The reverse remodeling of the aorta in patients after renal transplantation - the value of aortic stiffness index: prospective echocardiographic study

According to Windkessel’s concept [1] arterial system is the vascular network, which allows to modify an intermittent stream of blood outflowing from the heart to a continuous and stable blood flow through smaller vessels and capillaries. Among the many factors affecting the proper functioning of the system, one of the most important seems to be the compliance of the vessel wall, which is able to adapt (flow-dependent changes in diameter, cross sectional area of vessels) in response to changes in the pressure of blood flow [2]. A general term describing the resistance to deformation of the vessel under the influence of blood pressure is stiffness [3, 4].

Number of factors plays the role in the pathogenesis of aortic stiffness. Both physiological ones, which are especially important from a clinical point of view, as well as pathological, resulting from diseases directly or indirectly affecting the cardiovascular system, should be taken into consideration. It has been shown that the elastic properties of the aorta deteriorate with age. Except the age, also sex plays important role, because the process of stiffening of the aorta in women occurs about 10 years later than in men [5, 6]. The aging of the body is a crucial factor leading to reduced elasticity as a result of changes in the structure of collagen and elastin. However, congenital abnormalities of these proteins cannot be excluded, too. The study of Madeley et al. [7] indicates the important role of fibrillin-1 genotype in the pathogenesis of the aortic stiffness.

From the pathophysiological point of view, a common cause of aortic stiffness is undoubtedly atherosclerosis. Furthermore, atherosclerosis is now considered a combination of two major separate diseases: atherosis and sclerosis. Atherosis, developing as a result of the formation of atherosclerotic plaques, is a complicated process, in which inflammation plays a key role and one of the main and most common consequences of this condition is calcification of the plaque. The second element forming part of atherogenesis development is the deterioration of the large arteries elastic properties, which is defined as stiffness. Also crucial importance of metabolic factors like diabetes or end-stage renal disease (ESRD) should be mentioned [8].

In patients with ESRD aortic stiffness is increased [9]. Also renal function was described as a determinant of arterial stiffness despite of presence or absence of concomitant coronary artery disease [10]. In histological evaluation of arteries obtained from uraemic patients, some signs of fibroelastic intimal thickening, elastic lamellae calcification, and ground substance deposition were shown [11]. Regardless of the described morphological changes, there was proved, that in patients with ESRD, vascular endothelial function associated with the accumulation in the plasma of natural nitric oxide synthase (NOS) inhibitors, such as asymmetric dimethylarginine (ADMA) is seriously impaired [12]. These data suggest that ADMA seems to be a potential mediator linking the uremic milieu with the endothelial dysfunction underlying the increased arterial stiffness in patients with ESRD. Indeed ADMA as the endogenous NOS inhibitor accumulates in time of renal function deterioration [13].

Aortic stiffness affects the function of conducting through the aorta elevated blood pressure and changes the pressure curve, thus increasing the left ventricle (LV) afterload. This causes left ventricle hypertrophy (LVH) and also adversely modifies its diastolic and systolic function. Thickened LV becomes particularly sensitive to ischemia and both of these abnormalities increase the heterogeneity of the electrical activity of the heart [14].

This is a small-scale progressive study using current echocardiographic methodology. Forty two patients, aged 43.3 ± 12.6 years, including 19 women aged 49.9 ± 10.9 years and 23 men aged 41.5 ± 12.91 years were enrolled to the study group. All patients have undergone RT from unrelated donors because of ESRD. In every patient examined in the study, the arteriovenous fistula was closed. Reasons for ESRD in the study group included: glomerulonephritis, diabetes mellitus, polycystic kidney degeneration, hypertensive nephrosclerosis, chronic tubulointerstitial nephritis and other unspecified causes (Fig. 1). Exclusion criteria were: heart failure, manifest coronary artery disease, patent arterio-venous fistula and unstable graft function at any time during the follow-up. To ensure that only ESRD related causes of aortic dysfunction were assessed, patients with mild to severe aortic valve disease on echocardiography were excluded from the study. All patients were treated with the immunosuppresion regimen, which included methylprednisolone, mycophenolate mofetil and cyclosporine microemulsion or tacrolimus (Table 1). Treatment prior to RT are shown in Table 1.

In all patients a detailed medical history and physical examination were carried out. The following clinical parameters were evaluated: age, sex, duration of dialysis treatment to RT.

The study protocol consisted of 5 stages:

During the subsequent phases the following measurements were performed:

Phase I:

Then, on the basis of the above listed planimetric measurements the functional indices of the aorta have been calculated [3, 19]:

Based on planimetric parameters, indices of LV structure and function have been calculated as follows [21, 22]:

The conducted comparative assessment of the planimetric parameters of the LV showed a reduction of its dimensions during the 3-years follow-up, with a significant reduction of LVEDd, LVESd, LVEDV and LVESV noticeable already in the short term, after the first three months of observation. Similarly, the indices characterizing LVM also have been considerably reduced, but the time necessary for the existence of these changes was, as proven, much longer. The greatest reduction in LVM and LVMI was observed between measurement performed 1 year after RT and in the final phase of follow-up.

In the current study, during the 3-years after RT, LVMI decreased from 173.9 ± 38.6 g/m² to 149.3 ± 33.0 g/m². These results are similar to those outlined by Parffrey et al. [25], who found in patients after transplantation LVH reduction of this parameter from 166 g/m² to 135 g/m². Decreased LVM was accompanied by a reduction in its dimensions, that was reflected by a significant reduction LVEDV of LVEDV from 116 ml/m² to 89 ml/m². Montanaro et al. [26] in study conducted admittedly in a small, because consisting of 23 individuals, group of patients, demonstrated a reduction of LVMI from 161.4 g/m² to 122.1 g/m² after the 2-year follow-up. The recruitment to achieve the observed positive changes, however, is not only to perform the transplant, but also to maintain the adequate function of the transplanted organ. Indeed, Ferreira et al. [27] have shown that both, dimensions LV and LVM, decreased only in those patients after RT, in which the function of the transplanted organ was correct, what was manifested, on the one hand, as normalization of serum creatinine, and on the other as the normalization of blood pressure. In patients with poor-controlled mentioned above parameters, favorable reverse LV remodeling do not occur. Reduction of LVM, together with a reduction in planimetric and volumetric parameters of LV carries important prognostic information. This was proven by Sharma et al. [28], who underlined the fact, that LVESd and the maximum thickness of the LV wall, subsequent to the calcification of the mitral annulus, are independent predictors of survival after RT. They postulate to consider the recommendation of these echocardiographic parameters as standard prognostic factors used in assessing the risk of mortality in patients after RT.

Historically, LV systolic dysfunction was regarded as the limitation for the selection of patients appropriate for RT. That was probably the reason that observed in the study group parameters of LV systolic function were normal. However, initially normal EF and FS increased after 3 years and the improvement of these parameters, although seemingly little in absolute terms, was statistically significant. The data from the literature suggest that the greatest benefit of RT in relation to the LV systolic function refers to patients with very impaired contractility. Melchior et al. [29] investigated a group of 29 patients with low EF and showed an increase of the average EF from 37.8% to the value of almost normal, as much as 52% over the short, because only 1-month follow-up. Further observation showed further improvements in contractility, because after a year of follow-up EF was already 58.2%. Other studies conducted by Wali et al. [30] confirmed the beneficial effect of RT on LV systolic function. During the 6-month follow-up investigators showed an increase in EF from 31.6% to 47.2%, and over the next six months less dynamic growth of EF to 52.2% were noted. Improvement of contractile function was accompanied by a significant improvement in functional capacity expressed by a reduction in NYHA class. Other studies, as well as the presented research, indicate the growth of FS. Parfrey et al. [25] reported that RT is associated with an increase in FS from 21.5% to 33.4%. In all of these and most of other available studies the time of follow – up was relatively short and do not exceed a year of observation. In this context, it should be emphasized the importance of the current 3-years follow-up, revealing that in the long term, patients even with normal systolic function after RT could achieve further benefits of this form of treatment.

Indices of aortic function as ASI, AD and AS during the 3-year follow-up improved significantly. It may indicate, that changes occurring after RT allow for at least partial retrieve of the aorta elastic properties. Evaluation of the exact changes in the subsequent stages of the observation proves that the beneficial effect of the final transformation occurs between one year observation and the assessment made at the end of the follow-up after 3 years. This proves that the process of returning elastic properties of the aorta is a long-term phenomenon. Histopathological examination of the arteries performed in patients with ESRD indicates the presence of the process of remodeling, which consists of two main elements: atherosis and sclerosis [31, 32]. The coronary artery disease (CAD), as a form of arteriosclerosis, is particularly associated with increased aortic stiffness. Arteriosclerosis and atherosclerosis share similar pathobiologic processes [3]. Coronary artery calcification is associated with impaired aortic distensibility [33]. Arterial stiffness has long been viewed as a consequence of long-standing hypertension, which is the fixed component of kidney failure. However, recent studies have suggested that arterial stiffness may contribute to the pathogenesis of hypertension [34]. Other comorbidities have a large effect on aortic stiffness. Diabetes mellitus is independently associated with lower aortic distensibility, increased arterial stiffness and impaired flow-mediated dilatation [35]. Less common diseases like, aortic regurgitation, congenital heart disease (bicuspid aortic valve, tetralogy of Fallot), connective tissue disorders (Marfan syndrome, Ehlers-Danlos syndrome), aortic coarctation repair, hypertophic cardiomyopathy, can also cause impairment of aortic elastic properties [3].

From an epidemiological point of view, RT improves cardiovascular prognosis in this group of patients [36]. This improvement appears to be dependent on many factors, among which the recovery of normal glomerular filtration rate (GFR), enabling elimination of uremic toxins [37] as well as better control of cardiovascular risk factors [38] should be mentioned. The elastic properties of the aorta may be affected by a medication taken by patients. Mitchell et al. demonstrated, that long-term trandolapril treatment is associated with reduced aortic stiffness [39]. The angiotensin receptor blockers (sartans) may produce the same effect as ACE inhibitors. Treatment with ibersartan improved arterial compliance, whereas inflammatory and endothelial markers remained unchanged [40]. Additionally, it was proved, that in patients with chronic kidney disease a combination of ACE inhibitor and sartans allows to achieve even greater reduction of arterial stiffness than the treatment with only one of mentioned drugs [41]. Beta-blockers have different, often opposing action on the arterial elastic properties. Nebivolol, which is a selective beta-1 blocker with nitric oxide potentiating vasodilatatory effect, has been shown to slightly decrease the central pressure indices, when compared to atenolol [42]. The calcium channel blocker were evaluated among a large number of studies, where it proved to reduce central blood pressure and arterial stiffness [43]. In patients with CAD and normal blood pressure the treatment with statin provided significant decrease of PWV and improvement of arterial stiffness, what was not observed in patients with CAD and hypertension [44]. But we should not forget that the RT and the associated necessary drug therapy is connected with the new, previously absent factors, potentially adversely affecting the elastic properties of the aorta. Among them essential therapy with cyclosporine, corticosteroids, azathioprine and mycophenolate mofetil should be taken into consideration. These drugs, necessary to maintain the graft, cause hypertension, stimulate LVH and promote metabolic disorders as diabetes or hypercholesterolemia, potentially increasing the stiffness of the aorta.

Consequently, the altered elastic properties of the aorta represent the net, responsible for the disappearance of the old risk factors of aortic stiffness and the appearance and the potency of new ones. The evolution of aortic stiffness after RT is poorly understood. While much is already known about the relationship of ESRD and the pathogenesis of aortic stiffness and its prognostic significance, the issue of potential reverse remodeling of the aorta becomes a recent interest of researchers. Studies provided up to date, were based on the measurement of aorto-femoral pulse rate, which is an admitted method of assessing of arterial stiffness [45]. According to our knowledge, any study regarding aortic stiffness in patients after RT with using the direct serial assessment of aortic functions, as it was done in the present work, has not been carried out, yet. This method has been successfully validated in other clinical applications [3, 46].

Some authors have shown significant improvement in arterial elasticity [47], while in other studies, no improvement of the flexibility of vessels after RT has been observed [48]. Bachelet-Rousseau et al. [49] did not show a significant reduction in arterial stiffness after RT. Similarly, in the study provided by Zoungas et al. [48], evaluating 36 patients after RT, there were no improvement of elastic properties of the aorta, however, mentioned authors demonstrated a significant reduction of the femoral artery stiffness. All of these studies were provided in the relatively short, because the period of observation did not exceeding one year. In these conditions currently obtained data are even more valuable. Extending the time of patients monitoring, allows to notice, that a phenomenon of favorable remodeling of the aorta is possible, and to indicate that for the assessment of the available test methods quite a long time is required. In accordance with the results of the current study are the data presented by de Lima et al. [50]. In the group of 32 patients after RT followed for a relatively long time, lasting 40 months, cited above authors showed an improvement of indirect indices related to the stiffness of the aorta such as LVH and carotid arterial compliance and remodeling of the thickened at the baseline intima-media complex of the carotid artery. Although the present study indicate changes in the elastic properties of the arteries, beneficial in the long-term period, it cannot be expected to complete their restitution to the level observed in healthy subjects [51]. This depends in part on the irreversible changes, and partly on the appearance of previously mentioned, new immunosuppressive treatment-related factors, adversely modifying elastic properties of the aorta. The efficiency of the transplanted organ and the presence of subclinical inflammation features is also not without significance [51].

Aortic stiffness is also in direct connection with the rejection of the graft. In the study provided by Bahous et al. [52] it was demonstrated that the transplanted organ injury long time after the RT increases the stiffness of the aorta. This relationship occurs is a time-dependent menner and it does not depend on such factors as age, mean arterial pressure, atherosclerosis coexistence, drug therapy and even the presence of the recipient’s own kidneys. It is also not clear, whether these beneficial changes of the aorta elastic properties are at least partially dependent on decreasing, as far as the observation period extends, blood pressure. In the present study, a decrease in systolic blood pressure was observed over almost all of the observation periods. In contrast, the value of the pulse pressure evaluated at the beginning of the study, was significantly reduced after a year of the observation. Taking into consideration that the method of the calculation of the aorta elastic properties indicators includes both, the size of the aorta as well as blood pressure and pulse pressure, it can not to be excluded that the observed changes are not solely dependent on the regression changes or reverse remodeling of the aortic wall. On the other hand, it is well known, that the stiffness of the aorta and blood pressure are in mutual feedback [53]. This relationship concerns, on the one hand, the pathogenic mechanisms, resulting from elevated blood pressure, which stimulate the stiffening of the aorta. On the other hand, stiff aorta is the main cause of generating the higher blood pressure, particularly in mean arterial pressure and pulse pressure. This concept is supported by research provided by Bachelet-Rousseau et al. [49]. The authors although, as mentioned above, did not show during the annual observation a significant improvement in the elastic properties of the arteries, found a significant decrease of both diastolic and mean pressure. This allowed the authors to put forward suggestion, that perhaps the longer observation of patients would bring an answer, how the improving indices directly reflect the severity of the phenomenon of arterial stiffness.

Based on currently obtained results and approachable published data, it can be stated that the RT is a highly effective method of treatment, which allows to reverse the adverse structural and functional changes associated with ESRD and renal replacement therapy.

There is a relationship between renal transplantation and improvement of the aortic elastic properties. Withdrawal of renal insufficiency allows to initiate the reparative processes leading to at least partial restitution of structure and function of the aorta, which is called reverse remodelling. Improvement of aortic elastic properties after renal transplantation is a continuous and prolonged process.