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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 3  |  Page : 93-100

A disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 in children with end-stage renal disease on regular hemodialysis


1 Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Gharbia, Egypt
2 Department of Pediatrics, Faculty of Medicine, Aswan University, Aswan, Egypt

Date of Web Publication28-Sep-2017

Correspondence Address:
Mohamed Abdelaziz El-Gamasy
Assistant Professor of Pediatrics,Facuty of Medicine, Tanta University, El Giesh Street, Tanta, Algharbia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jina.jina_17_17

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  Abstract 


Background: In chronic kidney disease, systemic inflammation may contribute to the endothelial dysfunction and accelerated thrombosis. Vascular access thromboembolism is the most common cardiovascular complication of children with end-stage renal disease (ESRD). Recently, a disintegrate-like and metalloproteinase with thrombospondin type 1 repeats 13 (ADAMTS13) is suspected to be involved as a specific von Willebrand factor cleaving protease. Objectives: To evaluate serum ADAMTS13 level in children with ESRD on regular hemodialysis (HD) and its correlation to thrombotic episode in HD patients. Materials and Methods: The present study was carried out on forty children with ESRD on regular HD in Pediatric Department of Tanta and Aswan University hospitals and forty healthy age- and sex-matched children were serving as controls. All patients and controls were subjected to thorough history taking, especially history concerning vascular access thrombosis, clinical examination including anthropometric measurements, and routine laboratory assessment measuring complete blood count (CBC), blood urea, serum creatinine, parathormone, prothrombin time, partial thromboplastin time, bleeding time, clotting time, blood electrolytes, and urine analysis. Laboratory investigations also included serum ADAMTS 13 level in this study. Results: There was a positive history of thrombi formation in patients more than controls, especially in the vascular access, and there was a significant decrease in ADAMTS13 level in patients when compared to controls. Conclusions: Diminished serum ADAMTS13 level is an early biomarker for hypercoagulability and thrombotic tendency. Children with ESRD under regular HD have lower levels of serum ADAMTS 13 than controls which increases the risk for thrombosis.

Keywords: A disintegrin and metalloproteinase with thrombospondin type 1 repeats 13, children, end-stage renal disease, hemodialysis


How to cite this article:
Abdelhafez M, El-Gamasy MA, Mehrez MM, Fakhreldin AR. A disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 in children with end-stage renal disease on regular hemodialysis. J Integr Nephrol Androl 2017;4:93-100

How to cite this URL:
Abdelhafez M, El-Gamasy MA, Mehrez MM, Fakhreldin AR. A disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 in children with end-stage renal disease on regular hemodialysis. J Integr Nephrol Androl [serial online] 2017 [cited 2020 Jul 4];4:93-100. Available from: http://www.journal-ina.com/text.asp?2017/4/3/93/215740




  Introduction Top


Vascular access thrombosis (VAT) constitutes about 20% of all hospitalizations in dialyzed patients.[1] HD process is associated with increasing thrombotic tendency due to platelet and clotting factor activation, in addition to fibromuscular and intimal hyperplasia, that may result in reduction in vascular access blood flow which causes blood stasis and favors hypercoagulability.[2] von Willebrand factor (vWF) is a well-known index of endothelial damage and has been reported to increase in inflammatory conditions, for example, chronic kidney disease (CKD).[3] vWF directly contributes to thrombus formation by mediating platelet adhesion to subendothelial collagen and indirectly by being the carrier of FVIII and by preventing its plasma clearance.[4] A disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ADAMTS 13) works by cleaving the Tyr 1605-Met 1606 bond in the central domain of the vWF subunit and by regulating the adherence of platelets to the collagen embedded in subendothelial tissue. Diminished serum ADAMTS13 levels may be considered a marker for thrombotic tendency.[5] Recently, ADAMTS13 mRNA was detected in kidney, including glomerular endothelial cells, podocytes, glomerular basement membrane, and tubular epithelial cells.[6] ADAMTS13 deficiency and/or the presence of antibodies against this enzyme may increase ultra-large vWF (ULvWF) plasma levels, favoring the occurrence of thrombosis in small vessel.[7] Several studies have indicated that the ratio of vWF to ADAMTS13 may be beneficial in the diagnosis and treatment of patients in a prothrombotic state.[8] Low activity of vWF-cleaving protease contributes to the development of thrombotic thrombocytopenic purpura.[9]

The aim of the work was to evaluate serum ADAMTS13 levels in children with end-stage renal disease (ESRD) on regular hemodialysis (HD) and its relation with dialysis duration and thrombotic episode as an early predictor of hypercoagulability status in pediatric HD patients.


  Materials and Methods Top


Design of the study and setting

The present cross-sectional study was conducted after obtaining approval from the research Ethical Committee of the Faculty of Medicine, Tanta and Aswan Universities, Verbal or written informed consents from parents of included subjects were obtained prior to this research study and informed parental consents on forty children with ESRD on regular HD attending Pediatric Nephrology and Dialysis Unit of Tanta and Aswan University Hospitals, from June 2016 to June 2017. Their ages ranged from 3 to 17 years. There were 14 males and 26 females. Forty age- and sex- matched healthy children were serving as control group.

All patients were undergoing HD three times per week, with dialysis session lasting for 3–4 h. Patients were dialyzed on Fresenius 4008-B dialysis machine (Germany) at blood flow rate = 2.5 × weight (kg) +100 mL/min, using polysulphane hollow fiber dialyzers suitable for the surface area of the patients (Fresenius F3 = 0.4 m 2, F4 = 0.7 m 2, F5 = 1.0 m 2, and F6 = 1.2 m 2). Bicarbonate dialysis solutions were used.

Inclusion criteria

Children with ESRD on regular HD were included.

Exclusion criteria

Children with ESRD on conservative treatment or on peritoneal dialysis or posttransplantation were excluded.

All patients and controls were subjected to the following:

  1. History taking: Including duration of dialysis and thrombotic episodes
  2. Clinical examination: Anthropometric measurements (weight and height) and blood pressure estimation were taken in the dialysis-free day
  3. Laboratory investigations:
    1. Routine investigations which were done just predialysis including complete blood picture, serum creatinine, blood urea nitrogen (BUN), glomerular filtration rate (GFR), parathormone (PTH), blood electrolyte, prothrombin time (PT), partial thromboplastin time (PTT), and clotting and bleeding time
    2. Serum levels of ADAMTS13: Venous blood samples were taken immediately before HD session. Samples were drawn in tubes with EDTA. Serum was separated by low-speed centrifugation. ADAMTS13 levels were determined by automated enzymatic assays using commercially available reagents (Human ADAMTS13 ELISA Microplate). Its kit was based on sandwich enzyme-linked immune-sorbent assay technology. Anti-human ADAMTS13 antibody was precoated onto 96-well plates. Biotin-conjugated anti-human ADAMTS13 antibody was used as detection antibody.


Statistical analysis

“Data were collected and analyzed using Statistical Package for the Social Sciences (SPSS) for Windows” (version 12), Research Methodology, Methods and Techniques. 2nd ed. New Delhi, India. All quantitative data were expressed in terms of mean ± standard deviation or number and percentage. Comparisons among groups were made using paired t-test. “Two-group comparisons were performed nonparametrically using the Mann–Whitney U-test”. For qualitative data, comparison between two groups and more was done using the Chi-square test (χ2). “All statistical tests were two tailed and P< 0.05 was considered statistically significant.”[10]


  Results Top


Clinical and laboratory data of studied patients and controls are presented in [Table 1] and [Table 2]. There was no significant difference in age, sex, weight, or height between patients and controls [Table 1].
Table 1: Demographic data of studied patients and controls

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There was a significant decrease in hemoglobin level, total leukocyte count (TLC), and platelet count in patients when compared to the controls while there was a significant increase in serum creatinine, blood urea, and BUN in the studied patients when compared to the controls [Table 2]. There was no significant difference in patients' PT and PTT when compared to that of controls while there was a significant increase in patients' bleeding and coagulation time when compared to that of controls [Table 2]. There was a highly significant increase in PTH level, K level, and phosphorus level in patients as compared to controls while there was a highly significant decrease in Na level and Ca++ level in patients as compared to controls [Table 2].
Table 2: Laboratory date of studied patients and controls

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As regard to serum ADAMTS 13 levels, there was a highly significant decrease in patients when compared to controls, but there was no significant difference between male and female patients [Table 3]. There was a highly significant decrease in patients with thrombotic episodes in the form of VAT when compared to those without episodes of thrombi, but there was no significant difference between patients using transient catheter and patients using arteriovenous fistula (AVF) [Table 3]. [Figure 1] shows that 26 patients (65%) have a history of VAT in the studied patients. There was no significant correlation between serum level of ADAMTS13 and different demographic data of the studied patients [Table 4]. There was also no significant correlation between serum ADAMTS13 and most of the laboratory data of the studied patients while there was a significant negative correlation between serum ADAMTS13 and TLC/cm in studied patients [Figure 2] and a significant positive correlation between serum ADAMTS13 and bleeding time and coagulation time in studied patients [Figure 3] and [Figure 4], respectively].
Table 3: Serum a disintegrin and metalloproteinase with thrombospondin Type 1 repeats 13 levels in the studied patients and controls

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Figure 1: Incidence of vascular access thrombosis among studied patients

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Table 4: Correlations between serum level of a disintegrin and metalloproteinase with thrombospondin Type 1 repeats 13 and demographic and laboratory data of studied patients

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Figure 2: Correlations between a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ng/mL) and total leukocyte count/cm

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Figure 3: Correlations between a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ng/mL) and bleeding time (min)

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Figure 4: Correlations between a disintegrin and metalloproteinase with thrombospondin type 1 repeats 13 (ng/mL) and clotting time (min)

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  Discussion Top


Patients with CKD have an increased risk of vascular endothelial dysfunction and thromboembolism.[11] Thrombosis, especially in the vascular access, constitutes one of the most important causes of hospitalizations in HD patients.[12],[13] Vascular access complications contribute to increased morbidity and constitute about 20%–25% of all indications of hospitalization in dialysis patients. 85% of Vascular access complications caused by thrombosis as published in some studies.[1]

vWF is a blood clotting protein that attaches to cells and proteins to form a blood clot after injury and decrease bleeding. vWF interacts with platelets necessary for blood clotting. Since there is a deficiency in ADAMTS13 in CKD patients, large vWF accumulate in plasma causing clots.[12],[14]

In this study, patients have a characteristic anemia. This is in agreement with Fadrowski, et al., who stated that anemia of CKD is due to reduced renal erythropoietin production and shortened red cell survival.[13] In contrary to our results, Gilbertson et al. reported that, among chronic dialysis patients, hemoglobin levels have markedly increased due to the widespread use of erythropoiesis-stimulating agents and intravenous iron over the past 15 years.[14]

In this study, there is a significant decrease in TLC of patients when compared to controls. This is in agreement with Greer, who stated that, in patients with chronic renal failure undergoing dialysis, exposure of patient blood to artificial membranes of the dialyzer may result in the classic complement activation pathway, typically producing C3a or C5a, which induces neutrophil aggregation and adherence to endothelial surface with resultant fall in TLC.[15] On the contrary, Arogundade et al. reported that total white blood cell count is within normal limit due to the fact that uremia affects the function of leukocytes rather than granulopoiesis and this is the reason why there is poor leukocyte response to infection in CKD patients.[16]

In this study, there is a significant decrease in platelet count of patients when compared to controls. This may explain the relation between ADAMTS13 deficiency and low platelet count. Since this enzyme is required for cleavage and clearance of ULvWF from circulation, its reduction contributes to higher vWF levels and lower platelet count in HD patients which probably contributes to the hypercoagulable state seen in these patients. ADAMTS13 deficiency plays a vital role in causing thrombosis and consumption of platelets in the process of thrombosis. Diminished platelet synthesis in patients with CKD may be attributed to multiple factors including uremic toxins effects, deficiently secreted erythropoietin or heparin-induced thrombocytopenia. This is in agreement with the study of Abdu et al.[15],[17] due to the previously mentioned causes. However, our results were not in agreement with results of Akinsola A et al who reported that the platelets functions were affected in patients with CKD leading to platelets dysfunction which might be attributed to ureamic toxins without an effect on platelets count(18).[16],[18]

In this study, serum creatinine, blood urea, and BUN increased in patients than controls. This is in agreement with the study of Wong et al.[19] In this study, there is a significant decrease in patients' GFR when compared to control group. This is in agreement with the study of Furth et al.[20] and Kidney Disease Outcomes Quality Initiative.[21]

In this study, there was no difference in PT and PTT of patients when compared to that of controls. This is in agreement with the study of Zahit et al.,[22] but not in agreement with the study of Mohamed Ali et al. who showed prolongation of PTT and PT in HD patients. This controversy of results can be explained by the difference in the doses of heparin used, the variability of number of HD sessions, or inclusion of patients with renal transplant and peritoneal dialysis in their studies. (While our study included only HD patients with no prior renal transplant).[23]

In this study, there was a significant increase in bleeding time and coagulation time when compared to control group. This is in agreement with the studies of Sloand and Schiff (1995). This is due to platelet abnormality.[17],[18],[24]

Many studies tried to elucidate the pathogenesis of increased bleeding time and clotting time in HD patients and its relation to ADAMTS 13. One of them stated that low level of ADAMTS 13 leads to increased ULVWF level which in turn leads to platelet adhesion to subendothelial collagen and consumption of platelets and FVIII within the thrombi.[4] In addition, increased serum fibrinogen in HD patients results in its more attachment to glycoprotein on the surface of platelets leading to its activation and enhancement of platelets deposition on the surface of vascular access. Another explanation is that clotting factor deposition leads to local thrombin formation, platelet activation, and enhanced platelet deposition.[1]

From these studies, we can explain why our patients have low platelet count when compared to controls which may be one of the many factors affecting blood diathesis. This is in agreement with many studies which support that deficiency of ADAMTS13 enzyme that cuts vWF is associated with thrombocytopenia, affecting bleeding time.[1],[14],[15]

Our results were not in agreement with results of previous studyof Akinsola et al., 2000, who stated that platelet functions are affected more than platelet counts in patients with CKD and attributed these to uremic toxins in addition to impaired functions of platelet glycoprotein.[16]

Altered release of adenosine diphosphate and serotonin Both altered release of adenosine diphosphate and serotonin from platelets and faulty arachidonic acid and prostaglandin metabolism lead to impaired platelet adhesion without an effect on platelet count. Anemia also may plays a role in the pathogenesis of increased bleeding tendency in HD patients evidenced by that the proper correction of anemia in HD patients results in improved platelet function.[14]

In this study, there was a high significant decrease in Na level in patients when compared to controls. This is in agreement with the result of Graziani et al. which explained that excessive free water intake or reduced solute intake leads to low predialysis serum sodium concentrations.[25]

In this study, there was a high significant increase in K level in patients when compared to controls. This is in agreement with the result of Kaskel who reported that persistent hyperkalemia in dialysis patients is likely to be caused by disorders of external potassium balance: excessive potassium intake, inadequate potassium elimination, or a combination of the two.[26]

In the present study, there was a high significant decrease in calcium level and a high significant increase in phosphate level in patients as compared to controls. This is in agreement with the result of Taniguchi et al.,[27] but not in agreement with that of Tomasello et al.[28]

VAT is a common complication in HD children due to platelet and clotting factor activation in addition to reduction in vascular access blood flow secondary to fibromuscular and intimal hyperplasia, which may result in vascular access stenosis. Thus, blood flow is reduced causing blood stasis that favors hypercoagulability.[1],[2],[19]

In the present study, VAT was detected in 13 (65%) patients. Our result were in agreement with the result of Anstadt et al., who reported that multiple mechanisms could explain occurance of thromboembolism in HD patients. Endothelial injury probably results from uremia, hypertension, hyperparathyroidism, increased vWF levels or chronic activation of platelet or endothelial cells. Besides, inflammatory cytokines can promote release of ULvWF from endothelial cells to plasma.[20],[29]

In the present study, children with ESRD on regular HD were investigated for ADAMTS13 level as a risk factor of thromboembolism. ADAMTS13 synthesis was first detected in the liver cells as ADAMTS13 mRNA was expressed exclusively in the liver, specifically in stellate cells.[5],[9] In 2004, ADAMTS13 was detected in platelets and in endothelial cells in 2006.[22] However, some studies supported the role of the kidney in ADAMTS13 synthesis.

In 2007, Manea et al. found that ADAMTS13 mRNA was detected in kidney including glomerular endothelial cells, podocytes, glomerular basement membrane, and tubular endothelial cells.[6]

Rios et al., 2010, compared ADAMTS13 level in four patients before and after kidney transplantation and reported that ADAMTS13 level increased after transplantation. This may explain the important role of the kidney in ADAMTS13 synthesis.[2]

In fact, vWF is an important component of hemostatic system as it directly contributes to thrombus formation by mediating platelet adhesion to subendothelial collagen and indirectly by being the carrier of FVIII and by preventing its plasmatic clearance and occurrence of VAT in HD patients, thus it is considered a biomarker in hypercoagulation.[4]

ADAMTS13 cleaves and removes ULVWF from circulation so that its deficiency leads to accumulation of ULVWF, favoring the occurrence of thrombosis.[4],[7] In addition, increased endothelium expression of vWF has also been reported in HD patients.[23]

In this study, patients had a statistically significant low level of serum ADAMTS13 when compared to healthy controls. The present findings are consistent with a previous study of Smits et al., 2000.[1] The decrease of ADAMTS13 serum level in dialysis children can be explained partially by the deficient role of diseased kidneys in ADAMTS13 synthesis and partially by their deficient role in metabolism or release of ADAMTS 60 into plasma. This may explain the role of kidneys in ADAMTS13 synthesis, in metabolism or release of ADAMTS 60 into plasma by injured endothelial cells. Especially in patients with CKD. These results were also in agreement with many previously published studies, for example, Taniguchi et al.,[24],[27] who found that serum levels of ADAMTS13 decreased in patients with diabetic nephropathy. Others reported a relationship between renal functions and serum ADAMTS13 levels in patients with hemolytic uremic syndrome in which patients with severe ADAMTS13 deficiency had higher levels of serum creatinine.[24],[27] Ocak et al.[12],[30] also reported nearly similar results to our findings. However, these results differ from those of other published studies, for example, Scheiflinger [25],[31] and Bernardo et al.[23],[32] stated that the marked elevation in plasma level of vWF leads to increased ADAMTS13 synthesis as a compensatory mechanism. This compensatory elevation in ADAMTS13 Ag level leads to increase ADAMTS13 activity which may be responsible for keeping vWF/ADAMTS13 Ag and vWF/ADAMTS13 activity ratios unchanged.

Regarding VAT in our study, 26 patients (65%) had VAT. It is observed in our study that serum ADAMTS13 levels are significantly lower in patients with thrombotic episodes when compared to those without thrombotic episodes. Hence, serum ADAMTS13 levels can be used as a biomarker of hypercoagulability state in children with ESRD under regular HD. This result is in accordance with Taniguchi et al.[24],[27] and Ocak et al.[12],[30] who reported similar results.

This study showed no difference in ADAMTS13 level between males and females and in different types of vascular access (permanent catheter or AVF). In this study, there was no significant correlation between ADAMTS13 level and duration of dialysis of studied patients in spite of previously published relation between dialysis duration and serum ADAMTS13 level which may indicate the role of uremic state in the pathogenesis of decreased level of ADAMTS13.[26],[33]


  Conclusions Top


HD process, as well as ESRD, constitutes acquired risk factors for thrombosis due to platelet and clotting factor activation. Children with ESRD under regular HD have low levels of serum ADAMTS13 than controls which increases the risk for thrombosis, so reduced serum ADAMTS13 levels may be considered a marker for thrombotic tendency, especially in the vascular access. Coagulation control in HD patients is important, especially in vascular access for prevention of VAT, which constitutes one important cause of hospitalizations in HD children.

Recommendations

We recommend regular follow-up of children with ESRD and early evaluation of ADAMTS13 levels as an early biomarker of hypercoagulability to build strategies to control these risk factors of thrombosis in dialysis children, especially VAT. It is possible to re-engineer ADAMTS13 protease to improve specific activity, which may offer therapeutic benefits to children with ESRD. This cross-sectional study is essential to guide further longitudinal studies that explore further data about thromboembolic complications of children with ESRD under regular HD.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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[PUBMED]  [Full text]  
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