Nephrotic syndrome as a complication of immune tolerance in hemophilia B.

To the Editor: doses of Mononine, 100 U/kg, and remained clinically stable with inhibitor titers fluctuating between 1 and 8 BU. Nine months after the initiation of the IT regimen, the patient Inhibitors to factor IX (fIX) develop in approximately 1.5% to presented with edema and oliguria. His serum albumin was 0.6 g/ 3% of persons with severe hemophilia B and are commonly associdL. Serum blood urea nitrogen (BUN) and creatinine were normal. ated with the complete absence of fIX antigen due to large gene Urinalysis revealed 4/ protein, 20 to 50 red blood cells, and no deletions or nonsense mutations. The occurrence of high-titer inhibicasts, and he was diagnosed with nephrotic syndrome. Human immutors severely compromises the management of acute hemorrhage nodeficiency virus (HIV), hepatitis C, and hepatitis B serologies because therapeutic levels of fIX are not achieved even with the use were negative and complement C3 and C4 levels remained normal. of large quantities of fIX concentrates. Therapeutic options are furHe was begun on prednisone 2 mg/kg/d. After 6 weeks of treatment ther limited by the development of allergic reactions to fIX in a without clinical improvement, a renal biopsy was performed that sizable subset of patients. Although both standard and activated revealed membranous glomerulonephritis (GN) with electron microprothrombin complex concentrates (PCC and aPCC) can often proscopic findings of subepithelial, subendothelial, and mesangial devide an adequate degree of hemostasis, these products are not effecposits. Immunohistochemical staining by monoclonal antibodies to tive in all patients and in all clinical situations. Moreover, the use human factor IX was negative. The dose of Mononine was reduced of PCC or aPCC is problematic in patients with severe allergic to 25 U/kg every other day and the corticosteroid treatment was reactions to fIX. Recombinant factor VIIa (Novo Nordisk, Denmark) continued. The proteinuria slowly resolved and his current inhibitor may be the only logical alternative treatment in these settings, but titer is 1 BU. this product is not licensed in the United States and its use is highly restricted. For these reasons it is generally advantageous to attempt to eliminate the inhibiting antibody. CASE 2 Although no standard methodology to induce immune tolerance A 4.5-year-old boy with severe hemophilia B was treated exclu(IT) has thus far been defined, all regimens include frequent and sively with Mononine until the development of an inhibitor at age large doses of intravenously (IV) administered fIX over an extended 21 months. This inhibitor reached a maximum titer of 40 BU and period of time. Additional immune modulation is often attempted at was associated with allergic symptoms that restricted the use of the initiation of therapy through the use of IV gammaglobulin aPCC. IT was initiated with cyclophosphamide, IV, and a factor IX (IVIG), cyclophosphamide, and plasmapheresis with a staphylococconcentrate (Bebulin; Immuno-U.S.) at a dose of 100 U/kg/d. A cal protein A column, when available. We describe herein three reduction of the inhibitor titer to 8 BU was achieved approximately cases in which nephrotic syndrome developed in association with 8 months after the initiation of IT. At that time, the patient developed IT in severe hemophilia B patients with high-titer inhibitors and a generalized edema, proteinuria, and hypoalbuminemia and a clinical history of allergic reactions to fIX. diagnosis of nephrotic syndrome was made. Serum BUN and creatinine remained normal. The patient was treated empirically with predCASE 1 nisone at a starting dose of 3 mg/kg/d followed by a gradual taper A 2-year-old boy with a family history of hemophilia B associated but was largely unresponsive. Treatment with fIX concentrate was with a large gene deletion was similarly diagnosed at birth. At 10 interrupted briefly because of an increase in infusion-associated almonths of age, a computed tomography (CT) scan performed followlergic reactions but was resumed later with Bebulin at a dose of 100 ing mild head trauma showed a chronic subdural hemorrhage and U/kg three times per week following premedication with hydroxyventriculomegaly. He began treatment with monoclonal factor IX zine. He currently exhibits mild-moderate proteinuria and a serum (Mononine; Centeon L.L.C., Kankakee, IL), 100 U/kg every other albumin of 2.6 g/dL. His most recent inhibitor titer was 6 BU. day. At 11 months of age, the patient suffered a large intrathoracic and mediastinal hemorrhage after surgical placement of a central CASE 3 venous catheter. After 2 weeks of intensive replacement with fIX, a specific inhibitor was noted with a titer of 67 Bethesda units (BU). A 2-year-old boy with severe hemophilia B received Mononine after sustaining a traumatic intracranial hemorrhage at age 11 Concomitantly, the patient developed an urticarial rash after fIX administration. A positive skin test to three different fIX preparations months. On the 14th day of treatment he began to experience severe allergic reactions, which became progressively worse despite treatand a positive RAST to fIX were also noted at that time. Soon afterward the patient developed a life-threatening anaphylactic reacment with antihistamines and steroids. An inhibitor titer, which was zero before the intracranial hemorrhage, was measured to be 30 BU. tion to FEIBA (Immuno-U.S., Inc, Rochester, MI), an aPCC that contains fIX. He was placed on a desensitization regimen of gradually increasing amounts of fIX concentrate after pretreatment with antihistamines. At 14 months of age, the patient developed an acute expanding subdural right parietal hemorrhage and underwent neurosurgical deAfter desensitization, he was started on an IT regimen of daily infusions of fIX concentrate (Mononine), 100 U/kg. compression under coverage with recombinant factor VIIa. After recovery from surgery, he began antigen desensitization and IT with After 8 months on IT, the inhibitor titer decreased to 2.1 BU, there was improved recovery of infused fIX, and an amelioration of cyclophosphamide, IVIG, and Mononine, 100 U/kg/d. Because of the history of allergic manifestations, the daily dose of fIX concenallergic symptoms. Following an intercurrent febrile illness, he was noted to have mild blepharedema bilaterally. The serum albumin trate was initially administered over several hours and required premedication with diphenhydramine. The patient was placed on daily was 2.6 g/dL. Urinalysis revealed 4/ protein, 5 to 10 red blood