Background

Cardiovascular complications are the main cause of death in adults with stage 5 chronic kidney disease (CKD-5), but those complications undoubtedly start during childhood. Clinical and epidemiological studies have shown that CKD induces structural and functional changes in large arteries, thereby increasing mortality in adult uremic patients [1, 2]. This excessive arterial vulnerability is attributed to increased traditional cardiovascular risk factors, uremic condition, and cardiorenal syndrome (CRS). CRS has been defined as disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other [3].

The first pediatric kidney transplant (KT) was performed over 50 years ago. Morbidity and mortality after KT for CKD-5 remain high, with estimated mortality rates 30 times higher when compared to children without kidney failure. Cardiovascular disease (CD) is, as in adults, the most common cause of death (up to 45%) [4]. The combination of kidney and heart disease, which share common risk factors, is associated with worse prognosis [5]. Those risk factors are considered rare in children but data are scarce [6].

Our institutional practice includes at least one annual transthoracic echocardiography (TTE) in all patients with CKD or KT. In addition to the usual indices, we additionally looked for aortic root dilation. In adults, indeed, aortic root enlargement has shown to be a marker of cardiac and extra-cardiac target organ damage [7]. Subsequent aortic regurgitation [8] and aneurysm formation with rupture are reported [9]. Isolated dilatation of the aorta is on the contrary rare in children. The present study aimed to determine the cardiovascular impact of the uremic condition in a pediatric population with advanced CKD.

Methods

Study design

We retrospectively analyzed all TTE performed between 2016 and 2018 in 39 children with CKD-5, either on kidney replacement therapy (KRT—hemodialysis or peritoneal dialysis) or after KT. Patients with connective tissue disease and congenital heart disease were excluded from the analysis.

Clinical data

Demographic, clinical, biological, and TTE data were collected from medical records. The clinical parameters collected were those recorded on the day of the echocardiography. The biological parameters collected were those performed on the day or within the month of the echocardiography. The Dubois formula was used to estimate the BSA (BSA (m2) = 0.007184 × height (cm)0.725 × weight (kg)0.425) [10]. In order to determine the hypertensive status of each patient, we conducted 24-h ambulatory blood pressure monitoring. Hypertension was defined as BP ≥ 95th percentile adjusted for age, gender, and height, for more than 25% of the ambulatory measurements. Ongoing cardiovascular treatments were collected. The study was approved by the La Timone Children’s Hospital Clinical Investigation Committee.

Echocardiographic data

All measurements were performed with the children resting in the lateral supine position, using an Epic cardiology ultrasound machine (Philips, EPIQ CVx). The most recent study was selected and, if possible, the one performed 1 year earlier. Two TTE could be analyzed for all except 3 patients, for whom only one TTE was available. The measurements performed straightaway at the time of the TTE were used for the analysis and included two-dimensional (2D) and M-mode data acquired according to the recommendations of the European Society of Echocardiography [11].

The left ventricle (LV) mass calculations were made using the following formula: 0.8 × [1.04 × (LVIDd + PWTd + SWTd)3 − (LVIDd)3] + 0.6 and the left ventricular mass index (LVMI) was assessed as LVMI = LVM/m2.7. The aortic annular diameter was measured between the hinge points of the aortic valve leaflets in the left parasternal long-axis view during systole. For sinuses of Valsalva, sinotubular junction, and tubular ascending aorta dimensions, we measured the end-diastolic dimensions from inner edge to inner edge. Z-scores were remotely calculated for every measurement. The Detroit Z-score (Children’s Hospital of Michigan) was used for aortic and ventricular dimensions [12].

Statistical analysis

Continuous variables are expressed as mean or as median values (with ranges), where appropriate. Discrete or binary variables are presented as number (percentage). We divided the population into two groups:

  • Group 1: Dilated ascending aorta, n = 15

  • Group 2: Not dilated ascending aorta, n = 24

We used the χ2 test or Fisher’s exact test (if appropriate) for categorical variables and the Mann-Whitney test for continuous variables to assess influencing factors. The Wilcoxon test was used to determine whether there was statistical evidence that the size of the ascending aorta during follow-up varied significantly.

p values < 0.05 were considered as statistically significant. Kaplan-Meier methods were used to produce the survival curve. All statistics were performed using IBM SPSS Statistics 17.0.

Results

Mean age of our cohort was 9.7 ± 4.6 years. Seventeen (43.6%) patients received peritoneal dialysis and 24 (61.5%) had a history of hemodialysis. Twenty-two of them were transplanted at the end of the study period. Most patients were treated by two or three KRT modalities, as shown in Table 1. The most common causes of CKD were urinary tract malformation, hypoplasia of the kidney, and nephronophthisis (Fig. 1). Eight (20.5%) patients had an AVF and hypertension was present in 27 patients (69.2%). Biological data are detailed in Table 2. Left ventricular hypertrophy (LVH) was found in 13 (33.3%) patients. Dilatation of the ascending aorta (Z-score > 2) was found in 15 (38.4%) patients. Table 3 details the echocardiographic characteristics.

Table 1 Demographic characteristics
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Fig. 1
figure 1

The most common causes of CKD were urinary tract malformation, hypoplasia of the kidney, and nephronophthisis

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Table 2 Biological data
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Table 3 Echocardiographic characteristics
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Patients with dilated ascending aorta (group 1) were compared with those without (group 2). Univariate statistical analysis showed significant associations between dilated ascending aorta and gender, hypertension, the presence of AVF, and the use of hemodialysis (p = 0.024, p = 0.016, p = 0.006, p = 0.009 respectively). The results of the univariate analysis are shown in Table 4.

Table 4 Factors associated with dilated ascending aorta in univariate analysis
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Annual monitoring showed that dilatation of the ascending aorta tends to persist and even increase significantly (p = 0.029) (Table 5, Fig. 2). All hypertensive patients, except one, benefited from successful medical hypertension control during the year of follow-up. In one patient, hypertension remained uncontrolled despite triple therapy.

Table 5 Evolution of Z-scores of ascending aorta during 1-year follow-up (36 patients)
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Fig. 2
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Annual monitoring showed that dilatation of the ascending aorta tends to persist and even increase significantly

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Discussion

This study was conducted to evaluate, retrospectively, the cardiovascular impact of advanced CKD in a pediatric cohort. A high prevalence of dilatation of the ascending aorta was observed in our population. Knowledge regarding CD in CKD-5 patients mainly comes from adult studies describing atherosclerotic heart disease as the main cause of morbidity and mortality. Atherosclerosis is however very rare in younger patients. Recent papers focus on LVH [13], LV diastolic dysfunction [14], and increased carotid intima-media thickening [15] but dilatation of the ascending aorta in young CKD-5 patients has rarely been described.

Cardiac remodeling

The prevalence of LVH is high, as expected, in our cohort. Ventricular remodeling refers to changes in the size, shape, structure, and function of the heart. It can be physiological (as a result of exercise) and reversible or pathological and irreversible. In adults, ventricular remodeling typically occurs after acute myocardial infarction, at distance from the acute event. A series of histopathological and structural changes occur in the left ventricular myocardium, with cardiomyocytes being the major cells involved in the remodeling process. In children, where myocardial infarction is rare, other forms of strain including pressure and volume overload may lead to cardiac remodeling. In CKD children, chronic hypertension and reduced vessel compliance increase afterload while salt and fluid load, anemia, and intravascular volume expansion increase preload [16, 17]. Finally, CKD patients accumulate related factors with synergistic effects. The cardiorenal syndrome could then encompass concomitant cardiovascular and kidney disorders that result from systemic diseases with their related neurohormonal, inflammatory, immunologic, and fibrotic consequences [18]. This fibrogenic response may lead to parenchymal scarring, cellular dysfunction, and cardiac remodeling.

Aortic dilatation

The association between the dilated ascending aorta and kidney failure is rarely described in young patients. One of the reasons for this might be the fact that aortic root measurements are not routinely performed in those settings. Paris et al. found that aortic root dimensions were higher in hypertensive CKD children when compared to primary hypertensive ones, but they excluded patients with CKD-5 [19]. Kaddourah et al. found that out of 78 patients on KRT and 19 KT recipients, 30 patients (30.9%) had aortic dilatation [20]. Our cohort is characterized by a high prevalence of ascending aorta dilatation. Hypertension, the presence of AVF, and hemodialysis were associated with dilated ascending aorta. Except for hypertension [21], those associations have not been described in the adult population. Our hypothesis is that this is a pediatric peculiarity, which may be linked to the high flexibility of younger vessels compared to the adult population. Nayir et al. reported histopathological findings of internal iliac artery samples obtained at the time of kidney transplantation in 12 children [22]. The authors showed that 5 of the 12 arteries had evidence of atherosclerosis or arteriosclerotic lesions, including fibrous or fibroelastic intimal thickening, disruption of the internal elastic lamella, and atheromatous plaques. This evidence of early arterial damage and especially disruption of the internal elastic lamella could explain the distention of the ascending aorta. Increased preload and hypervolemia might be responsible for the dilatation of the aorta as observed in some pediatric congenital diseases. Other factors such as the uremic condition might be involved. Abnormal mineral metabolism (high phosphorus, calcium-phosphorus product, and PTH) has been identified as the major predictor of vascular changes in children on KRT and a recent study suggests that both low and high levels of 1.25-dihydroxyvitamin D are associated with high carotid intima-media thickness (cIMT) [23]. This hypothesis is supported by the fact that KT, while improving uremia-related risk factors, increases life expectancy when compared with long-term KRT [24]. While hypertension has already been described as a risk factor for ascending aorta dilation in adults [14, 23] and children [8], it remains however unanswered whether aggressive antihypertensive treatment (including beta-blockers) slows down the progression of ascending aorta dilation in children.

In this study, we measured the sinuses of Valsalva, the sinotubular junction, and the tubular ascending aorta. Sinuses of Valsalva and sinotubular junction were not significantly dilated. Similar findings have been described in hypertensive adults [25].

Study limitations

This study has several limitations. Only 39 patients were analyzed. This small sample size was insufficient to yield statistically significant results for some parameters (CKD etiologies and some biological parameters). Secondly, the impact of medication and blood pressure control was not fully analyzed because of the retrospective character of the study and the short follow-up (1 year). A long-term observational cohort is needed to study cardiac and vascular changes and analyze the impact of treatments, especially beta-blockers. It is of note that the inter-operator variability of the TTE analysis was not considered, as the same practitioner did all the measurements.

Conclusion

Our analysis shows that dilatation of the ascending aorta is a common phenomenon in children with advanced CKD, in the presence of hypertension, AVF, and in those who are on hemodialysis. The exact mechanisms of this aortic root dilatation have yet not been determined. We hypothesize the interaction between CKD-specific hemodynamics and hormonal conditions. Children with advanced CKD could potentially benefit from aggressive therapy to prevent and treat CD.