patients in the hemodiafiltration group, the absolute survival advantage may have varied between individual patients. Previously, we reported the most survival benefit from hemodiafiltration among patients who were younger, did not have diabetes or cardiovascular disease, and had increased serum creatinine and albumin levels.²⁵ Updating the hemodiafiltration-pooling project with individual-participant data from the present trial and from other trials (e.g., the High-Volume Hemodiafiltration vs. High-Flux Hemodialysis Registry [H4RT] trial²⁶) would allow more precise exploration of treatment effects across subgroups.⁹ Our trial results, together with those of several other trials and large observational studies,^9,10,27-29 seem to indicate that the safety of hemodiafiltration was acceptable, provided that hygienic and microbiologic rules are fully respected.
In our trial, at a median follow-up of 30 months after randomization, patients with kidney failure who received high-dose hemodiafiltration had a lower risk of death than those who received conventional high-flux hemodialysis.

NOTE: figures and tables in original article

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AUTHOR AFFILIATIONS

From the Department of Nephrology and Hypertension (P.J.B., R.W.M.V.) and the Julius Center for Health Sciences and Primary Care (R.W.M.V., M.L.B.), University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; George Institute for Global Health, School of Public Health, Imperial College London (C.H., M.W.), and the Department of Renal Medicine, Royal Free Hospital, Division of Medicine, University College London (A.D.) — both in London; the Department of Precision and Regenerative Medicine and Ionian Area, University of Bari, Bari, Italy (G.F.M.S.); the School of Public Health, University of Sydney (G.F.M.S.), and the George Institute for Global Health, University of New South Wales (M.W.) — both in Sydney; Montpellier University School of Medicine, Montpellier, France (B.C.); Fresenius Medical Care Deutschland, Global Medical Office, Bad Homburg, Germany (B.C., K.C.), Medical Scientific Affairs, B. Braun Avitum, Melsungen (C.B.), and Charité Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität zu Berlin, and the Center of Internal Medicine and Dermatology, Department of Psychosomatic Medicine, Berlin Institute of Health, Berlin (K.C., M.R.) — all in Germany; the Division of Nephrology, Department of Clinical Sciences, Lund University, Lund (J.H.), and Corporate Medical Office Diaverum, Malmö (M.T.) — both in Sweden; and the Department of Nephrology, Grigore T. Popa University of Medicine, Iasi (A. Covic), and Fresenius Nephocare Dialysis Center, Bucharest (A. Cucui, A. Covic) — both in Romania.