1. Introduction

Chronic kidney disease (CKD) ranks among the most widespread noncommunicable diseases globally [1]. In its advanced phases, CKD progressively culminates in end-stage renal disease (ESRD) [2]. Patients with ESRD may encounter hyperphosphatemia as a consequence of the condition [3]. A healthy adult's plasma inorganic phosphate level is usually between 2.5 and 4.5 mg/dl. About 60% of this is absorbed through an active uptake mechanism controlled by sodium-phosphate co-transporters, and the other 40% comes in through diffusional and non-saturable inflow mainly happening in the jejunum and ileum [4–6].

Phosphate binders function by binding dietary phosphate to form insoluble complexes, which are eliminated by the gastrointestinal tract, potentially decreasing phosphate absorption by up to 40% [7,8] The glomerulus readily filters phosphate under typical physiological conditions, reabsorbing the majority in the proximal tubules [9]. Hyperphosphatemia happens when the kidneys aren't working properly, which upsets the balance of phosphates that is controlled by parathyroid hormone, active vitamin D, and fibroblast growth factor 23 (FGF-23) [10]. Since hyperphosphatemia is a common effect of ESRD, it is important to keep blood phosphate levels within certain limits to improve patients' quality of life and lower death and illness rates during maintenance hemodialysis [11,12].

A lot of people who are getting renal replacement therapy have high phosphate levels and need to be treated with phosphate binders. The limited effectiveness of existing therapeutic agents, the adverse effects of specific medications, financial limitations, inadequate treatment adherence, and, notably, a substantial pill burden complicate the therapeutic strategy [13]. Dialysis treatments, even when combined with limiting phosphate intake, often fail to treat hyperphosphatemia, so most patients need to take phosphate binders to keep their condition under control [14].

The primary phosphate binders utilized consist of calcium-based binders (calcium carbonate and calcium acetate), non-absorbable polymers (sevelamer carbonate), and heavy metal salts (lanthanum carbonate and aluminum hydroxide) [15,16]. Calcium-based phosphate binders and non-absorbable polymers are commonly utilized for patients with ESRD; however, increased dosages of calcium-based binders are frequently required to adequately manage phosphate levels, leading to an augmented total body calcium load, stimulating dynamic bone activity, and potentially increasing the risk of cardiovascular and soft tissue calcification [17,18].

Non-absorbable polymer binders, such as Sevelamer Carbonate, effectively reduce phosphate levels without inducing hypercalcemia; nonetheless, they are frequently linked to elevated prices, increased pill burden, and gastrointestinal adverse effects, including bloating and constipation [19]. These factors can influence adherence, particularly in resource-constrained environments.

Ferric citrate, due to its advantageous side effect profile and iron-replenishing capabilities, offers a pragmatic and patient-centric alternative. Research indicates that iron-based phosphate binders, like ferric citrate, may effectively regulate hyperphosphatemia in ESRD patients by significantly lowering serum inorganic phosphate levels [13,20], while also mitigating iron deficiency anemia, a common complication among CKD patients [21].

Given the socioeconomic challenges and limited healthcare resources in Bangladesh, ferric citrate could be a promising option for managing hyperphosphatemia in ESRD patients. However, studies regarding the use of ferric citrate among ESRD patients in Bangladesh are scarce. Conducting a study to determine the efficacy of ferric citrate as a phosphate binder will contribute to evidence-based clinical practices tailored to the unique needs and socioeconomic conditions of Bangladeshi patients and improve the standard of care for ESRD patients on maintenance hemodialysis. The current study, on the other hand, looked at how well ferric citrate worked as a phosphate binder in ESRD patients in Bangladesh who were on maintenance hemodialysis.

2. Materials and Methods

This open-label, randomized controlled trial (RCT) was conducted in the Department of Nephrology of Bangabandhu Sheikh Mujib Medical University (BSMMU) and Dhaka Medical College Hospital (DMCH), Dhaka, Bangladesh, between August 2022 and March 2023. The Institutional Review Board (IRB) of BSMMU provided formal ethical approval for the study (Ref: BSMMU/2022/7428).

Selection of the participants

As per selection criteria, adult (age ≥ 18 years) patients diagnosed with CKD Stage 5D, receiving twice-weekly maintenance hemodialysis, were enrolled in the study. The study excluded CKD patients with corrected calcium levels of less than 8.5 mg/dl or more than 10.5 mg/dl, and inorganic phosphate levels of less than 2.5 mg/dl or more than 10 mg/dl. The study also excluded patients with active malignancy, pregnant or lactating women, and known intolerance to ferric citrate, sevelamer carbonate, or calcium acetate. Following informing the aims and objectives of the study, informed written consent was taken from the participants. Data were collected through face-to-face interviews using a semi-structured data collection tool. The study population underwent detailed history taking, physical examination, and relevant investigations. Assessment of serum inorganic phosphate, corrected calcium, and serum intact parathyroid hormone (iPTH) was done at baseline, before initiating the interventions.

Intervention allocation

This study consisted of three groups: one intervention group (Group A) and two control groups (Group B and Group C). People in the intervention group (Group A) were given two tablets a day for three months that contained 210 mg of ferric citrate, an iron-based phosphate binder. As a control, Group B was given 800 mg of Sevelamer Carbonate three times a day and Group C was given 667 mg of Calcium Acetate three times a day for three months. Initially, 52 CKD-5D patients meeting the selection criteria were enrolled and divided into three groups following the simple random sampling. Following the lottery technique, 17 patients were included in Ferric citrate (Group A) and Calcium Acetate (Group C) separately, and 18 were enrolled in Group B. Following the baseline assessment, intervention was initiated. The patients were followed up in a 7-day interval to check the drug compliance. Patients were advised to contact immediately over the phone if any adverse drug reaction occurred. Any adverse events resulting from the medications were managed accordingly. All the patients were counseled regarding a phosphate-restricted diet and adherence to phosphate binder intake. The total number of dropouts from the study was 7 patients. 6 patients discontinued intervention due to various reasons (blood transfusion, hospital admission, death, and consent withdrawal). Lost to follow-up was 1 patient. Finally, a total of 45 patients (15 from each group) completed the study. Follow-up assessments of serum inorganic phosphate, corrected calcium, and iPTH were done after 3 months of interventions (Figure 1).

Figure 1: Study flow chart

Statistical analysis

Statistical analysis was performed using the Windows®-based software program Statistical Packages for Social Sciences 25 (SPSS-25) (Chicago, IL, USA). After collection, all the data were checked and cleaned. Quantitative data were expressed as mean, standard deviation, median, and range, and qualitative data as frequency (percentage). The normality distribution of the data was assessed by the Shapiro-Wilk test. To determine statistical significance, one-way ANOVA, the chi-square test, and the Wilcoxon signed-rank test were considered according to applicability. The p-value of < 0.05 was considered statistically significant.

3. Results

The mean age of the patients of the intervention group (Group A) was 49.3 ± 13.5 years, and the mean age of the patients of Group B and Group C was 53.7 ± 12.3 and 54.3 ± 12.9 years, respectively. Patients of each group were male predominant. Patients of each group were demographically similar. Diabetes mellitus was more prevalent among control groups, 60% & 66.7% in Groups B and C, compared to 46.7% in the intervention group. Hypertension was also more prevalent among the control group, 93.3% for both groups B and C, compared to 86.7% in the intervention group. The proportion of comorbidities showed no statistically significant difference between the intervention and control groups (Table 1).

Table 1: Distribution of the patients according to demographic profile, and comorbidities (n = 45)

^a One-way ANOVA, and ^bChi-square test were used

Data presented as frequency (%), mean ± SD

A significant reduction in the serum phosphate level from baseline was observed in Group A [median (range): 4.5 (4.0-7.0) to 4.2 (3.2-6.9) (mg/dl)], Group B [median (range): 5.9 (4.37-7.80) to 5.4 (3.2-7.00) (mg/dl)], and Group C [median (range): 5.6 (4.2-7.0) to 5.0 (3.8-6.8) (mg/dl)] following treatment with ferric citrate, sevelamer carbonate, and calcium citrate, respectively, for three months (Figure 2).

Figure 2: Changes in serum phosphate level with phosphate-binder treatment at baseline and after 3 months (n = 45)

A significant reduction in the serum iPTH level was observed in Group A [median (range): 490.0 (190.0-717.0) to 333.6 ± 143.36 (ng/L)], Group B [median (range): 312.0 (24.60-700.0) to 230.0 (30.0-461.0) (ng/L)], and Group C [median (range): 400.0 (47.7-1900.0) to 299.0 (78.0-1200.0) (ng/L)] following treatment with ferric citrate, sevelamer carbonate, and calcium citrate, respectively, for three months. A significant increase in the corrected calcium was observed in Group C [median (range): 8.8 (8.2-9.9) to 10.0 (9.4-10.9) (mg/dl)]; however, no such variation was observed in Group A and Group B (Table 2).

Table 2: Changes in biochemical parameters with phosphate-binder treatment from baseline to after 3 months (n = 45)

SD: Standard Deviation, iPTH: Intact parathyroid hormone

Wilcoxon signed-rank test was used

Data presented as mean ± SD, median (range)

Discolored feces were the most prevalent side effects (73.3%) among the Group A patients treated with ferric citrate, followed by diarrhea (13.3%). Among the Group B patients treated with Sevelamer Carbonate, 20.0% were suffering from dyspepsia, followed by constipation (13.3%) and diarrhea (6.7%). Among the Group C patients treated with calcium acetate, 20.0% were suffering from nausea, followed by diarrhea (13.3%), dyspepsia (13.3%), and constipation (6.7%) (Table 3).

Table 3: Side effects of the phosphate binders (n=45)

Data presented as frequency (%)

4. Discussion

Hyperphosphatemia in ESRD markedly elevates morbidity and mortality risks. Addressing hyperphosphatemia is essential for preserving mineral equilibrium, averting cardiovascular disorders, and enhancing overall survival rates. The existing Kidney Disease Improving Global Outcomes (KDIGO) clinical guidelines recommend a tripartite strategy to manage serum phosphorus levels: dietary phosphate restriction, adequate maintenance dialysis, and the use of phosphate-lowering agents to impede intestinal phosphate absorption. About 80% of dietary phosphate is absorbed in the intestinal tract; thus, limiting dietary phosphate intake is essential for treating hyperphosphatemia in persons with CKD. However, this may pose challenges for patients who are already following several nutrient-restricted diets [14,22]. Patients with hyperphosphatemia undergoing dialysis often experience inadequate management of their condition despite dietary phosphate limitations, requiring phosphate binders for effective regulation to maintain mineral equilibrium, prevent cardiovascular diseases, and improve overall survival. This study aimed to assess the efficacy of ferric citrate as a phosphate binder in patients with ESRD receiving maintenance hemodialysis. According to this study, ferric citrate is equally or, to some extent, more effective than other phosphate binders.

In this study, the mean age of the patients was within their early fifties, and male predominance was observed, which was consistent with the findings of Kiss et al. (2013), where the mean age of the patients was between 50 and 60 years with male preponderance (52.8%) [23]. Among the patients of ESRD with hyperphosphatemia, the use of phosphate binders is essential for the management of ESRD patients and mitigates the consequences of it.

In this study, three different forms of phosphate binders were used in three distinct groups of participants. Serum phosphate concentrations were found to decline significantly in the group of patients receiving ferric citrate, sevelamer carbonate, and calcium citrate for three months. The study conducted by Wang et al. (2023) and Chen et al. (2014) reported that ferric citrate and sevelamer carbonate [24,25] potentially reduce the serum phosphate level. Wang et al. (2023) confirmed that ferric citrate is non-inferior to sevelamer carbonate to control hyperphosphatemia in CKD patients undergoing hemodialysis, which is similar to our study findings [24]. Wang et al. (2015) reported that calcium acetate is effective in lowering serum phosphate in chronic dialysis patients [26]. It is possible that the same effect of lowering serum phosphate levels could have been achieved by treating age-sex-matched participants, imposing the same dietary restrictions, and using the same mechanism of action by these three phosphate binders. This mechanism involves forming insoluble complexes with dietary phosphate in the gastrointestinal tract and excreting them in stool by means of the phosphate binder.

The reduction in glomerular filtration rate disrupts calcium and phosphorus equilibrium and decreases renal phosphorus excretion, leading to increased blood phosphorus concentrations [27]. As a result, hyperphosphatemia causes dystrophic calcification, secondary hyperparathyroidism, and other mineral metabolism abnormalities [11,28]. The current analysis revealed that all phosphate binders markedly reduced serum iPTH, alongside a decrease in blood phosphate levels, aligning with the results of Van Buren et al. (2015)[29] . After 3 months of treatment, patients administered calcium acetate exhibited a significant elevation in serum calcium levels, whereas no such increase was observed in persons receiving ferric citrate and sevelamer carbonate. The significant increase in corrected serum calcium levels may elevate the risk of cardiovascular and soft tissue calcification [17,18], indicating that ferric citrate offers a safety advantage by not elevating corrected serum calcium levels, thereby reducing the risk of cardiovascular and soft tissue calcification.

In the present study, it was found that discolored feces, dyspepsia, and nausea were the common adverse events in the Ferric Citrate, Sevelamer Carbonate, and Calcium Acetate groups, respectively. Other adverse events that were noted were diarrhea, vomiting, and constipation. Yoshida et al. (2022) showed diarrhea to be the most commonly reported adverse drug reaction among patients taking ferric citrate, which does not support the present study findings [30]. But, in the current study, patients who were known to have an intolerance to phosphate binders were excluded from the study, which might have influenced the study result. However, these reported side effects were well tolerated. Based on the above-mentioned findings, it can be concluded that ferric citrate is equally effective and cost-efficient with a considerable safety profile when compared to other phosphate binders like sevelamer carbonate and calcium acetate.

Limitations

The study was conducted only in two centers with a relatively small sample size, which limits the generalizability of the study findings. Blinding was not utilized in this study, which may perhaps lead to biases.

5. Conclusion

Patients with end-stage renal illness were primarily male and in their fifties. Ferric citrate, sevelamer carbonate, and calcium acetate significantly decreased serum phosphate concentrations. All three phosphate binders markedly reduced serum intact parathyroid hormone levels. Ferric citrate shows a significant safety benefit by not elevating corrected serum calcium levels; hence, it reduces the risk of cardiovascular and soft tissue calcification. Adverse effects, such as discolored feces, dyspepsia, and nausea, were documented but were mostly well tolerated. These results show that Ferric Citrate is a safe, effective, and cost-effective alternative that works just as well as Sevelamer Carbonate and Calcium Acetate. This supports its use as a first-line treatment for hyperphosphatemia management in people with ESRD who are on maintenance dialysis.

Acknowledgements

Special thanks to the participants for their cordial support.

Declarations

Funding

The authors received no specific funding for this work.

Conflict of interest

The authors declared no potential conflicts of interest to this article's research, authorship and publication

Ethical approval:

The Institutional Review Board (IRB) of BSMMU provided formal ethical approval for the study (Ref: BSMMU/2022/7428).

References

1. El Nahas AM, Bello AK. Chronic kidney disease: the global challenge. The Lancet 365 (2005): 331-40.
2. Rashid HU. Management of End Stage Renal Disease-Bangladesh Perspective. Open Urol Nephrol J 7 (2014): 108-112.
3. Ueda N, Takasawa K. Impact of Inflammation on Ferritin, Hepcidin and the Management of Iron Deficiency Anemia in Chronic Kidney Disease. Nutrients 10 (2018): 1173.
4. Bellasi A, Ferramosca E, Muntner P, et al., Correlation of simple imaging tests and coronary artery calcium measured by computed tomography in hemodialysis patients. Kidney Int 70 (2006): 1623-1628.
5. Gaasbeek A, Meinders AE. Hypophosphatemia: An update on its etiology and treatment. Am J Med 118 (2005): 1094-1101.
6. Sabbagh Y, Giral H, Caldas Y, et al., Intestinal Phosphate Transport. Adv Chronic Kidney Dis 18 (2011): 85-90.
7. Bellasi A, Kooienga L, Block GA. Phosphate binders: New products and challenges. Hemodial Int 10 (2006): 225-234.
8. Cupisti A, Morelli E, D’Alessandro C, Lupetti S, Barsotti G. Phosphate control in chronic uremia: don’t forget diet. J Nephrol 16 (2003): 29-33.
9. Uribarri J. Phosphorus Homeostasis in Normal Health and in Chronic Kidney Disease Patients with Special Emphasis on Dietary Phosphorus Intake. Semin Dial 20 (2007): 295–301.
10. Craver L, Marco MP, Martinez I, et al., Mineral metabolism parameters throughout chronic kidney disease stages 1-5--achievement of K/DOQI target ranges. Nephrol Dial Transplant (2007): 1171-1176.
11. Isaka Y, Hamano T, Fujii H, et al, Optimal Phosphate Control Related to Coronary Artery Calcification in Dialysis Patients. J Am Soc Nephrol 32 (2021): 723-735.
12. Mathias SD, Blum SI, Sikirica V, Johansen KL, Colwell HH, Okoro T. Symptoms and impacts in anemia of chronic kidney disease. J Patient-Rep Outcomes. 2020 Dec;4(1):64.
13. Yagil Y, Fadem SZ, Kant KS, et al., Managing hyperphosphatemia in patients with chronic kidney disease on dialysis with ferric citrate: latest evidence and clinical usefulness. Ther Adv Chronic Dis 6 (2015): 252-263.
14. Shaman AM, Kowalski SR. Hyperphosphatemia Management in Patients with Chronic Kidney Disease. Saudi Pharm J. 2016 Jul;24 (2016): 494-505.
15. Elseviers M, De Vos J. The use of phosphate binders: data from contributors to the European Practice Database. J Ren Care 35 (2009):14-18.
16. Tonelli M, Pannu N, Manns B. Oral Phosphate Binders in Patients with Kidney Failure. N Engl J Med 362 (2010): 1312-1324.
17. Salusky IB. A new era in phosphate binder therapy: What are the options? Kidney Int 70 (2006): S10-15.
18. Chiu YW, Teitelbaum I, Misra M, et al., Pill Burden, Adherence, Hyperphosphatemia, and Quality of Life in Maintenance Dialysis Patients. Clin J Am Soc Nephrol 4 (2009): 1089-1096.
19. Fishbane S, Delmez J, Suki WN, et al., A Randomized, Parallel, Open-Label Study to Compare Once-Daily Sevelamer Carbonate Powder Dosing with Thrice-Daily Sevelamer Hydrochloride Tablet Dosing in CKD Patients on Hemodialysis. Am J Kidney Dis 55 (2010): 307-315.
20. Lee CT, Wu IW, Chiang SS, et al., Effect of oral ferric citrate on serum phosphorus in hemodialysis patients: multicenter, randomized, double-blind, placebo-controlled study. J Nephrol 28 (2015): 105-113.
21. Wu MY, Chen YC, Lin CH, et al., Safety and efficacy of ferric citrate in phosphate reduction and iron supplementation in patients with chronic kidney disease. Oncotarget 8 (2017): 107283-107294.
22. Jumaa AK. Kidney disease: Improving global outcomes (KDIGO) anemia work group. KDIGO clinical practice guideline for anemia in chronic kidney disease. Kidney Int 2 (2012): 279–335.
23. Kiss I, Kiss Z, Ambrus C, et al., Age-dependent parathormone levels and different CKD-MBD treatment practices of dialysis patients in Hungary - results from a nationwide clinical audit. BMC Nephrol 14 (2013): 155.
24. Wang Y, Chen X, Zhu H, et al., Efficacy and Safety of Ferric Citrate on Hyperphosphatemia among Chinese Patients with Chronic Kidney Disease Undergoing Hemodialysis: A Phase III Multicenter Randomized Open-Label Active-Drug-Controlled Study. Am J Nephrol 54 (2023): 479-488.
25. Chen N, Wu X, Ding X, et al., Sevelamer carbonate lowers serum phosphorus effectively in haemodialysis patients: a randomized, double-blind, placebo-controlled, dose-titration study. Nephrol Dial Transplant 29 (2014): 152-160.
26. Wang Y, Xie G, Huang Y, et al., Calcium Acetate or Calcium Carbonate for Hyperphosphatemia of Hemodialysis Patients: A Meta-Analysis. PLoS ONE 10 (2015): e0121376.
27. Khairallah P, Isakova T, Asplin J, et al., Acid Load and Phosphorus Homeostasis in CKD. Am J Kidney Dis. 70 (2017): 541-550.
28. Adeney KL, Siscovick DS, Ix JH, et al., Association of Serum Phosphate with Vascular and Valvular Calcification in Moderate CKD. J Am Soc Nephrol 20 (2009): 381-387.
29. Van Buren PN, Lewis JB, Dwyer JP, et al., The Phosphate Binder Ferric Citrate and Mineral Metabolism and Inflammatory Markers in Maintenance Dialysis Patients: Results From Prespecified Analyses of a Randomized Clinical Trial. Am J Kidney Dis Off J Natl Kidney Found 66 (2015): 479-488.
30. Yoshida T, Morimoto K, Kaburagi N, et al., Long-term efficacy and safety of iron-based phosphate binders, ferric citrate hydrate and sucroferric oxyhydroxide, in hemodialysis patients. Int Urol Nephrol 54 (2022): 861-872.