1. Introduction

Hemoglobinopathies are known as the most prevalent monogenic inherited disorders in the world. The World Health Organization (WHO) reported that approximately 5% of the world’s population is potentially pathological hemoglobin (Hb) gene carriers, and approximately 300,000 infants are born with thalassemia syndromes (30%) or sickle cell anemia (70%) each year around the world [1]. At first, hemoglobinopathies were found mainly in the Mediterranean area and parts of Asia and Africa. Still, the broad migration of the community has caused them to be extended around the world [2]. Iran has a high incidence of hemoglobinopathies due to the medium malaria endemicity in some provinces and the high rate of consanguineous marriages [3, 4].

Thalassemia syndromes and structural Hb variants are two major groups of hemoglobinopathies resulting from mutations or deletions in the α- or beta-globin genes, leading to Hb synthesis or structural disorders [2, 5]. The most common forms of hemoglobinopathies include thalassemia and sickle cell disease (SCD) [6]. The disease presentation can range from asymptomatic to severe conditions such as beta-thalassemia minor to thalassemia major that require regular blood transfusions and extensive medical care [7].

Red blood cell (RBC) count with erythrocyte indices and a Hb test are known as part of the initial workup in the diagnosis of hemoglobinopathies [2]. If the various Hb variants are accurately detected, serious Hb disorders such as major thalassemia can be prevented in newborns [7]. Most patients die from anemia or infections in the early years of life without appropriate diagnosis and treatment [1]. For patients with severe forms of hemoglobinopathies, conventional management usually involves frequent blood transfusions and iron chelation therapy, which can be beneficial in improving the prognosis of the disease, particularly in the case of beta-thalassemia [6, 8]. However, a serious consequence in patients who receive chronic blood transfusions is that they are inevitably at risk of iron overload [9]. Iron overload is the result of iron toxicity, as iron accumulates in the body’s tissues and leads to organ dysfunction, such as in the liver, endocrine glands, and heart. Back in the day, renal dysfunctions were not been a major problem in patients due to the limited survival regarded as cardiac iron overloading as a result of multiple blood transfusions [10, 11]. However, with the management of iron overload by chelators that leads to an iron overload decrease and survival improvement, the risk of renal complications becomes more common [9, 10]. On the other hand, studies have shown that the kidney is a potential organ for toxicity in the exposure to some iron chelators by increasing levels of serum creatinine (Cr) [9, 12, 13]. Although some studies have reported numerous organ dysfunctions associated with hemoglobinopathies and their treatments, there are limited data on the effect of these diseases and their treatment on the kidney [14]. Considering the limited studies investigating renal function in patients with hemoglobinopathies and iron overload, this study aimed to assess the correlation between renal function markers and serum ferritin levels in patients with thalassemia who were referred to the Abu Reihan Thalassemia Clinic of the Payambar Azam Medical Center in Bandar Abbas in 2020.

2. Method

This cross-sectional study was conducted in the Abu Reihan Thalassemia Clinic of the Payambar Azam Medical Center in Bandar Abbas in 2020. Seventy patients with a definite diagnosis of hemoglobinopathy requiring treatment and chelation therapy were included in the study. Inclusion criteria comprised serum ferritin levels above 1000, and written informed consent was obtained from the patient to participate in the study. Patients with prior nephrotic syndrome, a family background of renal conditions, or those on medications that are known to alter kidney parameters were excluded from the study. Finally, 66 patients who met the inclusion criteria participated in the study.

We observed patients with thalassemia in our medical center and collected demographic, clinical, hematologic, and biochemical data from all patients. After patients consented to participate in the study, demographic data including, sex, age, and type of hemoglobinopathy were recorded. Fasting venous blood (5 mL) was drawn under sterile conditions into plain and EDTA tubes to measure serum levels of creatinine, sodium (FENa), potassium (FEK), calcium (FECa), phosphorus (FEP), magnesium (FEMg), and uric acid (FEUa) and ferritin. In addition, a 24-h urine specimen was collected to determine the level of urine albumin, creatinine, FENa, FEK, FECa, FEP, FEMg, FEUa, and β2-microglobulin (β2M). Fractional excretion of FENa, FEK, FECa, FEP, FEMg, and FEUa were calculated with standard formulas. Finally, all the information was recorded using checklists.

The study protocol was approved by the Ethics Committee of Hormozgan University of Medical Sciences, and each patient gave written informed consent before participating in the study (IR.HUMS.REC.1398.356).

Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) Version 20 software. Normal distribution fitting was assessed through the Kolmogorov–Smirnov Goodness of Fit test. Quantitative data are expressed as the mean (±SD), and qualitative data are expressed as frequency and percentage. For quantitative data, comparisons between study groups were tested using the Mann–Whitney and Kruskal–Wallis tests, as appropriate, based on the distribution of the data. The correlation between serum ferritin levels and other variables was examined using Spearman’s coefficient of correlation. All statistical tests were performed at the 95% confidence level, and p values of less than 0.05 were considered statistically significant.

3. Results

4. Discussion

Iron chelation therapy has significantly improved survival in beta-thalassemia patients but has also highlighted renal complications, particularly in those with elevated ferritin levels. These complications are thought to arise from mitochondrial impairment, tubulo-glomerular feedback activation, and imbalances in vasodilatory and vasoconstrictive substances [8].

Among iron chelation medications, deferiprone (DFP) and deferasirox (DFX) are generally well tolerated but can cause transient elevations in creatinine. Moreover, deferoxamine (DFO), administered parenterally, is associated with tubular dysfunction and infection-related kidney injury [8]. Notably, a review reported that 13% of DFX-treated patients required dose reductions, with 25% of these returning to baseline creatinine levels, while others stabilized or showed minor fluctuations. Similarly, 14% of DFO-treated patients experienced creatinine increases. These findings underscore the importance of individualized dose management to minimize renal dysfunction risks in thalassemia patients [14].

This study aims to analyze renal function markers and ferritin levels in individuals with thalassemia receiving iron chelation treatment, and explore how these findings are associated with relevant factors.

Microalbuminuria, an early marker of kidney damage, was observed in 27.3% of the studied patients, aligning with previous research highlighting varying incidences of proteinuria [15–17]. Economou et al. [15] reported impaired renal function with proteinuria in 24% of cases, while Voskaridou et al. [16] found proteinuria in 30% of patients. These similarities underline the widespread occurrence of renal complications in this population, reinforcing the importance of early detection. On the other hand, Quinn et al. [17] documented a higher incidence of albuminuria, affecting 59% of patients, possibly reflecting the impact of a broader sample size or differences in diagnostic criteria and methodologies. Furthermore, Economou et al. stated that 24% of patients demonstrated impaired renal function with proteinuria [15]. Our study also revealed a strong correlation between the serum ferritin level and microalbuminuria, indicating that the serum ferritin level in patients with microalbuminuria is significantly higher than that in patients without microalbuminuria. This unique finding emphasizes the potential role of serum ferritin as a marker of renal dysfunction in thalassemia patients, a correlation not extensively addressed in previous studies.

The mean age of our patients indicated that our studied population was young. Moreover, in similar cross-sectional studies by Adly et al., Economou et al., and Tanus et al., the age of patients with beta-thalassemia major was younger [15, 18, 19]. This may be due to the fact that we included the mean age of patients with sickle cell thalassemia, major thalassemia, and intermedia thalassemia, which affected our final results, whereas Adly et al. included major and intermedia thalassemia and Economou et al. included only major thalassemia patients, as did Tanus et al. On the other hand, in the study presented by Voskaridou et al., the mean age of sickle and thalassemia patients was higher (42.1 years) [16]. These findings were inconsistent with our study, which could be attributed to the lower life expectancy of thalassemia patients compared to sickle cell patients [20].

In our study, β2M levels were above the normal range in 15.15% of the patients. Previous studies reported a higher incidence of increased β2M levels [15, 21, 22]. Economou et al. reported an increased excretion of β2M in 33.5% of patients with major thalassemia [15]. On the other hand, Deveci et al. measured the ratio of β2M to Cr (BCR) to assess renal tubular damage, which was increased in 64.6% of patients with beta-thalassemia [21]. Moreover, in the study by Safaei et al., abnormal levels of urinary β2M were also found in 44 patients (55%) [22]. These differences in β2M levels reported in previous studies may be due to the improvement in the medical care of thalassemia patients, which probably caused a reduction in the extent of proximal tubular damage. Our study also showed that there was no significant correlation between serum ferritin level and β2M. This finding was in agreement with the study of Safaei et al. [22]. The observed similarity could be a result of shared underlying pathophysiological mechanisms or comparable patient characteristics in both studies. In contrast, Adly et al. reported that there was a positive correlation between serum ferritin and urinary β2M in all thalassemia patients [18]. The discrepancies between our findings and the Adly et al. study regarding the correlation between beta-2 microalbuminuria and serum ferritin levels may stem from differences in genetic and environmental factors influenced by the distinct national contexts of Iranian and Greek populations.

Moreover, based on the data on our studied population, the mean serum creatinine level falls within the normal range, which was in agreement with the results by Adly et al. [18]. Contrary to our findings, two further studies that assessed kidney function tests among thalassemia patients and a control group discovered a notable rise in serum creatinine levels in those with thalassemia [16, 23]. This inconsistency may be attributed to differences in study populations. In the earlier studies, males were more prevalent, while our research included a larger share of female participants. In addition, Mahmoud et al. study included only children, whereas our study encompassed both children and adults, potentially influencing the observed variations in serum creatinine levels [23].

In our study, abnormal FENa, FECa, and FEUa were identified, consistent with the results reported by Mohkem et al., who also observed abnormal values of FENa, FEK, and FEUa [24]. These similarities suggest a potential pattern of electrolyte dysregulation in thalassemia patients. However, conflicting findings from other studies, which reported no significant differences in FENa and FEK between thalassemia patients and control groups, highlight the need for further investigation [18, 25, 26]. These differences may be attributed to variations in patient populations, sample sizes, or methodologies, emphasizing the complexity of renal dysfunction in thalassemia and the necessity for more standardized research approaches.

Our results showed that there was a significant and negative correlation between serum ferritin levels and FENa, FECa, FEP, FEMg, and FEUa. To the best of our knowledge, there has been no study mentioning the correlation between fractional excretion of electrolytes and serum ferritin levels in patients with thalassemia. On the other hand, some studies found a significant correlation between serum ferritin levels and other predictors of renal damage and prevented us from making further comparisons and analyses [19, 21, 23]. Tanus et al. and Mahmoud et al. reported a significant correlation between serum ferritin levels and urinary N-acetyl-b-D-glucosaminidase (UNAG) suggesting a relationship between ferritin and tubular injury [19, 23]. Conversely, Deveci et al. showed that there was no correlation between serum ferritin levels and renal damage (predictor factors included the ratio of urine albumin and β2M to Cr) in beta-thalassemia patients [21]. These discrepancies underscore the variability in renal damage markers across different studies and populations, emphasizing the need for further investigations to elucidate the complex interactions between ferritin levels and renal function in thalassemia patients.

The current study had some limitations that should be acknowledged. First, it was a cross-sectional study with a small sample size. We suggest conducting similar studies with a larger study population for a longer period in the future. Another limitation was that during this study, due to international sanctions, it was not possible to use N-acetylglucosamine (NAG) measurement kits, and they were practically rare. Lastly, the absence of a regression model represents a limitation in this study, and we are looking to incorporate it in future research to better examine the predictive links between the variables involved.

In conclusion, we realized that serum ferritin levels had a strong correlation with FeNa, FeUa, FeCa, FeP, and FeMg with a negative correlation coefficient in patients with hemoglobinopathies, indicating that as ferritin levels increased, these variables decreased and vice versa. The study also revealed a significant correlation between serum ferritin levels and microalbuminuria, indicating that individuals with microalbuminuria exhibit considerably elevated serum ferritin levels in comparison to those without the condition. Further studies are needed to investigate the relationship between renal function markers and serum ferritin levels in thalassemia patients.

Ethics Statement

The study protocol was approved by the Ethics Committee of Hormozgan University of Medical Sciences. Written informed consent was obtained from all patients.

Consent

Please see the Ethics Statement.

Disclosure

A preprint has previously been published.

Conflicts of Interest

The authors declare no conflicts of interest.

Author Contributions

M.T. and A.V. designed the study and were responsible for patient follow-up, clinical data collection, and manuscript preparation. N.K.-N. participated in data interpretation and manuscript preparation (draft and final editing). All authors read and approved the final manuscript.

Funding

No funding was received for this manuscript.