Elevated Circulating Osteoprotegerin and Renal Dysfunction Predict 15-Year Cardiovascular and All-Cause Mortality: A Prospective Study of Elderly Women

Abstract

Background: Data on the predictive role of estimated glomerular filtration rate (eGFR) and osteoprotegerin (OPG) for cardiovascular (CVD) and all-cause mortality risk have been presented by our group and others. We now present data on the interactions between OPG with stage I to III chronic kidney disease (CKD) for all-cause and CVD mortality.

Methods and results: The setting was a 15-year study of 1,292 women over 70 years of age initially randomized to a 5-year controlled trial of 1.2 g of calcium daily. Serum OPG and creatinine levels with complete mortality records obtained from the Western Australian Data Linkage System were available. Interactions were detected between OPG levels and eGFR for both CVD and all-cause mortality (P < 0.05). Compared to participants with eGFR ≥60 ml/min/1.73 m2 and low OPG, participants with eGFR of <60 ml/min/1.73 m2 and elevated OPG had a 61% and 75% increased risk of all-cause and CVD mortality respectively (multivariate-adjusted HR, 1.61; 95% CI, 1.27-2.05; P < 0.001 and HR, 1.75; 95% CI, 1.22-2.55; P = 0.003). This relationship with mortality was independent of decline in renal function (P<0.05). Specific causes of death in individuals with elevated OPG and stage III CKD highlighted an excess of coronary heart disease, renal failure and chronic obstructive pulmonary disease deaths (P < 0.05).

Conclusion: The association between elevated OPG levels with CVD and all-cause mortality was more evident in elderly women with poorer renal function. Assessment of OPG in the context of renal function may be important in studies investigating its relationship with all-cause and CVD mortality.

Fig 1. Relationship between quartiles of circulating OPG dichotomized by eGFR categories (≥ 60ml/min/1.73m² and < 60ml/min/1.73m²) for all-cause mortality (top left, n = 547) and cardiovascular mortality (top right, n = 210) and relationship between quartiles of estimated glomerular filtration rate by the CKD-EPI equation (CKD-EPI eGFR) dichotomized by circulating OPG levels (< median and ≥ median) for all-cause mortality (bottom left) and cardiovascular mortality (bottom right).

Fig 2. Multivariable-adjusted hazard ratio (HR) and 95% confidence interval for 15-year all-cause mortality (n = 547) in participants dichotomized by OPG levels and eGFR.

Multivariable-adjustments were baseline age, body mass index, smoking history, history of hormone replacement therapy, treatment code (calcium or placebo) and comorbidity score.

Fig 3. Multivariable-adjusted hazard ratio (HR) and 95% confidence interval for 15-year cardiovascular mortality (n = 210) in participants dichotomized by baseline OPG levels and eGFR.

Multivariable-adjustments were baseline age, body mass index, smoking history, history of hormone replacement therapy, treatment code (calcium or placebo) and comorbidity score.

Fig 4. Multivariable model plus five-year change in eGFR-adjusted hazard ratio (HR) and 95% confidence interval for 10-year (2003–2013) all-cause (n = 339) and cardiovascular mortality (n = 135) in participants dichotomized by baseline OPG levels and eGFR.

Multivariable-adjustments included 5-year change in CKD-EPI eGFR (n = 970), age, body mass index, smoking history, history of hormone replacement therapy, treatment code (calcium or placebo) and comorbidity score.