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• W2140908812 abstract "Membranous nephropathy (MN), a major cause of glomerular disease and nephrotic syndrome in adults, is characterized by subepithelial deposits of immunoglobulin G (IgG) and complement activation, which leads to podocyte damage and proteinuria.1Ronco P. Debiec H. Pathogenesis of membranous nephropathy: recent advances and future challenges.Nat Rev Nephrol. 2012; 8: 203-213Crossref PubMed Scopus (122) Google Scholar Primary MN is associated with prominent deposition of IgG4 and variable amounts of IgG1, whereas secondary MN demonstrates primarily IgG1, IgG2, and IgG3. Diagnosis typically has depended on kidney biopsy, and proteinuria and serum creatinine values were the only criteria used to monitor patients and determine their need for treatment. There was an urgent need to identify more accurate biomarkers. During the last decade, several major breakthroughs have led to the identification of human podocyte membrane antigens. The first was neutral endopeptidase, which was identified in a rare subset of patients with alloimmune neonatal MN.2Debiec H. Guigonis V. Mougenot B. et al.Antenatal membranous glomerulonephritis due to anti-NEP antibodies.N Engl J Med. 2002; 346: 2053-2060Crossref PubMed Scopus (405) Google Scholar, 3Debiec H. Nauta J. Coulet F. et al.Role of truncating mutations in MME gene in feto-maternal allo-immunization and neonatal glomerulopathies.Lancet. 2004; 364: 1252-1259Abstract Full Text Full Text PDF PubMed Scopus (174) Google Scholar This finding provided the proof of concept that a podocyte membrane antigen could be used as the target for nephritogenic antibodies in humans and paved the way to identifying the M-type receptor for secretory phospholipase A2 (PLA2R1) in the more common forms of primary MN.4Beck Jr, L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic MN.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1419) Google Scholar Accumulating data indicate that anti-PLA2R1 antibodies are excellent biomarkers of primary MN, as defined by the National Institutes of Health,5Naylor S. Biomarkers: current perspectives and future prospects.Expert Rev Mol Diagn. 2003; 3: 525-529Crossref PubMed Scopus (92) Google Scholar with sensitivity close to 70%1Ronco P. Debiec H. Pathogenesis of membranous nephropathy: recent advances and future challenges.Nat Rev Nephrol. 2012; 8: 203-213Crossref PubMed Scopus (122) Google Scholar, 6Hofstra J.M. Debiec H. Short C.D. et al.Anti-phospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1735-1743Crossref PubMed Scopus (229) Google Scholar, 7Kanigicherla D, Gummadova J, McKenzie EA, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy [published online ahead of print January 30, 2013]. Kidney Int. doi:10.1038/ki.2012.486.Google Scholar and specificity >90% (Table 1). A low prevalence of anti-PLA2R1 antibodies has been observed in secondary MN,8Qin W. Beck Jr, L.H. Zeng C. et al.Anti-phospholipase A2 receptor antibody in membranous nephropathy.J Am Soc Nephrol. 2011; 22: 1137-1143Crossref PubMed Scopus (332) Google Scholar, 9Knehtl M. Debiec H. Kamgang P. et al.A case of phospholipase A2 receptor-positive membranous nephropathy preceding sarcoid-associated granulomatous tubulointerstitial nephritis.Am J Kidney Dis. 2011; 57: 140-143Abstract Full Text Full Text PDF PubMed Scopus (48) Google Scholar, 10Hoxha E. Kneiβler U. Stege G. et al.Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy.Kidney Int. 2012; 82: 797-804Crossref PubMed Scopus (215) Google Scholar, 11Svobodova B, Honsova E, Ronco P, Tesar V, DebiecH. Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy [published online ahead of print December 6, 2012]. Nephrol Dial Transplant. doi: 10.1093/ndt/gfs439.Google Scholar although it is impossible to exclude the coincidental occurrence of primary MN with the associated disease. Healthy people and individuals with nephrotic syndrome due to other causes have no detectable anti-PLA2R1 antibodies. Several studies now indicate that anti-PLA2R1 antibody titer correlates with outcome7Kanigicherla D, Gummadova J, McKenzie EA, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy [published online ahead of print January 30, 2013]. Kidney Int. doi:10.1038/ki.2012.486.Google Scholar, 12Hofstra J.M. Beck Jr, L.H. Beck D.M. Wetzels J.F. Salant D.J. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2011; 6: 1286-1291Crossref PubMed Scopus (278) Google Scholar and disease activity,7Kanigicherla D, Gummadova J, McKenzie EA, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy [published online ahead of print January 30, 2013]. Kidney Int. doi:10.1038/ki.2012.486.Google Scholar, 12Hofstra J.M. Beck Jr, L.H. Beck D.M. Wetzels J.F. Salant D.J. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2011; 6: 1286-1291Crossref PubMed Scopus (278) Google Scholar, 13Beck Jr, L.H. Fervenza F.C. Beck D.M. et al.Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.J Am Soc Nephrol. 2011; 22: 1543-1550Crossref PubMed Scopus (343) Google Scholar and that MN can be transmitted to the kidney transplant by anti-PLA2R1 antibodies.14Debiec H. Martin L. Jouanneau C. et al.Anti-PLA2R1 autoantibodies in recurrent and de novo membranous nephropathy.Am J Transplant. 2011; 11: 2144-2152Crossref PubMed Scopus (116) Google Scholar, 15Blosser C.D. Ayalon R. Nair R. Thomas C. Beck Jr, L.H. Very early recurrence of anti-phospholipase A2 receptor-positive membranous nephropathy after transplantation.Am J Transplant. 2012; 12: 1637-1642Crossref PubMed Scopus (35) Google Scholar, 16Debiec H. Hanoy M. François A. et al.Recurrent membranous nephropathy in an allograft caused by IgG3κ targeting the PLA2 receptor.J Am Soc Nephrol. 2012; 23: 1949-1954Crossref PubMed Scopus (80) Google ScholarTable 1A Comparison of Anti-PLA2R1 Antibodies With Antipodocyte Cytoplasm AntibodiesAnti-PLA2R1Antibodies to Podocyte Cytoplasmic AntigensAssayWestern blot4Beck Jr, L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic MN.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1419) Google Scholar, 8Qin W. Beck Jr, L.H. Zeng C. et al.Anti-phospholipase A2 receptor antibody in membranous nephropathy.J Am Soc Nephrol. 2011; 22: 1137-1143Crossref PubMed Scopus (332) Google Scholar, 12Hofstra J.M. Beck Jr, L.H. Beck D.M. Wetzels J.F. Salant D.J. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2011; 6: 1286-1291Crossref PubMed Scopus (278) Google Scholar; immunofluorescence microscopy,6Hofstra J.M. Debiec H. Short C.D. et al.Anti-phospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1735-1743Crossref PubMed Scopus (229) Google Scholar, 10Hoxha E. Kneiβler U. Stege G. et al.Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy.Kidney Int. 2012; 82: 797-804Crossref PubMed Scopus (215) Google Scholar, 11Svobodova B, Honsova E, Ronco P, Tesar V, DebiecH. Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy [published online ahead of print December 6, 2012]. Nephrol Dial Transplant. doi: 10.1093/ndt/gfs439.Google Scholar, 14Debiec H. Martin L. Jouanneau C. et al.Anti-PLA2R1 autoantibodies in recurrent and de novo membranous nephropathy.Am J Transplant. 2011; 11: 2144-2152Crossref PubMed Scopus (116) Google Scholar ELISA6Hofstra J.M. Debiec H. Short C.D. et al.Anti-phospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1735-1743Crossref PubMed Scopus (229) Google Scholar, 7Kanigicherla D, Gummadova J, McKenzie EA, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy [published online ahead of print January 30, 2013]. Kidney Int. doi:10.1038/ki.2012.486.Google ScholarDot blot18Bruschi M. Carnevali M.L. Murtas C. et al.Direct characterization of target podocyte antigens and auto-antibodies in human membranous glomerulonephritis: alfa-enolase and borderline antigens.J Proteomics. 2011; 74: 2008-2017Crossref PubMed Scopus (100) Google Scholar, 19Prunotto M. Carnevali M.L. Candiano G. et al.Autoimmunity in membranous nephropathy targets aldose reductase and SOD2.J Am Soc Nephrol. 2010; 21: 507-519Crossref PubMed Scopus (175) Google Scholar, 20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google ScholarSensitivity70%-75%1Ronco P. Debiec H. Pathogenesis of membranous nephropathy: recent advances and future challenges.Nat Rev Nephrol. 2012; 8: 203-213Crossref PubMed Scopus (122) Google Scholar, 6Hofstra J.M. Debiec H. Short C.D. et al.Anti-phospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1735-1743Crossref PubMed Scopus (229) Google Scholar, 7Kanigicherla D, Gummadova J, McKenzie EA, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy [published online ahead of print January 30, 2013]. Kidney Int. doi:10.1038/ki.2012.486.Google Scholar,aLower in Japanese population.28%-43%20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google ScholarSpecificity for primary MN>90%1Ronco P. Debiec H. Pathogenesis of membranous nephropathy: recent advances and future challenges.Nat Rev Nephrol. 2012; 8: 203-213Crossref PubMed Scopus (122) Google Scholar, 4Beck Jr, L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic MN.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1419) Google Scholar, 8Qin W. Beck Jr, L.H. Zeng C. et al.Anti-phospholipase A2 receptor antibody in membranous nephropathy.J Am Soc Nephrol. 2011; 22: 1137-1143Crossref PubMed Scopus (332) Google Scholar, 10Hoxha E. Kneiβler U. Stege G. et al.Enhanced expression of the M-type phospholipase A2 receptor in glomeruli correlates with serum receptor antibodies in primary membranous nephropathy.Kidney Int. 2012; 82: 797-804Crossref PubMed Scopus (215) Google Scholar, 11Svobodova B, Honsova E, Ronco P, Tesar V, DebiecH. Kidney biopsy is a sensitive tool for retrospective diagnosis of PLA2R-related membranous nephropathy [published online ahead of print December 6, 2012]. Nephrol Dial Transplant. doi: 10.1093/ndt/gfs439.Google ScholarAlso detectable in secondary MN17Wakui H. Imai H. Komatsuda A. Miura A.B. Circulating antibodies against alpha-enolase in patients with primary membranous nephropathy (MN).Clin Exp Immunol. 1999; 118: 445-450Crossref PubMed Scopus (64) Google Scholar,bH.I., unpublished data, 2013.; anti–α-enolase antibodies in a wide spectrum of diseases21Terrier B. Degand N. Guilpain P. Servettaz A. Guillevin L. Mouthon L. Alpha-enolase: a target of antibodies in infectious and autoimmune diseases.Autoimmun Rev. 2007; 6: 176-182Crossref PubMed Scopus (128) Google ScholarPathogenic effectsRecurrence of MN in transplanted kidney16Debiec H. Hanoy M. François A. et al.Recurrent membranous nephropathy in an allograft caused by IgG3κ targeting the PLA2 receptor.J Am Soc Nephrol. 2012; 23: 1949-1954Crossref PubMed Scopus (80) Google ScholarCell apoptosis36Magrys A. Anekonda T. Ren G. Adamus G. The role of anti-alpha-enolase autoantibodies in pathogenicity of autoimmune-mediated retinopathy.J Clin Immunol. 2007; 27: 181-192Crossref PubMed Scopus (74) Google Scholar; inhibition of proteolysis/fibrinolysis37Díaz-Ramos À. Roig-Borrellas A. García-Melero A. Llorens A. López-Alemany R. Requirement of plasminogen binding to its cell-surface receptor α-enolase for efficient regeneration of normal and dystrophic skeletal muscle.PLoS One. 2012; 7: e50477Crossref PubMed Scopus (9) Google ScholarCorrelation with baseline proteinuria and activityYes6Hofstra J.M. Debiec H. Short C.D. et al.Anti-phospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1735-1743Crossref PubMed Scopus (229) Google Scholar, 7Kanigicherla D, Gummadova J, McKenzie EA, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy [published online ahead of print January 30, 2013]. Kidney Int. doi:10.1038/ki.2012.486.Google Scholar, 12Hofstra J.M. Beck Jr, L.H. Beck D.M. Wetzels J.F. Salant D.J. Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy.Clin J Am Soc Nephrol. 2011; 6: 1286-1291Crossref PubMed Scopus (278) Google ScholarNo20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google ScholarCorrelation with outcomeYes6Hofstra J.M. Debiec H. Short C.D. et al.Anti-phospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1735-1743Crossref PubMed Scopus (229) Google Scholar, 7Kanigicherla D, Gummadova J, McKenzie EA, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy [published online ahead of print January 30, 2013]. Kidney Int. doi:10.1038/ki.2012.486.Google Scholar, 13Beck Jr, L.H. Fervenza F.C. Beck D.M. et al.Rituximab-induced depletion of anti-PLA2R autoantibodies predicts response in membranous nephropathy.J Am Soc Nephrol. 2011; 22: 1543-1550Crossref PubMed Scopus (343) Google ScholarYes, lower 1-year proteinuria in negative patients20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google ScholarAbbreviations: ELISA, enzyme-linked immunosorbent assay; MN, membranous nephropathy; PLA2R1, M-type phospholipase A2 receptor 1.a Lower in Japanese population.b H.I., unpublished data, 2013. Open table in a new tab Abbreviations: ELISA, enzyme-linked immunosorbent assay; MN, membranous nephropathy; PLA2R1, M-type phospholipase A2 receptor 1. In this editorial, we discuss whether another category of antipodocyte antibodies directed against cytoplasmic antigens have pathophysiologic or clinical relevance as biomarkers of primary MN. These antibodies were described first by Wakui et al,17Wakui H. Imai H. Komatsuda A. Miura A.B. Circulating antibodies against alpha-enolase in patients with primary membranous nephropathy (MN).Clin Exp Immunol. 1999; 118: 445-450Crossref PubMed Scopus (64) Google Scholar who reported the presence of antibodies against the glycolytic enzyme α-enolase in both primary and secondary MN. This finding was confirmed 12 years later by Ghiggeri's laboratory,18Bruschi M. Carnevali M.L. Murtas C. et al.Direct characterization of target podocyte antigens and auto-antibodies in human membranous glomerulonephritis: alfa-enolase and borderline antigens.J Proteomics. 2011; 74: 2008-2017Crossref PubMed Scopus (100) Google Scholar they also reported autoantibodies against aldose reductase (AR) and superoxide dismutase 2 (SOD2).19Prunotto M. Carnevali M.L. Candiano G. et al.Autoimmunity in membranous nephropathy targets aldose reductase and SOD2.J Am Soc Nephrol. 2010; 21: 507-519Crossref PubMed Scopus (175) Google Scholar, 20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google Scholar Anti–α-enolase antibodies have been reported in patients with a large variety of autoimmune and inflammatory diseases. In cancer-associated autoimmune retinopathy, rheumatoid arthritis, and systemic lupus erythematosus,21Terrier B. Degand N. Guilpain P. Servettaz A. Guillevin L. Mouthon L. Alpha-enolase: a target of antibodies in infectious and autoimmune diseases.Autoimmun Rev. 2007; 6: 176-182Crossref PubMed Scopus (128) Google Scholar the prevalence of antibodies is 30%, 25%, and 21%, respectively,22Adamus G. Ren G. Weleber R.G. Autoantibodies against retinal proteins in paraneoplastic and autoimmune retinopathy.BMC Ophthalmol. 2004; 4: 5Crossref PubMed Scopus (176) Google Scholar, 23Saulot V. Vittecoq O. Charlionet R. et al.Presence of autoantibodies to the glycolytic enzyme alpha-enolase in sera from patients with early rheumatoid arthritis.Arthritis Rheum. 2002; 46: 1196-1201Crossref PubMed Scopus (129) Google Scholar, 24Mosca M. Chimenti D. Pratesi F. et al.Prevalence and clinico-serological correlations of anti-alpha-enolase, anti-C1q, and anti-dsDNA antibodies in patients with systemic lupus erythematosus.J Rheumatol. 2006; 33: 695-697PubMed Google Scholar similar in magnitude to MN (43%).20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google Scholar Because these antibodies are found in a wide spectrum of diseases, they are of little help in the diagnosis of specific autoimmune disorders without disease-specific antibodies. The next step should be to identify the epitope(s). The α-enolase epitope associated with pathogenic sera is located between amino acids 56 and 63 in cancer-related retinopathy25Adamus G. Amundson D. Seigel G.M. Machnicki M. Anti-enolase-alpha autoantibodies in cancer-associated retinopathy: epitope mapping and cytotoxicity on retinal cells.J Autoimmun. 1998; 11: 671-677Crossref PubMed Scopus (107) Google Scholar and in the amino-terminal part in Hashimoto encephalopathy.26Fujii A. Yoneda M. Ito T. et al.Autoantibodies against the amino terminal of alpha-enolase are a useful diagnostic marker of Hashimoto's encephalopathy.J Neuroimmunol. 2005; 162: 130-136Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar Antibodies against the citrullinated form of α-enolase are specific to rheumatoid arthritis and primarily react to immunodominant citrullinated peptide 1 (CEP-1).27Lundberg K. Kinloch A. Fisher B.A. et al.Antibodies to citrullinated alpha-enolase peptide 1 are specific for rheumatoid arthritis and cross-react with bacterial enolase.Arthritis Rheum. 2008; 58: 3009-3019Crossref PubMed Scopus (303) Google Scholar, 28Mahdi H. Fisher B.A. Källberg H. et al.Specific interaction between genotype, smoking and autoimmunity to citrullinated alpha-enolase in the etiology of rheumatoid arthritis.Nat Genet. 2009; 41: 1319-1324Crossref PubMed Scopus (257) Google Scholar Unlike PLA2R1, α-enolase is not an MN-specific antigen; thus, fine epitope mapping of α-enolase is required in order to design an MN-specific immunoassay before these antibodies can be assessed routinely in patients with MN. There are still uncertainties about the subclass of anti–α-enolase antibodies in patients with MN. Wakui et al17Wakui H. Imai H. Komatsuda A. Miura A.B. Circulating antibodies against alpha-enolase in patients with primary membranous nephropathy (MN).Clin Exp Immunol. 1999; 118: 445-450Crossref PubMed Scopus (64) Google Scholar predominantly identified IgG1 and IgG3, whereas IgG4 was strongly prevalent in more recent studies (Murtas et al20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google Scholar; H.I., unpublished observations, 2013). These discrepancies may be due in part to the subclass-specific antibodies used for detection. Anti-AR and anti-SOD2 IgG4 have been reported to be detected in 34% and 28% of patients with MN, respectively.18Bruschi M. Carnevali M.L. Murtas C. et al.Direct characterization of target podocyte antigens and auto-antibodies in human membranous glomerulonephritis: alfa-enolase and borderline antigens.J Proteomics. 2011; 74: 2008-2017Crossref PubMed Scopus (100) Google Scholar The specificity of anti-SOD antibodies for MN is doubtful due to their presence in patients with lupus.29Mansour R.B. Lassoued S. Gargouri B. El Gaïd A. Attia H. Fakhfakh F. Increased levels of autoantibodies against catalase and superoxide dismutase associated with oxidative stress in patients with rheumatoid arthritis and systemic lupus erythematosus.Scand J Rheumatol. 2008; 37: 103-108Crossref PubMed Scopus (76) Google Scholar In a case of MN associated with IgG4-related disease, circulating IgG3 reacting to SOD2 has been identified.30Cravedi P. Abbate M. Gagliardini E. et al.Membranous nephropathy associated with IgG4-related disease.Am J Kidney Dis. 2011; 58: 272-275Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar We also found antibodies against enzymes involved in metabolic pathways (including α-enolase), cytoskeleton architecture, and cell stress in sera of patients with MN (H.D., unpublished observations, 2013). This suggests that several antigen-antibody complexes may be involved. Likewise, in a model of passive Heymann nephritis in mice, more than 20 intracellular proteins have been identified as potential antigens.31Meyer T.N. Schwesinger C. Wahlefeld J. et al.A new mouse model of immune-mediated podocyte injury.Kidney Int. 2007; 72: 841-852Crossref PubMed Scopus (30) Google Scholar, 32Meyer-Schwesinger C. Dehde S. Klug P. et al.Nephrotic syndrome and subepithelial deposits in a mouse model of immune-mediated anti-podocyte glomerulonephritis.J Immunol. 2011; 187: 3218-3229Crossref PubMed Scopus (35) Google Scholar In addition, immunoscreening of a renal complementary DNA library identified a synaptonemal complex protein as new autoimmune target in idiopathic MN.33Cavazzini F. Magistroni R. Furci L. et al.Identification and characterization of a new autoimmune protein in membranous nephropathy by immunoscreening of a renal cDNA library.PLoS One. 2012; 7: e48845Crossref PubMed Scopus (17) Google Scholar What is the pathophysiologic relevance of antibodies to cytoplasmic proteins in the podocyte? The podocyte cytoplasm antigens that have been identified are either not expressed or only weakly expressed on the podocyte membrane under basal conditions. However, complement activation and the production of reactive oxygen species may lead to intracellular proteins, cryptic epitopes, and neoepitopes becoming exposed on the cell membrane, as shown for SOD2 on podocytes19Prunotto M. Carnevali M.L. Candiano G. et al.Autoimmunity in membranous nephropathy targets aldose reductase and SOD2.J Am Soc Nephrol. 2010; 21: 507-519Crossref PubMed Scopus (175) Google Scholar and components of the glycolytic pathway on the surface of apoptotic cells.34Ucker D.S. Jain M.R. Pattabiraman G. Palasiewicz K. Birge R.B. Li H. Externalized glycolytic enzymes are novel, conserved, and early biomarkers of apoptosis.J Biol Chem. 2012; 287: 10325-10343Crossref PubMed Scopus (42) Google Scholar These molecules then can be recognized as autoantigens. Whether these antigens are involved in the formation of immune deposits remains a matter of debate; they are reported to colocalize with IgG4 and C5b-9 in these deposits, where they give a weak positive signal upon immunoelectron microscopy.18Bruschi M. Carnevali M.L. Murtas C. et al.Direct characterization of target podocyte antigens and auto-antibodies in human membranous glomerulonephritis: alfa-enolase and borderline antigens.J Proteomics. 2011; 74: 2008-2017Crossref PubMed Scopus (100) Google Scholar, 19Prunotto M. Carnevali M.L. Candiano G. et al.Autoimmunity in membranous nephropathy targets aldose reductase and SOD2.J Am Soc Nephrol. 2010; 21: 507-519Crossref PubMed Scopus (175) Google Scholar However, antibodies to these cytoplasmic proteins may be pathogenic through binding to endothelial or podocyte cell surfaces, thus increasing the permeability of the capillary wall and leading to enhanced access of anti-PLA2R1 antibodies. Because α-enolase is a multifunctional protein,35Pancholi V. Multifunctional alpha-enolase: its role in diseases.Cell Mol Life Sci. 2001; 58: 902-920Crossref PubMed Scopus (710) Google Scholar antibodies may perturb important cellular functions such as glycolysis, which in turn leads to ATP (adenosine triphosphate) depletion, apoptosis,36Magrys A. Anekonda T. Ren G. Adamus G. The role of anti-alpha-enolase autoantibodies in pathogenicity of autoimmune-mediated retinopathy.J Clin Immunol. 2007; 27: 181-192Crossref PubMed Scopus (74) Google Scholar and binding of plasminogen and plasmin, resulting in decreased proteolytic activity.37Díaz-Ramos À. Roig-Borrellas A. García-Melero A. Llorens A. López-Alemany R. Requirement of plasminogen binding to its cell-surface receptor α-enolase for efficient regeneration of normal and dystrophic skeletal muscle.PLoS One. 2012; 7: e50477Crossref PubMed Scopus (9) Google Scholar The interference of anti–α-enolase antibodies with the fibrinolytic system might explain the high frequency of thromboembolic events in patients with MN.38Singhal R. Brimble K.S. Thromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management.Thromb Res. 2006; 118: 397-407Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar Anti-SOD2 antibodies could aggravate oxidant-induced podocyte injury because SOD mimetics preserve the glomerular permeability barrier.39Duann P. Datta P.K. Pan C. Blumberg J.B. Sharma M. Lianos E.A. Superoxide dismutase mimetic preserves the glomerular capillary permeability barrier to protein.J Pharmacol Exp Ther. 2006; 316: 1249-1254Crossref PubMed Scopus (27) Google Scholar What is the clinical relevance of antibodies to podocyte cytoplasmic proteins? A reliable diagnostic test should be easy to perform and interpret and show high sensitivity and specificity for the disease. However, these antibodies are detected in fewer than half of patients, with a particularly low prevalence of anti-SOD2 (28%) and anti-AR (34%; Table 1). Anti–α-enolase antibodies are slightly more prevalent (43%), but also are found in many autoimmune and inflammatory diseases, as well as in secondary MN (Wakui et al17Wakui H. Imai H. Komatsuda A. Miura A.B. Circulating antibodies against alpha-enolase in patients with primary membranous nephropathy (MN).Clin Exp Immunol. 1999; 118: 445-450Crossref PubMed Scopus (64) Google Scholar; H.I., unpublished observations, 2013). The prevalence of anti-SOD2 and anti-AR antibodies in secondary MN remains to be established. Detecting antibodies to cytoplasmic proteins in the podocyte might be useful in PLA2R1-negative patients because 51% of them (n=75) have been reported to be positive for at least one other antibody.20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google Scholar However, it is not possible to draw an antibody profile of those PLA2R1-negative patients from published data. Another matter of concern is the relatively low level of antibodies to podocyte cytoplasmic proteins, with a median value only 2- to 3-fold higher than the median value for controls.20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google Scholar To date, assessment of anti-PLA2R1 antibodies by enzyme-linked immunosorbent assay and indirect immunofluorescence test is the only specific test for MN that shows high sensitivity and specificity.4Beck Jr, L.H. Bonegio R.G. Lambeau G. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic MN.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1419) Google Scholar, 6Hofstra J.M. Debiec H. Short C.D. et al.Anti-phospholipase A2 receptor antibody titer and subclass in idiopathic membranous nephropathy.J Am Soc Nephrol. 2012; 23: 1735-1743Crossref PubMed Scopus (229) Google Scholar, 7Kanigicherla D, Gummadova J, McKenzie EA, et al. Anti-PLA2R antibodies measured by ELISA predict long-term outcome in a prevalent population of patients with idiopathic membranous nephropathy [published online ahead of print January 30, 2013]. Kidney Int. doi:10.1038/ki.2012.486.Google Scholar With regard to predicting outcomes and monitoring patients, Murtas et al20Murtas C. Bruschi M. Candiano G. et al.Coexistence of different circulating anti-podocyte antibodies in membranous nephropathy.Clin J Am Soc Nephrol. 2012; 7: 1394-1400Crossref PubMed Scopus (115) Google Scholar did not find a relationship between levels of antibodies to podocyte cytoplasmic proteins and proteinuria, kidney function, or histologic stage at baseline. When proteinuria was modeled as a continuous variable, anti-AR IgG4 and anti–α-enolase IgG4 predicted proteinuria and serum albumin level, respectively, at 1 year. Participants for whom all antibodies were undetectable had significantly lower 1-year proteinuria values than those who were positive for at least one antibody. In the absence of longitudinal data, it is not yet possible to determine whether these antibodies to podocyte cytoplasmic proteins will be useful for monitoring patients. Although accumulating evidence indicates that anti-PLA2R1 antibodies represent a major breakthrough in the diagnosis of primary MN and may be helpful for predicting outcomes and monitoring therapy with easy-to-use assays, many uncertainties remain about the diagnostic and prognostic values of antibodies to podocyte cytoplasmic proteins. Prospective multicenter studies of patients with primary and secondary MN that include standardized assays for antibodies against PLA2R1 and all podocyte cytoplasm antigens are urgently needed before the latter start to be assessed in clinical practice. A careful time course of each of these antibodies is required to determine which comes first and whether their decrease precedes remission and their increase announces relapse. These data will have important clinical and also pathophysiologic implications. Support: This work was supported by a grant from Agence Nationale pour la Recherche ( ANR-07-Physio-016-01 ), Fondation pour la Recherche Médicale ( Equipe FRM 2012 ), and EUREnOmics (European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement 305608 ). Financial Disclosure: The authors declare that they have no relevant financial interests. Circulating Antipodocyte Antibodies in Membranous Nephropathy: New FindingsAmerican Journal of Kidney DiseasesVol. 62Issue 1PreviewMembranous nephropathy (MN) is now regarded as an autoimmune kidney disease.1 The recent discovery of antipodocyte antibodies in human MN has opened a new line of thinking about this disease, but this finding still requires confirmation in large cohorts of patients with MN with sufficient follow-up. Until now, pathogenic insight has been derived from animal models2-7 and involved renal antigens (megalin is the prime example) not detectable in human kidneys, leaving the question about autoantigens in human MN unresolved. Full-Text PDF" @default.
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