Plasma Osteoprotegerin Is Associated with Mortality in Hemodialysis Patients Marion Morena,* † Nathalie Terrier,* Isabelle Jaussent, ‡ He ´le `ne Leray-Moragues, § Lotfi Chalabi,  Jean-Pierre Rivory, ¶ Franc ¸ois Maurice, ¶ Ce ´cile Delcourt, # Jean-Paul Cristol,* Bernard Canaud, †§ and Anne-Marie Dupuy* *Biochemistry Laboratory and § 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, Universite ´ Victor Segalen Bordeaux 2, Bordeaux, France 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 contribu- tion 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  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. J Am Soc Nephrol 17: 262–270, 2006. doi: 10.1681/ASN.2005030260 D espite technical and pharmacologic improvements achieved over the past years in the management of patients with ESRD, long-term prognosis of hemodi- alysis (HD) patients is still poor (1). Cardiovascular disease is the leading cause of both morbidity and mortality in HD pa- tients (2– 4), suggesting that a proper management of specific cardiovascular risk factors is required for improving clinical outcome. Vascular calcifications now are recognized as a strong pre- dictor of all-cause and cardiovascular mortality in this popula- tion (5). In this context, hyperphosphatemia, increased cal- cium  phosphate product (Ca  PO 4 ) and secondary hyperparathyroidism were initially considered to be of central pathophysiologic relevance (6,7) because of passive deposition in mineralized hydroxyapatite when supersaturation concen- trations of calcium and phosphorus were reached in the serum. Under pathologic conditions, the expression of bone matrix proteins by vascular smooth muscle cells (VSMC) recently iden- tified in the arteries has suggested that vascular calcification is an active, cell-mediated process secondary to VSMC transdif- ferentiation into osteoblast-like cells (8,9). The precise mecha- nisms that drive vascular calcification and its clinical conse- quences are still unclear. However, new insights on the vascular calcification process are emerging on a recently dis- covered group of regulating molecules that belong to the TNF receptor superfamily, including osteoprotegerin (OPG) and re- ceptor activator of NF-B ligand (RANKL) (10). Indeed, OPG and RANKL, a key agonist/antagonist cytokine system, regu- late important aspects of osteoclast/osteoblast formation (11,12). RANKL increases the pool of active osteoclasts by activating its specific receptor RANK located partly on oste- oclastic cells, thus increasing bone resorption, whereas OPG, which neutralizes RANKL, has opposite effects. RANKL and OPG are produced by bone marrow– derived stromal cells and Received March 9, 2005. Accepted September 28, 2005. Published online ahead of print. Publication date available at www.jasn.org. M. Morena and N. Terrier contributed equally to this work. Address correspondence to: Dr. Jean-Paul Cristol, Biochemistry Laboratory, La- peyronie University Hospital, 371 Avenue du Doyen Gaston Giraud, 34295 Mont- pellier cedex 5, France. Phone: 33-467-338-314; Fax: 33-467-338-393; E-mail: jp- cristol@chu-montpellier.fr Copyright © 2006 by the American Society of Nephrology ISSN: 1046-6673/1701-0262