Mild-to-Moderate Kidney Dysfunction and Cardiovascular Disease: Observational and Mendelian Randomization Analyses

• Type of Material: Article
• Authors: Liam Gaziano, VA Boston Healthcare System; Luanluan Sun, University of Cambridge; Matthew Arnold, Independent Researcher; Steven Bell, University of Cambridge; Kelly Cho, VA Boston Healthcare System; Stephen K Kaptoge, University of Cambridge; Rebecca J Song, VA Boston Healthcare System; Stephen Burgess, University of Cambridge; Daniel C Posner, VA Boston Healthcare System; Katja Mosconi, University of Cambridge; Cassianne Robinson Cohen, Vanderbilt University Medical Center; Amy M Mason, University of Cambridge; Thomas R Bolton, University of Cambridge; Ran Tao, Vanderbilt University Medical Center; Elias Allara, University of Cambridge; Petra Schubert, VA Boston Healthcare System; Lingyan Chen, University of Cambridge; James R Staley, University of Cambridge; Natalie Staplin, University of Oxford; Servet Altay, Trakya University; Pilar Amiano, Ministry of Health of the Basque Government; Volker Arndt, German Cancer Research Center (DKFZ); Johan Ärnlöv,, Karolinska Institutet; Elizabeth LM Barr, Charles Darwin University; Cecilia Björkelund, University of Gothenburg; Jolanda MA Boer, National Institute for Public Health and the Environment (RIVM); Hermann Brenner, Karolinska Institutet; Edoardo Casiglia, University of Padua; Paolo Chiodini, Università degli Studi della Campania ‘Luigi Vanvitelli’; Jackie A Cooper, Queen Mary University London; Josef Coresh, Johns Hopkins Bloomberg School of Public Health; Mary Cushman, University of Vermont; Rachel Dankner, Sheba Medical Center; Karina W Davidson, Northwell Health; Renate T de Jongh, Amsterdam University Medical Centers; Chiara Donfrancesco, Istituto Superiore di Sanità; Gunnar Engstrom, Lund University; Heinz Freisling, World Health Organization, Lyon; Agustín Gómez de la Camara, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP); Vilmundur Gudnason, University of Iceland; Graeme J Hankey, University of Western Australia; Per-Olof Hansson, University of Gothenburg; Alicia K Heath, Imperial College London; Ewout J Hoorn, University Medical Center Rotterdam; Hironori Imano, Osaka University; Simerjot K Jassal, German Cancer Research Center (DKFZ); Rudolf Kaaks, German Cancer Research Center (DKFZ); Verena Katzke, German Cancer Research Center (DKFZ); Jussi Kauhanen, University of Eastern Finland (UEF); Stefan Kiechl, Medical University of Innsbruck; Wolfgang Koenig, Ulm University; Richard A Kronmal, University of Washington; Cecilie Kyrø, Danish Cancer Society Research Center; Deborah A Lawlor, University of Bristol; Börje Ljungberg, Umea University; Conor MacDonald, Universite Paris Saclay; Giovanna Masala, Institute for Cancer Research, Prevention and Clinical Network (ISPRO); Christa Meisinger, Helmholtz Zentrum Munchen; Olle Melander, Lund University; Conchi Moreno Iribas, Navarra Public Health Institute; Toshiharu Ninomiya, Kyushu University; Dorothea Nitsch, London School of Hygiene & Tropical Medicine; Børge G Nordestgaard, Copenhagen University Hospital; Charlotte OnlandMoret, Utrecht University; Luigi Palmieri, Ist Super Sanita; Dafina Petrova, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP); Ramón Quirós Garcia, Consejer Sanidad Principado Asturias Oviedo; Annika Rosengren, University of Gothenburg; Carlotta Sacerdote, Città della Salute e della Scienza University-Hospital; Masaru Sakurai, Kanazawa Medical University; Carmen Santiuste, Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP); Matthias B Schulze, German Institute of Human Nutrition Potsdam-Rehbruecke; Sabina Sieri, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano; Johan Sundström, Uppsala University; Valérie Tikhonoff, University of Padua; Anne Tjonneland, Danish Cancer Society Research Center; Tammy Tong, University of Oxford; Rosario Tumino, Hyblean Association for Epidemiological Reserach AIRE - ONLUS; Ioanna Tzoulaki, Imperial College London; Yvonne T van der Schouw, Utrecht University; Monique WM Verschuren, National Institute for Public Health and the Environment (RIVM); Henry Völzke, Universitätsmedizin Greifswald; Robert B Wallace, University of Iowa; Goya S Wannamethee, University College London; Elisabete Weiderpass, World Health Organization; Peter Willeit, University of Cambridge; Mark Woodward, Imperial College London; Kazumasa Yamagishi, University of Tsukuba; Raul ZamoraRos, Bellvitge Biomedical Research Institute (IDIBELL); Elvis A Akwo, Vanderbilt University Medical Center; Saiju Pyarajan, Harvard Medical School; David R Gagnon, Boston University; Philip S Tsao, VA Palo Alto Health Care System; Sumitra Muralidhar, Veterans Health Administration; Todd L Edwards, Vanderbilt University; Scott M Damrauer, University of Pennsylvania; Jacob Joseph, VA Boston Healthcare System; Lisa Pennells, University of Cambridge; Peter Wilson, Emory University; Seamus Harrison, University of Cambridge; Thomas A Gaziano, Harvard Medical School; Michael Inouye, University of Cambridge; Colin Baigent, University of Oxford; Juan P Casas, VA Boston Healthcare System; Claudia Langenberg, University of Cambridge; Nick Wareham, University of Cambridge; Elio Riboli, Imperial College London; Michael J Gaziano, VA Boston Healthcare System; John Danesh, University of Cambridge; Adriana M Hung, Tennessee Valley Health Care System; Adam S Butterworth, University of Cambridge; Angela M Wood, University of Cambridge; Emanuele Di Angelantonio, University of Cambridge
• Language: English
• Date: 2022-11-15
• Publisher: LIPPINCOTT WILLIAMS & WILKINS
• Publication Version: Final Published Version
• Copyright Statement: © 2022 The Authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1161/CIRCULATIONAHA.122.060700
• Title of Journal or Parent Work: CIRCULATION
• Volume: 146
• Issue: 20
• Start Page: 1507
• End Page: 1517
• Grant/Funding Information: This work was supported by Health Data Research UK, which is funded by the UK Medical Research Council, the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the Department of Health and Social Care (England), the Chief Scientist Office of the Scottish Government Health and Social Care Directorates, the Health and Social Care Research and Development Division (Welsh Government), the Public Health Agency (Northern Ireland), the BHF, and the Wellcome Trust. A variety of funding sources have supported recruitment, follow-up, and laboratory measurements in the studies contributing data to the ERFC, which are listed on the ERFC website (www.phpc.cam.ac.uk/ceu/erfc/list-of-studies). EPIC-CVD (European Prospective Investigation into Cancer and Nutrition–Cardiovascular Disease Study) was funded by the European Research Council (268834) and the European Commission Framework Programme 7 (HEALTH-F2-2012-279233).; Prof Wood was supported by the BHF-Turing Cardiovascular Data Science Award (BCDSA\100005). Prof Di Angelantonio holds a NIHR Senior Investigator Award.; Dr Tsao is supported by BX003362-01 from VA Office of Research and Development. Dr Robinson-Cohen is supported by R01DK122075. Dr Sun was funded by a BHF Programme Grant (RG/18/13/33946). Dr Arnold was funded by a BHF Programme Grant (RG/18/13/33946).; Dr Kaptoge is funded by a BHF Chair award (CH/12/2/29428).; Dr Mason is funded by the EU/EFPIA Innovative Medicines Initiative Joint Undertaking BigData@Heart grant 116074.; Prof Danesh holds a British Heart Foundation Professorship and a NIHR Senior Investigator Award.; The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition PotsdamRehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucía, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology - ICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council, United Kingdom (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford). The establishment of the EPIC-InterAct subcohort (used in the EPIC-CVD study) and conduct of biochemical assays was supported by the EU Sixth Framework Programme (FP6) (grant LSHM_CT_2006_037197 to the InterAct project) and the Medical Research Council Epidemiology Unit (grants MC_UU_12015/1 and MC_UU_12015/5). This research is based on data from the Million Veteran Program, Office of Research and Development, and Veterans Health Administration and was supported by award I01-BX004821 (principal investigators, Drs Peter W.F. Wilson and Kelly Cho) and I01-BX003360 (principal investigators, Dr Adriana M. Hung). Dr Damrauer is supported by IK2-CX001780. Dr Hung is supported by CX001897.; The Emerging Risk Factors Collaboration (ERFC) coordinating center was underpinned by program grants from the British Heart Foundation (BHF; SP/09/002; RG/13/13/30194; RG/18/13/33946), BHF Centre of Research Excellence (RE/18/1/34212), the UK Medical Research Council (MR/L003120/1), and the National Institute for Health and Care Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215-20014), with project-specific support received from the UK NIHR, British United Provident Association UK Foundation, and an unrestricted educational grant from GlaxoSmithKline.; Dr Bolton was funded by the NIHR BTRU in Donor Health and Genomics (NIHR BTRU-2014-10024). Dr Allara is funded by a BHF Programme Grant (RG/18/13/33946).; Prof Wood is part of the BigData@Heart Consortium, funded by the Innovative Medicines Initiative-2 Joint Undertaking under grant agreement No 116074.; Prof Inouye is supported by the Munz Chair of Cardiovascular Prediction and Prevention and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). Prof Inouye was also supported by the UK Economic and Social Research 878 Council (ES/T013192/1).
• Keywords: ASSOCIATION; Life Sciences & Biomedicine; CYSTATIN C; Cardiovascular System & Cardiology; DESIGN; cardiovascular diseases; Peripheral Vascular Disease; RENAL-DISEASE; EQUATION; stroke; Cardiac & Cardiovascular Systems; SERUM CREATININE; kidney diseases; INSTRUMENTAL VARIABLES; Science & Technology; BIOBANK; MORTALITY; GLOMERULAR-FILTRATION-RATE; coronary disease
• Research Categories: Health Sciences, Public Health; Health Sciences, Medicine and Surgery; Health Sciences, Epidemiology

Abstract

Background: End-stage renal disease is associated with a high risk of cardiovascular events. It is unknown, however, whether mild-to-moderate kidney dysfunction is causally related to coronary heart disease (CHD) and stroke. Methods: Observational analyses were conducted using individual-level data from 4 population data sources (Emerging Risk Factors Collaboration, EPIC-CVD [European Prospective Investigation into Cancer and Nutrition-Cardiovascular Disease Study], Million Veteran Program, and UK Biobank), comprising 648 135 participants with no history of cardiovascular disease or diabetes at baseline, yielding 42 858 and 15 693 incident CHD and stroke events, respectively, during 6.8 million person-years of follow-up. Using a genetic risk score of 218 variants for estimated glomerular filtration rate (eGFR), we conducted Mendelian randomization analyses involving 413 718 participants (25 917 CHD and 8622 strokes) in EPIC-CVD, Million Veteran Program, and UK Biobank. Results: There were U-shaped observational associations of creatinine-based eGFR with CHD and stroke, with higher risk in participants with eGFR values <60 or >105 mL·min-1·1.73 m-2, compared with those with eGFR between 60 and 105 mL·min-1·1.73 m-2. Mendelian randomization analyses for CHD showed an association among participants with eGFR <60 mL·min-1·1.73 m-2, with a 14% (95% CI, 3%-27%) higher CHD risk per 5 mL·min-1·1.73 m-2 lower genetically predicted eGFR, but not for those with eGFR >105 mL·min-1·1.73 m-2. Results were not materially different after adjustment for factors associated with the eGFR genetic risk score, such as lipoprotein(a), triglycerides, hemoglobin A1c, and blood pressure. Mendelian randomization results for stroke were nonsignificant but broadly similar to those for CHD. Conclusions: In people without manifest cardiovascular disease or diabetes, mild-to-moderate kidney dysfunction is causally related to risk of CHD, highlighting the potential value of preventive approaches that preserve and modulate kidney function.