Serum Fetuin-A Levels Are Associated with Vascular Calcifications and Predict Cardiovascular Events in Renal Transplant Recipients

Maréchal, Céline; Schlieper, Georg; Nguyen, Pauline; Krüger, Thilo; Coche, Emmanuel; Robert, Annie; Floege, Jorgen; Goffin, Éric; Jadoul, Michel; Devuyst, Olivier

doi:10.2215/cjn.06150710

Cited by 64 publications

(60 citation statements)

References 48 publications

(62 reference statements)

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“…It is plausible that inflammation and fetuin-A are factors in a shared pathophysiologic pathway, whereby chronic inflammation contributes to deficiency of fetuin-A, promoting dystrophic calcification and higher mortality risk (46). Lower fetuin-A levels have not been consistently associated with mortality or cardiovascular disease in populations not undergoing dialysis (16,(48)(49)(50)(51). In this study, we observed a threshold effect whereby only levels ,0.5 g/L were associated with increasing mortality, which may account for apparently conflicting results.…”

Section: Discussionmentioning

confidence: 99%

“…OPG, OPN, and BMP-7 are produced by a variety of cell types, including endothelial and vascular smooth muscle cells, with increased expression in the setting of active calcification (12,14,15). Numerous clinical studies have demonstrated associations between these biomarkers and measures of vascular calcification and stiffness (16)(17)(18)(19)(20)(21)(22). In this study, we evaluated the association between selected calcification biomarkers and long-term mortality in a large, prospective cohort of incident dialysis patients.…”

Section: Introductionmentioning

confidence: 99%

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Biomarkers of Vascular Calcification and Mortality in Patients with ESRD

Scialla

Kao

Crainiceanu

et al. 2014

Clinical Journal of the American Society of Nephrology

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Background Vascular calcification is common among patients undergoing dialysis and is associated with mortality. Factors such as osteoprotegerin (OPG), osteopontin (OPN), bone morphogenic protein-7 (BMP-7), and fetuin-A are involved in vascular calcification.Design, setting, participants, & measurements OPG, OPN, BMP-7, and fetuin-A were measured in blood samples from 602 incident dialysis patients recruited from United States dialysis centers between 1995 and 1998 as part of the Choices for Healthy Outcomes In Caring for ESRD Study. Their association with all-cause and cardiovascular mortality were assessed using Cox proportional hazards models adjusted for demographic characteristics, comorbidity, serum phosphate, and calcium. An interaction with diabetes was tested because of its known association with vascular calcification. Predictive accuracy of selected biomarkers was explored by C-statistics in nested models with training and validation subcohorts.Results Higher OPG and lower fetuin-A levels were associated with higher mortality over up to 13 years of follow-up (median, 3.4 years). The adjusted hazard ratios (HR) for highest versus lowest tertile were 1.49 (95% confidence interval [95% CI], 1.08 to 2.06) for OPG and 0.69 (95% CI, 0.52 to 0.92) for fetuin-A. In stratified models, the highest tertile of OPG was associated with higher mortality among patients without diabetes (HR, 2.42; 95% CI, 1.35 to 4.34), but not patients with diabetes (HR, 1.26; 95% CI, 0.82 to 1.93; P for interaction=0.001). In terms of cardiovascular mortality, higher fetuin-A was associated with lower risk (HR, 0.85 per 0.1 g/L: 95% CI, 0.75 to 0.96). In patients without diabetes, higher OPG was associated with greater risk (HR for highest versus lowest tertile, 2.91; 95% CI, 1.06 to 7.99), but not in patients with diabetes or overall. OPN and BMP-7 were not independently associated with outcomes overall. The addition of OPG and fetuin-A did not significantly improve predictive accuracy of mortality.Conclusions OPG and fetuin-A may be risk factors for all-cause and cardiovascular mortality in patients undergoing dialysis, but do not improve risk prediction.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Biomarkers of Vascular Calcification and Mortality in Patients with ESRD

Scialla

Kao

Crainiceanu

et al. 2014

Clinical Journal of the American Society of Nephrology

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“…All papers were observational studies: 11 were prospective, 10 analyzed the prevalence or progression of VC, and 3 studied the impact of VC and vascular outcomes. The prevalence of coronary artery calcification (CAC) in KTRs is higher (61-75%) than that assessed in stage 3 CKD [5,6,7] and lower than that found in hemodialysis patients [8], possibly due to a selection bias of KTRs upon admission to the waiting list. The determinants associated with its presence are: age, dialysis vintage, time on transplantation and high/low turnover bone disease [9].…”

Section: Cardiovascular Disease and Vascular Calcification In Kidney mentioning

confidence: 99%

“…Several studies carried out on dialysis patients and KTRs, as well as in the general population, have shown a strong association between a history of cardiovascular events and mortality with CAC [6]. Despite this, there is no clear indication for including non-contrast CT in the instrumental diagnostic procedure to detect the presence and entity of the calcium load and hence also subclinical atherosclerosis in kidney transplantation candidates and KTRs.…”

Section: Cac Assessmentmentioning

confidence: 99%

Importance of Vascular Calcification in Kidney Transplant Recipients

Cianciolo¹,

Capelli²,

Angelini³

et al. 2014

Am J Nephrol

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Background: Kidney transplantation is the treatment of choice for chronic kidney disease (CKD), but in kidney transplant recipients (KTRs) cardiovascular events are the first cause of death with a functioning graft, ranging from 36 to 55%. The impact of vascular calcification (VC) on morbidity and mortality of KTRs is not appreciated enough nowadays. Summary: This review summarizes 13 important studies on VC in KTRs, comparing the results with CKD and dialysis populations. We focused on VC evaluation and use of coronary artery calcification (CAC) and aorta calcification (AoC) scores. We also evaluated the influence of traditional and non-traditional progression risk factors. Key Messages: VC strongly predicts cardiovascular events and all-cause mortality in KTRs. VC assessment is important in KTRs and based essentially on multislice computed tomography or electron beam computed tomography recognition of lesions. Quantitative measurement of CAC and AoC scores is essential for a correct definition of the calcium burden before and after kidney transplant. Progression of CAC slows down but does not halt after kidney transplant. A variable association of both traditional and non-traditional risk factors is shown. There is a strong association between baseline CAC score and CAC progression. A significant improvement in secondary hyperparathyroidism after transplantation favorably affects the progression of CAC. Low 25(OH)D₃ levels are an independent determinant of CAC progression. Diabetes is a risk factor for the presence of CAC in KTRs, but has not been independently associated with CAC progression. The data published on the use of immunosuppressive drugs as progression factors are few and inconclusive.

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“…22 More recently, a direct link between decreased serum levels of Fetuin-A (a calcification inhibitor), aortic calcification, and CV outcome has been demonstrated in RTRs. 23 Increasing evidence supports the hypothesis that medial wall calcification is an important factor contributing to aortic stiffness, although studies comparing both calcification and stiffness in RTRs are not available. Calcineurin inhibitors, still a cornerstone in many immunosuppressive drug regimens, exert dose-dependent renal and systemic vasoconstrictive effects and may increase peripheral wave reflection.…”

Section: Verbeke Et Al Stiffness and Outcome In Renal Transplant Patimentioning

confidence: 99%

Aortic Stiffness and Central Wave Reflections Predict Outcome in Renal Transplant Recipients

et al. 2011

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Abstract-Although renal transplantation improves survival, cardiovascular morbidity and mortality remain significantly elevated compared with nonrenal populations. The negative impact of traditional, uremia-related, and transplantationrelated risk factors in this process remains, however, largely unexplored. Surrogate markers such as aortic stiffness and central wave reflections may lead to more accurate cardiovascular risk stratification, but outcome data in renal transplant recipients are scarce. We aimed to establish the prognostic significance of these markers for fatal and nonfatal cardiovascular events in renal transplant recipients. Carotid-femoral pulse wave velocity, central augmentation pressure, and central augmentation index were measured in a cohort of 512 renal transplant recipients using the SphygmoCor system. After a mean follow-up of 5 years, 20 fatal and 75 nonfatal cardiovascular events were recorded. Using receiver operating characteristic curves, the area under the curve for predicting cardiovascular events was 0. Key Words: cardiovascular events Ⅲ mortality Ⅲ pulse wave velocity Ⅲ augmentation pressure Ⅲ augmentation index Ⅲ transplantation Ⅲ kidney A lthough the survival advantage offered by successful renal transplantation 1 in large part can be attributed to a long-term reduction of the cardiovascular (CV) disease progression and mortality, 2 the annual risk of CV death still remains Ϸ50-fold higher than in the general population. 3 Nevertheless, CV death rates in transplanted patients are reduced by approximately 75% compared with wait-listed patients remaining on dialysis. 4 This decrease in CV risk by partial restoration of kidney function can be offset by the emergence or worsening of other risk factors due to transplant-specific causes, such as acute rejection, infection, or side effects of immunosuppressive drugs, including newonset diabetes after transplantation (tacrolimus, steroids), dyslipidemia (calcineurin inhibitors, mammalian target of rapamycin inhibitors), and anemia (mammalian target of rapamycin inhibitors). Part of the CV risk after transplantation may also relate to irreversible vascular damage accrued during the pretransplantation period.These numerous potential risk factors, together with the small number of randomized trials, render the management of CV risk in renal transplant recipients (RTRs) particularly difficult, whereas this population represents one of the largest groups of patients with chronic kidney disease regularly seen by the nephrologist. Therefore, surrogate markers of arterial damage, such as aortic stiffness and central wave reflections, have gained increasing interest for the assessment of overall CV risk in this heterogeneous population. Patient and donor characteristics that have been related to measures of arterial stiffness or wave reflection include donor age, 5 graft function, 6,7 microinflammation, 7 new-onset diabetes after transplantation, 8 hypomagnesemia, 9 and use of cyclosporine. 10 However, these cross-sectional relationships are on...

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Serum Fetuin-A Levels Are Associated with Vascular Calcifications and Predict Cardiovascular Events in Renal Transplant Recipients

Cited by 64 publications

References 48 publications

Biomarkers of Vascular Calcification and Mortality in Patients with ESRD

Biomarkers of Vascular Calcification and Mortality in Patients with ESRD

Importance of Vascular Calcification in Kidney Transplant Recipients

Aortic Stiffness and Central Wave Reflections Predict Outcome in Renal Transplant Recipients

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