Nephrology Dialysis Transplantation

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Nephrol Dial Transplant (2001) 16: 2041-2047
© 2001 European Renal Association-European Dialysis and Transplant Association

Arterial changes in paediatric haemodialysis patients undergoing renal transplantation

Ahmet Nayir^1,, Ilmay Bilge¹, Iin Kiliçaslan², Haluk Ander³, Sevinç Emre¹ and Aydan irin¹

¹ Departments of Pediatric Nephrology, ² Pathology and ³ Pediatric Urology, Faculty of Medicine, University of Istanbul, Turkey

	Abstract

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Background. The relationship between primary renal disease and arterial wall changes in paediatric haemodialysis patients has been little studied. The aim of the present work was to determine the influence of primary renal disease on arterial wall pathology in uraemic paediatric patients.

Methods. Twelve paediatric haemodialysis patients (seven girls, five boys) aged 11–17 years were included in the study. The primary renal diseases were urinary malformations in six patients (uropathy group) and acquired glomerular diseases (glomerulopathy group) in six patients. Age, sex distribution, duration of chronic renal failure, duration of haemodialysis, blood pressure, serum glucose, triglycerides, cholesterol, fibrinogen, calcium, phosphorus and parathyroid hormone levels were compared. Internal iliac artery samples were obtained at the time of related-donor renal transplantation. Artery samples were fixed in formaldehyde and sections were stained separately with haematoxylin and eosin, Orcein, Verhoef–van Gieson, and Masson trichrome.

Results. Five arteries had fibrous or fibroelastic intimal thickening, medial mucoid ground substance and disruption of the internal elastic lamella. Two of these had microcalcification in the intimal layer; another two demonstrated atheromatous plaques; the remaining five were normal. These pathological changes were found in the arteries of all six patients with uropathy, whereas of the six patients with glomerulopathy only one had arterial changes (P<0.001). The duration of chronic renal failure was 4.8±1.9 years in the uropathy group and 2.2±1.2 in the glomerulopathy group (P<0.05). The two groups were comparable in terms of serum glucose, triglycerides, cholesterol, fibrinogen, calcium, and parathyroid hormone levels, presence of hypertension, sex distribution, and duration of haemodialysis. Plasma phosphorus and the calciumxphosphate product were higher in the uropathy group than in the glomerulopathy group (P<0.05).

Conclusions. This study demonstrated that pathological changes are common in the arteries of uraemic paediatric patients, and that calcification and atherosclerosis are integral to this disease process. In our study, these alterations were more common in the patients with uropathy. We speculate that the patients with uropathy are more prone to these alterations due to slower progression and a longer duration of renal insufficiency.

Keywords: arterial disease; atherogenesis; haemodialysis; hyperparathyroidism; hyperphosphataemia; paediatric

	Introduction

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In adults with chronic renal failure (CRF), cardiovascular disease is responsible for 7.5 to 26% of deaths [1,2]. Arterial disease is also an important factor in uraemic paediatric patients [3,4]. In a limited number of studies, attempts have been made to correlate arterial pathological changes with several of the atherogenic risk factors present in uraemic paediatric patients [5,6]. However, the relationship between the primary disease and arterial wall changes has rarely been studied.

The aim of the present work was to determine the influence of primary renal disease on arterial-wall pathology in paediatric patients on haemodialysis.

	Subject and methods

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Twelve children who had undergone living-related kidney transplantation between 1993 and 1996 in our paediatric nephrology department were included in the study. There were seven girls and five boys with a mean age of 14.6±2.1 years (range 11–17 years) on haemodialysis treatment. The clinical and laboratory characteristics of the patient population are presented in Table 1. The mean duration of CRF was 3.5±2.1 years and the mean duration of haemodialysis treatment was 2.3±1.2 years.

View this table: [in this window] [in a new window]   Table 1. The clinical and laboratory characteristics of the patient population

 
Informed parental consent was obtained, and the patients were divided into two series according to the primary renal disease.

In the first series, six patients (mean age 15.3±1.9 years) with urinary malformations were defined as the uropathy group. Primary diseases were vesicoureteral reflux in five patients and renal dysplasia in one. The mean duration of CRF was 4.8±1.9 years and the duration of dialysis treatment was 2.8±1.6 years.

In the second series, six patients (mean age 13.8+2.13 years) with different acquired glomerular diseases were defined as the glomerulopathy group. Primary diseases were diffuse mesangial proliferative glomerulonephritis in three patients, and one each with membranoproliferative glomerulonephritis, haemolytic–uraemic syndrome, and rapidly progressive glomerulonephritis respectively. The mean duration of CRF was 2.2±1.2 years and the mean duration of dialysis treatment was 1.8±0.4 years.

All patients had been undergoing treatment with the same dialysis modality, and all were regularly receiving recombinant human erythropoietin (rHuEpo) to achieve haemoglobin concentrations of 10–12 g/dl (rHuEpo 50–75 IE/kg i.v. three times per week). To control parathyroid hormone activity, 1-25 vitamin D was administered in doses ranging from 0.5 to 1.5 µg/day. No patient had hypercalcaemic episodes. Calcium carbonate (CaCO₃) was used to maintain predialysis phosphataemia at <6.25 mg/dl. All patients with blood pressures in excess of 130/85 mmHg were given antihypertensive drug treatment. The preferred initial therapy was an ACE inhibitor (captopril), with the dose titrated upwards to the high dose range (maximal dose 4 mg/kg). A calcium-channel blocker (verapamil), selective alpha blocker (prazosin), and beta blocker (propranolol) were used as the second and third treatments for reducing blood pressure. In the glomerulopathy group, two patients were taking a single antihypertensive drug, three were taking two drugs, and one patient was taking three drugs. In the uropathy group, two patients were taking one, and four patients were taking two antihypertensive drugs. None of the patients was on a lipid-lowering therapy. Arteriovenous fistula blood specimens were taken in the morning after an overnight fast before the first weekly haemodialysis session, four times before the transplantation. The biochemical values reported here are the averages of four measurements taken over a 1-month period.

Plasma parathyroid hormone (i-PTH peptide) concentrations were measured once by a two-site immunoradiometric assay. All other analyses were performed using routine laboratory methods (total cholesterol, cholesterol oxidase; triglycerides, glycerol 3-phosphate oxidase-peroxidase; calcium, o-cresolphthalein complexone (enzymatic); phosphorus, phosphomolybdate; glucose, hexokinase; creatinine, alkaline picrate; and fibrinogen, clotting method).

Brachial blood pressure (BP) was measured with a mercury sphygmomanometer. Phases I and V of the Korotkoff sounds were taken respectively as the systolic BP (SBP) and diastolic BP (DBP). Blood pressure measurements were taken during the haemodialysis session, 10 times over the 1-month period preceding transplantation, and average values were calculated. The mean BP (MBP) was calculated by using the formula MBP=DBP+(SBP-DBP/3).

Living-related kidney transplantation was performed in all 12 children using standard surgical techniques. Internal iliac artery samples were obtained at the time of renal transplantation. Tissue samples were immediately placed in physiological saline and transported to the laboratory. The samples were fixed in phosphate-buffered formaldehyde solution. H&E, Orcein, Verhoef–Van Gieson, and Masson trichrome staining were performed on 3- to 4-µm sections for light microscopy. The pathologist responsible for evaluating the samples was blind to the subject group.

CRF duration was defined as the time from the beginning of CRF (serum creatinine level >1.5 mg/dl) until the start of haemodialysis. The duration of haemodialysis was defined as the period from beginning of haemodialysis until renal transplantation.

Statistics
The two-sample t-test, Mann–Whitney U test, and Fisher's exact tests were used for statistical comparison of parameters. Minitab software was used. Unless indicated otherwise, means±SD are given and P values of <0.05 were considered as statistically significant.

	Results

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A comparison of the uropathy and glomerulopathy groups is given in Table 2. Age, sex distribution, duration of haemodialysis, SBP, DBP, and MBP were not different between the two groups. Additionally, there were no differences in rHuEpo, 1-25-vitamin D, calcium carbonate, or antihypertensive drug consumption at the time of evaluation. There were no differences in glucose, triglyceride, cholesterol, fibrinogen, calcium, or PTH levels between the uropathy and glomerulopathy groups.

View this table: [in this window] [in a new window]   Table 2. Comparison of uropathy and glomerulopathy groups

 
The duration of CRF, serum phosphorus levels, and the calciumxphosphate product were significantly higher in the uropathy group than in the glomerulopathy group. The duration of CRF was 4.8±1.9 years in the uropathy group and 2.2±1.2 years in the glomerulopathy group (P<0.05).

The plasma phosphorus concentration was 6.38±1mg/dl in the uropathy group and was 5.06±0.6 mg/dl in the glomerulopathy group (P<0.05). The calciumxphosphate product in the uropathy group was also higher than in the glomerulopathy group (P<0.05).

Histopathological evaluation revealed that five of the twelve arteries (four patients from the uropathy group and one from glomerulopathy group (patient 8) showed fibrous or fibroelastic intimal thickening, medial mucoid ground substance, and disruption of the internal elastic lamella. In addition, two patients had microcalcification in the intimal layer (Figures 1 and 2). Atheromatous plaques were observed in two samples from the uropathy group (Figures 3 and 4). The remaining five samples from the glomerulopathy group were normal (Figure 5). Thus pathological changes were found in the arteries of all six patients with uropathy, while only one artery from the six glomerulopathy patients had pathological changes (P<0.001).

View larger version (62K): [in this window] [in a new window]   Fig. 1. Transverse section of iliac artery from a 12-year-old boy (patient 4) showing intimal thickening of the artery. The media can be clearly distinguished from the adventitia. H&E-stained section; original magnification x125.

 

View larger version (57K): [in this window] [in a new window]   Fig. 2. Transverse section of iliac artery from a 17-year-old boy with uropathy (patient 2) showing microcalcification in the intima. H&E-stained section; original magnification x125.

 

View larger version (62K): [in this window] [in a new window]   Fig. 3. Transverse section of iliac artery from a 16-year-old girl with uropathy (patient 1) showing atheromatous plaque. H&E-stained section, original magnification x125.

 

View larger version (57K): [in this window] [in a new window]   Fig. 4 Transverse section of iliac artery from a 16-year-old girl with uropathy (patient 6) showing large atheromatous plaque. PAS-stained section, original magnification x32.

 

View larger version (75K): [in this window] [in a new window]   Fig. 5. Transverse section of normal iliac artery from a 17-year-old boy with glomerulopathy (patient 9). PAS-stained section; original magnification x32.

 

	Discussion

Top Abstract Introduction Subject and methods Results Discussion References

 
In a previous study, Ibels et al. [7] demonstrated that in-vitro arteries from uraemic patients had fibroelastic intimal thickening, calcification of elastic lamellae, and ground substance deposition. Clyne et al. [8] evaluated 94 autopsied cases of CRF and concluded that most deaths among patients with end-stage renal failure were due to cardiovascular disease. The results of the present study show that pathological changes can be seen even in the arteries of uraemic paediatric patients.

In the current study, the frequency of changes in arterial walls was greater in the uropathy group. To explain this difference between the two groups, the most important factors that promote atherogenesis in CRF (blood pressure, glucose metabolism, lipid metabolism, and fibrinogen, calcium, phosphorus, and PTH levels) were compared [9].

Hypertension, a well-known clinical risk factor for arterial changes and atherosclerosis [10–12], causes three major alterations: calcification, thickening, and stiffening of the arterial wall. However, we found no statistically significant differences in blood pressure between the two groups.

It is well known that insulin-mediated glucose metabolism is impaired in uraemia [13]. Some adult patients with CRF have mild fasting hyperglycaemia and an abnormal response to oral and i.v. glucose tolerance tests. Abnormalities in glucose metabolism in patients with CRF may be important risk factors for the accumulation of advanced glycosylation end-products in various tissues and for the development of atherosclerosis [14,15]. In this study, however, the fasting glucose levels were normal in all patients.

Lipids also play an important role in the progression of atherogenesis. In a study by Dimeny et al. [16], patients with hypercholesterolaemia showed severe vascular intimal changes. Moreover, hypertriglyceridaemia has also been reported to be an important risk factor [17]. Whether atherogenesis is related to the dialysis procedure itself or to the uraemic state is still a matter of debate [18]. In any case, cholesterol and triglyceride levels were not different between the glomerulopathy and uropathy groups in the present study.

Guerin et al. [19] have recently demonstrated that plasma fibrinogen concentrations are independently and significantly associated with the extent of arterial calcifications in CRF. In addition, hyperfibrinogenaemia is one of the factors present in CRF [20]. Nevertheless, in the present study the fibrinogen levels between the glomerulopathy and uropathy groups were not different.

Chronic renal failure creates a state of secondary hyperparathyroidism with elevated blood levels of PTH. The degree of arterial wall changes in uraemia correlates with calcium, phosphate, and PTH levels [21–23]. In our study the uropathy group had higher levels of plasma PTH than the glomerulopathy group, but the difference was not statistically significant.

In the present study, the two CRF groups had similar age, sex distribution, duration of haemodialysis, hypertension, antihypertensive treatment, serum glucose, cholesterol, triglyceride, fibrinogen, calcium and PTH concentrations. Although these represent major risk factors for atherosclerosis in adults, they were not different between the uropathy and glomerulopathy groups in this study.

We found differences in the serum phosphorus levels and calciumxphosphate products between the groups. These values were significantly higher in the uropathy group than in the glomerulopathy group (P<0.05). Amann et al. [24] described hyperphosphataemia as a silent killer of patients with renal failure. In addition, Block et al. [25] reported that elevated serum phosphorus levels were an independent risk factor for death in adults undergoing dialysis.

Another important difference was the duration of chronic renal failure. In uropathy patients, CRF begins insidiously in the early days of life, maintaining the subjects in an unhealthy milieu. Under these conditions, metabolic changes can occur without clinical signs. For example, brown tumour, a late stage of osteitis fibrosa due to secondary hyperparathyroidism, has been observed in early childhood [26].

As a result the paediatric CRF patients with uropathy are more prone to alterations in mineral metabolism due to the long duration of metabolic disturbances. Adequate dialysis, new aluminium-free and calcium-free phosphate-binding agents, and vitamin D derivates to normalize calcium, phosphate, and PTH would be beneficial in preventing not only bone disease, but also arterial changes and atherosclerosis [27].

Whether paediatric patients with uropathy should be treated earlier with dialysis or transplantation to prevent arterial changes is a question that remains to be resolved.

	Notes

 
Correspondence and offprint requests to: Dr Ahmet Nayir, Tarik Zafer Tunaya sok, 2/6 Gümüsuyu, Istanbul 80040, Turkey. Email: nayir{at}ttnet.net.tr

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Received for publication: 3. 3.00
Revision received 22. 2.01.
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