{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T08:48:20Z","timestamp":1791967700475,"version":"4.3.4"},"update-to":[{"DOI":"10.3310\/nihropenres.14213.1","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000}}],"reference-count":24,"publisher":"National Institute for Health and Care Research","license":[{"start":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T00:00:00Z","timestamp":1785801600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"EME","award":["NETSCC17\/61\/04"],"award-info":[{"award-number":["NETSCC17\/61\/04"]}]}],"content-domain":{"domain":["openresearch.nihr.ac.uk"],"crossmark-restriction":false},"short-container-title":["NIHR Open Res"],"abstract":"<ns3:p>Background The mortality rate of kidney dialysis patients remains high, predominantly due to cardiovascular disease. The clearance of uraemic solutes with standard high-flux haemodialysis (HD) is mainly mediated by diffusion. More recently, haemodiafiltration (HDF), which adds convection, thus increasing the spectrum of cleared uraemic toxins, has been introduced into clinical practice. Recent reports have suggested that HDF treatment improves patient outcomes. However, it is unclear as to the amount of HDF treatment required or why HDF should improve patient outcomes. The UK High-Volume Haemodiafiltration vs. High-Flux Haemodialysis Registry Trial (H4RT) study compared a composite of non-cancer mortality or hospital admission with a cardiovascular event or infection over 3 years. However, this study was not designed to investigate why HDF may have improved patient outcomes; therefore, the STITCHED study (Study To Investigate The Change in Hypotensive Episodes during Dialysis) was designed to be nested within the larger H4RT study. Objective The STITCHED study was designed to investigate the potential mechanisms underlying the improved survival reported with HDF. Design and methods The STITCHED study was designed to investigate changes in intra- and inter-dialytic blood pressure; differences in the clearance of uraemic toxins, temperature, sodium, and calcium balance between HDF and HD treatments; and the effects on the heart and brain by measuring differences in arterial stiffness, cardiac dimensions, and cognitive function. Setting and participants Nine acute hospital trusts across England were contacted and involved in the STITCHED study. However, after delays due to covid-19 only the Royal Free Hospital in London recruited participants. Results After disruptions due to the covid-19 pandemic the study was stopped before any results were obtained. Conclusion The STITCHED study was halted before any relevant information was obtained, and as such was unable to answer the question of why one mode of dialysis should improve patient survival.<\/ns3:p>","DOI":"10.3310\/nihropenres.14213.2","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T11:34:06Z","timestamp":1785843246000},"page":"27","update-policy":"https:\/\/doi.org\/10.3310\/nihropenres.crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Understanding possible differences between haemodialysis and haemodiafiltration which affect survival in end-stage kidney disease dialysis patients: the STITCHED study\u00a0halted by the COVID-19 epidemic"],"prefix":"10.3310","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4467-6833","authenticated-orcid":false,"given":"Andrew","family":"Davenport","sequence":"first","affiliation":[{"name":"UCL Centre for Kidney & Bladder Health London England NW3 2PF University College London Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"MacNeil","sequence":"additional","affiliation":[{"name":"Bristol Trials Centre Bristol England BS8 1NU University of Bristol Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5199-3925","authenticated-orcid":false,"given":"Fergus","family":"Caskey","sequence":"additional","affiliation":[{"name":"UK Population Health Sciences Bristol England BS8 2PS University of Bristol Medical School"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"6221","published-online":{"date-parts":[[2026,8,4]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1186\/s13063-022-06357-y","article-title":"The high-volume haemodiafiltration vs high-flux haemodialysis registry trial (H4RT): a multi-centre, unblinded, randomised, parallel-group, superiority study to compare the effectiveness and cost-effectiveness of high-volume haemodiafiltration and high-flux haemodialysis in people with kidney failure on maintenance dialysis using linkage to routine healthcare databases for outcomes.","volume":"23","author":"F Caskey","year":"2022 Jun 27","journal-title":"Trials."},{"key":"ref2","first-page":"192-202","article-title":"Mortality and cardiovascular events in online haemodiafiltration (OL-HDF) compared with high-flux dialysis: results from the Turkish OL-HDF Study.","volume":"28","author":"E Ok","year":"2013","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref3","doi-asserted-by":"publisher","first-page":"1087-1096","DOI":"10.1681\/ASN.2011121140","article-title":"Effect of online hemodiafiltration on all-cause mortality and cardiovascular outcomes.","volume":"23","author":"M Grooteman","year":"2012","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref4","doi-asserted-by":"publisher","first-page":"1495-1509","DOI":"10.1016\/j.kint.2017.01.013","article-title":"Treatment tolerance and patient-reported outcomes favor online hemodiafiltration compared to high-flux hemodialysis in the elderly.","volume":"91","author":"M Morena","year":"2017","journal-title":"Kidney Int."},{"key":"ref5","doi-asserted-by":"crossref","first-page":"978-984","DOI":"10.1093\/ndt\/gfv349","article-title":"HDF Pooling Project Investigators. Haemodiafiltration and mortality in end-stage kidney disease patients: a pooled individual participant data analysis from four randomized controlled trials.","volume":"31","author":"S Peters","year":"2016","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref6","doi-asserted-by":"publisher","first-page":"193-199","DOI":"10.1038\/ki.2015.264","article-title":"HDF Pooling Project Investigators. Higher convection volume exchange with online hemodiafiltration is associated with survival advantage for dialysis patients: the effect of adjustment for body size.","volume":"89","author":"A Davenport","year":"2016","journal-title":"Kidney Int."},{"key":"ref7","doi-asserted-by":"publisher","first-page":"548-555","DOI":"10.1093\/ndt\/gfw381","article-title":"Mortality reduction by post-dilution online-haemodiafiltration: a cause-specific analysis.","volume":"32","author":"M Nub\u00e9","year":"2016 Dec 26","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref8","doi-asserted-by":"publisher","first-page":"487-497","DOI":"10.1681\/ASN.2012080875","article-title":"High-efficiency post-dilution online hemodiafiltration reduces all-cause mortality in hemodialysis patients.","volume":"24","author":"F Maduell","year":"2013","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref9","doi-asserted-by":"publisher","first-page":"162-167","DOI":"10.1111\/j.1542-4758.2006.00088.x","article-title":"Intradialytic complications during haemodialysis.","volume":"10","author":"A Davenport","year":"2006","journal-title":"Hemodial. Int."},{"key":"ref10","doi-asserted-by":"publisher","first-page":"724-734","DOI":"10.1681\/ASN.2014020222","article-title":"Association of mortality risk with various definitions of intradialytic hypotension.","volume":"26","author":"J Flythe","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref11","doi-asserted-by":"publisher","first-page":"ii22-ii44","DOI":"10.1093\/ndt\/gfm019","article-title":"EBPG guideline on haemodynamic instability.","volume":"22","author":"J Kooman","year":"2007","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref12","doi-asserted-by":"crossref","first-page":"552-557","DOI":"10.1093\/joneph\/16.4.552","article-title":"Thermal effects of different dialysis techniques and blood pump speeds: an in vitro study.","volume":"16","author":"C Beerenhout","year":"2003","journal-title":"J. Nephrol."},{"key":"ref13","doi-asserted-by":"publisher","first-page":"853-856","DOI":"10.1093\/ndt\/gfv412","article-title":"Lower cardiovascular mortality with high-volume hemodiafiltration: a cool effect?","volume":"31","author":"J Daugirdas","year":"2016 Jun","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref14","doi-asserted-by":"publisher","first-page":"957-965","DOI":"10.1681\/ASN.2013101086","article-title":"Randomized clinical trial of dialysate cooling and effects on brain white matter.","volume":"26","author":"M Eldehni","year":"2015","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref15","doi-asserted-by":"publisher","first-page":"229-231","DOI":"10.1111\/j.1525-139X.2008.00429.x","article-title":"How should dialysis fluid be individualized for the chronic hemodialysis patient?","volume":"21","author":"N Selby","year":"2008","journal-title":"Temperature. Semin Dial."},{"key":"ref16","doi-asserted-by":"publisher","first-page":"1102-1110","DOI":"10.1161\/HYPERTENSIONAHA.115.06896","article-title":"Hypertension in Chronic Kidney Disease Part 2: Role of Ambulatory and Home Blood Pressure Monitoring for Assessing Alterations in Blood Pressure Variability and Blood Pressure Profiles.","volume":"67","author":"G Parati","year":"2016 Jun","journal-title":"Hypertension."},{"key":"ref17","doi-asserted-by":"publisher","first-page":"2046-2053","DOI":"10.1093\/ndt\/gfv090","article-title":"Ambulatory aortic blood pressure, wave reflections and pulse wave velocity are elevated during the third in comparison to the second interdialytic day of the long interval in chronic haemodialysis patients.","volume":"30","author":"G Koutroumbas","year":"2015 Dec","journal-title":"Nephrol. Dial. Transplant."},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1539-1547","DOI":"10.1056\/NEJMoa0904655","article-title":"Functional status of the elderly before and after dialysis initiation.","volume":"361","author":"M Kurella Tamura","year":"2009 Oct 15","journal-title":"N. Engl. J. Med."},{"key":"ref19","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1186\/s12882-015-0131-4","article-title":"Cross-sectional association of volume, blood pressure, and aortic stiffness with left ventricular mass in incident haemodialysis patients: Predictors of Arrhythmic and Cardiovascular Risk in End-Stage Renal Disease (PACE) study.","volume":"16","author":"E Kim","year":"2015 Aug 7","journal-title":"BMC Nephrol."},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1856-1869","DOI":"10.1016\/j.ekir.2020.08.031","article-title":"Dialysis-induced cardiovascular and multiorgan morbidity.","volume":"5","author":"B Canaud","year":"2020 Sep 9","journal-title":"Kidney Int. Rep."},{"key":"ref21","doi-asserted-by":"publisher","first-page":"489-496","DOI":"10.1038\/ki.2014.207","article-title":"The role of bioimpedance and biomarkers in aiding clinical decision-making in volume assessments in dialysis patients.","volume":"86","author":"S Davies","year":"2014","journal-title":"Kidney Int."},{"key":"ref22","doi-asserted-by":"publisher","first-page":"111-118","DOI":"10.1053\/j.ajkd.2014.01.420","article-title":"Bioimpedance-guided fluid management in maintenance hemodialysis: a pilot randomized controlled trial.","volume":"64","author":"M Onofriescu","year":"2014","journal-title":"Am. J. Kidney Dis."},{"key":"ref23","doi-asserted-by":"publisher","DOI":"10.5281\/zenodo20154880","article-title":"Study To Investigate The Change in Hypotensive Episodes during Dialysis (STITCHED) (version 2).","author":"A Davenport","journal-title":"Zenodo repository."},{"key":"ref24","doi-asserted-by":"crossref","first-page":"700-709","DOI":"10.1056\/NEJMoa2304820","article-title":"Effect of hemodiafiltration or haemodialysis on mortality in kidney failure.","volume":"389","author":"P Blankestijn","year":"2023 Aug 24","journal-title":"N. Engl. J. 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The pathophysiological rationale is well articulated across the thermal-haemodynamic axis, blood-pressure variability, middle-molecule clearance, and hypoperfusion-related cerebral injury. The proposed measurement battery (ABPM with PWV, MoCA, echocardiography, bioimpedance, cardiac biomarkers, \u03b22-microglobulin) is clinically appropriate and operationally realistic. Patient involvement through the Renal Registry advisory board and the Royal Free Kidney Patients' Association is exemplary. Transparent publication of a halted NIHR-funded study is itself a contribution to research integrity; it pulls the work out of the file drawer where most halted studies remain.  \n<b>Proposed revisions<\/b> \n<b>1. Realign title and genre with the actual content.<\/b> The manuscript functions as a hybrid protocol-and-closure report, a revised title along the lines of \n<i>&quot;The STITCHED study: protocol and closure report of a mechanistic sub-study of H4RT&quot;<\/i>, paired with one explicit framing sentence at the end of the Background, will orient readers correctly and resolve the principal concern raised by both reviewers.  The title was revised in a previous version, , which unfortunately could not be uploaded into the website by the F1000 team &nbsp;  \n<b>2. State the position on the link between mediators and survival outcome.<\/b> The current objectives are pairwise HD-vs-OL-HDF comparisons, the narrative speaks of \n<i>explaining<\/i> survival. A short Methods sub-section, \n<i>&quot;Statistical analysis plan and link to H4RT outcomes&quot;<\/i>, should declare which framework applies. If a pre-closure SAP included formal mediation analysis (modality as exposure, STITCHED parameters as candidate mediators, H4RT survival and cardiovascular events as outcomes), summaries it in five to eight lines: framework type (causal mediation, counterfactual), handling of correlated mediators, planned software. If STITCHED was conceived as descriptive\/hypothesis-generating with mediation deferred to a successor study, state this directly and sketch the successor design in the Conclusion (mediation-driven sample size, biologically prioritised mediators, prospective integration with H4RT\/CONVINCE outcomes).  This was amended in a previous version, which unfortunately could not be uploaded into the website by the F1000 team  \n<b>3. Expand the reflective section, the manuscript's most distinctive potential contribution.<\/b> The most instructive material, pandemic disruption, research-staff attrition, the NIHR review process, the CRF subcontracting arrangement, funding withdrawal despite revised milestones being met, currently sits in the Discussion, while \n<i>&quot;Reflective\/critical perspective&quot;<\/i> is nearly empty. Relocating and expanding this content, with generalisable lessons attached, will give the paper lasting value. Concrete questions to address: what contractual safeguards would protect a mechanistic sub-study nested within a larger trial during an external shock? What milestone flexibility from funders would be appropriate? How should sponsor-substudy relationships be structured to preserve continuity of funding? A well-developed reflective section will become the most-cited part of the paper and a genuine resource for anyone designing mechanistic sub-studies in the post-CONVINCE era.  Unless one had worked in London during the 2 main waves of the COVID-19 it is difficult for someone to understand the issues that arose. There is a current UK government enquiry into the preparedness and the response to the COVID pandemic. In essence all clinical research was halted as clinical, and non0clinical staff were re-deployed to support the acute clinical service. Subsequently COVID research was then permitted, and over time in a step wise fashion other research projects were re-activated. Renal projects were in the last tranche.&nbsp; As such decisions had to be made as to which projects should be re-opened and refinanced. Unfortunately, the authors do not have access to the information that would be required to answer these questions raised by the reviewer.  \n<b>4. Report the data that were collected with greater granularity.<\/b> A short descriptive paragraph should report: number of the randomised patients within the sub-study (with arm allocation, if known), number of completed baseline ABPM, PWV, MoCA, BIA, and echocardiographic assessments, and explicit confirmation of the fate of the blood samples (destroyed on closure request). Even with numbers too small for inference, descriptive reporting strengthens the closure report's credibility.  As written the funder required that all baseline samples and data were destroyed without analysis.  \n<b>5. Reconcile the sample-size figures.<\/b> The discrepancy between the 288 calculated in the manuscript and the 346 registered in the trial registry deserves one explanatory sentence in the \n<i>Sample size<\/i> section, most likely drop-out inflation, mid-study revision, or conservative registry registration.  The higher number dates from the original grant application. The reviewers of the grant insisted on some changes in the investigational plan, as such the patient numbers were then recalculated based on the investigations requested by the reviewers.   \n<b>6. Correct editorial inconsistencies.<\/b> Unify the ethics code (18\/EM\/0213 vs 18\/EM\/0212), the second author's surname (McNeil vs MacNeill), correct &quot;SITCHED&quot; \u2192 &quot;STITCHED&quot; in the Discussion, add \n<i>N Engl J Med<\/i> to reference 24 (Blankestijn 2023, CONVINCE), and verify the Zenodo DOI (10.5281\/zenodo18526386), which is currently non-functional and is self-cited as reference 23.  This was corrected in a previous version but unfortunately the F1000 team could not post this into their web site  \n<b>7. Optional update on H4RT.<\/b> Given that H4RT is described as &quot;in final analysis stage&quot; and the OL-HDF landscape is moving quickly, a brief status update, or incorporation of any preliminary findings available by final submission will increase the manuscript's temporal relevance. Once these revisions have been implemented, the manuscript will be suitable for publication and will address a genuine unmet need within the field. Halted, partial, and null-result studies are infrequently disseminated in the nephrology literature, and this under-representation perpetuates publication This is not possible.","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/6-27\/v2#referee-comment-3603","order":3,"name":"referee-comment-3603","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.3310\/nihropenres.15640.r41561, Saquiba Yesmine, Jahangirnagar University, Savar, Dhaka Division, 02 Sep 2026, version 2, indexed","URL":"https:\/\/openresearch.nihr.ac.uk\/articles\/6-27\/v2#referee-response-41561","order":4,"name":"referee-response-41561","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This project was funded by the National Institute for Health and Care Research (NIHR) Under its under its  Efficacy Mechanism and Evaluation program project award number NETSCC 17\/61\/04.","order":5,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}