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Case Report: THSD7A-Positive Membranous Nephropathy Caused by Tislelizumab in a Lung Cancer Patient.

ABSTRACT: Immune checkpoint inhibitors (ICIs) became the standard treatment for many different kinds of cancers and can result in a variety of immune-related adverse events (irAEs). IrAEs of kidney are uncommon and consists of different pathology types. Among the different types, membranous nephropathy (MN) is rare and have not been well-described. Since MN can also be associated with malignancies, differential diagnosis in patients receiving ICIs who develop MN can be very difficult. We present the case of a 74-year-old man with metastatic non-small cell lung cancer who developed MN after ICIs therapy. The patient tested positive for thrombospondin type-1 domain-containing 7A antibodies (THSD7A) when diagnosed with MN. Supplementary examinations revealed the predisposing antigen in the primary tumor and present of the antibody after immunotherapy, which corresponded to the patient's clinical course of nephropathy. Treatment consisting of systemic glucocorticoids and rituximab resulted in a good clinical response, and the THSD7A antibodies were no longer detected. In this case, we first discuss the potential mechanism of immunotherapy related MN, in which the activation of humoral immunity may play an important role.

SUBMITTER: Chen M

PROVIDER: S-EPMC8141750 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Characterization of THSD7A-antibodies not binding to glomerular THSD7A in a patient with diabetes mellitus but no membranous nephropathy.

Project description:Membranous nephropathy (MN) is an autoimmune disease caused by autoantibodies against the podocyte antigens phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain containing protein 7A (THSD7A) in 80% and 2-3% of patients, respectively. THSD7A antibodies are considered to be pathogenic and highly specific for MN patients. Using an indirect immunofluorescence test (IIFT) we detected THSD7A-antibodies (titre 1:10) in the serum of a patient with high proteinuria who, however, in the kidney biopsy was diagnosed with diabetic nephropathy and MN was excluded as a possible cause of proteinuria. Different immunofluorescence assays and Western blot techniques using recombinant THSD7A (rTHSD7A) or THSD7A from different human tissues revealed that the circulating THSD7A-autoantibodies were only of the IgG3 subclass. The patient serum reacted exclusively with rTHSD7A and only when the antigen was present in reducing Western blot conditions, or on formaldehyde-fixed cells for the IIFT. Our findings show for the first time the existence of circulating THSD7A-antibodies recognizing denatured/reduced rTHSD7A, which do not react with glomerular THSD7A in vivo and are thus presumptively non-pathogenic. As a consequence, kidney biopsy or Western blot analyses of THSD7A under non-reducing conditions should be performed to confirm the diagnosis of THSD7A-associated MN, especially in cases with low THSD7A-antibody levels in the IIFT.

| S-EPMC8355258 | biostudies-literature

The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy.

Project description:Background Thrombospondin type 1 domain-containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown.Methods We performed an in silico analysis of the THSD7A multidomain structure, expressed the folded domains in HEK293 cells, and tested for domain reactivity with 31 serum samples from patients with THSD7A-associated MN using Western and native blotting. Immunogenicity of the antigen domains was further investigated by cDNA immunization of rabbits and mice.Results We characterized the extracellular topology of THSD7A as a tandem string of 21 thrombospondin type 1 domains. Overall, 28 serum samples (90%) recognized multiple epitope domains along the molecule. Detailed epitope mapping revealed that the complex consisting of the first and second N-terminal domains (amino acids 48-192) was recognized by 27 of 31 patient serum samples (87%). Serum recognizing one or two epitope domains showed lower anti-THSD7A antibody levels than serum recognizing three or more epitope domains. During follow-up, a loss of epitope recognition was observed in seven of 16 patients, and it was accompanied by decreasing antibody levels and remission of proteinuria. In four of 16 patients, epitope recognition patterns changed during follow-up. Notably, immunization experiments in rabbits and mice revealed that induced antibodies, like patient autoantibodies, preferentially bound to the most N-terminal domains of THSD7A.Conclusions Our data show that the immune response in THSD7A-associated MN is polyreactive and that autoantibodies predominantly target the most N-terminal part of THSD7A.

| S-EPMC5967759 | biostudies-literature

Case Report: Membranous Nephropathy Secondary to Cobalamin C Disease.

Project description:BackgroundMutation of MMACHC causes inherited cobalamin C disease with methylmalonic academia (MMA) and homocysteinemia. Renal complications may also be present in patients with this deficiency. However, membranous nephropathy secondary to cobalamin C disease has not been reported to date.Case presentationWe encountered a 17-year-old female patient with a trans-compound mutation of MMACHC who presented with membranous nephropathy, MMA, homocysteinemia, and hyperuricemia. The mutations of c.80A>G (chr1:45966084) and c.482G>A (chr1:45974520) (predicting p.Gln27Arg and p.Arg161Gln missense changes at the amino acid level) had been inherited from her father and mother, respectively. Hydroxocobalamin, betaine, and L-carnitine were administered. The patient achieved complete remission of the membranous nephropathy and resolution of the MMA, homocysteinemia, and hyperuricemia.ConclusionMembranous nephropathy secondary to cobalamin C disease is reversible with timely intervention.

| S-EPMC8814342 | biostudies-literature

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

Project description: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.

| S-EPMC4837089 | biostudies-literature

Membranous nephropathy with acquired factor V inhibitor: a case report.

Project description:BackgroundMembranous nephropathy is one of the most common causes of nephrotic syndrome in adults. In contrast, acquired factor V inhibitor is a rare bleeding disorder.Case presentationA 62-year-old Asian man with a history of cerebral hemorrhage, purpura, eosinophilia and hyper immunoglobulin E syndrome developed proteinuria. The bleeding disorder was diagnosed with acquired factor V inhibitors. A renal biopsy revealed that he suffered from membranous nephropathy with glomerular endothelial damage which is reported to be involved in another factor disorder. After the steroid administration, the coagulation test and proteinuria were improved.ConclusionsThe presence of factor V inhibitors may have been involved in the development of membranous nephropathy.

| S-EPMC3892019 | biostudies-literature

Membranous Nephropathy With Monoclonal IgM Lambda Deposits in a Patient With IgM Monoclonal Gammopathy: A Case Report.

Project description:We report a case of membranous nephropathy with monoclonal immunoglobulin (Ig)M lambda deposits in a patient with IgM monoclonal gammopathy, in whom histological changes were observed on repeat renal biopsy. A 72-year-old Japanese woman was referred to our hospital because of massive proteinuria. A prominent increase in monoclonal IgM lambda level was identified, and she was diagnosed as having IgM monoclonal gammopathy of undetermined significance. Renal biopsy showed glomerular subepithelial electron-dense deposits that were found to be granular deposits of IgM lambda but not kappa or IgG by immunofluorescence staining, resulting in a diagnosis of membranous nephropathy with monoclonal IgM deposits. The second biopsy, which was performed 2 years later because of exacerbation of her nephrotic syndrome, demonstrated less immunofluorescence staining of IgM, and dominant IgG2 deposition without light chain restriction. Interestingly, immunostaining for thrombospondin-type-1-domain-containing-7A was positive in both renal biopsy tissues, although the second biopsy showed clearly stronger immunoreactivity. The effect of steroid therapy was limited; however, rituximab treatment improved both the hematological and renal abnormalities. Solitary deposition of IgM in membranous nephropathy is a quite rare condition. To our knowledge, this is the first case of monoclonal gammopathy of renal significance presenting as membranous nephropathy with monoclonal IgM deposits, in which chronological immunohistochemical changes were observed and rituximab therapy was effective.

| S-EPMC8185035 | biostudies-literature

A Case Report of Cronkhite-Canada Syndrome Complicated by Membranous Nephropathy.

Project description:Cronkhite-Canada syndrome (CCS) is a very rare disorder with less than 500 reported cases. It is characterized by extensive gastrointestinal polyposis and ectodermal anomalies including alopecia, cutaneous hyperpigmentation, and onychodystrophy. Only 3 cases of associated kidney disease (membranous nephropathy [MN]) have been reported. A 71-year-old male with CCS was referred for further evaluation of proteinuria. The patient initially presented with abdominal discomfort, weight loss, dysgeusia, skin hyperpigmentation, alopecia, and dystrophic nails. Endoscopic evaluation showed widespread gastrointestinal nodular inflammation and polyps. Histopathology was consistent with CCS. Initial treatment was with prednisone, azathioprine, and ranitidine. He had moderate clinical improvement but developed nephrotic-range proteinuria. Renal biopsy showed MN, and cyclosporine was started. The patient had significant improvement in his CCS manifestations; however, his proteinuria and renal function worsened. Rituximab was added to his regimen of cyclosporine and azathioprine, which resulted in remission of his MN, marked improvement in his polyposis, and near resolution of his cutaneous symptoms. This case represents a unique presentation of CCS associated with MN treated with rituximab. The excellent clinical response observed for both CCS and MN advocates consideration of this treatment, especially for refractory disease.

| S-EPMC6323406 | biostudies-other

Case Report: Life-threatening pancytopenia with tislelizumab followed by cerebral infarction in a patient with lung adenocarcinoma.

Project description:Immune checkpoint inhibitors (ICIs) are an integral antitumor therapy for many malignancies. Most patients show very good tolerability to ICIs; however, serious immune-related adverse events (irAEs) with ICIs have been well documented and prevent some patients from continuing ICIs or even become the direct cause of patient death. Cytopenia is a rare irAE but can be life-threatening. Here, we present the case of a 66-year-old male patient with metastatic lung adenocarcinoma who received two doses of chemotherapy + PD-1 antibody tislelizumab and developed pancytopenia after each dose. Although the first episode of pancytopenia resolved with a treatment regimen of granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), and red blood cell and platelet transfusion, the second episode showed extreme resistance to these treatments and improved only after the administration of steroids. His second pancytopenia episode resolved after a long course of treatment with methylprednisolone, G-CSF, TPO, hetrombopag and multiple red blood cell and platelet transfusions. However, he suffered a cerebral infarction when his platelet count was in the normal range and gradually recovered 1 week later. This case highlights the importance of the early recognition and management of hematological irAEs.

| S-EPMC10409480 | biostudies-literature

Meta-Analysis of the Diagnostic Efficiency of THSD7A-AB for the Diagnosis of Idiopathic Membranous Nephropathy.

Project description:Thrombospondin type I domain-containing 7A (THSD7A), is a specific autoantigen of adult idiopathic membranous nephropathy (IMN), whose circulating antibody (THSD7A-AB) represents a promising biomarker for diagnosis of IMN. The objective of this meta-analysis is to investigate the diagnostic efficiency of THSD7A-AB for IMN. After rigorous data extraction, quality assessment, and data analysis, 10 articles (4545 patients) are included. For IMN, the summary sensitivity is 4% (2-7%), and the specificity is 99% (98-100%). The summary positive likelihood ratio (PLR) and negative likelihood ratio (NLR) are 5.40 (2.40-11.90) and 0.97 (0.95-0.99), respectively. The diagnostic odds ratio (DOR) is 6.00 (2.00-12.00). The area under the summary receiver operating characteristic curve (AUC) is 0.78 (0.74-0.81). For M-type phospholipase A2 receptor (PLA2R)-negative IMN, the summary sensitivity is 8% (6-10%), specificity is 100% (99-100%). The summary PLR and NLR are 15.80 (5.70-44.00) and 0.93 (0.91-0.95), respectively. The DOR is 17.00 (6.00-48.00). The AUC is 0.99 (0.98-1.00). THSD7A-AB has higher diagnostic value in PLA2R-negative patients than in IMN patients. These results suggest that THSD7A-AB could possibly be applied as an auxiliary non-invasive diagnostic method for PLA2R-negative IMN.

| S-EPMC7607246 | biostudies-literature

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

Project description: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.

| S-EPMC8258946 | biostudies-literature

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