Membranous Nephropathy as a Paraneoplastic Syndrome in Cancer of Unknown Primary.

BACKGROUND/AIM: Membranous nephropathy (MN) is a nephrotic syndrome with both idiopathic and secondary etiologies. The mechanism of cancer-associated MN is presumed to involve the immunological production of antibodies against a tumor antigen, although little is known about the detailed mechanism. Lung cancer is a major neoplasm associated with cancer-associated MN. However, the simultaneous occurrence of secondary MN in patients with cancer of unknown primary (CUP) remains unclear. CASE REPORT: Here, we present a case of secondary MN in a 72-year-old female as a paraneoplastic syndrome in CUP. Thoracic radiotherapy up to a total of 60 Gy was initially performed on the right subclavian and mediastinal lymph nodes. Computed tomography revealed marked shrinking of these lymph nodes, and the secondary MN also improved without any symptoms. CONCLUSION: The presence of proteinuria in patients with CUP suggests the possibility of secondary MN as a rare differential diagnosis.

Syphilis as the great mimicker: A case of full-house pattern membranous nephropathy.

Syphilis is a known cause of membranous nephropathy. We describe a case of a patient presenting with nephrotic syndrome whose renal biopsy demonstrated a 'full house' immunohistochemical pattern with positive IgG, IgM, C1q, IgA, C3c, and C4d staining. He was treated with immunosuppressive agents for minimal change nephropathy and subsequently class V lupus nephritis, before syphilis infection was confirmed. Following treatment with a single dose of intramuscular benzathine penicillin there was complete and rapid resolution of nephrotic syndrome. With progressive rising incidence in the western world, syphilis is an important and under-recognised differential diagnosis in cases of nephrotic syndrome.

Chronic Graft-versus-host Disease-associated Membranous Nephropathy Following Bone Marrow Transplantation, Successfully Treated with Rituximab.

A 67-year-old woman who had undergone bone marrow transplantation 2 years previously for acute myeloid leukemia (AML) developed complications of chronic graft-versus-host disease (cGVHD). She thereafter also developed nephrotic syndrome, and membranous nephropathy (MN) was diagnosed by a renal biopsy. Although the causative antigens of the MN were not detected, immunofluorescence staining showed codominant deposition of immunoglobulins G2 and G3, a finding indicating secondary MN, thereby suggesting an association between MN and cGVHD. Rituximab treatment was initiated, and her nephrotic syndrome gradually improved without relapse of AML. Our present case suggests that rituximab is a safe and effective therapeutic option for cGVHD-associated MN.

A girl with membranous nephropathy associated with ventriculoperitoneal shunt infection.

Glomerulopathy associated with shunt infection is commonly membranoproliferative glomerulonephritis, whereas the causative organisms of secondary membranous nephropathy are usually viruses. We report a case of membranous nephropathy associated with shunt infection. The patient was born at 29-week gestation with a birth weight of 1178 g. Ventriculoperitoneal shunt surgery had been performed for congenital hydrocephalus. Thereafter, she had experienced seven shunt infections. At the age 13 years, proteinuria was detected in a school urinary screening. Urinalysis at our hospital demonstrated 3 + protein and 3 + blood. Laboratory testing demonstrated a serum creatinine 0.5 m/dl, albumin 2.5 g/dl, C-reactive protein (CRP) 13.7 mg/dl, and C3 182 mg/dl. Prior to repeat urinalysis, the patient developed vomiting and was admitted with suspected shunt infection. On admission, her body temperature was 36.0 ºC. Physical examination was unremarkable other than small stature and a palpable mass in the left upper quadrant. Urinalysis demonstrated 2 + protein and 1 + blood with no cells or casts. The urinary protein excretion was 3 g/day. Abnormal laboratory tests included erythrocyte sedimentation rate 102 mm/hr, CRP 11.67 mg/dl, IgG 2442 mg/dl, C3 177 mg/dl, and C4 44 mg/dl. Antibiotic therapy was initiated for a presumptive diagnosis of shunt infection and the shunt catheter was removed. Cultures obtained after antibiotic administration were negative. Proteinuria persisted after control of the shunt infection. Histology of a renal biopsy demonstrated membranous nephropathy with diffuse granular IgG staining and subepithelial deposits. Three possible pathomechanisms for her membranous nephropathy were considered.

Membranous Nephropathy Secondary to Graves' Disease: A Case Report.

Membranous nephropathy (MN) is a form of kidney disease that is idiopathic in 70%-80% of cases. Glomerular involvement in autoimmune thyroiditis can occur in 10%-30% of patients, and MN manifests in association with Hashimoto thyroiditis in up to 20% of the cases with glomerular involvement. Reports of MN associated with Graves' disease (GD) are extremely rare in the current literature. Herein, we report the case of a 46-year-old man admitted to the hospital with nephrotic syndrome and symptomatic hyperthyroidism due to GD. Kidney biopsy revealed a secondary MN pattern. Immunohistochemical staining for PLA2R was negative, and thyroglobulin showed weak and segmental staining along the glomerular capillary. Anti-thyroid peroxidase (TPO) antibody test was not performed. The patient was treated for GD with methimazole and prednisone, and despite reaching clinical improvement after 8 months, proteinuria remained close to nephrotic levels. In this scenario, the patient was submitted to radioactive iodine, and there was a dramatic reduction in proteinuria levels after treatment. In conclusion, GD association with MN is rare, and when present, diagnosis using PLA2R and immunohistochemistry can be useful in determining association. In addition, radioactive iodine therapy can be an effective treatment modality when preceded with immunosuppressive corticosteroid therapy.

De Novo Membranous Nephropathy Associated With Antibody-Mediated Rejection in Kidney Transplant Recipients.

BACKGROUND: Membranous nephropathy (MN) is a rare autoimmune disease that can develop a persistent nephrotic syndrome and end-stage kidney disease, with a recurrence rate of 30% to 40% after kidney transplant. METHODS: Retrospective case series of membranous nephropathy observed in a cohort of kidney transplant recipients with donor-specific anti-human leukocyte antigen antibodies and biopsy-proven antibody-mediated rejection (AMR). RESULTS: We report 4 cases of membranous nephropathy associated with AMR. MN was diagnosed 10 to 92 months posttransplant, associated with de novo donor-specific antibodies, specific to class I in 2 cases, and class II in another 2. All cases presented typical morphology of membranous nephropathy, with subepithelial deposits with spikes at electron microscopy. Immunostaining for immunoglobulin G4 was negative in all cases, and podocyte-expressed M-type phospholipase A2 receptor was detected in glomerular basement membrane of 3 cases. Biopsy specimens from patients with longer follow-up showed more intense microvascular inflammation and chronic injury markers, possibly because of subclinical immunologic injury. AMR therapy included immunoglobulin 2g/kg in 3 patients, isolated or associated with plasmapheresis. One patient was not treated because of an active disseminated infection. Two patients remain with functioning grafts and under antiproteinuric therapy. Two grafts were lost, 1 because of chronic failure and the other because of death secondary to infection. Despite treatment, donor-specific antibodies remain detectable in a 6-month follow-up. CONCLUSIONS: De novo MN is a rare manifestation associated with AMR in kidney transplant recipients. The occurrence of podocyte-expressed M-type phospholipase A2 receptor in de novo MN suggests antibody-mediated activation, despite the use of maintenance immunosuppression.

A case of treatment-resistant membranous nephropathy associated with graft versus host disease successfully treated with daratumumab.

BACKGROUND: Membranous nephropathy (MN) is the most common cause of glomerulopathy after hematopoietic cell transplantation (HCT), most often occurring in the setting of graft versus host disease (GVHD). Twenty percent of patients will fail to respond to standard therapy and may progress to end stage renal disease. Here we present the case of a pediatric patient who developed chronic oral GVHD more than one-year post-HCT, who subsequently developed nephrotic syndrome (anasarca, nephrotic range proteinuria, hypoalbuminemia) and had a renal biopsy consistent with MN. Treated with ibrutinib for her GVHD, and steroids, tacrolimus, and rituximab for her MN, she failed to achieve even partial remission of her kidney disease after 8 months. Due to steroid toxicity and 0% CD19 cells on lymphocyte subpopulation flow cytometry, the decision was made to trial plasma cell depletion therapy with daratumumab. METHOD: She received three doses of daratumumab at weeks 1, 4, and 17. RESULTS: Her nephrotic syndrome resolved and her serum albumin was greater than 3.0 gm/dl by week 10. She was weaned off of both steroids and tacrolimus by week 16, at which time she had near-complete remission of her renal disease. CONCLUSION: Daratumumab may be an important, novel therapeutic option for post-HCT MN patients who are not responsive to standard therapies.

A case of membranous nephropathy secondary to asymptomatic Graves' disease.

Although cases of secondary membranous nephropathy associated with autoimmune thyroid disease (AITD) have been reported, most of them, if not all, present with symptomatic thyroid disease. Here we report an asymptomatic case of AITD complicated with secondary membranous nephropathy. A 16-year-old girl was referred to our institute because of proteinuria found by an annual medical checkup. Urinalysis showed a urinary protein creatinine ratio (UPCR) of 3.0 g/gCre. Blood examination revealed that she had Graves' disease, although she did not have any symptoms of hyperthyroidism such as weight loss, anxiety, tremor, tachycardia, or eye symptoms. In a kidney biopsy, periodic acid silver-methenamine staining showed spike formation in the basement membrane. Electron microscopy showed electron-dense deposits on the epithelial side of the glomerular basement membrane. Immunofluorescent staining showed co-localization of thyroid peroxidase and IgG deposition along the glomerular capillary walls. A diagnosis of membranous nephropathy secondary to asymptomatic Graves' disease was made on the basis of results of the examinations. Treatment with thiamazole added to enalapril improved proteinuria (reduction of UPCR to 0.83 g/gCr) and hypoalbuminemia. Consideration should be given to the possibility of AITD in differential diagnosis of etiologies of membranous nephropathy even when typical symptoms of AITD are lacking.

Clinicopathological characteristics and prognosis of hepatitis B associated membranous nephropathy and idiopathic membranous nephropathy complicated with hepatitis B virus infection.

The main objective of this study is to analyze the clinical and pathological features and prognosis of patients with Hepatitis B associated membranous nephropathy (HBV-MN) and idiopathic membranous nephropathy (IMN) complicated with hepatitis B virus (HBV) infection. This study will provide more basis for diagnosis and prognosis evaluation. A total of 50 patients with HBV-MN were included in this study. 56 IMN patients complicated with HBV infection diagnosed during the same period formed the control group. Parameters including blood routine, urine routine and plasma levels of albumin (ALB), serum creatinine (SCR), blood urea nitrogen (BUN), urea acid (UA), total cholesterol (T-CHO), triglycerides (TG), complement C3 and C4, glutamic pyruvic transaminase (ALT), glutamic pyruvic transaminase (AST), 24-h urinary protein quantification (24 h-TP), renal phospholipase A2 receptor (PLA2R) and HBV related markers during the hospitalization and outpatient follow-up study period were collected for all the patients. The proportion of male patients was high in both groups. The average age of the HBV-MN group was 37.2 ± 14.187 years old, it was younger compared with the IMN group (P = 0.003). Nephrotic syndrome was the major clinical manifestation among patients. There was no significant difference between the two groups in the levels of anemia, microscopic hematuria, renal dysfunction, liver dysfunction, liver cirrhosis. The level of serum C3 and C4 in the HBV-MN group was lower compared with the IMN group (P = 0.002, P = 0.014). In the HBV-MN group, serum HBV markers were negative in 6 (12%) patients, 4 patients (8%) were positive for PLA2R in serum, and 5 patients (10%) were positive for PLA2R in renal tissue. Stronger IgG1 and C1q and weaker IgG4 staining were found in HBV-MN group renal tissues (P = 0.003, P = 0.025, and P = 0.001, respectively). There were no statistical differences compared with serum and renal PLA2R between HBV-MN and IMN groups (P = 0.098, P = 0.109). During the 1-year follow-up, there was no significant difference in complete remission rate between the two groups (P = 0.7739). Renal biopsy is crucial to diagnose HBV-MN. IgG subtypes in the HBV-MN group were mainly IgG1 deposition, while those in IMN complicated with HBV infection group were mainly IgG4 deposition. When HBV-associated antigen and PLA2R are present in renal tissue, lower level of serum C3 and C4, high intensity of renal C1q and IgG1 is more supportive of HBV-MN. The positive of PLA2R in serum and renal tissue in differentiating HBV from IMN complicated with HBV infection remains to be discussed.

Development and validation of a discrimination model between primary PLA2R-negative membranous nephropathy and minimal change disease confirmed by renal biopsy.

Membranous nephropathy (MN) and minimal change disease (MCD) are two common causes leading to nephrotic syndrome (NS). They have similar clinical features but different treatment strategies and prognoses. M-type phospholipase A2 receptor (PLA2R) is considered as a specific marker of membranous nephropathy. However, its sensitivity is only about 70%. Therefore, there is a lack of effective and noninvasive tools to distinguish PLA2R-negative MN and MCD patients without renal biopsy. A total 949 patients who were pathologically diagnosed as idiopathic MN or MCD were enrolled in this study, including 805 idiopathic MN and 144 MCD. Based on the basic information and laboratory examination of 200 PLA2R-negative MN and 144 MCD, we used a univariate and multivariate logistic regression to select the relevant variables and develop a discrimination model. A novel model including age, albumin, urea, high density lipoprotein, C3 levels and red blood cell count was established for PLA2R-negative MN and MCD. The discrimination model has great differential capability (with an AUC of 0.904 in training group and an AUC of 0.886 in test group) and calibration capability. When testing in all 949 patients, our model also showed good discrimination ability for all idiopathic MN and MCD.

Horseshoe kidney with PLA2R-positive membranous nephropathy.

BACKGROUND: Horseshoe kidney (HSK) is a common congenital defect of the urinary system. The most common complications are urinary tract infection, urinary stones, and hydronephrosis. HSK can be combined with glomerular diseases, but the diagnosis rate of renal biopsy is low due to structural abnormalities. There are only a few reports on HSK with glomerular disease. Here, we have reported a case of PLA2R-positive membranous nephropathy occurring in a patient with HSK. CASE PRESENTATION: After admission to the hospital due to oedema of both the lower extremities, the patient was diagnosed with nephrotic syndrome due to abnormal 24-h urine protein (7540 mg) and blood albumin (25 g/L) levels. Abdominal ultrasonography revealed HSK. The patient's brother had a history of end-stage renal disease due to nephrotic syndrome. Therefore, the patient was diagnosed with PLA2R-positive stage II membranous nephropathy through renal biopsy under abdominal ultrasonography guidance. He was administered adequate prednisone and cyclophosphamide, and after 6 months of treatment, urinary protein excretion levels significantly decreased. CONCLUSION: The risk and difficulty of renal biopsy in patients with HSK are increased due to structural abnormalities; however, renal biopsy can be accomplished through precise positioning with abdominal ultrasonography. In the literature, 20 cases of HSK with glomerular disease have been reported thus far. Because of the small number of cases, estimating the incidence rate of glomerular diseases in HSK is impossible, and the correlation between HSK and renal pathology cannot be stated. Further studies should be conducted and cases should be accumulated to elucidate this phenomenon.

Syphilis-associated membranous nephropathy successfully treated with amoxicillin.

A 33-year-old Japanese man with no significant past medical history was admitted to our hospital for evaluation of weight gain and pitting edema. A laboratory test confirmed nephrotic-range proteinuria. Renal biopsy showed subepithelial deposits, and membranous nephropathy (MN) was diagnosed. Closer examination clarified an active syphilis infection. After renal biopsy, we prescribed amoxicillin for 8 weeks to treat the syphilis infection. Three weeks later, the patient's proteinuria dramatically decreased. This case is of interest because syphilis can become a cause of acute-onset MN in younger adults, and the incidence of syphilis is increasing in Japan.
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Sjögren's syndrome complicated with membranous nephropathy, a cause or coincidence?

BACKGROUND: Sjögren's syndrome (SS) has been a well-documented cause of secondary membranous nephropathy (MN); however, the prevalence is quite low. Since primary MN is also a common disease in middle age, whether MN is secondary to SS or just coincidence remains uncertain. The detection of phospholipase A2 receptor (PLA2R), which is most often positive in idiopathic MN, has been rarely reported in such cases. METHODS: We retrospectively studied 13 cases diagnosed with MN and SS in Huashan Hospital between 2009 and 2020, and performed PLA2R detection. We also review the literature by searching in the PubMed database. RESULTS: Among the 13 patients, 8 were found to be PLA2R-positive and 5 were negative. Nine patients were female. All but 1 patients had normal renal function at the time of biopsy. All patients showed positive anti-nuclear antibody and anti-SSA. Two of the 8 PLA2R-positive patients showed positive anti-SSB and 1/8 had mild hypocomplementemia, while all 5 PLA2R-negative patients had positive anti-SSB and 3 showed hypocomplementemia. Renal biopsy revealed focal MN and markedly mesangial hyperplasia in PLA2R-negative patients. Mesangial electron deposits were observed in 1 PLA2R-positive patient in small amounts, and in 3 PLA2R-negative patients with 2 in large amounts. During follow-up, 2 patients in the PLA2R-negative group presented with progressively decreasing serum complement levels, and another one was diagnosed with systemic lupus erythematosus (SLE). CONCLUSIONS: In patients with both MN and SS, PLA2R-negative MN should be considered as a secondary form. Careful screen for SLE is necessary in these patients during follow-up.

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

BACKGROUND: Phospholipase 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 PRESENTATION: A 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. CONCLUSIONS: This 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.

Primary membranous glomerulonephritis with negative serum PLA2R in haemophilia A successfully managed with rituximab - case report and review of the literature.

BACKGROUND: Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate. CASE PRESENTATION: We present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results. CONCLUSIONS: Pursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

Membranous nephropathy associated with multicentric Castleman's disease that was successfully treated with tocilizumab: a case report and review of the literature.

BACKGROUND: Multicentric Castleman's disease is a life-threatening disorder involving a systemic inflammatory response and multiple organ failure caused by the overproduction of interleukin-6. Although renal complications of Castleman's disease include AA amyloidosis, thrombotic microangiopathy, and membranoproliferative glomerulonephritis, membranous nephropathy is relatively rare. We experienced a case of secondary membranous nephropathy associated with Castleman's disease. CASE PRESENTATION: The patient was a 43-year-old Japanese man who had shown a high zinc sulfate value in turbidity test, polyclonal hypergammaglobulinemia, anemia, and proteinuria. A physical examination revealed diffuse lymphadenopathy, an enlarged spleen and papulae of the body trunk. A skin biopsy of a papule on the patient's back showed plasma cells in the perivascular area and he was diagnosed with multicentric Castleman's disease, plasma cell variant. Kidney biopsy showed the appearance of bubbling in the glomerular basement membranes in Periodic acid methenamine silver stain and electron microscopy revealed electron dense deposits within and outside the glomerular basement membranes. Since immunofluorescence study showed predominant granular deposition of IgG1 and IgG2, he was diagnosed with secondary membranous nephropathy associated with Castleman's disease. He was initially treated with prednisolone alone, however his biochemical abnormalities did not improve. After intravenous tocilizumab (700 mg every 2 weeks) was started, his C-reactive protein elevation, anemia, and polyclonal gammopathy improved. Furthermore, his urinary protein level declined from 1.58 g/gCr to 0.13 g/gCr. The prednisolone dose was gradually tapered, then discontinued. He has been stable without a recurrence of proteinuria for more than 6 months. CONCLUSIONS: Tocilizumab might be a treatment option for secondary membranous nephropathy associated with Castleman's disease.

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

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.

Posttransplant nephrotic syndrome resulting from NELL1-positive membranous nephropathy.

Membranous nephropathy (MN) constitutes a major cause of nephrotic syndrome (NS) in adults. After kidney transplantation (KTx), both recurrent and de novo MN has been reported. In addition to PLA2R and THSD7A, recent identification of neural EGFL-like-1 protein, NELL1, as a potential disease antigen has enriched our understanding of MN pathogenesis. To date, NELL1-positive MN has only been described in native kidneys, but never been diagnosed in renal allografts. We here report on a 56-year-old male kidney transplant recipient suffering from amyotrophic lateral sclerosis (ALS), who developed NS 25 years after KTx. Allograft biopsy revealed NELL1-positive MN. Using specifically established immunoblotting techniques, we detected new-onset NELL1-IgG1, IgG3, and IgG4 antibodies in the patient´s serum correlating with the course of proteinuria. While primary renal disease was undetermined, MN recurrence seemed unlikely given the long-time span since KTx. By clinical investigation of de novo etiologies, we did not detect an underlying malignancy. However, previous self-medication with dimercaptopropane sulfonate (DMPS) and alpha lipoic acid (ALA) represented a potential trigger and cessation associated with partial remission of proteinuria. This report illustrates the first case of posttransplant NS due to NELL1-positive MN. Monitoring NELL1 antibodies in the serum promise to be a non-invasive diagnostic tool guiding disease management.