Hypocalcemia in a Dialysis Patient Treated With Deferasirox for Iron Overload

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  • CASE REPORTS

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    AmCASE PRESENTATION 43-year-old woman with end-stage renal disease on

    itoneal dialysis therapy for 1 year secondary to sickle cellhropathy and hypertension remained dependent on long- blood transfusions and erythropoietin for treatment of

    mia. This resulted in severe iron overload, with ferritinues consistently greater than 7,000 ng/mL (7,000 g/L).fore initiation of deferasirox therapy, she had a serumritin concentration of 7,866 ng/mL (7,866 g/L), ironcentration of 150 g/dL (27 mol/L), iron saturation of, calcium level of 8.2 mg/dL (2.05 mmol/L), ionized

    cium level of 3.7 mEq/L (1.85 mmol/L), albumin level of g/dL (32 g/L), phosphate level of 4.2 mg/dL (1.36ol/L), and intact parathyroid hormone level of 1,034

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

    changes to her medication regimen. When it normalized,

    From the 1Section of Nephrology and Departments of2Internal Medicine and 3Laboratory Medicine (Hematol-ogy), Yale University School of Medicine, New Haven, CT.

    Received December 28, 2007. Accepted in revised formMarch 6, 2008. Originally published online as doi:10.1053/j.ajkd.2008.03.034 on June 5, 2008.

    Address correspondence to Ursula C. Brewster, MD,Assistant Professor of Medicine, Section of Nephrology, YaleUniversity School of Medicine, FMP 107, 330 Cedar St, POBox 208029, New Haven, CT 06520-8029. E-mail:ursula.brewster@yale.edu

    2008 by the National Kidney Foundation, Inc.0272-6386/08/5203-0022$34.00/0doi:10.1053/j.ajkd.2008.03.034

    erican Journal of Kidney Diseases, Vol 52, No 3 (September), 2008: pp 587-590 587Hypocalcemia in a Dialysis for Iron

    Bushra Yusuf, MD,1 Peter McPhedra

    Deferasirox is a new iron chelator approvpatients. It is considered safe and efficaciouspatients with end-stage renal disease. We resecondary to sickle cell nephropathy who devtherapy and later reexposure with this medicsions. This is the first case report of this cend-stage renal disease.Am J Kidney Dis 52:587-590. 2008 by the Na

    INDEX WORDS: Hypocalcemia; ferritin; iron over

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

    patients treated by dialysis has decreased. How-er, particular patients remain at risk of this com-cation, including patients with hematologic dis-ers. Long-term blood transfusion therapy maylong and improve these patients lives.1 Unfor-ately, the resultant iron overload leads to signifi-t morbidity and mortality. Deferasirox (ICL670;

    jade; Novartis, Basel, Switzerland) is a new oraln chelator shown to have efficacy equal to defer-amine mesylate (DFO) that was approved by theod and Drug Administration in 2005. Patients onlysis therapy were not included in the clinicalls of this drug, but its favorable mechanism ofion and pharmacokinetics make it an attractivetion for this group.We report the first case of severe symptomaticpocalcemia in a peritoneal dialysis patientinciding with initiation of deferasirox therapyent Treated With Deferasiroxrload,2,3 and Ursula C. Brewster, MD1

    cently for chelation therapy in iron-overloadedost patients, but has not been tested formally in case of a patient with end-stage renal disease recurrent symptomatic hypocalcemia while onfor iron overload from long-term blood transfu-ation with deferasirox therapy in a patient with

    Kidney Foundation, Inc.

    xjade; chelation; end-stage renal disease.

    amlodipine, lisinopril, losartan, lanthanum carbonate,purinol, renal multivitamin, folic acid, paricalcitol, andbepoetin alfa. Peritoneal dialysate solutions contained mEq/L (1.25 mmol/L) of ionized calcium.he patient started on deferasirox therapy at a dose of

    00 mg/d (corresponding to 20 mg/kg for her weight). Sheponded well to the therapy, with a progressive decrease inum ferritin levels over the next several months. Herum calcium concentration decreased to 5.9 mg/dL (1.47ol/L), with an ionized calcium level of 3.0 mEq/L (1.5ol/L), during the same period without a change in intact

    athyroid hormone concentration (Fig 1). In response toocalcemia, we increased the oral paricalcitol dose andsequently switched to increasing doses of calcitriol be-se of its tendency to increase serum calcium concentra-. We also started the patient on oral calcium supplemen-on and increased the calcium ion concentration of herlysate solutions to 3.5 mEq/L (1.75 mmol/L). Despitese measures, serum calcium levels continued to de-ase, and she developed periorbital paresthesias andntal slowing. She was admitted to the hospital andeived intravenous calcium, with resolution of all symp-s. Deferasirox, the only recent change in her medical

    imen, was discontinued. Her serum calcium concentra-

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    Yusuf, McPhedran, and Brewster588restarted deferasirox therapy. At this point, no otherdication changes were made; she remained on highcium dialysate and oral supplementation, and her se-

    calcium concentration again decreased. Serum albu-levels remained constant. She again discontinued

    erasirox therapy, with a subsequent improvement inum calcium concentration.

    DISCUSSION

    Patients treated by dialysis who have a hema-ogic disorder may remain dependent on trans-ions, resulting in iron deposition in tissues,luding liver, heart, and endocrine organs. Thisy lead to significant morbidity and mortality.2DFO was introduced in the 1960s and becamendard therapy for iron chelation because it im-ves overall quality/quantity of life.1,3 DFO is a

    renteral hexadentate chelator, and the iron-DFOmplex is excreted predominantly by the kidneys.spite its beneficial effects, compliance with thisrapy is poor because of challenges of administra-n.4,5 In patients treated by dialysis, it is adminis-ed less frequently. In peritoneal dialysis patients,O has been administered intravenously, intraperi-eally, and intramuscularly with limited clinicalcess.6,7 Severe life-threatening infections occur,ich makes it less useful.8,9Deferasirox (4-[3,5-bis(2-hydroxyphenyl)-,4-triazole-1-yl]-benzoic acid) is a new oraln chelating agent. It is a tridentate ligand thatds iron with high affinity in a 2:1 ratio. Theod and Drug Administration approved the drugNovember 2005 for transfusion-related ironerload in patients older than 2 years.10 Thisproval was based on results of phase 3 random-d controlled trials of deferasirox versus DFO.11dosage of 20 mg/kg/d of deferasirox was

    fficient to maintain and stabilize ferritin levels,d a dosage of 30 mg/kg/d resulted in a de-ase in serum ferritin concentrations. The effi-

    cy, tolerability, and safety of deferasirox intients with normal kidney function were shown,d notably, there were no changes in bloodemistry test results or copper and zinc concen-tions during the study period.12 Minor sideects (mainly gastrointestinal and dermatologi-) and mild nonprogressive increases in serumatinine levels were described.11,12Severe symptomatic hypocalcemia has neveren reported previously with deferasirox. In ourtient, measures were taken to combat the devel-ing hypocalcemia by increasing calcium in-e, oral vitamin D preparation, and the calcium

    ncentration in the peritoneal dialysate, butum calcium concentrations continued to de-ase. Rechallenge produced similar results.The mechanism by which deferasirox causedpocalcemia is unclear. One hypothesis ist the drug may cause chelation of calcium.is effect was not seen in clinical trials,ich included only patients with normal kid-

    y function and an intact vitamin D andrathyroid axis. Perhaps healthy patients re-ond to subtle hypocalcemia in a way ourtient could not. However, given the differ-

    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 andg/L are equivalent.bepaoptakcosercre

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    Hypocalcemia From Deferasirox 589ces in charge and atomic weight betweenn and calcium, this seems an unlikely expla-tion.Another possible mechanism is that chelationiron by deferasirox from the patients bonesows for increased bone uptake of calcium.cently, investigators implicated iron overloada cause of osteopenia and osteoporosis in menth genetic hemochromatosis (HFE gene muta-n) and those with thalassemia major.13,14 Ratsth experimental kidney failure and iron over-d showed a decrease in bone-forming activity

    mpatible with adynamic bone disease.15 Also,s fed a diet containing 50,000 ppm (5%) irontate for 13 weeks developed osteomalaciath an iron-positive reaction at the interfacetween osteoid and mineralized bone.16 Thispression of bone remodeling and increased os-id thickness mimics aluminum-associated ady-

    mic bone disease. Five of 12 long-term dialysistients with predominant iron deposition on bonepsy had adynamic bone disease.17DFO therapy improves bone histological char-teristics and mineralization in long-term dialy-patients with aluminum-associated adynamic

    ne disease.18,19 It has also been used in pa-nts with aluminum overload related to totalrenteral nutrition. Hypocalcemia was seen in8-month-old infant treated with DFO for totalrenteral nutritionassociated aluminum over-d without an increase in urinary calcium excre-n, suggesting bone uptake of calcium afterelation of aluminum.20 A similar hypocalce-c effect was reported in 2 patients with dialysis-ociated aluminum osteomalacia treated withO.19 These anecdotal reports support our hy-

    thesis that chelation of iron from our patientsnes by deferasirox may have led to increasedcium uptake, the so-called hungry-bone syn-me, and resultant hypocalcemia.

    In conclusion, deferasirox is an effective, safe,d well-tolerated iron chelating agent for pa-nts with iron overload. Hypocalcemia, al-ugh apparently not a concern in patients with

    rmal kidney, vitamin D, and parathyroid func-ns, may be a potentially severe adverse effectpatients treated by dialysis. Calcium levels

    ould be checked routinely in these patientsile on deferasirox therapy. In some patients,

    ferasirox therapy may need to be discontinued.ACKNOWLEDGEMENTS

    upport: None.inancial Disclosure: None.

    REFERENCES. Borgna-Pignatti C, Rugolotto S, De Stefano P, et al:vival and complications in patients with thalassemiajor treated with transfusion and deferoxamine. Haemato-ica 89:1187-1193, 2004. Schrier SL, Angelucci E: New strategies in the treat-

    nt of the thalassemias. Annu Rev Med 56:157-171, 2005. Olivieri NF, Brittenham GM: Iron-chelating therapythe treatment of thalassemia. Blood 89:739-761, 1997. Arboretti R, Tognoni G, Alberti D, Italian Colaborativeup on Thalassemia: Pharmacosurveillance and quality of

    e of thalassemic patients. A large scale epidemiologicalvey. Eur J Clin Pharmacol 56:915-922, 2001. Cohen A: Management of iron overload in the pediat-patient. Hematol Oncol Clin North Am 1:521-544, 1987. Kingswood C, Banks RA, Bunker T, Harrison P, Mack-ie C: Fracture osteomalacia, CAPD, and aluminium.cet 1(8314-5):70-71, 1983. Payton CD, Junor BJ, Fell GS: Successful treatment of

    minium encephalopathy by intraperitoneal desferrioxam-. Lancet 1(8386):1132-1133, 1984. Boelaert JR, van Roost GF, Vergauwe PL, Verbanck JJ,Vroey C, Segaert MF: The role of desferrioxamine inlysis-associated mucormycosis: Report of three cases andiew of the literature. Clin Nephrol 29:261-266, 1988. de Locht M, Boelaert JR, Schneider YJ: Iron uptake

    m ferrioxamine and from ferrirhizoferrin by germinatingres of rhizopus microsporus. Biochem Pharmacol 47:3-1850, 19940. Neufeld EJ: Oral chelators deferasirox and deferipronetransfusional iron overload in thalassemia major: New data,questions. Blood 107:3436-3441, 2006

    1. Cappellini MD, Cohen A, Piga A, et al: A phase 3 studydeferasirox (ICL670), a once-daily oral iron chelator, inients with beta-thalassemia. Blood 107:3455-3462, 20062. Nisbet-Brown E, Olivieri NF, Giardina PJ, et al:ectiveness and safety of ICL670 in iron-loaded patientsh thalassaemia: A randomised, double-blind, placebo-trolled, dose-escalation trial. Lancet 361:1597-1602, 20033. Guggenbuhl P, Deugnier Y, Boisdet JF, et al: Boneeral density in men with genetic hemochromatosis and

    E gene mutation. Osteoporos Int 16:1809-1814, 20054. Voskaridou E, Terpos E: New insights into the patho-siology and management of osteoporosis in patients with

    a thalassaemia. Br J Haematol 127:127-139, 20045. Mandalunis P, Ubios A: Experimental renal failureiron overload: A histomorphometric study in rat tibia.

    icol Pathol 33:398-403, 20056. Matsushima S, Torii M, Ozaki K, Narama I: Iron

    tate-induced osteomalacia in association with osteoblastamics. Toxicol Pathol 31:646-654, 20037. Van de Vyver FL, Visser WJ, DHaese PC, De Broe: Iron overload and bone disease in chronic dialysis

    ients. Nephrol Dial Transplant 5:781-787, 1990

  • 18. Andress DL, Nebeker HG, Ott SM, et al: Bonehistologic response to deferoxamine in aluminum-relatedbone disease. Kidney Int 31:1344-1350, 1987

    19. Brown DJ, Dawborn JK, Ham KN, Xipell JM: Treat-ment of dialysis osteomalacia with desferrioxamine. Lancet2(8294):343-345, 1982

    20. Klein GL, Snodgrass WR, Griffin MP, Miller NL,Alfrey AC: Hypocalcemia complicating deferoxaminetherapy in an infant with parenteral nutrition-associatedaluminum overload: Evidence for a role of aluminum in thebone disease of infants. J Pediatr Gastroenterol Nutr 9:400-403, 1989

    Yusuf, McPhedran, and Brewster590

    Hypocalcemia in a Dialysis Patient Treated With Deferasirox for Iron OverloadCASE PRESENTATIONDISCUSSIONACKNOWLEDGEMENTSREFERENCES

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