Anti–Phospholipase A2 Receptor Antibodies and Malignancy in Membranous Nephropathy

In developed countries, the vast majority (70%-80%) of membranous nephropathy cases are idiopathic (iMN), whereas the remainder are due to various secondary causes, such as autoimmune or infectious diseases, drugs, or malignancies.1Glassock R.J. The pathogenesis of idiopathic membranous nephropathy: a 50-year odyssey.Am J Kidney Dis. 2010; 56: 157-167Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar An association between MN and malignancy has been described for decades and accounts for ∼10% of patients with MN.2Brueggemeyer C.D. Ramirez G. Membranous nephropathy: a concern for malignancy.Am J Kidney Dis. 1987; 9: 23-26PubMed Scopus (46) Google Scholar, 3Burstein D.M. Korbet S.M. Schwartz M.M. Membranous glomerulonephritis and malignancy.Am J Kidney Dis. 1993; 22: 5-10PubMed Scopus (153) Google Scholar Previous studies reported that MN could appear as a paraneoplastic syndrome months and sometimes years before a (most often solid) tumor can be detected.3Burstein D.M. Korbet S.M. Schwartz M.M. Membranous glomerulonephritis and malignancy.Am J Kidney Dis. 1993; 22: 5-10PubMed Scopus (153) Google Scholar Differentiation between iMN and malignancy-associated MN (M-MN) is of clinical importance4Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis Work GroupChapter 7: idiopathic membranous nephropathy.Kidney Int Suppl. 2012; 2: 186-197Crossref Scopus (80) Google Scholar because treatment strategies differ. Recently, Beck et al5Beck L.H. Bonegio R.G.B. Lambeau G.R. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1685) Google Scholar identified a circulating antibody reactive with the transmembrane glycoprotein M-type phospholipase A2 receptor (PLA2R) on the human podocyte. It has been demonstrated that antibodies to PLA2R (anti-PLA2R) are very specific for iMN, with anti-PLA2R detected in up to 82% of patients.6Qin 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 (360) Google Scholar We hypothesized that testing for circulating anti-PLA2R could be a useful biomarker to differentiate iMN from M-MN. Between August 1980 and May 2011, we recruited 91 patients with biopsy-proven MN without clinical suspicion of a secondary cause (Table 1). Serum samples were obtained at the time of kidney biopsy. The presence of circulating anti-PLA2R was determined by Western blot.5Beck L.H. Bonegio R.G.B. Lambeau G.R. et al.M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy.N Engl J Med. 2009; 361: 11-21Crossref PubMed Scopus (1685) Google Scholar Sixty-four (70%) patients had detectable anti-PLA2R. Clinical data for these patients were obtained from medical records within the Limburg Renal Registry (see Item S1). Mean follow-up was 10.7 (0.1-30.9) years.Table 1Baseline Characteristics and Clinical OutcomesTotal (n = 91)PLA2R Antibody TestPPositive (n = 64)Negative (n = 27)Baseline characteristics Male sex63%66%56%0.5 Age (y)53.4 ± 16.251.8 ± 15.757.3 ± 17.20.2 Anti-PLA2R70% Proteinuria (g/d)7.1 ± 4.77.3 ± 5.16.6 ± 3.40.9 Nephrotic-range proteinuria77%76%81%0.8 Serum creatinine (mg/dL)1.2 ± 0.91.3 ± 1.01.1 ± 0.70.06 eGFR (mL/min/1.73 m2)114 ± 102118 ± 119104 ± 430.9Follow-up Duration (y)10.7 ± 7.511.3 ± 8.19.2 ± 5.80.4 Malignancy occurrence18%9%37%0.005 Malignancy-free survival (y)23.3 ± 1.626.1 ± 1.714.9 ± 2.3<0.001Note: Continuous variables given as mean ± SD. There were data missing for positive (proteinuria, n = 2; creatinine, n = 1; eGFR, n = 3) and negative (eGFR, n = 1) subgroups. Open table in a new tab Note: Continuous variables given as mean ± SD. There were data missing for positive (proteinuria, n = 2; creatinine, n = 1; eGFR, n = 3) and negative (eGFR, n = 1) subgroups. Malignancies were observed in 16 (18%) patients, of which 15 were carcinomas. Four malignancies occurred during early (ie, <2 years' follow-up) and 12 during late follow-up (Item S1 table a). All malignancies were detected during the past decade. The mean malignancy-free survival as calculated by Kaplan-Meier estimation was 23.3 ± 1.6 (95% CI, 20.1-26.5) years. Malignancy-free survival was significantly shorter among patients with undetectable anti-PLA2R (P < 0.001; Fig 1). Two of 3 patients with early malignant disease and successful tumor treatment entered remission in terms of proteinuria, while disease persisted in the other (Item S1 table a). Ten of 12 patients with late malignant disease entered remission prior to the diagnosis of cancer. Two patients reached ESRD. The clinical significance of anti-PLA2R status was analyzed by performing a multiple Cox regression. HRs for malignancy were 9.705 (95% CI, 2.324-40.537; P = 0.002) and 0.103 (95% CI, 0.025-0.430) for negative and positive anti-PLA2R test results, respectively. In line with earlier studies,7Lefaucheur C. Stengel B. Nochy D. et al.Membranous nephropathy and cancer: epidemiologic evidence and determinants of high-risk cancer association.Kidney Int. 2006; 70: 1510-1517Crossref PubMed Scopus (189) Google Scholar, 8Bjorneklett R. Vikse B.E. Svarstad E. et al.Long-term risk of cancer in membranous nephropathy patients.Am J Kidney Dis. 2007; 50: 396-403Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar age (HR, 1.080; 95% CI, 1.029-1.132; P = 0.002) also was associated with malignant disease (Item S1 table b). Our study is the first indicating a prognostic role for anti-PLA2R because a negative test result emerged as the most pronounced prognostic factor for malignancy occurrence. However, late malignancies also were observed in patients with anti-PLA2R. Qin et al6Qin 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 (360) Google Scholar described anti-PLA2R in 3 patients with M-MN. Remarkably, all had persistent or recurrent proteinuria despite successful tumor treatment. In our study, most patients with late malignancy entered remission prior to the diagnosis of cancer, which suggests that the 2 diseases might have occurred coincidentally. Hence, we postulate that these patients may have had 2 diseases, ie, iMN and an unrelated malignancy. Complementary to anti-PLA2R, circulating anti-podocyte antibodies directed against cytoplasmic antigens have been found in iMN.9Murtas 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 (124) Google Scholar At present, it is unknown whether patients with M-MN express such autoantibodies. Bjørneklett et al8Bjorneklett R. Vikse B.E. Svarstad E. et al.Long-term risk of cancer in membranous nephropathy patients.Am J Kidney Dis. 2007; 50: 396-403Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar found an increased risk of developing cancer in relation to the diagnosis of MN, which persists for many years. Two explanations were stated: (1) a long preclinical phase of the tumor in which kidney disease may be caused through immunologic mechanisms, and (2) many patients with iMN are treated with immunosuppressive therapy. In our study, we could not find an association with immunosuppressive therapy in our patients with M-MN. Of note, the anti-PLA2R–negative cohort likely represents a mixture of distinct causes, only some of which may be associated with occult malignancy. Although serum samples were tested at the time of biopsy, it is possible that a few of these patients could have had anti-PLA2R–associated disease and already entered immunologic remission. Staining the kidney biopsy specimens for the PLA2R antigen or the predominance of the IgG4 subclass could have given further evidence of the presence or absence of anti-PLA2R-associated disease.10Hoxha E. Kneissler 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 (233) Google Scholar In conclusion, our results suggest that patients with newly diagnosed MN are unlikely to have an associated malignancy if they have detectable anti-PLA2R. This does not mean that they may not develop a malignant tumor during extended follow-up, but it is likely that such tumors would be coincidental in an aging population. However, the absence of anti-PLA2R at the time of biopsy increases the (small) risk of M-MN and merits more careful surveillance for an occult malignancy. We thank all participating nephrologists of the Limburg Renal Registry: F. de Heer, M.M.E. Krekels, F. Stifft (Orbis Medical Center); S. Boorsma, W. Grave, J.J. Huitema (St Laurentius Hospital); N. ter Braak, S. Gaertner, J. Wolters (Atrium Medical Center); and J.P. Kooman, K.M.L. Leunissen, F.M. van der Sande (Maastricht University Medical Center). This work was supported in part by NIH research grants DK090029 (D.J.S.) and DK097053 to (L.H.B.) and a research grant from the NephCure Foundation (R.A.). Download .pdf (.32 MB) Help with pdf files Supplementary Item S1 (PDF)Detailed methods, malignancy during follow up, and Cox regression analysis.