Umut Selamet1, Ronit Katz2, Charles Ginsberg3, Dena E Rifkin4, Linda F Fried5, Stephen B Kritchevsky6, Andrew N Hoofnagle7, Kirsten Bibbins-Domingo8, David Drew9, Tamara Harris10, Anne Newman11, Orlando M Gutiérrez12, Mark J Sarnak9, Michael G Shlipak13, Joachim H Ix14. 1. Division of Nephrology, Department of Medicine, University of California Los Angeles, Los Angeles, CA. 2. Kidney Research Institute, Division of Nephrology, Department of Medicine, University of Washington, Seattle, WA. 3. Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA. 4. Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA; Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA. 5. Nephrology Section, Veterans Affairs Hospital, University of Pittsburgh, Pittsburgh, PA; Division of Nephrology, Department of Medicine, University of Pittsburgh, Pittsburgh, PA; Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA. 6. Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC. 7. Department of Laboratory Medicine, University of Washington, Seattle, WA; Department of Medicine, University of Washington, Seattle, WA. 8. Department of Medicine, University of California San Francisco, San Francisco, CA. 9. Division of Nephrology, Department of Medicine, Tufts Medical Center, Boston, MA. 10. Laboratory of Epidemiology and Population Sciences, National Institute on Aging, Bethesda, MD. 11. Department of Epidemiology, University of Pittsburgh, Pittsburgh, PA. 12. Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL. 13. Kidney Health Research Collaborative, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, CA; Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA. 14. Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA; Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA. Electronic address: joeix@ucsd.edu.
Abstract
RATIONALE & OBJECTIVES: Lower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored. STUDY DESIGN: Case-cohort study. SETTING & PARTICIPANTS: Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study. PREDICTOR: Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry. OUTCOMES: Major kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up. ANALYTIC APPROACH: Baseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression. RESULTS: During 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1-standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations. LIMITATIONS: Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race. CONCLUSIONS: Lower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether these associations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function. Published by Elsevier Inc.
RATIONALE & OBJECTIVES: Lower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored. STUDY DESIGN: Case-cohort study. SETTING & PARTICIPANTS: Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study. PREDICTOR: Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry. OUTCOMES: Major kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up. ANALYTIC APPROACH: Baseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression. RESULTS: During 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1-standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations. LIMITATIONS: Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race. CONCLUSIONS: Lower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether these associations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function. Published by Elsevier Inc.
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Keywords:
1,25-dihydroxyvitamin D; 24,25 dihydroxyvitamin D; 25-hydroxyvitamin D; Calcitriol; Health ABC; chronic kidney disease (CKD); death; disease progression; elderly; heart failure (HF); incident HF; kidney function decline; vitamin D metabolite ratio (VMR)
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