The present study evaluated different parameters of vascular dynamics in patients with non-dialytic CKD and demonstrated some important results.
First, patients in stage 3 CKD had higher values of PWV, PP, and Aix compared to the controls, despite similar BP values between the groups. Central arterial stiffness is one of the best biomarkers to stratify the risk of CVD in patients with end stage renal disease (ESRD), especially those who require dialysis. 10,11,31 Other studies have also demonstrated increased arterial stiffness even in patients with incipient kidney damage. 32–34 Therefore, increased arterial stiffness may be an important factor in identifying the phenotype of vascular disease present in CKD.
Second, OPG showed weak but significant correlations with peripheral and central BP values, and moderate correlations with PWV, PP, and AIx variables. These findings suggest that increased arterial stiffness in patients with stage 3 CKD (moderate renal dysfunction) is related to early vascular arterial calcification in the middle layer of the vessels. Previous studies demonstrated an independent association between serum OPG and the degree of vascular stiffness, measured by PWV in patients with various stages of CKD.35–38
In the KNOW-CKD study, a strong correlation was found between PWV and age. Moreover, the second most correlated variable with OPV was OPG in a multivariate regression of non-dialysis patients. Hyun et al. also found a positive correlation between OPG and PP levels. Furthermore, they demonstrated that increasing OPG by 1 pmol/L, led to a raised PWV by an average of approximately 17.1 cm/second. 36
OPG was not associated with albuminuria in the present study. However, it is known that albuminuria is a marker of endothelial injury and previous studies have demonstrated a correlation between serum OPG and albuminuria, especially in patients with DM2. 39,40 This association was not detected in this study, possibly because of our small sample size and the pairing of patients with DM, in which the finding of albuminuria is more frequent.
Every 1 pmol/L increase in serum OPG increases the risk of CV death by 4% in patients with CKD.41 The higher the OPG level, the higher the all-cause mortality in patients with CKD stages 3–5. 42,43In our case-control study, it was not possible to assess the direct association of OPG with CVR and mortality. However, this is possibly a good early marker of incipient vascular dysfunction in patients with moderate CKD.
Third, patients in the RD group did not have higher FMD values (p = 0.671) and a correlation with OPG was not detected (p = 0.959). The association between FMD and CKD was seen more prevalently in patients with advanced CKD, DM, and albuminuria, even without the presence of established coronary artery disease.6,44,45 In contrast, in patients with CKD in less advanced stages, studies are limited and the results are controversial. 5,7,45 In the current study, the FMD values were similar between the groups, which suggests that endothelial damage may intensify only in more advanced stages of CKD.
In the Hoorn study, in which the assessment of vascular dysfunction in patients with incipient CKD was performed through the measurement of laboratory biomarkers: Von Willebrand factor, intercellular adhesion molecule-1, and albumin/creatinine ratio, there was an inverse correlation of these markers, and the degree of endothelial dysfunction.7 However, this same association was not repeated in other studies that evaluated endothelial dysfunction by means of FMD in patients with moderate CKD.7,33 Notably, the biomarkers evaluated in the Hoorn study are also markers of hemostasis and thrombosis, and thus, may reflect processes other than endothelial function.
In the study by Iwamoto et al., endothelial dysfunction was found in non-dialytic patients with CKD by means of nitroglycerin-induced vasodilation (NIV), which detects atherosclerosis by assessing the vascular smooth muscle function.45 Our findings, in contrast, corroborate with the findings of The Framingham Heart Study, which also evaluated patients with CKD (stage 3), which showed no significant positive correlation in endothelial dysfunction (assessed by FMD), in individuals with less advanced stages of CKD. 5
A previous study showed that the association of endothelial dysfunction (measured by the FMD) in patients with CKD was more evident in patients who were not taking antihypertensive drugs.46 This is possibly due to the drug actions, affecting the release of nitric oxide and increasing its production or activity, which may contribute to an increase of up to 2 points in the % FMD value.47
OPG is released mainly by osteoblasts and endothelial cells. This molecule may be implicated in the pathophysiology of vascular calcification and endothelial dysfunction in patients with CKD.48 Importantly, few studies have evaluated the association between FMD and OPG in patients with less advanced CKD. Yilmaz et al.49 found an independent association between OPG and FMD, but only 30.6% of patients were on ACEI/ARB, 25% of patients were hypertensive, and the study also included patients in more advanced stages of CKD, which differed from our study population.
FMD may not be an ideal way for detecting very early endothelial changes in patients with CKD. In addition, the pathophysiology of endothelial changes in CKD is not well known and may occur through several different pathways, and not only through the release of nitric oxide. It is also possible that the high CV risk found in these patients even in the early stages of CKD may be related to other pathophysiological mechanisms, such as vascular calcification, inflammation, and arterial stiffness. In the future, further prospective studies to better evaluate the relationship between FMD and various stages of CKD are warranted.
In summary, the findings of this study may be directly related to the pathophysiology of calcification and vascular inflammation in incipient CKD. Intima tunica calcification is more related to lipid deposition and inflammatory infiltration, which would lead to endothelial dysfunction.50 In the tunica media, calcification is more related to the transformation of the vascular smooth muscle cells into osteoblastic-like cells. 16 It is possible that in this stage of CKD, calcification occurs earlier in the tunica media than in the vascular intima, which would explain the higher OPG levels and the significantly higher arterial stiffness among these patients. Atherosclerotic disease increases as the GFR reduces. It is possible that even in patients with incipient renal damage, endothelial dysfunction, and inflammation play an important role in the development of early atherosclerotic disease in these patients.7
The study has several limitations. It is a case-control study conducted in a single center. The sample size was small with a limited number of patients with CKD, mainly representing an older population. Our patients extensive use of antihypertensive medications may have altered the endothelial nitric oxide release and influenced the FMD measurements. Moreover, endothelial dysfunction was assessed using only one biomarker, which may not fully represent the pathophysiology underlying the endothelial alteration in CKD. More longitudinal studies are needed to better understand the correlations among these biomarkers.
In conclusion, we found higher PWV, PP, and Aix values and a moderate correlation between OPG and PWV, PP, and AIx variables among patients with stage 3 CKD. These data corroborate that vascular dysfunction is usually already present in patients with moderate stages of renal dysfunction.