Epidemiology and Outcomes

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
JASN January 2006, 17 (1) 262-270; DOI: https://doi.org/10.1681/ASN.2005030260

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-κB 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 × 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.

Despite 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 × phosphate product (Ca × PO4) 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-κB 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 osteoblasts and are regulated by various calciotropic cytokines, hormones, and drugs. It is interesting that it was shown recently in general population that increased levels of OPG (13,14) and low levels of RANKL (15) were associated with an increased rate of cardiovascular mortality, probably as a result of vascular calcifications. Therefore, we prospectively assessed the associations of all-cause and cardiovascular mortality with parameters involved in vascular calcifications (divalent ion abnormalities and bioactive process including OPG and RANKL) in a cohort of HD patients who were followed up for 2 yr.

Materials and Methods

Study Design

A total of 185 stable HD patients who originated from one of the three dialysis facilities of Montpellier, France (an hospital-based facility [Lapeyronie University Hospital], a public nonprofit association [Aide pour l’Installation à Domicile de l’Epuration extra Rénale], and a private dialysis clinic [Centre d’Hamodialyse Languedoc Méditerranéen]) were evaluated for inclusion from October to November 2001. Informed consent was obtained from all participants. We excluded patients with symptoms or signs of acute inflammatory or infectious diseases. The included patients then were followed up prospectively yearly until January 1, 2004.

Patients and Baseline Data

The patients received either high-flux polysulfone HD or on-line hemodiafiltration treatments with ultrapure bicarbonate-buffered dialysate three times a week (mean duration 11.5 ± 1.5 h/wk) with a dialysate calcium concentration of 1.50 mmol/L (in 41.4% of patients) or 1.75 mmol/L (in 58.6% of patients). Dialysis efficiency was estimated using single pool Kt/V ratio (16).

Medical charts were reviewed for age, gender, weight, height, underlying renal disease, dialysis vintage, history of transplantation, diabetes, comorbid conditions, past or current smoking, current medication, and current hypertension. Concerning treatment of mineral metabolism disorders, 132 patients were receiving calcium carbonate, 14 were receiving sevelamer, and 77 were receiving 1 α hydroxy vitamin D3.

Existence of hypertension was defined by predialysis brachial BP ≥140/90 mmHg and/or by a current antihypertensive treatment. Pulse pressure, as an index of aortic stiffness, was defined by the difference between systolic and diastolic BP (17). A clinical examination was carried out. Presence of atherosclerotic cardiovascular disease was defined by the presence of at least one of the three following manifestations: Coronary artery disease, cerebrovascular disease, or peripheral atherosclerotic disease.

Coronary artery disease was defined as documented angina pectoris or history of myocardial infarction. Angina pectoris was described as chest pain arising at exertion and disappearing with nitroglycerine or rest. The diagnosis may also have been done by a positive evaluation in nuclear medicine or a coronary stenosis >75% of luminal diameter. Myocardial infarction was defined as clinical symptoms, such as chest pain or dyspnea, associated with a positive electrocardiogram and elevated cardiac markers (cardiac enzymes or troponins). Cerebrovascular disease was defined as previous clinical cerebral disease (transient ischemic attack or stroke) or the presence of atheromatous plaques on internal carotid arteries. Peripheral vascular disease included clinical symptoms such as intermittent claudication, abolished peripheral pulses or diminished arterial pulses or signs of atheromatous involvement of the lower limb.

Follow-Up Period and End Point

Patients were followed yearly during 2 yr. No major modifications were made in dialysis treatment and schedules during this follow-up period. On January 1, 2003, and January 1, 2004, all patients were re-evaluated by the physicians in the dialysis centers. The dates of death, transplantation, or transfer to another dialysis center were documented. The causes of death were classified as cardiac events (myocardial infarction, congestive heart failure, and sudden death) or noncardiovascular events (infection, neoplasm, other, and unknown causes).

Laboratory Measurements

Blood samples were collected at baseline at a single midweek dialysis session (as part of our routine patient follow-up and quality insurance process) and centrifuged, and plasma samples were finally stored at −80°C for processing C-reactive protein (CRP), Ca, PO4, intact [1-84] parathyroid hormone (PTH), bone-type alkaline phosphatase (bALP), OPG and soluble RANKL (sRANKL), and albumin.

Ca and PO4 were assessed by colorimetric method (Olympus Apparatus, Rungis, France). CRP and albumin were determined by immunoturbidimetry method (Olympus Apparatus). Ca was adjusted for albumin levels according to the following formula: corrected calcium (mmoL/L) = measured calcium (mmol/L) + (40 − albumin [g/L]) × 0.025. PTH was measured by immunoradiometric assay (N-Tact PTH SP IRMA Kit; DiaSorin, Stillwater, MN). bALP was measured by immunochemiluminescence technique (Access Beckman Coulter, Villepinte, France). OPG (interassay CV = 6.5% [472.8 pg/ml] and 8.6% [1430.4 pg/ml]; intra-assay CV = 4.8% [477.0 pg/ml] and 3.7% [7074.0 pg/ml]) was performed by ELISA (Biovendor Laboratory Medicine, Brno, Czech Republic; normal range previously obtained in the laboratory 300 ± 102 pg/ml [18,19]). To evaluate the long-term variability of this bone marker, we repeated determination at 1 yr on 133 HD patients. Clear correlation was obtained between the two measures (OPG[+1 yr] = 0.95*OPG + 250.95; r = 0.81; P < 0.0001). In addition, the scatter of differences between the two determinations was described according to the Bland-Altman approach. More than 95% of the differences between the two levels were within the 2 SD limit. sRANKL (interassay CV = 3.9% and 7.3% [2.67 pmol/L and 3.04 pmol/L, respectively]; intra-assay CV = 5% and 3% [1.00 pmol/L and 3.20 pmol/L, respectively]) was performed by ELISA (Biomedica, Wien, Austria; normal range previously obtained in the laboratory 0.80 ± 0.40 pmol/L [19]).

Statistical Analyses

Data were expressed as mean ± SEM for normally distributed variables and as median (minimum to maximum) for nonnormally distributed variables. The Kaplan-Meier method was used to describe survival curves. Cox proportional hazards regression analysis was used to examine the associations of baseline variables with all-cause and cardiovascular mortality. Adjustments for age, gender, and dialysis vintage were initially performed to calculate adjusted relative risks (RR). Fully adjusted RR were calculated further after adjustment for age, gender, dialysis vintage, diabetes, hypertension, and smoking. Results were reported as RR with the respective 95% confidence interval (CI). P = 0.05 was considered to be significant. All analyses were carried out with SAS software, version 9.1 (SAS Institute, Cary, NC).

PTH levels and Ca/PO4 parameters were analyzed according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) recommendations for ESRD (20). The recommended normal range was chosen as the reference value for statistical analysis. Because no consensus was reported about normal value of CRP, OPG, and sRANKL in HD patients, these variables were divided into tertile values.

We tested the potential interactions between CRP and markers of mineral metabolism (OPG, sRANKL, and PTH), by comparing separately for each marker the likelihood of the complete model (including the terms for CRP, mineral marker, and their interaction) to the likelihood of the simple model (including only the terms for CRP and the mineral marker), using the likelihood ratio.

Results

Baseline Characteristics of Patients

Clinical characteristics of the 185 HD patients are summarized in Table 1. Diabetes and hypertension were found in 21.6 and 22.7%, respectively. Pulse pressure median was 56 mmHg (24 to 112). Evidence of cardiovascular disease was present in 31.3% for coronary heart disease, 44.8% for cerebrovascular disease, and 43.8% for peripheral atherosclerotic disease.

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Table 1.

Baseline characteristics of HD patientsa

Distribution of inflammation and mineral and bone metabolism parameters are reported in Table 1. According to the K/DOQI definitions, the majority (67.6%) of patients had low PTH levels (<150 pg/ml), indicating low bone remodeling. In addition, 84 (45.4%) patients had PTH levels <100 pg/ml. OPG levels were greater (median 1894.2 pg/ml [559.8 to 7491.6]) than the normal range obtained in the laboratory, whereas sRANKL levels were decreased (median 0.20 pmol/L [0.08 to 4.43] for men; median 0.18 pmol/L [0.08 to 2.55] for women). No significant association was observed between bone metabolism markers and prevalence of cardiovascular disease.

All-Cause Mortality

After a 2-yr follow-up, 50 patients (23 men and 27 women) had died from cardiovascular causes (n = 27), infectious diseases (n = 10), malignancies (n = 4), severe malnutrition (n = 4), or miscellaneous causes (n = 5).

Inflammation, Mineral Metabolism, and Mortality Rate

A reported in Tables 2 and 3, high CRP level was predictive of poor outcome (RR 2.63; 95% CI 1.25 to 5.55; P = 0.01, after adjustment for age, gender, and dialysis vintage). However, its relationship with cardiovascular deaths did not reach significance. In addition, no significant association between pulse pressure and all-cause or cardiovascular deaths was observed. Regarding mineral metabolism markers, Ca, PO4, Ca × PO4, and bALP were not independent predictors of mortality at 2 yr, whatever the cause of mortality or the statistical adjustment for potential confounders.

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Table 2.

Cox proportional hazards analysis of factors that predict all-cause mortality among HD patients (n = 50)a

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Table 3.

Cox proportional hazards analysis of factors that predict cardiovascular disease–related mortality among HD patients (n = 27).

PTH Levels and Mortality Rate

PTH values, divided into three groups (<150 pg/ml, 150 to 300 pg/ml, and ≥300 pg/ml), did not show any significant association with all-cause and cardiovascular disease–related mortality. However, low PTH level (<100 pg/ml) was predictive of all-cause mortality rate (RR 2.03; 95% CI 1.12 to 3.69; P = 0.02, after adjustment for age, gender, and dialysis vintage; Tables 2 and 3).

OPG and sRANKL as Predictors of Mortality

As the median tertile of OPG (1550.4 to 2438.4 pg/ml) was associated with the lowest mortality rate, it was taken as the reference tertile (Tables 2 and 3). It is interesting that elevated levels of OPG predicted all-cause (RR 2.67; 95% CI 1.32 to 5.41; P = 0.01, after adjustment for age, gender, and dialysis vintage) and cardiovascular mortality rates (RR 3.15; 95% CI 1.14 to 8.69; P = 0.03 after adjustment for age, gender, and dialysis vintage). The lowest tertile of OPG was not significantly associated with all-cause and cardiovascular mortality (RR 1.42 [95% CI 0.59 to 3.40; NS] and RR 2.33 [0.72 to 7.50; NS], respectively). No correlation was observed between OPG or sRANKL and any other bone metabolism markers such as PTH levels, Ca × PO4, PO4 level, or bALP. Similarly, no significant correlation was observed between CRP and OPG levels (r = −0.037, P = NS) and between pulse pressure and OPG (r = 0.12, P = 0.10). 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, after adjustment for age, gender, and dialysis vintage), whereas its association with cardiovascular mortality did not reach statistical significance (RR 0.48; 95% CI 0.17 to 1.31; NS, after adjustment for age, gender, and dialysis vintage).

Multivariate Analysis

Table 4 describes the proportional hazards model using all of the parameters that were significantly associated with an enhanced mortality in the first model, which includes CRP, PTH, OPG, and sRANKL. In addition, classical risk factors, such as age, gender, dialysis vintage, diabetes, hypertension, and smoking, were included. There was a significant interaction among CRP and OPG (P = 0.02); in Table 4, therefore, we present results separately for patients with CRP <12.52 mg/L and for patients with CRP ≥12.52 mg/L. In patients with CRP <12.52 mg/L, classical risk factors, such as age, gender, dialysis vintage, or diabetes, were the strongest risk factors for mortality. In this group, OPG and PTH were not significantly associated with mortality, whereas low sRANKL values were associated with decreased mortality (RR 0.27, P = 0.03). By contrast, in patients with CRP ≥12.52 mg/L, among traditional risk factors, only hypertension was significantly associated with mortality. OPG was strongly associated with mortality, with both low levels and high levels showing increased risk for mortality (RR 5.37 [P = 0.01] and RR 5.68 [P = 0.01], respectively). PTH and sRANKL were not significantly associated with mortality in this multivariate model.

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Table 4.

Final multivariate Cox proportional hazards analysis of factors that predict all-cause mortality among HD patients (n = 24 for CRP <12.52 mg/L and n = 26 for CRP ≥12.52 mg/L)

Discussion

This prospective study investigated markers of total and cardiovascular mortality in HD patients. Our results revealed for the first time that among mineral metabolism markers, elevated levels of circulating OPG were the strongest predictors of all-cause mortality in this population. It is interesting that low PTH levels (<100 pg/ml), as an indicator of adynamic bone, were also associated with poor survival. Low levels of RANKL were associated with a protective effect for all-cause mortality. No association was observed between bone mineral metabolism markers (including Ca, PO4, Ca × PO4, and bALP) and mortality in these HD patients. Similarly, pulse pressure, as a marker of aortic stiffness (17), was not significantly associated with mortality, whereas large database studies report this parameter as an independent risk factor in HD patients (21,22). In addition, no significant correlation between OPG and pulse pressure was observed. Because pulse pressure is not a direct marker of changes in vascular compliance, better correlation with OPG could be expected with aortic pulse wave velocity. This complex parameter, which increases with arterial stiffness and vascular Ca load, has been reported as an independent predictor of mortality (23). A number of cross-sectional studies have reported the high prevalence of vascular calcifications in the HD population, independent of age or diabetes (24,25). In addition, prospective studies have demonstrated that vascular calcifications are associated with cardiovascular mortality (5,6,26) and could account in part for the enhanced mortality observed in the HD population (5,6,26). Hyperphosphatemia, hypercalcemia, increased Ca × PO4, and secondary hyperparathyroidism long have been considered to play a key role in this vascular insult (6,7,27). However, conflicting results from large studies have been reported (26,28), showing that low levels of phosphorus, Ca × PO4, and PTH levels could also be associated with a high risk for mortality (6,29–31). Thus, growing data converge to conclude that U curves are the best representation for the relationship between mineral bone markers and cardiovascular diseases (29). Although significance was not reached, our results agree with this concept, showing that phosphate and PTH levels in the range of the K/DOQI recommendations are associated with the lowest mortality rates (Table 2). The lack of a significant association between hyperphosphatemia and mortality is probably due to the small number of patients (33% of the study population, n = 61) who presented with high plasma phosphorus levels (≥1.78 mmol/L). In addition, in agreement with the recent report by London et al. (32), PTH levels <100 pg/ml, as a marker of adynamic bone, were associated with a statistically significant increase in all-cause mortality. Furthermore, we investigated the possibility that combinations of plasma Ca × PO4 and PTH values might function as risk factors, as recently proposed by Stevens et al. (33) Considering low Ca × PO4 (<4.5 mmol2/L2) together with high PTH levels (≥300 pg/ml) as the reference group, none of the other potential combinations reached significance as a risk factor for all-cause mortality: low Ca × PO4 and low PTH levels (RR 1.57; 95% CI 0.55 to 4.51), high Ca × PO4 and high PTH levels (RR 2.11; 95% CI 0.47 to 9.42), and high Ca × PO4 and low PTH levels (RR 1.06; 95% CI 0.32 to 3.49).

Vascular calcification long has been regarded as a passive process in which disturbances in calcium phosphorus metabolism played a central role. However, expression of bone matrix proteins by VSMC in arteries recently suggested that vascular calcification was not simply passive but rather an active, cell-mediated process secondary to VSMC transdifferentiation into osteoblast-like cells (8,9). It has been shown that this transdifferentiation could be achieved in vitro by many uremic toxins (34). In addition, chondrocytes, osteoblasts, and osteoclasts have been identified in calcified atherosclerotic plaques (35,36). These cell types can express both activating proteins (osteonectin, osteocalcin, and bone morphogenic protein-2) and inhibiting proteins (osteopontin, matrix GLA-protein, and bone sialoprotein) and finally regulatory factors (Cbfa1 and OPG/RANKL) (34,37,38) of calcification. Evidence supports the assumption that the OPG/RANKL complex cytokine network may be expressed, regulated, and function in vascular physiology and pathology to regulate VSMC osteogenesis and calcification (10). Indeed, RANKL is one of the major osteoclast maturation factors, whereas OPG functions as a soluble decoy receptor for RANKL and inhibits its effects (39). Therefore, at the bone level, OPG promotes bone formation, whereas RANKL promotes bone resorption (11). In the vessel wall, several epidemiologic studies strongly suggested that elevated levels of OPG are associated with the vascular risk in the general population (13,14,40). RANKL effect is still unclear, even though preliminary results from Schoppet et al. (15) reported that low levels of RANKL were also associated with vascular risk.

In the context of HD, it is more difficult to interpret results regarding OPG and RANKL, first because OPG is not removed correctly (41), and therefore its accumulation leads to a decrease in circulating RANKL. This imbalance constitutes a major vascular risk factor (13,15,40) and is observed in our population because OPG levels were much greater and sRANKL was lower than those reported in the normal population (19). In the age-, gender-, and dialysis vintage–adjusted analysis, only the highest tertile of OPG was significantly associated with increased mortality rate, suggesting that levels >2400 pg/ml should be interpreted as a risk factor. The multivariate analysis demonstrates for the first time that OPG is an independent variable associated with mortality rate, highlighting previous observation on extent (42,43) and progression (44) of vascular calcifications. Moreover, this multivariate analysis suggests an interaction between CRP and OPG, although no direct correlation was observed between these parameters. In fact, OPG seems to be a predictor of poor outcome only in the presence of inflammation (Table 4). In this condition, as previously observed for mineral metabolism markers particularly for PTH, association of OPG with all-cause mortality tended to describe a U-shaped curve. This relationship could be dependent in part on the bone turnover rate, because preliminary works suggest that PTH levels determine OPG/RANKL in bone tissue and serum (42,44). In addition, a symmetric opposite curve was observed with sRANKL. Such observation is in agreement with the general concept that OPG and RANKL are agonist/antagonist molecules that lead to opposite effects in both bone and vascular biology. From this clinical study, it is difficult to speculate on the molecular mechanisms involved in the vasculature, especially in the presence of inflammation. Because it has been shown that OPG knockout mice develop severe and diffuse arterial calcifications (45), it could be postulated that OPG partly exerts a protective role against vascular Ca deposition. The high mortality rate observed with the lowest tertile of OPG in the presence of an inflammatory reaction could in part reflect this hypothesis (RR 5.37; 95% CI 1.47 to 19.68; Table 4). The recent finding that uremic serum enhances the expression of calcification inhibitors such as OPG and matrix GLA protein in bovine VSMC further supports an intravascular regulatory mechanism (46). However, the clear link observed with high OPG and mortality rate in age-, gender-, and dialysis vintage–adjusted analysis (Tables 2 and 3) is enhanced further in the presence of inflammation (RR 5.68; 95% CI 1.42 to 22.73; Table 4). These data suggest that the putative OPG-related compensatory mechanism could be overwhelmed in the presence of inflammation. Because in our study OPG and CRP are not directly correlated, it could be hypothesized further that OPG and CRP act through different mechanisms in HD-linked arteriopathy. Indeed, OPG, which is known as a marker of the complex process that leads to the osteoblastic transdifferentiation associated with bone matrix formation, could participate in the vascular cytokine network (13) and modulate local inflammation in the arterial wall (14). In addition, systemic inflammation could be involved further in Ca deposition on this bone-like tissue. The hepatic synthesis of circulating Ca-binding protein fetuin A, which inhibits tissue calcification, has been shown to be downregulated with inflammation (47).

Finally, in this study, multivariate adjustment for a number of potential confounders, including age and diabetes, did not materially affect the associations of OPG with mortality, whereas these two classical risk factors have been reported to influence OPG levels. This result is in agreement with our recent report showing that, in diabetes, OPG is influenced by coronary vascular disease (18).

In conclusion, this study clearly shows that among mineral metabolism markers, including PO4, Ca × PO4, PTH, and combination indices, OPG levels are the strongest predictors of all-cause mortality in HD patients, in particular in patients who have high CRP levels. We therefore strongly suggest the annual determination of this marker as part of the biologic follow-up of these patients in addition to inflammatory parameters.

Acknowledgments

We acknowledge the nephrologists J.L. Flavier, J.Y. Bosc, M. Galy, C. Formet, F. Gérard, C. Rouanet, and I. Selcer for collaboration. The bALP reagents used in this study were generously provided by Beckman-Coulter France.

Footnotes

  • Published online ahead of print. Publication date available at www.jasn.org.

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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, Anne-Marie Dupuy
JASN Jan 2006, 17 (1) 262-270; DOI: 10.1681/ASN.2005030260
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