The administration of deferasirox in an iron-overloaded
dialysis patient
Tsai CW, Yang FJ, Huang CC, Kuo CC, Chen YM.
Iron overload has been implicated as a nontraditional risk factor for
cardiovascular diseases in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD).[1, 2] Given this fact, iron overload not only offers clinical prognostic value, but will be an emerging therapeutic target in CKD and dialysis patients. Here, we present a case involving a dialysis patient with severe hemochromatosis who underwent successful treatment. Since January 2008, a 59-year-old male patient had been suffering from an intractable malaise. He had a history of paroxysmal nocturnal hemoglobinuria (PNH) and received maintenance dialysis therapy for ESRD since September 2007. The PNH was initially diagnosed in 1984 and gradually became
transfusion dependent. In the 1990s, the frequency of transfusion was seasonal, and then became monthly in the 2000s. The first biochemical examination in our hospital revealed serum iron levels to be 181 μg/dL (normal 30–180 μg/dL), total iron-binding capacity to be 192 μg/dL (normal 250–450 μg/dL), transferrin saturation to be 94.3%, and ferritin levels to be
7420 ng/mL (normal 21.8–274.66 ng/mL). After developing into ESRD, the patient required frequent transfusions with packed red blood cells (PRBC; 500 mL biweekly) in addition to the aggressive use of an erythropoiesis-stimulating agent for refractory anemia to maintain hemoglobin levels at approximately 8.0–9.0 g/dL. Given the history of refractory anemia and regular component therapy accompanied by severe intractable malaise and a soaring serum ferritin level, a clinical diagnosis of chronic iron overload was made. Chelating therapy with deferoxamine (DFO, Desferal; Novartis
Pharmaceuticals, Basel, Switzerland) was initiated in May 2008. One year later, the patient's serum ferritin concentration exceeded 12,000 ng/mL, and was accompanied by severe exertional dyspnea and chronic hepatitis. Abdominal magnetic resonance imaging (MRI) revealed a decreasing signal in both the liver and the spleen (Figure 1). Given the poor response to DFO, an alternative chelating agent, deferasirox (Exjade; Novartis
Pharmaceuticals), was considered despite it not being approved for the ESRD population in either Taiwan or by the US Food and Drug Administration (FDA). After obtaining the patient's consent, 750 mg (15 mg/kg/d) of deferasirox was administered daily since July 2009. The patient's serum ferritin levels declined
steadily to 3252 ng/mL under the maintenance dosage of 500 mg/d (10 mg/kg/d) that was initiated in December 2010 (Figure 2).
In this PNH patient with ESRD, renal anemia further aggravated the
transfusion demand for this rare disorder that is characterized by defective hematopoiesis.[3] Iron overload was therefore inevitable in our patient given the multiple and frequent blood transfusions, approximating at least 300 units of PRBC (unit of blood = 250 mL) so far. Although the symptoms of secondary hemochromatosis are nonspecific, intolerable weakness, abdominal pain, and anorexia are symptoms that allowed the clinicians to direct their attention to iron overload; this diagnosis was supported by extremely high serum levels of ferritin, transferrin saturation of >45%, and typical iron overload on liver MRI. The challenge that followed was determining how to successfully conduct chelating therapy in a dialysis patient with extreme iron accumulation. Borrowing from the experience of treating dialysis patients suffering from aluminum overload, DFO was titrated gradually from a dosage of 10–40 mg/kg/week and administered during a period of 1 year.[4] However, no sign of clinical improvement was observed and serum ferritin levels progressively increased to 12,123 ng/mL. Considering iron chelation therapy, deferasirox
offered an alternative option.[5] Thus, we replaced the administration of intravenous DFO with that of oral deferasirox. We began with a dose of 15 mg/kg/d and slowly titrated the dosage to a maximum of 30 mg/kg/d. The patient responded well with a progressive decrease in serum ferritin levels during the follow-up period. Currently, under a daily dosage of 10 mg/kg/d, the patient remains free from iron overload symptoms, with serum ferritin levels controlled at 3000–3500 ng/mL. Furthermore, our patient did not experience any significant complications from deferasirox administration, including skin rash, fever, or intolerable abdominal pain. It is also worth noting that
hypocalcemia, which is the only adverse effect known to result from deferasirox use in a ESRD patient, was also absent in our patient.[6] This case demonstrates the effectiveness, safety, and tolerability of deferasirox administration in dialysis patients. Given that deferasirox may cause acute renal failure, creatinine clearance <40 mL/min and serum creatinine >2-fold the upper limit of normal are listed as contraindications by Novartis and the FDA.[7] However, deferasirox has not been studied in patients with renal impairment. Its mechanism of iron excretion is predominantly fecal, and both deferasirox and its metabolites are primarily excreted in feces.[7] Based on our experience, deferasirox can be hypothesized to be safe for patients with
ESRD undergoing renal replacement therapy, for whom acute renal failure is no longer a concern.
References
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3. Rimola J, Martin J, Puig J, Darnell A, Massuet A. The kidney in
paroxysmal nocturnal haemoglobinuria: MRI findings. Br J Radiol. 2004; 77:953–956.
4. McCarthy JT, Milliner DS, Schmidt DF, Schniepp BJ, Kurtz SB, Johnson WJ. Deferoxamine and coated charcoal hemoperfusion to remove aluminum in dialysis patients. Kidney Int. 1988; 34:804–808.
5. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al. Effectiveness and safety of ICL670 in iron-loaded patients with thalassaemia: A randomised, double-blind, placebo-controlled, dose-escalation trial. Lancet. 2003; 361:1597– 1602.
6. Yusuf B, McPhedran P, Brewster UC. Hypocalcemia in a dialysis patient treated with deferasirox for iron overload. Am J Kidney Dis. 2008; 52:587– 590
7. Hohneker JA. Exjade (deferasirox): Boxed warning. In: MedWatch: The FDA Safety Information and Adverse Event Reporting Program; 2010.
Figure 1. Secondary hemochromatosis. Axial magnetic resonance imaging with the T2-weighted fast-recovery fast spin-echo (FRFSE) sequence demonstrated significant accentuated decreases in liver and spleen signal intensities.
Figure 2. Trends in serum ferritin levels and the dosages of deferoxamine and deferasirox administered from 2008 to 2010. *Axis scale of deferoxamine (DFO) is mg week and of deferasirox is mg per day.
