Association between serum osteoprotegerin level and mortality in kidney transplant recipients - a prospective observational cohort study.

Paradoxically, higher serum levels of osteoprotegerin (OPG: a vascular calcification inhibitor) have been associated with increased arterial stiffness, risk of cardiovascular disease and all-cause mortality. A few studies reported that post-transplant OPG levels are associated with mortality in kidney transplant (KT) recipients. In this study, this association was assessed in a cohort of prevalent KT recipients, adjusting for previously untested potential confounders, including fibroblast growth factor 23 (FGF23) and interleukin 6 (IL-6). Socio-demographic and clinical parameters, medical and transplant history, and laboratory data were collected from 982 prevalent KT recipients. The association between serum OPG and all-cause mortality over a 6-year follow-up period was examined using Kaplan-Meier survival curves and multivariable-adjusted Cox regression models. Participants with high serum OPG were more likely female, older, deceased donor KT recipients and have more comorbidity, lower eGFR, higher FGF23, higher IL-6, and longer dialysis vintage. Each 1 pmol/l higher serum OPG level was associated with a 49% higher risk of mortality (hazard ratio (HR) [95% confidence interval (CI)]: 1.49 [1.40-1.61]). This association persisted after adjusting for confounders (HR [95% CI]: 1.20 [1.10-1.30]). In conclusion, serum OPG was associated with all-cause mortality independent of several novel confounders in prevalent KT recipients.

The role of laser Doppler flowmetry tests, serum angiopoietin-2, asymmetric and symmetric dimethylarginine to predict outcome in chronic kidney disease.

OBJECTIVE: The role of biochemical and functional markers of microvascular dysfunction to predict cardiovascular outcomes in nondialyzed chronic kidney disease (CKD) remains unclear. In this prospective cohort study, we assessed whether biochemical [serum level of angiopoietin-2 (Ang-2), asymmetric and symmetric dimethylarginin] and functional (laser Doppler flowmetry) measures of microvascular function predicted cardiovascular events, cardiovascular and all-cause mortality in CKD patients. METHODS: Postocclusive reactive hyperemia area (PORHHA), acetylcholine and sodium nitroprusside-mediated flow changes were estimated by laser Doppler flowmetry, and Ang-2, asymmetric and symmetric dimethylarginin were assessed in 105 CKD patients at baseline. Multiple failure time Cox-regression analyses with backward elimination were performed to determine the predictors of the combined endpoint of cardiovascular mortality and cardiovascular events or all-cause mortality and cardiovascular events during a median of 66.6 (interquartile range 39.8-80.4) months of follow-up. RESULTS: In univariate models lnAng-2 and lnPORHHA both predicted the cardiovascular outcome besides age, diabetes, baseline cardiovascular disease, brachial pulse pressure and log C-reactive protein. In multivariate analysis lnPORHHA [hazard ratio: 0.66 (95% confidence interval: 0.49-0.89) per ln(mU s)], age [1.03 (1.01-1.06) per year], log C-reactive protein [1.31 (1.06-1.64) per ln(mg/l)] and diabetes [3.33 (1.70-6.53)] remained significant predictors of the cardiovascular outcome, whereas lnAng-2 did not enter the model. Neither of the microvascular variables were an independent predictor of all-cause mortality and cardiovascular events. CONCLUSION: Among the functional and biochemical microvascular parameters PORHHA seems to improve cardiovascular risk assessment in CKD. Nevertheless the robustness of traditional risk factors seems to outweigh the role of microvascular biomarkers on all-cause mortality and cardiovascular events at this time.

Serum osteoprotegerin is associated with pulse pressure in kidney transplant recipients.

Pulse pressure (PP) reflects increased large artery stiffness, which is caused, in part, by arterial calcification in patients with chronic kidney disease. PP has been shown to predict both cardiovascular and cerebrovascular events in various patient populations, including kidney transplant (KTX) recipients. Osteoprotegerin (OPG) is a marker and regulator of arterial calcification, and it is related to cardiovascular survival in hemodialysis patients. Here we tested the hypothesis that OPG is associated with increased pulse pressure. We cross-sectionally analyzed the association between serum OPG and PP in a prevalent cohort of 969 KTX patients (mean age: 51 +/- --13 years, 57% male, 21% diabetics, mean eGFR 51 +/- 20 ml/min/1.73 m2). Independent associations were tested in a linear regression model adjusted for multiple covariables. PP was positively correlated with serum OPG (rho = 0.284, p < 0.001). Additionally, a positive correlation was seen between PP versus age (r = 0.358, p < 0.001), the Charlson Comorbidity Index (r = 0.232, p < 0.001), serum glucose (r = 0.172, p < 0.001), BMI (r = 0.133, p = 0.001) and serum cholesterol (r = 0.094, p = 0.003). PP was negatively correlated with serum Ca, albumin and eGFR. The association between PP and OPG remained significant after adjusting for multiple potentially relevant covariables (beta = 0.143, p < 0.001). We conclude that serum OPG is independently associated with pulse pressure in kidney transplant recipients.

The method of distance measurement and torso length influences the relationship of pulse wave velocity to cardiovascular mortality.

BACKGROUND: The method of estimating distance traveled by the pulse wave, used in the calculation of pulse wave velocity (PWV), is not standardized. Our objective was to assess whether different methods of distance measurement influenced the association of PWV to cardiovascular mortality in hemodialysis (HD) patients. METHODS: Ninety-eight chronic HD patients had their PWV measured using three methods for distance estimation; PWV1: suprasternal notch-to-femoral site minus suprasternal notch-to-carotid site, PWV2: carotid-to-femoral site, PWV3: carotid-to-femoral site minus suprasternal notch-to-carotid site. Carotid-to-femoral distance was used to approximate torso length. Patients were followed for a median of 30 months and the association of PWV and cardiovascular mortality was assessed using survival analysis before and after stratification for torso length. RESULTS: The three methods resulted in significantly different PWV values. During follow-up 50 patients died, 32 of cardiovascular causes. In log-rank tests, only tertiles of PWV1 was significantly related to outcome (P values 0.017, 0.257, 0.137, for PWV1, PWV2, and PWV3, respectively). In adjusted Cox, proportional hazards regression only PWV1 was related to cardiovascular mortality. In stratified analysis, however, among patients with below median torso length all PWV values were related to outcome, whereas in patients with above median torso length none of the PWV methods resulted in significant relationship to outcome. CONCLUSIONS: PWV calculated using suprasternal notch-to-femoral distance minus suprasternal notch-to-carotid distance provides the strongest relationship to cardiovascular mortality. Longer torso weakens the predictive value of PWV, possibly due to more tortuosity of the aorta hence, more error introduced when using surface tape measurements.

Arterial stiffness in hemodialysis: which parameter to measure to predict cardiovascular mortality?

In previous studies, different parameters of arterial stiffness were related to cardiovascular mortality in hemodialysis patients, but their relative prognostic value has not previously been evaluated in 1 cohort. Carotid-femoral pulse wave velocity (PWV), the carotid augmentation index, carotid pulse pressure (CPP) and carotid-brachial pulse pressure amplification (AMP) were measured in 98 patients before and after hemodialysis. Patients were followed for a median of 29 months (1-34) and the association of these parameters with cardiovascular mortality were assessed using log-rank tests and Cox proportional hazards regressions. During follow-up, 25 patients died of cardiovascular causes. Increasing pre- and postdialysis PWV tertiles and decreasing predialysis AMP tertiles were significantly related to cardiovascular mortality (p = 0.012 and 0.011 for PWV, respectively; < 0.001 for AMP). Neither the carotid augmentation index nor carotid pulse pressure were related to cardiovascular mortality. The adjusted hazard ratios for 1 m/s higher pre- and postdialysis PWV were 1.24 (1.07-1.44) and 1.17 (1.06-1.28), respectively. The hazard ratio for 10% lower predialysis AMP was 1.41 (1.03-1.92). When included in the same model, both predialysis PWV and AMP remained significantly associated with cardiovascular mortality. Among different stiffness parameters, PWV is consistently related to cardiovascular mortality, irrespective of the timing of measurement. Predialysis AMP seems to provide additional prognostic information.

Serum osteoprotegerin level, carotid-femoral pulse wave velocity and cardiovascular survival in haemodialysis patients.

BACKGROUND: Osteoprotegerin (OPG) is a marker and regulator of arterial calcification, and it is related to cardiovascular survival in haemodialysis patients. The link between OPG and aortic stiffening--a consequence of arterial calcification--has not been previously evaluated in this population, and it is not known whether OPG-related mortality risk is mediated by arterial stiffening. METHODS: At baseline, OPG and aortic pulse wave velocity (PWV) were measured in 98 chronic haemodialysis patients who were followed for a median of 24 months. The relationship between OPG and PWV was assessed by multivariate linear regression. The role of PWV in mediating OPG related cardiovascular mortality was evaluated by including both OPG and PWV in the same survival model. RESULTS: At baseline mean (standard deviation) PWV was 11.2 (3.3) m/s and median OPG (interquartile range) was 11.1 (7.5-15.9) pmol/L. There was a strong, positive, linear relationship between PWV and lnOPG (P = 0.009, model R(2) = 0.540) independent of covariates. During follow-up 23 patients died of cardiovascular causes. In separate univariate survival models both PWV and lnOPG were related to cardiovascular mortality [hazard ratios 1.31 (1.14-1.50) and 8.96 (3.07-26.16), respectively]. When both PWV and lnOPG were entered into the same model, only lnOPG remained significantly associated with cardiovascular mortality [hazard ratio 1.11 (0.93-1.33) and 7.18 (1.89-27.25), respectively). CONCLUSION: In haemodialysis patients OPG is strongly related to PWV and OPG related cardiovascular mortality risk is, in part, mediated by increased PWV.