Escapade with Exjade®: Deferasirox-Induced Kidney Injury and Fanconi

Syndrome

Murphy N, Elramah M, Boddipali V, Torrealba J, Chan MR

University of Wisconsin School of Medicine and Public Health, Madison, WI

Renal Consult

• 5March2012, renal consulted for: “21yr old M s/p L nephrectomy for Ewing sarcoma with AKI on CKD appears lost to follow-up”

• Quick review of the medical record reveals the patient was admitted two days earlier for pancreatitis; he had been treated with IV fluids, pain medication, and bowel rest

Case

• CC: 21-year-old admitted with nausea, vomiting, abdominal pain, body aches, anorexia, and elevated lipase; diagnosed with and treated for pancreatitis

• PMH: – Ewing sarcoma (11/2006) s/p vincristine, doxorubicin,

anthracycline, cyclophosphamide, ifosfamide, etoposide, and radiation to periaortic LN & left renal fossa

– Cardiomyopathy (mild, EF 55% 6/2011)

– Gastritis

– Iron overload (6/2011) • Ferritin 1502 and MRI w/ severely elevated hepatic iron content

and severe splenic transfusional hemosiderosis

Additional History

• Medications: – Metoprolol succinate

– Morphine PRN

– Quetiapine PRN

– Sertraline

– Senna docusate

– Neutra-phos BID

– RPH note indicates recent significant past medication: Exjade stopped on 2/29/2012

• PSH:

– Left nephrectomy

– IVC resection

– Thoracotomy

• Social Hx:

– Denies tobacco use, alcohol, and drug use

Significant Physical Exam Findings

• VS: 36.6, 106, 94/58, 16, 99%

• Gen: Thin, frail appearing male

• HEENT: Conjunctivae/corneas clear; anicteric; PERRL; teeth in good repair; oropharynx unremarkable

• Neck: No adenopathy or masses

• Chest: Symmetrical; lungs clear

• Cardiac: Tachycardia

• Abd: Tenderness in epigastrium and RUQ

• Extremities: No deformities, edema, or discoloration

• Neuro: Unremarkable

2.7 16 2.582

34105134

Labs – 3/3/12 @ 2051

• Phosphorous: 2.4 mg/dL (nl 2.5-4.5mg/dL)

• Anion gap: 13

13

38115

Date Cr Urine glucose

5/3/2011 1.10 Trace

8/26/2011 1.26

8/30/2011 1.25

11/29/2011 1.51 2+

12/9/2011 1.50 2+

1/10/2012 1.51 2+

1/24/2012 1.84 3+

2/6/2012 2.03 3+

2/7/2012 1.92 2+

2/21/2012 1.97 3+

Urinalysis: 3/4/2012 @ 0011

Color Yellow

Clarity Hazy

Specific gravity 1.008

pH 5.0

Leukocyte esterase Negative

Nitrites Negative

Protein 1+

Glucose 2+

Ketones Moderate

Urobilinogen 0.2

Bilirubin Negative

WBC 0-1

RBC 0-1

Urine Studies

• Urine phosphate: 36 in the setting of low phos

• Urine potassium: 39 in the setting of low K

• Urine osm: 379

• Urine sediment: bland

• Urine eosinophils: negative

• Fractional excretion of sodium: 4.67

• Transtubular potassium gradient (TTKG): 11

TTKG = (Posm * UK)/(PK * Uosm)

Assessment:

• 21y/o M w/ hx of Ewing sarcoma s/p left nephrectomy, chemotherapy, and radiotherapy and adriamyacin induced cardiomyopathy admitted with:– Acute pancreatitis – Acute on chronic renal failure – Proteinuria – Glycosuria– Hypokalemia – Hypophosphatemia – Metabolic acidosis– Inappropriate renal potassium excretion– Phosphaturia

Differential Diagnosis

• Metabolic acidosis (non-gap)• Renal tubular acidosis types

1, 2, and 4• Diarrhea and other GI losses• Renal failure• Acetazolamide• Ureteral diversion• Saline administration

• Glycosuria• Renal tubular acidosis type 2

(Fanconi syndrome)• Starvation • Diabetes• Inherited disorders

• Phosphaturia• Renal tubular acidosis type 2

(Fanconi syndrome)• Hyperparathyroid• Diuretic use• Hypophosphatemic rickets

• Hypokalemia• Renal tubular acidosis types

1 and 2• Diarrhea• Vomiting• Drugs (diuretics, ampho B)• Cushing syndrome• Hyperaldosteronism

Fanconi Syndrome

• A disorder of proximal tubules that causes urinary loss of:

– Glucose

– Protein

– Potassium

– Phosphate

– Bicarbonate

– Amino acids

Nephron-molar.svg

Nephron-molar.svg

Causes of Fanconi Syndrome:

• Children: (typically inherited)

– Cystinosis – Wilson’s disease

• Adults: (typically acquired)

– Light chain disease• Multiple myeloma • Amyloidosis

– Heavy metal toxicity • Lead poisoning

– Drugs• Deferasirox (Exjade)• Ifosfamide• 6MP• Tetracyclines

V

Deferasirox Renal Injury

• Clinical trials: 113/296 patients (38%) developed >33% increase in creatinine

• 10 case reports with patients age 7-78yrs– Underlying illnesses: MDS, sickle cell, pure red

cell aplasia, Beta thalassemia, sideroblastic anemia, and multiple myeloma

– Renal injuries: Fanconi syndrome(6), AIN(2), hypocalcemia, hematuria and proteinuria

– Outcomes: full recovery with discontinuation of deferasirox

Conclusions

• Fanconi syndrome: – Acidosis

– Hypokalemia

– Hypophosphatemia

– Glycosuria

• Deferasirox associated Fanconi syndrome and renal failure

• Monitoring of renal function with serial urinalyses, electrolyte levels, and creatinine levels during treatment

References

• Andreoli T., Carpenter C. Griggs, R., & Loscalzo,J. Cecil Essentials of Medicine 6th ed. W.B. Saunders: Philadelphia, Pennsylvania. 2004: 256-257 and 572-573.

• Rafat C, Fakhouri, F, Ribeil JA, et al. Fanconi syndrome due to deferasirox. Am J Kidney Dis 2009;54:931-934.

• Olivieri NF, Brittenham GM, Iron chelating therapy and the treatment of thalassemia. Blood 1997;89:739-761.

• Hershko C. Treating iron overload: The state of the art. Semin Hematol 2005;42(1):S2–S4.

• Piga A, Longo F, Consolati A, et al: Mortality and morbidity in thalassemia with conventional treatment. Bone Marrow Transplant 1997;19:11-13.

• Exjade (deferasirox) Prescribing Information. Novartis Pharmaceuticals Corporation 2011. http://www.pharma.us.novartis.com/product/pi/pdf/exjade.pdf. Accessed 8 August 2012.

• Hider RC. Charge states of deferasirox-ferric iron complexes. Am J Kidney Dis 2010;55:614-615.

• Brosnahan G, Gokden N, and Swaminathan S. Acute interstitial nephritis due to deferasirox: A case report. Nephrol Dial Transplant 2008;23:3356-3358.

References

• Yusuf B, McPhedran P, Brewster UC. Hypocalcemia in a dialysis patient treated with defereasirox for iron overload. AM J Kidney Dis 2008;52:587-590.

• Even-Or E, Becker-Cohen R, Miskin H. Deferasirox treatment may be associated with reversible Fanconi syndrome. Am J Hematol 2010;85:132-134.

• Grange S, Bertrand D, Guerrot D, Eas F, Godin M. Acute renal failure and Fanconi syndrome due to deferasirox. Nephrol Dial Transplant 2010;25:2376-2378.

• Yew CT, Talaulikar GS, Falk MC, et al. Acute interstitial nephritis secondary to deferasirox causing acute renal injury needing short-term dialysis. Nephrology 2010;15:377.

• Wei H, Yang C, Cheng C, Lo F. Fanconi syndrome in a patient with beta-thalassemia major after using deferasirox for 27 months. Transfusion. 2011;51(5):949–954.

• Rheault M, Bechtel H, Neglia J, Kashtan C. Reversible Fanconi syndrome in a pediatric patient on deferasirox. Pediatr Blood Cancer 2011;56:674-676.

• European Medicines Agency. Exjade: EPAR – Scientific Discussion. 17Apr2007.

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