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Fanconi Syndrome Due to Deferasirox

Cédric Rafat, MD,1,2 Fadi Fakhouri, MD,1,2 Jean-Antoine Ribeil, MD,1,3 Richard Delarue, MD,1,3

and Moglie Le Quintrec, MD1,2

Deferasirox is an innovative iron-chelating treatment. However, preliminary data have suggested thatkidney toxicity may be a major issue in the management of patients receiving this drug. We report a caseof Fanconi syndrome associated with acute renal insufficiency in a patient receiving deferasirox. Thelatter has to be added to the expanding list of drugs that may induce Fanconi syndrome. Carefulmonitoring of kidney function and markers of proximal tubular injury are mandatory in patientsundergoing treatment with deferasirox.Am J Kidney Dis 54:931-934. © 2009 by the National Kidney Foundation, Inc.

INDEX WORDS: Deferasirox; Fanconi syndrome; iron; renal toxicity.

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atients receiving multiple transfusions for suchchronic anemias as �-thalassemia, sickle cell

isease, or myelodysplastic syndromes are at greatisk of developing secondary hemochromatosis.ron overload represents a major concern be-ause it is a leading cause of morbidity andortality in patients who do not receive proper

ron chelation therapy.1 Unlike deferoxamine,he most commonly used drug in this setting,eferasirox, a novel iron chelator, can be admin-stered once daily and orally, resulting in bettercceptance in patients.2 However, preliminaryata have suggested that renal toxicity may be aajor issue in the management of patients receiv-

ng deferasirox.3

We report here on a case of Fanconi syndromeFS) induced by deferasirox.

CASE REPORTSideroblastic anemia was diagnosed in a 78-year-old man

n 2001. His medical history was remarkable for type 2iabetes mellitus since 1994 without diabetic microvascularomplications, nonprogressing grade A chronic lymphocyticeukemia, aortic valve replacement, and essential hyperten-ion. The patient’s medications included perindopril, 4 mg/d;libenclamide, 2.5 mg twice daily; metformin, 850 mg 3imes daily; and erythropoietin. Despite treatment with eryth-opoietin, his anemia worsened and became symptomatic,equiring a twice-monthly transfusion program in May 20064 units/mo of packed red blood cells).

Blood transfusion improved the patient’s anemia, but anncrease in serum ferritin levels from 620 ng/mL (620 �g/L)efore the start of the transfusions to 1,610 ng/mL (1,610g/L; normal laboratory levels, 41 to 421 �g/L) prompted

he initiation of iron-chelating treatment with deferasirox24 mg/kg/d) in February 2007. Before the introduction ofeferasirox, laboratory examinations showed normal kidneyunction with a serum creatinine (SCr) level of 0.9 mg/dL

82 �mol/L; estimated glomerular filtration rate, 84 mL/min

merican Journal of Kidney Diseases, Vol 54, No 5 (November), 2

1.40 mL/s] according to the Modification of Diet in Renalisease [MDRD] Study equation); absence of microalbumin-ria; and no hydroelectrolytic abnormality. Furthermore,phthalmoscopy disclosed no evidence for diabetic retinop-thy. Apart from deferasirox, no other drug was added to theatient’s regimen.One month after the start of deferasirox therapy, an

ncrease in SCr level to 1.4 mg/dL (122 �mol/L) led theatient’s physician to refer him to the nephrology depart-ent. On admission, no history of diarrhea, vomiting, cuta-

eous rash, or new drugs administrated was noted. Bloodressure was normal, no weight loss was mentioned, andlinical examination was unremarkable. Urine dipstickhowed isolated glycosuria.

Laboratory test results were remarkable for decreasedidney function (SCr, 2 mg/dL [177 �mol/L]; estimatedlomerular filtration rate, 35 mL/min [0.58 mL/s] accordingo the MDRD Study equation) and proximal renal tubuleysfunction (hypophosphatemia, glycosuria, low plasma uriccid level, metabolic acidosis, and increased �2-microglobulinrinary level; Table 1). Serum and urinary protein immuno-lectrophoresis did not show evidence of monoclonal gam-opathy. Renal Doppler ultrasonography showed normal-

ized kidneys with no evidence of obstruction or renovascularisease. The patient declined kidney biopsy.Deferasirox and perindopril therapy were discontinued.

ne month later, SCr level had decreased to 1.2 mg/dL (107mol/L), and all features of proximal tubulopathy had

esolved, with the exception of minimal proteinuria. Treat-

From the 1Université Paris Descartes; and Departmentsf 2Nephrology and 3Hematology, Hôpital Necker, APHP,aris, France.Received December 7, 2008. Accepted in revised formarch 10, 2009. Originally published online as doi: 10.1053/

.ajkd.2009.03.013 on June 4, 2009.Address correspondence to Moglie Le Quintrec, MD,

ervice de Néphrologie, Hôpital Foch, 40, rue Worth, 92151uresnes, France. E-mail: m.lequintrec@hopital-foch.org

© 2009 by the National Kidney Foundation, Inc.0272-6386/09/5405-0018$36.00/0

doi:10.1053/j.ajkd.2009.03.013

009: pp 931-934 931

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ent with deferasirox was not resumed considering itsmplication in the triggering of the patient’s kidney failurend was substituted by deferiprone. At last follow-up 17onths later, SCr level was 1.2 mg/dL (105 �mol/L; esti-ated glomerular filtration rate, 63 mL/min [1.05 mL/s]

ccording to the MDRD Study equation).

DISCUSSION

Long-term transfusion therapy leads to ironverload and results in significant morbidity andortality if untreated.4 Using iron-overload che-

ation therapy improves patient survival.5,6 Par-nteral deferoxamine is the reference iron chela-or therapy; however, an estimated one-third tone-half of patients are not adherent because ofhe discomfort of the regimen caused by therolonged subcutaneous infusion 5 to 7 dayseekly.7

Deferasirox, a novel iron chelator, can be admin-stered once daily and orally, resulting in bettercceptance in patients.2 Deferasirox is highly selec-ive for ferric iron, with which it forms a stableomplex in a 2:1 ratio. The deferasirox-ferricron is eliminated predominantly through feces,lthough 5% to 10% is excreted in urine. Its highioavailability and long half-life means it isuitable as a once-daily oral treatment.8

However, renal toxicity is a major concern inatients receiving this drug. Phase 3 studies have

Table 1. Laboratory Tests Before,

Laboratory TestsAt the Start ofDeferasirox

erumCreatinine (mg/dL) 0.9Potassium (mEq/L) 4.6Phosphate (mg/dL) 3Uric acid (mg/dL) 5.8Total carbon dioxide (mEq/L) 24Glucose (mg/dL) 117Calcium (mg/dL) 9.2Protein (g/dL) —Ferritin (ng/mL) 1,610rineTmP (%) —Uric acid excretion fraction (%) —Glucose (g/L) 0�2-Microglobulin (mg/L) —

Note: Conversion factors for units: creatinine in mg/dL tog/dL to mmol/L, �0.2495; glucose in mg/dL to mmol/L,

arbon dioxide in mEq/L and mmol/L and ferritin in ng/mL aAbbreviation: TmP, tubular maximum for the reabsorptio

lready noted that decreased kidney function is e

requent, occurring in up to one-third of patientsreated with deferasirox.9 Although SCr leveleturned spontaneously to baseline values in mostases, deferasirox dose reduction was required inome patients and decreased kidney functionroved to be not always reversible.9 Recently, aase of severe hypocalcemia induced by defera-irox in a dialysis patient has been reported.10

To our best knowledge, we report the first casef FS associated with the use of deferasirox.FS is a generalized disturbance of proximal

ubular function leading to renal losses of glu-ose, phosphate, calcium, uric acid, amino acids,icarbonates, and other organic compounds. Itay be acquired and most frequently is related to

rugs (tenofovir, cisplatinum, and gentamicin;able 2) and more rarely to multiple myeloma oruch inherited disorders as Dent disease, cystino-is, and fructose intolerance.

FS features were typical in our patient, with aarticularly impressive increase in urinary �2-icroglobulin level, one of the most specificarkers of proximal tubule dysfunction. More-

ver, FS was associated with decreased kidneyunction. Other potential causes of FS have beenuled out in our case because our patient did noteceive other drugs known to induce FS, andultiple myeloma diagnosis can be reasonably

, and After Deferasirox Treatment

1 mo Aftereferasirox

1 mo After DeferasiroxDiscontinuation

At LastFollow-up

2.0 1.2 1.24.8 3.9 4.51.7 3 2.73 — 6.5

13.4 — 22126 — —

9.7 — —6.4 — —

1,150 — 1,510

72 — —32 — —10 5 —35 — —

L, �88.4; uric acid in mg/dL to �mol/L, �59.48; calcium in55. No conversion is necessary for potassium and total

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Fanconi Syndrome Due to Deferasirox 933

iscontinuation of deferasirox therapy, substanti-ting its responsibility in the occurrence of proxi-al tubular dysfunction.The mechanisms of deferasirox nephrotoxic-

ty are not fully understood. Experimental datarom the early phase of the drug’s developmentave noted alterations in proximal tubular epithe-ium.11 The improvement in kidney function afterose adjustment in patients who presented withncreased SCr levels after the introduction of defera-irox therapy suggest a dose effect.12 Moreover,ecreased kidney function was observed mostly inatients with sharp decreases in serum ferritinnd liver iron concentrations.9 Some patientsay be particularly susceptible to deferasirox

enal toxicity, such as old patients and those withhronic kidney disease.3,13,14

Nephrotoxicity is not a hallmark of defera-irox because kidney toxicity has been describedith other iron-depleting therapies, including defer-xamine, although to a lesser extent.15

In contrast to deferoxamine, deferasirox showsipophilic properties, and deferasirox-iron com-lexes carry a net charge of zero. Thus, defera-irox is more likely to penetrate cell membranesnd scavenge iron from intracellular sites.16 Che-ation of mitochondrial iron could in turn resultn adenosine triphosphate depletion in tubularpithelial cells, leading to impaired tubular func-ion.15 Pharmacological studies have establishedhat deferasirox shows greater iron-chelating abil-ty and prolonged plasma clearance.17 Thus, re-al toxicity may derive from the accumulation ofeferasirox, the drug’s metabolites, or iron com-

Table 2. Agents Implicated in

ntiretroviralsNucleoside reverse transcriptase inhibitorsAcyclic nucleoside phosphonates

ntibioticsAminoglycosidesTetracyclineshemotherapiesAlkylating and platinum agentsAntimetabolites

ntiparasitic drugsntiepileptic drugsistamine2-blocking agentsarbonic anhydrase inhibitoralicylate intoxication

ron-chelating treatment

lexes in tubular cells.3,13 1

Our case illustrates these potential risk factorsor deferasirox-induced renal toxicity; the patienteceived a relatively high deferasirox dose (24g/kg/d) and had a rapid and significant decrease

n ferritin level (�460 ng/mL).18 Incipient diabeticephropathy and glomerular hyperfiltration statusn the patient may have increased the risk foreferasirox toxicity. The patient declined kidneyiopsy. Hence, the coexistence of acute tubulointer-titial nephritis with FS remains a possibility.

In summary, clinicians must be aware that defera-irox use is associated with FS and/or renal insuffi-iency. Careful monitoring of kidney function andarkers of proximal tubular injury are mandatory

or patients undergoing treatment with deferasirox.ecreased kidney function associated with defera-

irox may not always be reversible.

ACKNOWLEDGEMENTSSupport: None.Financial Disclosure: None.

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