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NDT Advance Access originally published online on March 22, 2006
Nephrology Dialysis Transplantation 2006 21(7):1906-1914; doi:10.1093/ndt/gfl098
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© The Author [2006]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Original Articles: Dialysis and Transplantation

Arterial and cardiac disease in young adults with childhood-onset end-stage renal disease—impact of calcium and vitamin D therapy

Sonia Briese1, Sandra Wiesner1, Joachim C. Will2, Alexander Lembcke3, Bernd Opgen-Rhein2, Richard Nissel1, Klaus-Dieter Wernecke4, Judit Andreae1, Dieter Haffner1,5 and Uwe Querfeld1,5

1 Department of Pediatric Nephrology, 2 Department of Pediatric Cardiology, 3 Department of Radiology, 4 Department of Medical Biostatistics, Charité Universitätsmedizin and 5 Center for Cardiovascular Research, Charité Universitätsmedizin, Berlin, Germany

Correspondence and offprint requests to: Uwe Querfeld, MD, Department of Pediatric Nephrology, Charité Universitätsmedizin, Berlin, Augustenburger Platz 1, 13353 Berlin, Germany. Email: uwe.querfeld{at}charite.de



   Abstract
Top
 Abstract
Introduction
 Patients
 Methods
 Results
 Discussion
 Historical note
 References
 
Background. Studies in patients with childhood-onset end-stage renal disease (ESRD) provide a diagnostic window to the evolution of cardiovascular disease (CVD) in this population. Hyperphosphataemia and renal osteodystrophy are particularly difficult to treat in paediatric patients, but there is only limited information regarding the effect of calcium-containing phosphate binders and vitamin D preparations on the development of CVD in the young.

Methods. We studied 40 adult patients (mean age 23.6 years) who developed ESRD at the age of 11.5± 4 years and 40 matched healthy control subjects. Nine patients were on dialysis and 31 had a functioning kidney transplant. Measurements included intima-media thickness (IMT) of the common carotid artery, electron beam computed tomography (EBCT) for the detection of coronary artery calcifications (CAC), echocardiography and post-ischaemic arterial blood flow by venous occlusion plethysmography. Patient characteristics, atherosclerotic risk factors and a complete account of prescribed medications were analysed for correlations with arterial and cardiac changes.

Results. The IMT was not significantly different in patients and controls; four patients (10%) had coronary calcifications on EBCT. Twenty-five patients (62.5%) had left ventricular hypertrophy. Patients had a 40% reduction of post-ischaemic arterial flow. Morphological alterations of the heart and arteries were significantly correlated with the duration of ESRD and dialysis time, and with the cumulative intake of calcium-containing phosphate binders and active vitamin D preparations. Functional changes (vascular reactivity) were correlated with duration of ESRD and non-traditional risk factors.

Conclusions. Young adults with ESRD since childhood have systemic CVD characterized by a decrease in arterial elasticity, the occurrence of CAC and changes in left ventricular morphology. Treatment with calcium-containing phosphate binders and active vitamin D preparations is independently associated in a dose-dependent manner with surrogate markers for CVD.

Keywords: atherosclerosis; calcium; calcifications; children; end-stage renal disease; vitamin D



   Introduction
Top
 Abstract
 Introduction
Patients
 Methods
 Results
 Discussion
 Historical note
 References
 
Children and adolescents with end-stage renal disease (ESRD) have a good chance for long-term survival because of the advances of renal replacement therapy (RRT) during the last decades [1]. Today, survival is limited mainly by the manifestations of cardiovascular disease (CVD), and the relative risk is highest in the young [2]. Young adults with childhood-onset ESRD are a unique population harbouring CVD [3]; while the analysis of risk factors in elderly patients may be obscured by comorbid conditions such as diabetes or pre-existing atherosclerosis, studies in young patients may provide a diagnostic window to the evolution of CVD in uraemia.

Previous studies in children and young adults with childhood-onset ESRD have not only shown a high prevalence of left ventricular hypertrophy and dysfunction [4], but also of coronary artery calcifications (CAC) [5,6]. Importantly, CAC have been found associated with disturbances of calcium and phosphorus metabolism in ESRD and their management, such as elevations of the serum calcium x phosphorus (CaxP) product [7], the intake of calcium-containing phosphate binders [5,8], and treatment with active vitamin D preparations [9]. Hyperphosphataemia and renal osteodystrophy are particularly difficult to treat in paediatric patients with ESRD; children require comparatively higher doses of phosphate binders and frequently, active vitamin D preparations [10]. Use of these medications may lead to prolonged exposure to a high serum calcium–phosphate product and is indeed often complicated by hypercalcaemia [11]. Inspite of growing concerns regarding the long-term implications, there is yet limited evidence whether the cumulative doses of phosphate binders and/or vitamin D derivates could promote systemic cardiac and arterial disease in these patients. In addition, since mortality from CVD continues to be high after successful renal transplantation, immunosuppressive drugs might also increase the risk of CVD.

We have studied the impact of medication on the evolution of CVD in uraemia by measuring surrogate endpoints of CVD in young adults. Several non-invasive measurements have been validated to predict survival in adult ESRD patients, including carotid artery intima-media thickness (IMT) [12,13], left ventricular hypertrophy [14,15], arterial calcifications [16] and post-ischaemic reactive blood flow [17]. We performed a case-control study of these surrogate endpoints in a population of young adults who had been treated with RRT in a single institution, carefully analysing patient records for a complete account of prescribed medications.



   Patients
Top
 Abstract
 Introduction
 Patients
Methods
 Results
 Discussion
 Historical note
 References
 
All the patients who were treated with any form of RRT before the age of 18 at our institution and who were older than 18 years of age (on 1 January 2004) were eligible for the study.

A total of 280 patients, born between 1964 and 1985, could be identified from hospital records. Of these, 90 were lost to follow-up and of the remaining 190, 66 had died (24%). Cardiovascular events were responsible for 35% of the deaths, 43% were related to other causes and 21% were of unknown cause. The median survival was 30.6 years. A total of 40 patients participated in the study (Table 1). All patient records were reviewed and the duration of ESRD (defined by the first day of dialysis or transplantation, respectively) and of treatment with dialysis and transplantation was calculated. Patients had started treatment between 1972 and 1996. At the time of study, seven were on haemodialysis, two on peritoneal dialysis and 31 had a functioning transplant. No patient was diabetic; three patients had undergone subtotal parathyroidectomy.


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  		Table 1. Clinical and biochemical characteristics and medication

 
The prescribed doses of phosphate binders, vitamin D preparations and immunosuppressants were used for analysis at monthly intervals.

All examinations were performed on day one according to a protocol that included a standardized interview, physical examination and anthropometric measurements, blood drawing in the fasting state and the performance of imaging procedures as described.

Forty healthy volunteers served as controls. For ethical reasons, published normal data served as control for the CAC scores on electron beam computed tomography (EBCT). Echocardiographic measurements were compared with standard published reference values obtained in 2036 healthy German subjects [18].

The institutional Ethics Committee approved the study protocol, and all participants gave written informed consent prior to study.



   Methods
Top
 Abstract
 Introduction
 Patients
 Methods
Results
 Discussion
 Historical note
 References
 
IMT
IMT measurements were performed with a EUB-525 Duplex ultrasound scanner (Hitachi) equipped with a 12 MHz linear array transducer by one of the researchers (S.B.) as described [19]. The mean of four measurements performed on both carotid arteries was used for analysis.

EBCT
All the patients were examined for the presence of CAC on an electron beam CT scanner (Evolution C-150 XP, software version 12.4/GE Imatron, San Francisco, CA) in a supine position at 625 mA and 130 kV, according to a standardized protocol as described [20,21].

Echocardiography
Two-dimensional M-Mode measurements and Doppler studies were performed and standard M-Mode parameters were obtained [22]. Left ventricular mass (LVM) was measured using the Penn convention [23]. Relative wall thickness (RWT) was measured as described [24]. Using LVM index (LVMI) for body surface area (BSA) and RWT, different patterns of left ventricular geometry were distinguished. Elevated RWT and increased LVMI was identified as concentric hypertrophy, normal RWT and increased the LVMI as eccentric hypertrophy, and normal LVMI and elevated RWT as concentric remodelling.

Diastolic cardiac function analysis of E/A Doppler measurements via the mitral valve was performed and the isovolumetric relaxation time (IVRT) was measured as described elsewhere [25,26]. Left ventricular systolic dysfunction was defined as a shortening fraction <28% and diastolic dysfunction was defined as E/A ratio <1.0 and/or IVRT ≥85 ms. With respect to aortic parameters, any calcification seen or Doppler flow >1.9 m/s or aortic regurgitation (judged by colour Doppler flow>grade 0) was considered abnormal.

Venous occlusion plethysmography
Blood flow was measured on both the lower legs. Subjects were lying with legs and ankles above the heart level, supported by foam blocks. A pneumatic occlusion cuff was placed around each upper leg and connected with an automatic inflator (Compactus; Gutmann-Medizinelektronik, Germany). Mercury strain gauges were placed on the largest part of the lower legs distal to the knee. After calibration, venous occlusion was achieved by cuff inflation to 60 mmHg for the measurement of baseline blood flow (LBF, expressed in ml/100 ml/min). After inflating the occlusion cuffs to at least 50 mmHg above the systolic pressure (or 180 mmHg) for a period of 5 min, reactive hyperaemic blood flow was measured every 10 s for 1 min. The post-ischaemic peak flow (PIPF) was defined as the highest flow (percent increase of LBF) measured during this period. The total post-ischaemic flow during this period (TPIF; percent multiplied by seconds) was defined as the area under the plethysmography curve (AUC).

Laboratory methods
Blood was drawn in the fasting state and serum biochemistry was performed with routine laboratory techniques for calcium, phosphorus, albumin, high-sensitivity C-reactive protein (CRP), total serum homocystein (tHcy), parathyroid hormone (PTH), apolipoprotein (apo A-I) and lipoprotein (a)[Lp(a)]. Cholesterol and triglycerides were measured in whole plasma and in lipoprotein fractions after separating VLDL and HDL/LDL-fraction by ultracentrifugation. Cholesterol in the HDL-fraction was measured after microprecipitation of apolipoprotein B containing lipoproteins (LDL). Cholesterol in the LDL-fraction was calculated (HDL/LDL-fraction – HDL-fraction).

The conjugated dienes (CD) were quantified by the method of Ahotupa et al. [27]. To measure the CD in VLDL and LDL, lipoproteins were separated by ultracentrifugation.

For the quantitative measurement of oxidized LDL (oxLDL), a commercially available ELISA (Mercodia AB, Uppsala/Sweden) was used.

Statistical analysis
Results were expressed as mean value±SD. Because of the limited sample sizes and/or non-symmetrically distributed observations, differences between patients and controls were analysed using the non-parametric Mann–Whitney U-test and the exact U-test comparing patients with and without calcifications, respectively. Spearman's rank correlation coefficients were calculated for univariate correlations. The obtained P-values are to be understood as exploratory ones, therefore no multiple adjustments were made. Multiple linear regression analysis was used to evaluate the contribution of measured variables to the outcome variables of interest, i.e. IMT, PIPF and LVMI. Because of the large number of independent variables, these were grouped in three categories (A–C) and tested in separate blocks for relationships with the outcome variables (inclusion model). Those variables remaining significant in blocks A–C were again tested in a multiple linear regression model by stepwise analysis. P-values <0.05 were considered significant. The SPSS version 12 software program was used for all statistical calculations.



   Results
Top
 Abstract
 Introduction
 Patients
 Methods
 Results
Discussion
 Historical note
 References
 
Patient characteristics and medication
Clinical characteristics and the results of laboratory examinations, are given in Table 1.

The cumulative intake of calcium-containing drugs, vitamin D preparations and immunosuppressive medication is given in Table 2. The mean annual elemental calcium load was 0.1±0.15 kg/year (range 0–0.65) during the total ESRD period, and 0.61±0.77 kg/year (range 0–3.44) during the dialysis period. The prescribed mean annual calcitriol intake for the ERSD period was 36.6±39.6 µg/year (range 0–183.8) and during the dialysis period, 434±1232 µg/year. The respective values for active vitamin D preparations (calcitriol and alphacalcidol) combined were 37.6±39.7 µg/year for the total ESRD period and 444.8±1248 µg/year for the dialysis period. Table 2 lists the doses of these medications for the total time of treatment.


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  		Table 2. Medication*

 
EBCT
Thirty-three patients had no calcifications on the EBCT examination (Agatston score 0), three patients had scores between 1 and 10, and four patients (10%) had scores >100 (range 133–2105), indicating moderate to severe CAC [20]. None of the patients with CAC (Table 3) had undergone parathyroidectomy. No calcifications of the cardiac valves were observed on EBCT.


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  		Table 3. Significant differences between patients with vs without coronary calcifications on EBCT

 
IMT
Mean IMT of dialysis patients was 0.60 mm and of transplanted patients, 0.57 mm and not different from controls (0.55 mm; range 0.4–0.68). The mean IMT in all patients (n = 40) was 0.578 mm (range 0.45–0.8) and not significantly different from controls (P = 0.092). Plaques could not be demonstrated in any subject.

IMT in the patients showed significant correlations with several variables (Table 4). Only the total calcium intake from medication (cumulative and yearly dose), and the intake of cholecalciferol and corticosteroids remained significant in the final multivariate regression model (Table 6).


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  		Table 4. Spearman's correlation analysis

 

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  		Table 6. Multivariate linear regression models for surrogate endpoints

 

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  		Table 5. Echocardiographic measurements in male and female patients

 
Venous occlusion plethysmography
The plethysmography studies showed distinctive differences between patients and controls, with a significant decrease of post-ischaemic blood flow in the patients at all time points. The mean PIPF was 726% of baseline flow (range 287–2010) in patients and 1200% (range 471–3013) in controls and the mean TPIF was 1704 (range 545–4103) in patients and 2856 (range 1293–7167) in controls. Thus, both the PIPF and TPIF were decreased by a mean of 39.5 and 40.3%, respectively, as compared with controls (P<0.0001). PIPF and TPIF were significantly correlated with non-traditional risk factors (Table 4); however, only the duration of therapy remained significant in the final multivariate regression model (Table 6).

Echocardiography
The results of the echocardiographic examinations are shown in Table 5. Left ventricular hypertrophy (LVH) was present in 25 patients (62.5%), with different patterns of remodelling (Figure 1). Left ventricular diastolic dysfunction was present in 22.5% of the population and systolic function was normal in all but one patient.


Figure 1
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  		Fig. 1. Echocardiography: ventricular geometric adaptation and patterns of ventricular remodelling. (A) Diagram divided into four fields by the upper 95% confidence limits of the LVMI and of relative wall thickness [24]. The four fields correspond to different patterns of left ventricular geometry: normal left ventricle (bottom left), concentric remodelling (top left), concentric hypertrophy (top right) and eccentric hypertrophy (bottom right). (B) Patterns of adaptation (%) in 40 patients.

 

Figure 2
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  		Fig. 2. Venous occlusion plethysmography was performed on both lower legs as described. (A) Box plots of measurements of post-ischaemic blood flow in the right leg. Time period (1–5) corresponding to 10 s intervals after release of the cuff. Patients and controls showed significant differences in blood flow at all time points (P = 0.0001). (B) Mean post-ischaemic blood flow curves, constructed from original data (plot A). Height (P = 0.00003) and slope (P = 0.0021) of the curves show significant differences in patients and control.

 
The LVMI was positively correlated with several patient-related variables as well as the cumulative intake of calcium and active vitamin D preparations (Table 4). In the multivariate regression analysis (Table 6), only the PTH serum level and the intake of calcium and vitamin D preparations remained as independent variables. No patient had detectable valve calcifications. All patients with coronary calcifications on EBCT showed LVH, but had different remodelling patterns.



   Discussion
Top
 Abstract
 Introduction
 Patients
 Methods
 Results
 Discussion
Historical note
 References
 
This study shows that young adults with childhood-onset ESRD have systemic CVD characterized by a profound decrease in post-ischaemic vascular reactivity, the occurrence of CAC and changes in left ventricular morphology. It is likely that these alterations represent an early stage in the development of uraemic arterial and cardiac disease.

The IMT is a validated surrogate parameter for atherosclerotic complications in the adult population [28]. No significant increase in IMT could be detected, in contrast to previous studies in young patients with ESRD [29,30]. Since IMT was correlated with the cumulative time of dialysis treatment in both studies, a possible explanation is the shorter duration of dialysis treatment in our patients. Indeed, cumulative treatment time on dialysis emerged as the only significant variable in a multiple stepwise regression model in our study. No significant increase in IMT was similarly found in a nationwide study of young adults with childhood-onset ESRD in Holland with a mean dialysis treatment time of 4.5 years [31]. Most of our patients had a functioning transplant which may be associated with partial reversibility of the carotid arteriopathy [30]. Therefore, dialysis times and/or other differences in risk factor load may be involved, but these data could also indicate that our patients had generally less advanced changes in arterial morphology; this impression is supported by the finding of a much lower prevalence of calcifications.

In view of the high prevalence of CAC in previous studies in young adults [5,29,32] one might have predicted a prevalence of 50% (or more) in our patients; however, only 10% had CAC. In addition, there was a lack of valve calcifications, whereas in a population-based study of 140 young adults with childhood-onset ESRD, these were found in 19% [4].

In our study, patients with CAC were older, had longer treatment times with dialysis and a 2–3-fold higher intake of calcium and of active vitamin D metabolites than patients without CAC. In the study by Goodman et al. [5], the amount of calcium (contained in phosphate binders) prescribed in the 6 months prior to study was almost twice as high in patients with calcifications than in those without. While these findings are similar to ours, they may not reflect the cumulative doses prescribed during total time of treatment.

In the only other study reporting cumulative drug exposure in a similar population of young adults treated in Heidelberg, Oh et al. [29] found a prevalence of CAC of 92%. Our patients were slightly younger (23 vs 27 years) and had a shorter duration of dialysis and ESRD, which could in part explain the difference in CAC prevalence. However, there were dramatic differences in the amount of prescribed calcium-containing phosphate binders and vitamin D preparations, which was 8-fold and 30-fold higher, respectively, in the Heidelberg patients. Both the duration of CKD (18–19 years) and of ESRD (12–15 years) were longer in these patients, but they still received considerably more calcium-containing phosphate binders and calcitriol if medication was calculated per total treatment time or per year of dialysis; this likely reflects differences in treatment regimens.

It should be noted that patients in Berlin could not be regularly monitored for calcium, phosphorus and PTH levels because of economic reasons, resulting in a more ‘permissive’ approach to the treatment of renal osteodystrophy. We cannot exclude that the use of aluminium-containing preparations was higher in the Berlin patients, thus contributing to the difference in the use of calcium-containing phosphate binders, since no such data were given in the study by Oh et al. [29]. Moreover, both the use of phosphate binders and vitamin D could largely reflect PTH levels and therefore, we cannot rule out that the degree of renal osteodystrophy was different in these populations. Taken together, the data from both studies likely illustrate the same issue, i.e. treatment of secondary hyperparathyroidism; they indicate that besides duration of ESRD and dialysis, CAC in young adults are related to the amount of calcium and vitamin D preparations given during this period.

In our patients, post-ischaemic flow in the lower legs was significantly decreased. This may be primarily due to endothelial dysfunction, since markers of oxidative stress, inflammation and tHcy levels showed significant univariate associations; these factors are known to interfere with endothelial function [33]. However, duration of ESRD remained the only significant variable in a stepwise regression model.

Besides endothelial dysfunction, a reduced vascular reactivity in patients with CKD may also be due to arterial remodelling. Recent animal studies have confirmed the presence of such remodelling in resistance arteries of uraemic rats in the absence of increased myogenic tone [34] or arterial hypertrophy [35]. Furthermore, post-ischaemic flow could be affected by capillary disease, i.e. the additional presence of a micro-angiopathy [36,37].

The LVH is found early in the course of renal failure and progresses with further impairment of renal function [38,39]. While the LVMI is an independent predictor of survival in adults with ESRD [15], left ventricular geometry seems of prognostic importance [40] and may influence the response to therapeutic attempts [41].

Only 25% of the patients had normal left ventricular geometry; changes in ventricular geometry were not uniform and the small number of patients precluded a subgroup analysis. In a study reporting echocardiographic data in a similar population, the prevalence of LVH was 47% in males and 39% in females [4]. In the present study, the cumulative intake of calcium and vitamin D preparations, as well as the PTH level at the time of investigation were independent predictors of LVMI in a multivariate regression analysis.

Previous studies have shown an increased risk for CAC progression during therapy with calcium-containing phosphate binders [5,8]. In the present study, calcium intake was higher in patients with CAC and correlated with IMT and LVMI, pointing to the systemic nature of calcium overload [42], which probably induces conduit artery remodelling leading to an increased ventricular work load. These data support the notion that calcium overload is associated with arterial calcifications and stiffness of conduit arteries [43], as well as LVH [39].

Concomitant treatment with vitamin D preparations increases intestinal calcium and phosphorus absorption. Autopsy data in children with ESRD (age 10–13 years) suggest that active vitamin D metabolites may significantly contribute to vascular and tissue calcifications [9]. In the present study, intake of active vitamin D preparations was associated with CAC and independently correlated with LVMI suggesting that active vitamin D metabolites could promote arterial calcifications and ventricular remodelling by direct effects, i.e. independent of the calcium load. In vitro, 1,25(OH)2D3 increases expression of alkaline phosphatase, an enzyme involved in osteogenesis; dose-dependent effects on calcium deposition [44] and migration of smooth muscle cells are further potential mechanisms contributing to vascular remodelling [45]. In vivo, we could show that severe media calcification can be produced by non-hypercalcaemic doses of 1,25(OH)2D3 in uraemic rats [46].

The major limitations of the present study are its retrospective nature and a variable exposure time to ESRD and different forms of RRT (dialysis, transplantation). It is a further limitation of our study that, due to economical constraints, serum biochemistry had not been routinely obtained in many patients. We, therefore, could not retrospectively correlate time-averaged serum concentrations of calcium, phosphorus or PTH, with the surrogate end points measured in this study. Many patients were lost to follow-up and many patients had already died at the time of investigation, resulting in a potentially major selection bias; nevertheless, the median survival of 30.5 years is close to that reported in other studies and CVD was the most frequent single cause of death, confirming previous data from single center studies [29,47] and national registry data [3,48].

In conclusion, in this systematic study of the impact of medication on surrogate end points in young adults with childhood-onset ESRD, patients had evidence of early systemic CVD. In particular, there was a profound decrease in vascular reactivity of resistance arteries, which was associated with the duration of uraemia and non-traditional risk factors for atherosclerosis. Other endpoints showed modest changes; LVH was present in 68.2% and CAC in 10% of patients, and there was no significant increase in IMT. Treatment with calcium-containing phosphate binders and vitamin D metabolites (but not with immunosuppressive drugs) was independently associated with morphological changes (CAC, IMT and LVMI). Thus, the current treatment of renal osteodystrophy in children with calcium-containing phosphate binders and active vitamin D preparations is associated in a dose-dependent manner with surrogate markers for CVD.



   Historical note
Top
 Abstract
 Introduction
 Patients
 Methods
 Results
 Discussion
 Historical note
References
 
Calcium-containing phosphate binders and calcitriol were introduced in the Charité University Hospital (formerly East Germany) in the early 1980s (S. Devaux, personal communication). Previously, patients were mainly treated with aluminium-containing phosphate binders, which were prescribed ‘with meals’ in the form of powder, gels and tablets and in the case of children, as cookies. For this reason, we could calculate the time of treatment, but not quantify aluminium intake. Aluminium-containing preparations were prescribed in 11 patients for 29% of the total treatment time with phosphate binders and for 18% of the total treatment time of all patients combined.



   Acknowledgments
 
We thank Dr C. Budde for helping us in the identification of patients, Prof. E. Mönch for performing the assays for tHcy, and Kerstin Sommer for skilled laboratory assistance in performing lipoprotein analyses and measurements of oxidation parameters.

Conflict of interest statement. The work was sponsored by a grant from Genzyme Europe, BV, Naarden, The Netherlands and by funds dedicated to clinical research by the Charité Universitätsmedizin, Berlin.



   References
Top
 Abstract
 Introduction
 Patients
 Methods
 Results
 Discussion
 Historical note
 References
 

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Received for publication: 21.11.05
Accepted in revised form: 17. 2.06


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