Plasma Osteoprotegerin Is Associated with Mortality in Hemodialysis Patients

Abstract

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 KaplanMeier 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. D espite technical and pharmacologic improvements achieved over the past years in the management of patients with ESRD, long-term prognosis of hemodialysis (HD) patients is still poor (1). Cardiovascular disease is the leading cause of both morbidity and mortality in HD patients (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 predictor of all-cause and cardiovascular mortality in this population (5). In this context, hyperphosphatemia, increased calcium ϫ phosphate product (Ca ϫ 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 concentrations 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 identified in the arteries has suggested that vascular calcification is an active, cell-mediated process secondary to VSMC transdifferentiation into osteoblast-like cells (8,9). The precise mechanisms that drive vascular calcification and its clinical consequences are still unclear. However, new insights on the vascular calcification process are emerging on a recently discovered group of regulating molecules that belong to the TNF receptor superfamily, including osteoprotegerin (OPG) and receptor activator of NF-B ligand (RANKL) (10). Indeed, OPG and RANKL, a key agonist/antagonist cytokine system, regulate important aspects of osteoclast/osteoblast formation (11,12). RANKL increases the pool of active osteoclasts by activating its specific receptor RANK located partly on osteoclastic 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

Persistent Inflammation as a Catalyst for Other Risk Factors in Chronic Kidney Disease

“…Osteoprotegerin (OPG), a member of the TNF-␣ receptor superfamily, inhibits osteoclastogenesis, osteoclast activation, and osteoclast-like formation in arteries and atherosclerotic plaques. Because Morena et al (40) showed that OPG is associated with vascular calcification and mortality in dialysis patients, their findings seem to contradict the calcification inhibitory properties of this protein. Elevated OPG levels have been interpreted as a failed compensatory mechanism trying to counteract the ongoing calcification process; however, because OPG production and expression are highly regulated by several inflammatory cytokines (41), it could also be speculated that increased OPG levels in CKD may in part be a consequence of systemic inflammation (42).…”

“…Elevated OPG levels have been interpreted as a failed compensatory mechanism trying to counteract the ongoing calcification process; however, because OPG production and expression are highly regulated by several inflammatory cytokines (41), it could also be speculated that increased OPG levels in CKD may in part be a consequence of systemic inflammation (42). Indeed, Morena et al (40) showed that whereas elevated OPG in the context of an inflammatory milieu strongly predicted survival, such effect was not observed in dialysis patients without inflammation and with elevated OPG. We recently confirmed their finding in a larger cohort of 265 incident dialysis patients ( Figure 3B) (43).…”

Receptor activator of nuclear factor κB ligand/osteoprotegerin axis and vascular calcifications in patients with chronic kidney disease

“…Since OPG inhibits osteoclast activity and OPG knockout mice develop arterial calcifications, it appears reasonable to assume that it plays some regulatory and/or inhibitory role against ectopic calcifications and thus its increased levels could be interpreted as an attempt to compensate for the ongoing calcification process [9][10][11] . The above speculation contradicts the reported association of high OPG levels with cardiovascular mortality [22,23,25,26] and moreover, increase of OPG levels could be due to its production by calcified vascular cells in conditions of diffuse calcification. Thus, it remains to be clarified whether the elevated OPG levels induce arterial wall sclerosis or represent a compensatory mechanism to prevent further arterial damage or are just a marker of initiation of vascular calcification process [4] .…”

“…In addition, high OPG levels have been found to correlate with faster progression of aortic calcifications during a 5-year follow-up [21] . Finally, several studies in patients with various CKD stages as well as in renal transplant recipients demonstrated that OPG levels were a significant independent predictor of allcause and cardiovascular mortality during the follow-up period [22][23][24][25][26] . However, one study in ESRD and pre-dialysis CKD patients showed that renal function rather than OPG levels were mostly associated with the progression of aortic and coronary calcifications [27] , whereas another one correlated elevated OPG levels only with moderate CAC [28] .…”

The Relationship Between Osteoprotegerin/RANKL Axis and Arterial Stiffness in Osteopenic/Osteoporotic Renal Transplantation Recipients

“…Osteoprotegerin (OPG) is a member of the tumour necrosis factor receptor superfamily and this molecule can be produced by osteoblasts and various cells of the vasculature. OPG was accepted as a cardiovascular risk factor in ESRD patients receiving hemodialysis (HD) (8) and undergoing Rtx (9). In this regard, increased serum OPG levels were found to be associated with increased coronary artery and aorta calcification in these populations indicating that OPG may be involved in the pathogenesis of VC (10).…”