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Plasma Osteoprotegerin Is Associated with Mortality in Hemodialysis Patients

Marion Morena^*,, Nathalie Terrier^*, Isabelle Jaussent, Hélène Leray-Moragues, Lotfi Chalabi^||, Jean-Pierre Rivory^¶, François Maurice^¶, Cécile Delcourt^#, Jean-Paul Cristol^*, Bernard Canaud^, and Anne-Marie Dupuy^*

^* Biochemistry Laboratory; Department of Nephrology, Lapeyronie University Hospital, Montpellier; Renal Research and Training Institute, Montpellier; French National Institute of Health and Medical Research, Inserm E 0361, Montpellier; ^|| AIDER, Montpellier; ^¶ Centre Hemodialyse Languedoc Mediterranee, Montpellier; and ^# French National Institute of Health and Medical Research, Inserm U593, Université Victor Segalen Bordeaux 2, Bordeaux, France

Address correspondence to: Dr. Jean-Paul Cristol, Biochemistry Laboratory, Lapeyronie University Hospital, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier cedex 5, France. Phone: 33-467-338-314; Fax: 33-467-338-393; jp-cristol{at}chu-montpellier.fr

Received for publication March 9, 2005. Accepted for publication September 28, 2005.

Expression of bone proteins resulting from transdifferentiation of vascular smooth muscle cells into osteoblasts suggests that vascular calcifications are a bioactive process. Regulating molecules such as osteoprotegerin (OPG) and receptor activator of NF-B ligand (RANKL) could play a key role in bone-vascular calcification imbalance. This study investigated the contribution of these proteins as well as mineral metabolism disorders in hemodialysis (HD) patient outcome. A total of 185 HD patients were followed up prospectively for 2 yr. In addition to clinical characteristics, mineral metabolism markers as well as OPG and soluble RANKL (sRANKL) were measured at baseline. After 2 yr, survival rates were described with Kaplan-Meier and compared with Cox regression analyses; 50 patients died (27 from cardiovascular diseases). Calcium, phosphate, and calcium x phosphate product were not associated with mortality. Both hyperparathyroidism (parathyroid hormone 300 pg/ml) and hypoparathyroidism (parathyroid hormone <150 pg/ml) were poorly associated with all-cause and cardiovascular mortality. By contrast, elevated OPG levels predicted all-cause (relative risk [RR] 2.67; 95% confidence interval [CI] 1.32 to 5.41; P = 0.006) and cardiovascular mortality (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03). Low levels of sRANKL were associated with a protective effect for all-cause mortality (RR 0.45; 95% CI 0.21 to 0.94; P = 0.03). The association of OPG with all-cause mortality was stronger in patients with C-reactive protein 12.52 mg/L. In this condition, both highest (RR 5.68; 95% CI 1.48 to 22.73; P = 0.01) and lowest tertiles (RR 5.37; 95% CI 147 to 1968; P = 0.01) significantly predicted poor outcome. These results show that regulating-bone molecules, especially OPG, are strong predictors of mortality in HD patients, suggesting that OPG is a vascular risk factor, in particular in patients who have high C-reactive protein levels. OPG determination therefore should be added to the biologic follow-up of these patients.

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