Hemoadsorption combined with hemodialysis versus hemodialysis alone on mortality in end-stage kidney disease: a randomized, open-label, multicenter trial

Domain: biology
Published: 2026-03-28
Editorial outcome: major_revision

Abstract
The objective of this completed, randomized, open-label trial across 11 hemodialysis centers in
Shanghai, China, was to evaluate whether hemoadsorption combined with hemodialysis (HAHD)
reduces mortality compared to hemodialysis (HD) alone in end-stage kidney disease patients
(maintenance HD ≥3 months, Kt/V≥1.2). We randomized 1362 patients 1:1 to receive HAHD (n =
683) or HD alone (n = 679; mainly low-flux HD plus intermittent HDF). All 1362 randomized patients
were analyzed. The primary outcome was all-cause mortality, while secondary outcomes included
cardiovascular mortality and major cardiovascular events. Over a median follow-up of 39.5 months, all-
cause mortality occurred in 117 (17.1%) of HAHD patients compared to 144 (21.2%) of HD patients
(hazard ratio [HR]: 0.778, 95% confidence interval [CI ]: 0.609–0.994; P = 0.045). HAHD also
significantly reduced cardiovascular mortality (HR: 0.659, 95% CI: 0.481–0.901; P=0.009) and major
cardiovascular events (HR: 0.772, 95% CLI: 0.621–0.959; P=0.019). Important adverse events, primarily
infections and abnormal blood pressure, were comparable between the two groups. Adding
hemoadsorption significantly reduced all-cause mortality, cardiovascular mortality, and major
cardiovascular events compared to HD alone (mainly low-flux HD plus intermittent HDF). Trial
Registration: ClinicalTrials.gov NCT03227770.

Introduction
End-stage kidney disease (ESKD) is a prevalent and life-threatening condition that imposes a substantial
burden on patients’ quality of life and healthcare systems due to its association with high mortality,
morbidity and healthcare expenditures. According to the Chinese National Renal Data System
(CNRDS)1, 916,647 patients were receiving maintenance hemodialysis (HD) in China by the end of
2023. However, only 52.6%, 33.4% and 10.2% of these patients had been on dialysis for more than 3, 5
and 10 years, respectively. Despite considerable improvements in survival over the past six decades2,
high rates of complications, hospitalizations, and mortality highlight the limitations of current treatment
strategies with unsatisfactory long-term outcomes3. These challenges are partly attributed to the
retention and accumulation of uremic toxins, which appear to contribute to inflammation, anemia, and a
range of osteoarticular and cardiovascular disorders.

Globally and in China, conventional hemodialysis modalities — such as low-flux hemodialysis (LFHD),
high-flux hemodialysis (HFHD), and hemodiafiltration (HDF) — remain the primary blood purification
techniques for ESKD patients4. However, these therapies rely primarily on diffusion and convection,
limiting their ability to effectively remove middle-to-large molecular weight and protein-bound uremic
toxins5,6. Despite significant technological advances, these limitations are associated with persistent
morbidity, hospitalizations, diminished quality of life, and poor survival outcomes7,8. Furthermore,
technical challenges, including those related to vascular access, can constrain the adoption of advanced
methods like HDF, particularly in regions with limited healthcare resources9.

Given the constraints of membrane-based toxin removal, there has been a growing interest in adjunctive
blood purification technologies. Sorbent-based hemoadsorption represents a promising approach to
enhanced toxin removal, offering a relatively safe and straightforward method to target large or protein-
bound solutes that conventional dialysis fails to adequately clear10. Recent studies have suggested that
hemoadsorption combined with hemodialysis (HAHD) could yield clinical benefits, alleviation of
severe uremic symptoms such as chronic kidney disease-associated pruritus11, sleep disturbances12,
microinflammation13, dialysis-related amyloidosis14, thereby improving patients’ quality of life15-17.
Preliminary evidence from a systematic review and meta-analysis of seven randomized controlled trials
(RCTs) revealed HAHD significantly reduced overall mortality rates at 1 and 2 years compared to
conventional hemodialysis18. However, these findings were derived from small-scale and single-center
trials, limiting their generalizability.

To address this gap, we conducted a randomized, open-label, multicenter study to investigate whether
HAHD could reduce mortality compared to HD alone in patients with ESKD.

Results
Patients
Between December 1, 2017 and December 31, 2019, 1419 patients were screened, and 1362 eligible
patients (median age 64 years [interquartile range 54–68]; 62.2% males) were randomly assigned to
receive either HAHD (n = 683) or HD (n = 679) (Figure 1). Thirteen patients (1.90%) in the HAHD
group and 7 patients (1.03%) in the HD group were lost to follow-up.

Baseline characteristics, including demographic features and laboratory values were well balanced
between the groups at baseline (Table 1 and Supplementary Table 1). With the exception of 4
participants in the HAHD and 5 participants in the HD groups, all participants received low-flux HD.
Additionally, participants received intermittent HDF with a mean frequency of 0.77 (± 0.41) sessions
per week. In the HAHD group, 614 patients (90.0%) received HAHD once every two weeks, 27 patients
(3.95%) received HAHD a median of 1.4 times every two weeks (equivalent to three times a month),
and 42 patients (6.15%) received HAHD twice every two weeks.

All-cause mortality
By December 31, 2021, the median duration of follow-up of the overall cohort was 39.5 months
(interquartile range: 27.0–45.0). The all-cause mortality rate was 17.1% (n = 117) in the HAHD group
compared to 21.2% (n = 144) in the HD group (hazard ratio [HR]: 0.778, 95% confidence interval [CI]:
0.609–0.994; P = 0.045; Figure 2A). Of the 261 total deaths, 163 (62.5%) were attributed to
cardiovascular disease, and 69 (26.4%) to infections (Supplementary Table 2). When kidney
transplantation was considered as a competing risk (HAHD: 14, HD: 5), the P value improved to 0.039
(log-rank test). Notably, the decreased mortality effect of HAHD was most pronounced in patients with
a dialysis vintage of ≥ 3 years (HR: 0.612, 95% CI: 0.449–0.855) or β -microglobulin (β -MG) levels >
2 2
30mg/L (HR: 0.681; 95% CI: 0.486–0.954), whereas no significant mortality effect was observed in
those with a dialysis vintage of < 3 years or β -MG levels ≤ 30 mg/L (Figure 2B).
2

Cardiovascular mortality and major cardiovascular events risk
Cardiovascular mortality was 9.66% (n = 66) in the HA HD group and 14.3% (n = 97) in the HD group
(HR: 0.659, 95% CI: 0.481–0.901; P = 0.009; Figure 3). After adjusting for the competing risk of kidney
transplantation, the P value improved to 0.007 (log-rank test; Figure 3A). HAHD demonstrated a greater
effect on cardiovascular mortality in the subgroup of patients with a dialysis vintage of ≥ 3 years (HR:
0.394, 95% CI: 0.249–0.623) or β -MG levels of > 30mg/L (HR: 0.575, 95% CI: 0.372–0.887) (Figure
2
3B).

Additionally, there was a significant reduction in major cardiovascular events (MACE) with HAHD
(HR: 0.772, 95% CI: 0.621–0.959; P = 0.019), with a P value of 0.013 (log-rank test) when considering
the competing risk from kidney transplantation (Figure 4A). Subgroup analysis revealed that HAHD had
a more substantial effect on reducing MACE in patients with a dialysis vintage ≥ 3 years (HR: 0.703,
95% CI: 0.525–0.941) and/or β -MG levels > 30mg/L (HR: 0.645, 95% CI: 0.481–0.865), (Figure 4B).
2

Sensitivity analyses
The sensitivity analyses among Per Protocol (PP) population (660 in the HAHD group and 667 in the
HD group) showed a consistent reduction in risk for CVD-specific mortality and MACE, but a marginal
reduction in all-cause mortality from HAHD (Table 2). We further post-hoc adjusted for sex and found a
consistent reduction risks for mortality (all-cause and CVD mortality) and MACE.

Laboratory tests
Changes in baseline plasma levels of laboratory measurements during 24-month follow-up are presented
in Supplementary Table 3. HAHD resulted in a lower accumulation of β -MG and homocysteine
2
compared to HD. Additionally, median changes from baseline were more pronounced in the HAHD
group for high-sensitivity C-reactive protein, ferritin, creatine kinase, creatine kinase-MB, and pro B-
type natriuretic peptide.

Safety
Adverse events were reported in 47 (6.88%) of 683 patients in the HAHD group and 64 (9.42%) of 679
patients in the HD group (Table 3). Of these, 3 events (two episodes bleeding, one of abnormal blood
pressure) in the HAHD and 2 events (two infections) in the HD group were reported as serious adverse
reactions believed to be related to treatment. Changes in baseline plasma levels of safety indices over
the 24-month follow-up indicated that median changes in baseline levels of white blood cell, red blood
cell, platelets, aspartate aminotransferase (AST), alanine aminotransferase (ALT), albumin, and glucose
showed no differences between the two groups (Supplementary Table 3).

Methods
Study design
This randomized, open-label, multicenter study evaluated the effects of HAHD versus HD alone on all-
cause mortality, cardiovascular mortality and MACE in patients with ESKD. The study protocol,
previously published in detail32, was carried out across 11 hemodialysis centers in Shanghai, China.
The study adhered to Good Clinical Practice guidelines and the principles of the Declaration of
Helsinki. The study protocol was approved by the Ethics Committees at each of the 11 participating
study sites: the Ethics Committee of Xinhua Hospital affiliated to Shanghai Jiaotong University School
of Medicine, the Ethics Committee of Shanghai Changhai Hospital, the Ethics Committee of Longhua
Hospital, Shanghai University of Traditional Chinese Medicine, the Ethics Committee of Renji Hospital
affiliated to Shanghai Jiao Tong University School of Medicine, the Ethics Committee of Yangpu
Hospital, School of Medicine, Tongji University, the Ethics Committee of Shanghai Sixth People's
Hospital Affiliated to Shanghai JiaoTong University School of Medicine, the Ethics Committee of
Tongji Hospital, School of medicine, Tongji University, the Ethics Committee of Zhongshan Hospital,
Fudan University, the Ethics Committee of Shanghai General Hospital, Shanghai Jiaotong University,
the Ethics Committee of Shanghai Ninth People's Hospital affiliated to Shanghai Jiao Tong University
School of Medicine, and the Ethics Committee of Rui Jin Hospital affiliated to Shanghai Jiao Tong University
School of Medicine. All participants provided written informed consent before enrollment.
The study was registered with ClinicalTrials.gov (NCT03227770). The reporting of this study conforms
to the CONSORT 2010 guidelines (Supplementary Note 1).

Participants
Participants were recruited from December 1, 2017, to December 31, 2019. Eligible participants were
adults aged 18 ≥ years, with a diagnosis of ESKD, undergoing regular HD treatment for at least 3
months, with a standard Kt/V ≥ 1.2. Exclusion criteria included: white cell count < 4 × 109 cells/L or
platelet count < 100 × 109 cells/L, cerebral hemorrhage within the previous twelve weeks, MACE within
the previous eight weeks, severe heart failure (New York Heart Association class IV), active
gastrointestinal bleeding or coagulation disorders, active malignancy or infection, pregnancy or
breastfeeding, and significant cognitive impairment.

Randomization and interventions
Following a 1-month washout period during which all enrolled participants received LFHD, HFHD, or
HDF, eligible participants were randomly assigned in a 1:1 ratio to receive HAHD or a conventional
dialysis regimen (described below). Randomization was stratified by study center, and the
randomization sequence was generated by an independent statistician with allocation concealed in
opaque envelopes. Allocation concealment was ensured by revealing group assignments only after
baseline data registration. At each clinical center, unmasked study personnel prepared treatments, but
investigator and participant remained masked to the allocation prior to enrollment.

In the HAHD group, participants received conventional HD supplemented hemoadsorption at least once
every two weeks. Hemoadsorption was performed using an HA130 cartridge (Jafron Biomedical,
Zhuhai, China), placed in series before the filter. Cartridges were prepared following the manufacturer’s
instruction. Each cartridge was primed with 12,500 IU of heparin, gently shaken and rotated, and
allowed to rest for at least 30 minutes. They were subsequently primed with 2,000-3000 mL of normal
saline after being connected to the filter. During HAHD sessions, the HA130 cartridge was integrated
into the HD circuit for the first 2 hours with a blood flow rate of 150-200 mL/min. The blood flow was
increased to 200–250 mL/min after discontinuing the HA cartridge at the 2-hour mark, to optimize the
efficacy of the subsequent HD-only phase.

In the conventional HD group, participants received LFHD, HFHD, or HDF based on their pre-washout
dialysis regimen, with a minimum treatment duration of 10 h/week (two 5-hour sessions or three 4-hour
sessions per week). Polysulfone filters with a surface area of 1.4–1.8 m2 were utilized. HD prescription
included the following parameters: dialysis time: 4–5 h, blood flow rate: 200-300 mL/min, average
dialysate flow rate: 500 mL/min, bicarbonate dialysate with calcium ion concentrations of 1.25–1.5
mmol/L. For HDF, treatments adhered to the Standard Operating Procedures for Blood Purification
(Chinese Edition)33: blood flow rate: > 250 mL/min, dialysate flow rate: 500-800 mL/min, pre-dilution
volume: 30–50 L, or a post-dilution volume: 15-25 L. Low molecular weight heparin or unfractionated
heparin served as anticoagulants, with dosages tailored to patient body weight. The baseline dialysis
prescription was intended to be maintained throughout the study for all participants. Any adjustments
were infrequent and not systematically different between the groups, thus minimizing the risk of bias
influencing the outcomes.

Outcomes
The primary outcome of study was all-cause mortality, while secondary outcomes included
cardiovascular mortality and MACE. These outcomes were initially assessed over a minimum planned
follow-up period of 24 months. Due to slow initial recruitment, the enrollment period was extended
until December 2019. The observation period concluded in December 2021, ensuring that all
participants had a planned follow-up of at least 24 months, with the earliest enrollees having a
maximum follow-up duration of 49 months.

MACE was defined as the occurrence of any of the following events: angina pectoris, myocardial
infarction, severe arrhythmia, progression of heart failure, pericarditis, myocarditis, cardiac or
peripheral vascular surgery, stroke, or peripheral vascular disease. The mortality of the patients was
documented by attending physicians at the respective hospital or reported by relevant parties and
subsequently verified by physicians. Causes of death were classified in accordance with China’s
National Disease Surveillance Points (DSP) system, which provides standardized and reliable mortality
reporting. The timing and cause of death, as well as MACE occurrences, were documented by treating
physicians, and all classifications were reviewed and verified by study investigators. In addition,
information on primary kidney disease and comorbidities was carefully reviewed and confirmed using
medical records.

Safety monitoring was conducted throughout the study. Given that the most severe safety outcomes
(death and MACE) were analyzed as the primary and secondary endpoints, the reporting of other
adverse events was focused on those deemed by investigators to be potentially related to the treatment
procedure, thereby providing a targeted assessment of procedural safety.

Laboratory assessments were performed at baseline and at 6, 12, 18, and 24 months after study initiation
(Supplementary Table 4). The measured parameters included renal and metabolic markers (intact
parathyroid hormone [iPTH], β -MG, blood urea nitrogen, serum sodium, potassium, calcium,
2
phosphate, and glucose), inflammatory markers (high-sensitivity C-reactive protein and homocysteine),
liver function tests (total bilirubin, direct bilirubin, alanine aminotransferase, aspartate aminotransferase,
γ-glutamyltransferase, alkaline phosphatase, total protein, and albumin), cardiac biomarkers (troponin I,
myoglobin, lactate dehydrogenase, hydroxybutyrate dehydrogenase, and pro B-type natriuretic peptide,
creatine kinase, creatine kinase-MB), and dialysis efficiency (standard Kt/V).

Statistical analysis
We determined that the enrollment of 1364 patients (200 primary outcome events) would provide 80%
power to determine a 30% relative risk reduction in mortality with HAHD compared with the HD at a
two-sided type I error of 5% and a follow-up duration of 2 years. Further details on the power
calculation have been previously reported32.

The intention-to-treat analysis, which included all randomized patients, was used to evaluate baseline
characteristics. For the analyses of primary and secondary outcomes, a mITT set was employed,
consisting of all patients who received at least one treatment session. The per-protocol population,
comprising all patients who adhered to the prescribed treatment plan, was used for sensitivity analyses.
Follow-up was defined as the time interval from the time of randomization to the date of death, loss to
follow-up, withdrawal, or December 31, 2021, whichever occurred first.

A Cox proportional hazards regression model adjusted for study center was used to estimate HRs and
95% CIs for all-cause and cardiovascular mortality and MACE. Kaplan–Meier analysis with the log-
rank test was used to compare time to event for all-cause and cardiovascular mortality and MACE rate
between the HAHD and HD groups. For primary and secondary outcomes, all analyses were performed
with kidney transplantation defined as a competing event. Follow-up was right-censored at the time of
transplantation, and deaths occurring after transplantation were not included, as they could not be
reliably attributed to the effects of dialysis treatment. We graphically assessed the model assumption of
proportionality using log cumulative hazard plots and by examining scaled Schoenfeld residuals. The
proportional hazards assumption was met for all outcomes.

We additional performed subgroup analysis to assess for possible heterogeneity of treatment effect.
Predefined subgroups were based on age (< 65 and ≥ 65 years), sex (males and females), dialysis
vintage (< 3 and ≥ 3 years), baseline β -MG levels (≤ 30 and > 30 mg/L), cause of kidney failure
2
(chronic glomerulonephritis, hypertension nephrosclerosis, diabetic nephropathy, polycystic kidney, and
others), baseline ferritin levels (< 151 and ≥ 151 μg/L), baseline homocysteine levels (< 30.8 and ≥ 30.8
μmol/L), baseline pro B-type natriuretic peptide levels (< 2421 and ≥ 2421 pg/L), and baseline iPTH (<
600 and ≥ 600 pg/mL).

All analyses were performed using the SAS 9.4 software (SAS Institute, Cary, NC).

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "This randomized, open-label, multicenter study aimed to compare the effects of hemoadsorption combined with hemodialysis (HAHD) vs. hemodialysis (HD) alone on mortality in patients with end-stage kidney disease (ESKD). Conducted across 11 dialysis centers in Shanghai, China, the study enrolled 1,362 patients, who were randomized into two groups: HAHD (n=683) and HD (n=679).\nThe primary outcome was all-cause mortality, while secondary outcomes included cardiovascular mortality and major cardiovascular events (MACE).\nThe authors have conducted a well-designed study, providing important clinical evidence on the impact of hemoadsorption combined with hemodialysis (HAHD) in patients with end-stage kidney disease. This randomized, multicenter trial adds meaningful data to the growing body of research on hemoadsorption devices. The findings, showing a reduction in mortality and cardiovascular events, highlight the potential benefits of this approach as an adjunct to conventional dialysis. Further studies will be valuable to confirm these results and explore their broader applicability. Congratulations to the authors on this important contribution to nephrology research.\nNevertheless, some consideration should be reported.\nIntroduction\n1. 1.- line 86. HDF could be safely used in elderly patients. A population of patients that is increasing over the years. Include this could create confusion in the decision of use HDF in elderly patients. One of the recet articles regarding this is:\nHemodiafiltration versus Hemodialysis in End-Stage Kidney Disease: A Systematic Review and Meta-Analysis\n10.1016/j.xkme.2024.100829\n2. Line 93. Pruritus. Please, used the concepts Chronic Kidney Diseases-associated pruritus.\nMethods\n1.- Line 127. “conventional HD alone”. This creates confusion, because some patients maintain their usual prescription with HDF, therefore no the “conventional HD”.\n2.- Line 142. What is the reason for the reduction of blood flow and reduce the efficacy of the entire treatment?. The blood flow after the removal of HA cartridges was increased again?\n3.- Line 164. Please use the word Stroke instead cerebrovascular accident.\nResults\n1.- Line 256. The phrase has a redundancy issue (“risk reduction risk”) and could be clearer. A corrected option would be:\n“The sensitivity analyses in the Per Protocol (PP) population showed a consistent reduction in risk for CVD-specific mortality and MACE”\n2.- In the control group, some patients received the best treatment option for dialysis (HDF). The comparison between HAHD and low flux alone is unfair; therefore, since the authors have data on HDF patients, they should consider incorporating it as a sub-analysis comparing HAHD to HDF patients, indicating the convective volume achieved.\nDIscussion\n1.- Line 301: I highly recommend incorporating the possible reduction in advance glycation end products in the mechanisms.\ndoi: 10.1111/aor.14954", "reviewer_2": "Thanks for asking me to review this manuscript which reports a randomised study of the addition of hemoperfusion (HP) to routine hemodialysis at 11 sites in China. The team randomised 1419 people and found an impressive 22% reduction in all- cause mortality over median follow up of 39 months, largely driven by a significant difference in cardiovascular events. Given the pre-eminence of cardiovascular disease and mortality in the kidney failure population this potentially represents a paradigm shifting publication, with particular impact on low and middle income countries where access to more frequent high flux dialysis is limited. The generalizability of these findings will be subject to significant scrutiny as, while the findings of this study are in line with those of prior smaller RCTs, all the available randomised data still originates in China.\nThe study has many strengths including its size and duration and use of allocation concealment.\nMy comments are as follows\nThe following weaknesses need to be acknowledged in the manuscript:\n1. Blinding of patients and clinicians was not performed and may not have been practicable.\n2. There does not appear to have been independent adjudication of cardiovascular events or cause of mortality and if the verification of events described in the manuscript was not performed blind to allocation this represents a potential source of bias. Similarly, without an independent review of adverse events there is the risk of underestimation of adverse events in the intervention group.\n3. There is a significant (chi2-value 13.8, p<0.001) baseline imbalance between males and females. And while the authors have conducted an analysis adjusted for sex (finding consistent results) it remains conceivable that this influenced results.\nThe characteristics of dialysis need to be completely described.\n4. The published protocol is a little hard to follow, it states that the control group received two seesions of low-flux HD and one of HDF per week with session times of 4 hours. I assume that this means 3 sessions per week, of 4 hours, and that two sessions were low flux HD and 1 session was HDF. Is this correct? Please state it in this or a related form in the methods.\n5. Baseline dialysis hours per week\n6. Baseline sessions per week (total, and specifying what membrane types and including HDF sessions)\n7. Baseline blood and dialysate flow rates\n8. Baseline kt/v\n9. Also, these characteristics of dialysis should also be presented for each follow up time point, including Kt/V (this can be a supplementary), along with estimates of the variability in these parameters.\nand,\n10. The reduction in apparent effect in the per protocol population requires some explanation.\n11. What was the purpose of the run-in period? This appears to have been simply a screening window - did any study related activites take place? Was HP trialled during this period?\n12. Kidney failure is the preferred term (not ESKD)\n13. Did any patients in the conventional HD group receive HP (HAHD)? Figure 1 states not, but was this complete in that no control patients ever received a session of HP?\n14. The subgroup analyses require the estimation of a p-value for interaction. It is not sufficient simply to compare the CIs.\n15. What were the quality of life outcomes?\n16. How many people were in the mITT population (per group)\n17. There are excessive numbers of decimal places throughout. Percentages should have no more than one dp, and HRs shoudl not have more than two dp.\n18. Please provide the event rates (per 100 or 1000 patient years) in all Figure Bs, including a line that shows event rates in the main analysis.", "reviewer_3": "This well written manuscript presents the primary results of a multicenter clinical trial that compared mortality and cardiovascular outcomes between patients randomized to Hemoadsorption Combined with Hemodialysis (HAHD) vs. Hemodialysis (HD) alone for patients with ESKD undergoing maintenance HD. The trial appears to have been well conducted, the results are presented clearly, and the conclusions are well constructed and appear to be justified. Thus all of my comments are relative minor in nature:\n1. The authors state that secondary outcomes included cardiovascular mortality and MACE were secondary outcomes. Were these the only secondary outcomes, or, if other secondary outcomes were designated, did the study protocol stipulate that these two particular secondary outcomes would be emphasized in the interpretation of the study results? If so, this would be useful to describe in the methods to justify the article’s focus on these two specific secondary outcomes in addition to morality as opposed to other possible secondary outcomes.\n2. Can the authors briefly state the purpose of the washout period?\n3. Line 157 – suggest writing “… minimum planned follow-up period of 24 months …” since patients who died or were lost to follow-up would have had shorter actual follow-up periods.\n4. Lines 159-160 – Suggest writing “….all participants had a planned follow-up of at least 24 months…” for the same reason as above.\n5. When summarizing the power calculations, consider provided also the planned number of primary outcome events required to obtain 80% power. This will allow readers to compared the actual number of events to the planned number of events to assess the extent to which the original target number of events was achieved.\n6. Can the authors clarify in the text how transplants were handled in the primary statistical analysis? That is, was follow-up right censored at the time of transplant, or were any deaths following transplant included in the primary analysis?\n7. The article indicates very few patients were lost to follow-up. Did the lost-to-follow-up numbers include patients who transferred to non-study dialysis units?\n8. The expressions for mortality rates in the results should indicates these rates are expressed as deaths per year.\n9. If possible, interaction p-values should be provided for the subgroup analyses to indicate if differences in HRs between subgroups are compatible with chance variation. Ideally these interaction p-values would be added to the forest plots that display the subgroup results.\n10. The presentation of the subdistribution HRs after accounting for the competing risk of transplantation is a little incomplete since p-values are presented without accompanying HRs or CIs, and because only the mortality or CV subdistribution HRs are provided and not some corresponding statistic for transplantation. The idea of competing risk analysis is to view the outcome as 2-dimensional, and to jointly present results for both competing risks. These results have to be viewed jointly for the competing risk analysis to make sense. If just one is presented (as currently in the text), the resulting subdistribution HR (and associated CI and pvalue) is potentially misleading and less valid than the cause – specific HR which is already presented for the primary analysis. (This is a very common error in the medical literature.) In this case, there are very view transplants, which makes providing subdistribution HRs for transplants problematic. A possible solution here would be to report something like: “In the competing risk analysis, there were XX and XX transplants prior to death in the HAHD and HD groups, respectively, and the sudistribution hazard ratio for morality with transplant as a competing risk was XX (95 % CI XX- XX), p-value = XX.” Given the small number of transplants, it is probably not necessary to repeat similar statements for the secondary outcomes, but if desired similar language could be used for them as well."}, "author_response": "RE: We really appreciate for all your comments and suggestions. We have revised the manuscript accordingly.\n\n[...]"}, {"round": 2, "reviewer_comments": {"reviewer_1": "I have carefully reviewed the authors’ responses and the revised manuscript. I appreciate the clarity and depth of their replies, and I am satisfied that all my comments have been addressed appropriately. The manuscript has been significantly improved.\nI would only suggest two minor additional points:\nThat the authors consider explicitly incorporating, within the limitations section, a clarification regarding the differences in HDF practice in China compared to Western standards. This would help readers—particularly those in Europe or the Americas—understand that the HDF regimens used in the study (often once or twice monthly) differ substantially from the high-volume, thrice-weekly HDF commonly applied in trials such as CONVINCE. Including this would enhance the generalizability discussion and prevent misinterpretation regarding the comparator treatments.\nFor consistency with international nomenclature, I suggest replacing the term “hemodialyzers” with “filters” throughout the manuscript, as this is the more widely used term in global nephrology literature.\nWith these minor additions, I believe the manuscript is suitable for publication.", "reviewer_2": "The manuscript is substantially improved but I believe the authors have only partially addressed my comments. I seek clarification on the following points:\nRe my point 5, 6, and 7. I should have been more explicit in my initial review.\nIt is vital that the baseline median and IQR for number of dialysis sessions per week, session length (hrs), and total dialysis time per week, and membrane type (high or low flux), dialysate and blood flow rates are reported in Table 1.\nI note that the protocol specifies a certain range, but it is useful to know if there were baseline differences in these parameters.\nLikewise for point 9.\nSupp table 2 is not sufficient. It would be more useful to see the median/mean/% values for dialysis prescription parameters (dialysis sessions per week, session length (hrs), and total dialysis time per week, and membrane type (high or low flux), dialysate and blood flow rates)\nIt is conceivable that in an unblinded study, the physicians varied the dialysis prescription (within the study protocol parameters) in the non-HP arm. Understanding how dialysis was delivered in both groups is important to assessing any potential biases in these results.\nRe point 10:\nYour response in the discussion \" Also, the observed reduction in effect size in the PP population compared to mITT population may be due to reduced sample size, loss of statistical power, and potential selection bias from excluding nonadherent participants. These factors may attenuate the apparent treatment effect, although the consistency in direction across analyses supports the robustness of our findings.\" does not provide the required clarity. Reduced sample size will widen the confidence intervals but will not per se change the effect size. Loss of statistical power is in this context just another way of saying that your sample size is smaller - and similarly does not effect the effect size estimate. Finally, excluding non-adherent patients usually increases the apparent treatment effect (the opposite of what you have stated).\nCan you provide some reasons why the impact of HP might have been less prominent in those who were using it as directed in the protocol?\nWas there an issue with tolerance or adherence to HP in that younger or fitter patients were more likely to skip the HP treatment?\nPoint 11:\nOk so were all patients on HP when recruited? That would also be interesting to know in case there was a legacy effect from HP. Can you please present pre-run in use of HP in Table 1?\nPoint 16:\nCould you add n for mITT and n for PP to Table 2?\nIn addition, I note an addition to line 126: \"routinely conventional dialysis regimen.\" is not grammatically correct and also doesn't help clarify for the reader - in many high income countries routine dialysis is 3x per week. But in this case routine was minimum 10hrs..\nYou could revise to \"a conventional dialysis regimen (described below)\" as you do describe this regimen in the following page (lines 143-145)", "reviewer_4": "This report presents a large scale study of the usage of Hemoadsorption Combined with Hemodialysis (HAHD) vs. Hemodialysis (HD) alone for patients with ESKD undergoing maintenance HD.\n1. The overall study didn't closely follow the industry practices, which lead to concerns about data quality. Template tables recommended to add was provided in the attached.\na) The protocol was published online but didn't appear to be complete. A complete one was required to get the ethics approval.\nb) Safety is missing in the Objectives, which should be a primary one. One would naturally expect a novel technology to be more effective than the existing one but not as safe. The real comparison here would be whether the clinical benefit outweighs the safety concerns.\nc) The protocol stated their AE monitoring plan but didn’t specify the safety analysis plan and the safety analysis was incomplete. An AE table was offered, which was not a standard one and the cases were too few and only considered related cases. It is against the industry practice to record only related cases as bias could be introduced in the process and the comparison would be inconclusive.\nGenerally, two tables are expected, an AE summary table and an individual AE one. For this study, I would recommend to include more AE tables to better justify the safety of HAHD.\nd) There are concerns about efficacy analysis:\ni. The primary hypothesis is on superiority, but the sample size calculation is two-sided, which is based on equivalency.\nii. The primary analysis table is not industry-standard. Analyses on those two populations (mITT and PP) would usually be separated.\niii. Those two populations (mITT and PP) would usually be well specified in the protocol before conducting the trial.\niv. The contemporary trend would be to use mITT as the primary analysis population but since this is an open-label study, one would think PP to be the primary one to eliminate subjective bias in the trial.\nv. How to calculate HRs was not specified in the table. The one specified in the protocol doesn't seem to be conducted.\nMultivariate Cox regression will be used to analysed factors that could influence all-cause mortality and CVD mortality after the adjustment for multiple relevant traditional and uraemia-related risk factors for mortality.\nvi. Though partially shown in the Figure on Enrollment, one would expect to have a table of subject disposition.\nvii. The baseline doesn't seem to be balanced between two methods, e.g., there are more males in the HAHD group than the HD group. It appears that the randomization was not well conducted.\nviii. The HRs are not consistent for those two populations with one being statistically significant and the other not. A more detailed statistical analysis need to be conducted in addition to the discussion.\nviiii. Quality of life (QoL) was excluded from the analyses. This is unusal. A more appropriate approach is to present the results according to the protocol and discuss the data issue.\n2. The Covid-19 pandemic would have impacts on the study and interfere with the results. Since that period has overlaps with the trial and requires patients to receive interventions frequently, I wonder how the study was impacted and what measures have been taken to offset the impacts.", "reviewer_5": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": "Response to R3\n1. The authors state that secondary outcomes included cardiovascular mortality and MACE were secondary outcomes. Were these the only secondary outcomes, or, if other secondary outcomes were designated, did the study protocol stipulate that these two particular secondary outcomes would be emphasized in the interpretation of the study results? If so, this would be useful to describe in the methods to justify the article’s focus on these two specific secondary outcomes in addition to morality as opposed to other possible secondary outcomes.\nRE: Quality of life (QoL) was initially registered as a secondary outcome. However, during data collection, we encountered significant challenges in obtaining complete and reliable QoL data due to logistical constraints (e.g., inconsistent patient follow-up and incomplete survey responses). Moreover, during the later stages of data collection, the COVID-19 pandemic significantly disrupted study operations. Consequently, QoL assessments were excluded from the final analysis.\nDue to the impact of the COVID-19 pandemic, we were unable to collect complete Quality of Life (QoL) data. Consequently, after thorough discussions among investigators from our 11 centers, we decided to exclude QoL from the current analysis. This decision was made to ensure the accuracy and reliability of our study results, given the data deficiencies.\nNot fully responded. It is not scientific to mask some data, especially on an endpoint. The authors need to present it even if it is incomplete. Meanwhile, a further question raises: is QoL the only endpoint affected by the pandemic? I am concerned that the whole trial was compromised.\n5. When summarizing the power calculations, consider provided also the planned number of primary outcome events required to obtain 80% power. This will allow readers to compared the actual number of events to the planned number of events to assess the extent to which the original target number of events was achieved.\nRE: Thank you for your comment on the calculation of power. Specifically, our sample size calculation was based on detecting a 30% relative risk reduction in the HAHD group compared to the conventional hemodialysis group, with 80% power, a two-sided alpha of 0.05, and a follow-up period of 2 years. Under these assumptions, we estimated that approximately 200 primary outcome events would be required to achieve the desired statistical power. This addition allows readers to compare the planned versus observed event numbers to assess the adequacy of the study power. As recommended, we have now included the planned number of primary outcome events required to achieve 80% power in the revised methods section.\nThe original sample size calculation was based on a two-sided test. Even though the authors didn’t specify their hypotheses in the article, which is a major issue, one can infer that they are interested in one-sided hypotheses (HR < 1). This raises another major issue, the sample size was not correctly calculated, and the actually required sample size should be bigger than the calculated one.\n7. The article indicates very few patients were lost to follow-up. Did the lost-to-follow-up numbers include patients who transferred to non-study dialysis units?\nRE: Thank you for prompting this critical clarification. The reported lost-to-follow-up numbers included patients who transferred to non-study dialysis units. The 11 participating centers are all top-tier Class 3A tertiary hospitals in Shanghai (China’s highest hospital accreditation tier), which serve as regional referral hubs for dialysis care. This centralized structure, combined with China’s healthcare policies mandating chronic disease management at designated centers, inherently minimizes patient transfers.\nAuthors’ Responses to 1 raises concerns about losses-to-follow-up due to the Covid-19 pandemic, which, in Shanghai, should be a city lockdown for nearly 3 months.\n9. If possible, interaction p-values should be provided for the subgroup analyses to indicate if differences in HRs between subgroups are compatible with chance variation. Ideally these interaction p-values would be added to the forest plots that display the subgroup results.\nRE: Thank you for your comment, we have added the P-value for interaction in all figure Bs.\nForest plots don’t serve as a good test of interaction. Therefore, there is no need to include p-values.\n10. The presentation of the subdistribution HRs after accounting for the competing risk of transplantation is a little incomplete since p-values are presented without accompanying HRs or CIs, and because only the mortality or CV subdistribution HRs are provided and not some corresponding statistic for transplantation. The idea of competing risk analysis is to view the outcome as 2-dimensional, and to jointly present results for both competing risks. These results have to be viewed jointly for the competing risk analysis to make sense. If just one is presented (as currently in the text), the resulting subdistribution HR (and associated CI and pvalue) is potentially misleading and less valid than the cause – specific HR which is already presented for the primary analysis. (This is a very common error in the medical literature.) In this case, there are very view transplants, which makes providing subdistribution HRs for transplants problematic. A possible solution here would be to report something like: “In the competing risk analysis, there were XX and XX transplants prior to death in the HAHD and HD groups, respectively, and the sudistribution hazard ratio for morality with transplant as a competing risk was XX (95 % CI XX- XX), p-value = XX.” Given the small number of transplants, it is probably not necessary to repeat similar statements for the secondary outcomes, but if desired similar language could be used for them as well.\nRE: Thank you for your valuable suggestions. We apologize for the confusion caused by the previous wording. Actually, all HRs and their 95% CIs presented in the manuscript have already accounted for kidney transplantation as a competing risk. This approach was applied throughout the main analyses, not just as a sensitivity analysis. The sensitivity analysis for competing risk is only for the log-rank test. We have revised the method section accordingly.\nThe impact of the kidney transplant is unclear, which worths careful analyses. Subjects could be having bad results from dialysis, which promotes a transplant. In this scenario, to exclude those transplants from the analyses would lead to biases. (The analysis results partially support such a possibility.)"}, {"round": 3, "reviewer_comments": {"reviewer_2": "I appreciate all authors comments and revisions.\nI do have further comments since the issue of high v low flux has now emerged.\nThe admission that (effectively, all bar 9) all participants used low flux dialysers is important. While randomised studies showed no overall difference in outcomes with high- v low-flux dialysis there were important subgroups in which high flux was superior. \"Conventional\" HD now means high flux in high-income countries. As such the conclusions to the abstract and in the discussion need the addition of the caveat that the comparator was low-flux HD\ne.g. in the abstract: \" In patients with ESKD undergoing maintenance HD, adding hemoadsorption significantly reduced allcause mortality, cardiovascular mortality, and major cardiovascular events compared to HD alone.\" should be \"In patients with ESKD undergoing maintenance low-flux HD, adding hemoadsorption significantly reduced allcause mortality, cardiovascular mortality, and major cardiovascular events compared to low-flux HD alone. \"\ne.g. in the discussion: \"In this randomized, open-label, multicenter study involving 1362 ESKD patients with a median of 39.5 months follow-up demonstrated that conventional HD plus hemoadsorption at least once every two weeks significantly reduced the risks of allcause and cardiovascular-specific mortality, and MACE compared to conventional HD...\" should be \"In this randomized, open-label, multicenter study involving 1362 ESKD patients with a median of 39.5 months follow-up demonstrated that conventional low-flux HD plus hemoadsorption at least once every two weeks significantly reduced the risks of allcause and cardiovascular-specific mortality, and MACE compared to conventional low flux HD alone.\"\nFinally, the results section could have a sentence to make explicit the use of low v high flux. E.g. at line 233, before the sentence about loss to follow up, the authors could add something like \"With the exception of X participants in the HAHD and Y participants in the HD groups, all participants received low-flux haemodialysis.\" [where X and Y are the numbers in each group]. But this info could be conveyed in Table 1. I don't mind so long as it's there somewhere.\nNote that the addition of this caveat does not undermine the importance of the findings, but it is essential contextual information.", "reviewer_4": "This report presents a large scale study of the usage of Hemoadsorption Combined with Hemodialysis (HAHD) vs. Hemodialysis (HD) alone for patients with ESKD undergoing maintenance HD.The rebuttal has fairly addressed comments and the main conclusion is sound:\n1. Table 1 Baseline characteristics: This table is too long and also needs separating lines for better visualization. Suggest to remove some unimportant variables.\n2. Table 2 Primary and secondary outcomes: Footnotes are needed to show the used Cox model, especially the coviates used.\n3. Table 3 Adverse events: Summary for those individual AE terms can be included as a subcategory. E.g.,\nTotal *** ***\nInfections *** ***\nrespiratory tract infections *** ***\nurinary tract infections *** ***\n4. Figure 1 Patient enrollment and follow-up: There are some inconsistent numbers. Please check and update.\n5. Figure 2. All-cause mortality. (A) Kaplan-Meier analysis: Remove 95% CIs for the KM plots.\n6. Figure 4. Major cardiovascular events. (A) Kaplan-Meier analysis: There is no need to have (0,0.6) for Survival.", "reviewer_5": "I reviewed this manuscript with one of the reviewers who provided the listed report. This is part of a Nature Communications initiative aimed at promoting peer review training and providing appropriate recognition for early-career researchers who co-review manuscripts.;"}, "author_response": "Response to R2\n[...]\nResponse to R4\n[...]\nResponse to R5\n[...]"}, {"round": 4, "reviewer_comments": {"reviewer_4": "The manuscript was well revised and all comments are addressed. Suggest to accept as is."}, "author_response": ""}]

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