Is primary membranous nephropathy a complement mediated disease?
Reinhard Linda,Stahl Rolf A K,Hoxha Elion
Molecular immunology
Membranous nephropathy (MN) is an immune complex mediated disease. Although limited to the kidney, in up to 20% of patients MN is associated with other autoimmune, infectious or malignant diseases. The initial pathogenetic event in what is still considered "primary" MN is the binding of circulating autoantibodies to proteins (autoantigens) expressed in glomerular podocytes. This antibody binding leads to the formation of immune complexes in the glomerular basement membrane. There is clinical and experimental evidence that these immune deposits lead to the activation of the complement system. Experimental studies in the MN model of Heymann's nephritis show that the terminal membrane attack complex (MAC) of the complement system induces a disturbance of the glomerular filtration barrier and leads to proteinuria, the clinical hallmark of MN. After the discovery of the phospholipase A receptor 1 and thrombospondin type 1 domain containing protein 7A as endogenous antigens, it is assumed that IgG4 antibodies directed against these proteins induce MN in over 85% of patients with primary MN. As a result, the role of complement in the pathogenesis of MN needs to be defined in light of these developments. In this review we describe the current knowledge on the function of the complement system in primary MN and discuss the open questions, which have to be solved for a better understanding of the potential role of complement in the pathophysiology of primary MN.
10.1016/j.molimm.2020.10.017
Multi-Autoantibody Signature and Clinical Outcome in Membranous Nephropathy.
Clinical journal of the American Society of Nephrology : CJASN
BACKGROUND AND OBJECTIVES:Patients with membranous nephropathy can have circulating autoantibodies against membrane-bound (phospholipase A2 receptor 1 [PLA2R1] and thrombospondin type-1 domain containing 7A [THSD7A]) and intracellular (aldose reductase, SOD2, and α-enolase) podocyte autoantigens. We studied their combined association with clinical outcomes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Serum levels of anti-PLA2R1, anti-THSD7A, anti-aldose reductase, anti-SOD2, and anti-α-enolase autoantibodies were determined in 285 patients at diagnosis and during follow-up using standardized and homemade assays. An eGFR>60 ml/min per 1.73 m and remission of proteinuria (<0.3/<3.5 g per d) after 12 months were the outcomes of interest. RESULTS:At diagnosis, 182 (64%), eight (3%), and 95 (33%) patients were anti-PLA2R1, anti-THSD7A, and double negative, respectively. The prevalence of a detectable antibody to at least one intracellular antigen was similarly distributed in patients who were anti-PLA2R1 (=118, 65%) and double negative (=64, 67%). Positivity for anti-PLA2R1, anti-SOD2, and anti-α-enolase antibodies and higher titers at diagnosis were associated with poor clinical outcome independently to each other. Combined positivity for anti-PLA2R1, anti-SOD2, and anti-α-enolase was associated with highest risk of poor outcome (odds ratio, 5.5; 95% confidence interval, 1.2 to 24; =0.01). In Kaplan-Meier analysis, patients who were anti-PLA2R1/anti-SOD2 or anti-PLA2R1/anti-α-enolase had lower eGFR at 12 months compared with patients who were anti-PLA2R1/anti-SOD2 or anti-α-enolase. Predictive tests (net reclassification index and area under the curve-receiver-operating characteristic analysis) showed that combined assessment of antibodies improved classification of outcome in 22%-34% of cases for partial remission of proteinuria and maintenance of normal eGFR. For patients with nephrotic syndrome at diagnosis, anti-SOD2 positivity and high anti-PLA2R1 titer were associated with a lack of complete remission. Patients who were anti-PLA2R1/anti-intracellular antigens had the lowest proteinuria and the highest eGFR at diagnosis and the lowest risk of lower eGFR at 12 months. Epitope spreading was present in 81% of patients who were anti-PLA2R1 and was associated with increased positivity for intracellular antigens and poor eGFR at diagnosis and 12 months. CONCLUSIONS:Combined serological analysis of autoantibodies targeting membrane-bound and intracellular autoantigens identifies patients with poor clinical outcomes.
10.2215/CJN.02500220
Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era.
Safar-Boueri Luisa,Piya Albina,Beck Laurence H,Ayalon Rivka
Pediatric nephrology (Berlin, Germany)
Membranous nephropathy (MN) is an immune complex-mediated cause of the nephrotic syndrome that can occur in all age groups, from infants to the very elderly. However, nephrotic syndrome in children is more frequently caused by conditions such as minimal change disease or focal segmental glomerulosclerosis, and much less commonly by MN. While systemic conditions such as lupus or infections such as hepatitis B may more commonly be associated as secondary causes with MN in the younger population, primary or "idiopathic" MN has generally been considered a disease of adults. Autoantibodies both to the M-type phospholipase A2 receptor (PLA2R) and to thrombospondin type-1 domain-containing 7A (THSD7A), initially described in adult MN, have now been identified in children and adolescents with MN and serve as a useful diagnostic and monitoring tool in this younger population as well. Whereas definitive therapy for secondary forms of MN should be targeted at the underlying cause, immunosuppressive therapy is often necessary for primary disease. Rituximab has been successfully used in the treatment of MN, and is likely effective in children with MN as well, although dosing in the pediatric population is not well established. This review highlights the new findings in adult and pediatric MN since last reviewed in this journal.
10.1007/s00467-019-04425-1
Rituximab for the management of idiopathic membranous nephropathy: a meta-analysis.
Huang Lan,Dong Qiao-Rong,Zhao Ya-Juan,Hu Gui-Cai
International urology and nephrology
PURPOSE:The aim of this study was to evaluate the efficacy of rituximab therapy in the management of idiopathic membranous nephropathy (IMN). METHODS:After literature search, data from eligible studies were used to perform random-effects meta-analyses to estimate remission rates and changes in proteinuria at the latest follow-up after rituximab therapy. The outcomes were used for metaregression to identify the factors affecting the efficacy of rituximab. RESULTS:Twenty-one studies were included in the analysis (602 patients; age 50 years [95% CI 46.8, 53.3]; 30% females [95% CI 23, 31]). Follow-up duration was 20.3 months [95% CI 17.1, 23.5]. Remission rate (67% [95% CI 61, 73]) was higher in studies with below average baseline proteinuria (76% [95% CI 61, 88]) than in studies with above average baseline proteinuria (61% [95% CI 54, 68]). The complete and partial remission rates were 26% [95% CI 20, 33] and 37% [95% CI 31, 43], respectively. Rituximab therapy significantly reduced proteinuria (mean difference between final and baseline values: - 4.90 g/day [95% CI - 6.18, - 3.63]; p < 0.00001; % reduction: 62% [95% CI 57, 68]). The reduction in proteinuria was inversely associated with baseline serum albumin levels (p = 0.021) and the estimated glomerular filtration rate (p < 0.00001) and was positively associated with baseline proteinuria (p < 0.00001). The remission rate or decrease in proteinuria was not significantly related to the anti-PLAR antibody status or previous immunosuppressant therapy. CONCLUSION:Rituximab therapy in IMN patients can provide approximately 67% remission rate. The reduction in proteinuria was greater in patients who had higher baseline proteinuria.
10.1007/s11255-020-02633-5
Clinical significance of glomerular C3 deposition in primary membranous nephropathy.
Oto Ozgur Akin,Demir Erol,Mirioglu Safak,Dirim Ahmet Burak,Ozluk Yasemin,Cebeci Egemen,Basturk Taner,Ucar Ali Riza,Soltanova Lala,Nuriyev Kanan,Kilicaslan Isin,Yazici Halil,Caliskan Yasar
Journal of nephrology
BACKGROUND:We aimed to investigate the effects of glomerular C3 deposition on clinical, histopathological features, and outcomes of patients with primary membranous nephropathy (MN). METHODS:A total of 261 patients with biopsy-proven primary MN, who were on follow up for at least 6 months, were included in the study. The patients were grouped according to their C3 immunostaining in kidney biopsy samples at the time of diagnosis: Low intensity [LI; (C3 1 +)] and high intensity [HI; (C3 2 + or C3 3 +)]. The primary outcome was the development of kidney failure. Complete (CR) or partial remission (PR) was defined as secondary outcome. RESULTS:Sixteen patients reached the primary outcome after a median follow-up of 33.8 months. Patients in the high intensity group (119 cases) had lower eGFR and higher proteinuria at admission and last follow-up compared to patients in the low intensity group (142 cases). Also, more patients in the high intensity group reached the primary outcome compared to patients in the low intensity group: twelve patients (10.1%) in the high intensity group and four patients (2.8%) in the low intensity group reached the primary outcome (p = 0.015). Kaplan-Meier analysis demonstrated that patients in the high intensity group had a higher risk for kidney failure (p = 0.02). In multivariate logistic regression analysis, high intensity C3 deposition and initial estimated glomerular filtration rate (eGFR) indepenently predicted primary outcome. CONCLUSION:Extensive glomerular C3 deposition is a predictor of kidney failure in patients with MN.
10.1007/s40620-020-00915-w
Membranous Nephropathy: Core Curriculum 2021.
Alsharhan Loulwa,Beck Laurence H
American journal of kidney diseases : the official journal of the National Kidney Foundation
The understanding and management of membranous nephropathy, a common cause of nephrotic syndrome that is more frequently encountered in adults than in children, has rapidly evolved over the past decade. Identification of target antigens has allowed for more precise molecular diagnoses, and the ability to monitor circulating autoantibodies has added a new vantage point in terms of disease monitoring and decisions about immunosuppression. Although immunosuppression with alkylating agents combined with corticosteroids, or with calcineurin inhibitor-based regimens, has been the historical mainstay of treatment, observational and now randomized controlled trials with the B-cell-depleting agent rituximab have moved this agent to the forefront of therapy for primary membranous nephropathy. In this Core Curriculum, we discuss the typical features of primary and secondary disease; highlight the target antigens such as the phospholipase A receptor, thrombospondin type 1 domain-containing 7A, neural epidermal growth factor-like 1, and semaphorin-3B; describe the relationship between the immunologic and clinical courses of disease; and review modern management with supportive care or immunosuppressive treatment based on these composite parameters.
10.1053/j.ajkd.2020.10.009