In the present study we show a positive association between plasma fibulin-1 concentration and several cardiovascular risk markers in patients with CKD. Our findings are in accordance with findings from earlier experimental and clinical studies which suggested links between fibulin-1, cardiovascular disease and diabetes [7, 9, 16, 17].
In the present study, plasma fibulin-1 concentration was found to increase with age in the study population. This is in agreement with our data previously published . A multivariable analysis of the current data showed that the importance of age is not retained in the simultaneous context of kidney function, presence of diabetes, CAP and fibrinogen status.
Correlations were also observed between markers of deteriorating kidney function and increasing plasma fibulin-1 concentrations, with creatinine being an independent predictor of plasma fibulin-1 concentration. These findings are in accordance with findings from a multiplex proteomic study showing that plasma fibulin-1 could be a marker of renal impairment .
We also found an independent association between fibulin-1 and fibrinogen, a positive acute phase protein whose blood levels are increased in CKD. Fibrin clot characteristics in CKD differ from non-CKD patients in close correlation to inflammatory level rather than to the extent of uremia . Not only has fibulin-1 been shown to bind to fibrinogen and incorporate into fibrin thrombi, but fibulin-1 also qualitatively influences the polymerization of fibrin [7, 9, 10]. We regard these findings as important in the context of increased plasma fibulin-1 concentrations that we report here.
Our previous studies demonstrated elevated plasma concentrations of fibulin-1 in diabetic patients . We confirmed these results and again saw a correlation between higher plasma fibulin-1 concentrations and higher HbA1C values. The presence of diabetes was an independent predictor of elevated plasma fibulin-1 levels.
The mechanism underlying the increase of plasma fibulin-1 is not known. In patients with diabetes we showed that it exists also in those patients without microalbuminuria hence without signs of initial kidney damage . It should be noted, that diabetes and CKD share important features at the molecular level, e.g. an increase in oxidative stress and advanced protein glycation [20, 21]. One or several factors from this group might be involved in the regulation of plasma fibulin-1 concentration. This should be the subject of future experimental work.
An important dimension of the present study was the analysis of central hemodynamics and vascular stiffness in relation to plasma fibulin-1 concentrations. We found a correlation with aortic AIx and central augmentation pressure (CAP). CAP was retained as independent variable in the multivariable analysis. When we performed analyses of arterial stiffness markers we did not find a correlation of plasma fibulin-1 concentrations to aortic PWV and heart rate normalized aortic AIx. Thus, plasma fibulin-1 seems to be unrelated to arterial changes that result in changes of aortic PWV. Also, increased arterial stiffness that results in an increased heart rate normalized aortic AIx  was unrelated to plasma fibulin-1. By contrast, a relationship was found to exist between plasma fibulin-1 and the actual central augmentation the left ventricle faces in the late systole. The pressure effort of the ventricle to overcome this augmented pressure was termed “wasted” since it does not contribute to blood flow production .
Several potential new biomarkers for cardiovascular diseases in diabetes have appeared during recent years. These biomarkers are associated with dysfunctions in different disease pathways and consequently display both, similarities and discrepancies in their clinical appearance.
While it was shown that plasma fibulin-1 was able to predict all-cause mortality in patients with diabetes  the underlying mechanisms which regulate the protein amount in certain disease entities are still uncertain. A similar dilemma applies for another interesting protein that has extensively been studied in cardiovascular disease – osteoprotegerin. Plasma osteoprotegerin concentrations are positively correlated to the presence of coronary, carotid and peripheral artery disease in diabetic patients [24, 25]. Elevated plasma osteoprotegerin concentrations also predicted all-cause mortality in diabetes . Several interesting mechanisms for the involvement of osteoprotegerin in cardiovascular morbidity, like an increased expression of adhesion molecules by endothelial cells or a regulative effect on vascular calcification, were described (for review see ). Although the function of fibulin-1 in the cardiovascular system is not well defined it could be speculated that it is different from osteoprotegerin; more related to changes in the structure of the extracellular matrix. Such functional differences between biomarkers are likely to give rise to a different clinical meaning. Nevertheless, the proof of a cause-effect relation between cardiovascular disease in humans and osteoprotegerin or fibulin-1 is still lacking and the role of both proteins for diagnosis or assessment of progression of cardiovascular disease awaits further study.
The exact role of fibulin-1 in cardiovascular disease may be complex since it is associated with pathologies in both, arterial and heart tissue. In diabetes an accumulation of fibulin-1 in the arterial wall and in plasma has been described. Plasma fibulin-1 correlated significantly with left atrial volume index and plasma N-terminal pro-B-type natriuretic peptide . On the other hand, a down-regulation of fibulin-1 has been described in atrial fibrillation .
With respect to the above described results from our study and from previously presented investigations we find it reasonable to speculate that in clinical conditions with increased plasma fibulin-1 such as diabetes or chronic kidney disease plasma fibulin-1 may be involved in disease pathways which contribute to thrombotic and cardiovascular complications. Furthermore, plasma fibulin-1 displays a potential as cardiovascular biomarker which awaits further studies.