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 Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 43  |  Issue : 1  |  Page : 28-35

Serum cystatin-C and urinary N-acetyl-β-d-glucosaminidase as biomarkers for early renal dysfunction in adult Egyptian patients with β-thalassemia major


1 Department of Internal Medicine, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Submission11-Jan-2015
Date of Acceptance11-Mar-2015
Date of Web Publication6-Apr-2015

Correspondence Address:
Tamer A Elbedewy
Department of Internal Medicine, Faculty of Medicine, Tanta University, 31527, Tanta
Egypt
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DOI: 10.4103/1110-1415.154563

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  Abstract 

Background/aims
β-Thalassemia syndromes are the most common inherited hemoglobinopathies. In Egypt, 1000/1.5 million/year live borns suffered from thalassemia. β-Thalassemia major (β-TM) is the most severe form. Advances in the care of patients with β-TM, have allowed previously unrecognized complications to emerge, including several renal abnormalities. Therefore, the aim of the present study is to investigate the presence of glomerular and/or tubular dysfunctions in adults with β-TM, using biomarkers of glomerular and tubular dysfunctions.
Subjects and methods
Forty patients with β-TM (group I) were selected with 20 age-matched and sex-matched healthy participants as a control (group II). Patients were subjected to full medical history taking and complete clinical examination. Serum cystatin-C and urinary N-acetyl-β-d-glucosaminidase (UNAG) levels were measured.
Results
Significantly higher levels of serum cystatin-C and UNAG in thalassemic patients were observed when compared with the control group. Significantly higher levels were observed for serum cystatin-C and UNAG in patients with renal affection, poorly chelated and inadequately transfused patients. A significant positive correlation between serum cystatin-C and serum ferritin was observed and significantly negative correlations between serum cystatin-C on one hand and pretransfusional hemoglobin and estimated glomerular filtration rate on the other hand were observed. A significantly positive correlation between UNAG and the urinary albumin creatinine ratio (ACR) and significantly negative correlations between UNAG on one hand and pretransfusional hemoglobin and estimated glomerular filtration rate on the other hand were observed.
Conclusion
β-TM patients had glomerular and tubular dysfunctions. Serum cystatin-C and UNAG are promising biomarkers for monitoring glomerular and tubular dysfunction.

Keywords: β-thalassemia major, renal dysfunction, serum cystatin-C, urinary N-acetyl-β-d-glucosaminidase


How to cite this article:
Elbedewy TA, Gawaly AM, Abd El-Naby AY. Serum cystatin-C and urinary N-acetyl-β-d-glucosaminidase as biomarkers for early renal dysfunction in adult Egyptian patients with β-thalassemia major. Tanta Med J 2015;43:28-35

How to cite this URL:
Elbedewy TA, Gawaly AM, Abd El-Naby AY. Serum cystatin-C and urinary N-acetyl-β-d-glucosaminidase as biomarkers for early renal dysfunction in adult Egyptian patients with β-thalassemia major. Tanta Med J [serial online] 2015 [cited 2019 Nov 17];43:28-35. Available from: http://www.tdj.eg.net/text.asp?2015/43/1/28/154563


  Introduction Top


β-Thalassemia syndromes are the most common inherited hemoglobinopathies in the world caused by an autosomal recessive genetic deficiency in the β-globin chain synthesis leading to accumulation of unpaired α-globin chains [1] . In Egypt, it was estimated that 1000/1.5 million per year live borns suffer from thalassemia. β-Thalassemia is the most common type with a carrier rate ranging from 5.3 to 9% [2] .

β-Thalassemia major (β-TM) is the most severe form and is typically diagnosed with profound anemia during infancy, requiring long-term transfusion and iron chelation therapy for survival [3] . Several different transfusional regimens have been used, but the most widely accepted one aims at a pretransfusional hemoglobin level of 9-10 g/dl [4] . Serum ferritin is most commonly measured as an indicator of iron stores. Ferritin levels below 2500 mg/ml are associated with improved survival [5] . Patients with thalassemia develop several complications including cardiac, endocrinal, and hepatic dysfunctions. Several factors are responsible for these abnormalities including hemolysis and excess iron deposition [6] .

Advances in the care of patients with β-TM, especially with the use of effective chelating agents, translate into better patients' survival; this success has allowed previously unrecognized complications to emerge, including thalassemia-related nephropathy [7] . Renal dysfunction among β-TM patients might be caused by chronic hypoxia and iron overload and desferrioxamine toxicity [8],[9] . Proximal tubular dysfunction, proteinuria, aminoaciduria, and low urine osmolarity had been documented in several studies [10],[11] .

Researches in renal dysfunction in adult thalassemic patients have been limited in number. Therefore, the aim of the present study was to investigate the presence of glomerular and/or tubular dysfunctions in adults with β-TM, using biomarkers of glomerular and tubular dysfunctions for early detection of thalassemia-related nephropathy.


  Subjects and methods Top


Subjects

This cross-sectional study was carried out on 40 patients with β-TM; they were randomly selected from in and out-patients of the Hematology Unit, Internal Medicine Department, Faculty of Medicine, Tanta University during the period from October 2013 to October 2014. Twenty age-matched and sex-matched healthy participants were also included in the study as a control group. This study was conducted in accordance with the guidelines of the declaration of Helsinki, 1975 and its subsequent amendments (1983). The study was approved by the local ethics committee. Participation in the study was voluntary after an informed written consent was obtained from the participants before the study after a full explanation of benefits and risks of the study.

The studied patients with β-TM had in their history the following criteria at the time of initial diagnosis (age at presentation was less than 2 years with a mean hemoglobin level of 6-7 g/dl, HbF >50%, and HbA2< 4% [12] . Patients with other hemoglobinopathies, patients with other hemolytic anemia, patients with systemic illness (heart failure, hepatic diseases, or diabetes mellitus), and patients with clinical or laboratory evidence of other causes of renal diseases were excluded from this study.

No urinary tract infection was noted at the time of urine sampling. No diuretic therapy or history of intake of trimethoprim, corticosteroids, or cephalosporin was observed in the past 7 days of sampling.

All patients were on regular blood transfusion and iron chelation therapy with desferrioxamine (40 mg/kg/day administered subcutaneously through a battery-operated portable pump over a period of 8-12 h overnight, for 5-7 nights per week) [4] .

The mean pretransfusion hemoglobin level and mean serum ferritin level in each patient over the last year of follow-up were obtained to evaluate the transfusion therapy and the hemosiderosis level (hemoglobin was measured before each transfusion and serum ferritin was measured every 3 months).

According to the mean serum ferritin level: β-TM patients were subdivided into a well chelated group (with mean serum ferritin <2500 ng/ml) and a poorly chelated group (with mean serum ferritin ≥2500 ng/ml) [5] . According to the mean pretransfusional hemoglobin level β-TM patients were subdivided into an adequately transfused group (with mean pretransfusional hemoglobin ≥9 g/dl) and an inadequately transfused group (with mean pretransfusional hemoglobin <9 g/dl) [4] .

Methods

All patients included in this study were subjected to full medical history taking and complete clinical examination including age, sex, weight, height, disease duration, first time of blood transfusion, number of blood transfusions/year, history of splenectomy, postsplenectomy duration, and type and duration of chelation therapy were obtained.

Laboratory assessment

Patients were instructed to fast overnight before attending the clinic in the morning and advised to abstain from taking any medications (including chelation) in the previous 24 h. Blood samples from patients were collected immediately before blood transfusion, 10 ml of venous blood after fasting and fresh second-morning midstream urine samples were collected from all the participants for biochemical analysis.

Peripheral blood samples were collected on EDTA (1.2 mg/ml) for complete blood count. Complete blood count was done using SysmexXT-1800i (Sysmex, Hyogo, Japan). Serum ferritin analysis was done using Cobas Integra 800 (Roche Diagnostics, Mannheim, Germany).

Serum samples were recovered and immediately divided into aliquots and frozen at −70°C till serum cystatin-C levels were measured using the quantikine human cystatin-C immunosorbent assay (ELISA) kit (Cat. No.: RD191009100; R&D Systems Inc., Minneapolis, Minnesota, USA). Samples were incubated in microtitrate plate wells precoated with polyclonal anti-human cystatin-C antibody. After 30 min of incubation and washing, polyclonal anti-human cystatin-C antibody, conjugated with horseradish peroxidase is added to the wells and incubated for 30 min with the captured cystatin-C. Following another washing step, the remaining horseradish peroxidase conjugate is allowed to react with the substrate solution (TMB). The reaction is stopped by addition of an acidic solution and absorbance of the resulting yellow product is measured. The absorbance is proportional to the concentration of cystatin-C. A standard curve is constructed by plotting absorbance values against concentrations of cystatin-C standards, and concentrations of unknown samples are determined using this standard curve.

Five milliliters of urine was collected and divided into two aliquots; one for the immediate assessment of urinary creatinine (creatinine-Jaffe enzymatic assay) and urinary albumin colorimetrically (Egypt Company for Biotechnology, Cairo, Egypt) and the other aliquot was stored at −20°C for the subsequent assay of urinary N-acetyl-β-d-glucosaminidase (UNAG) by a chemical method using the rapid colorimetric assay (FAR srl Pescantina, Verona, Italy). The principle of this assay is that N-acetyl-β-d-glucosaminidase (NAG) catalyzes the hydrolysis of p-nitrophenyl N-acetyl-β-d-glucosaminide into p-nitrophenol and N-acetylglucosamine. The liberated p-nitrophenol is proportional to the enzymatic activity and is colorimetrically defined in an alkaline medium which is expressed in IU/l [13] . To minimize the urine flow rate on urinary enzyme levels, enzymes levels were expressed as a ratio of enzyme activity to the urinary creatinine level.

Patients were considered to have preclinical glomerular damage if the urinary albumin creatinine ratio (ACR) was 30-300 mg/g Cr and to have glomerular proteinuria if the urinary ACR was greater than 300 mg/g Cr [14] .

The estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault formula for adults [15] : eGFR (ml/min/1.73 m 2 ) = [(140−age in years) ×weight in kg ×0.85 if female]/[72× serum creatinine (mg/dl)]. Renal dysfunction was defined as eGFR less than 90 ml/min/1.73 m 2 [16] .

Renal affection in this study was considered if eGFR less than 90 ml/min/1.73 m 2 and/or if the urinary ACR was greater than 30 mg/g Cr.

Statistical analysis

The collected data were tabulated and analyzed using SPSS version 17 software (SPSS Inc., Chicago, Illinois, USA). Categorical data were presented as numbers and percentages while quantitative data were expressed as means and SDs. Comparison of continuous data between two groups was made by using the unpaired t-test for parametric data and the Mann-Whitney test for nonparametric data. Fisher's exact was used for comparison between categorical data. The Spearman test was used for correlations between different nonparametric parameters. The accepted level of significance in this work was stated at 0.05 (P < 0.05 was considered significant).


  Results Top


Our study included 40 adult patients with β-TM (group I) (26 males, 14 females), their ages ranging between 18 and 29 years (mean age: 23.28 ± 3.595 years) and the control group (group II) included 20 healthy participants (12 males, eight females) and their ages ranged between 19 and 27 years (mean age: 22.5 ± 2.705 years). There were insignificant differences between group I and II as regards age and sex ([Table 1]). Twenty-one (52.5%) patients were poorly chelated, 17 (42.5%) patients were inadequately transfused, and all the patients (100%) were splenectomized. Twelve (30%) patients had renal affection; all patients with renal affection were inadequately transfused and 10 of them were poorly chelated.
Table 1: Comparison between the two studied groups as regards different variables

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Our results showed significantly higher levels of serum ferritin, urinary ACR, serum cystatin-C, and UNAG and lower levels of pretransfusional hemoglobin in β-TM patients in comparison with control participants ([Table 1]).

Also our results showed significantly higher levels of serum creatinine, urinary ACR, serum cystatin-C, and UNAG and showed lower levels of eGFR in poorly chelated and inadequately transfused patients when compared with well chelated and adequately transfused patients respectively. Other comparisons between poorly and well chelated or inadequately and adequately transfused patients are shown in [Table 2] and [Table 3].
Table 2: Comparison between well and poorly chelated patients as regards different variables in thalassemic group

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Table 3: Comparison between adequately and inadequately transfused patients as regards different variables in the thalassemic group

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Significantly higher levels of serum cystatin-C and UNAG were noted in patients with renal affection when compared with patients without renal affection. Other comparisons between patients with renal affection and patients without renal affection are shown in [Table 4].
Table 4: Comparison between renal affected patients and renal nonaffected patients as regards different variables in the thalassemic group

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Our results for renal affected thalassemic patients showed significantly positive correlations between serum cystatin-C and serum ferritin and significantly negative correlations between serum cystatin-C on one hand and pretransfusional hemoglobin and eGFR on the other hand ([Figure 1]). Other correlations between serum cystatin-C and other variables are shown in [Table 5]. Our results for renal affected thalassemic patients showed significantly positive correlations between UNAG and urinary ACR ([Figure 2]) and significantly negative correlations between UNAG on one hand and pretransfusional hemoglobin and eGFR on the other hand. Other correlations between UNAG and other variables are shown in [Table 5].
Figure 1: Correlation between serum cystatin-C and the estimated glomerular filtration rate in the renal affected thalassemic group.

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Figure 2: Correlation between urinary N-acetyl-¦Â-D-glucosaminidase (UNAG) and the urinary albumin creatinine ratio in the renal affected thalassemic group.

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Table 5: Correlations between (serum cystatin-C and urinary N-acetyl-¦Â-D-glucosaminidase) and different variables in the renal affected thalassemic group

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  Discussion Top


The survival of patients with β-TM has increased in the last decade and the effects of iron overload in the liver, pancreas, and heart has become more severe; however, renal involvement has received little attention [17] . Renal dysfunction may occur in β-TM asymptomatic patients and before the manifestation of any other complications [18] . Several major factors may be responsible for the renal dysfunction associated with β-TM that includes shortened red cell life span, chronic hypoxia, rapid iron turnover, and tissue deposition of excess iron. Moreover, the use of specific iron chelators may harm the kidney [19] .

Several investigations on renal involvement in β-TM patients were reported but there is a dearth of data for adults [8, 17, 20, 21, 22] . This study aimed to investigate the presence of glomerular and/or tubular dysfunctions in adults with β-TM, using biomarkers of glomerular and tubular dysfunctions for early detection of thalassemia-related nephropathy.

β-TM as a type of anemia reduces the systemic vascular resistance, leading to increase of the renal blood flow and glomerular filtration rate (GFR) [23] . These changes can eventually lead to stretching of the glomerular capillary and subsequent capillary injury, together with transudation of macromolecules into the mesangium associated with glomerular dysfunction [24] . Moreover, chronic hypoxia and heavy iron overload of tubular cells causes apoptosis, cytokines release, tubulointerstitial injury, and consequent glomerulosclerosis. In the long-term, such changes may lead to a progressive decrease in GFR [19],[25],[26] .

Our results showed insignificant differences between β-TM patients and control participants as regards serum creatinine and eGFR.

In accordance with our results, Li Volti et al. [27] , Aldudak et al. [17] , Smolkin et al. [10] , and Kacar et al. [28] , found that, there was no statistically significant difference between β-thalassemic patients and control participants as regards levels of creatinine and eGFR.

On the other hand, Hamed and El-Melegy [29] ; Ali and Mahmoud [30] , reported significantly higher serum creatinine and lower eGFR in thalassemic patients when compared with the control group. Also, Al-Mukhtar et al. [31] ; found that the adult thalassemic patients group (19-25 years) had significantly higher serum creatinine when compared with the control and children thalassemic patients group (3-10 years) and not with the adolescent thalassemic patients group (11-18 years).

Albuminuria was attributed mainly to the destruction of the glomerular filtration membrane which could be due to massive iron deposition in the tissues, resulting in an increase of free radical production, leading to apoptosis [32],[33] . In addition, albuminuria could result from prolonged hyperfiltration, prostaglandin secretion, and chronic anemia [34] .

The results of our study showed significantly higher levels of the urinary ACR in thalassemic patients when compared with the control group.

These results are in agreement with Aldudak et al. [17] , Hamed and El-Melegy [29] , and Ali and Mahmoud [30] , who found statistically significant higher levels of the urinary ACR in the thalassemic group when compared with the control group.

The results of our study showed that 12 (30%) patients had renal affection (eGFR <90 ml/min/1.73 m 2 and/or the urinary ACR was >30 mg/g Cr).

In accordance with our results, Economou et al. [9] , found that a considerable number of patients demonstrated impaired renal function with glomerular dysfunction with proteinuria (24%). Also, Tantawy et al. [35] ; found that, microalbuminuria was present in 29% of the patients.

On the other hand, higher frequencies of renal affection were reported by Hamed and El-Melegy [29] who found that impaired renal functions (eGFR <90 ml/min/1.73 m 2 ) was reported in 47.83%. Also, Mohkam et al. [18] , Hamed and El-Melegy [29] and Dimitriadou et al. [36] , found proteinuria or abnormal ACR in 89.3, 82.61, and 68% of β-TM patients respectively.

Also our results showed significantly higher levels of serum creatinine and the urinary ACR and lower levels of eGFR in poorly chelated and inadequately transfused patients when compared with well chelated and adequately transfused patients respectively.

On the other hand, Ali and Mahmoud [30] , who made a comparison between chelated and nonchelated groups demonstrated that the chelated group had a significantly lower eGFR than the nonchelated group.

Cystatin-C is a cysteine protease inhibitor that is synthesized from all human cells and secreted into the blood. The advantage of cystatin-C measurement in comparison with creatinine clearance is that it is not affected by height, sex, diet, and muscle mass [37] . Serum cystatin-C is believed to be a more robust endogenous marker of GFR than creatinine as it is thought to be produced at a constant rate by all nucleated cells, freely filtered by the glomeruli, minimally bound to proteins, and totally reabsorbed and metabolized in the proximal tubule [38],[39] . The cystatin-C molecule is more than 100 times larger than creatinine. In theory, narrowing of the glomerular filter could impair filtration of cystatin-C but still allow free passage of creatinine. This has led researchers to investigate whether an increase in plasma cystatin-C precedes the conventional creatinine [40] .

Our results showed significantly higher levels of serum cystatin-C in thalassemic patients when compared with the control group. Also, significantly higher levels of serum cystatin-C were observed in patients with renal affection, poorly chelated and inadequately transfused patients when compared with patients without renal affection, well chelated and adequately transfused patients respectively. Also, our results for renal affected thalassemic patients showed a significantly positive correlation between serum cystatin-C and serum ferritin and a significantly negative correlation between serum cystatin-C on one hand and pretransfusional hemoglobin and eGFR on the other hand.

In accordance with our results, Hamed and El-Melegy [29] found statistically significant higher levels of serum cystatin-C in the thalassemic group when compared with the control group and a negative correlation with eGFR and no correlation with age, ACR, and UNAG. Papassotiriou et al. [41] , found that serum cystatin-C and serum ferritin concentrations correlated positively. Kacar et al. [28] , found an insignificant relationship between serum cystatin-C and levels of creatinine. Ali and Mahmoud [30] , found statistically significant higher levels of serum cystatin-C in the thalassemic group when compared with the control group and a statistically significant strong negative correlation between serum cystatin-C and eGFR.

On the other hand, Hamed and El-Melegy [29] ; found that in patients with chelation, serum cystatin-C was significantly higher when compared with the nonchelated group and found also, a statistically significant strong positive correlation between serum cystatin-C and serum creatinine. Kacar et al. [28] , found an insignificant difference between β-thalassemic patients and control participants as regards level of serum cystatin-C and an insignificant relationship between serum cystatin-C and creatinine clearance.

NAG is a high molecular weight lysomal enzyme found in several human cells including the renal tubules. NAG cannot be freely filtered at the glomerulus, and raised urinary concentrations are believed to have a tubular origin, but could also be due to the increased lysosomal activity without cell damage. Urinary NAG activity has been shown to be high during active renal disease and widely used as an early marker of proximal convoluted tubular damage [42],[43] .

Our results showed significantly higher levels of UNAG in thalassemic patients when compared with the control group. Also, significantly higher levels of UNAG were noted in patients with renal affection, poorly chelated and inadequately transfused patients when compared with patients without renal affection, well chelated and adequately transfused patients respectively. Our results for renal affected thalassemic patients showed a significantly positive correlation between UNAG and urinary ACR and significantly negative correlations between UNAG on one hand and pretransfusional hemoglobin and eGFR on the other hand.

In accordance with our results, Mohkam et al. [18] , Smolkin et al. [10] , Hamed and El-Melegy [29] , Al-Mukhtar et al. [31] , and Tantawy et al. [35] ; found significantly higher UNAG in thalassemic patients when compared with the control group. Mohkam et al. [18] ; found that there was a significant relationship between UNAG and urinary protein/creatinine. Smolkin et al. [10] ; found UNAG levels were not correlated to the actual ferritin level. Hamed and El-Melegy [29] ; found a significant positive correlation between UNAG and ACR and no correlations with age, serum creatinine, and serum cystatin-C. Tantawy et al. [35] ; found that UNAG was positively correlated with total urinary protein and negatively correlated with creatinine clearance.

On the other hand, Mohkam et al. [18] ; found that there was a significant relationship between UNAG and the age of the patient. Hamed and El-Melegy [29] ; found no correlation with eGFR. Jalali et al. [44] ; found that the mean value of UNAG activity for thalassemic patients and controls showed an insignificant difference and also, found that the increase in serum ferritin is significantly correlated with the increase in NAG activity. Tantawy et al. [35] ; found that UNAG was positively correlated with serum ferritin.


  Conclusion Top


This study has shown that β-TM patients had glomerular and tubular dysfunctions, which could be attributed to poor chelation and inadequate transfusion. Periodic renal assessment of those patients is mandatory as they may be affected by hidden renal dysfunction. Serum cystatin-C and UNAG are promising biomarkers to assist in monitoring glomerular and tubular dysfunction.

Our study is not without limitations; the main limitation of our study was that it was a cross-sectional analysis and we did not follow the β-TM patients over time. Also our study lacked an examination of renal biopsy to certify patients with renal dysfunction. Indeed, we found it unethical to expose the patient to this aggressive technique without any direct benefit to them.


  Acknowledgements and authors' contributions Top


Concept, design, definition of intellectual content, data acquisition, and statistical analysis: Tamer A. Elbedewy; literature search, manuscript preparation, manuscript review, manuscript editing, and data analysis: Tamer A. Elbedewy, Amr M. Gawaly, Amira Y. Abd El-Naby; clinical studies: Tamer A. Elbedewy, Amr M. Gawaly; experimental studies: Amira Y. Abd El-Naby. All authors have read and approved the final version of the manuscript.

Conflicts of interest

There are no conflicts of interest.

 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]


This article has been cited by
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European Journal of Radiology. 2018; 103: 65
[Pubmed] | [DOI]



 

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