A Proposal for a Serology-Based Approach to Membranous Nephropathy (original) (raw)
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Recent Progress in Deciphering the Etiopathogenesis of Primary Membranous Nephropathy
BioMed Research International
Primary membranous nephropathy (MN) is the leading cause of nephrotic syndrome in adults. Discovery of several antibodies has contributed to an increased understanding of MN. Antibodies against the M-type phospholipase A2 receptor (PLA2R) are present in 50–100% with primary MN and are associated with a lower frequency of spontaneous remission. High levels are linked with a higher probability of treatment resistance, higher proteinuria, and impaired renal function, as well as a more rapid decline of kidney function during follow-up. Immunologic remission precedes reduction of proteinuria by months. Pretransplant evaluation of PLA2R antibodies is warranted to predict recurrence of disease following renal transplantation. Several risk alleles related to the PLA2R1 gene and within the HLA loci have been identified, whereas epitope spreading of PLA2R may predict treatment response. More recently, thrombospondin type 1 domain-containing 7A (THSD7A) antibodies have been discovered in prima...
Idiopathic membranous nephropathy and anti-phospholipase A2 receptor antibodies
Journal of nephropathology, 2013
Idiopathic membranous nephropathy anti-phospholipase A2 receptor antibodies nephrotic syndrome End-stage renal disease Implication for health policy/practice/research/medical education: Membranous nephropathy (MN) is a glomerular disease due to subepithelial immune deposits and local complement activation resulting in podocyte injury and proteinuria. Patients with idiopathic (but not secondary) MN had circulating autoantibodies, predominantly of the IgG4 subclass, directed against M-type phospholipase A2 receptor (PLA2R) located on podocytes. It is also possible that the binding of anti-PLA2R antibodies to PLA2R on podocytes could alter receptor function resulting in podocyte dysfunction.
PLOS ONE, 2019
Background Membranous nephropathy (MN) is an autoimmune disease induced by circulating antibodies against the podocyte protein phospholipase A 2 receptor 1 (PLA 2 R1-ab) in 80% of patients and represents the leading cause of nephrotic syndrome in adults. PLA 2 R1-ab levels correlate with disease activity and treatment response. However, their predictive role for long-term renal outcome is not clear. Methods The aim of this prospective observational multicenter study was to investigate the predictive role of PLA 2 R1-ab levels at the time of diagnosis for long-term outcome in a cohort of 243 patients with newly diagnosed biopsy-proven PLA 2 R1-associated MN. Statistical analyses included Cox proportional hazard models. The primary study endpoint was defined prior to data collection as doubling of serum creatinine or development of end-stage renal disease. Results During the median follow-up time of 48 months, 36 (15%) patients reached the study endpoint. Independent predictors for reaching the study endpoint were baseline PLA 2 R1-ab levels (HR = 1.36, 95%CI 1.11-1.66, p = 0.01), percentage of tubular atrophy and interstitial fibrosis (HR = 1.32, 95%CI 1.03-1.68, p = 0.03), PLA 2 R1-ab relapse during follow-up (HR = 3.22, 95%CI 1.36-7.60, p = 0.01), and relapse of proteinuria (HR = 2.60, 95%CI 1.17-5.79, p = 0.02). Fifty-four (22%) patients received no immunosuppressive treatment during the study, in 41 (76%) of them PLA 2 R1-ab spontaneously disappeared during follow-up, 29 (54%) patients had a complete remission of proteinuria, and 19 (35%) had a partial remission. Patients not treated with immunosuppression were more often females and had lower PLA 2 R1-ab levels, proteinuria, and serum creatinine at baseline compared to patients receiving immunosuppression. However, no conclusion on the efficacy of immunosuppressive PLOS ONE |
Primary Membranous Nephropathy
Clinical Journal of the American Society of Nephrology
Membranous nephropathy (MN) is a unique glomerular lesion that is the most common cause of idiopathic nephrotic syndrome in nondiabetic white adults. About 80% of cases are renal limited (primary MN, PMN) and 20% are associated with other systemic diseases or exposures (secondary MN). This review focuses only on PMN. Most cases of PMN have circulating IgG4 autoantibody to the podocyte membrane antigen PLA2R (70%), biopsy evidence PLA2R staining indicating recent immunologic disease activity despite negative serum antibody levels (15%), or serum anti-THSD7A (3%-5%). The remaining 10% without demonstrable anti-PLA2R/THSd7A antibody or antigen likely have PMN probably secondary to a different, still unidentified, anti-podocyte antibody. Considerable clinical and experimental data now suggests these antibodies are pathogenic. Clinically, 80% of patients with PMN present with nephrotic syndrome and 20% with non-nephrotic proteinuria. Untreated, about one third undergo spontaneous remission, especially those with absent or low anti-PLA2R levels, one-third progress to ESRD over 10 years, and the remainder develop nonprogressive CKD. Proteinuria can persist for months after circulating anti-PLA2R/THSD7A antibody is no longer detectable (immunologic remission). All patients with PMN should be treated with supportive care from the time of diagnosis to minimize protein excretion. Patients with elevated anti-PLA2R/THSD7A levels and proteinuria >3.5 g/d at diagnosis, and those who fail to reduce proteinuria to <3.5 g after 6 months of supportive care or have complications of nephrotic syndrome, should be considered for immunosuppressive therapy. Accepted regimens include steroids/cyclophosphamide, calcineurin inhibitors, and B cell depletion. With proper management, only 10% or less will develop ESRD over the subsequent 10 years.
International Journal of Clinical Practice, 2020
Background Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in nondiabetic adults. M-type phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A) are known as target podocyte antigens in membranous nephropathy (MN). Antibodies against these podocyte antigens are used in the initiation of treatment and response monitoring. However, the relationship between renal podocyte antigens and treatment response is not clear yet. We evaluated the relationship between immunohistochemical PLA2R, THSD7A, and IgG4 staining, clinical findings, and treatment response in kidney biopsies. Methods Fifty-eight patients with MN were included in this retrospective study. In the renal biopsy samples of the patients, PLA2R, THSD7A, and IgG4 were stained immunohistochemically and evaluated by light microscopy. The clinical, laboratory, and treatment results of the patients were obtained from the hospital records.
Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era
Pediatric Nephrology, 2019
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.
Pathophysiological advances in membranous nephropathy: time for a shift in patient's care
The Lancet, 2015
Membranous nephropathy is a major cause of nephrotic syndrome of non-diabetic origin in adults. It is the second or third leading cause of end-stage renal disease in patients with primary glomerulonephritis, and is the leading glomerulopathy that recurs after kidney transplantation (occurring in about 40% of patients). Treatment with costly and potentially toxic drugs remains controversial and challenging, partly because of insuffi cient insight into the pathogenesis of the disease and absence of sensitive biomarkers of disease activity. The disease is caused by the formation of immune deposits on the outer aspect of the glomerular basement membrane, which contain podocyte or planted antigens and circulating antibodies specifi c to those antigens, resulting in complement activation. In 2002, podocyte neutral endopeptidase was identifi ed as an antigenic target of circulating antibodies in alloimmune neonatal nephropathy, and in 2009, podocyte phospholipase A 2 receptor (PLA 2 R) was reported as an antigenic target in autoimmune adult membranous nephropathy. These major breakthroughs were translated to clinical practice very quickly. Measurement of anti-PLA 2 R antibodies in serum and detection of PLA 2 R antigen in glomerular deposits can now be done routinely. Anti-PLA 2 R antibodies have high specifi city (close to 100%), sensitivity (70-80%), and predictive value. PLA 2 R detection in immune deposits allows for retrospective diagnosis of PLA 2 R-related membranous nephropathy in archival kidney biopsies. These tests already have a major eff ect on diagnosis and monitoring of treatment, including after transplantation.
Antigen Identification in Membranous Nephropathy Moves toward Targeted Monitoring and New Therapy
Journal of the American Society of Nephrology, 2010
Membranous nephropathy, a disease characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane, is the most common cause of idiopathic nephrotic syndrome in Caucasian adults. In the rat model described by Heymann in 1959, the target antigen of antibodies is megalin, a multiligand receptor expressed in the rat glomerulus but absent from the human glomerulus. In the past few years, two major antigens have been identified in human membranous nephropathy. The first is neutral endopeptidase, the alloantigen involved in neonatal cases of membranous nephropathy that occur in newborns from neutral endopeptidase-deficient mothers. The second is the type-M phospholipase A2 receptor (PLA 2 R), the first autoantigen identified in idiopathic membranous nephropathy in the adult. Megalin, neutral endopeptidase, and PLA 2 R are all expressed on the podocyte surface where they serve as targets for circulating antibodies, which lead to in situ immune complex formation, complement activation, and proteinuria. The recent discovery of neutral endopeptidase and PLA 2 R provides new tools for monitoring human disease activity and should be of value in designing new antigen-driven therapeutic strategies.
Advances in membranous nephropathy: Success stories of a long journey
Clinical and Experimental Pharmacology and Physiology, 2011
is characterized by an accumulation of immune deposits on the outer aspect of the glomerular basement membrane. 2. In the rat model described by Heymann in 1959, the target antigen of antibodies is megalin, a multiligand receptor expressed in the rat glomerulus but absent from the human glomerulus. 3. In recent years, two major antigens have been identified in human membranous nephropathy (MN). The first is neutral endopeptidase (NEP), the alloantigen involved in neonatal cases of MN that occur in newborns from NEP-deficient mothers. The second is the M-type phospholipase A 2 receptor (PLA 2 R), the first autoantigen identified in idiopathic MN in the adult. Megalin, NEP and PLA 2 R are all expressed on the podocyte surface, where they can serve as targets for circulating antibodies, leading to in situ immune complex formation, complement activation and proteinuria. 4. In addition to podocyte antigens, we recently showed that some patients with childhood MN had both circulating cationic bovine serum albumin (BSA) and anti-BSA antibodies, with BSA being present in immune deposits. This suggests that food antigens may be involved in MN through charge-dependent binding to the anionic glomerular capillary wall and in situ formation of immune complexes.
Applied Immunohistochemistry & Molecular Morphology, 2019
Membranous nephropathy represents the most frequent cause of nephrotic syndrome in the adult, leading to end-stage renal disease in one third of all the patients. In the last years, the discovery of circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 containing 7A domain (THSD7A), shed light on the pathogenesis of idiopathic forms, being responsible for 70% and 3% of all the cases, respectively. These identifications allowed the development of serological and histologic tests to detect autoantibodies and relative targets for diagnostic and prognostic purposes. Rising evidences suggest that serum titer correlates with disease activity and response to therapy. For these reasons, for patients with nephrotic syndrome, a serum-based approach has been proposed, reserving renal biopsy only in cases with doubtful/negative serology. However, the recent introduction of useful criteria for the interpretation of PLA2R/THSD7A immunohistochemistry could lead to high values of sensitivity and specificity for the in situ detection of target antigens. The present multicentric study on a series of membranous nephropathy cases with available serum/histologic correlation will show the importance of the crosstalk among the different techniques, recovering the possible role of electron microscopy in challenging situations.