Andrew Bostom1, Andreas Pasch2, Tracy Madsen3, Mary B Roberts1, Nora Franceschini4, Dominik Steubl5, Pranav S Garimella6, Joachim H Ix6, Katherine R Tuttle7, Anastasia Ivanova4, Theresa Shireman8, Reginald Gohh9, Basma Merhi9, Petr Jarolim10, John W Kusek11, Marc A Pfeffer12, Simin Liu13, Charles B Eaton1,14. 1. Center For Primary Care and Prevention, Memorial Hospital of Rhode Island, Pawtucket, Rhode Island, USA. 2. University of Bern, Bern, Switzerland. 3. Department of Emergency Medicine, Rhode Island Hospital, Providence, Rhode Island, USA. 4. Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 5. Klinikum rechts der Isar, Technische Universität, Munich, Germany. 6. Department of Medicine, Division of Nephrology-Hypertension, University of California, San Diego, California, USA. 7. Providence Medical Research Center, University of Washington, Spokane, Washington, USA. 8. Center for Gerontology and Healthcare Research, Brown University, Providence, Rhode Island, USA. 9. Department of Medicine, Division of Hypertension and Kidney Diseases, Rhode Island Hospital, Providence, Rhode Island, USA. 10. Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA. 11. National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. 12. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA. 13. Department of Epidemiology, School of Public Health, Brown University, Providence, Rhode Island, USA. 14. Department of Family Medicine, Warren Alpert Medical School, Brown University, Providence, Rhode Island, USA.
Abstract
BACKGROUND: "T50," shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant. METHODS: The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization. RESULTS: During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20-2.89); fetuin-A, (HR 2.25; 95% CI 1.38-3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. CONCLUSIONS: Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.
BACKGROUND: "T50," shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant. METHODS: The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization. RESULTS: During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20-2.89); fetuin-A, (HR 2.25; 95% CI 1.38-3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. CONCLUSIONS: Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.
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