Membranous nephropathy (MN), a disease characterized by an accumulation of immune deposits on the... more Membranous nephropathy (MN), a disease characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane, is the most common cause of idiopathic nephrotic syndrome in Caucasian adults. In the rat model of Heymann nephritis, the target antigen of antibodies is megalin, a multiligand receptor expressed at the podocyte cell surface. This review summarizes key findings provided by this experimental model and by our discovery of neutral endopeptidase being the alloantigen involved in neonatal cases of membranous nephropathy. We discuss the role of alloimmunization as a new mechanism of renal disease and recent findings related to the identification of target antigens in adult membranous nephropathy. We believe that the substantial progress made in understanding molecular mechanisms of membranous nephropathy should lead to novel therapeutic approaches and the development of more specific biomarkers than proteinuria.
The development of well-tolerated and effective therapies that target the pathogenesis of membran... more The development of well-tolerated and effective therapies that target the pathogenesis of membranous nephropathy (MN) would be useful. Our objective was to evaluate the efficacy of rituximab in MN. We analyzed the outcome of 28 patients treated with rituximab for idiopathic MN. Anti-PLA 2 R antibodies in serum and PLA 2 R antigen in kidney biopsy were assessed in 10 and 9 patients, respectively. Proteinuria was significantly decreased by 56, 62 and 87% at 3, 6 and 12 months, respectively. At 6 months, 2 patients achieved complete remission (CR) and 12 partial remission (PR; overall renal response, 50%). At 12 months (n = 23), CR was achieved in 6 patients and PR in 13 patients (overall renal response, 82.6%). Three patients suffered a relapse
is not exaggerated to state that they have induced a paradigm shift in the monitoring of patients... more is not exaggerated to state that they have induced a paradigm shift in the monitoring of patients with MN, thus opening a new era of personalized medicine.
Rare associations of immunological disorders can often tell more than mice and rats about the pat... more Rare associations of immunological disorders can often tell more than mice and rats about the pathogenesis of immunologically mediated human kidney disease. Cases of glomerular disease with thyroiditis and Graves' disease and of minimal change disease with lymphoepithelioma-like thymic carcinoma and lymphomatoid papulosis were recently reported in Pediatric Nephrology. These rare associations can contribute to the unraveling of the pathogenesis of membranous nephropathy (MN) and minimal change disease (MCD) and lead to the testing of novel research hypotheses. In MN, the target antigen may be thyroglobulin or another thyroid-released antigen that becomes planted in the glomerulus, but other scenarios can be envisaged, including epitope spreading, polyreactivity of pathogenic antibodies, and dysregulation of T regulatory cells, leading to the production of a variety of auto-antibodies with different specificities [immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX syndrome)]. The occurrence of MCD with hemopathies supports the role of T cells in the pathogenesis of proteinuria, although the characteristics of those T cells remain to be established and the glomerular permeability factor(s) identified.
Clinical Journal of The American Society of Nephrology, Jul 24, 2019
Background and objectives Different rituximab protocols are used to treat membranous nephropathy.... more Background and objectives Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy. Design, setting, participants, & measurements Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m 2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses. Results Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3-9] and 9 [IQR, 6-12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.
Journal of The American Society of Nephrology, May 6, 2019
Background In membranous nephropathy (MN), which is characterized by deposition of immune complex... more Background In membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A are target antigens in approximately 70% and 1%-5% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown. Methods We studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry. Results Mass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2Rnegative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 patients); only one of the 14 cases of mixed class 5 and 3/4 lupus nephritis was positive for EXT1/EXT2. Tests in seven patients with EXT1/EXT2-associated MN found no circulating anti-exostosin antibodies. Conclusions A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.
Nous présentons, dans cette revue, les dernières avancées concernant la modélisationin vitrode la... more Nous présentons, dans cette revue, les dernières avancées concernant la modélisationin vitrode la barrière de filtration glomérulaire. Ces systèmes, permettant de réduire l’utilisation des modèles animaux, connaissent un intérêt croissant et bénéficient du développement de nos connaissances des cellules souches et de la bioingénierie. Nous discuterons les limites des modèles cellulaires glomérulaires actuels et nous introduirons les méthodes permettant d’obtenir des cellules glomérulaires à partir des cellules souches. Enfin, nous discuterons de l’importance du microenvironnement dans le maintien du phénotype, quels que soient les systèmes utilisés tels que la co-culture, les biomatériaux ou la microfluidique.
ABSTRACTFor a long time, kidney biopsy was the only diagnostic means for membranous nephropathy (... more ABSTRACTFor a long time, kidney biopsy was the only diagnostic means for membranous nephropathy (MN) and proteinuria and serum creatinine were the only markers of disease activity. The discovery of the phospholipase A2 receptor (PLA2R) antibody in 2009 has induced a paradigm shift in both the diagnosis and monitoring of patients. Two serological tests are routinely used: the enzyme-linked immunosorbent assay (ELISA), which is quantitative, and the immunofluorescence assay (IFA), which is more sensitive. In centres where the two assays are available, the recommendation is to use IFA for screening and diagnosis of immunological remission and ELISA for monitoring the effectiveness of therapy. In patients with positive PLA2R antibody serology, normal kidney function and no evidence of an underlying disease, a kidney biopsy is not mandatory given the almost 100% specificity of the assays. Because MN has different phases, one cannot base a clinical or therapeutic decision on a single meas...
Journal of the American Society of Nephrology, 2021
Significance Statement Membranous nephropathy (MN) results from antibodies targeting an antigen i... more Significance Statement Membranous nephropathy (MN) results from antibodies targeting an antigen in the glomerular basement membrane (GBM). The target antigens identified so far include PLA2R, THSD7A, NELL1, SEMA3B, and EXT1/EXT2. Using laser microdissection and mass spectrometry analysis, the authors identified a novel protein, protocadherin 7 (PCDH7), that is present in the GBM of a subset of patients with MN who are negative for all of the known antigens associated with MN. PCDH7 shows granular GBM staining and colocalizes with Ig in the GBM. Furthermore, antibodies to PCDH7 were detected in both the serum and kidney biopsy tissue from individuals with PCDH7-associated MN but not from controls. These findings suggest that PCDH7-associated MN defines a distinct type of MN. Background Membranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%–90% of target antigens i...
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-... more To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P[4.94E-20, odds ratio (OR) [1.90
Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Cauca... more Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. Phospholipase A2 receptor (PLA2R)-and exostosin 1 (EXT1)/exostosin 2 (EXT2)associated MN represent the most common primary and secondary forms of MN. The complement profile using a proteomics approach has not been studied in these 2 common forms of MN. Methods: We used laser microdissection and mass spectrometry (MS/MS) to dissect glomeruli and identify glomerular complement proteins in PLA2R-associated (n ¼ 7), EXT1/EXT2-associated MN (n ¼ 21), and 11 control cases (time 0 transplant biopsies). Results: MS/MS identified high total spectral counts for PLA2R and EXT1/EXT2 in corresponding cases of PLA2R-and EXT1/EXT2-positive MN. Both PLA2R-and EXT1/EXT2-associated MN had high spectral counts of complement proteins C3, C4, C5, C6, C7, C8, and C9. Complement protein C1 was present in low spectral counts in EXT1/EXT2-associated MN. Regulators of complement activation that were detected in MN included higher spectral counts of FH, FHR-1, FHR-5, clusterin, vitronectin and lower spectral counts of FHR-3, FHR-4, and CD59. Low spectral counts of FB and properdin, key components of the alternative pathway, also were detected. IgG4 and IgG1 were the most abundant IgG subclasses in PLA2R-and EXT1/ EXT2-associated MN. Lower spectral counts for C3, C4, and C5 were detected in control cases when compared with MN. Significant complement activation is present in MN as evidenced by large spectral counts of complement proteins from C3-and C4-based pathways, including regulatory proteins of complement pathways. These data suggest that anticomplement drugs may be effective in treatment for MN.
Membranous nephropathy (MN), a disease characterized by an accumulation of immune deposits on the... more Membranous nephropathy (MN), a disease characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane, is the most common cause of idiopathic nephrotic syndrome in Caucasian adults. In the rat model of Heymann nephritis, the target antigen of antibodies is megalin, a multiligand receptor expressed at the podocyte cell surface. This review summarizes key findings provided by this experimental model and by our discovery of neutral endopeptidase being the alloantigen involved in neonatal cases of membranous nephropathy. We discuss the role of alloimmunization as a new mechanism of renal disease and recent findings related to the identification of target antigens in adult membranous nephropathy. We believe that the substantial progress made in understanding molecular mechanisms of membranous nephropathy should lead to novel therapeutic approaches and the development of more specific biomarkers than proteinuria.
The development of well-tolerated and effective therapies that target the pathogenesis of membran... more The development of well-tolerated and effective therapies that target the pathogenesis of membranous nephropathy (MN) would be useful. Our objective was to evaluate the efficacy of rituximab in MN. We analyzed the outcome of 28 patients treated with rituximab for idiopathic MN. Anti-PLA 2 R antibodies in serum and PLA 2 R antigen in kidney biopsy were assessed in 10 and 9 patients, respectively. Proteinuria was significantly decreased by 56, 62 and 87% at 3, 6 and 12 months, respectively. At 6 months, 2 patients achieved complete remission (CR) and 12 partial remission (PR; overall renal response, 50%). At 12 months (n = 23), CR was achieved in 6 patients and PR in 13 patients (overall renal response, 82.6%). Three patients suffered a relapse
is not exaggerated to state that they have induced a paradigm shift in the monitoring of patients... more is not exaggerated to state that they have induced a paradigm shift in the monitoring of patients with MN, thus opening a new era of personalized medicine.
Rare associations of immunological disorders can often tell more than mice and rats about the pat... more Rare associations of immunological disorders can often tell more than mice and rats about the pathogenesis of immunologically mediated human kidney disease. Cases of glomerular disease with thyroiditis and Graves' disease and of minimal change disease with lymphoepithelioma-like thymic carcinoma and lymphomatoid papulosis were recently reported in Pediatric Nephrology. These rare associations can contribute to the unraveling of the pathogenesis of membranous nephropathy (MN) and minimal change disease (MCD) and lead to the testing of novel research hypotheses. In MN, the target antigen may be thyroglobulin or another thyroid-released antigen that becomes planted in the glomerulus, but other scenarios can be envisaged, including epitope spreading, polyreactivity of pathogenic antibodies, and dysregulation of T regulatory cells, leading to the production of a variety of auto-antibodies with different specificities [immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX syndrome)]. The occurrence of MCD with hemopathies supports the role of T cells in the pathogenesis of proteinuria, although the characteristics of those T cells remain to be established and the glomerular permeability factor(s) identified.
Clinical Journal of The American Society of Nephrology, Jul 24, 2019
Background and objectives Different rituximab protocols are used to treat membranous nephropathy.... more Background and objectives Different rituximab protocols are used to treat membranous nephropathy. We compared two rituximab protocols in patients with membranous nephropathy. Design, setting, participants, & measurements Twenty-eight participants from the NICE cohort received two infusions of 1-g rituximab at 2-week intervals, whereas 27 participants from the Prospective Randomized Multicentric Open Label Study to Evaluate Rituximab Treatment for Membranous Nephropathy (GEMRITUX) cohort received two infusions of 375 mg/m 2 at 1-week interval. We measured serum rituximab levels and compared remission at month 6 and before any treatment modification and analyzed factors associated with remission and relapses. Results Remissions occurred in 18 (64%) versus eight (30%) from the NICE and GEMRITUX cohort (P=0.02) at month 6, respectively, and in 24 (86%) versus 18 (67%) participants (P=0.12) before treatment modification, respectively. Median time to remission was 3 [interquartile range (IQR), 3-9] and 9 [IQR, 6-12] months for NICE and GEMRITUX cohorts respectively (P=0.01). Participants from the NICE cohort had higher circulating level of rituximab and lower CD19 counts (3.
Journal of The American Society of Nephrology, May 6, 2019
Background In membranous nephropathy (MN), which is characterized by deposition of immune complex... more Background In membranous nephropathy (MN), which is characterized by deposition of immune complexes along the glomerular basement membrane (GBM), phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A are target antigens in approximately 70% and 1%-5% of cases of primary MN, respectively. In other cases of primary MN and in secondary MN, the target antigens are unknown. Methods We studied 224 cases of biopsy-proven PLA2R-negative MN and 102 controls (including 47 cases of PLA2R-associated MN) in pilot and discovery cohorts. We also evaluated 48 cases of PLA2R-negative presumed primary MN and lupus MN in a validation cohort. We used laser microdissection and mass spectrometry to identify new antigens, which were localized by immunohistochemistry. Results Mass spectrometry detected exostosin 1 (EXT1) and exostosin 2 (EXT2) in 21 cases of PLA2Rnegative MN, but not in PLA2R-associated MN and control cases. Immunohistochemistry staining revealed bright granular GBM staining for EXT1 and EXT2. Clinical and biopsy findings showed features of autoimmune disease, including lupus, in 80.7% of the 26 EXT1/EXT2-associated MN cases we identified. In the validation cohort, we confirmed that EXT1/EXT2 staining was detected in pure class 5 lupus nephritis (eight of 18 patients) and in presumed primary MN associated with signs of autoimmunity (three of 16 patients); only one of the 14 cases of mixed class 5 and 3/4 lupus nephritis was positive for EXT1/EXT2. Tests in seven patients with EXT1/EXT2-associated MN found no circulating anti-exostosin antibodies. Conclusions A subset of MN is associated with accumulation of EXT1 and EXT2 in the GBM. Autoimmune disease is common in this group of patients.
Nous présentons, dans cette revue, les dernières avancées concernant la modélisationin vitrode la... more Nous présentons, dans cette revue, les dernières avancées concernant la modélisationin vitrode la barrière de filtration glomérulaire. Ces systèmes, permettant de réduire l’utilisation des modèles animaux, connaissent un intérêt croissant et bénéficient du développement de nos connaissances des cellules souches et de la bioingénierie. Nous discuterons les limites des modèles cellulaires glomérulaires actuels et nous introduirons les méthodes permettant d’obtenir des cellules glomérulaires à partir des cellules souches. Enfin, nous discuterons de l’importance du microenvironnement dans le maintien du phénotype, quels que soient les systèmes utilisés tels que la co-culture, les biomatériaux ou la microfluidique.
ABSTRACTFor a long time, kidney biopsy was the only diagnostic means for membranous nephropathy (... more ABSTRACTFor a long time, kidney biopsy was the only diagnostic means for membranous nephropathy (MN) and proteinuria and serum creatinine were the only markers of disease activity. The discovery of the phospholipase A2 receptor (PLA2R) antibody in 2009 has induced a paradigm shift in both the diagnosis and monitoring of patients. Two serological tests are routinely used: the enzyme-linked immunosorbent assay (ELISA), which is quantitative, and the immunofluorescence assay (IFA), which is more sensitive. In centres where the two assays are available, the recommendation is to use IFA for screening and diagnosis of immunological remission and ELISA for monitoring the effectiveness of therapy. In patients with positive PLA2R antibody serology, normal kidney function and no evidence of an underlying disease, a kidney biopsy is not mandatory given the almost 100% specificity of the assays. Because MN has different phases, one cannot base a clinical or therapeutic decision on a single meas...
Journal of the American Society of Nephrology, 2021
Significance Statement Membranous nephropathy (MN) results from antibodies targeting an antigen i... more Significance Statement Membranous nephropathy (MN) results from antibodies targeting an antigen in the glomerular basement membrane (GBM). The target antigens identified so far include PLA2R, THSD7A, NELL1, SEMA3B, and EXT1/EXT2. Using laser microdissection and mass spectrometry analysis, the authors identified a novel protein, protocadherin 7 (PCDH7), that is present in the GBM of a subset of patients with MN who are negative for all of the known antigens associated with MN. PCDH7 shows granular GBM staining and colocalizes with Ig in the GBM. Furthermore, antibodies to PCDH7 were detected in both the serum and kidney biopsy tissue from individuals with PCDH7-associated MN but not from controls. These findings suggest that PCDH7-associated MN defines a distinct type of MN. Background Membranous nephropathy (MN) results from deposition of antigen-antibody complexes along the glomerular basement membrane (GBM). PLA2R, THSD7A, NELL1, and SEMA3B account for 80%–90% of target antigens i...
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés. HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific r... more HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.
To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-... more To understand the genetics of steroid-sensitive nephrotic syndrome (SSNS), we conducted a genome-wide association study in 987 childhood SSNS patients and 3,206 healthy controls with Japanese ancestry. Beyond known associations in the HLA-DR/DQ region, common variants in NPHS1-KIRREL2 (rs56117924, P[4.94E-20, odds ratio (OR) [1.90
Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Cauca... more Introduction: Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. Phospholipase A2 receptor (PLA2R)-and exostosin 1 (EXT1)/exostosin 2 (EXT2)associated MN represent the most common primary and secondary forms of MN. The complement profile using a proteomics approach has not been studied in these 2 common forms of MN. Methods: We used laser microdissection and mass spectrometry (MS/MS) to dissect glomeruli and identify glomerular complement proteins in PLA2R-associated (n ¼ 7), EXT1/EXT2-associated MN (n ¼ 21), and 11 control cases (time 0 transplant biopsies). Results: MS/MS identified high total spectral counts for PLA2R and EXT1/EXT2 in corresponding cases of PLA2R-and EXT1/EXT2-positive MN. Both PLA2R-and EXT1/EXT2-associated MN had high spectral counts of complement proteins C3, C4, C5, C6, C7, C8, and C9. Complement protein C1 was present in low spectral counts in EXT1/EXT2-associated MN. Regulators of complement activation that were detected in MN included higher spectral counts of FH, FHR-1, FHR-5, clusterin, vitronectin and lower spectral counts of FHR-3, FHR-4, and CD59. Low spectral counts of FB and properdin, key components of the alternative pathway, also were detected. IgG4 and IgG1 were the most abundant IgG subclasses in PLA2R-and EXT1/ EXT2-associated MN. Lower spectral counts for C3, C4, and C5 were detected in control cases when compared with MN. Significant complement activation is present in MN as evidenced by large spectral counts of complement proteins from C3-and C4-based pathways, including regulatory proteins of complement pathways. These data suggest that anticomplement drugs may be effective in treatment for MN.
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