Malignancy-associated Membranous Nephropathy Research Articles

Nerve Epidermal Growth Factor-Like 1 Protein (NELL-1) Expression in Mercury-Related Membranous Nephropathy: Is It a True Association or a Chance Occurrence?

Background: Neural epidermal-like growth factor-like 1 (NELL-1) is a protein kinase C binding protein expressed in osteoblasts and renal tubules. It is expressed in 5%–25% glomerular cells at the mRNA level. Membranous Nephropathy (MN) is characterized by the presence of antibodies against certain types of antigens on the glomerular basement membrane. The most common one implicated in primary MN is an antibody against PLA2R. Many newer antigens have been discovered in the recent past, which are proven to cause secondary MN, one of which is NELL-1. NELL-1 has been associated with malignancy-associated MN and also recently associated with traditional indigenous medications containing mercury. In this study, we study the expression of NELL-1 in mercury-associated MN. Materials and Methods: Records of ten cases of Mercury -associated MN were retrieved from the Institute medical archives and NELL-1 Immunohistochemistry was performed in all ten cases. Results: NELL-1 was found to be positive in 50% of the cases of Mercury associated MN. In addition, mass spectrometric studies was performed, which revealed the common Mercuric compound associated to be ‘Swaskalpa’, Sudarshana Melugu’ and Rasagandhi Mezhugu’. Conclusion: This study highlights why it is important to diagnose mercury-associated MN by a pathologist by picking up the finer histopathological clues and by using NELL-1 immunohistochemistry, especially in PLA2R-negative patients. The former is true as most of the time a history of mercuric compound intake is missed out.

Malignancy-associated membranous nephropathy: focus on diagnosis and treatment.

The clinicopathological features of malignancy-associated membranous nephropathy have been described previously, but information about diagnosis and treatment remains limited. Patients with malignancy-associated membranous nephropathy in a tertiary hospital in China between June 2012 and October 2021 were retrospectively reviewed. Forty-two patients with malignancy-associated membranous nephropathy were identified. Compared to patients with idiopathic membranous nephropathy, patients with malignancy-associated membranous nephropathy were older and less frequently showed glomerular phospholipase A2 receptor staining (37.9% vs 85.0%) and IgG4 predominant deposition (66.7% vs 95.0%). At diagnosis of membranous nephropathy, themalignancy was unknown in 67% (28/42) of patients and was detected only by tumor screening. Among the 19 patients with concurrent diagnosis of cancer and biopsy-proven membranous nephropathy, 15 received anticancer treatment alone initially. Six of the 10 patients who attained cancer remission achieved remission of membranous nephropathy, while none of the 5 patients without remission of cancer did, suggesting a causal relationship between the two diseases. Some patients with persistent or relapsing membranous nephropathy following cancerremissionachieved remission of membranous nephropathy after immunosuppressive therapy. Over a median follow-up of 24months, 25% (10/40) of patients died, mainly due to neoplasia. Tumor screening is important in patients with membranous nephropathy, especially in elderly patients and patients with negative phospholipase A2 receptor or non-IgG4 predominant deposition. Remission of membranous nephropathy can be observed following remission of cancer in some cases. Immunosuppressive therapy may be considered if membranous nephropathy does not remit after remission of cancer.

Construction of a Nomogram Discriminating Malignancy-Associated Membranous Nephropathy From Idiopathic Membranous Nephropathy: A Retrospective Study.

BackgroundBased on the etiology, membranous nephropathy (MN) can be categorized into idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy. Malignancy-associated membranous nephropathy (MMN) is a common type of secondary MN. Its incidence is only second to that of lupus nephritis. As the treatment and prognosis of MMN differ significantly from those of other MNs, the identification of MMN is crucial for clinical practice. The purpose of this study was to develop a model that could efficiently discriminate MMN, to guide more precise selection of therapeutic strategies.MethodsA total of 385 with IMN and 62 patients with MMN, who were hospitalized at the First Affiliated Hospital of Zhengzhou University between January 2017 and December 2020 were included in this study. We constructed a discriminant model based on demographic information and laboratory parameters for distinguishing MMN and IMN. To avoid an increased false positivity rate resulting from the large difference in sample numbers between the two groups, we matched MMN and IMN in a 1:3 ratio according to gender. Regression analysis was subsequently performed and a discriminant model was constructed. The calibration ability and clinical utility of the model were assessed via calibration curve and decision curve analysis.ResultsWe constructed a discriminant model based on age, CD4+ T cell counts, levels of cystatin C, albumin, free triiodothyronine and body mass index, with a diagnostic power of 0.860 and 0.870 in the training and test groups, respectively. The model was validated to demonstrate good calibration capability and clinical utility.ConclusionIn clinical practice, patients demonstrating higher scores after screening with this model should be carefully monitored for the presence of tumors in order to improve their outcome.

Recurrent membranous nephropathy with a possible alteration in the etiology: a case report

BackgroundPhospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) are the two major pathogenic antigens for membranous nephropathy (MN). It has been reported that THSD7A-associated MN has a higher prevalence of comorbid malignancy than PLA2R1-associated MN. Here we present a case of MN whose etiology might change from idiopathic to malignancy-associated MN during the patient’s clinical course.Case presentationA 68-year-old man with nephrotic syndrome was diagnosed with MN by renal biopsy. Immunohistochemistry showed that the kidney specimen was negative for THSD7A. The first course of corticosteroid therapy achieved partial remission; however, nephrotic syndrome recurred 1 year later. Two years later, his abdominal echography revealed a urinary bladder tumor, but he did not wish to undergo additional diagnostic examinations. Because his proteinuria increased consecutively, corticosteroid therapy was resumed, but it failed to achieve remission. Another kidney biopsy was performed and revealed MN with positive staining for THSD7A. PLA2R1 staining levels were negative for both first and second biopsies. Because his bladder tumor had gradually enlarged, he agreed to undergo bladder tumor resection. Pathological examination indicated that the tumor was THDS7A-positive bladder cancer. Subsequently, his proteinuria decreased and remained in remission.ConclusionsThis case suggests that the etiology of MN might be altered during the therapeutic course. Intensive screening for malignancy may be preferable in patients with unexpected recurrence of proteinuria and/or change in therapy response.

NELL1 is a target antigen in malignancy-associated membranous nephropathy

Patients with membranous nephropathy have an increased risk of malignancy compared to the general population, but the target antigen for malignancy-associated membranous nephropathy is unknown. To explore this, we utilized mass spectrometry for antigen discovery in malignancy-associated membranous nephropathy examining immune complexes eluted from frozen kidney biopsy tissue using protein G bead immunoglobulin capture. Antigen discovery was performed comparing cases of membranous nephropathy of unknown and known type. Mass spectrophotometric analysis revealed that nerve epidermal growth factor-like 1 (NELL1) immune complexes were uniquely present within the biopsy tissue in membranous nephropathy. Additional NELL1-positive cases were subsequently identified by immunofluorescence. In a consecutive series, 3.8% of PLA2R- and THSD7A-negative cases were NELL1-positive. These NELL1-positive cases had segmental to incomplete IgG capillary loop staining (93.4%) and dominant or co-dominant IgG1-subclass staining (95.5%). The mean age of patients with NELL1-positive membranous nephropathy was 66.8 years, with a slight male predominance (58.2%) and 33% had concurrent malignancy. Compared with PLA2R- and THSD7A-positive cases of membranous nephropathy, there was a greater proportion of cases with malignancies in the NELL1-associated group. Thus, NELL1-associated membranous nephropathy has a unique histopathology characterized by incomplete capillary loop staining, IgG1-predominance, and is more often associated with malignancy than other known types of membranous nephropathy.

MON-013 A CASE OF MEMBRANOUS NEPHROPATHY THAT DEVELOPPED AFTER USE OF NIVOLUMAB

Immune checkpoint inhibitors (ICIs) are novel medicines for cancer immunotherapy that have increasingly been used in recent years.Nivolumab is a human anti-programmed cell death 1(PD-1) monoclonal antibody that serves as an ICI. It activates anti-tumor immunity by interfering with the interaction between PD-1 and PD-1 ligand. However, by activating the immune system, ICIs also cause unique side effects, termed immune-related adverse events (irAE). Although renal irAEs are considered less common, case reports related to renal irAEs are becoming more frequent with the increasing use of ICIs. Most renal irAEs involve acute interstitial nephropathy, and glomerulonephritis is rarely reported. Here, we present the first case of membranous nephropathy (MN) that developed after use of nivolumab. ［HPI］ A 69-year-old man was referred to our hospital with nephrotic syndrome. Sixteen months previously, he commenced chemotherapy with docetaxel for stage IV non-small cell lung carcinoma. However, docetaxel was discontinued because of drug-induced lung injury and immunotherapy with nivolumab was initiated 5 months previously. He subsequently developed leg edema and increasing proteinuria. Despite discontinuation of nivolumab after the seventh course, his symptoms did not improve. He was admitted and underwent renal biopsy. ［Investigations］ His urine protein/creatinine ratio was 19 g/g Cre and serum albumin was 2.3 g/dL. Light microscopic examination of the biopsy specimen, which contained 19 glomeruli, showed global sclerosis in one of the glomeruli. The remaining glomeruli demonstrated diffuse thickening and spikes in the glomerular basement membrane. There was no evidence of acute interstitial nephritis. Immunofluorescence staining showed IgG and C3 deposition on the capillary walls. IgA, IgM, C4, and Ciq were not stained. These observations led to the diagnosis of MN. Staining for IgG subclasses and phospholipase A2 receptor (PLA2R), a membrane protein expressed on podocytes, indicated only IgG1 deposition on the capillary wall. ［In-hospital course］ Glucocorticoid therapy was started with 50 mg/day prednisolone as the standard treatment for irAEs, with recovery of proteinuria from the nephrotic range in 4 weeks. During tapering of glucocorticoids, proteinuria decreased and he attained incomplete remission in 7 months. Thereafter, chemotherapy was resumed with pemetrexed, anantimetabolic drug, which maintained the lung carcinoma at a steady disease state. ［Discussion］ It is well-documented that about 10% of MN cases are associated with malignancy. In previous studies, the absence of IgG4 and PLA2R deposition was a common finding in malignancy-associated MN (M-MN) and was useful for distinguishing M-MN from idiopathic MN. Our case was considered as M-MN because of the staining pattern. Although previous reports show that M-MN improves after successful treatment of malignancy, our patient’s proteinuria increased even though his lung carcinoma remained stable during chemotherapy with nivolumab. This suggests that his M-MN was induced by immune activation caused by nivolumab. Additionally, the favorable response to glucocorticoid therapy supports the association between nivolumab and MN. With the increasing use of ICIs, renal irAEs will likely increase. Our case report demonstrates that ICIs can cause M-MN, which can be successfully treated with glucocorticoids.

SUN-030 PHOSPHOLIPASE A2 RECEPTOR AND THROMBOSPONDIN TYPE-1 DOMAIN-CONTAINING 7A IN MALIGNANCY MEMBRANOUS NEPHROPATHY

Phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) have recently been identified as pathogenic antigens in patients with membranous nephropathy (MN). Notably, PLA2R is detected in a few patients with malignancy-associated MN. Furthermore, a high incidence of cancer is reported in patients with THSD7A-associated MN. It is thus necessary to clarify the usefulness of PLA2R and THSD7A in malignancy-associated MN. Serum anti-PLA2R antibodies and glomerular PLA2R expression were first screened in 36 patients with malignancy-associated MN by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence, respectively, followed by examination of serum anti-THSD7A antibodies and glomerular THSD7A. THSD7A expression in cancer tissues was also assessed in 9 of the 36 patients. Among the 36 patients, 12 (33%) were positive for both glomerular PLA2R staining and serum anti-PLA2R antibodies, and 2 were positive for either glomerular PLA2R staining or serum anti-PLA2R antibodies. IgG4 was the dominant IgG subclass in PLA2R-related patients. One patient with positve glomerular PLA2R staining was also positive for THSD7A staining. Among the remaining 22 (61%) patients who were double negative for glomerular PLA2R staining and serum anti-PLA2R antibodies, 17 of 20 (85%) had IgG1 dominant deposits in glomeruli, and 2 (9%) were positive for glomerular THSD7A staining. Serum anti-THSD7A antibody was not detected in any of the 36 patients. Among the 9 patients with available cancer tissues, enhanced expression of THSD7A in the cancer tissues was observed for 5 (56%), and one also showed enhanced glomerular expression of THSD7A. Screening of glomerular PLA2R antigen and serum anti-PLA2R antibodies is necessary in patients with malignancy-associated MN, whereas the incidence of glomerular THSD7A antigen or circulating anti-THSD7A antibodies is uncommon.

Features of phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A in malignancy-associated membranous nephropathy

AimsPhospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) were identified as pathogenic antigens in patients with membranous nephropathy (MN). Notably, PLA2R is detected in few patients with malignancy-associated...

167 Malignancy-Associated Membranous Nephropathy with Positive anti-PLA2R – Connection or Co-incidence?

167 Malignancy-Associated Membranous Nephropathy with Positive anti-PLA2R – Connection or Co-incidence?

Antigen-Specific IgG Subclasses in Primary and Malignancy-Associated Membranous Nephropathy.

Membranous nephropathy (MN) is an autoimmune disease caused by binding of circulating antibodies to podocyte antigens in the kidney. For decades and still today primary MN has been considered to have an unspecified IgG4-driven autoimmune genesis, while secondary MN has been associated with other diseases, most notably cancer, and not linked to IgG4. Immunologic mechanisms of primary and malignancy-associated MN are assumed to be different, however, this has never been systematically evaluated. The identification of Phospholipase A2 Receptor 1 (PLA2R1) and Thrombospondin Type-1 Domain-Containing 7A (THSD7A) as target antigens in MN allows a pathogenesis-driven differential diagnosis. Recent data showing a molecular link between increased THSD7A-expression in tumors and THSD7A-antibody positive MN suggest a similar pathogenesis of malignancy-associated and primary MN. In order to better define the underlying immunologic processes, we systematically analyzed circulating antigen-specific IgG subclasses in the serum of 76 patients with PLA2R1-associated MN and 41 patients with THSD7A-associated MN in relationship to concurrent malignancy and disease outcome. Twenty-three patients in the study had malignancy-associated MN. We analyzed antigen-specific IgG subclasses in the serum of all patients at baseline and in 55 patients during follow-up by Western blot applying antigens derived from human kidney and lung. At baseline all 117 patients were positive for IgG4-antibodies against either PLA2R1 or THSD7A, while IgG3, IgG1, and IgG2-antibodies were found in 87, 72, and 26% of patients, respectively. There were no differences in the IgG subclass distribution between patients with primary vs. cancer-associated MN and no association with disease outcome. Moreover, levels of antigen-specific IgG4-antibodies were not different between primary and malignancy-associated MN and levels of all IgG subclasses did not differ between these groups. Both podocytes and lung bronchioles showed expression of both PLA2R1 and THSD7A when analyzed by immunofluorescence and Western blot. Every antigen-specific IgG subclass showed identical binding in both organs and autoantibodies bound the respective antigen only under non-reducing conditions. We conclude that antigen-specific IgG subclasses do not differentiate primary from malignancy-associated MN or predict disease prognosis. These data support the view that one common pathway may lead to primary and cancer-associated MN induced by PLA2R1- or THSD7A-antibodies.

Retrospective Study of Phospholipase A2 Receptor and IgG Subclasses in Glomerular Deposits in Chinese Patients with Membranous Nephropathy

Background and objectivesThe research work in the past years showed that detection of phospholipase A2 receptor (PLA2R) antigen and its dominant IgG4 autoantibody in glomerular deposits of patients with membranous nephropathy (MN) was useful for the differentiation between primary MN (PMN) and secondary MN (SMN), but so far such research data from large Chinese patient series is little. Here, we are going to report a research work in a Chinese cohort.Design, setting, participants, & measurementsThis study enrolled 179 patients with PMN, 40 patients with membranous lupus nephritis (LN-MN), 26 patients with hepatitis B virus-associated MN (HBV-MN), 2 patients with malignancy-associated MN (M-MN) and one patient with IgG4-related MN (IgG4-MN). PLA2R and IgG subclasses in glomerular deposits of these patients were examined by immunofluorescence and/or immunohistochemical staining, and the potential value of the above examinations for differential diagnosis of PMN and SMN was evaluated.ResultsGlomerular PLA2R deposition was present in 92.2% patients with PMN and 7.7% patients with HBV-MN, but none of the patients with LN-MN. Predominant/codominant IgG4 deposition was found in 93.3% patients with PMN and 11.5% patients with HBV-MN, but none of the patients with LN-MN. The two M-MN patients both had glomerular PLA2R and predominant/codominant IgG4 deposition. The one IgG4-MN patient had deeply staining IgG4 but no PLA2R in glomeruli.ConclusionsThe glomerular PLA2R and predominant/codominant IgG4 deposition is frequently observed in Chinese patients with PMN. Immunofluorescence and immunohistochemical staining of renal biopsy tissue for detection of glomerular PLA2R and IgG subclasses deposition can help to distinguish PMN from LN-MN and most of HBV-MN.

Glomerular IgG subclasses in idiopathic and malignancy-associated membranous nephropathy.

BackgroundIn idiopathic membranous nephropathy (MN), antibodies directed towards the glomerular phospholipase A2 receptor (PLA2R) have mainly been reported to be of IgG4 subclass. However, the role of the different IgG subclasses in the pathogenesis of MN, both in idiopathic MN and in secondary cases, is still unclear. In this retrospective study, we test the hypothesis that the absence of glomerular IgG4 and PLA2R in patients with MN indicates malignant disease.MethodsThe distribution pattern of glomerular IgG subclasses and PLA2R was studied in 69 patients with idiopathic MN and 16 patients with malignancy-associated MN who were followed up for a mean of 83 months.ResultsA significant correlation between the absence of IgG4 and PLA2R and malignancy-associated MN was found. Thus, IgG4 was positive in 45 of 69 patients (65%) with idiopathic MN but only in 5 of 16 patients (31%) with malignancy-associated MN. The other IgG subclasses did not differ statistically between the groups, IgG2-positivity being present in more than 94% of patients in both groups. Thirty-five of 63 patients (56%) with idiopathic MN and 3 of 16 (19%) patients with malignancy-associated MN had glomerular deposits of PLA2R.ConclusionsWe have found that the absence of glomerular IgG4 and PLA2R is common in patients with malignancy-associated MN. In our material, IgG2 could not be used as a marker of underlying malignant disease. Finally, neither IgG1 nor IgG3 seems to be involved in the pathogenesis of MN.

Absence of glomerular IgG4 deposition in patients with membranous nephropathy may indicate malignancy

The renal pathological manifestations of malignancy-associated membranous nephropathy (M-MN) and idiopathic membranous nephropathy (I-MN) are similar. It has been suggested that glomerular IgG4 deposition may play an important role in the pathogenesis of I-MN. In the present study, we compared the IgG subclass of immune complex deposition, clinical data and pathological data of patients with M-MN and I-MN. Eight patients with M-MN and 42 patients with I-MN diagnosed between 1997 and 2009 in our hospital were enrolled. The clinical and pathological data were retrospectively collected, and glomerular IgG subclass deposition was detected by immunohistochemistry. Patients with M-MN were older (P = 0.003), with lower serum albumin (P = 0.034) and higher serum C-reactive protein (CRP) level (P = 0.003) than patients with I-MN. The majority of patients with M-MN had earlier pathological stages (P = 0.003) and less IgG deposition in glomeruli (P = 0.029). Absence of IgG4 deposition in glomeruli was notably observed in patients with M-MN (7/8 in M-MN versus 6/42 in I-MN, P < 0.001) and it was an independent predictor for occurrence of malignancy (hazard ratio 0.065, 95% confidence intervals 0.007-0.571, P = 0.014). Absence of glomerular IgG4 deposition, together with older age, severe hypoalbuminemia and high serum CRP level could be useful clues to differentiate M-MN from I-MN.

Membranous Nephropathy and Malignancy

An association between the glomerular disease membranous nephropathy (MN) and malignancy has long been appreciated, but evidence supporting this relationship remains limited, speculative, and, at times, controversial. Reports that the two disease processes often evolve in parallel, as well as the occasional findings of tumor antigens or tumor-reactive antibodies within glomerular immune deposits, are all supportive of an association. However, the diagnosis of both MN and malignancy in the same individual also may be coincidental, especially in an older demographic group in which both diseases tend to occur. This article briefly reviews the proposed pathogenetic mechanisms of idiopathic and secondary forms of MN, as well as the arguments for and against the contention that malignancy-associated MN is itself a distinct clinical entity. In addition, the recent identification of the M-type phospholipase A₂ receptor as a major glomerular antigen in idiopathic MN has the potential to offer fresh tools that might help resolve some of the controversy, and ultimately aid in the decision of how aggressively to screen for malignancy in an individual diagnosed with MN.

Membranous Nephropathy Complicating Nasopharyngeal Carcinoma

The patient was a 38-year-old woman diagnosed with nephrotic syndrome. Steroid pulse therapy and mizoribine was started in late October 2002 and continued for about 10 months, but no apparent therapeutic effect was obtained. During this period, the patient was diagnosed with nasopharyngeal carcinoma. As nephrotic syndrome did not improve, renal biopsy was performed and membranous nephropathy (MN) was diagnosed. After resection of nasopharyngeal carcinoma was performed, the urinary protein level decreased rapidly. Since MN caused by nasopharyngeal carcinoma is very rare, this represents an interesting case of malignancy-associated MN.

Distribution of glomerular IgG subclass deposits in malignancy-associated membranous nephropathy.

Several studies have shown a predominant glomerular deposition of IgG4 in patients with idiopathic membranous nephropathy (MN), whereas significant depositions of other IgG subclasses have been shown in patients with lupus-associated MN and bucillamine-induced MN. We examined the distribution patterns of glomerular IgG subclass deposits in 10 patients with malignancy-associated MN (M-MN) and in 15 patients with idiopathic MN by immunofluorescence (IF) microscopy. The glomerular IF intensities of IgG1 and IgG2 were significantly stronger in the malignancy group than in the idiopathic group (P<0.05). In contrast, there were no differences in glomerular IF intensities of IgG3 and IgG4 between the two groups. Our findings suggest that the distribution patterns of glomerular IgG subclass deposits are different in idiopathic MN and M-MN. The strong IF intensity of glomerular IgG1 and IgG2 in M-MN may provide a possible predictor for this condition.

Membranous nephropathy associated with renal cell carcinoma: Evidence against a role of renal tubular or tumor antibodies in pathogenesis

A patient with the nephrotic syndrome due to membranous nephropathy was found to have renal cell carcinoma. Since membranous nephropathy in patients with malignancies has been attributed to a tumor antigen-antibody complex form of glomerulonephritis, an attempt was made to implicate tumor antigens and/or renal tubular epithelial antigens in the pathogenesis of membranous nephropathy in our patient with renal cell carcinoma. Antibodies directed against tumor antigens and renal tubular epithelial antigens were sought in his serum and in eluates of his glomeruli; no such antibodies were found. The concurrence of the two renal lestons may have been fortuitous in this patient. However, their association temporally suggests that they were related, and our immunologic studies demonstrate that tumor antigen-antibody complexes are not invariably involved In the pathogenesis of malignancy-associated membranous nephropathy.