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Membranous nephropathy (MN) is a frequent cause of nephrotic syndrome in adults. In recent years, many progresses have been made, both in terms of diagnosis and treatment. For diagnosis, the discovery of new antigens and diseases that may be associated with MN led to the establishment of a new classification of MNs. In terms of treatment, many progresses have also been made with increasingly effective management, particularly with the help of immunosuppressive drugs. However, there are still cases of MN refractory to conventional treatments. Numerous molecules are being developed to manage these refractory MNs. Among them, Obinutuzumab, a type II anti-CD20, allows a more profound depletion of B cells compared to Rituximab classically used in clinical routine. To illustrate this point, we present the case of a patient suffering from MN with anti-THSD7A antibodies in whom a clinical and biological improvement was observed with obinutuzumab, after failure of conventional therapies.
La glomérulonéphrite extra-membraneuse (GEM) est une cause fréquente de syndrome néphrotique de l'adulte. Au cours des dernières années, de nombreux progrès ont été réalisés, tant au niveau diagnostic que thérapeutique. D'un point de vue diagnostic, la découverte de nouveaux antigènes et de pathologies qui peuvent leur être associées a permis d'établir une nouvelle classification des GEM. Au niveau des traitements, de nombreux progrès ont également été réalisés, avec une prise en charge de plus en plus efficace, notamment à l'aide de traitements immunosuppresseurs. Cependant, il persiste des cas de GEM réfractaires aux traitements classiques. De nombreuses molécules sont en cours de développement pour permettre la prise en charge de ces GEM réfractaires. Parmi celle-ci, on retrouve l'obinutuzumab, un anti-CD20 de type II permettant une meilleure déplétion des cellules B que le rituximab déjà utilisé dans cette indication. Pour illustrer ce propos, nous présentons le cas d'un patient souffrant d'une GEM à anticorps anti-thrombospondine (THSD7A) chez lequel une amélioration clinique et biologique a été observée sous obinutuzumab, après échec des traitements conventionnels.
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Anticorpos Monoclonais Humanizados , Glomerulonefrite Membranosa , Humanos , Masculino , Anticorpos Monoclonais Humanizados/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Glomerulonefrite Membranosa/diagnóstico , Imunossupressores/uso terapêutico , Trombospondinas/imunologiaRESUMO
Membranous nephropathy (MN) continues to be a leading cause of nephrotic syndrome in non-diabetic adults. As a unique subtype in the serology-based classification of MN, thrombospondin type 1 domain containing 7A (THSD7A)-associated MN has attracted increasing interest, because, unlike other autoantigens, THSD7A is also expressed in preclinical species, facilitating the study of its role in MN. A heterologous mouse model of THSD7A-associated MN was previously established using a proprietary in-house antibody that was unfortunately not available to the research community. Here, we developed a mouse model of THSD7A-associated MN by administering a commercially available antibody targeting the most N-terminal part of THSD7A. Our model was characterized by heavy proteinuria and pathological features of human MN without sex differences. Complement depletion with cobra venom factor only partially attenuated proteinuria and glomerular injury in this model, entailing that complement-independent pathomechanisms also contribute. Consistently, in vitro in primary podocytes, exposure to the anti-THSD7A antibody caused evident podocytopathic changes, including disruption of actin cytoskeleton integrity, podocyte hypermobility, oxidative stress, and apoptotic cell death. These signs of podocytopathy were preserved, albeit to a lesser extent, after complement inactivation, indicating autonomous podocyte injury. Furthermore, as the first FDA-approved treatment for primary MN, adrenocorticotropic hormone therapy with repository corticotropin injection (Purified Cortrophin Gel®) appeared to be beneficial and significantly attenuated proteinuria and glomerular injury, suggesting that this model may be useful for developing novel treatments or understanding the pathogenesis of MN. Collectively, our model, based on the use of a commercially available anti-THSD7A antibody, will be an important tool for MN research.
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The most characteristic feature of membranous nephropathy (MN) is the presence of subepithelial electron dense deposits and the consequential thickening of the glomerular basement membrane. There have been great advances in the understanding of the destiny of immune complexes in MN by the benefit of experimental models represented by Heymann nephritis. Subepithelial immune complexes are formed in situ by autoantibodies targeting native autoantigens or exogenous planted antigens such as the phospholipase A2 receptor (PLA2R) and cationic BSA respectively. The nascent immune complexes would not be pathogenic until they develop into immune deposits. Podocytes are the major source of autoantigens in idiopathic membranous nephropathy. They also participate in the modulation and removal of the immune complexes to a large extent. The balance between deposition and clearance is regulated by a wide range of factors such as the composition and physicochemical properties of the immune complexes and the complement system. Complement components such as C3 and C1q have been reported to be precipitated with the deposits whereas a complement regulatory protein CR1 expressed by podocytes is involved in the phagocytosis of immune complexes by podocytes. Podocytes regulate the dynamic change of immune complexes which is disturbed in membranous nephropathy. To elucidate the precise fate of the immune complexes is essential for developing more rational and novel therapies for membranous nephropathy.
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Complexo Antígeno-Anticorpo , Glomerulonefrite Membranosa , Podócitos , Glomerulonefrite Membranosa/imunologia , Humanos , Complexo Antígeno-Anticorpo/imunologia , Complexo Antígeno-Anticorpo/metabolismo , Podócitos/imunologia , Podócitos/metabolismo , Animais , Autoanticorpos/imunologia , Autoantígenos/imunologia , Receptores da Fosfolipase A2/imunologiaRESUMO
Objective: Serum-specific antibodies as a non-invasive means to effectively diagnose idiopathic membranous nephropathy and assess clinicopathology. Methods: Immunofluorescence of anti-PLA2R and THSD7A antibodies and kidney tissue PLA2R, THSD7A and IgG4 expression in IMN and non-IMN (2020-2021) was detected to assess the efficacy of diagnosing IMN. IMN patients were divided into two groups, anti-PLA2R antibody positive (161 cases) and negative (26 cases), and two groups, kidney tissue PLA2R (40 cases) and PLA2R+THSD7A (6 cases), to compare the clinical and pathological features, and to carry out a prognostic analysis of THSD7A-positive patients, with a focus on correlation with malignancy. Results: The positive rate of anti-PLA2R antibodies was significantly higher in IMN (P<0.05); anti-PLA2R antibodies, kidney tissue PLA2R and IgG4 and THSD7A had some diagnostic value. Anti-PLA2R antibodies correlated with proteinuria levels in IMN patients, and their levels were negatively correlated with blood albumin (r=-0.146, P=0.042); correlated with pathological stage and C3 and IgG4 immunodeposition; there was no significant difference in clinical pathology between kidney tissue THSD7A+PLA2R positive compared to kidney tissue PLA2R positive patients, but the probability of achieving complete remission was low and time longer, and no malignancy events were detected during follow-up. Conclusion: Anti-PLA2R antibodies, kidney tissue PLA2R, THSD7A and IgG4 have high diagnostic efficacy for IMN; anti-PLA2R antibodies can be used as diagnostic markers to assist in the assessment of clinical and pathological features; co-expression of kidney tissue PLA2R and THSD7A is not significantly different from kidney tissue PLA2R in assessing the clinical features, pathological manifestations and prognosis, but requires long-term. However, long-term follow-up is needed to monitor the potential risk, and a larger multicentre study with long-term follow-up is expected to be conducted to comprehensively assess IMN characteristics.
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Purpose: In recent years, the incidence of malignancy patients with membranous nephropathy (MN) has gradually increased, but the clinical and pathological characteristics of these patients are still unclear. Our study aims at elucidating the clinical and pathological characteristics of malignancy patients with MN, especially the expression patterns of MN-specific antigens in both kidney and tumor tissue. Patients and Methods: A retrospective analysis was performed to summarize the clinical and pathological data of MN patients with malignancy at Beijing Anzhen Hospital from January 1, 2012, to December 31, 2022, followed by a thorough review of relevant literature published between May 1, 2000 to May 1, 2023 and case aggregation. Results: 19 patients in our center's MN cohort and 21 patients from literature review were diagnosed with malignancy either before or after being diagnosed with MN. Among them, 16 (40.0%) and 17 (42.5%) patients tested PLA2R-only and THSD7A-only positive in renal tissue, respectively. And 16 of 26 patients showed similar staining in tumor and kidney tissues. Compared to the idiopathic membranous nephropathy (IMN) patients at our center, patients with malignancy were older, had a lower estimated glomerular filtration rate, and had a lower rate of partial or complete response to treatment. Renal tissue from MN patients with concomitant malignancy was less frequently PLA2R-positive, more frequently THSD7A-positive, and more often glomerular IgG subclass IgG2 (P = 0.033) but less frequently IgG4 (P < 0.001). Conclusion: The clinical and pathological characteristics of MN patients with concomitant malignancy are different from those of IMN patients. Active screening for malignancy should be performed in non-PLA2R-positive elderly MN patients with a poor therapeutic response. Staining for MN target antigens in kidney and tumor tissues may be inconsistent, and the role of MN target antigens needs to be further explored.
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Membranous nephropathy (MN) is a glomerular disease mediated by autoimmune complex deposition, with approximately 30% of cases attributed to secondary causes. Among them, malignant tumors are a significant cause of secondary MN. Recent advancements in the identification of MN-specific antigens, such as THSD7A and NELL-1, suggest a potential association with malignant tumors, yet definitive proof of this relationship remains elusive. Therefore, this article aims to review the distribution of MN-specific antigens in patients with MN caused by malignant tumors and the possible role of these antigens in the pathogenesis of the disease.
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Membranous nephropathy (MN) occurs predominantly in middle-aged and elderly individuals and ranks among the most prevalent etiologies of elderly nephrotic syndrome. As an autoimmune glomerular disorder characterized by glomerular basement membrane thickening and immune complex deposition, conventional MN animal models, including the Heymann nephritis rat model and the c-BSA mouse model, have laid a foundation for MN pathogenesis research. However, differences in target antigens between rodents and humans have impeded this work. In recent years, researchers have created antigen-specific MN animal models, primarily centered on PLA2R1 and THSD7A, employing diverse techniques that provide innovative in vivo research platforms for MN. Furthermore, significant advancements have been made in the development of in vitro podocyte models relevant to MN. This review compiles recent antigen-specific MN animal models and podocyte models, elucidates their immune responses and pathological characteristics, and offers insights into the future of MN experimental model development. Our aim is to provide a comprehensive resource for research into the pathogenesis of MN and the development of targeted therapies for older patients with MN to prolong lifespan and improve quality of life.
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Glomerulonefrite Membranosa , Podócitos , Idoso , Camundongos , Humanos , Ratos , Animais , Pessoa de Meia-Idade , Glomerulonefrite Membranosa/etiologia , Glomerulonefrite Membranosa/patologia , Qualidade de Vida , Podócitos/patologia , Modelos Animais de Doenças , Receptores da Fosfolipase A2RESUMO
BACKGROUND: Membranous nephropathy (MN) is an immunocomplex glomerular disease, which is the most common cause of nephrotic syndrome in adults. Numerous studies have established that autoantibodies against the target podocyte autoantigens, including the thrombospondin type 1 domain containing 7A (THSD7A), play a leading role in the development of idiopathic MN. AIM: To evaluate the prevalence of anti-THSD7A autoantibodies (anti-THSD7A AB) in a group of Russian patients with MN. MATERIALS AND METHODS: Serum titers of anti-THSD7A AB were tested in 61 patients with biopsy-proven MN and 12 healthy controls. RESULTS: The prevalence of anti-THSD7A AB was not differing significantly in patients with MN and in the control group (110.9 [71.63; 210.62] and 159.25 [125.64; 231.97] pg/ml, respectively; p=0.111). When comparing subgroups of anti-PLA2R-negative patients and patients who did not receive immunosuppressive therapy with the control group, there were also no statistically significant differences in the Anti-THSD7A AB levels (p>0.05). In the MN group, 1 (1.6%) patient was anti-THSD7A-positive: a 60-year-old man with anti-PLA2R-negative MN and the presence of hormonally inactive adenomas of both adrenal glands and colon polyps (villous adenoma with focal moderate dysplasia, tubulo-villous and tubular adenoma with focal moderate severe dysplasia). CONCLUSION: THSD7-associated MN is a rare variant of MN and is usually detected in PLA2R-negative patients. Screening for malignancies in THSD7A-positive MN patients is proposed.
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Glomerulonefrite Membranosa , Podócitos , Adulto , Masculino , Humanos , Pessoa de Meia-Idade , Trombospondinas , Relevância Clínica , Podócitos/patologia , AutoanticorposRESUMO
Angiogenesis promotes neurological recovery after acute ischemic stroke (AIS), and microRNAs play crucial roles in cerebral angiogenesis. This study found that Homo sapiens-microRNA-1303(miR-1303) was reduced in blood specimens of AIS patients and human umbilical vein endothelial cells after suffering from oxygen-glucose deprivation/reperfusion. The experiment detected the effect of miR-1303 on angiogenesis by wound healing assay, tube formation assay, and transwell assay. Down-regulation of miRNA-1303 promotes angiogenesis in vitro experiments, while miR-1303 over-expression reverses this effect. Based on bioinformatics analyses and dual-luciferase reporter assay, the thrombospondin type 1 domain containing 7A (THSD7A) was investigated and further validated as the downstream gene of miR-1303. Furthermore, the knockdown of miR-1303 decreased the protein translation and mRNA transcript levels of THSD7A. Our results reveal a novel miR-1303/THSD7A pathway for angiogenesis and further imply that miR-1303 can be a promising biomarker and therapeutic target for AIS.
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The biological role and prognostic value of thrombospondin domain-containing 7A (THSD7A) in gastric cancer remain unclear. Our purpose was to determine the molecular mechanisms underlying the functioning of THSD7A and its prognostic value in gastric cancer. Gastric cancer-associated single cell and bulk RNA sequencing data obtained from two databases, were analyzed. We used bulk RNA sequencing to examine the differential expression of THSD7A in gastric cancer and normal gastric tissues and explored the relationship between THSD7A expression and clinicopathological characteristics. Kaplan-Meier survival and Cox analyses revealed the prognostic value of THSD7A. Gene set enrichment and immune infiltration analyses were used to determine the cancer-promoting mechanisms of THSD7A and its effect on the immune microenvironment. We explored the relationship between THSD7A expression and sensitivity of anti-tumor drugs and immune checkpoint levels. Biological functions of THSD7A were validated at single-cell and in vitro levels. THSD7A expression was significantly increased in gastric cancer samples. High THSD7A expression was associated with poor clinical phenotypes and prognoses. Cox analysis showed that THSD7A was an independent risk factor for patients with gastric cancer. Enrichment analysis suggested that epithelial-mesenchymal transition and inflammatory responses may be potential pro-cancer mechanisms of THSD7A. Upregulation of THSD7A promoted infiltration by M2 macrophages and regulatory T cells. High THSD7A expression suppressed the sensitivity of patients with gastric cancer to drugs, such as 5-fluorouracil, bleomycin, and cisplatin, and upregulated immune checkpoints, such as HAVCR2, PDCD1LG2, TIGIT, and CTLA4. At the single cell level, THSD7A was an endothelial cell-associated gene and endothelial cells overexpressing THSD7A showed unique pro-oncogenic effects. In vitro experiments confirmed that THSD7A was overexpressed in gastric cancer samples and cells, and that knocking out THSD7A significantly inhibited gastric cancer cell proliferation and invasion. THSD7A overexpression may be a unique prognostic marker and therapeutic target in gastric cancer. Therefore, our study provides a new perspective on the precise treatment of gastric cancer.
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Células Endoteliais , Neoplasias Gástricas , Humanos , Prognóstico , Células Endoteliais/metabolismo , Neoplasias Gástricas/genética , Trombospondinas/genética , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Primary membranous nephropathy (PMN) frequently causes nephrotic syndrome and declining kidney function. Disease progression is likely modulated by patient-specific and therapy-associated factors awaiting characterization. These cofactors may facilitate identification of risk groups and could result in more individualized therapy recommendations. METHODS: In this single-center retrospective observational study, we analyze the effect of patient-specific and therapy-associated covariates on proteinuria, hypoalbuminemia, and estimated glomerular filtration rate (eGFR) in 74 patients diagnosed with antibody positive PMN and nephrotic-range proteinuria (urine-protein-creatinine-ratio [UPCR] ≥ 3.5 g/g), treated at the University of Freiburg Medical Center between January 2000 - November 2022. The primary endpoint was defined as time to proteinuria / serum-albumin response (UPCR ≤ 0.5 g/g or serum-albumin ≥ 3.5 g/dl), the secondary endpoint as time to permanent eGFR decline (≥ 40% relative to baseline). RESULTS: The primary endpoint was reached after 167 days. The secondary endpoint was reached after 2413 days. Multivariate time-to-event analyses showed significantly faster proteinuria / serum-albumin response for higher serum-albumin levels (HR 2.7 [95% CI: 1.5 - 4.8]) and cyclophosphamide treatment (HR 3.6 [95% CI: 1.3 - 10.3]). eGFR decline was significantly faster in subjects with old age at baseline (HR 1.04 [95% CI: 1 - 1.1]). CONCLUSION: High serum-albumin levels, and treatment with cyclophosphamide are associated with faster proteinuria reduction and/or serum-albumin normalization. Old age constitutes a risk factor for eGFR decline in subjects with PMN.
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Glomerulonefrite Membranosa , Síndrome Nefrótica , Humanos , Glomerulonefrite Membranosa/diagnóstico , Síndrome Nefrótica/diagnóstico , Ciclofosfamida/uso terapêutico , Proteinúria/complicações , Albumina SéricaRESUMO
Lung cancer is the leading cause of cancer-related deaths in the western world, with squamous cell carcinoma being one of the most common histological subtypes. Prognostic and predictive markers are still largely missing for squamous cell carcinoma of the lung (LSCC). Several studies indicate that THSD7A might at least play a role in the prognosis of different tumors. FAK seems to play an important role in lung cancer and is discussed as a potential therapeutic target. In addition, there is evidence that FAK-dependent signaling pathways might be affected by THSD7A. For that reason, we investigated the role of THSD7A as a potential tumor marker in LSCC and whether THSD7A expression has an impact on the expression level of FAK. A total of 101 LSCCs were analyzed by immunohistochemistry using tissue microarrays. THSD7A positivity was associated with poor overall survival in female patients and showed a relation to high FAK expression in this subgroup. To our knowledge, we are the first to report these correlations in lung cancer. The results might be proof of the assumed activation of FAK-dependent signaling pathways by THSD7A and that as a membrane-associated protein, THSD7A might serve as a putative therapeutic target in LSCC.
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Carcinoma de Células Escamosas , Neoplasias Laríngeas , Neoplasias Pulmonares , Humanos , Feminino , Carcinoma de Células Escamosas/patologia , Pulmão/patologia , Neoplasias Pulmonares/metabolismo , Imuno-Histoquímica , Transdução de Sinais , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias Laríngeas/patologia , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismoRESUMO
Prostate cancer is one of the most common malignancies worldwide, showing a wide range of clinical behaviors. Therefore, several treatment options arise out of the diagnosis "prostate cancer". For this reason, it is desirable to find novel prognostic and predictive markers. In former studies, we showed that THSD7A expression is associated with unfavorable prognostic parameters in prostate cancer and is linked to a high expression of focal adhesion kinase (FAK). Recently, scavenger receptor class A member 5 (SCARA5) was reported to be the downstream gene of THSD7A in esophageal squamous cell carcinoma. SCARA5 is believed to play an important role in the development and progression of several different tumor types. Most studies describe SCARA5 as a tumor suppressor. There is also evidence that SCARA 5 interacts with FAK. To examine the role of SCARA5 as a potential biomarker in prostate cancer, a total of 461 prostate cancers were analyzed via immunohistochemistry using tissue microarrays. Furthermore, we compared the expression level of SCARA5 with our previously collected data on THSD7A and FAK. High SCARA5 expression was associated with advanced tumor stage (p < 0.001), positive nodal status (p < 0.001) and high Gleason-score (p < 0.001). At least, strongly SCARA5-positive cancers were associated with THSD7A-positivity. There was no significant association between SCARA5 expression level and FAK expression level. To our knowledge, we are the first to investigate the role of SCARA5 in prostate cancer and we demonstrated that SCARA5 might be a potential biomarker in prostate cancer.
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Síndrome de Fanconi , Glomerulonefrite Membranosa , Neoplasias Pulmonares , Humanos , Autoanticorpos , Células Epiteliais/metabolismo , Síndrome de Fanconi/diagnóstico , Glomerulonefrite Membranosa/diagnóstico , Nefrologistas , Receptores da Fosfolipase A2/metabolismo , Trombospondinas/metabolismoRESUMO
Membranous nephropathy (MN) is one of the most common causes of non-diabetic nephrotic syndrome in adults. About 80% of cases are renal limited (primary MN) and 20% are associated with other systemic diseases or exposures (secondary MN). Autoimmune reaction is the main pathogenic factor of MN, and the discovery of autoantigens including the phospholipase A2 receptor and thrombospondin type-1 domain-containing protein 7A has led to new insights into the pathogenesis, they can induce humoral immune responses led by IgG4 makes them suitable for the diagnosis and monitoring of MN. In addition, complement activation, genetic susceptibility genes and environmental pollution are also involved in MN immune response. In clinical practice, due to the spontaneous remission of MN, the combination of supportive therapy and pharmacological treatment is widely used. Immunosuppressive drugs are the cornerstone of MN treatment, and the dangers and benefits of this approach vary from person to person. In summary, this review provides a more comprehensive review of the immune pathogenesis, interventions and unresolved issues of MN in the hope of providing some new ideas for clinical and scientific researchers in the treatment of MN.
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Glomerulonefrite Membranosa , Síndrome Nefrótica , Adulto , Humanos , Glomerulonefrite Membranosa/tratamento farmacológico , Trombospondinas/metabolismo , Receptores da Fosfolipase A2/metabolismo , Rim/patologia , Síndrome Nefrótica/complicações , AutoanticorposRESUMO
Idiopathic membranous nephropathy also known as primary membranous nephropathy (PMN) is a common cause of nephrotic syndrome often seen in nondiabetic adults worldwide, rising as high as 40% in adults over the age of 60. Most PMN is mediated by antibodies to the M-type phospholipase A2 receptor (anti-PLA2R) in nearly 70%-80% of individuals. Thrombospondin type 1 domain-containing 7A (THSD7A) accounts for 1%-5% of individuals with PMN. In these individuals, malignancies have a varying incidence of 6%-25%. We present a case of idiopathic membranous nephropathy with anti-PLA2R negative and THSD7A positive with an underlying metastatic neuroendocrine carcinoma. Our goal is to highlight the importance of cancer screening in individuals with THSD7A-positive PMN. In addition, although nonspecific, a negative anion gap may be an indicator of an underlying malignancy.
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Prostate cancer is one of the most common malignancies, and there are a wide range of treatment options after diagnosis. Most prostate cancers behave in an indolent manner. However, a given sub-group has been shown to exhibit aggressive behavior; therefore, it is desirable to find novel prognostic and predictive (molecular) markers. THSD7A expression is significantly associated with unfavorable prognostic parameters in prostate cancer. FAK is overexpressed in several tumor types and is believed to play a role in tumor progression and metastasis. Furthermore, there is evidence that THSD7A might affect FAK-dependent signaling pathways. To examine whether THSD7A expression has an impact on the expression level of FAK in its unphosphorylated form, a total of 461 prostate cancers were analyzed by immunohistochemistry using tissue microarrays. THSD7A positivity and low FAK expression were associated with adverse pathological features. THSD7A positivity was significantly associated with high FAK expression. To our knowledge we are the first to show that THSD7A positivity is associated with high FAK expression in prostate cancer. This might be proof of the actual involvement of THSD7A in FAK-dependent signaling pathways. This is of special importance because THSD7A might also serve as a putative therapeutic target in cancer therapy.
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Membranous nephropathy (MN) is a common cause of nephrotic syndrome after kidney transplantation (KT); however, scarce is known regarding post-KT thrombospondin type-1 domain-containing 7A (THSD7A)-positive MN. Herein, we report on a 72-year-old woman with end-stage kidney disease due to chronic interstitial nephritis (1996). In February 2020, she received a second deceased-donor KT, achieving optimal kidney function but presenting early post-KT proteinuria, reaching up to 1800mg/24h six months after transplantation, controlled with renin-angiotensin-aldosterone system (RAAS) blockade. In July 2021, a kidney allograft biopsy revealed features consistent with MN. Immunohistochemical stains showed diffuse and granular THSD7A and C4d deposition in glomerular capillary walls and negative PLA2R and IgG4 staining. No anti-THSD7A antibodies were detected in the serum. The pre-implantation biopsy showed no MN-associated lesions and negative THSD7A staining. Secondary triggers such as malignancy were discarded. The present report illustrates a THSD7A-positive MN in a KT recipient. Despite lacking native kidney biopsy and early presentation, a recurrent MN seemed unprovable due to documented native kidney disease and a long time span between native kidney disease and MN diagnosis. We, therefore, presumed primary de novo disease. Two years after KT, kidney function remains stable, and the patient has reached complete remission of proteinuria.
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Glomerulonefrite Membranosa , Transplante de Rim , Feminino , Humanos , Idoso , Glomerulonefrite Membranosa/diagnóstico , Transplante de Rim/efeitos adversos , Trombospondinas , Glomérulos Renais , ProteinúriaRESUMO
Recently, the association between membranous nephropathy (MN) and malignancy has been recognized in about 30% of epidermal growth factor-like 1 (NELL-1) positive cases. However, the mechanism of association with MN and malignancy remains under search. In this report, we present a unique case of MN with positive staining for both thrombospondin type-1 domain-containing 7A (THSD7A) and NELL-1. An 80-year-old Japanese woman with nephrotic syndrome (NS) was diagnosed as an immunoglobulin (Ig)G1 subclass predominant secondary MN with weakly positive for THSD7A staining. Then, advanced cancer in the sigmoid colon was found during screening tests for malignancy. After the removal of colon carcinoma, complete remission was achieved at 28 weeks follow-up after operation. Five years later, she remained in remission and passed without recurrence. Thereafter, we examined again newly reported NELL-1 in renal biopsy specimens and found very strong staining along the glomerular capillary walls. Moreover, in resected tumor tissues, NELL-1 was strongly positive at the basal side of adenocarcinoma cells, but THSD7A staining was negative. This case report provides clinical details and highlights the utility of autoantibodies, especially NELL-1, in the diagnosis and treatment of secondary MN with malignancy.
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Background: Idiopathic membranous nephropathy (IMN) is the most common pathological type in adults with nephrotic syndrome. Many target antigens have been discovered. However, dual antigen-positive IMN patients are very rare, with only a few such cases being briefly described in various studies. There is no specific study on the clinicopathological and prognostic characteristics of dual antigen-positive IMN patients, and the disease characteristics of such patients remain unclear. Methods: Immunohistochemical staining of PLA2R, THSD7A, and NELL-1 was conducted on kidney tissue samples obtained from patients diagnosed with IMN. Simultaneously, the presence of corresponding serum antibodies was determined. Patients exhibiting positivity for dual antigens were included in the study, identified either through tissue staining or serum antibody detection. We retrospectively collected their clinical, pathological, and follow-up data and measured their serum antibody levels at multiple time points. Additionally, the same type of dual antigen-positive IMN cases reported in the literature were reviewed to extract clinical, pathological, and prognostic information. We compared the data for all of the above dual antigen-positive and PLA2R single-positive IMN cases at our center. Results: We identified 6 IMN patients with dual antigen positivity at our center, approximately 0.7% of whole MN series; the previous literature reports 43 IMN patients with dual antigen positivity, the proportion ranged from 0.2% to 2.8%. The IgG1 positivity rate in the renal tissue of the dual antigen-positive patients at our center was significantly lower than that of dual antigen-positive patients previously reported (16.7% vs. 100.0%, p=0.015), but there was no significant difference in clinical or prognostic aspects. Patients with dual antigen positivity reported at our center and in the literature were combined and compared with PLA2R single-positive IMN reported at our center. Compared with PLA2R single-positive IMN patients, dual antigen-positive IMN patients had a higher renal tissue IgG1 positivity rate (58.3% vs. 22.3%, p=0.016), and the time required to achieve remission was longer [13.5 (3.3,35.0) vs. 3.0 (1.0,8.0), p=0.052]. Overall, The changes in urine protein were consistent with the changes in serum PLA2R antibody levels in dual antigen-positive IMN patients. Conclusions: For patients with primary membranous nephropathy who did not attain remission following prolonged treatment, multiple target antigen staining should still be actively performed, even with positivity for the PLA2R target antigen.