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1 TITLE PAGE Title: Albuminuria, lung function decline, and risk of incident COPD: the NHLBI Pooled Cohorts Study Authors: Elizabeth C Oelsner, MD1 Pallavi P Balte, PhD1 Morgan E Grams, MD2 Patricia A Cassano, PhD3 David R Jacobs, MD4 R Graham Barr, MD1 Kristin M Burkart, MD1 Ravi Kalhan, MD5 Richard Kronmal, PhD6 Laura R Loehr, MD, PhD7 George T O'

Connor, MD8 Joseph E Schwartz, PhD1,9 Michael Shlipak, MD10 Russell P Tracy, PhD11 Michael Y Tsai, PhD12 Wendy White, PhD13 Sachin Yende, MD14

2 Author affiliations:

1 Columbia University College of Physicians &

Surgeons, Department of Medicine, New York, NY, USA.

2 Johns Hopkins University, Department of Medicine, Baltimore, MD, USA.

3 Cornell University, College of Human Ecology, Division of Nutritional Sciences, Cornell, NY, USA.

4 University of Minnesota, Division of Epidemiology and Community Health, Minneapolis, MN, USA.

5 Northwestern University, Department of Medicine, Chicago, IL, USA.

6 University of Washington, School of Public Health, Department of Statistics, Seattle, WA, USA.

7 University of North Carolina, Department of Epidemiology, Chapel Hill, NC, USA.

8 Boston University, Department of Medicine, Boston, MA, USA.

9 Stony Brook University, Department of Psychiatry and Behavioral Sciences, Stony Brook, NY, USA.

10 University of California, San Francisco, Department of Medicine, San Francisco, CA, USA.

11 University of Vermont, Laboratory for Clinical Biochemistry Research, Burlington, VT, USA.

12 University of Minnesota, Department of Laboratory Medicine and Pathology, Minneapolis, MN, USA.

13 Tougaloo College, Jackson Heart Study, Undergraduate Training and Education Center, Jackson, MS, USA.

14 Veterans Affairs Pittsburgh Healthcare System and University of Pittsburgh, Department of

3 Critical Care Medicine, Pittsburgh, PA, USA Corresponding Author: Elizabeth C Oelsner, MD, MPH Department of Medicine, Columbia University Medical Center

630 West 168th Street, Presbyterian Hospital 9th Floor, Suite

105 New York, NY

10032 Tel: (212) 305-9056 / Fax: (212) 305-9349 [email protected] Author'

s contributions: Elizabeth C Oelsner: study design, data collection, data quality control and harmonization, data analysis, and manuscript preparation Pallavi Balte: data collection, quality control, harmonization, and analyses Morgan E Grams: data collection, critical review of manuscript Patricia Cassano: data collection, critical review of manuscript David R Jacobs: study design, data collection, statistical plan, critical review of manuscript R Graham Barr: study design, data collection, critical review of manuscript Kristin Burkart: study design, critical review of manuscript Ravi Kalhan: data collection, critical review of manuscript Richard Kronmal: data collection, statistical plan, critical review of manuscript Laura R Loehr: data collection, critical review of manuscript George T O'

Connor: data collection, critical review of manuscript

4 Joseph E. Schwartz: statistical plan, critical review of manuscript Michael Shlipak: data collection, critical review of manuscript Russell P Tracy: data collection, critical review of manuscript Michael Y Tsai: data collection, critical review of manuscript Wendy White: data collection, critical review of manuscript Sachin Yende: study design, data collection, critical review of manuscript Sources of funding and support: ? NHLBI Pooled Cohorts Study: NIH/NHLBI R21-HL121457, R21-HL-129924, K23-HL- 130627. ? Atherosclerosis Risk In Communities (ARIC) Study: The authors thank the staff and participants of the ARIC study for their important contributions The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I, HHSN2682017000021). ? Coronary Artery Risk Development in Young Adults (CARDIA) Study: CARDIA is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with the University of Alabama at Birmingham (HHSN268201300025C &

HHSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine

5 (HHSN268200900041C). CARDIA is also partially supported by the Intramural Research Program of the National Institute on Aging (NIA) and an intra-agency agreement between NIA and NHLBI (AG0005 ), as well as an NHLBI grant (to Dr. Kalhan) R01 HL122477. This manuscript has been reviewed by CARDIA for scientific content. ? Cardiovascular Health Study (CHS): This research was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI), with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided by R01AG023629 from the National Institute on Aging (NIA). A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. ? Framingham Heart Study (FHS): From the Framingham Heart Study of the National Heart Lung and Blood Institute of the National Institutes of Health and Boston University School of Medicine. This work was supported by the National Heart, Lung and Blood Institute'

s Framingham Heart Study (Contract No. N01-HC-25195;

HHSN268201500001I). ? Health Aging and Body Composition (Health ABC) Study: This research was supported by National Institute on Aging (NIA) contracts #N01-AG-6-2101;

N01-AG-6-2103;

N01- AG-6-2106;

NIA grant R01-AG028050;

NINR grant R01-NR012459. ? Multi-Ethnic Study of Atherosclerosis (MESA): NIH/NHLBI R01-HL-077612, R01-HL- 093081, RC1-HL-100543, N01-HC-95159, N01-HC-95160, N01-HC-95161, N01-HC-

6 95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC- 95167, N01-HC-95168 and N01-HC-95169. This publication was also developed under a STAR research assistance agreement, No. RD831697 (MESA Air), awarded by the U.S Environmental Protection Agency. It has not been formally reviewed by the EPA. The views expressed in this document are solely those of the authors and the EPA does not endorse any products or commercial services mentioned in this publication. Previous presentations: Preliminary results were presented in abstract form at the American Thoracic Society meeting in May

2016 (San Francisco, CA) and May

2017 (Washington, DC). Running title: Albuminuria, lung function, and risk of COPD Subject: COPD Epidemiology (9.6) Manuscript Word Count: 3,476

7 At a Glance Commentary Scientific Knowledge on the Subject Albuminuria is a commonly used biomarker of endothelial damage in the kidneys and correlates with microvascular dysfunction throughout the body, including in the pulmonary circulation. Cross-sectional studies suggest albuminuria is increased in COPD patients, among whom it is adversely associated with lung function, gas exchange, and hypoxia. Co-occurrence of pulmonary and renal endothelial cell injury was recently demonstrated on pathological samples in COPD patients and cigarette smoke-exposed mice, among whom extent of angiopathy in both organs was correlated cross-sectionally with albuminuria. Nonetheless, no large-scale, prospective study has tested whether albuminuria is associated with the development of COPD. What This Study Adds to the Field This study, using six population-based observational cohort studies, demonstrates associations between greater albuminuria and accelerated decline in the FEV1 and FEV1/FVC ratio;

incident spirometry-defined COPD;

and, increased rates of incident clinical chronic lower respiratory disease events, especially COPD events. These associations were identified in adults without prevalent clinical lung disease, and were independent of smoking, diabetes, hypertension, renal function, and cardiovascular disease. This work adds to mounting evidence supporting a role for pulmonary endothelial dysfunction in COPD pathogenesis, suggesting that microvascular mechanisms may be promising targets for COPD prevention and treatment.

8 This article has an online data supplement, which is accessible from this issue'

s table of content online at www.atsjournals.org.

1 ABSTRACT Rationale: Chronic lower respiratory diseases (CLRD), including COPD and asthma, are the fourth leading cause-of-death. Prior studies suggest that albuminuria, a biomarker of endothelial injury, is increased in COPD patients. Objectives: To test if albuminuria was associated with lung function decline and incident CLRD. Metho........