Biomarkers of vascular calcification and mortality in patients with ESRD.
BACKGROUND
Vascular calcification is common among patients undergoing dialysis and is associated with mortality. Factors such as osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP-7), and fetuin-A are involved in vascular calcification.


METHODS
OPG, OPN, BMP-7, and fetuin-A were measured in blood samples from 602 incident dialysis patients recruited from United States dialysis centers between 1995 and 1998 as part of the Choices for Healthy Outcomes In Caring for ESRD Study. Their association with all-cause and cardiovascular mortality were assessed using Cox proportional hazards models adjusted for demographic characteristics, comorbidity, serum phosphate, and calcium. An interaction with diabetes was tested because of its known association with vascular calcification. Predictive accuracy of selected biomarkers was explored by C-statistics in nested models with training and validation subcohorts.


RESULTS
Higher OPG and lower fetuin-A levels were associated with higher mortality over up to 13 years of follow-up (median, 3.4 years). The adjusted hazard ratios (HR) for highest versus lowest tertile were 1.49 (95% confidence interval [95% CI], 1.08 to 2.06) for OPG and 0.69 (95% CI, 0.52 to 0.92) for fetuin-A. In stratified models, the highest tertile of OPG was associated with higher mortality among patients without diabetes (HR, 2.42; 95% CI, 1.35 to 4.34), but not patients with diabetes (HR, 1.26; 95% CI, 0.82 to 1.93; P for interaction=0.001). In terms of cardiovascular mortality, higher fetuin-A was associated with lower risk (HR, 0.85 per 0.1 g/L: 95% CI, 0.75 to 0.96). In patients without diabetes, higher OPG was associated with greater risk (HR for highest versus lowest tertile, 2.91; 95% CI, 1.06 to 7.99), but not in patients with diabetes or overall. OPN and BMP-7 were not independently associated with outcomes overall. The addition of OPG and fetuin-A did not significantly improve predictive accuracy of mortality.


CONCLUSIONS
OPG and fetuin-A may be risk factors for all-cause and cardiovascular mortality in patients undergoing dialysis, but do not improve risk prediction.
Department of Medicine, University of Miami, Miami, Florida;, †Department of Epidemiology,, §Department of Biostatistics, and, ‡Department of Medicine, Johns Hopkins University, Baltimore, Maryland;, ‖Department of Medicine, San Francisco General Hospital and University of California San Francisco, San Francisco, California;, ¶Department of Epidemiology, Emory University, Atlanta, Georgia;, *Nephrology Center of Maryland, Baltimore, Maryland, ††Hospital for Sick Children, University Health Network and University of Toronto, Toronto, Ontario, Canada.
Julia J
JJ
Scialla
W H Linda
WH
Kao
Ciprian
C
Crainiceanu
Stephen M
SM
Sozio
Pooja C
PC
Oberai
Tariq
T
Shafi
Josef
J
Coresh
Neil R
NR
Powe
Laura C
LC
Plantinga
Bernard G
BG
Jaar
Rulan S
RS
Parekh
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D055419:Bone Morphogenetic Protein 7 / Q000097:blood; D016009:Chi-Square Distribution; D015897:Comorbidity; D003920:Diabetes Mellitus / Q000097:blood / Q000401:mortality; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000097:blood* / Q000401:mortality* / Q000628:therapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D053495:Osteopontin / Q000097:blood; D053244:Osteoprotegerin / Q000097:blood*; D011237:Predictive Value of Tests; D011379:Prognosis; D016016:Proportional Hazards Models; D011446:Prospective Studies; D006435:Renal Dialysis / Q000401:mortality; D018570:Risk Assessment; D012307:Risk Factors; D014481:United States / Q000453:epidemiology; D061205:Vascular Calcification / Q000097:blood* / Q000401:mortality*; D060749:alpha-2-HS-Glycoprotein / Q000032:analysis*
C556354:AHSG protein, human; C525819:BMP7 protein, human; D015415:Biomarkers; D055419:Bone Morphogenetic Protein 7; D053244:Osteoprotegerin; C506895:SPP1 protein, human; C506030:TNFRSF11B protein, human; D060749:alpha-2-HS-Glycoprotein; D053495:Osteopontin
diabetes; end-stage renal disease; vascular calcification