|Year : 2019 | Volume
| Issue : 3 | Page : 116-123
Study of the effect of different iron-chelating agents on early renal glomerular and tubular function markers in children with beta-thalassemia
Maha Y Kamal Zeid1, Hoda M.A Hassab1, Doreen N Younan2, Omneya Arab1
1 Department of Pediatrics, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt
|Date of Submission||02-Feb-2019|
|Date of Decision||04-Apr-2019|
|Date of Acceptance||04-Apr-2019|
|Date of Web Publication||27-Apr-2020|
MD Maha Y Kamal Zeid
Department of Pediatric department, Alexandria University, Alexandria University Children Hospital, Alexandria
Source of Support: None, Conflict of Interest: None
Background Advances in the management of patients of beta-thalassemia major (BTM) and the advent of effective chelators have led to the discovery of many renal complications. Mechanisms of renal impairment in BTM are still not fully investigated. Chronic anemia and hypoxia, iron overload and its complications, and direct nephrotoxic effects of some chelators are the commonly used explanations.
Objectives In this cross-sectional study, the aim was to investigate the prevalence of renal impairment in patients with BTM using some of both conventional and early markers of glomerular and tubular renal function and to investigate the relation between them and iron overload (s. ferritin) and the use of a specific chelator.
Patients and methods The study included 60 transfusion-dependent patients with BTM without overt renal disease or risk factors, for example, diabetes mellitus, and 30 age-matched and sex-matched healthy children as a control group (group C). Patients were divided into two equal groups according to type of chelator: group A children receiving standard deferoxamine (DFO) and/or deferiprone and group B children receiving deferasirox (new treatment). Serum levels of ferritin, creatinine, and blood urea nitrogen; albumin/creatinine ratio (ACR) in urine; estimated glomerular filtration rate using Schwartz formula; urinary beta 2 microglobulin (UB2MG); and urinary calcium/creatinine ratio were measured in all patients and healthy control children.
Results Serum creatinine was within the normal range in most of the patients, and no significant differences were found between the two thalassemic groups and the control group (P=0.473). ACR in urine and UB2MG were significantly higher in the two thalassemic groups, and the deferasirox group showed significantly higher levels than both DFO and/or deferiprone group and control group (P1=0.05 and P2=0.005, respectively, for ACR and P1=0.025 and P2=0.000, respectively, for UB2MG). UB2MG was abnormally high in 67 and 76% of the DFO and/or deferiprone group and deferasirox group, respectively, followed by microalbuminuria (16 and 30%, respectively). Glomerular hyperfiltration was prevalent, but there were no significant differences in the median of the three groups (P=0.766). Hypercalciuria was also prevalent in the two thalassemic groups with abnormally elevated urinary calcium/creatinine ratio in 30% of both groups but without significant differences in the median of the three groups (P=0.123). Serum ferritin was significantly positively correlated with ACR (P=0.002) and with UB2MG (P=0.000).
Conclusions ACR can be used as an early marker of glomerular function. Deferasirox use is probably safe in the usual doses in low-risk patients, keeping into consideration that high doses of deferasirox cause disruption of the renal function.
Keywords: chelators, renal function, thalassemia
|How to cite this article:|
Kamal Zeid MY, Hassab HM, Younan DN, Arab O. Study of the effect of different iron-chelating agents on early renal glomerular and tubular function markers in children with beta-thalassemia. Alex J Pediatr 2019;32:116-23
|How to cite this URL:|
Kamal Zeid MY, Hassab HM, Younan DN, Arab O. Study of the effect of different iron-chelating agents on early renal glomerular and tubular function markers in children with beta-thalassemia. Alex J Pediatr [serial online] 2019 [cited 2020 Jun 2];32:116-23. Available from: http://www.ajp.eg.net/text.asp?2019/32/3/116/283324
| Introduction|| |
Thalassemia contains a spectrum of hereditary anemias characterized by reduced or absent production of one or more of globin chains. Thalassemia syndromes are characterized by varying degrees of ineffective hematopoiesis and increased hemolysis. As a group, thalassemias are the most common monogenetic disorders worldwide, presenting a significant public health concern for developing countries ,.
Beta-thalassemia syndromes are a group of hereditary disorders characterized by a genetic deficiency in the synthesis of beta-globin chains. In the homozygous state, beta-thalassemia (i.e. thalassemia major) causes severe, transfusion-dependent anemia .
Patients with beta-thalassemia major (BTM) usually present early in life with profound anemia that necessitates regular blood transfusion to survive. Repeated blood transfusions are inevitably associated with iron overload, leading to multiple organ dysfunctions, namely, heart, liver, and endocrine glands ,.
Advances in the management of patients of BTM and the advent of effective chelators have led to the discovery of many renal complications .
The availability of three chelating agents has allowed effective treatment that can reduce iron burden, extend patients’ survival, improve compliance, and limit adverse effects. The renal dysfunction caused by chelation therapy is a recognized surrogate and independent risk factor for an increase in mortality and cardiac disease .
Deferoxamine (DFO; desferal and others) has been the standard iron chelator since the 1970s. DFO was considered both safe and effective for transfusional hemosiderosis . However, parenteral administration and the daily nuisance of an infusion pump hinder optimal compliance . DFO does not affect the kidneys unless it is given intravenously, especially at high doses .
Deferiprone (Ferriprox; Apopharma, Toronto, Ontario, Canada) is an orally active hydroxypyridinone. An advantage of this compound is that the iron(III) chelate of deferiprone carries no net charge and therefore can penetrate membranes easily, allowing removal of potentially toxic iron from tissues .
Deferasirox (November 2005, ICL670, Exjade; Novartis, Massachusetts, USA) belongs to a new class of oral tridentate chelators. With a plasma half-life of 8–16 h, once-daily dosing permits circulating drug at all times to scavenge nontransferrin-bound ‘labile plasma iron’ . Renal complications were detected with deferasirox. It can cause increases in serum creatinine, proteinuria, and even renal failure .
Fluctuations in levels of serum creatinine with deferasirox therapy have been the subject of concern . The causes of this mostly reversible nonprogressive increase in serum creatinine in patients treated with deferasirox are still controversial. It has been hypothesized that the underlying mechanism is related, not to a nephrotoxic effect of the drug itself but to overchelation leading to a relative depletion of iron and reduction in estimated glomerular filtration rate (GFR) .
Mechanisms of renal impairment in BTM were discussed by many authors but are still not fully investigated. Chronic anemia and hypoxia, iron overload and its complications, and direct nephrotoxic effects of some chelators are the commonly used explanations .
| Aim|| |
The aim of the study was to investigate the prevalence of renal impairment in patients with BTM population using some of both conventional and early markers of glomerular and tubular renal function and to investigate the relation between them and iron overload (serum ferritin) and the use of a specific chelator.
| Patients and methods|| |
This case–control study included 60 transfusion-dependent patients with BTM without overt renal disease or risk factors, for example, diabetes mellitus, followed at the Hematology Clinic of Alexandria University Children’s Hospital at El-Shatby with their age ranging from 3 to 14 years and have received packed red blood cells transfusion more than 20 times or serum ferritin more than 1000 μg/l, and 30 age-matched and sex-matched healthy children as a control group. Patients were divided into two groups according to type of chelator: group A children received DFO and/or deferiprone and group B children received deferasirox. DFO was given at 25–40 mg/kg body weight subcutaneously 5–7 days/week. Deferiprone was given at 75 mg/kg body weight/24 h in divided doses orally. Group C was the healthy control group, which was selected by matching age and sex with the cases.
All children were subjected to detailed history taking, with emphasis on age of start of transfusion, age of start and type of chelation, compliance, and any history of renal troubles, and thorough clinical examination included anthropometric measures and abdominal examination.
Blood samples were collected in the fasting state, and urine specimens were collected. Transaminases (AST and ALT) were done to exclude children with elevated liver enzymes (three-fold rise) and fasting blood sugar to exclude children with diabetes mellitus or impaired glucose tolerance. Hemoglobin electrophoresis at time of the diagnosis was taken from the patients’ files.
Pretransfusional complete blood count and serum ferritin were obtained . Serum levels of creatinine and blood urea nitrogen (BUN) were measured by chemical methods. Albumin/creatinine ratio (ACR) in urine was measured in spot urine samples . Estimated glomerular filtration rate (eGFR) was estimated using Schwartz formula as follows: CrCl (ml/min/1.73 m2)=[length (cm)×k]/Scr (24), depending on serum creatinine, height, and a constant that varies with age . Urinary beta 2 microglobulin (UB2MG) was measured using an ELISA kit . Urinary calcium/creatinine ratio (UCa : Ucr) was calculated using spot urine samples .
The study was approved by the Medical Ethics Committee of Human Experimentation of Alexandria, University and informed consents were obtained from parents or legal guardians.
Data were collected and entered to the computer using Statistical Package for Social Science program for statistical analysis (version 21). Data were entered as numerical or categorical, as appropriate . Kolmogorov–Smirnov test of normality revealed significance in the distribution of some variables, so the nonparametric statistics was adopted . Data were described using minimum, maximum, median, and interquartile range for not-normally distributed data. Categorical variables were described using frequency and percentage of total. Comparisons were carried out between two studied independent not-normally distributed subgroups using Mann–Whitney U test . Comparisons were carried out between more than two studied independent not-normally distributed subgroups using Kruskal–Wallis test . Post-hoc pairwise comparison when Kruskal–Wallis test was significant was carried out using Dunn–Sidak test for multiple comparison . c2 test was used to test association between qualitative variables. Monte–Carlo and Yate’s (continuity) corrections were carried out when indicated (expected cells<5) ,. An alpha level was set to 5% with a significance level of 95%, and a beta error accepted up to 20% with a power of study of 80%. The analysis was done IBM Corp., released 2012 (IBM SPSS Statistics for Windows, Version 21.0.;IBM Corp., Armonk, New York, USA).
| Results|| |
This study included 60 thalassemic children and 30 matched healthy control children. The age of the patients on DFO and/or deferiprone (30 patients; 13 males and 17 females) ranged from 4 to 12 years, with a mean of 7.26±2.5 years (median, 7.00 and interquartile range, 5.00–10.00 years). The age of the patients on deferasirox (30 patients; 13 males and 17 females) ranged from 3 to 14 years, with a mean of 7.63±2.9 years (median, 7.5 and interquartile range, 5–10 years), and the age of the control group (30; 13 males and 17 females) ranged from 3 to 10 years, with mean of 6.03±2.18 years (median, 5.5 and interquartile range, 4–8 years). The results of this study showed no statistically significant increase in serum creatinine among the two thalassemic groups when compared with healthy control and that almost all patients had normal levels for age and sex.
The considered cutoff normal values were BUN up to 20 mg/dl, serum creatinine up to 0.7, eGFR 100–130, urinary ACR up to 30 μg/mg, B2MG up to 0.3, and UCa : Ucr up to 0.2 ,,.
BUN was significantly higher in the deferasirox group when compared with both DFO and/or deferiprone-deferasirox (P=0.003) and control group (P=0.003). Microalbuminuria was found in 16.67 and 30% of DFO and/or deferiprone-deferasirox and deferasirox groups, respectively ([Table 1]).
|Table 1 Comparison of markers of glomerular standard renal function in new line of treatment in the studied three groups of children|
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ACR in urine was statistically significantly different among the three studied groups (P=0.0056). It was higher in the deferasirox when compared with the control group (P=0.05).
Hyperfiltration was prevalent. Overall, 83.3% of DFO and/or deferiprone and 80.00% of deferasirox group had abnormally high eGFR using Schwartz formula. There were no statistically significant differences among all three groups ([Table 1]).
In this study, UB2MG was found to be the most frequent abnormal indicator. It was abnormally high in 67 and 76% of the DFO and/or deferiprone group and deferasirox group, respectively. There were strong significant differences between groups A and C (P=0.02) and groups B and C (P≤0.001). Hypercalciuria was prevalent among patients (30% of groups A and B). However, there were no significant differences among the median of the three groups ([Table 2]).
|Table 2 Comparison of markers of renal tubular function in the studied three groups of children|
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There was a statistically significant positive correlation between ACR in urine and serum ferritin levels (P=0.002) and between UB2MG and serum ferritin (P≤0.001) ([Figure 1] and [Figure 2]).
|Figure 1 Correlation between serum ferritin and urinary albumin/creatinine ratio in the two thalassemic groups (n=60).|
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|Figure 2 Correlation between serum ferritin and urinary beta 2 microglobulin in the two thalassemic groups (n=60).|
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| Discussion|| |
Patients with BTM usually present early in life with profound anemia that necessitates regular blood transfusion to survive. Repeated blood transfusions are inevitably associated with iron overload, which leads to multiple organ dysfunctions, namely, heart, liver, and endocrine glands .
Reports investigating renal dysfunction in thalassemia have been limited in number and mainly studying adult patients. Additionally, most of them did not assess early markers of glomerular and tubular functions, such as serum cystatin-C, UB2MG, and Urinary (N-Acetyl-ß-D Glucosaminidase) (UNAG), and none of these reports have compared between the effects of different chelators on renal function.
Several major factors are responsible for renal abnormalities found in BTM, which include shortened red cell life span, rapid iron turnover, and tissue deposition of excess iron. Moreover, the use of specific iron chelators is not without harm to the kidney . The cardiorenal syndrome, hepatorenal syndrome, and hepatitis-induced glomerulonephritis should be remembered as potential causes of renal diseases in patients with thalassemia. Renal stones are not uncommon in thalassemic patients ,.
The rapid improvement in biochemical parameters (serum creatinine) after discontinuation of the drug and the lack of other potential etiologies suggest that deferasirox is at least in part potentially responsible in this cohort of patients. The increase in serum creatinine observed with deferasirox-associated iron chelation therapy is thought to be owing to a reduction in GFR and renal blood flow in some patients. Therefore, this apparent nephrotoxicity is in part hemodynamic, reversible, and may account for some of the cases of acute kidney injury (AKI) and would appear safe in low-risk patients with no underlying renal disease. The mechanism for this change in renal blood flow may be in part related to chelator-induced iron depletion, affecting the afferent arteriole via an up-regulation of prostaglandin production and arteriole vasoconstriction .
Other commonly used chelators, DFO and deferiprone, may also be harmful to the kidneys. AKI and acute changes in renal function have been reported in up to 40% of patients given DFO when higher doses and overdoses occurred. Diarrhea and vomiting are common, and this may lead to volume depletion and pre-renal AKI ,. The relatively high incidence of Yersinia More Details infection with DFO therapy should be considered to cause AKI if sepsis follows . Likewise, deferiprone may cause, in ∼1% of the treated patients, agranulocytosis, which might lead to severe sepsis and acute tubular necrosis .
Manifestations of renal disease in thalassemia include glomerular and tubular dysfunction. Many early rather than conventional markers are used nowadays for these purposes. Lack of studies from Egypt on the effect of BTM, as well as the effect of different iron chelators on the renal function in the pediatric age group, has led to the necessity of such a study.
In the current study, starting with glomerular function tests, BUN was within the normal range in most of the children. Only 4/30 (13.33%) children of the deferasirox group had abnormally high levels. There was a statistically significant difference between the deferasirox group and the DFO and/or deferiprone group and the control group (P=0.003 and 0.003, respectively). These results may be explained by the fact that BUN is not an accurate indicator of renal function and is highly affected by the hydration state and nitrogen balance of the body.
In contrast to these results, Tantawy et al.  did not find significant differences between thalassemic and control groups. Fathi et al.  in Iraq, in 2013, found no significant differences between the group receiving and the group not receiving deferasirox and the control group. Moreover, Mula-Abed and colleagues did not find any abnormalities regarding urea in their study in 2011 in Oman.
Serum creatinine was within the normal range in most of the children. Only 1/30 (3.3%) of the deferasirox group showed levels higher than normal. Results showed no statistically significant difference among the three groups.
In agreement with these results, in Egypt, Tantawy et al. , in 2014, reported that, serum creatinine and BUN were not statistically different between thalassemic patients and controls.
Similarly, Mula-Abed et al.  reported that all patients in their study had normal creatinine levels. Similarly, Quinn et al. , reported that, most patients had values of BUN and creatinine that were in the normal range. Twenty-five had a BUN above the upper limit of normal for age, which were mostly mild elevations.
In another study, Cappellini et al. , reported, isolated serum creatinine values above the upper limit of normal were detected in six patients (three each) during the study. However, no patient had consecutive measurements of serum creatinine above the upper limit of normal.
In contrast, Hamed and El-Melegy  reported significantly elevated levels of creatinine in both thalassemic groups than the control (P<0.001, P<0.008).
Regarding ACR for microalbuminuria, as an early marker for glomerular integrity, the results of the current study showed that there was a statistically significant difference between the deferasirox group and control group (P=0.005) and between the DFO and deferiprone group and the control group (P=0.054). In agreement with these results, Quinn et al. , in 2011, reported that microalbuminuria was found in 59% of their patients and found that greater albuminuria was associated with increasing age. Similarly, Hamed and El-Melegy , in 2010, reported that microalbuminuria was found in 47 and 25.7% and proteinuria was found in 47 and 45.7% of patients with and without chelation, respectively (P<0.003 and <0.006). Tantawy et al.  reported that urinary total protein and microalbuminuria were significantly increased in all thalassemic (BTM and β-TI) patients (P<0.01). In contrast, Mula-Abed et al.  found that all of their patients had no microalbuminuria (<2.5 mg/mmol).
In the current study, there was no statistically significant difference between all groups in the eGFR using the Schwartz formula. Most of the studied children [25/30 in group A, 25/30 in group B, and 29/30 in group C] had GFR levels above the expected (>130 ml/min/1.73 m2). Only 1/30 of group A and 2/30 of group B had abnormally low eGFR. These results may be explained by the effect of anemia causing hyperdynamic circulation and resulting in glomerular hyperfiltration in the short term. Having such high results in most of the studied children including the control may also be explained by the fact that the GFR calculated by Schwartz formula is not very accurate and tends to overestimate the actual creatinine clearance. Some investigators reported hyperfiltration and explained this by anemia causing hyperdynamic circulation, and others, on the contrary, reported diminished GFR and assumed this a part of glomerular dysfunction.
In agreement with these results, Quinn et al. , in 2011, in their cross-sectional study including five thalassemia centers in North America, studied 216 thalassemic patients of different age groups and thalassemia subtypes (39% were children) to evaluate the prevalence of renal dysfunction in thalassemia patients; their results showed that hyperfiltration was common, involving one-third of the cases. It was significantly correlated with age and increased significantly among the subgroup, which was not regularly transfused. They used 24-h urine samples for the timed measurement of creatinine clearance and compared the results with GFR calculated by Schwartz formula for pediatric population and concluded that this formula mostly overestimates GFR with a mean difference of 30 ml/min/1.73 m2 between the two methods. They supposed that hyperfiltration could be a consequence of chronic anemia, similar to that observed in children with sickle cell anemia.
In contrast, Tantawy et al.  reported that corrected creatinine clearance was significantly lowered in both groups A and B (P<0.05 and 0.01, respectively). The same result was found by Hamed and El-Melegy . Moreover, Fathi et al. , in Iraq, found a significant decrease in creatinine clearance in group B receiving deferasirox, when compared with the control group. Deferasirox has characteristics such as marked iron chelating ability and prolonged plasma clearance that could contribute to renal toxicity. In addition, Cappellini et al.  have reported that creatinine clearance decreased during the first 6 months of deferasirox treatment, which then remained stable for the remainder of the study. Cappellini et al.  found a decrease in renal functions in up to one-third of patients treated with deferasirox; accordingly, kidney toxicity may be a major issue in the management of patients receiving deferasirox.
Regarding MB2MG, a marker of proximal tubular function, the present study shows a strong statistically significant difference between the two thalassemic groups on one side and the control group on the other side. Differences between groups A and C and differences between groups B and C, respectively (P=0.025 and 0.000), but showed no significant difference between the two thalassemic groups. From another point, in the DFO and/or deferiprone group, we had 19/30 (63.33%) children with abnormal high levels. and in the deferasirox group, we had 23/30 (76.67%) children with abnormally high results.
In agreement with these results, Hamed and El-Melegy , reported elevated UB2MG with significantly higher levels in both thalassemic groups than control (P<0.005 and 0.010).
Similarly, in Iran, in 2008, Sadeghi-Bojd et al.  studied 166 patients with BTM (96 male and 70 female). They found that patients with BTM showed significant signs of renal tubulopathy, such as hypercalciuria (12.9%), proteinuria (8.6%), phosphaturia (9.2%), magnesiumuria (8.6%), hyperuricosuria (38%), and excretion of MB2MG (13.5%).
In contrast, Quinn et al.  reported that UB2MG was detectable in only 4% of their patients. This discrepancy is most probably because they used a qualitative method to detect the B2MG protein in urine, whereas we used a quantitative method. Moreover, Mula-Abed et al.  reported that only 10% had elevated B2MG in urine, and their results may be explained by the small in size and highly selected sample of patients.Regarding UCa : Ucr, the current results showed that almost one-third of the patients had hypercalciuria. There was no statistically significant difference between the median of the three groups.
In agreement with these results, Quinn et al.  reported hypercalciuria in almost one-third of their patients and found more abnormalities in the regularly transfused BTM group than the not regularly transfused one. Hypercalciuria was not associated with vitamin D deficiency. They explained hypercalciuria by iron-mediated tubular injury but they did not find a correlation between serum ferritin and Uca : Ucr, but mentioned that ferritin may be a too poor marker of iron burden for this purpose.
Similarly, Mohkam et al. , found it in 23% of their patients. Smolkin et al. , also found hypercalciuria in six (16%) patients with BTM and nephrolithiasis in three (8%) of them, but they noted that all patients with hypercalciuria experienced hypoparathyroidism and were treated with calcium and vitamin D.
In the current study, ACR in urine was significantly positively correlated with serum ferritin levels (P=0.002). UB2MG is strongly positively correlated with serum ferritin (P=0.000).
These results illustrate the possible effects of iron overload on renal function. Massive iron deposit in tissues results in an increase of free-radical production via Fenton reaction, leading to cell death by binding cell proteins and disturbing their functions . Sumboonnanonda et al.  and Aldudak et al.  reported high urine levels of malondialdehyde, a lipid peroxidation metabolite, in thalassemic patients, suggesting a role of lipid peroxidation in renal injury.
Similarly, Hamed and El-melegy  reported that oxidative stress markers were disturbed in thalassemic patients more than the control, and these markers were correlated with renal function abnormalities. Hence, they attributed renal dysfunction in BTM to oxidative stress that results from iron overload.
| Conclusions|| |
- Renal dysfunction is prevalent in children with transfusion-dependent BTM.
- The use of early markers of glomerular and tubular renal function is much valuable and better applicable for screening and monitoring of the possible renal complications, than the conventional renal function tests (BUN and serum creatinine).
- Use of urinary ACR for microalbuminuria as a predictor for glomerular function and UB2MG as a predictor of tubular function is applicable and most probably cost effective.
- Iron overload was found to affect the renal function, as predictors of renal dysfunction are positively correlated with serum ferritin.
- Deferasirox, although carries more hazards to the renal function, is most probably considered safe when used within the usual doses and in low-risk patients.
The research was supported by Alexandria Faculty of Medicine.
This study was approved by Medical Research Ethics Committee at Alexandria Faculty of Medicine, and an informed consent was obtained from children guardians.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]