Membranous nephropathy: diagnosis, treatment, and monitoring in the post-PLA2R era.

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.

Pre-transplant phospholipase A2 receptor autoantibody concentration is associated with clinically significant recurrence of membranous nephropathy post-kidney transplantation.

Previous studies that have assessed the association of pre-transplant antiphospholipase A2 receptor autoantibody (PLA2R-Ab) concentration with a recurrence of membranous nephropathy (rMN) post-kidney transplant have yielded variable results. We tested 16 consecutive transplant patients with a history of iMN for pre-transplant PLA2R-Ab. Enzyme-linked immunosorbent assay titers (Euroimmun, NJ, USA) >14 RU/mL were considered positive. A receiver operating characteristic (ROC) analysis was performed after combining data from Quintana et al. (n = 21; Transplantation February 2015) to determine a PLA2R-Ab concentration which could predict rMN. Six of 16 (37%) patients had biopsy-proven rMN at a median of 3.2 yr post-transplant. Of these, five of six (83%) had a positive PLA2R-Ab pre-transplant with a median of 82 RU/mL (range = 31-1500). The only patient who had rMN with negative PLA2R-Ab was later diagnosed with B-cell lymphoma. One hundred percent (n = 10) of patients with no evidence of rMN (median follow-up = five yr) had negative pre-transplant PLA2R-Ab. In a combined ROC analysis (n = 37), a pre-transplant PLA2R-Ab > 29 RU/mL predicted rMN with a sensitivity of 85% and a specificity of 92%. Pre-transplant PLA2R-Ab could be a useful tool for the prediction of rMN. Patients with rMN in the absence of PLA2R-Ab should be screened for occult malignancy and/or alternate antigens.

Pregnancy in a Patient With Primary Membranous Nephropathy and Circulating Anti-PLA2R Antibodies: A Case Report.

There is little information about pregnancy outcomes in patients with active membranous nephropathy (MN), especially those with circulating autoantibodies to M-type phospholipase A2receptor (PLA2R), the major autoantigen in primary MN. We present what we believe to be the first known case of successful pregnancy in a 39-year-old woman with PLA2R-associated MN. In the year prior to pregnancy, the patient developed anasarca, hypoalbuminemia (albumin, 1.3-2.2g/dL), and proteinuria (protein excretion, 29.2 g/d). Kidney biopsy revealed MN with staining for PLA2R, and the patient was seropositive for anti-PLA2R autoantibodies. She did not respond to conservative therapy and was treated with intravenous rituximab (2 doses of 1 g each). Several weeks after presentation, she was found to be 6 weeks pregnant and was closely followed up without further immunosuppressive treatment. Proteinuria remained with protein excretion in the 8- to 12-g/d range. Circulating anti-PLA2R levels declined but were still detectable. At 38 weeks, a healthy baby girl was born, without proteinuria at birth or at her subsequent 6-month postnatal visit. At the time of delivery, the mother still had detectable circulating anti-PLA2R of immunoglobulin G1 (IgG1), IgG3, and IgG4 subclasses, although at low titers. Only trace amounts of IgG4 anti-PLA2R were found in cord blood. Potential reasons for the discrepancy between anti-PLA2R levels in the maternal and fetal circulation are discussed.

Membranous nephropathy: not just a disease for adults.

Membranous nephropathy (MN) is an immune complex-mediated cause of the nephrotic syndrome that can occur in all age groups, from infants to the elderly. While systemic disorders such as hepatitis B infection or lupus may more frequently cause secondary MN in the younger population, primary or "idiopathic" MN has generally been considered a disease of adults. Recent progress in our understanding of primary disease was recently made when the target antigen in primary MN was identified as the M-type phospholipase A2 receptor (PLA2R). Circulating anti-PLA2R antibodies may serve both as a diagnostic tool for distinguishing primary from secondary disease and as a biomarker for monitoring the immunologic activity of this organ-specific autoimmune disease during treatment. Whereas definitive therapy for secondary forms of MN should be targeted at the underlying cause, immunosuppressive therapy is often necessary for primary disease. Alkylating agents in combination with corticosteroids, as well as calcineurin inhibitors (± steroids), are first line agents due to randomized controlled trials in an adult population with relatively long durations of follow-up. However, rituximab, mycophenolate and adrenocorticotropic hormone have shown promise in smaller and/or observational studies. The optimal therapy for children and adolescents with MN is less well defined.

Evaluation of anti-PLA2R1 as measured by a novel ELISA in patients with idiopathic membranous nephropathy: a cohort study.

OBJECTIVES: Autoantibodies against the M-type phospholipase A2 receptor 1 (anti-PLA2R1) have been demonstrated to be very specific for idiopathic membranous nephropathy (MN). We studied a novel enzyme-linked immunosorbent assay (ELISA) and compared results with results obtained using an indirect immunofluorescence (IIF) and a Western blotting test (WB). METHODS: One-hundred nine patients with idiopathic MN were recruited between November 1979 and March 2011. The control cohort comprised serum samples from patients with secondary MN (n = 16) and nephrotic controls (n = 17). The presence of anti-PLA2R1 in serum samples obtained at the time of renal biopsy was determined using ELISA, IIF, and WB. RESULTS: With similar specificity (≥ 97%), sensitivity varied from 68% (IIF) to 72% (ELISA, WB). Remarkably, patients who were seronegative for anti-PLA2R1 more often entered spontaneous remission (P = .038), whereas seropositive patients were more frequently treated with immunosuppressive agents (P < .001). CONCLUSIONS: ELISA performs excellently in differentiating idiopathic from secondary MN. Furthermore, ELISA shared high agreement with WB and IIF.

A pilot study to determine the dose and effectiveness of adrenocorticotrophic hormone (H.P. Acthar® Gel) in nephrotic syndrome due to idiopathic membranous nephropathy.

BACKGROUND: H.P. Acthar(®) Gel is currently the only Food and Drug Administration therapy approved for the treatment of nephrotic syndrome. Active drug ingredients include structurally related melanocortin peptides that bind to cell surface G-protein-coupled receptors known as melanocortin receptors, which are expressed in glomerular podocytes. In animal models of membranous nephropathy, stimulation has been demonstrated to reduce podocyte injury and loss. We hypothesized that H.P. Acthar(®) Gel would improve symptoms of the nephrotic syndrome in patients with idiopathic membranous nephropathy. METHODS: Twenty patients received a subcutaneous dose of 40 or 80 IU twice weekly. Changes in proteinuria, albumin, cholesterol profile, estimated glomerular filtration rate and serum anti-PLA2R antibodies were assessed at baseline and in response to treatment along with tolerance and safety. RESULTS: Baseline characteristics included mean proteinuria (9.1 ± 3.4 g/day), albumin (2.7 ± 0.8 g/dL), estimated glomerular filtration rate (77 ± 30 mL/min) along with elevated total and low-density lipoprotein (LDL) cholesterol. By 12 months of follow-up, there was a significant improvement in proteinuria in the entire cohort, decreasing to 3.87 ± 4.24 g/day (P < 0.001) with significant improvements in serum albumin, total and LDL cholesterol. A >50% decrease in proteinuria was noted in 65% of the patients with a trend toward better outcomes among patients who received greater cumulative doses. No significant adverse effects were documented. Clearing of serum anti-PLA2R antibodies prior to or in parallel with proteinuria improvement was noted in some, but not all patients. CONCLUSIONS: H.P. Acthar(®) Gel is a potential therapy for nephrotic syndrome secondary to idiopathic membranous nephropathy that deserves further study.

Development of IgG4-related disease in a patient diagnosed with idiopathic membranous nephropathy.

We report a case of IgG4-related disease (IgG4-RD) diagnosed after 3 years of follow-up for idiopathic membranous nephropathy (MN). MN has been considered as glomerular lesion of IgG4-related kidney diseases in recent years and was diagnosed simultaneously with or after a diagnosis of IgG4-RD in previously reported cases. In the present case, IgG4-RD developed 3 years after the diagnosis of idiopathic MN, indicating a possible relationship between idiopathic MN and IgG4-RD through common underlying mechanisms of development.

Coexistence of ANCA-associated glomerulonephritis and anti-phospholipase A(2) receptor antibody-positive membranous nephropathy.

Antibodies to myeloperoxidase (MPO) and proteinase 3 (PR3) have been demonstrated to mediate anti-neutrophil cytoplasmic antibody (ANCA)-associated disease. For membranous nephropathy, antibodies to the podocyte-expressed phospholipase A(2) receptor (anti-PLA(2)R) are highly associated with disease activity and have been reported in at least 70% of patients with idiopathic membranous nephropathy (IMN). We present a case of a 56-year-old male with a 1 year history of hypertension, leg edema, and proteinuria, who presented with advanced renal failure and was found to have both ANCA-associated glomerulonephritis (GN) and IMN on kidney biopsy. Consistent with the idea that this is due to the chance occurrence of two independent diseases, we found both anti-MPO and anti-PLA(2)R antibodies in the patient's sera. Treatment with methylprednisolone, plasmapheresis, and cyclophosphamide resulted in improvement in kidney function and proteinuria, together with the simultaneous decrease in both autoantibodies. This is the first demonstration of two pathogenic antibodies giving rise to ANCA-associated GN and IMN in the same patient. It confirms the importance of classifying disease based upon the underlying mechanism, in addition to renal histopathology, to both optimize therapy and predict prognosis.

IgG4-Related Disease Is Not Associated with Antibody to the Phospholipase A2 Receptor.

Patients with IgG4-related disease (IgG4-RD) share histopathological characteristics that are similar across affected organs. The finding of infiltration with IgG4+ plasma cells in the proper clinical and histopathological contexts connects a large number of clinical entities that were viewed previously as separate conditions. The renal involvement in IgG4-RD is usually characterized by tubulointerstitial nephritis, but membranous nephropathy has also been reported to be one of the renal complications of IgG4-RD. The recent discovery that a high proportion of patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies to the M-type phospholipase A2 receptor (PLA2R) in the circulation and glomerular immune deposits, together with the profound IgG4 hypergammaglobulinemia and occasional reports of membranous nephropathy in IgG4-RD, raised the question of a common antigen. To assess the presence of anti-PLA2R antibody in patients with IgG4-RD, we screened sera from 28 IgG4-RD patients by immunoblot. None of the patients in this cohort had detectable circulating anti-PLA2R antibodies. This study suggests that despite some clinical and serological overlaps between IgG4-RD and IMN,anti-PLA2R antibodies do not play a role in the pathogenesis of IgG4-RD. Additional studies of IgG4-RD with evidence of membranous nephropathy are important to exclude any definite relationship.

Treatment of resistant glomerular diseases with adrenocorticotropic hormone gel: a prospective trial.

BACKGROUND: Adrenocorticotropic hormone (ACTH) has shown promising results in glomerular diseases resistant to conventional therapies, but the reported data have solely been from retrospective, observational studies. METHODS: In this prospective, open-label study (NCT01129284), 15 subjects with resistant glomerular diseases were treated with ACTH gel (80 units subcutaneously twice weekly) for 6 months. Resistant membranous nephropathy (MN), minimal change disease (MCD), and focal segmental glomerulosclerosis (FSGS) were defined as failure to achieve sustained remission of proteinuria off immunosuppressive therapy with at least 2 treatment regimens; resistant IgA nephropathy was defined as >1 g/g urine protein:creatinine ratio despite maximally tolerated RAAS blockade. Remission was defined as stable or improved renal function with ≥50% reduction in proteinuria to <0.5 g/g (complete remission) or 0.5-3.5 g/g (partial remission). RESULTS: The study included 5 subjects with resistant idiopathic MN, 5 subjects with resistant MCD (n = 2)/FSGS (n = 3), and 5 subjects with resistant IgA nephropathy. Two resistant MN subjects achieved partial remission on ACTH therapy, although 3 achieved immunologic remission of disease (PLA(2)R antibody disappeared by 4 months of therapy). One subject with resistant FSGS achieved complete remission on ACTH; one subject with resistant MCD achieved partial remission but relapsed within 4 weeks of stopping ACTH. Two subjects with resistant IgA nephropathy demonstrated >50% reductions in proteinuria while on ACTH, with proteinuria consistently <1 g/g by 6 months. Three of 15 subjects reported significant steroid-like adverse effects with ACTH, including weight gain and hyperglycemia, prompting early termination of therapy without any clinical response. CONCLUSIONS: ACTH gel is a promising treatment for resistant glomerular diseases and should be studied further in controlled trials against currently available therapies for resistant disease.

Relationship of plasma galectin-3 to renal function in patients with heart failure: effects of clinical status, pathophysiology of heart failure, and presence or absence of heart failure.

BACKGROUND: Galectin-3 (GAL-3), a ß-galactoside-binding protein, is a new clinical biomarker believed to reflect cardiac remodeling/fibrosis in patients with heart failure (HF). Plasma GAL-3 is inversely related to renal function. It is not known whether the relationship between renal function and GAL-3 is influenced by clinical decompensation, type of HF, or the presence or absence of clinical HF. METHODS AND RESULTS: Patients were prospectively categorized as having acute decompensated HF or stable HF on the basis of clinical status and as having HF with reduced left ventricular ejection fraction or HF with preserved left ventricular ejection fraction. Plasma GAL-3 was measured by enzyme-linked immunosorbent assay in patients with HF (n=75), control patients without HF (n=32), and control patients without HF with moderate renal insufficiency (n=12). Compared to controls without HF (14±4 ng/mL), GAL-3 was higher in patients with both acute decompensated HF (23±11 ng/mL) and stable HF (22±10 ng/mL) (P<0.001 versus controls for both) but did not differ between acute decompensated HF and stable HF (P=0.75). Likewise, GAL-3 was elevated in both HF with preserved left ventricular ejection fraction (23±9 ng/mL) and HF with reduced left ventricular ejection fraction (22±11 ng/mL) (P<0.001 versus controls for both) but did not differ between HF with preserved ejection fraction and HF with reduced ejection fraction (P=0.37). GAL-3 correlated strongly with estimated glomerular filtration rate, both in patients with HF (r=-0.75, P<0.001) and in patients without HF (r=-0.82, P<0.001), and this relationship was unaffected by the presence or absence of clinical HF. CONCLUSIONS: Plasma GAL-3 is inversely related to renal function in patients with and without clinical HF. Concentrations of plasma GAL-3 do not seem to depend on the level of compensation or type of HF. Furthermore, the relationship between GAL-3 and renal function seems to be affected little or not at all by the presence or absence of clinical HF.