- Primer
- Published:
Membranous nephropathy
- Pierre Ronco1,2,
- Laurence Beck3,
- Hanna Debiec1,
- Fernando C. Fervenza ORCID:orcid.org/0000-0002-9952-209X4,
- Fan Fan Hou ORCID:orcid.org/0000-0003-3117-74185,
- Vivekanand Jha ORCID:orcid.org/0000-0002-8015-94706,7,8,
- Sanjeev Sethi ORCID:orcid.org/0000-0002-4536-77099,
- Allison Tong10,11,
- Marina Vivarelli12 &
- …
- Jack Wetzels ORCID:orcid.org/0000-0002-0650-692113
Nature Reviews Disease Primersvolume 7, Article number: 69 (2021)Cite this article
70kAccesses
239Citations
139Altmetric
Abstract
Membranous nephropathy (MN) is a glomerular disease that can occur at all ages. In adults, it is the most frequent cause of nephrotic syndrome. In ~80% of patients, there is no underlying cause of MN (primary MN) and the remaining cases are associated with medications or other diseases such as systemic lupus erythematosus, hepatitis virus infection or malignancies. MN is an autoimmune disease characterized by a thickening of the glomerular capillary walls due to immune complex deposition. Identification of the phospholipase A2 receptor (PLA2R) as the major antigen in adults in 2009 induced a paradigm shift in disease diagnosis and monitoring and several other antigens have since been characterized. Disease outcome is difficult to predict and around one-third of patients will undergo spontaneous remission. In those at high risk of progression, immunosuppressive therapy with cyclophosphamide plus corticosteroids has substantially reduced the need for kidney replacement therapy. Owing to carcinogenic risk, other treatments (calcineurin inhibitors and CD20-targeted B cell depletion therapy (rituximab)) have been developed. However, disease relapses are frequent when calcineurin inhibitors are stopped and the remission rate with rituximab is lower than with cyclophosphamide, particularly in patients with high PLA2R antibody titres. Other new drugs are already available and antigen-specific immunotherapies are being developed.
This is a preview of subscription content,access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
9,800 Yen / 30 days
cancel any time
Subscribe to this journal
Receive 1 digital issues and online access to articles
￥14,900 per year
only ￥14,900 per issue
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Couser, W. G. Primary membranous nephropathy.Clin. J. Am. Soc. Nephrol.12, 983–997 (2017).
Debiec, H. et al. Antenatal membranous glomerulonephritis due to anti-neutral endopeptidase antibodies.N. Engl. J. Med.346, 2053–2060 (2002).A landmark article that reports the first description of a podocyte antigen involved in a rare subset of neonatal MN.
Beck, L. H. et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N. Engl. J. Med.361, 11–21 (2009).A landmark article that first characterizes the major antigen in adult MN, leading to a paradigm shift in the diagnosis and monitoring of patients.
Tomas, N. M. et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy.N. Engl. J. Med.371, 2277–2287 (2014).The first report of an antigen found to be associated with cancer in a subset of patients.
Ronco, P. & Debiec, H. Membranous nephropathy: current understanding of various causes in light of new target antigens.Curr. Opin. Nephrol. Hypertens.30, 287–293 (2021).
Sethi, S. New ‘antigens’ in membranous nephropathy.J. Am. Soc. Nephrol.32, 268–278 (2021).
Cattran, D. C. & Brenchley, P. E. Membranous nephropathy: integrating basic science into improved clinical management.Kidney Int.91, 566–574 (2017).
Dahan, K. et al. Rituximab for severe membranous nephropathy: a 6-month trial with extended follow-up.J. Am. Soc. Nephrol.28, 348–358 (2017).
Fervenza, F. C. et al. Rituximab or cyclosporine in the treatment of membranous nephropathy.N. Engl. J. Med.381, 36–46 (2019).This landmark randomized clinical trial provides the first comparison of rituximab and cyclosporine.
Fernández-Juárez, G. et al. The STARMEN trial indicates that alternating treatment with corticosteroids and cyclophosphamide is superior to sequential treatment with tacrolimus and rituximab in primary membranous nephropathy.Kidney Int.99, 986–998 (2021).This important randomized clinical trial provides the first comparison of cyclophosphamide (with corticosteroids) with a sequential combination of tacrolimus and rituximab.
Scolari, F. et al. Rituximab or cyclosphamide in the treatment of membranous nephropathy.J. Am. Soc. Nephrol.32, 972–982 (2021).
De Vriese, A. S., Glassock, R. J., Nath, K. A., Sethi, S. & Fervenza, F. C. A proposal for a serology-based approach to membranous nephropathy.J. Am. Soc. Nephrol.28, 421–430 (2017).
Kumar, V. et al. Antibodies to m-type phospholipase A2 receptor in children with idiopathic membranous nephropathy.Nephrology20, 572–575 (2015).
Debiec, H. & Ronco, P. Immunopathogenesis of membranous nephropathy: an update.Semin. Immunopathol.36, 381–397 (2014).
McGrogan, A., Franssen, C. F. & de Vries, C. S. The incidence of primary glomerulonephritis worldwide: a systematic review of the literature.Nephrol. Dial. Transplant.26, 414–430 (2011).
Rychlik, I. et al. The Czech registry of renal biopsies. Occurrence of renal diseases in the years 1994-2000.Nephrol. Dial. Transplant.19, 3040–3049 (2004).
Hogan, S. L., Muller, K. E., Jennette, J. C. & Falk, R. J. A review of therapeutic studies of idiopathic membranous glomerulopathy.Am. J. Kidney Dis.25, 862–875 (1995).
Xu, X. et al. Long-term exposure to air pollution and increased risk of membranous nephropathy in China.J. Am. Soc. Nephrol.27, 3739–3746 (2016).
Ronco, P. & Debiec, H. Pathophysiological advances in membranous nephropathy: time for a shift in patient’s care.Lancet385, 1983–1992 (2015).
Arapovic, A. et al. Epidemiology of 10-year paediatric renal biopsies in the region of southern Croatia.BMC Nephrol.21, 65 (2020).
Chen, A. et al. Idiopathic membranous nephropathy in pediatric patients: presentation, response to therapy, and long-term outcome.BMC Nephrol.8, 11 (2007).
Eddy, A. A. & Symons, J. M. Nephrotic syndrome in childhood.Lancet362, 629–639 (2003).
Nie, S. et al. The spectrum of biopsy-proven glomerular diseases among children in China: a national, cross-sectional survey.Clin. J. Am. Soc. Nephrol.13, 1047–1054 (2018).
Johnson, R. J. & Couser, W. G. Hepatitis B infection and renal disease: clinical, immunopathogenetic and therapeutic considerations.Kidney Int.37, 663–676 (1990).
Moroni, G. & Ponticelli, C. Secondary membranous nephropathy. a narrative review.Front. Med.7, 611317 (2020).
Xu, X., Nie, S., Ding, H. & Hou, F. F. Environmental pollution and kidney diseases.Nat. Rev. Nephrol.14, 313–324 (2018).
Narasimhan, B. et al. Characterization of kidney lesions in Indian adults: towards a renal biopsy registry.J. Nephrol.19, 205–210 (2006).
Li, J. et al. Primary glomerular nephropathy among hospitalized patients in a national database in China.Nephrol. Dial. Transpl.33, 2173–2181 (2018).
Schieppati, A. et al. Prognosis of untreated patients with idiopathic membranous nephropathy.N. Engl. J. Med.329, 85–89 (1993).
Ponticelli, C. et al. A 10-year follow-up of a randomized study with methylprednisolone and chlorambucil in membranous nephropathy.Kidney Int.48, 1600–1604 (1995).
Jha, V. et al. A randomized, controlled trial of steroids and cyclophosphamide in adults with nephrotic syndrome caused by idiopathic membranous nephropathy.J. Am. Soc. Nephrol.18, 1899–1904 (2007).
Maisonneuve, P. et al. Distribution of primary renal diseases leading to end-stage renal failure in the United States, Europe, and Australia/New Zealand: results from an international comparative study.Am. J. Kidney Dis.35, 157–165 (2000).
Troyanov, S. et al. Idiopathic membranous nephropathy: definition and relevance of a partial remission.Kidney Int.66, 1199–1205 (2004).
Fervenza, F. C., Sethi, S. & Specks, U. Idiopathic membranous nephropathy: diagnosis and treatment.Clin. J. Am. Soc. Nephrol.3, 905–919 (2008).
Klouda, P. T. et al. Strong association between idiopathic membranous nephropathy and HLA-DRW3.Lancet2, 770–771 (1979).
Vaughan, R. W., Demaine, A. G. & Welsh, K. I. A DQA1 allele is strongly associated with idiopathic membranous nephropathy.Tissue Antigens34, 261–269 (1989).
Stanescu, H. C. et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy.N. Engl. J. Med.364, 616–626 (2011).
Coenen, M. J. et al. Phospholipase A2 receptor (PLA2R1) sequence variants in idiopathic membranous nephropathy.J. Am. Soc. Nephrol.24, 677–683 (2013).
Lv, J. et al. Interaction between PLA2R1 and HLA-DQA1 variants associates with anti-PLA2R antibodies and membranous nephropathy.J. Am. Soc. Nephrol.24, 1323–1329 (2013).
Le, W. B. et al. HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-Related membranous nephropathy.J. Am. Soc. Nephrol.28, 1642–1650 (2017).
Cui, Z. et al. MHC class II risk alleles and amino acid residues in idiopathic membranous nephropathy.J. Am. Soc. Nephrol.28, 1651–1664 (2017).
Xie, J. et al. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis.Nat. Commun.11, 1600 (2020).The most extensive multi-ethnic genome-wide association study performed in membranous nephropathy revealing the complexity of HLA-D alleles associated with membranous nephropathy in different ethnic populations and signals in the NF-κB and interferon pathways.
Wang, H. Y. et al. HLA class II alleles differing by a single amino acid associate with clinical phenotype and outcome in patients with primary membranous nephropathy.Kidney Int.94, 974–982 (2018).
Van Damme, B. J., Fleuren, G. J., Bakker, W. W., Vernier, R. L. & Hoedemaeker, P. J. Experimental glomerulonephritis in the rat induced by antibodies directed against tubular antigens. V. Fixed glomerular antigens in the pathogenesis of heterologous immune complex glomerulonephritis.Lab. Invest.38, 502–510 (1978).
Couser, W. G., Steinmuller, D. R., Stilmant, M. M., Salant, D. J. & Lowenstein, L. M. Experimental glomerulonephritis in the isolated perfused rat kidney.J. Clin. Invest.62, 1275–1287 (1978).
Kerjaschki, D. & Farquhar, M. G. Immunocytochemical localization of the Heymann nephritis antigen (GP330) in glomerular epithelial cells of normal Lewis rats.J. Exp. Med.157, 667–686 (1983).
Prabakaran, T. et al. Receptor-mediated endocytosis of α-galactosidase A in human podocytes in Fabry disease.PLoS ONE6, e25065 (2011).
Debiec, H. et al. Role of truncating mutations in MME gene in feto-maternal allo-immunization and neonatal glomerulopathies.Lancet364, 1252–1259 (2004).
Turner, A. J., Isaac, R. E. & Coates, D. The neprilysin (NEP) family of zinc metalloendopeptidases: genomics and function.Bioessays23, 261–269 (2001).
Lu, B. et al. The control of microvascular permeability and blood pressure by neutral endopeptidase.Nat. Med.3, 904–907 (1997).
Platt, J. L., Tucker, W. L. & Michael, A. F. Stages of renal ontogenesis identified by monoclonal antibodies reactive with lymphohematopoietic differentiation antigens.J. Exp. Med.157, 155–172 (1983).
Vivarelli, M. et al. Genetic homogeneity but IgG subclass-dependent clinical variability of alloimmune membranous nephropathy with anti-neutral endopeptidase antibodies.Kidney Int.87, 602–609 (2015).
Hogan, M. C. et al. Subfractionation, characterization, and in-depth proteomic analysis of glomerular membrane vesicles in human urine.Kidney Int.85, 1225–1237 (2014).
Ancian, P., Lambeau, G., Mattei, M. G. & Lazdunski, M. The human 180-kDa receptor for secretory phospholipases A2. Molecular cloning, identification of a secreted soluble form, expression, and chromosomal localization.J. Biol. Chem.270, 8963–8970 (1995).
Fresquet, M. et al. Identification of a major epitope recognized by PLA2R autoantibodies in primary membranous nephropathy.J. Am. Soc. Nephrol.26, 302–313 (2015).
Seitz-Polski, B. et al. Epitope spreading of autoantibody response to PLA2R associates with poor prognosis in membranous nephropathy.J. Am. Soc. Nephrol.27, 1517–1533 (2016).
Reinhard, L. et al. Clinical relevance of domain-specific phospholipase A2 receptor 1 antibody levels in patients with membranous nephropathy.J. Am. Soc. Nephrol.31, 197–207 (2020).
Seitz-Polski, B. et al. Phospholipase A2 receptor 1 epitope spreading at baseline predicts reduced likelihood of remission of membranous nephropathy.J. Am. Soc. Nephrol.29, 401–408 (2018).
Kanigicherla, D. et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy.Kidney Int.83, 940–948 (2013).
Godel, M., Grahammer, F. & Huber, T. B. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy.N. Engl. J. Med.372, 1073 (2015).
Herwig, J. et al. Thrombospondin type 1 domain-containing 7A localizes to the slit diaphragm and stabilizes membrane dynamics of fully differentiated podocytes.J. Am. Soc. Nephrol.30, 824–839 (2019).
Seifert, L. et al. The most N-terminal region of THSD7A Is the predominant target for autoimmunity in THSD7A-associated membranous nephropathy.J. Am. Soc. Nephrol.29, 1536–1548 (2018).
Hoxha, E. et al. A mechanism for cancer-associated membranous nephropathy.N. Engl. J. Med.374, 1995–1996 (2016).
Hoxha, E. et al. An indirect immunofluorescence method facilitates detection of thrombospondin type 1 domain-containing 7A-specific antibodies in membranous nephropathy.J. Am. Soc. Nephrol.28, 520–531 (2017).
Sethi, S. et al. Exostosin 1/exostosin 2-associated membranous nephropathy.J. Am. Soc. Nephrol.30, 1123–1136 (2019).This article reports the first use of a technological leap combining microdissection of glomeruli and mass spectrometry for the identification of the first biomarker of lupus membranous nephropathy.
Ravindran, A. et al. In patients with membranous lupus nephritis, exostosin-positivity and exostosin-negativity represent two different phenotypes.J. Am. Soc. Nephrol.32, 695–706 (2021).
Saidi, M. et al. The exostosin immunohistochemical status differentiates lupus membranous nephropathy subsets with different outcomes.Kidney Int. Rep.6, 1977–1980 (2021).
Caza, T. et al. NELL1 is a target antigen in malignancy-associated membranous nephropathy.Kidney Int.99, 967–976 (2021).
Sethi, S. et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy.Kidney Int.97, 163–174 (2020).This article reports the identification of the second prevalent antigen (after PLA2R) in MN using glomerular microdissection followed by mass spectrometry.
Kudose, S. et al. The clinicopathologic spectrum of segmental membranous glomerulopathy.Kidney Int.99, 247–255 (2021).
Sethi, S. et al. Semaphorin 3B-associated membranous nephropathy is a distinct type of disease predominantly present in pediatric patients.Kidney Int.98, 1253–1264 (2020).
Caza, T. et al. Neural cell adhesion molecule 1 is a novel autoantigen in membranous lupus nephritis.Kidney Int.100, 171–181 (2021).
Sethi, S. et al. Protocadherin 7-associated Membranous Nephropathy.J. Am. Soc. Nephrol.32, 1249–1261 (2021).
Al-Rabadi, L. F. et al. Serine protease HTRA1 as a novel target antigen in primary membranous nephropathy.J. Am. Soc. Nephrol.https://doi.org/10.1681/ASN.2020101395 (2021).
Meyer-Schwesinger, C. et al. A novel mouse model of phospholipase A2 receptor 1-associated membranous nephropathy mimics podocyte injury in patients.Kidney Int.97, 913–919 (2020).
Blosser, C. D., Ayalon, R., Nair, R., Thomas, C. & Beck, L. H. Jr. Very early recurrence of anti-Phospholipase A2 receptor-positive membranous nephropathy after transplantation.Am. J. Transplant.12, 1637–1642 (2012).
Stahl, R., Hoxha, E. & Fechner, K. PLA2R autoantibodies and recurrent membranous nephropathy after transplantation.N. Engl. J. Med.363, 496–498 (2010).
Beck, L. H. Jr et al. Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.J. Am. Soc. Nephrol.22, 1543–1550 (2011).
Ruggenenti, P. et al. Anti-phospholipase A2 receptor antibody titer predicts post-rituximab outcome of membranous nephropathy.J. Am. Soc. Nephrol.26, 2545–2558 (2015).
Debiec, H. et al. Early-childhood membranous nephropathy due to cationic bovine serum albumin.N. Engl. J. Med.364, 2101–2110 (2011).A landmark article that identifies the first food antigen involved in rare cases of membranous nephropathy in children.
Border, W. A., Ward, H. J., Kamil, E. S. & Cohen, A. H. Induction of membranous nephropathy in rabbits by administration of an exogenous cationic antigen.J. Clin. Invest.69, 451–461 (1982).
Adler, S. G., Wang, H., Ward, H. J., Cohen, A. H. & Border, W. A. Electrical charge. Its role in the pathogenesis and prevention of experimental membranous nephropathy in the rabbit.J. Clin. Invest.71, 487–499 (1983).
Hunley, T. E. et al. Nephrotic syndrome complicating α-glucosidase replacement therapy for Pompe disease.Pediatrics114, e532–e535 (2004).
Debiec, H. et al. Allo-immune membranous nephropathy and recombinant aryl sulfatase replacement therapy: a need for tolerance induction therapy.J. Am. Soc. Nephrol.25, 675–680 (2013).
Burbelo, P. D. et al. Detection of PLA2R autoantibodies before the diagnosis of membranous nephropathy.J. Am. Soc. Nephrol.31, 208–217 (2020).
Cremoni, M. et al. Th17-immune response in patients with membranous nephropathy is associated with thrombosis and relapses.Front. Immunol.11, 574997 (2020).
Motavalli, R. et al. Altered Th17/Treg ratio as a possible mechanism in pathogenesis of idiopathic membranous nephropathy.Cytokine141, 155452 (2021).
Rosenzwajg, M. et al. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab.Kidney Int.92, 227–237 (2017).
Cantarelli, C. et al. A comprehensive phenotypic and functional immune analysis unravels circulating anti-phospholipase A2 receptor antibody secreting cells in membranous nephropathy patients.Kidney Int. Rep.5, 1764–1776 (2020).
Berchtold, L. et al. HLA-D and PLA2R1 risk alleles associate with recurrent primary membranous nephropathy in kidney transplant recipients.Kidney Int.99, 671–685 (2021).
Segerer, S. & Schlondorff, D. B cells and tertiary lymphoid organs in renal inflammation.Kidney Int.73, 533–537 (2008).
Kolovou, K. et al. B-cell oligoclonal expansions in renal tissue of patients with immune-mediated glomerular disease.Clin. Immunol.217, 108488 (2020).
Prunotto, M. et al. Proteomic analysis of podocyte exosome-enriched fraction from normal human urine.J. Proteom.82, 193–229 (2013).
Kerjaschki, D. & Neale, T. J. Molecular mechanisms of glomerular injury in rat experimental membranous nephropathy (Heymann nephritis).J. Am. Soc. Nephrol.7, 2518–2526 (1996).
Huang, C. C. et al. IgG subclass staining in renal biopsies with membranous glomerulonephritis indicates subclass switch during disease progression.Mod. Pathol.26, 799–805 (2013).
Val-Bernal, J. F., Garijo, M. F., Val, D., Rodrigo, E. & Arias, M. C4d immunohistochemical staining is a sensitive method to confirm immunoreactant deposition in formalin-fixed paraffin-embedded tissue in membranous glomerulonephritis.Histol. Histopathol.26, 1391–1397 (2011).
Hayashi, N. et al. Glomerular mannose-binding lectin deposition in intrinsic antigen-related membranous nephropathy.Nephrol. Dial. Transplant.33, 832–840 (2018).
Bally, S. et al. Phospholipase A2 receptor-related membranous nephropathy and mannan-binding lectin deficiency.J. Am. Soc. Nephrol.27, 3539–3544 (2016).
Ravindran, A. et al. Proteomic analysis of complement proteins in membranous nephropathy.Kidney Int. Rep.5, 618–626 (2020).
Cybulsky, A. V., Quigg, R. J. & Salant, D. J. Experimental membranous nephropathy redux.Am. J. Physiol. Ren. Physiol.289, F660–F671 (2005).
Tomas, N. M. et al. Autoantibodies against thrombospondin type 1 domain-containing 7A induce membranous nephropathy.J. Clin. Invest.126, 2519–2532 (2016).
Tomas, N. M. et al. A heterologous model of thrombospondin type 1 domain-containing 7A-associated membranous nephropathy.J. Am. Soc. Nephrol.28, 3262–3277 (2017).
Petrosyan, A. et al. A glomerulus-on-a-chip to recapitulate the human glomerular filtration barrier.Nat. Commun.10, 3656 (2019).
Haddad, G. et al. Altered glycosylation of IgG4 promotes lectin complement pathway activation in anti-PLA2R1 associated membranous nephropathy.J. Clin. Invest.131, e140453 (2021).This article provides the first demonstration of the pathogenic role of modified IgG4 specific for PLA2R in lectin pathway activation.
Ghiggeri, G. M. et al. Multi-autoantibody signature and clinical outcome in membranous nephropathy.Clin. J. Am. Soc. Nephrol.15, 1762–1776 (2020).
Seikrit, C., Ronco, P. & Debiec, H. Factor H autoantibodies and membranous nephropathy.N. Engl. J. Med.379, 2479–2481 (2018).
Barbour, S. J. et al. Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis.Kidney Int.81, 190–195 (2012).
Kerlin, B. A., Ayoob, R. & Smoyer, W. E. Epidemiology and pathophysiology of nephrotic syndrome-associated thromboembolic disease.Clin. J. Am. Soc. Nephrol.7, 513–520 (2012).
Lionaki, S. et al. Venous thromboembolism in patients with membranous nephropathy.Clin. J. Am. Soc. Nephrol.7, 43–51 (2012).
Cattran D. C. et al. (eds)National Kidney Foundation’s Primer on Kidney Diseases 7th Edn 188–197 (Elsevier, 2018).
Agrawal, S., Zaritsky, J. J., Fornoni, A. & Smoyer, W. E. Dyslipidaemia in nephritic syndrome: mechanisms and treatment.Nat. Rev. Nephrol.14, 57–70 (2018).
Rodriguez, E. F. et al. Membranous nephropathy with crescents: a series of 19 cases.Am. J. Kidney Dis.64, 66–73 (2014).
Fogo, A. B., Lusco, M. A., Najafian, B. & Alpers, C. E. Atlas of renal pathology: membranous nephropathy.Am. J. Kidney Dis.66, e43–e45 (2015).
Beck, L. H., Fervenza, F. C. InMolecular Mechanisms in the Pathogenesis of Idiopathic Nephrotic Syndrome (ed. Kaneko, K.) 181–205 (Springer Japan, 2016).
Markowitz, G. S. Membranous glomerulopathy: emphasis on secondary forms and disease variants.Adv. Anat. Pathol.8, 119–125 (2001).
Kuroki, A. et al. Glomerular and serum IgG subclasses in diffuse proliferative lupus nephritis, membranous lupus nephritis, and idiopathic membranous nephropathy.Intern. Med.41, 936–942 (2002).
Ronco, P., Plaisier, E. & Debiec, H. Advances in membranous nephropathy.J. Clin. Med.10, 607 (2021).
Qu, Z. et al. Absence of glomerular IgG4 deposition in patients with membranous nephropathy may indicate malignancy.Nephrol. Dial. Transplant.27, 1931–1937 (2012).
von Haxthausen, F. et al. Antigen-specific IgG subclasses in primary and malignancy-associated membranous nephropathy.Front. Immunol.9, 3035 (2018).
van de Logt, A. E., Hofstra, J. M. & Wetzels, J. F. Serum anti-PLA2R antibodies can be initially absent in idiopathic membranous nephropathy: seroconversion after prolonged follow-up.Kidney Int.87, 1263–1264 (2015).
Debiec, H. & Ronco, P. PLA2R autoantibodies and PLA2R glomerular deposits in membranous nephropathy.N. Engl. J. Med.364, 689–690 (2011).
Svobodova, B., Honsova, E., Ronco, P., Tesar, V. & Debiec, H. Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy.Nephrol. Dial. Transplant.28, 1839–1844 (2013).
Luo, J., Zhang, W., Su, C., Zhou, Z. & Wang, G. Seropositive PLA2R-associated membranous nephropathy but biopsy-negative PLA2R staining.Nephrol. Dial. Transplant.https://doi.org/10.1093/ndt/gfaa239 (2020).
Poggio, E. D. et al. Systematic review and meta-analysis of native kidney biopsy complications.Clin. J. Am. Soc. Nephrol.15, 1595–1602 (2020).
Pombas, B. et al. Risk factors associated with major complications after ultrasound-guided percutaneous renal biopsy of native kidneys.Kidney Blood. Press. Res.45, 122–130 (2020).
Palsson, R. et al. Bleeding complications after percutaneous native kidney biopsy: results from the Boston Kidney Biopsy cohort.Kidney Int. Rep.5, 511–518 (2020).
Atwell, T. D. et al. The timing and presentation of major hemorrhage after 18,947 image-guided percutaneous biopsies.Am. J. Roentgenol.205, 190–195 (2015).
Bobart, S. A. et al. Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies.Kidney Int.95, 429–438 (2019).
Bobart, S. A. et al. Kidney biopsy is required for nephrotic syndrome with PLA2R+ and normal kidney function: the Con View.Kidney360, 890–893 (2020).
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerular Diseases Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases.Kidney Int.100, S1–S276 (2021).A milestone for the management of glomerular diseases.
Bobart, S. A. et al. A target antigen-based approach to the classification of membranous nephropathy.Mayo Clin. Proc.96, 577–591 (2021).
Larsen, C. P. et al. Determination of primary versus secondary membranous glomerulopathy utilizing phospholipase A2 receptor staining in renal biopsies.Mod. Pathol.26, 709–715 (2013).
Stehle, T. et al. Phospholipase A2 receptor and sarcoidosis-associated membranous nephropathy.Nephrol. Dial. Transplant.30, 1047–1050 (2015).
Xie, Q. et al. Renal phospholipase A2 receptor in hepatitis B virus-associated membranous nephropathy.Am. J. Nephrol.41, 345–353 (2015).
Berchtold, L. et al. Efficacy and safety of rituximab in hepatitis B virus-associated PLA2R-positive membranous nephropathy.Kidney Int. Rep.3, 486–491 (2018).
Qin, W. et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy.J. Am. Soc. Nephrol.22, 1137–1143 (2011).
Hanset, N. et al. Podocyte antigen staining to identify distinct phenotypes and outcomes in membranous nephropathy: a retrospective multicenter cohort study.Am. J. Kidney Dis.76, 624–635 (2020).
Zhang, Z. et al. Duodenal schwannoma as a rare association with membranous nephropathy: a case report.Am. J. Kidney Dis.73, 278–280 (2019).
Zaghrini, C. et al. Novel ELISA for thrombospondin type 1 domain-containing 7A autoantibodies in membranous nephropathy.Kidney Int.95, 666–679 (2019).
Sharma, S. G. & Larsen, C. P. Tissue staining for THSD7A in glomeruli correlates with serum antibodies in primary membranous nephropathy: a clinicopathological study.Mod. Pathol.31, 616–622 (2018).
Schlumberger, W. et al. Differential diagnosis of membranous nephropathy with autoantibodies to phospholipase A2 receptor 1.Autoimmun. Rev.13, 108–113 (2014).
Timmermans, S. A. et al. Evaluation of anti-PLA2R1 as measured by a novel ELISA in patients with idiopathic membranous nephropathy: a cohort study.Am. J. Clin. Pathol.142, 29–34 (2014).
Liu, Y. et al. Serum anti-PLA2R antibody as a diagnostic biomarker of idiopathic membranous nephropathy: the optimal cut-off value for Chinese patients.Clin. Chim. Acta476, 9–14 (2018).
Behnert, A. et al. Antiphospholipase A2 receptor autoantibodies: a comparison of three different immunoassays for the diagnosis of idiopathic membranous nephropathy.J. Immunol. Res.2014, 143274 (2014).
Pourcine, F. et al. Prognostic value of PLA2R autoimmunity detected by measurement of anti-PLA2R antibodies combined with detection of PLA2R antigen in membranous nephropathy. A single-centre study over 14 years.PLoS ONE12, e0173201 (2017).
Plaisier, E. & Ronco, P. Screening for cancer in patients with glomerular diseases.Clin. J. Am. Soc. Nephrol.15, 886–888 (2020).
Cambier, J. F. & Ronco, P. Onco-nephrology: glomerular diseases with cancer.Clin. J. Am. Soc. Nephrol.7, 1701–1712 (2012).
Timmermans, S. A. et al. Anti-phospholipase A2 receptor antibodies and malignancy in membranous nephropathy.Am. J. Kidney Dis.62, 1223–1225 (2013).
Wang, G. et al. Neural epidermal growth factor-Like 1 protein-positive membranous nephropathy in Chinese patients.Clin. J. Am. Soc. Nephrol.8, 727–735 (2021).
Ayalon, R. & Beck, L. H. Jr Membranous nephropathy: not just a disease for adults.Pediatr. Nephrol.30, 31–39 (2015).
Debiec, H., Ronco, P. & Vivarelli, M. Congenital membranous nephropathy due to fetomaternal anti-neutral endopeptidase alloimmunization. Orphanethttps://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=69063 (2020).
Bhimma, R. & Coovadia, H. M. Hepatitis B virus-associated nephropathy.Am. J. Nephrol.24, 198–211 (2004).
Safar-Boueri, L., Piya, A., Beck, L. H. Jr & Ayalon, R. Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era.Pediatr. Nephrol.36, 19–30 (2021).
Debiec, H. et al. Allo-immune membranous nephropathy and recombinat arylsulfatase replacement therapy: a need for tolerance induction therapy.J. Am. Soc. Nephrol.25, 675–680 (2014).
Wang, R. et al. Long-term renal survival and related risk factors for primary membranous nephropathy in Chinese children: a retrospective analysis of 217 cases.J. Nephrol.34, 589–596 (2021).
Ramachandran R. & Jha, V. inGlomerulonephritis (eds Trachtman H., Hogan J. J., Herlitz L. & Lerma E. V.) (Springer, 2020).
Htay, H. et al. Global access of patients with kidney disease to health technologies and medications: findings from the Global Kidney Health Atlas project.Kidney Int. Suppl.8, 64–73 (2018).
Hepatitis B Foundation. World Health Organization. Addressing Hepatitis B in Africa.Hepatitis B Foundationhttps://www.hepb.org/blog/addressing-hepatitis-b-africa/ (2020).
Kumar, M. N. et al. Membranous nephropathy associated with indigenous Indian medications containing heavy metals.Kidney Int. Rep.5, 1510–1514 (2020).
Landrigan, P. J. et al. The Lancet Commission on pollution and health.Lancet391, 462–512 (2018).
Gupta, S., Pepper, R. J., Ashman, N. & Walsh, S. B. Nephrotic syndrome: oedema formation and its treatment with diuretics.Front. Physiol.9, 1868 (2019).
Hinrichs, G. R., Jensen, B. L. & Svenningsen, P. Mechanisms of sodium retention in nephrotic syndrome.Curr. Opin. Nephrol. Hypertens.29, 207–212 (2020).
Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work Group. KDIGO clinical practice guideline for glomerulonephritis.Kidney Int. Suppl.2, 186–197 (2012).
Polanco, N. et al. Spontaneous remission of nephrotic syndrome in idiopathic membranous nephropathy.J. Am. Soc. Nephrol.2, 697–704 (2020).
Pincus, K. J. & Hynicka, L. M. Prophylaxis of thromboembolic events in patients with nephrotic syndrome.Ann. Pharmacother.47, 725–734 (2013).
Medjeral-Thomas, N. et al. Retrospective analysis of a novel regimen for the prevention of venous thromboembolism in nephrotic syndrome.Clin. J. Am. Soc. Nephrol.9, 478–483 (2014).
Hofstra, J. M. & Wetzels, J. F. M. Should aspirin be used for primary prevention of thrombotic events in patients with membranous nephropathy?Kidney Int.89, 981–983 (2016).
Sexton, D. J. et al. Direct-acting oral anticoagulants as prophylaxis against thromboembolism in the nephrotic syndrome.Kidney Int. Rep.3, 784–793 (2018).
Reynolds, M. L., Nachman, P. H., Mooberry, M. J., Crona, D. J. & Derebail, V. K. Recurrent venous thromboembolism in primary membranous nephropathy despite direct Xa inhibitor therapy.J. Nephrol.32, 669–672 (2019).
van de Logt, A. E., Hofstra, J. M. & Wetzels, J. F. Pharmacological treatment of primary membranous nephropathy in 2016.Expert Rev. Clin. Pharmacol.9, 1463–1478 (2016).
van den Brand, J. A., van Dijk, P. R., Hofstra, J. M. & Wetzels, J. F. Long-term outcomes in idiopathic membranous nephropathy using a restrictive treatment strategy.J. Am. Soc. Nephrol.25, 150–158 (2014).
Reichert, L. J., Koene, R. A. & Wetzels, J. F. Prognostic factors in idiopathic membranous nephropathy.Am. J. Kidney Dis.31, 1–11 (1998).
Hladunewich, M. A., Troyanov, S., Calafati, J. & Cattran, D. C. Metropolitan Toronto Glomerulonephritis Registry. The natural history of the non-nephrotic membranous nephropathy patient.Clin. J. Am. Soc. Nephrol.4, 1417–1422 (2009).
Hoxha, E., Harendza, S., Pinnschmidt, H., Panzer, U. & Stahl, R. A. PLA2R antibody levels and clinical outcome in patients with membranous nephropathy and non-nephrotic range proteinuria under treatment with inhibitors of the renin-angiotensin system.PLoS ONE9, e110681 (2014).
Pei, Y., Cattran, D. & Greenwood, C. Predicting chronic renal insufficiency in idiopathic membranous glomerulonephritis.Kidney Int.42, 960–966 (1992).
Howman, A. et al. Immunosuppression for progressive membranous nephropathy: a UK randomised controlled trial.Lancet381, 744–751 (2013).
Cattran, D. C. et al. Validation of a predictive model of idiopathic membranous nephropathy: its clinical and research implications.Kidney Int.51, 901–907 (1997).
van den Brand, J. A., Hofstra, J. M. & Wetzels, J. F. Prognostic value of risk score and urinary markers in idiopathic membranous nephropathy.Clin. J. Am. Soc. Nephrol.7, 1242–1248 (2012).
van de Logt, A. E. et al. Anti-PLA2R1 antibodies as prognostic biomarker in membranous nephropathy.Kidney Int. Rep.6, 1677–1686 (2021).
Lerner, G. B., Virmani, S., Henderson, J. M., Francis, J. M. & Beck, L. H. Jr. A conceptual framework linking immunology, pathology, and clinical features in primary membranous nephropathy.Kidney Int.100, 289–300 (2021).
Faul, C. et al. The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A.Nat. Med.14, 931–938 (2008).
Ramachandran, R. et al. Two-year follow-up study of membranous nephropathy treated with tacrolimus and corticosteroids versus cyclical corticosteroids and cyclophosphamide.Kidney Int. Rep.2, 610–616 (2017).
van de Logt, A. E. et al. Immunological remission in PLA2R-antibody-associated membranous nephropathy: cyclophosphamide versus rituximab.Kidney Int.93, 1016–1017 (2018).
Hanset, N. et al. Rituximab in patients with phospholipase A2 receptor-associated membranous nephropathy and severe CKD.Kidney Int. Rep.5, 331–338 (2019).
Dahan, K. et al. Retreatment with rituximab for membranous nephropathy with persistently elevated titers of anti-phospholipase A2 receptor antibody.Kidney Int.95, 233–234 (2019).
van de Logt, A. E. et al. The bias between different albumin assays may affect clinical decision-making.Kidney Int.95, 1514–1517 (2019).
Bech, A. P., Hofstra, J. M., Brenchley, P. E. & Wetzels, J. F. Association of anti-PLA2R antibodies with outcomes after immunosuppressive therapy in idiopathic membranous nephropathy.Clin. J. Am. Soc. Nephrol.9, 1386–1392 (2014).
Filler, G. et al. Another case of HBV associated membranous glomerulonephritis resolving on lamivudine.Arch. Dis. Child.88, F154–F156 (2003).
O’Shaughnessy, M. M. et al. Treatment patterns among adults and children with membranous nephropathy in the Cure Glomerulonephropathy Network (CureGN).Kidney Int. Rep.4, 1725–1734 (2019).
Riaz, P. et al. Workforce capacity for the care of patients with kidney failure across world countries and regions.BMJ Glob. Health6, e004014 (2021).
Jha, V. et al. Understanding kidney care needs and implementation strategies in low- and middle-income countries: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) controversies conference.Kidney Int.90, 1164–1174 (2016).
Cosio, F. G. & Cattran, D. C. Recent advances in our understanding of recurrent primary glomerulonephritis after kidney transplantation.Kidney Int.91, 304–314 (2017).
Grupper, A. et al. Recurrent membranous nephropathy after kidney transplantation: treatment and long-term implications.Transplantation100, 2710–2716 (2016).
Seitz-Polski, B. et al. Prediction of membranous nephropathy recurrence after transplantation by monitoring of anti-PLA2R1 (M-type phospholipase A2 receptor) autoantibodies: a case series of 15 patients.Nephrol. Dial. Transplant.29, 2334–2342 (2014).
Quintana, L. F. et al. Antiphospholipase A2 receptor antibody levels predict the risk of posttransplantation recurrence of membranous nephropathy.Transplantation99, 1709–1714 (2015).
Andrésdóttir, M. B. & Wetzels, J. F. Increased risk of recurrence of membranous nephropathy after related donor kidney transplantation.Am. J. Transplant.12, 265–266 (2012).
Gupta, G. et al. Pre-transplant phospholipase A2 receptor autoantibody concentration is associated with clinically significant recurrence of membranous nephropathy post-kidney transplantation.Clin. Transplant.30, 461–469 (2016).
Batal, I. et al. Association of HLA typing and alloimmunity with posttransplantation membranous nephropathy: a multicenter case series.Am. J. Kidney Dis.76, 374–383 (2020).
Kattah, A. et al. Anti-phospholipase A2 receptor antibodies in recurrent membranous nephropathy.Am. J. Transplant.15, 1349–1359 (2015).
WHO.Programme on Mental Health. WHOQOL User Manual (World Health Organization, 1998).
Wyld, M., Morton, R. L., Hayen, A., Howard, K. & Webster, A. C. A systematic review and meta-analysis of utility-based quality of life in chronic kidney disease treatments.PLoS Med.9, e1001307 (2012).
Chuasuwan, A., Pooripussarakul, S., Thakkinstian, A., Ingsathit, A. & Pattanaprateep, O. Comparisons of quality of life between patients underwent peritoneal dialysis and hemodialysis: a systematic review and meta-analysis.Health Qual. Life. Outcomes18, 191 (2020).
Canetta, P. A. et al. Health-related quality of life in glomerular disease.Kidney Int.95, 1209–1224 (2019).
Cattran, D. Management of membranous nephropathy: when and what for treatment.J. Am. Soc. Nephrol.16, 1188–1194 (2005).
Libório, A. B. et al. Proteinuria is associated with quality of life and depression in adults with primary glomerulopathy and preserved renal function.PLoS ONE7, e37763 (2012).
Floege, J. et al. Management and treatment of glomerular diseases (part 1): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) controversies conference.Kidney Int.95, 268–280 (2019).
Murphy, S. L. et al. Longitudinal changes in health-related quality of life in primary glomerular disease: results from the CureGN study.Kidney Int. Rep.5, 1679–1689 (2020).
Center for Drug Evaluation and Research, Center for Devices and Radiological Health and Center for Biologics Evaluation and Research.Guidance for Industry. Patient-Reported Outcome Measures: Use in Medical Product Development To Support Labeling Claims (FDA, 2009).
Bansal, D., Bhagat, A., Schifano, F. & Gudala, K. Role of patient-reported outcomes and other efficacy endpoints in the drug approval process in Europe (2008-2012).J. Epidemiol. Glob. Health5, 385–395 (2015).
Carter, S. A. et al. Identifying outcomes important to patients with glomerular disease and their caregivers.Clin. J. Am. Soc. Nephrol.15, 673–684 (2020).
Henkel, C. & Hoffmann, P. (Eds) MALDI Imaging.Biochim. Biophys. Acta1865, 725–978 (2017).
Neumann, E. K., Djambazova, K. V., Caprioli, R. M. & Spraggins, J. M. Multimodal imaging mass spectrometry: next generation molecular mapping in biology and medicine.J. Am. Soc. Mass. Spectrom.31, 2401–2415 (2020).
Unnersjö-Jess, D., Scott, L., Blom, H. & Brismar, H. Super-resolution stimulated emission depletion imaging of slit diaphragm proteins in optically cleared kidney tissue.Kidney Int.89, 243–247 (2016).
Park, J., Liu, C. L., Kim, J. & Susztak, K. Understanding the kidney one cell at a time.Kidney Int.96, 862–870 (2019).
Ellebrecht, C. T. et al. Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.Science353, 179–184 (2016).
Wraith, D. Autoimmunity: antigen-specific immunotherapy.Nature530, 422–423 (2016).
Abedini, A. et al. Urinary single-cell profiling captures the cellular diversity of the kidney.J. Am. Soc. Nephrol.32, 614–627 (2021).
Unlu, G. et al. GRIK5 genetically regulated expression associated with eye and vascular phenomes: discovery through iteration among biobanks, electronic health records, and Zebrafish.Am. J. Hum. Genet.104, 503–519 (2019).
Reddy, V. et al. Obinutuzumab induces superior B-cell cytotoxicity to rituximab in rheumatoid arthritis and systemic lupus erythematosus patient samples.Rheumatology56, 1227–1237 (2017).
Klomjit, N., Fervenza, F. C. & Zand, L. Successful treatment of patients with refractory PLA2 R-associated membranous nephropathy with obinutuzumab: a report of 3 cases.Am. J. Kidney Dis.76, 883–888 (2020).
Podestà, M. A., Ruggiero, B., Remuzzi, G. & Ruggenenti, P. Ofatumumab for multirelapsing membranous nephropathy complicated by rituximab-induced serum- sickness.BMJ Case. Rep.13, e232896 (2020).
Schmidt, T., Schulze, M., Harendza, S. & Hoxha, E. Successful treatment of PLA2R1-antibody positive membranous nephropathy with ocrelizumab.J. Nephrol.34, 603–606 (2021).
Samy, E., Wax, S., Huard, B., Hess, H. & Schneider, P. Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases.Int. Rev. Immunol.36, 3–19 (2017).
Mahévas, M. et al. Efficacy, safety and immunological profile of combining rituximab with belimumab for adults with persistent or chronic immune thrombocytopenia: results from a prospective phase 2b trial.Haematologicahttps://doi.org/10.3324/haematol.2020.259481 (2020).
Furie, R. et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis.N. Engl. J. Med.383, 1117–1128 (2020).
Barrett, C. et al. Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy.Nephrol. Dial. Transplant.35, 599–606 (2020).
Crickx, E., Weill, J. C., Reynaud, C. A. & Mahévas, M. Anti-CD20-mediated B-cell depletion in autoimmune diseases: successes, failures and future perspectives.Kidney Int.97, 885–893 (2020).
US National Library of Medicine.ClinicalTrials.govhttps://clinicaltrials.gov/ct2/show/NCT04145440 (2021).
Weinmann-Menke, J. et al. Treatment of membranous nephropathy in patients with THSD7A antibodies using immunoadsorption.Am. J. Kidney Dis.74, 849–852 (2019).
Podestà, M. A. et al. Accelerating the depletion of circulating anti-phospholipase A2 receptor antibodies in patients with severe membranous nephropathy: preliminary findings with double filtration plasmapheresis and ofatumumab.Nephron144, 30–35 (2020).
Zipfel, P. F. et al. Complement inhibitors in clinical trials for glomerular diseases.Front. Immunol.10, 2166 (2019).
Low, J. H. et al. Generation of human PSC-derived kidney organoids with patterned nephron segments and a de novo vascular network.Cell Stem. Cell25, 373–387 (2019).
Maas, R. J. et al. Kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin as prognostic markers in idiopathic membranous nephropathy.Ann. Clin. Biochem.53, 51–57 (2016).
van den Brand, J. A., Hofstra, J. M. & Wetzels, J. F. Low-molecular-weight proteins as prognostic markers in idiopathic membranous nephropathy.Clin. J. Am. Soc. Nephrol.6, 2846–2853 (2011).
Acknowledgements
L.B. acknowledges institutional funding for the Glomerular Disease Center at Boston Medical Center in support of the preparation of this manuscript. J.W. acknowledges support from grants from the Dutch Kidney Foundation (grant nrNSN 17PhD12), funding from European Union Seventh Framework Programme FP7/2007-2013 grant 305608: European Consortium for High-Throughput Research in Rare Kidney Diseases. V.J. acknowledges research grants from Baxter Healthcare, GSK, and NephroPlus and honoraria/speaker fees from Baxter Healthcare and AstraZeneca (all monies paid to the employer). P.R. acknowledges support from grants from the National Research Agency: MNaims (ANR-17-CE17-0012-01) and SeroNegMN (ANR-20-CE17-0017-01). F.C.F. acknowledges unrestricted research grants from Genentech Inc., Roche and MorphoSys for research on Membranous Nephropathy (all funds paid to the institution). M.V., P.R. and J.W. acknowledge the European Rare Kidney Disease Network (ERKNet). A.T. is supported by a National Health and Medical Research Council Investigator Award (1197324). F.F.H. acknowledges support from the Clinical Innovation Research Program of Guangzhou Regenerative Medicine and Health Guangdong Laboratory (2018GZR0201003).
Author information
Authors and Affiliations
Sorbonne Université, and Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche, S1155, Paris, France
Pierre Ronco & Hanna Debiec
Department of Nephrology, Centre Hospitalier du Mans, Le Mans, France
Pierre Ronco
Section of Nephrology, Department of Medicine, Boston Medical Center and Boston University School of Medicine, Boston, MA, USA
Laurence Beck
Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
Fernando C. Fervenza
National Clinical Research Center for Kidney Disease, Nanfang Hospital, State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
Fan Fan Hou
George Institute for Global Health, UNSW, New Delhi, India
Vivekanand Jha
School of Public Health, Imperial College, London, UK
Vivekanand Jha
Prasanna School of Higher Education, Manipal Academy of Higher Education, Manipal, India
Vivekanand Jha
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
Sanjeev Sethi
Sydney School of Public Health, University of Sydney, Sydney, NSW, Australia
Allison Tong
Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, NSW, Australia
Allison Tong
Division of Nephrology and Dialysis - Bambino Gesù Pediatric Hospital IRCCS, Rome, Italy
Marina Vivarelli
Department of Nephrology, Radboud University Medical Center, Nijmegen, Netherlands
Jack Wetzels
- Pierre Ronco
You can also search for this author inPubMed Google Scholar
- Laurence Beck
You can also search for this author inPubMed Google Scholar
- Hanna Debiec
You can also search for this author inPubMed Google Scholar
- Fernando C. Fervenza
You can also search for this author inPubMed Google Scholar
- Fan Fan Hou
You can also search for this author inPubMed Google Scholar
- Vivekanand Jha
You can also search for this author inPubMed Google Scholar
- Sanjeev Sethi
You can also search for this author inPubMed Google Scholar
- Allison Tong
You can also search for this author inPubMed Google Scholar
- Marina Vivarelli
You can also search for this author inPubMed Google Scholar
- Jack Wetzels
You can also search for this author inPubMed Google Scholar
Contributions
Introduction (P.R.); Epidemiology (P.R. and F.F.H.); Mechanisms/pathophysiology (L.B., H.D. and S.S.); Diagnosis/screening/prevention (F.C.F., V.J. and M.V.); Management (V.J., M.V. and J.W.); Quality of life (V.J. and A.T.); Outlooks (P.R. and L.B.); Overview of the Primer (P.R.).
Corresponding author
Correspondence toPierre Ronco.
Ethics declarations
Competing interests
L.B. is co-inventor on the patent “Diagnostics for Membranous Nephropathy” and has received consultancy fees from Alexion, Ionis, Genentech and Visterra for topics related to membranous nephropathy as well as research support from Sanofi Genzyme and Pfizer. P.R. has received consultancy fees from Alexion and MorphoSys for topics related to membranous nephropathy. F.C.F. has received consultancy fees from Alexion and MorphoSys for topics related to membranous nephropathy. F.F.H. has received consultancy fees from AbbVie and AstraZeneca. J.W. has received consultancy fees from Novartis and MorphoSys for topics related to membranous nephropathy. The other authors declare no competing interests.
Additional information
Peer review information
Nature Reviews Disease Primers thanks L. Barisoni, S. Maruyama and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Glossary
- Podocytopathy
A disease of the podocyte, the main glomerular cell controlling the filtration of proteins.
- Glomerular filtration rate
(GFR). The most reliable parameter to assess renal function and can be evaluated with formulas (eGFR) or measured (mGFR).
- Heymann nephritis
A model of membranous nephropathy developed by Walter Heymann in the rat in the 1950s that is still the most reliable experimental model for human membranous nephropathy.
- Allo-immunization
Immunization against a non-self human antigen (protein or sugar) as occurs after blood transfusions or in case of Rhesus incompatibility during pregnancy, resulting in the production of allo-antibodies.
- Epitope spreading
Diffusion of the immune response to additional epitopes on the same molecule or different molecules.
- Full-house pattern
Immunofluorescence studies show staining for IgA, IgG, IgM, C1q, C3, κ and λ light chains.
- Xeno-antibodies
Production of xeno-antibodies results from immunization against a non-self, non-human antigen (protein or sugar); a process termed xeno-immunization.
- Anaphylatoxins
One of several proteolytic fragments generated by complement activation that promote acute inflammation and mediation of the immune response.
- Anasarca
Severe and generalized form of oedema, with subcutaneous tissue swelling, that usually involves the cavities of the body.
- Thrombophilic state
A pathological condition that predisposes to thrombosis.
Rights and permissions
About this article
Cite this article
Ronco, P., Beck, L., Debiec, H.et al. Membranous nephropathy.Nat Rev Dis Primers7, 69 (2021). https://doi.org/10.1038/s41572-021-00303-z
Accepted:
Published:
Share this article
Anyone you share the following link with will be able to read this content:
Sorry, a shareable link is not currently available for this article.
Provided by the Springer Nature SharedIt content-sharing initiative
This article is cited by
Targeting endoplasmic reticulum stress: an innovative therapeutic strategy for podocyte-related kidney diseases
- Jiao Lv
- Honghai Yu
- Xiuge Wang
Journal of Translational Medicine (2025)
Risk factors for relapse and aggravation in membranous nephropathy after COVID-19 infection
- Yue Shu
- Jing Huang
- Zhao Cui
BMC Nephrology (2025)
Impact of immune cell metabolism on membranous nephropathy and prospective therapy
- Xuemei Duan
- Xin Lv
- Yukai Jing
Communications Biology (2025)
To biopsy or not to biopsy a teenager with typical idiopathic nephrotic syndrome? Start steroids first
- Olivia Boyer
- Silvia Bernardi
- Evgenia Preka
Pediatric Nephrology (2025)
Causality between diabetes and membranous nephropathy: Mendelian randomization
- Zhihang Su
- Ziqi Luo
- Qijun Wan
Clinical and Experimental Nephrology (2025)
