Inflammation modifies the association of osteoprotegerin with mortality in chronic kidney disease.
BACKGROUND
The production and expression of osteoprotegerin (OPG), a bone regulating protein, is regulated by inflammatory cytokines.


METHODS
As clinical and experimental studies have implicated OPG in atherogenesis, we investigated serum OPG in relation to inflammation, endothelial dysfunction and oxidative stress markers in 265 chronic kidney disease (CKD) stage 5 patients. Cardiovascular disease (CVD), carotid plaques (n=69) and mortality (5 years) in relation to OPG were also analyzed, and the impact of inflammation on the association of OPG with mortality was evaluated.


RESULTS
OPG correlated positively with circulating surrogate markers of inflammatory, endothelial dysfunction and oxidative stress. Patients with clinical CVD or carotid plaques had higher concentrations of OPG than their respective counterparts. Increased OPG levels per se were related to higher cardiovascular and all-cause mortality even after adjustment for age, sex, C-reactive protein, diabetes mellitus and baseline CVD. Moreover, the presence of inflammation further and independently aggravated the hazard ratios (HR) for both cardiovascular (HR=2.8; 95% confidence interval [95% CI], 1.3-6.4; p=0.01) and all-cause (HR=2.5; 95% CI, 1.4-4.5; p<0.01) mortality.


CONCLUSIONS
Elevated OPG levels are associated with surrogate markers of inflammation, endothelial dysfunction, oxidative stress and CVD in CKD patients. Moreover, inflammation and OPG levels seem to have additive effects on survival.
Matsubara
Keisuke
K
Divisions of Renal Medicine and Baxter Novum, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.
Stenvinkel
Peter
P
Qureshi
Abdul Rashid
AR
Carrero
Juan Jesús
JJ
Axelsson
Jonas
J
Heimbürger
Olof
O
Bárány
Peter
P
Alvestrand
Anders
A
Lindholm
Bengt
B
Suliman
Mohamed E
ME
D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000276:immunology / Q000401:mortality* / Q000503:physiopathology; D002423:Cause of Death; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004730:Endothelium, Vascular / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000401:mortality* / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood*; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000276:immunology / Q000401:mortality* / Q000503:physiopathology / Q000628:therapy; D008297:Male; D008875:Middle Aged; D053244:Osteoprotegerin / Q000097:blood*; D018384:Oxidative Stress; D016016:Proportional Hazards Models; D011502:Protein-Energy Malnutrition / Q000276:immunology / Q000401:mortality; D017582:Renal Replacement Therapy; D018570:Risk Assessment; D012307:Risk Factors; D012720:Severity of Illness Index; D013997:Time Factors; D015854:Up-Regulation; D055815:Young Adult
D015415:Biomarkers; D018836:Inflammation Mediators; D053244:Osteoprotegerin; C506030:TNFRSF11B protein, human