Deferasirox in Patients with Chronic Kidney Disease: Assessing the Potential Benefits and Challenges

Abstract Chronic kidney disease (CKD) is a major global health concern, affecting millions of people worldwide. The progressive decline in kidney function often necessitates renal replacement therapy, such as hemodialysis (HD) or peritoneal dialysis (PD), to maintain a patient’s health. Iron overload, which is common in CKD patients on dialysis, can lead to severe complications, including cardiovascular disease and infections where most of the existing iron chelators are deemed unsuitable due to their suboptimal clearance in patients with compromised renal function, it becomes a significant challenge to effectively manage iron overload. Deferasirox (DFX), an oral iron chelator, has emerged as a promising treatment option for managing iron overload in these patients. However, the use of DFX comes with its unique set of challenges, such as its cost, potential side effects, and the need for close monitoring of patients, as well as the noticeable scarcity of comprehensive and rigorous clinical studies confirming its efficacy and safety of DFX. In this review, we delve into both the promising prospects and the emerging challenges associated with DFX use in managing CKD patients on HD or PD, striving for a comprehensive understanding that informs better clinical practice and patient care.


Introduction & Background
Chronic kidney disease (CKD) is a major public health concern which affects around 10% of the global population and is the 6th fastest growing cause of death worldwide. 1In the United States, approximately 37 million adults, or 15% of the population, have CKD. 1 In the United States, around 88% of patients with end-stage renal disease (ESRD) are treated with hemodialysis (HD), while 12% are treated with peritoneal dialysis (PD). 2 Globally, HD is the most used renal replacement therapy, with approximately 3.4 million patients receiving treatment, while PD is used by approximately 11% of the ESRD population. 2 Iron overload is a common complication in patients with CKD, particularly those on HD or PD. 3 It is associated with increased risk of cardiovascular disease, infections, and other complications.A recent systematic review and metaanalysis 4 estimated the pooled prevalence of severe and mild to moderate hepatic iron overload quantified by MRI was 0.23 and 0.52, respectively.The review revealed a high prevalence of severe hepatic iron overload in patients with ESRD treated by HD. 4 There has been some controversy over the use of DFX in CKD patients due to concerns over its safety and efficacy.While DFX has been shown to effectively reduce iron overload in CKD patients, its use in this population is still not fully understood.Some studies have suggested that DFX may increase the risk of renal impairment, while others have found no significant adverse effects on kidney function.Additionally, there have been concerns over the potential interactions between DFX and other medications commonly used in CKD patients.There is also some controversy over the optimal dosing of DFX in CKD patients, with some studies suggesting that lower doses may be safer and more effective than higher doses.Therefore, this review highlights the potential benefits and challenges associated with the use of DFX in patients with CKD on HD or PD.

Potential Benefits
Efficacy in Reducing Iron Overload Deferasirox (DFX) has demonstrated efficacy in reducing iron overload or hemosiderosis in various clinical settings, including in patients with transfusion-dependent thalassemia and sickle cell disease. 5Its mechanism of action involves binding to excess iron and promoting its excretion in the feces, thereby reducing the risk of iron-related complications. 6his potential to mitigate iron overload makes DFX an attractive treatment option for CKD patients on dialysis, who often receive frequent blood transfusions and intravenous iron therapy to manage anemia. 6

Oral Administration
One of the key advantages of DFX is its oral formulation, which offers patients a more convenient alternative to parenteral iron chelators, such as deferoxamine. 7Oral administration may improve patient adherence and enhance their overall quality of life. 7Moreover, the once-daily dosing regimen of DFX is an added benefit, further simplifying the treatment process for patients on dialysis. 7

Preservation of Kidney Function
Emerging evidence suggests that DFX may have nephroprotective effects in animal models. 8Iron chelation therapy with DFX has been associated with improved kidney function in patients with transfusion-dependent anemias. 9Although the exact mechanisms are not fully understood, DFX's ability to reduce iron deposition in the kidneys may contribute to preserving renal function. 9Consequently, DFX may offer additional benefits for CKD patients on dialysis by slowing the progression of renal decline.

Challenges and Concerns Limited Data in CKD Patients on Dialysis
Despite the potential benefits of DFX, there is a limited amount of data regarding its use in patients with CKD on HD or PD.Most studies have focused on patients with transfusion-dependent anemias, and the evidence for DFX in CKD patients remains scarce.Therefore, more research is needed to confirm the safety and efficacy of DFX in this population, as well as to establish appropriate dosing guidelines.
Maker et al 10 evaluated the safety and pharmacokinetics of DFX, an iron chelator, in eight hemodialysis-dependent patients with chronic kidney disease (CKD) who were receiving intravenous iron therapy.Two doses of DFX were administered (10 mg/kg and 15 mg/kg) either acutely or at steady state. 10The results showed that a dose of 10 mg/kg was insufficient to achieve therapeutic plasma concentrations, while 15 mg/kg-maintained plasma concentrations well above the therapeutic range. 10However, the observed plasma concentration was higher than expected for this dose, highlighting the importance of profiling drugs in specific patient groups such as CKD with iron overload. 10No adverse clinical events were observed in the study. 10n the other hand, Chen et al 11 evaluated the efficacy, safety, and tolerability of DFX, an iron chelating agent, in eight HD patients with iron overload caused by transfusion-induced renal anemia.DFX treatment (15 mg/kg/day) caused significant reductions in transferrin saturation (TSAT) and ferritin levels and increases in unsaturated and total ironbinding capacity. 11Although there were no significant changes in hematocrit or erythropoietin levels, monthly transfusion volumes decreased significantly. 11DFX was generally well-tolerated, with common adverse effects being nausea, vomiting, diarrhea, and abdominal pain. 11The study concludes that DFX is effective, safe, and tolerable in improving iron metabolism in HD patients with iron overload.
Moreover, Yii et al 12 reported a case of 54-year-old male with b-thalassemia major and end-stage renal disease (ESRD) was managed with continuous ambulatory peritoneal dialysis (CAPD) and required management of iron overload despite not being able to receive transfusions.DFX was administered orally at a dose of 1000 mg/day, and a total of 12.7L of peritoneal dialysate was collected over a 24-hour period with low levels of iron seen in the fluid. 12Over a 6-month period, serum ferritin levels decreased from 3869μg/l to 1545μg/l, and there were no episodes of peritonitis. 12These findings suggest that DFX may be a safe and effective agent for iron removal in iron-overloaded CAPD patients with relatively low dialysate iron levels, which reduces the risk of iron-dependent infections.
Another case reported a patient with ESRD secondary to sickle cell nephropathy who developed recurrent symptomatic hypocalcemia while receiving DFX therapy for iron overload from long-term blood transfusions. 13As per the authors, this is the first reported case of this complication with DFX therapy in a patient with ESRD, highlighting the need for caution and close monitoring of electrolyte levels in such patients. 13urthermore, patients with transfusion-dependent thalassemia and ESRD are at risk of iron overload, which can be managed by iron chelating agents such as DFX.A report by Beydoun et al 14 described two thalassemia patients on hemodialysis who were treated with DFX, resulting in a decrease in ferritin levels without any significant adverse events except for asymptomatic hypocalcemia in one patient.The dose used (up to 25 mg/kg/day) was higher than previously reported, indicating that DFX may be safe and effective for iron overload management in thalassemia patients with ESRD. 14Further studies are needed to confirm these findings.
A recent study by Bekhechi et al 15 evaluated the efficacy of DFX on reducing liver iron concentration (LIC) in 31 dialysis patients (30 HD, and 1 PD) with secondary hemosiderosis quantified by magnetic resonance imaging (MRI).The chelation therapy resulted in a significant reduction in LIC, mean ferritin level, and a gain in mean hemoglobin and albumin levels. 15The therapeutic response was influenced by the cause and degree of overload. 15These findings suggest that DFX, prescribed at a dose of 10 mg/kg/day, can be effective in reducing iron overload in dialysis patients and may have additional benefits in improving anemia and hypoalbuminemia. 15able 1 presents a comprehensive overview of significant research findings pertaining to the utilization of DFX in managing patients with CKD who are undergoing HD or PD.

Adverse Effects
The use of DFX is not without potential risks.Common side effects include gastrointestinal symptoms, such as abdominal pain, nausea, and diarrhea.More serious adverse effects, although rare, can include hypocalcemia, 13,14 renal impairment, hepatic dysfunction, and hematologic abnormalities. 16These potential complications may be of particular concern in CKD patients on dialysis, who often have multiple comorbidities and are more susceptible to drugrelated adverse events. 16Careful patient monitoring and dose adjustments may be necessary to minimize the risks associated with DFX therapy.

Drug Interactions
DFX is metabolized by the liver and may interact with other medications commonly prescribed to CKD patients, such as phosphate binders, antihypertensive drugs, and erythropoiesis-stimulating agents. 17These interactions can potentially alter the effectiveness of the medications and increase the risk of adverse effects. 17Therefore, healthcare providers must carefully consider potential drug interactions and adjust treatment regimens accordingly to optimize patient outcomes.

Cost and Access
The cost of DFX can be a significant barrier to its widespread adoption in CKD patients on dialysis. 18DFX is generally more expensive than traditional parenteral iron chelators, which may limit its accessibility, particularly for patients in low-resource settings or those without adequate insurance coverage.Efforts to address cost-related concerns and improve access to DFX will be crucial for ensuring that more patients can benefit from this therapy.

Table 1
Summary of Key Findings on the Use of DFX in Patients with Chronic Kidney Disease on Hemodialysis or Peritoneal Dialysis