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Hanna Debiec - One of the best experts on this subject based on the ideXlab platform.
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development of a standardized chemiluminescence immunoassay for the detection of autoantibodies against human m type Phospholipase A2 Receptor in primary membranous nephropathy
Kidney International Reports, 2020Co-Authors: Cornelia Dahnrich, Hanna Debiec, Pierre Ronco, Sandra Saschenbrecker, Iva Gunnarsson, Wolfgang SchlumbergerAbstract:Introduction Autoantibodies against the M-type Phospholipase A2 Receptor (PLA2R) are important markers in the diagnosis and monitoring of primary membranous nephropathy (pMN). For the detection of anti-PLA2R autoantibodies, a standardized recombinant cell-based indirect immunofluorescence assay (RC-IFA) and enzyme-linked immunosorbent assay (ELISA) are widely used, the former providing higher sensitivity but lacking a finely graduated quantification of antibody titers. In this study, we evaluated the diagnostic performance characteristics of a novel standardized chemiluminescence immunoassay (ChLIA) by comparison with the established anti-PLA2R test systems. Methods Sera from 155 patients with biopsy-proven pMN and 154 disease controls were analyzed for autoantibodies against PLA2R by the novel ChLIA as well as by ELISA and RC-IFA. Results The clinical sensitivity of the ChLIA (83.9%) was higher compared with ELISA (73.5%) and equaled that of RC-IFA (83.2%), at similar specificities (≥99.4%). Among ELISA-negative pMN samples, ChLIA and RC-IFA yielded positive results in 39.0% and 36.6%, respectively. The qualitative agreement amounted to 94.5% (ChLIA vs. ELISA) and 99.4% (ChLIA vs. RC-IFA). Conclusion The novel anti-PLA2R ChLIA outperforms the ELISA in detecting patients with pMN and demonstrates almost perfect agreement with RC-IFA. It thus presents a promising alternative tool for accurate anti-PLA2R testing, with the advantage of rapid turnaround times and fully automated random-access processing.
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Phospholipase A2 Receptor 1 epitope spreading at baseline predicts reduced likelihood of remission of membranous nephropathy
Journal of The American Society of Nephrology, 2017Co-Authors: Barbara Seitzpolski, Gérard Lambeau, Hanna Debiec, Alexandra Rousseau, Karine Dahan, Christelle Zaghrini, C Payre, V Esnault, Pierre RoncoAbstract:The Phospholipase A2 Receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab ( n =29) or antiproteinuric therapy alone ( n =29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer ( P P =0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P =0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy.
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circulating antibodies to α enolase and Phospholipase A2 Receptor and composition of glomerular deposits in japanese patients with primary or secondary membranous nephropathy
Clinical and Experimental Nephrology, 2017Co-Authors: Yukihiro Kimura, Hanna Debiec, Naoto Miura, Hiroyuki Morita, Harutaka Yamada, Shogo Banno, P Ronco, Hirokazu ImaiAbstract:Background Phospholipase A2 Receptor (PLA2R) is recognized as a target antigen in primary membranous nephropathy (MN); Anti-α-enolase antibody in primary and secondary MN has been proposed, however, little is known about the potential contribution of α-enolase to the pathogenesis of MN.
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Phospholipase A2 Receptor related membranous nephropathy and mannan binding lectin deficiency
Journal of The American Society of Nephrology, 2016Co-Authors: Stephane Bally, Hanna Debiec, D Ponard, Frederique Dijoud, John Rendu, Julien Faure, Pierre Ronco, Chantal DumestreperardAbstract:Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against Phospholipase A2 Receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2.
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Phospholipase A2 Receptor–Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency
Journal of The American Society of Nephrology, 2016Co-Authors: Stephane Bally, Hanna Debiec, D Ponard, Frederique Dijoud, John Rendu, Julien Faure, Pierre Ronco, Chantal Dumestre-pérardAbstract:Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against Phospholipase A2 Receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2.
Laurence H Beck - One of the best experts on this subject based on the ideXlab platform.
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Phospholipase A2 Receptor antibody positive pregnancy a case report
American Journal of Kidney Diseases, 2020Co-Authors: Mala Sachdeva, Laurence H Beck, Ilene Miller, Vanessa Bijol, Steven FishbaneAbstract:Renal course and clinical outcomes in pregnant women with primary membranous nephropathy are not completely understood. In addition, the use of autoantibodies to M-type Phospholipase A2 Receptor (PLA2R) as a serologic marker throughout pregnancy and postpartum in the mother and baby is not yet fully elucidated. We followed up a pregnant woman with primary membranous nephropathy during pregnancy and postpartum and describe the clinical course and outcomes of mother and baby and the course of PLA2R antibody titers. We show evidence of transplacental transfer of PLA2R antibody from mother to fetus. In addition, we observe the effect of breastfeeding in a PLA2R antibody–positive pregnancy and describe the transfer of this antibody into breast milk. Although pregnancy in women with underlying PLA2R antibody–positive membranous nephropathy is possible, there is an increase in risk to both mother and fetus, requiring a multidisciplinary team approach and careful monitoring of both neonate and mother during pregnancy and postpartum.
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M-type Phospholipase A2 Receptor (PLA2R) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) in Membranous Nephropathy
Molecular Mechanisms in the Pathogenesis of Idiopathic Nephrotic Syndrome, 2016Co-Authors: Laurence H Beck, Sanjeev M Sethi, Fernando Custodio FervenzaAbstract:Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasians adults. It is defined by the presence of subepithelial immune deposits localized between the podocyte and the glomerular basement membrane (GBM) on electron microscopy examination (EM). Clinical course is variable: although up to 30 % of patients may go into spontaneous remission, approximately 40 % of patients eventually develop ESRD. The discovery of two major podocytes antigens in adults: first, the M-type Phospholipase A2 Receptor 1 (PLA2R1) and more recently, the thrombospondin type-1 domain-containing 7A (THSD7A) protein has revolutionized our understanding of the pathogenesis of human MN. Approximately 75 % of patients with active disease have circulating anti-PLA2R autoantibodies, and up to 10 % of the patients with MN that are anti-PLA2R negative have antibodies against THSD7A. Quantification and follow-up of anti-PLA2R levels have major implications regarding prognosis and treatment response. The presence of anti-PLA2R antibodies can also predict disease recurrence following kidney transplantation. Genetic studies are elucidating predisposing factors for development of the disease. Further research into the antigen-autoantibody systems is likely to elucidate a clearer understanding of the pathophysiology and treatment of patients with MN.
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anti Phospholipase A2 Receptor antibodies in recurrent membranous nephropathy
American Journal of Transplantation, 2015Co-Authors: Andrea G Kattah, David J Salant, Rivka Ayalon, Laurence H Beck, Sanjeev M Sethi, D G Sandor, Fernando G Cosio, M J Gandhi, Elizabeth C Lorenz, Fernando Custodio FervenzaAbstract:About 70% of patients with primary membranous nephropathy (MN) have circulating anti-Phospholipase A2 Receptor (PLA2R) antibodies that correlate with disease activity, but their predictive value in post-transplant (Tx) recurrent MN is uncertain. We evaluated 26 patients, 18 with recurrent MN and 8 without recurrence, with serial post-Tx serum samples and renal biopsies to determine if patients with pre-Tx anti-PLA2R are at increased risk of recurrence as compared to seronegative patients and to determine if post-Tx changes in anti-PLA2R correspond to the clinical course. In the recurrent group, 10/17 patients had anti-PLA2R at the time of Tx versus 2/7 patients in the nonrecurrent group. The positive predictive value of pre-Tx anti-PLA2R for recurrence was 83%, while the negative predictive value was 42%. Persistence or reappearance of post-Tx anti-PLA2R was associated with increasing proteinuria and resistant disease in 6/18 cases; little or no proteinuria occurred in cases with pre-Tx anti-PLA2R and biopsy evidence of recurrence in which the antibodies resolved with standard immunosuppression. Some cases with positive pre-Tx anti-PLA2R were seronegative at the time of recurrence. In conclusion, patients with positive pre-Tx anti-PLA2R should be monitored closely for recurrent MN. Persistence or reappearance of antibody post-Tx may indicate a more resistant disease.
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The Dominant Humoral Epitope in Phospholipase A2 Receptor-1: Presentation Matters When Serving Up a Slice of π
Journal of The American Society of Nephrology, 2014Co-Authors: Laurence H BeckAbstract:Phospholipase A2 Receptor-1 (PLA2R), the major autoimmune target in primary membranous nephropathy,[1][1] is one of four mammalian members of the mannose Receptor (MR) family, which consists of the MR (encoded by the MRC1 gene), Endo180 ( MRC2 ), DEC205 ( LY75 ), and PLA2R itself.[2][2] An
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very early recurrence of anti Phospholipase A2 Receptor positive membranous nephropathy after transplantation
American Journal of Transplantation, 2012Co-Authors: C D Blosser, Rivka Ayalon, R Nair, Christie P Thomas, Laurence H BeckAbstract:Membranous nephropathy is a common cause of adult nephrotic syndrome, with recent evidence suggesting that 70% of idiopathic disease is associated with anti-Phospholipase A2 Receptor autoantibodies. We describe a 63-year-old man with membranous nephropathy who underwent a kidney transplant and developed recurrent membranous nephropathy with fine granular co-localization of Phospholipase A2 Receptor and IgG evident on transplant biopsy on day 6 and elevated circulating levels of serum anti-Phospholipase A2 Receptor autoantibody that declined over time in conjunction with improvement in the serum creatinine and urinary protein. This is a very early case of Phospholipase A2 Receptor-associated recurrent membranous nephropathy with circulating anti-Phospholipase A2 Receptor autoantibody, which supports the emerging evidence that idiopathic membranous nephropathy is an autoimmune disease.
Rolf A K Stahl - One of the best experts on this subject based on the ideXlab platform.
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clinical relevance of domain specific Phospholipase A2 Receptor 1 antibody levels in patients with membranous nephropathy
Journal of The American Society of Nephrology, 2020Co-Authors: Linda Reinhard, Gunther Zahner, Rolf A K Stahl, Stephan Menzel, Friedrich Kochnolte, Elion HoxhaAbstract:BACKGROUND: Antibodies against Phospholipase A2 Receptor 1 (PLA2R1) are found in 80% of patients with membranous nephropathy, and previous studies described three autoantibody-targeted PLA2R1 epitope regions. Although anti-PLA2R1 antibody levels are closely associated with treatment response and disease prognosis, the clinical role of epitope regions targeted by autoantibodies is unclear. METHODS: In a prospective cohort of 150 patients with newly diagnosed PLA2R1-associated membranous nephropathy, we investigated the clinical role of epitope-recognition patterns and domain-specific PLA2R1 antibody levels by western blot and ELISA. RESULTS: We identified a fourth epitope region in the CTLD8 domain of PLA2R1, which was recognized by anti-PLA2R1 antibodies in 24 (16.0%) patients. In all study patients, anti-PLA2R1 antibodies bound both the N-terminal (CysR-FnII-CTLD1) region and the C-terminal (CTLD7-CTLD8) region of PLA2R1 at study enrollment. The total anti-PLA2R1 antibody levels of patients determined detection of domain-specific PLA2R1 antibodies, and thereby epitope-recognition patterns. A remission of proteinuria occurred in 133 (89%) patients and was not dependent on the domain-recognition profiles. A newly developed ELISA showed that domain-specific PLA2R1 antibody levels targeting CysR, CTLD1, and CTLD7 strongly correlate with the total anti-PLA2R1 antibody level (Spearman's rho, 0.95, 0.64, and 0.40; P<0.001, P<0.001, and P=0.002, respectively) but do not predict disease outcome independently of total anti-PLA2R1 antibody levels. CONCLUSIONS: All patients with PLA2R1-associated membranous nephropathy recognize at least two epitope regions in the N- and C-terminals of PLA2R1 at diagnosis, contradicting the hypothesis that PLA2R1 "epitope spreading" determines the prognosis of membranous nephropathy. Total anti-PLA2R1 antibody levels, but not the epitope-recognition profiles at the time of diagnosis, are relevant for the clinical outcome of patients with this disease.
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spontaneous remission of proteinuria is a frequent event in Phospholipase A2 Receptor antibody negative patients with membranous nephropathy
Nephrology Dialysis Transplantation, 2015Co-Authors: Elion Hoxha, Ulf Panzer, Sigrid Harendza, Udo M Helmchen, Hans O Pinnschmidt, Nicola M. Tomas, Rolf A K StahlAbstract:Abstract Phospholipase A2 Receptor antibodies (PLA2R-Ab) and thrombospondin type-1 domain-containing 7A antibodies (THSD7A-Ab) are present in 70-80% of patients with membranous nephropathy (MN). Little, however, is known about the pathogenesis of MN and the clinical outcome in PLA2R-Ab- and THSD7A-Ab-negative patients. In this prospective multicentre observational study, the clinical outcome of 37 patients with biopsy-proven MN who were negative for PLA2R-Ab and THSD7A-Ab in the serum was analysed. A total of 198 patients were screened for inclusion in the study. Of these, 157 patients were positive for PLA2R-Ab and 4 patients for THSD7A-Ab. The remaining 37 patients were negative for both antibodies were and included in this study. Six patients died during the follow-up, five because of malignant diseases and one of an infection. One patient went into end-stage renal disease, and two patients were lost to follow-up. The remaining 28 patients were followed for at least 24 months (35.6 ± 8.9 months). Seventeen patients received immunosuppressive (IS) therapy, and 11 received supportive care only. At the end of the follow-up, 14 of the 17 patients treated with immunosuppressants and 10 of 11 patients on supportive therapy had a remission of proteinuria. The time to reach remission of proteinuria and serum creatinine levels at the end of the follow-up were not different between both groups. A univariate Cox regression analysis indicated that the use of immunosuppression did not alter the chance to reach a remission of proteinuria. A high number of PLA2R-Ab- and THSD7A-Ab-negative patients with MN have a good prognosis and might not need IS therapy.
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m type Phospholipase A2 Receptor autoantibodies and renal function in patients with primary membranous nephropathy
Clinical Journal of The American Society of Nephrology, 2014Co-Authors: Elion Hoxha, Ulf Panzer, Sigrid Harendza, Hans O Pinnschmidt, Rolf A K StahlAbstract:Background and objectives Loss of renal function in patients with primary membranous nephropathy cannot be reliably predicted by laboratory or clinical markers at the time of diagnosis. M-type Phospholipase A2 Receptor autoantibodies have been shown to be associated with changes in proteinuria. Their eventual effect on renal function, however, is unclear. Design, setting, participants, & measurements In this prospective, open, multicenter study, the potential role of M-type Phospholipase A2 Receptor autoantibodies levels on the increase of serum creatinine in 118 consecutive patients with membranous nephropathy and positivity for serum M-type Phospholipase A2 Receptor autoantibodies was analyzed. Patients were included in the study between April of 2010 and December of 2012 and observed until December of 2013. The clinical end point was defined as an increase of serum creatinine by ≥25% and serum creatinine reaching ≥1.3 mg/dl. Results Patients were divided into tertiles according to their M-type Phospholipase A2 Receptor autoantibody levels at the time of inclusion in the study: tertile 1 levels=20–86 units/ml (low), tertile 2 levels=87–201 units/ml (medium), and tertile 3 levels ≥202 units/ml (high). The median follow-up time of all patients in the study was 27 months (interquartile range=18–33 months). The clinical end point was reached in 69% of patients with high M-type Phospholipase A2 Receptor autoantibodies levels (tertile 3) but only 25% of patients with low M-type Phospholipase A2 Receptor autoantibodies levels. The average time to reach the study end point was 17.7 months in patients with high M-type Phospholipase A2 Receptor autoantibodies levels and 30.9 months in patients with low M-type Phospholipase A2 Receptor autoantibodies levels. A multivariate Cox regression analysis showed that high M-type Phospholipase A2 Receptor autoantibodies levels—in addition to men and older age—are an independent predictor for progressive loss of renal function. Conclusions High M-type Phospholipase A2 Receptor autoantibodies levels were associated with more rapid loss of renal function in this cohort of patients with primary membranous nephropathy and therefore, could be helpful for treatment decisions.
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Phospholipase A2 Receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy
Journal of The American Society of Nephrology, 2014Co-Authors: Elion Hoxha, Gunther Zahner, Ina Thiele, Ulf Panzer, Sigrid Harendza, Rolf A K StahlAbstract:Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, with an uncertain clinical outcome. The characterization of the Phospholipase A2 Receptor (PLA2R) as the major target antigen in primary MN and the detection of circulating autoantibodies in these patients is a major advance in understanding this disease. To test whether PLA2R antibody levels reflect disease activity or clinical outcome, we performed a prospective multicenter study of 133 adult patients with primary MN and detectable serum PLA2R antibodies who had not received immunosuppressive therapy. Patients were followed ≤24 months. PLA2R antibody levels associated with clinical disease activity (proteinuria) in patients with immunosuppressive therapy (n=101) or supportive care (n=32). Within 3 months, immunosuppressive therapy led to a sustained 81% reduction in PLA2R antibody levels paralleled by a 39% reduction in proteinuria. Patients who experienced remission of proteinuria after 12 months had significantly lower PLA2R antibody levels at the time of study inclusion compared with patients with no remission. Patients with high PLA2R antibody levels achieved remission of proteinuria significantly later than patients with low PLA2R antibody levels. PLA2R antibody levels fell over time in patients with spontaneous remission but remained elevated in patients who did not show a reduction in proteinuria. Multivariable Cox regression analysis confirmed PLA2R antibody level as an independent risk factor for not achieving remission of proteinuria. We conclude that a decrease in PLA2R antibody level is associated with a decrease of proteinuria in patients with primary MN.
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development of a standardized elisa for the determination of autoantibodies against human m type Phospholipase A2 Receptor in primary membranous nephropathy
Clinica Chimica Acta, 2013Co-Authors: Cornelia Dahnrich, Elion Hoxha, Julia M. Hofstra, Barbara Seitzpolski, V Esnault, Jack F M Wetzels, Lars Komorowski, Christian Probst, Rolf A K StahlAbstract:Abstract Background Autoantibodies against the M-type Phospholipase A2 Receptor (PLA 2 R1) are specific markers for primary membranous nephropathy (pMN) and anti-PLA 2 R1 serum levels may be useful to monitor disease activity. So far, a recombinant cell-based indirect immunofluorescence assay (RC-IFA) using recombinant PLA 2 R1 as a substrate has been widely available but lacks a finely graduated assessment of antibody concentrations. Methods In order to setup a standardized ELISA, the extracellular domain of human PLA 2 R1 was expressed in HEK293. The purified protein was used to form the solid-phase in an ELISA which was then employed to analyze sera from 200 patients with primary MN, 27 patients with secondary MN, 230 patients with other glomerular diseases, 316 patients with systemic autoimmune diseases, and from 291 healthy blood donors. Results At a set specificity of 99.9% the sensitivity of the anti-PLA 2 R1 IgG ELISA was found to be 96.5%. A similar sensitivity (98.5%) was obtained when binding of only subclass IgG 4 was analyzed. The calibrated assay showed a good class correlation with the results of the RC-IFA, was robust and could be stored for several months without any loss of quality. Conclusion The results demonstrate that the new test system is qualified for routine use and that it has an almost perfect agreement with both, the clinical characterization of the patients and the results generated with RC-IFA.
Elion Hoxha - One of the best experts on this subject based on the ideXlab platform.
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clinical relevance of domain specific Phospholipase A2 Receptor 1 antibody levels in patients with membranous nephropathy
Journal of The American Society of Nephrology, 2020Co-Authors: Linda Reinhard, Gunther Zahner, Rolf A K Stahl, Stephan Menzel, Friedrich Kochnolte, Elion HoxhaAbstract:BACKGROUND: Antibodies against Phospholipase A2 Receptor 1 (PLA2R1) are found in 80% of patients with membranous nephropathy, and previous studies described three autoantibody-targeted PLA2R1 epitope regions. Although anti-PLA2R1 antibody levels are closely associated with treatment response and disease prognosis, the clinical role of epitope regions targeted by autoantibodies is unclear. METHODS: In a prospective cohort of 150 patients with newly diagnosed PLA2R1-associated membranous nephropathy, we investigated the clinical role of epitope-recognition patterns and domain-specific PLA2R1 antibody levels by western blot and ELISA. RESULTS: We identified a fourth epitope region in the CTLD8 domain of PLA2R1, which was recognized by anti-PLA2R1 antibodies in 24 (16.0%) patients. In all study patients, anti-PLA2R1 antibodies bound both the N-terminal (CysR-FnII-CTLD1) region and the C-terminal (CTLD7-CTLD8) region of PLA2R1 at study enrollment. The total anti-PLA2R1 antibody levels of patients determined detection of domain-specific PLA2R1 antibodies, and thereby epitope-recognition patterns. A remission of proteinuria occurred in 133 (89%) patients and was not dependent on the domain-recognition profiles. A newly developed ELISA showed that domain-specific PLA2R1 antibody levels targeting CysR, CTLD1, and CTLD7 strongly correlate with the total anti-PLA2R1 antibody level (Spearman's rho, 0.95, 0.64, and 0.40; P<0.001, P<0.001, and P=0.002, respectively) but do not predict disease outcome independently of total anti-PLA2R1 antibody levels. CONCLUSIONS: All patients with PLA2R1-associated membranous nephropathy recognize at least two epitope regions in the N- and C-terminals of PLA2R1 at diagnosis, contradicting the hypothesis that PLA2R1 "epitope spreading" determines the prognosis of membranous nephropathy. Total anti-PLA2R1 antibody levels, but not the epitope-recognition profiles at the time of diagnosis, are relevant for the clinical outcome of patients with this disease.
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M-Type Phospholipase A2 Receptor as a Biomarker in Kidney Disease
2016Co-Authors: Elion HoxhaAbstract:The identification of the M-type Phospholipase A2 Receptor as a major antigen in membranous nephropathy is leading to a paradigm shift in our understanding of the pathomechanisms involved in this disease as well as the clinical management of these patients. On the one side, the autoimmune nature of the disease, in which circulating autoantibodies bind to podocytic antigens, is confirmed, and on the other side, a whole new area of research on this condition has opened. Genomewide association studies show an association of membranous nephropathy with PLA2R and HLA loci, and major antibody-binding epitope regions have been identified on the PLA2R. These findings might enable us in the future to better E. Hoxha • R.A.K. Stahl (*) University Medical Center Hamburg-Eppendorf, Hamburg, Germany e-mail: ehoxha@uke.de; rstahl@uke.de # Springer Science+Business Media Dordrecht 2015 V.B. Patel, V.R. Preedy (eds.), Biomarkers in Kidney Disease, DOI 10.1007/978-94-007-7743-9_42-1 1 characterize the processes leading to the development of these antibodies, thus leading to new treatment options. At the same time, PLA2R antibody findings are playing an increasing role in the differential diagnosis of primary from secondary membranous nephropathy and treatment management helping to better adapt therapy to the risk profile and disease activity of an individual patient and are a perfect example of how experimental research can lead to individualized medicine.
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spontaneous remission of proteinuria is a frequent event in Phospholipase A2 Receptor antibody negative patients with membranous nephropathy
Nephrology Dialysis Transplantation, 2015Co-Authors: Elion Hoxha, Ulf Panzer, Sigrid Harendza, Udo M Helmchen, Hans O Pinnschmidt, Nicola M. Tomas, Rolf A K StahlAbstract:Abstract Phospholipase A2 Receptor antibodies (PLA2R-Ab) and thrombospondin type-1 domain-containing 7A antibodies (THSD7A-Ab) are present in 70-80% of patients with membranous nephropathy (MN). Little, however, is known about the pathogenesis of MN and the clinical outcome in PLA2R-Ab- and THSD7A-Ab-negative patients. In this prospective multicentre observational study, the clinical outcome of 37 patients with biopsy-proven MN who were negative for PLA2R-Ab and THSD7A-Ab in the serum was analysed. A total of 198 patients were screened for inclusion in the study. Of these, 157 patients were positive for PLA2R-Ab and 4 patients for THSD7A-Ab. The remaining 37 patients were negative for both antibodies were and included in this study. Six patients died during the follow-up, five because of malignant diseases and one of an infection. One patient went into end-stage renal disease, and two patients were lost to follow-up. The remaining 28 patients were followed for at least 24 months (35.6 ± 8.9 months). Seventeen patients received immunosuppressive (IS) therapy, and 11 received supportive care only. At the end of the follow-up, 14 of the 17 patients treated with immunosuppressants and 10 of 11 patients on supportive therapy had a remission of proteinuria. The time to reach remission of proteinuria and serum creatinine levels at the end of the follow-up were not different between both groups. A univariate Cox regression analysis indicated that the use of immunosuppression did not alter the chance to reach a remission of proteinuria. A high number of PLA2R-Ab- and THSD7A-Ab-negative patients with MN have a good prognosis and might not need IS therapy.
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m type Phospholipase A2 Receptor autoantibodies and renal function in patients with primary membranous nephropathy
Clinical Journal of The American Society of Nephrology, 2014Co-Authors: Elion Hoxha, Ulf Panzer, Sigrid Harendza, Hans O Pinnschmidt, Rolf A K StahlAbstract:Background and objectives Loss of renal function in patients with primary membranous nephropathy cannot be reliably predicted by laboratory or clinical markers at the time of diagnosis. M-type Phospholipase A2 Receptor autoantibodies have been shown to be associated with changes in proteinuria. Their eventual effect on renal function, however, is unclear. Design, setting, participants, & measurements In this prospective, open, multicenter study, the potential role of M-type Phospholipase A2 Receptor autoantibodies levels on the increase of serum creatinine in 118 consecutive patients with membranous nephropathy and positivity for serum M-type Phospholipase A2 Receptor autoantibodies was analyzed. Patients were included in the study between April of 2010 and December of 2012 and observed until December of 2013. The clinical end point was defined as an increase of serum creatinine by ≥25% and serum creatinine reaching ≥1.3 mg/dl. Results Patients were divided into tertiles according to their M-type Phospholipase A2 Receptor autoantibody levels at the time of inclusion in the study: tertile 1 levels=20–86 units/ml (low), tertile 2 levels=87–201 units/ml (medium), and tertile 3 levels ≥202 units/ml (high). The median follow-up time of all patients in the study was 27 months (interquartile range=18–33 months). The clinical end point was reached in 69% of patients with high M-type Phospholipase A2 Receptor autoantibodies levels (tertile 3) but only 25% of patients with low M-type Phospholipase A2 Receptor autoantibodies levels. The average time to reach the study end point was 17.7 months in patients with high M-type Phospholipase A2 Receptor autoantibodies levels and 30.9 months in patients with low M-type Phospholipase A2 Receptor autoantibodies levels. A multivariate Cox regression analysis showed that high M-type Phospholipase A2 Receptor autoantibodies levels—in addition to men and older age—are an independent predictor for progressive loss of renal function. Conclusions High M-type Phospholipase A2 Receptor autoantibodies levels were associated with more rapid loss of renal function in this cohort of patients with primary membranous nephropathy and therefore, could be helpful for treatment decisions.
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Phospholipase A2 Receptor autoantibodies and clinical outcome in patients with primary membranous nephropathy
Journal of The American Society of Nephrology, 2014Co-Authors: Elion Hoxha, Gunther Zahner, Ina Thiele, Ulf Panzer, Sigrid Harendza, Rolf A K StahlAbstract:Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in adults, with an uncertain clinical outcome. The characterization of the Phospholipase A2 Receptor (PLA2R) as the major target antigen in primary MN and the detection of circulating autoantibodies in these patients is a major advance in understanding this disease. To test whether PLA2R antibody levels reflect disease activity or clinical outcome, we performed a prospective multicenter study of 133 adult patients with primary MN and detectable serum PLA2R antibodies who had not received immunosuppressive therapy. Patients were followed ≤24 months. PLA2R antibody levels associated with clinical disease activity (proteinuria) in patients with immunosuppressive therapy (n=101) or supportive care (n=32). Within 3 months, immunosuppressive therapy led to a sustained 81% reduction in PLA2R antibody levels paralleled by a 39% reduction in proteinuria. Patients who experienced remission of proteinuria after 12 months had significantly lower PLA2R antibody levels at the time of study inclusion compared with patients with no remission. Patients with high PLA2R antibody levels achieved remission of proteinuria significantly later than patients with low PLA2R antibody levels. PLA2R antibody levels fell over time in patients with spontaneous remission but remained elevated in patients who did not show a reduction in proteinuria. Multivariable Cox regression analysis confirmed PLA2R antibody level as an independent risk factor for not achieving remission of proteinuria. We conclude that a decrease in PLA2R antibody level is associated with a decrease of proteinuria in patients with primary MN.
Pierre Ronco - One of the best experts on this subject based on the ideXlab platform.
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development of a standardized chemiluminescence immunoassay for the detection of autoantibodies against human m type Phospholipase A2 Receptor in primary membranous nephropathy
Kidney International Reports, 2020Co-Authors: Cornelia Dahnrich, Hanna Debiec, Pierre Ronco, Sandra Saschenbrecker, Iva Gunnarsson, Wolfgang SchlumbergerAbstract:Introduction Autoantibodies against the M-type Phospholipase A2 Receptor (PLA2R) are important markers in the diagnosis and monitoring of primary membranous nephropathy (pMN). For the detection of anti-PLA2R autoantibodies, a standardized recombinant cell-based indirect immunofluorescence assay (RC-IFA) and enzyme-linked immunosorbent assay (ELISA) are widely used, the former providing higher sensitivity but lacking a finely graduated quantification of antibody titers. In this study, we evaluated the diagnostic performance characteristics of a novel standardized chemiluminescence immunoassay (ChLIA) by comparison with the established anti-PLA2R test systems. Methods Sera from 155 patients with biopsy-proven pMN and 154 disease controls were analyzed for autoantibodies against PLA2R by the novel ChLIA as well as by ELISA and RC-IFA. Results The clinical sensitivity of the ChLIA (83.9%) was higher compared with ELISA (73.5%) and equaled that of RC-IFA (83.2%), at similar specificities (≥99.4%). Among ELISA-negative pMN samples, ChLIA and RC-IFA yielded positive results in 39.0% and 36.6%, respectively. The qualitative agreement amounted to 94.5% (ChLIA vs. ELISA) and 99.4% (ChLIA vs. RC-IFA). Conclusion The novel anti-PLA2R ChLIA outperforms the ELISA in detecting patients with pMN and demonstrates almost perfect agreement with RC-IFA. It thus presents a promising alternative tool for accurate anti-PLA2R testing, with the advantage of rapid turnaround times and fully automated random-access processing.
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Phospholipase A2 Receptor 1 epitope spreading at baseline predicts reduced likelihood of remission of membranous nephropathy
Journal of The American Society of Nephrology, 2017Co-Authors: Barbara Seitzpolski, Gérard Lambeau, Hanna Debiec, Alexandra Rousseau, Karine Dahan, Christelle Zaghrini, C Payre, V Esnault, Pierre RoncoAbstract:The Phospholipase A2 Receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab ( n =29) or antiproteinuric therapy alone ( n =29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer ( P P =0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P =0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy.
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Phospholipase A2 Receptor related membranous nephropathy and mannan binding lectin deficiency
Journal of The American Society of Nephrology, 2016Co-Authors: Stephane Bally, Hanna Debiec, D Ponard, Frederique Dijoud, John Rendu, Julien Faure, Pierre Ronco, Chantal DumestreperardAbstract:Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against Phospholipase A2 Receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2.
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Phospholipase A2 Receptor–Related Membranous Nephropathy and Mannan-Binding Lectin Deficiency
Journal of The American Society of Nephrology, 2016Co-Authors: Stephane Bally, Hanna Debiec, D Ponard, Frederique Dijoud, John Rendu, Julien Faure, Pierre Ronco, Chantal Dumestre-pérardAbstract:Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against Phospholipase A2 Receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2.