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Allo-Immune Membranous Nephropathy and Recombinant Arylsulfatase Replacement Therapy: A Need for Tolerance Induction Therapy Hanna Debiec, Vassili Valayannopoulos, Olivia Boyer, Laure- Hélène Nöel, Patrice Callard, Hélène Sarda, Pascale de Lonlay, Patrick Niaudet, Pierre Ronco This work identifies a new antigen responsible for secondary membranous nephropathy (MN) in a patient with mucopolysaccharidosis type VI due to aryl sulfatase B (ASB) deficiency. Enzyme replacement therapy (ERT) started at the age of 4 years (dose 1mg/kg/week) dramatically improved clinical manifestations. Sixteen months later and one week after orthopedic surgery, the patient who had a high anti-rhASB antibody titer, suddenly developed nephrotic syndrome resistant to steroid therapy. The kidney biopsy revealed glomerular deposition of IgG, mostly IgG4, C3 and C5b-9 in a granular pattern typical of MN. Double immunofluorescence staining with anti-rhASB and anti-human IgG showed that subepithelial granular deposits contained rhASB co- localized with IgG. Ig eluted from the patient’s biopsy specimen reacted specifically with rhASB. ERT was discontinued, proteinuria progressively decreased, but the patient's clinical condition markedly deteriorated. Induction of tolerance to rhASB was initiated by co-administration of low-dose corticosteroids, rituximab, intravenous immunoglobulins and oral methotrexate. ERT was resumed after nine months, eight weeks after starting immunosuppressive therapy, without inducing a rebound of antibody titer or an increase in proteinuria. We conclude that the allo-immune response to the recombinant enzyme is the cause of the disease. Considering the critical requirement for ERT in patients with such enzyme deficiencies, immune tolerance induction should be advocated in the patients with allo-immune MN. 0.5 mg/kg/week 1mg/kg Steroids 60 mg/m²qd 4 weeks + 3 MP pulses Progressively tapered to 2.5 mg qod DEC 2010 Rituximab MAR 2010 AVR 2010 Methotrexate IV Ig SEP 2010 1mg/kg rhASB dose 0 100000 200000 300000 400000 500000 600000 0 10 20 30 40 50 60 0 2 4 6 8 10 12 14 16 0.3 mg/kg 0.5 mg/kg/week NS 17-JUN-08 Urinary GAG (mg/mmol creatinine) Proteinuria (g/g creatinine) A B C D E J K E F H G I IgG3 E INSERM UMR_S 702, F-75020, Paris, France Reference Center for Inherited Metabolic Diseases, Necker-Enfants-Malades Hospital, AP-HP, F-75015, Paris Descartes University, Paris, France Time course of proteinuria and urinary glucosaminoglycan ( GAG) excretion Light microscopy and immunofluorescence study of specimens of the first kidney biopsy (August 2008). Glomerular basement membranes have diffuse spikes and clubber aspects (Jone’s staining) Electron microscopy showing subepithelial electron dense deposits Glomerulus with diffuse, finely granular deposition of IgG, C3 and C5b-9 along the outer surface of all capillary walls. IgG C3 C5b-9 Patient has anti-rhASB antibodies in serum, and rhASB and anti-rhASB in glomerular immune deposits. Anti-rhASB IgG antibody titer measured by ELISA. Time course of administration of rhASB and combined therapy 1 2 3 4 kDa 1 2 3 4 1 2 3 4 5 6 72 55 Equal amounts of rhASB were resolved by SDS-PAGE and incubated with patient’s serum (1), normal serum (2), and sera from patients with membranous nephropathy (3) and IgA nephropathy 4 (A). Other patients on rhASB enzymotherapy had low titer of anti- rhASB antibodies or were negative (B). Distribution of rhASB- specific IgG subclasses in the patient’s serum (C). Staining of the second kidney biopsy (March 2009) with anti- IgG subclass antibodies Anti-rhASB antibody revealed granular staining along capillary loops only in our patient (A). Shows an adjacent section in which the anti-rhASB antiserum was preincubated with 20µg of rhASB protein (B). Patient with idiopathic MN (G). Antenatal manifestations of storage disorder (hygroma coli, pericardial effusion) confirmed at birth: dysmorphic features, hepatomegaly Diagnosis of aryl sulfatase B (ASB) deficiency = mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome Enzyme replacement therapy (ERT) was started at age 4 IV rhASB (Naglazyme®, Biomarin) : 1mg/kg/week. Results (1st year) better general condition reduced frequency of ENT infections liver volume normalized growth improve infusion well tolerated and no infusion related reactions were noted reduction in urinary GAG ( biomarker) At age 4 1/2 years : orthopedic surgery and post-surgical immobilization (June 10, 2008) A week following surgery (June 17, 2008): nephrotic syndrome No reported renal complications in MPS VI or in patients receiving rh ASB Patient Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Why did this patient develop MN? Shortly after surgery Integrity of the glomerular filtration barrier and function of podocytes is destroyed Effect of anasthetics Y Y Y Y Immune complex formation exceeds resorption Naglazyme is mainly trapped in GBM Increased permeability to IgG He developed membranous nephropath y Surgery 10-JUN-08 NS 17-JUN-08 0.3 mg/kg Confocal images of cryosections of the patient’s second kidney biopsy specimen which have been double- labeled with rabbit polyclonal anti-rhASB antibody (A green) and anti-human IgG antibodies (B red). (C) Shows the merged image. Before surgery Immune complex resorption exceeds formation Naglazyme is taken by podocytes Other patients A B C IgG was eluted from the patient’s second kidney biopsy (1) and from a patient with MN (2). Only IgG eluted from the patient’s biopsy identified rhASB. 1 2 kDa 72 55 IgG1 IgG2 IgG4 A B C A B C The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 2012-305608 (EURenOmics) SUMMARY
description
60 mg/m²qd 4 weeks + 3 MP pulses. Progressively tapered to 2.5 mg qod. DEC 2010. Steroids. Allo -Immune Membranous Nephropathy and Recombinant Arylsulfatase Replacement Therapy: A Need for Tolerance Induction Therapy. MAR 2010. Rituximab. 1 2 3 4 5 6. 1 2 3 4 . 72. - PowerPoint PPT Presentation
Transcript of 0.5 mg/kg/ week
Allo-Immune Membranous Nephropathy and Recombinant Arylsulfatase Replacement Therapy: A Need for Tolerance
Induction Therapy Hanna Debiec, Vassili Valayannopoulos, Olivia Boyer, Laure-Hélène Nöel, Patrice Callard,
Hélène Sarda, Pascale de Lonlay, Patrick Niaudet, Pierre Ronco
This work identifies a new antigen responsible for secondary membranous nephropathy (MN) in a patient with mucopolysaccharidosis type VI due to aryl sulfatase B (ASB) deficiency. Enzyme replacement therapy (ERT) started at the age of 4 years (dose 1mg/kg/week) dramatically improved clinical manifestations. Sixteen months later and one week after orthopedic surgery, the patient who had a high anti-rhASB antibody titer, suddenly developed nephrotic syndrome resistant to steroid therapy. The kidney biopsy revealed glomerular deposition of IgG, mostly IgG4, C3 and C5b-9 in a granular pattern typical of MN. Double immunofluorescence staining with anti-rhASB and anti-human IgG showed that subepithelial granular deposits contained rhASB co-localized with IgG. Ig eluted from the patient’s biopsy specimen reacted specifically with rhASB. ERT was discontinued, proteinuria progressively decreased, but the patient's clinical condition markedly deteriorated. Induction of tolerance to rhASB was initiated by co-administration of low-dose corticosteroids, rituximab, intravenous immunoglobulins and oral methotrexate. ERT was resumed after nine months, eight weeks after starting immunosuppressive therapy, without inducing a rebound of antibody titer or an increase in proteinuria. We conclude that the allo-immune response to the recombinant enzyme is the cause of the disease. Considering the critical requirement for ERT in patients with such enzyme deficiencies, immune tolerance induction should be advocated in the patients with allo-immune MN.
0.5 mg/kg/week1mg/kg
Steroids
60 mg/m²qd 4 weeks
+ 3 MP pulsesProgressively tapered to 2.5 mg qod
DEC 2010
Rituximab MAR 2010
AVR 2010Methotrexate
IV IgSEP 2010
1mg/kgrhASB dose
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0.3 mg/kg 0.5 mg/kg/weekNS
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INSERM UMR_S 702, F-75020, Paris, France Reference Center for Inherited Metabolic Diseases, Necker-Enfants-Malades Hospital, AP-HP, F-75015, Paris Descartes University, Paris, France
Time course of proteinuria and urinary glucosaminoglycan ( GAG) excretion
Light microscopy and immunofluorescence study of specimens of the first kidney biopsy (August 2008).
Glomerular basement membranes have diffuse spikes and clubber
aspects (Jone’s staining)
Electron microscopy showing subepithelial electron dense deposits
Glomerulus with diffuse, finely granular deposition of IgG, C3 and C5b-9 along the outer surface of all capillary walls.
IgG C3 C5b-9
Patient has anti-rhASB antibodies in serum, and rhASB and anti-rhASB in glomerular immune deposits.
Anti-rhASB IgG antibody titer measured by ELISA.
Time course of administration of rhASB and combined therapy
1 2 3 4kDa1 2 3 4 1 2 3 4 5 6
72
55
Equal amounts of rhASB were resolved by SDS-PAGE and incubated with patient’s serum (1), normal serum (2), and sera from patients with membranous nephropathy (3) and IgA nephropathy 4 (A). Other patients on rhASB enzymotherapy had low titer of anti-rhASB antibodies or were negative (B). Distribution of rhASB-specific IgG subclasses in the patient’s serum (C).
Staining of the second kidney biopsy (March
2009) with anti-IgG subclass antibodies
Anti-rhASB antibody revealed granular staining along capillary loops only in our patient (A). Shows an adjacent section in
which the anti-rhASB antiserum was preincubated with 20µg of rhASB protein (B).
Patient with idiopathic MN (G).
Antenatal manifestations of storage disorder (hygroma coli, pericardial effusion) confirmed at birth: dysmorphic features, hepatomegaly Diagnosis of aryl sulfatase B (ASB) deficiency = mucopolysaccharidosis type VI (MPS VI) or Maroteaux-Lamy syndrome
Enzyme replacement therapy (ERT) was started at age 4 IV rhASB (Naglazyme®, Biomarin) : 1mg/kg/week.
Results (1st year)better general conditionreduced frequency of ENT infectionsliver volume normalized growth improveinfusion well tolerated and no infusion related reactions were notedreduction in urinary GAG ( biomarker)
At age 4 1/2 years : orthopedic surgery and post-surgical immobilization (June 10, 2008)A week following surgery (June 17, 2008): nephrotic syndrome No reported renal complications in MPS VI or in patients receiving rh ASB
Patient
Y Y
Y
YYY
Y
YYY
Y
YY YY
Y
Why did this patient develop MN?
Shortly aftersurgery
Integrity of the glomerular filtration
barrier and function of podocytes is destroyed
Effect of anastheticsYYY
Y Immune complex formation exceeds
resorption
Naglazyme is mainly trapped in GBM
Increased permeability to IgG
He developed membranous nephropathy
Surgery10-JUN-08
NS17-JUN-08
0.3 mg/kg
Confocal images of cryosections of the patient’s second kidney biopsy specimen which have been double-labeled with rabbit polyclonal anti-rhASB antibody (A green) and anti-human IgG antibodies (B red). (C) Shows the merged image.
Before surgery
Immune complex resorption exceeds
formation
Naglazyme is taken by podocytes
Other patients
A B C
IgG was eluted from the patient’s second kidney biopsy (1) and from a patient
with MN (2). Only IgG eluted from the patient’s biopsy identified rhASB.
1 2kDa
72
55
IgG1 IgG2 IgG4
A B C
A B C
The research leading to these results has received funding from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement n° 2012-305608 (EURenOmics)
SUMMARY
