Professors Ronco and Debiec from Sorbonne University, France, recently published a review in TheLancet on new advances in the research and treatment of membranous nephropathy, summarizing the new advances in the pathogenesis, diagnosis, and treatment of membranous nephropathy (MN) in the past 13 years. In this article, we have compiled the clinically relevant parts of the review for our colleagues to learn together. Epidemiology and clinical features of membranous nephropathy Worldwide, the annual incidence of MN in adults is 1 new case/100,000 persons/year, i.e. 10,000 new cases per year in Europe.MN affects patients of all ages and races but is more prevalent in males than in females (sex ratio = 2:1), with a peak incidence in the 30s and 50s. MN in young women should be highly suspicious of lupus. MN is uncommon in children (<5% of renal biopsies from children). it is often associated with hepatitis B, and less frequently with autoimmune or thyroid disease. 60-80% of patients with MN present with lupus. 60-80% of patients with MN present with nephrotic syndrome, with the remainder presenting with asymptomatic proteinuria (<3.5 g/24h), of which 60% progress to full nephrotic syndrome. Microscopic hematuria occurs in 50% of patients with MN, but massive hematuria and erythrocyte tubular patterns are rare. 80% of patients with MN have normal blood pressure and glomerular filtration rate at onset. Acute kidney injury is rare and may result from hypovolemia due to overdiuresis, acute bilateral deep vein thrombosis, drug-induced interstitial nephritis, or superimposed crescentic glomerulonephritis. MN is a chronic disease with spontaneous remissions and relapses. Often, spontaneous remission occurs in approximately 40% of cases, within the first 2 years of disease onset. Predictors of spontaneous remission are a proteinuria level of <8 g/d at baseline, being female, <50 years of age, and having good renal function at the onset of the disease. Another 2/3 of patients can be equally divided into those with persistent proteinuria but long-term maintenance of renal function and those who progress to renal failure despite immunosuppressive therapy.MN remains the second or third leading cause of end-stage renal disease (ESRD) in primary glomerulonephritis. Pathologic Changes in Membranous Nephropathy In the early stages of MN, the glomerular structure is normal on light microscopy and the diagnosis can only be made by immunofluorescence and electron microscopy. The next stage is characterized by uniform thickening of the capillary wall. Early reflections of deposits between the glomerular basement membranes are called spikes. As the disease progresses, the deposits merge into the glomerular basement membrane and it appears as if the immunodeposits are absorbed. As the disease progresses further, interstitial fibrosis and glomerulosclerosis develop. Diagnosis of both idiopathic and secondary MN relies on the finding of IgG granular-like deposits in glomerular capillary collaterals. Complement C3 and C4 are often seen in these deposits.The presence of C1q is suggestive of secondary MN, especially in association with SLE. In addition biopsy specimens should be routinely stained for PLA2R antigen and IgG subtypes. Electron microscopy shows significant injury with deposition of subepithelial electron dense material and fusion of podocyte peduncles. Disease can be staged according to the extent to which subepithelial immune complexes are surrounded by the glomerular basement membrane. Identification of target antigens and risk genes in human membranous nephropathy Major advances in the study of the pathophysiologic aspects of MN began in the early 2000's. In 2002, podocyte neutral endopeptidase was identified as a target antigen for circulating antibodies in isoimmune neonatal nephropathy. Neutral endopeptidase-associated homozygous immune glomerulopathy defined a novel organ-specific disease caused by mother-infant incompatibility, and although this disease is rare, analysis of its pathogenic mechanisms provided evidence for the concept that footcell antigens could lead to MN in humans, laying the groundwork for the later identification of the involvement of PLA2R in adult MN. Many years of research in search of target antigens for idiopathic MN have since been unsuccessful. Between 2009-2014, two podocyte proteins were identified through the use of human glomerular microdissection, metabolomics techniques, and high-throughput technologies. The first major autoantigen was M-type PLA2R. autoantibodies against PLA2R were detected in the circulation of 70% of patients with idiopathic MN. The second autoantigen was THSD7A, and autoantibodies against this protein were detected in the circulation of 5-10% of patients with idiopathic MN who were negative for anti-PLA2R.PLA2R and THSD7A were detected in normal human glomeruli, and both antigens were co-localized with IgG4 within the subepithelial deposits. In addition, IgG eluted from biopsy specimens reacts with recombinant PLA2R and THSD7A.PLA2R and THSD7A have similar structural and biochemical properties. The autoantibodies recognizing these two antigens are predominantly of the IgG4 subtype. Interestingly, patients with idiopathic MN either mount an autoimmune response to PLA2R or an autoimmune response to THSD7A, but do not respond to both antigens. This suggests that PLA2R-associated MN and THSD7A-associated MN are two separate molecular mechanisms and that these antigens are the primary targets of idiopathic MN. Nonpedunculated antigens are the main effectors of secondary MN. Cationized bovine serum albumin (BSA) was identified as the major antigen in children younger than 5 years of age, with high titers of serum anti-BSA antibodies (IgG1 and IgG4). If BSA is a common dietary antigen due to early exposure to bovine dairy products, then other dietary and environmental antigens may cause disease through similar mechanisms. For example, hepatitis B and C viruses, the enzymes used in replacement therapy for enzyme deficiencies in the treatment of lysosomal storage disease, may also be involved in secondary MN. Although MN is not a typically inherited disease, the influence of genetic factors has been demonstrated in models of the disease in rats and mice, as well as in European Caucasian populations, showing stronger associations between the haplotype HLA-B8DR3 and other HLA class III immune-responsive genes and MN. association. Genome-wide association (GWAS) studies have reported a high correlation between the 6p21HLA-DQA1 and 2q24PLA2R1 loci and idiopathic MN in Caucasian Europeans. Diagnosis of membranous nephropathy Over the past 3 years, many studies on the incidence of anti-PLA2R antibodies in different pathology types have shown these antibodies to be biomarkers of MN specificity and sensitivity. In a 2014 meta-analysis that included 9 articles with 15 studies totaling 2,212 patients, anti-PLA2R antibodies had a specificity of 99% (95% CI 96-100) and a sensitivity of 78% (95% CI 66-87). Anti-PLA2R antibodies were not found in other renal or autoimmune diseases or in healthy individuals. The specificity of anti-PLA2R antibodies is so high that some clinicians are reconsidering the utility of renal biopsy, especially in some elderly patients in less good health and in patients with life-threatening complications (e.g., renal vein thrombosis or pulmonary embolism) requiring anticoagulation. The incidence of anti-PLA2R antibodies in secondary MN is low, but it is difficult to exclude a coincidence of MN with related diseases. The increased incidence of anti-PLA2R antibodies associated with hepatitis B virus replication and active tuberculosis in secondary MN suggests that these two diseases associated with immune disorders may induce or enhance immune responses against PLA2R. PLA2R antigen can also be detected in deposits in the absence of circulating antibodies. There are several explanations for this, including rapid clearance of antibodies from the blood due to high affinity for PLA2R, immune remission, or renal biopsy performed long after the onset of the disease. Detection of antigens in immune complexes has made it possible to retrospectively study PLA2R-associated MN. Conversely, in some patients, circulating anti-PLA2R antibodies do not correlate with PLA2R in deposits, suggesting that these antibodies may not be pathogenic. Combined serum (antibody) and biopsy tissue (antigen) analysis is recommended in all patients with MN. Detection of PLA2R antigen in immune complexes is also an important clue to the diagnosis of primary MN, in which PLA2R is usually associated with predominantly IgG4 deposits. However, the presence of PLA2R in immune complexes is usually reported in patients with replicating hepatitis B virus infection and active nodular disease. Predictive Value of Anti-PLA2R Antibodies Numerous studies conducted over the past 3 years have shown that anti-PLA2R antibody levels correlate with urinary protein excretion and disease activity. Antibody levels are undetectable in spontaneous remission or treatment-induced remission, and reappear or levels increase when the disease recurs. Antibody levels also predicted prognosis, as high titer antibody levels were associated with a decreased risk of spontaneous remission or immunosuppressant-induced remission and an increased risk of nephrotic syndrome and worsening of renal function in patients without nephrotic syndrome. The time interval between initiation of immunosuppressive therapy and remission was significantly increased in patients in the highest antibody titer group. Patient Follow-Up and Monitoring of Treatment Effectiveness Several studies have shown partial or complete reductions in anti-PLA2R antibodies weeks or months before renal remission. In a collaborative study that included 132 patients with severe nephrotic syndrome given rituximab therapy, 81 patients were positive for anti-PLA2R antibodies, and five important findings were identified. First, although the remission rate in anti-PLA2R antibody-positive patients was negatively correlated with the antibody titer, remission rates were similar in patients with PLA2R-related or unrelated MN. Second, in a multifactorial analysis, complete remission with antibodies at 6 months was strongly and independently associated with renal function remission. Third, complete remission tended to occur before complete antibody depletion. Fourth, decreased antibody titers appeared approximately 10 months before decreased urinary protein excretion. Fifth, reappearance or elevation of antibodies appeared before recurrence of renal disease. The interval of several months from immunologic remission to renal remission may be explained by sediment remodeling and glomerular capillary wall recovery. In addition, antibody titers at the end of immunosuppression predict the onset of disease relapse. Five years after immunosuppression was discontinued, 58% of patients whose anti-PLA2R antibodies cleared did not relapse, whereas relapses tended to occur in those patients who still had antibodies at the end of treatment. In conclusion, the presence or absence of anti-PLA2R antibodies does not predict response to immunosuppressive therapy, but immune remission is a strong predictor of clinical remission in patients with PLA2R-related MN. Surveillance of renal transplant patients Because of the high recurrence rate of MN after renal transplantation, frequent antibody screening should be initiated from the date of transplantation.50-80% of recurrent MN and all early relapses are associated with anti-PLA2R antibodies. These results and atypical MN recurrence with monoclonal IgG3κ deposition support a pathogenic role for anti-PLA2R antibodies. In contrast, certain patients with high anti-PLA2R antibody titers never experience relapse, even histologically. The risk of relapse seems to increase when, after transplantation, the patient's IgG4-type anti-PLA2R antibody titer does not decrease. In ab initio MN, which may be an isoimmune disease, detection of anti-PLA2R antibodies in serum and PLA2R antigen in deposits is almost always negative. From pathophysiologic progression to new therapeutic avenues The pathomechanisms of MN have opened new doors for treatment over the past 13 years. First, anti-PLA2R antibody titers play an important role in selecting patients for immunosuppressive therapy, the first step in individualized therapy. Second, nonspecific immunosuppressive therapy is replaced or combined with more specific and less toxic therapies. Although 1/3 of patients with persistent nephrotic syndrome do not respond to treatment, anti-CD20 antibodies (rituximab) are still an advance in this right direction. More specific epitope-driven therapies based on specific immunoadsorption are also needed. Growing knowledge of the molecular structure of so-called nephritic antigenic epitopes has allowed investigators to design nonpeptide receptor antagonists to be used as decoys for antibody attenuation. Third, clinicians should always keep in mind that even if the immune response is rapid in responding patients, full activation and damage to podocytes still persists up to the time of complete antibody reduction. Thus, opportunities abound for the development of complement antagonists that block the formation of C5b-9 membrane attack complexes and cytoprotective therapies that favor glomerular capillary wall recovery. Research in this area should be intensified. Conclusions Over the past 13 years, advances in the study of the molecular pathogenesis of membranous nephropathy have provided clinicians with sensitive and specific biomarkers (e.g., anti-PLA2R antibodies in serum and PLA2R antigens in immune deposits), opening the door to individualized drug therapy. Nephrologists will need to use these biomarkers when designing future clinical trials for membranous nephropathy.