[en] [en] BACKGROUND: Despite the increasing number of biomarker studies published in the transplant literature over the past 20 years, demonstrations of their clinical benefit and their implementation in routine clinical practice are lacking. We hypothesized that suboptimal design, data, methodology and reporting might contribute to this phenomenon.
METHODS: A systematic literature search was performed in PubMed, Embase, Scopus, Web of Science, and Cochrane Library between 1 January 2005 and 12 November 2022 (PROSPERO ID: CRD42020154747). All English language, original studies investigating the association between a biomarker and kidney-allograft outcome were included. The final set of publications was assessed by expert reviewers. After data collection, two independent reviewers randomly evaluated the inconsistencies for 30% of the references for each reviewer. If more than 5% of inconsistencies were observed for one given reviewer, a re-evaluation was conducted for all the references of the reviewer. The biomarkers were categorized according to their type and the biological milieu from which they were measured. The study characteristics related to the design, methods, results, and their interpretation were assessed, as well as reproducible research practices and transparency indicators.
RESULTS: A total of 7372 publications were screened and 804 studies met the inclusion criteria. A total of 1143 biomarkers were assessed among the included studies from blood (n=821, 71.8%), intragraft (n=169, 14.8%), or urine (n=81, 7.1%) compartments. The number of studies significantly increased, with a median, yearly number of 31.5 studies (IQR: 23.8-35.5) between 2005 and 2012, and 57.5 (IQR: 53.3-59.8) between 2013 and 2022 (p<0.001). A total of 655 studies (81.5%) were retrospective, while 595 (74.0%) used data from a single center. The median number of patients included was 232 (IQR: 96-629) with a median follow-up posttransplant of 4.8 years (IQR: 3.0-6.2). Only 4.7% of studies were externally validated. A total of 346 studies (43.0%) did not adjust their biomarker for key prognostic factors while only 3.1% of studies adjusted the biomarker for standard-of-care patient monitoring factors. Data sharing, code sharing, and registration occurred in 8.8%, 1.1%, and 4.6% of studies, respectively. A total of 158 studies (20.0%) emphasized the clinical relevance of the biomarker despite the reported nonsignificant association of the biomarker with the outcome measure. A total of 288 studies assessed rejection as an outcome. We showed that these rejection studies shared the same characteristics as other studies.
CONCLUSIONS: and Relevance Biomarker studies in kidney transplantation lack validation, rigorous design, methods and interpretation, and transparency. Higher standards in biomarker research may improve the clinical utility and clinical use.
Disciplines :
General & internal medicine
Author, co-author :
Raynaud, Marc; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Al-Awadhi, Solaf ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Louis, Kevin ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Zhang, Huanxi ; The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Su, Xiaojun; The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Goutaudier, Valentin ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Wang, Jiali; The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Demir, Zeynep ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Wei, Yongcheng ; The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Truchot, Agathe; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Bouquegneau, Antoine ; Centre Hospitalier Universitaire de Liège - CHU > > Service de néphrologie
Del Bello, Arnaud ; Université Paul Sabatier, INSERM, Department of Nephrology and Organ Transplantation, CHU Rangueil & Purpan, Toulouse, France
Bailly, Élodie ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France ; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
Lombardi, Yannis ; Kidney Transplant Department, Tenon Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
Maanaoui, Mehdi; Lille University, CHU Lille, Nephrology Department, F-59037, Lille, France, INSERM U1190, Translational Research for Diabetes, Lille, France
Giarraputo, Alessia ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France ; Department of Cardiac, Thoracic, Vascular Sciences and Public Health, University of Padua, Padua, Italy
Naser, Sofia ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Divard, Gillian ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Aubert, Olivier ; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
Murad, Mohammad Hassan ; Evidence-Based Practice Center, Mayo Clinic, Rochester, Minnesota, USA
Wang, Changxi; The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Liu, Longshan ; The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Naesens, Maarten ; Department of Microbiology, Immunology and Transplantation, Nephrology and Renal Transplantation Research Group, KU Leuven, Leuven, Belgium
Friedewald, John J ; Division of Transplantation, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA
Lefaucheur, Carmen ; Kidney Transplant Department, Saint-Louis Hospital, Assistance Publique - Hôpitaux de Paris, Paris, France
Riella, Leonardo ; Schuster Family Transplantation Research Center, Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
Collins, Gary ; Center for Statistics in Medicine, NDORMS, Botnar Research Center, University of Oxford, Oxford, UK
Ioannidis, John P A ; Departments of Medicine, of Epidemiology and Population Health, of Biomedical Data Science, and of Statistics and Meta-Research Innovation Center at Stanford (METRICS), Stanford University, USA
Loupy, Alexandre; Université de Paris Cité, INSERM, PARCC, Paris Institute for Transplantation and Organ Regeneration, F-75015 Paris, France
H2020 - 754995 - EU-TRAIN - The EUropean TRAnsplantation and INnovation (EU-TRAIN) consortium for improving diagnosis and risk stratification in kidney transplant patients
Funders :
ANR - Agence Nationale de la Recherche EU - European Union MSD Avenir OrganX
Funding text :
ANR-17-RHUS-0010/French government financial support managed by the National Research Agency (ANR) under the program for Investissements d'avenir KTD-Innov; 754995/European Union's Horizon 2020 research and innovation program EU-TRAIN
WHO International Programme on Chemical Safety Biomarkers in Risk Assessment: Validity and Validation. 2001. http://www.inchem.org/documents/ehc/ehc/ehc222.htm
Kraus VB,. Biomarkers as drug development tools: discovery, validation, qualification and use. Nat Rev Rheumatol. 2018; 14 (6): 354-362. doi: 10.1038/s41584-018-0005-9
Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001; 69 (3): 89-95. doi: 10.1067/mcp.2001.113989
Selleck MJ, Senthil M, Wall NR,. Making meaningful clinical use of biomarkers. Biomarker Insights. 2017; 12: 1177271917715236. doi: 10.1177/1177271917715236
Zhang WR, Craven TE, Malhotra R,. Kidney damage biomarkers and incident chronic kidney disease during blood pressure reduction: a case-control study. Ann Intern Med. 2018; 169 (9): 610-618. doi: 10.7326/M18-1037
US Food and Drug Administration. Qualified Biomarkers and Supporting Information. 2021. Accessed November 24, 2022. https://www.fda.gov/drugs/biomarker-qualification-program/list-qualified-biomarkers
Coemans M, Süsal C, Döhler B,. Analyses of the short-and long-term graft survival after kidney transplantation in Europe between 1986 and 2015. Kidney Int. 2018; 94 (5): 964-973. doi: 10.1016/j.kint.2018.05.018
Loupy A, Aubert O, Orandi BJ,. Prediction system for risk of allograft loss in patients receiving kidney transplants: international derivation and validation study. BMJ. 2019; 366: l4923. doi: 10.1136/bmj.l4923
Lefaucheur C, Loupy A, Hill GS,. Preexisting donor-specific HLA antibodies predict outcome in kidney transplantation. J Am Soc Nephrol. 2010; 21 (8): 1398-1406. doi: 10.1681/ASN.2009101065
Naesens M, Lerut E, Emonds MP,. Proteinuria as a noninvasive marker for renal allograft histology and failure: an observational cohort study. J Am Soc Nephrol. 2016; 27 (1): 281-292. doi: 10.1681/ASN.2015010062
Yilmaz S, Tomlanovich S, Mathew T,. Protocol core needle biopsy and histologic Chronic Allograft Damage Index (CADI) as surrogate end point for long-term graft survival in multicenter studies. J Am Soc Nephrol. 2003; 14 (3): 773-779. doi: 10.1097/01.ASN.0000054496.68498.13
Bhangoo RS, Hall IE, Reese PP, Parikh CR,. Deceased-donor kidney perfusate and urine biomarkers for kidney allograft outcomes: a systematic review. Nephrol Dial Transplant. 2012; 27 (8): 3305-3314. doi: 10.1093/ndt/gfr806
Jamshaid F, Froghi S, Di Cocco P, Dor FJ,. Novel non-invasive biomarkers diagnostic of acute rejection in renal transplant recipients: a systematic review. Int J Clin Pract. 2018; 72 (8): e13220. doi: 10.1111/ijcp.13220
Guzzi F, Knight SR, Ploeg RJ, Hunter JP,. A systematic review to identify whether perfusate biomarkers produced during hypothermic machine perfusion can predict graft outcomes in kidney transplantation. Transpl Int. 2020; 33 (6): 590-602. doi: 10.1111/tri.13593
Ioannidis JPA, Bossuyt PMM,. Waste, leaks, and failures in the biomarker pipeline. Clin Chem. 2017; 63 (5): 963-972. doi: 10.1373/clinchem.2016.254649
Bossuyt PM,. The thin line between hope and hype in biomarker research. JAMA. 2011; 305 (21): 2229-2230. doi: 10.1001/jama.2011.729
Serghiou S, Contopoulos-Ioannidis DG, Boyack KW, Riedel N, Wallach JD, Ioannidis JPA,. Assessment of transparency indicators across the biomedical literature: How open is open? PLoS Biol. 2021; 19 (3): e3001107. doi: 10.1371/journal.pbio.3001107
Moher D, Liberati A, Tetzlaff J, Altman DG,.; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009; 151 (4): 264-269, W64. doi: 10.7326/0003-4819-151-4-200908180-00135
Kempf E, de Beyer JA, Cook J,. Overinterpretation and misreporting of prognostic factor studies in oncology: a systematic review. Br J Cancer. 2018; 119 (10): 1288-1296. doi: 10.1038/s41416-018-0305-5
Loupy A, Haas M, Roufosse C,. The Banff 2019 Kidney Meeting Report (I): updates on and clarification of criteria for T cell-and antibody-mediated rejection. Am J Transplant. 2020; 20 (9): 2318-2331. doi: 10.1111/ajt.15898
Bouquegneau A, Loheac C, Aubert O,. Complement-activating donor-specific anti-HLA antibodies and solid organ transplant survival: a systematic review and meta-analysis. PLoS Med. 2018; 15 (5): e1002572. doi: 10.1371/journal.pmed.1002572
Eikmans M, Gielis EM, Ledeganck KJ, Yang J, Abramowicz D, Claas FFJ,. Non-invasive biomarkers of acute rejection in kidney transplantation: novel targets and strategies. Front Med (Lausanne). 2018; 5: 358. doi: 10.3389/fmed.2018.00358
Quaglia M, Merlotti G, Guglielmetti G, Castellano G, Cantaluppi V,. Recent advances on biomarkers of early and late kidney graft dysfunction. Int J Mol Sci. 2020; 21 (15): 5404. doi: 10.3390/ijms21155404
Swanson KJ, Aziz F, Garg N, Role of novel biomarkers in kidney transplantation. World J Transplant. 2020; 10 (9): 230-255. doi: 10.5500/wjt.v10.i9.230
Mas VR, Mueller TF, Archer KJ, Maluf DG,. Identifying biomarkers as diagnostic tools in kidney transplantation. Expert Rev Mol Diagn. 2011; 11 (2): 183-196. doi: 10.1586/erm.10.119
Yordanov Y, Dechartres A, Porcher R, Boutron I, Altman DG, Ravaud P,. Avoidable waste of research related to inadequate methods in clinical trials. BMJ. 2015; 350: h809. doi: 10.1136/bmj.h809
Al-Shahi Salman R, Beller E, Kagan J,. Increasing value and reducing waste in biomedical research regulation and management. Lancet. 2014; 383 (9912): 176-185. doi: 10.1016/S0140-6736(13)62297-7
Tzoulaki I, Siontis KC, Evangelou E, Ioannidis JP,. Bias in associations of emerging biomarkers with cardiovascular disease. JAMA Intern Med. 2013; 173 (8): 664-671. doi: 10.1001/jamainternmed.2013.3018
Henkens M, Remmelzwaal S, Robinson EL,. Risk of bias in studies investigating novel diagnostic biomarkers for heart failure with preserved ejection fraction. A systematic review. Eur J Heart Fail. 2020; 22 (9): 1586-1597. doi: 10.1002/ejhf.1944
Raynaud M, Aubert O, Divard G,. Dynamic prediction of renal survival among deeply phenotyped kidney transplant recipients using artificial intelligence: an observational, international, multicohort study. Lancet Digit Health. 2021; 3 (12): e795-e805. doi: 10.1016/S2589-7500(21)00209-0
Fletcher RH, Black B,. "Spin" in scientific writing: scientific mischief and legal jeopardy. Med Law. 2007; 26 (3): 511-525. PMID: 17970249.
Boutron I, Dutton S, Ravaud P, Altman DG,. Reporting and interpretation of randomized controlled trials with statistically nonsignificant results for primary outcomes. JAMA. 2010; 303 (20): 2058-2064. doi: 10.1001/jama.2010.651
Chavalarias D, Wallach JD, Li AH, Ioannidis JP,. Evolution of reporting P values in the biomedical literature, 1990-2015. JAMA. 2016; 315 (11): 1141-1148. doi: 10.1001/jama.2016.1952
Ghannad M, Olsen M, Boutron I, Bossuyt PM,. A systematic review finds that spin or interpretation bias is abundant in evaluations of ovarian cancer biomarkers. J Clin Epidemiol. 2019; 116: 9-17. doi: 10.1016/j.jclinepi.2019.07.011
Olsen M, Ghannad M, Lok C, Bossuyt PM,. Shortcomings in the evaluation of biomarkers in ovarian cancer: a systematic review. Clin Chem Lab Med. 2019; 58 (1): 3-10. doi: 10.1515/cclm-2019-0038
Ioannidis JP, Greenland S, Hlatky MA,. Increasing value and reducing waste in research design, conduct, and analysis. Lancet. 2014; 383 (9912): 166-175. doi: 10.1016/S0140-6736(13)62227-8
McKinney WP, Young MJ, Hartz A, Lee MB,. The inexact use of Fisher's Exact Test in six major medical journals. JAMA. 1989; 261 (23): 3430-3433. doi: 10.1001/jama.261.23.3430
