Allo-Immune Membranous Nephropathy and Recombinant Aryl Sulfatase Replacement Therapy: a Need for Tolerance Induction Therapy

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Allo-Immune Membranous Nephropathy and Recombinant Aryl Sulfatase 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,§ and Pierre Ronco*

*Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche_S 702, Paris, France; †Université ‡

Pierre et Marie Curie University, Paris, France; Reference Center for Inherited Metabolic Diseases, Necker-Enfants- BRIEF COMMUNICATION Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris Descartes University, Paris, France; §Department of Pediatric Nephrology, Institut National de la Santé et de la Recherche Médicale U983, Imagine Institut, Enfants-Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris-Descartes Sorbonne Paris-Cité University, Paris, France; |Laboratory of Pathology and Institut National de la Santé et de la Recherche Médicale U845, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; Departments of ¶Pathology and ††Nephrology and Dialysis, Tenon Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France; and **Department of Pediatrics, René Dubos Hospital, Pontoise, France

ABSTRACT Nephrotic syndrome was reported in a highly-sensitized patient receiving enzyme collagen type IV in Alport syndrome3 replacement therapy (ERT) for Pompe disease, but the prevalence of ERT-induced and nephrin in severe congenital Finnish renal complications and mechanisms to facilitate readministration of ERT in these syndrome.4 A third category of allo- patients remain unexplored. This work identifies a new antigen responsible for immune reactions occurs during secondary membranous nephropathy (MN) in a patient with mucopolysaccharidosis enzyme replacement therapy (ERT).5–7 type VI caused by aryl sulfatase B (ASB) deficiency. ERT (recombinant human ASB Because of the absence or very low levels [rhASB]; 1 mg/kg per week) started at the age of 4 years led to a high anti-rhASB titer of enzyme in many patients, therapeutic and dramatically improved clinical manifestations. However, 16 months later, the proteins are potential allo-antigens that patient suddenly developed nephrotic syndrome resistant to steroid therapy 1 week commonly trigger immunization. Allo- after orthopedic surgery. Examination of the kidney biopsy specimen revealed antibodies may be without clinical signif- glomerular deposition of IgG (mostly IgG4, C3, and C5b-9) in a granular pattern icance or lead to hypersensitivity typical of MN. Double immunofluorescence staining showed that subepithelial reactions, decreased bioavailability, granular deposits contained rhASB colocalized with IgG. Ig eluted from the patient’s and reduced efficacy of the therapeu- biopsy specimen reacted specifically with rhASB. On discontinuation of ERT, pro- ticproteins.Asinglecaseofnephro- teinuria progressively decreased, but the patient’s clinical condition markedly tic syndrome with mesangial and deteriorated. Induction of tolerance to rhASB was initiated by coadministration of subepithelial Ig deposits was reported low-dose corticosteroids, rituximab, intravenous Igs, and oral methotrexate. ERT in a highly-sensitized patient with was resumed 8 weeks after starting immunosuppressive therapy without inducing a Pompe disease,8 but the prevalence of rebound of antibody titer or an increase in proteinuria. We conclude that the allo- immune response to the recombinant rhASB caused the nephropathy. Considering fi Received March 25, 2013. Accepted October 11, the critical requirement for ERT in patients with such enzyme de ciencies, immune 2013. tolerance induction should be advocated in the patients with allo-immune MN. H.D., V.V., P.N., and P.R. contributed equally to this J Am Soc Nephrol 25: 675–680, 2014. doi: 10.1681/ASN.2013030290 work. Published online ahead of print. Publication date available at www.jasn.org.

In 2002, we described allo-immune when neoantigens are presented by the Correspondence: Prof. Pierre Ronco, Hôpital Tenon, Institut National de la Santé et de la Recherche membranous nephropathy (MN) in a grafted kidney. Next to histocompatibil- Médicale 489, 4 rue de la Chine, 75020 Paris, France. neonate born to a mother genetically ity antigens, potential targets include an- Email: [email protected] ﬁ 1,2 de cient in neutral endopeptidase. tigens genetically absent in the native Copyright © 2014 by the American Society of Allo-immunization may also occur kidney, such as the a3/4/5 trimer of Nephrology

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ERT-induced renal complications is probably underestimated. Here, we report the case of a boy age 5.5 years born to consanguineous parents who was diagnosed at birth with mucopolysaccharidosis type VI (MPS VI), or Maroteaux–Lamy syndrome, and developed an allo-immune MN in the setting of ERT. MPS VI is an autosomal recessive lysosomal storage disorder caused by mutations in the ARSB gene encoding the aryl sulfatase B (ASB) enzyme. It leads to cellular and tissular accumula- tion of undegraded glycosaminoglycans. If untreated, patients experience pro- gressive physical multiorgan deteriora- tion and premature death without renal involvement.9,10 Our patient had an ho- mozygous ARSB missense mutation c.176A.T (p.Asp59Val) responsible for the absence of ASB protein (not shown). Weekly infusions of 1 mg/kg body wt recombinant human ASB (rhASB), galsulfase (Naglazyme; Biomarin, Novato), was started at the age of 4 years. During the first 1 year of ERT, the child’sgeneral condition and growth markedly improved, upper airway infections decreased, and liver volume normalized. Regular dipstick urine controls did not detect proteinuria. After 18 months of ERT, the child underwent orthopedic surgery for hip dysplasia. Drugs used in the perianes- thetic period are shown in Supplemental Table 1. One week later, the patient developed peripheral edema and arterial Figure 1. Beneficial effects of immune tolerance induction therapy. Time course of ad- hypertension (145/95 mmHg). Labora- ministration of rhASB, combined therapy, and anti-rhASB IgG antibody titer measured by tory investigations showed nephrotic ELISA and Western blot. (A) Dates (abscissa) when the sera were taken for Western blot range proteinuria (38.4 g/L; 9.7 g/g cre- analysis are marked with an asterisk. TheWesternblot is shown on the graph. IV,intravenous; atinine) with hypoalbuminemia (10.8 g/L), NS, nephrotic syndrome; qd, every day; qod, every other day. (B) Time course of proteinuria microscopic hematuria, normal serum and urinary glucosaminoglycan (GAG) excretion. creatinine (0.2 mg/dl; 21 mmol/L), and normal levels of complement component (C3, 1.0 g/L; C4, 0.35 g/L). Anti-nuclear methylprednisolone pulses (1 g/1.73 m2), C5b-9 (Figure 2, B–D), but not C1q antibodies were absent, and screening for proteinuria persisted (3.7 g/L; 15 g/g cre- (not shown). Electron microscopy con- hepatitis B and C and HIV infection was atinine) and a kidney biopsy was per- firmed the presence of subepithelial negative. Ultrasound examination of formed. electron-dense deposits associated with kidney was normal. Anti-rhASB antibodies Light microscopy showed thickened foot process effacement without mesan- in patient’s sera were markedly elevated at glomerular basement membranes with- gial deposits (Figure 2E). time of surgery (Figure 1A). out cell proliferation, interstitium infil- One week after the kidney biopsy, ERTwas suspendedfor 2 weeksandthen tration, and vascular lesion (Figure 2A, prednisone was progressively tapered to resumed at the same dose. Despite pred- Supplemental Figure 1). Immunofluo- 2.5 mg four times per day. Given the nisone therapy given for 4 weeks at a dose rescence examination revealed granular possible implication of rhASB, ERT was of 60 mg/m2 per day followed by three subepithelial deposits of IgG, C3, and discontinued 1 month later. Anti-rhASB

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binding of rhASB antibody was con- firmed by extinction of fluorescence when the antibody was preincubated with an excess of rhASB (Figure 3F). Normal human kidney sections and bi- opsies from patients with other types of glomerulopathies, including idiopathic MN, showed a negative staining (Figure 3G, Supplemental Figure 2). No PLA2R antigen could be detected in deposits (Figure 3H). Colocalization of rhASB and IgG in the immune deposits was es- tablished by confocal microscopy. Many areas of colocalization were seen as the yellow staining in the merge image, whereas other areas of the glomerular capillary wall mostly featured the green staining of rhASB (Figure 3, I–K). Fi- nally, to confirm that the IgG deposited in the glomeruli was reactive with rhASB, we eluted IgG from the biopsy specimens of our patient and a patient with idiopathic MN. Reactivity of IgG was analyzed by Western blotting with rhASB. Only IgG eluted from the biopsy specimen of our patient reacted with rhASB (Figure 3L). As the patient’s clinical condition de- Figure 2. Characteristics of membranous nephropathy. Light microscopy and immunofluorescence study of specimens of the first kidney biopsy (August 2008). (A) Glomerular teriorated, with a marked increase in basement membranes have diffuse spikes and clubber aspects (Jone’s staining, 3400). (B– urinary glucosaminoglycans (Figure D) Glomerulus with diffuse, finely granular deposition of (B) IgG, (C) C3, and (D) C5b-9 1B), we started a treatment with low- along the outer surface of all capillary walls. (E) Electron microscopy showing subepithelial dose prednisone, four weekly rituximab electron dense deposits (310,000). M, mesangium; P, podocyte; RBC, red blood cell. infusions (375 mg/m2), intravenous Igs Original magnification, 3400 in A–D; 310,000 in E. (0.5 g/kg per month), and oral methotrexate (0.5 mg/kg per week) to induce tolerance to rhASB (Figure 1A). Galsulfase antibody titer dramatically decreased IgG4 (Figure 3C).The reactivity profile was restarted at a lower dose (0.3 mg/kg after stopping galsulfase (Figure 1A). observed in the patient’s serum matched per day) after a washout period of 9.5 During the next 6 months, proteinuria the distribution of IgG subclasses in the months (8 weeks after starting high- progressively decreased to 0.57 g/L (0.8 subepithelial deposits in the patient’sbi- dose immunosuppressive therapy). g/g creatinine) (Figure 1B). opsy specimen (Figure 3D). The pa- When ERT was resumed, CD19 and In the meantime, we showed a strong tient’s serum did not cross-react with CD20 were undetectable, proteinuria reactivity of the patient’s serum by West- glomerular proteins lysates (Supple- and microalbuminuria were in the nor- ern blot with rhASB at the expected mo- mental Figure 3) and PLA2R as tested mal range, and anti-rhASB antibody was lecular mass of 60 kDa (Figure 3A). No by immunofluorescence test (data not below detection threshold. Galsulfase reactive band appeared when rhASB was shown). We could not detect circulating dose was increased to 0.5 mg/kg 3 incubated with control sera, including immune complexes by C1q and Raji en- months later. The patient’s clinical con- sera from patients with idiopathic MN zymatic immunoassay (Supplemental dition markedly improved, with rapid and IgA nephropathy as well as healthy Table 2). decrease in liver and spleen volume and controls (Figure 3A). Other patients re- We then searched for the presence of less frequent upper airway infectious ep- ceiving galsulfase produced anti-rhASB rhASB in glomeruli. By using a specific isodes. He remained free from protein- antibodies, albeit at a much lower titer rabbit anti-rhASB antibody, we found a uria 14 months after discontinuation of (Figure 3B). Anti-rhASB antibodies be- granular pattern of fluorescence along the immunosuppressive treatment and longed to all Ig subclasses, although the the capillary wall in the patient’sbiopsy only developed a transient small rise highest reactivity was observed with specimen (Figure 3E). Specificity of the of anti-rhASB titer together with

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in a patient who had no measurable enzyme activity and no detectable anti- PLA2R or antiglomerular antibody. The clinical circumstances in this case (par- ticularly, the resolution of proteinuria when ERT was suspended), the colocal- izationofrhASBantigenandIgwithin immune deposits, and the finding that IgG eluted from the biopsy specimen reacted specifically with rhASB strongly suggest that the allo-immune response to the recombinant enzyme is the cause of the disease. This case, thus, adds a new cause to the list of MN etiologies. Con- sidering the critical requirement for ERT in patients with such enzyme deficiencies, it also shows that intensive immunosuppressive therapy can allow reintroduction of ERT, resulting in a dramatic improvement of the patient’s condition. Another case of ERT-induced ne- phroticsyndromewaspreviouslyreported in a patient with Pompe disease treated with recombinant human a-glucosidase (rhGAA).8 However, both the setting and glomerular lesions were different. First, the nephrotic syndrome occurred during an experimental immune tolerance regi- men based on escalating doses of rhGAA, whereas our patient was receiving rec- ommended stable doses of rhARB. Sec- ond, subepithelial immune deposits were Figure 3. Patient has anti-rhASB antibodies in serum and rhASB and anti-rhASB in glo- associated with mesangium expansion, merular immune deposits. (A) Equal amounts of rhASB were resolved by SDS-PAGE and numerous mesangial deposits by immu- incubated with (lane 1) patient’s serum, (lane 2) normal serum, and sera from patients with nofluorescence and electron microscopy, (lane 3) idiopathic MN and (lane 4) IgA nephropathy. (B) Other patients on rhASB enzy- and presence of rhGAA antigen in the motherapy had low titer of anti-rhASB antibodies or were negative. (C) Distribution of mesangium. These findings recapitulate fi ’ rhASB-speci c IgG subclasses in the patient s serum. (D) Staining of the second kidney theimmunecomplexGNobservedin biopsy (March 2009) with anti-IgG subclass antibodies. (E–K) Confocal images of the early chronic serum sickness induced by second kidney biopsy specimen. (E) Anti-rhASB antibody revealed granular staining along capillary loops only in our patient. F shows an adjacent section, in which the anti-rhASB repeated injections of exogenous pro- 11 antiserum was preincubated with 20 mg rhASB protein. (G) Patient with idiopathic MN. (H) tein. The nephrotic syndrome resolved PLA2R is not present in subepithelial deposits in our patient. I, J, and K show confocal after enzymotherapy was decreased. Our images of cryosections of the patient’s second kidney biopsy specimen, which have been patient showed a typical MN without double-labeled with (I) rabbit polyclonal anti-rhASB antibody (green) and (J) anti-human mesangium involvement. IgG antibodies (red). L and K show the merged image. Original magnification, 3400 in D–H; Our case leads to discussion of the 31200 in I, J, and K. (L) IgG was eluted from (lane 1) the patient’s second kidney biopsy and mechanisms of subepithelial immune (lane 2) a patient with MN. Only IgG eluted from the patient’s biopsy identified rhASB. deposit formation and the reason why the nephrotic syndrome suddenly ap- reappearance of CD19-positive cells, This report is the first report of MN peared 1 week after surgery. There are which were controlled with rituximab. in a patient with MPS VI treated with three possible, nonmutually exclusive He died at age 9 years and 2 months after human rhASB. The finding of high titers mechanisms of the formation of subepi- severe anoxia secondary to an acute of circulating anti-rhASB antibodies, thelial deposits in experimental models laryngospasm during anesthesia induction which peaked at the onset of the ne- of and patients with MN.12,13 The first for cervical spine decompression, a com- phrotic syndrome, indicates a mecha- mechanism is the deposition of immune monneurosurgicalcomplicationofMPSVI. nism of allo-immunization against ASB complexes from the circulation. We

678 Journal of the American Society of Nephrology J Am Soc Nephrol 25: 675–680, 2014 www.jasn.org BRIEF COMMUNICATION could not find such complexes using two resume rhASB treatment with dramatic IgG4 antibodies (commercially provided by different methods, although we cannot improvement of the patient’s condition Margaret Goodall, University of Birmingham, exclude the presence of low levels of and without rebound of antibody re- Birmingham, UK) followed by peroxidase- small-size IgG4–containing immune sponse and relapse of renal manifesta- conjugated sheep anti-mouse IgG (GE Health- complexes, which are not detected by tions. care). Glomeruli were isolated from kidneys usual methods. The second mechanism that were unsuitable for transplantation with involves in situ formation of immune the use of graded sieving, and glomerular complexes through the reaction of circu- CONCISE METHODS proteins were extracted with RIPA buffer lating autoantibody to a native podocyte (Pierce). Contaminating IgG was removed antigen, such as PLA2R.14 We could not Analysis of Kidney Biopsy Specimen through incubation with Immobilized Protein detect a specific reactivity with mem- The patient’s biopsy specimen was prepared G Plus (Fisher Scientific). Circulating immune brane glomerular antigens or PLA2R an- for light, immunofluorescence, and electron complexes containing C1q or C3d were detec- tigen in subepithelial immune deposits. microscopy using standard techniques.24 We ted with the use of ELISA kits (Quidel). The third mechanism also involves the in analyzed cryosections from the patient’sbi- situ formation of immune complexes opsy specimen as well as from patients with Elution of IgG but with a nonnative (extrinsic) antigen MN(10cases),lupusMN(3cases),membrano- Igs were acid-eluted from the cores of kidney bound to the capillary wall.15 proliferative GN (1 case), IgA nephropathy (2 biopsy specimens obtained from our patient Why did our patient develop a ne- cases), and normal kidney. For detection of and a patient with idiopathic MN. The eluted phrotic syndrome, whereas other patients IgG subclasses and complement components, IgGwasusedtoimmunoblottherhASBdirectly. receiving galsulfatase did not, although cryosections of the biopsy specimen were in- anti-rhASB antibodies that do not seem cubated with the following antibodies: mouse Assessment of Anti-rhASB Antibody to affect urinary glucosaminoglycan levels, monoclonal anti-human IgG1, IgG2, IgG3, Anti-rhASB antibodies in patient’s sera were efficacy, or safety are detected in most of and IgG4 antibodies (commercially provided tested in the Biomarin Laboratory using an them?16,17 First, our patient produced a by Margaret Goodall, University of Birming- in-house routine test of ELISA (noncommercial relatively high level of anti-rhASB anti- ham, Birmingham, UK), anti-human C3 assay). bodies. Second, he underwent surgery complement (Dako), and monoclonal anti- requiring a cocktail of anesthetic drugs, human C5b-9 (Dako). which were shown to increase glomerular ACKNOWLEDGMENTS permeability to proteins and alter podo- Analysis of the Composition of cyte function.18 Third, sevoflurane, which Glomerular Immune Deposits by We are grateful to Adrian Quartel (Biomarin, was used in our patient, can affect the con- Confocal Microscopy Novato) for helpful discussion and financial ductance of Ca2+-activated K+ channel Cryosections of the patient’s biopsy specimen support. expressed on podocytes.19,20 Because of were first incubated with rabbit polyclonal Research is supported by European Research the rapid onset of nephrotic syndrome anti-rhASB antibodies (Biomarin) and then Council Grant ERC-2012-ADG_20120314 only 1 week after surgery in a patient goat Alexa488-conjugated anti-rabbit Fab (Grant Agreement 322947), Agence Natio- with regular negative controls of protein- IgG antibodies and goat Alexa 568–conju- nale pour la Recherche Programme Blanc uria, we suggest that anesthetics might gated anti-human IgG (Molecular Probes). SVSE1 (2012) Decision ANR-12-BSE1-0002- have been a triggering factor. After being washed, sections were examined 01, Fondation pour la Recherche Médicale A limitation to ERT is the production under a confocal microscope (TCS-SP2; Equipe FRM 2012 grant, and 7th Framework of antienzyme allo-antibodies that are Leica) and analyzed with Leica Confocal Soft- Programme of the European Community reported in all lysosomal storage disor- ware, version 2.61. Contract 2012-305608 (European Consortium ders,16,17,21,22 which may compromise for High-Throughput Research in Rare Kidney the efficacy of treatment. We identified Western Blots and Detection of Diseases). a mutation in ARSB responsible for the Circulating Immune Complexes absence of protein and enzymatic activ- rhASB and glomerular extracts were electro- ity, a situation where a high rate of allo- phoresed under nonreducing conditions and DISCLOSURES immune response is expected.23 For transferred to poly(vinylidene difluoride) patients with antibody-mediated severe membranes according to standard proto- None. adverse effects, it is of paramount im- cols. Detection antibodies were peroxidase- portance to develop tolerance-inducing conjugated goat anti-human antibodies REFERENCES protocols aimed to reintroduce ERT. We (Chemicon). Immunoreactive proteins were used a combination of high-dose cortico- visualized with SuperSignal West Pico 1. Debiec H, Guigonis V, Mougenot B, Decobert steroids, rituximab, intravenous Ig, and Chemiluminescent substrate (Pierce). 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680 Journal of the American Society of Nephrology J Am Soc Nephrol 25: 675–680, 2014 Supplementary appendix

Table 1. List of drugs received by the patient during orthopedic surgery at onset of nephropathy

SEVORANE (sevoflurane) volatile anesthetic SUFENTA (sufentanil) opioid analgesic drug DIPRIVAN (propofol) hypnotic agent PERFALGAN (paracetamol) analgesic CELOCURINE (curare) succinylcholine chloride neuromuscular blocking drug TRACRIUM (atracuriumbesilate) non-depolarizing neuromuscular blocking drug ZOPHREN (ondansetron) antagonist of serotonine MORPHINE Dextrose 5%

Table 2. Circulating immune complexes in patient’s sera

2008 2009 CIC-C1q EIA Less than 4µg Eq/ml Nearly equal to 4 µg Eq/ml Both values considered negative for significant levels of CIC CIC-Raji EIA Around 3µg Eq/ml Around 10 µg Eq/ml Both values considered negative for significant levels of CIC Figure 1

Masson’s trichrome staining.

Glomerular basement membranes are thickened by diffuse epimembranous deposits.

The podocytes are swelled Figure 2

rhASB in glomerular immune deposits

Control kidney Lupus MN

Rabbit anti-rhASB does not reveal granular staining along capillary loops in control kidney or in lupus MN

Figure 3 A B

In Panels A and B, glomerular extracts were used as source of antigens in Western blot analysis and incubated with the serum of our patient (A) or with the serum of patient receiving another (idursulfatase) enzymotherapy (B)