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ASE REPORTS

Hypocalcemia in a Dialysis Patient Treated With Deferasiroxfor Iron Overload

Bushra Yusuf, MD,1 Peter McPhedran, MD,2,3 and Ursula C. Brewster, MD1

Deferasirox is a new iron chelator approved recently for chelation therapy in iron-overloadedpatients. It is considered safe and efficacious in most patients, but has not been tested formally inpatients with end-stage renal disease. We report a case of a patient with end-stage renal diseasesecondary to sickle cell nephropathy who developed recurrent symptomatic hypocalcemia while ontherapy and later reexposure with this medication for iron overload from long-term blood transfu-sions. This is the first case report of this complication with deferasirox therapy in a patient withend-stage renal disease.Am J Kidney Dis 52:587-590. © 2008 by the National Kidney Foundation, Inc.

INDEX WORDS: Hypocalcemia; ferritin; iron overload; Exjade; chelation; end-stage renal disease.

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ince the advent of erythropoietin in the late1980s, the overall incidence of iron overload

n patients treated by dialysis has decreased. How-ver, particular patients remain at risk of this com-lication, including patients with hematologic dis-rders. Long-term blood transfusion therapy mayrolong and improve these patients’ lives.1 Unfor-unately, the resultant iron overload leads to signifi-ant morbidity and mortality. Deferasirox (ICL670;xjade; Novartis, Basel, Switzerland) is a new oral

ron chelator shown to have efficacy equal to defer-xamine mesylate (DFO) that was approved by theood and Drug Administration in 2005. Patients onialysis therapy were not included in the clinicalrials of this drug, but its favorable mechanism ofction and pharmacokinetics make it an attractiveption for this group.

We report the first case of severe symptomaticypocalcemia in a peritoneal dialysis patientoinciding with initiation of deferasirox therapyor iron overload.

CASE PRESENTATIONA 43-year-old woman with end-stage renal disease on

eritoneal dialysis therapy for 1 year secondary to sickle cellephropathy and hypertension remained dependent on long-erm blood transfusions and erythropoietin for treatment ofnemia. This resulted in severe iron overload, with ferritinalues consistently greater than 7,000 ng/mL (�7,000 �g/L).efore initiation of deferasirox therapy, she had a serum

erritin concentration of 7,866 ng/mL (7,866 �g/L), irononcentration of 150 �g/dL (27 �mol/L), iron saturation of7%, calcium level of 8.2 mg/dL (2.05 mmol/L), ionizedalcium level of 3.7 mEq/L (1.85 mmol/L), albumin level of.2 g/dL (32 g/L), phosphate level of 4.2 mg/dL (1.36mol/L), and intact parathyroid hormone level of 1,034

g/mL (1,034 ng/L). Her medication regimen included ateno-

merican Journal of Kidney Diseases, Vol 52, No 3 (September),

ol, amlodipine, lisinopril, losartan, lanthanum carbonate,llopurinol, renal multivitamin, folic acid, paricalcitol, andarbepoetin alfa. Peritoneal dialysate solutions contained.5 mEq/L (1.25 mmol/L) of ionized calcium.

The patient started on deferasirox therapy at a dose of,500 mg/d (corresponding to 20 mg/kg for her weight). Sheesponded well to the therapy, with a progressive decrease inerum ferritin levels over the next several months. Hererum calcium concentration decreased to 5.9 mg/dL (1.47mol/L), with an ionized calcium level of 3.0 mEq/L (1.5mol/L), during the same period without a change in intact

arathyroid hormone concentration (Fig 1). In response toypocalcemia, we increased the oral paricalcitol dose andubsequently switched to increasing doses of calcitriol be-ause of its tendency to increase serum calcium concentra-ion. We also started the patient on oral calcium supplemen-ation and increased the calcium ion concentration of herialysate solutions to 3.5 mEq/L (1.75 mmol/L). Despitehese measures, serum calcium levels continued to de-rease, and she developed periorbital paresthesias andental slowing. She was admitted to the hospital and

eceived intravenous calcium, with resolution of all symp-oms. Deferasirox, the only recent change in her medicalegimen, was discontinued. Her serum calcium concentra-ion continued to increase as an outpatient without otherhanges to her medication regimen. When it normalized,

From the 1Section of Nephrology and Departments ofInternal Medicine and 3Laboratory Medicine (Hematol-gy), Yale University School of Medicine, New Haven, CT.Received December 28, 2007. Accepted in revised formarch 6, 2008. Originally published online as doi:

0.1053/j.ajkd.2008.03.034 on June 5, 2008.Address correspondence to Ursula C. Brewster, MD,

ssistant Professor of Medicine, Section of Nephrology, Yaleniversity School of Medicine, FMP 107, 330 Cedar St, POox 208029, New Haven, CT 06520-8029. E-mail:rsula.brewster@yale.edu© 2008 by the National Kidney Foundation, Inc.0272-6386/08/5203-0022$34.00/0

doi:10.1053/j.ajkd.2008.03.034

2008: pp 587-590 587

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Yusuf, McPhedran, and Brewster588

he restarted deferasirox therapy. At this point, no otheredication changes were made; she remained on high

alcium dialysate and oral supplementation, and her se-um calcium concentration again decreased. Serum albu-in levels remained constant. She again discontinued

eferasirox therapy, with a subsequent improvement inerum calcium concentration.

DISCUSSION

Patients treated by dialysis who have a hema-ologic disorder may remain dependent on trans-usions, resulting in iron deposition in tissues,ncluding liver, heart, and endocrine organs. Thisay lead to significant morbidity and mortality.2

DFO was introduced in the 1960s and becametandard therapy for iron chelation because it im-roves overall quality/quantity of life.1,3 DFO is aarenteral hexadentate chelator, and the iron-DFOomplex is excreted predominantly by the kidneys.espite its beneficial effects, compliance with this

herapy is poor because of challenges of administra-ion.4,5 In patients treated by dialysis, it is adminis-ered less frequently. In peritoneal dialysis patients,FO has been administered intravenously, intraperi-

oneally, and intramuscularly with limited clinicaluccess.6,7 Severe life-threatening infections occur,hich makes it less useful.8,9

Deferasirox (4-[3,5-bis(2-hydroxyphenyl)-,2,4-triazole-1-yl]-benzoic acid) is a new oralron chelating agent. It is a tridentate ligand thatinds iron with high affinity in a 2:1 ratio. Theood and Drug Administration approved the drug

n November 2005 for transfusion-related iron p

verload in patients older than 2 years.10 Thispproval was based on results of phase 3 random-zed controlled trials of deferasirox versus DFO.11

dosage of 20 mg/kg/d of deferasirox wasufficient to maintain and stabilize ferritin levels,nd a dosage of 30 mg/kg/d resulted in a de-rease in serum ferritin concentrations. The effi-acy, tolerability, and safety of deferasirox inatients with normal kidney function were shown,nd notably, there were no changes in bloodhemistry test results or copper and zinc concen-rations during the study period.12 Minor sideffects (mainly gastrointestinal and dermatologi-al) and mild nonprogressive increases in serumreatinine levels were described.11,12

Severe symptomatic hypocalcemia has nevereen reported previously with deferasirox. In ouratient, measures were taken to combat the devel-ping hypocalcemia by increasing calcium in-ake, oral vitamin D preparation, and the calciumoncentration in the peritoneal dialysate, buterum calcium concentrations continued to de-rease. Rechallenge produced similar results.

The mechanism by which deferasirox causedypocalcemia is unclear. One hypothesis ishat the drug may cause chelation of calcium.his effect was not seen in clinical trials,hich included only patients with normal kid-ey function and an intact vitamin D andarathyroid axis. Perhaps healthy patients re-pond to subtle hypocalcemia in a way our

Figure 1. Trends in serumferritin and calcium concentra-tions with deferasirox therapy.Serum calcium concentrationsin our patient decreased whileon deferasirox therapy despitemultiple interventions and re-curred upon rechallenge. Ab-breviations: Vit D, Vitamin D;Ca, calcium. To convert serumcalcium in mg/dL to mmol/L,multiply by 0.25. Serum ferritinlevels expressed in ng/mL and�g/L are equivalent.

atient could not. However, given the differ-

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Hypocalcemia From Deferasirox 589

nces in charge and atomic weight betweenron and calcium, this seems an unlikely expla-ation.Another possible mechanism is that chelation

f iron by deferasirox from the patient’s bonesllows for increased bone uptake of calcium.ecently, investigators implicated iron overloads a cause of osteopenia and osteoporosis in menith genetic hemochromatosis (HFE gene muta-

ion) and those with thalassemia major.13,14 Ratsith experimental kidney failure and iron over-

oad showed a decrease in bone-forming activityompatible with adynamic bone disease.15 Also,ats fed a diet containing 50,000 ppm (5%) ironactate for 13 weeks developed osteomalaciaith an iron-positive reaction at the interfaceetween osteoid and mineralized bone.16 Thisuppression of bone remodeling and increased os-eoid thickness mimics aluminum-associated ady-amic bone disease. Five of 12 long-term dialysisatients with predominant iron deposition on boneiopsy had adynamic bone disease.17

DFO therapy improves bone histological char-cteristics and mineralization in long-term dialy-is patients with aluminum-associated adynamicone disease.18,19 It has also been used in pa-ients with aluminum overload related to totalarenteral nutrition. Hypocalcemia was seen inn 8-month-old infant treated with DFO for totalarenteral nutrition–associated aluminum over-oad without an increase in urinary calcium excre-ion, suggesting bone uptake of calcium afterhelation of aluminum.20 A similar hypocalce-ic effect was reported in 2 patients with dialysis-

ssociated aluminum osteomalacia treated withFO.19 These anecdotal reports support our hy-othesis that chelation of iron from our patient’sones by deferasirox may have led to increasedalcium uptake, the so-called “hungry-bone” syn-rome, and resultant hypocalcemia.In conclusion, deferasirox is an effective, safe,

nd well-tolerated iron chelating agent for pa-ients with iron overload. Hypocalcemia, al-hough apparently not a concern in patients withormal kidney, vitamin D, and parathyroid func-ions, may be a potentially severe adverse effectn patients treated by dialysis. Calcium levelshould be checked routinely in these patientshile on deferasirox therapy. In some patients,

eferasirox therapy may need to be discontinued. p

ACKNOWLEDGEMENTS

Support: None.Financial Disclosure: None.

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