Hoxha E, Kneissler U, Stege G, et al. 9 patients with available renal tissue specimens displayed enhanced expression of PLA2R in glomeruli whereas PLA2R was not expressed in liver parenchyma from these patients or in normal liver tissue. The study of immunoglobulin (Ig) subclasses of deposits in glomeruli revealed that the most frequent pattern was the coexistence of IgG1 and IgG4 immune deposits with IgG4 predominating. Detection of PLA2R antibodies in glomeruli but not in liver parenchyma is a common finding in patients with MN associated with autoimmune liver disease, suggesting that these autoantibodies are not exclusively detected in idiopathic MN. INTRODUCTION Membranous nephropathy (MN) is considered as a primary glomerular disease, also referred to as idiopathic, in 80% of cases, whereas it occurs in association with various clinical conditions including systemic autoimmune disease, chronic infection, malignancies, or drug exposure in about 20% of cases (secondary MN).1C3 Idiopathic MN is currently considered as an autoimmune disease whereas secondary forms may be related to the accumulation exogenous antigens (viral, tumor) without a clear evidence for a direct pathogenic role.4 Numerous studies have investigated the antigens involved in human MN and have led to major advances in understanding the pathogenesis of adult MN.2 M-type phospholipase A2 receptor (PLA2R) LG-100064 was the first protein identified as a target antigen in human idiopathic MN.5 PLA2R antibodies were initially found in the serum of 70% idiopathic, but not in secondary forms of MN.5 Subsequent studies demonstrated that circulating PLA2R antibodies are exclusively detected in cases of idiopathic MN, but not in healthy individuals, in patients with other glomerular diseases, or in patients with autoimmune disorders. These autoantibodies may therefore be a useful biomarker LG-100064 for the diagnosis of MN and monitoring of idiopathic MN treatment.1,2,6 In some patients, circulating PLA2R antibodies are not found whereas PLA2R antigens are present in their glomerular immune deposits.7,8 Circulating PLA2R antibodies seem to be rarely detected in patients with an apparent secondary form of MN occurring in patients with neoplasia, viral hepatitis B infection, systemic lupus erythematous (SLE), sarcoidosis, or graft-versus-host disease.9C11 The systemic diseases most frequently associated with MN are SLE, immunoglobulin (Ig)G4-related immunological disorders, and sarcoidosis.12C14 Nevertheless, some case reports suggest a strong association between MN and liver diseases associated with immune dysfunction, such as primary biliary cirrhosis (PBC), autoimmune hepatitis (AIH), and primary sclerosing cholangitis (PSC), pointing out a possible pathophysiological link.15C25 We therefore assessed the significance of this LG-100064 association, by reviewing clinical, histological, biological, and therapeutic data for 10 patients with a diagnosis of MN occurring in the context of PBC, PSC, and/or AIH. We also studied by immunohistochemistry whether the PLA2R LG-100064 antigen could be expressed in kidney and liver biopsy specimens in these patients. METHODS This multicenter retrospective survey, approved by our local Ethics Committee, was conducted in 13 French health departments. A questionnaire to identify patients with MN, occurring in the context of PBC or PSC or AIH, was sent to all French hepatology and nephrology centers. Ten adult patients ( 18 years) were retrospectively identified. Demographic, clinical, biological, and histological data were assessed for each patient at the time of MN diagnosis. MN Diagnosis All LG-100064 patients included in this study underwent a renal biopsy for a nephrotic syndrome (NS) or a significant proteinuria (albumin excretion rate of 0.3?g/d). Immunofluorescence (IF) on renal biopsies was performed using monoclonal antibodies specific for IgG1, IgG2, IgG3, and IgG4 (Sigma-Aldrich : Saint Louis, MO, USA; 1 in 30 dilution). IF staining intensity was graded on a scale of 0 to 3+ by one observer (A.M.). In one case with interstitial nephritis associated with glomerular lesions, IgG4 labeling was performed by immunohistochemistry (monoclonal antibody against human IgG4, binding site; 1:200 dilution). Reduced kidney function was defined as a permanent (at least 3 months) decrease of estimated glomerular filtration rate (eGFR) to 60?mL/min/1.73?m2 according to the modification of diet in renal disease formula.26 Acute renal failure was defined according HA6116 to Acute Kidney Injury Network (AKIN) criteria.27 Complete remission was defined as proteinuria of 0.3?g/d at the.