Objective To investigate the clinical significance of thrombospondin type 1 domain-containing 7A (THSD7A) and neural epidermal growth factor-like 1 protein (NELL1) in phospholipase A2 receptor (PLA2R)-negative membranous nephropathy (MN). Methods A total of 116 PLA2R-negative MN patients treated in Hangzhou TCM Hospital Affiliated to Zhejiang Chinese Medical University from 2014 to 2021 were enrolled in this study.Immunohistochemistry was employed to detect THSD7A and NELL1 in the renal tissue.The pathological characteristics,treatment,and prognosis were compared between positive and negative groups. Results The 116 PLA2R-negative MN patients included 23 THSD7A-positive patients and 9 NELL1-positive patients.One patient was tested positive for both proteins.The THSD7A-positive group showed higher positive rate of IgG4 (P=0.010),more obvious glomerular basement membrane (GBM) thickening (P=0.034),and higher proportion of stage Ⅱ MN and lower proportion of stage I MN (P=0.002) than the THSD7A-negative group.The NELL1-positive group had lower positive rates of C1q and IgG2 (P=0.029,P=0.001),less obvious GBM thickening (P<0.001),more extensive inflammatory cell infiltration (P=0.033),lower proportion of deposits on multi-locations (P=0.001),and lower proportion of atypical MN (P=0.010) than the NELL1-negative group.One patient with THSD7A-positive MN was diagnosed with colon cancer,while none of the NELL1-positive patients had malignancy.Survival analysis suggested that THSD7A-positive MN had worse composite remission (either complete remission or partial remission) of nephrotic syndrome than the negative group (P=0.016),whereas NELL1-positive MN exhibited better composite remission of nephrotic syndrome than the negative group (P=0.015).The MN patients only positive for NELL1 showed better composite remission of nephrotic syndrome than the MN patients only positive for THSD7A (P<0.001). Conclusions THSD7A- and NELL1-positive MN is more likely to be primary MN,and there is no significant malignancy indication.However,it might have a predictive value for the prognosis of MN.
Humans ; Autoantibodies ; Clinical Relevance ; Colonic Neoplasms ; EGF Family of Proteins ; Glomerulonephritis, Membranous/diagnosis* ; Nephrotic Syndrome ; Receptors, Phospholipase A2/metabolism* ; Thrombospondins/metabolism*

OBJECTIVE: To evaluate the value of pharmacogenetic testing for improving the efficacy and safety of treatment with cyclosporine, tacrolimus, and cyclophosphamide (CTX) for PLA2R-related membranous nephropathy and for determing individualized and precise treatment plans for the patients. METHODS: A total of 63 patients with PLA2R-related membranous nephropathy hospitalized in the Department of Nephrology at our hospital from January, 2019 to October, 2021 were enrolled in this study. Thirty-three of the patients underwent pharmacogenetic testing before taking the immunosuppressive drugs selected based on the results of genetic screening for sensitive targets, and the other 30 patients were empirically given immunosuppressive drugs according to the guidelines (control group). The clinical efficacy and adverse effects of the immunosuppressive drugs were analyzed for all the patients. The two groups of patients were compared for demographic and biochemical parameters including 24-h urine protein, serum albumin, renal function, and serum anti-phospholipase A2 receptor antibody both before and at 3 months after the beginning of the treatment. RESULTS: Among the 33 patients undergoing pharmacogenetic testing, 51.5% showed a GG genotype for cyclosporine, and 61.6% had an AG genotype for tacrolimus; for CTX, 51.5% of the patients showed a homozygous deletion and 63.6% had an AA genotype. After treatment for 3 months, serum anti-phospholipase A2 receptor antibody, 24-h urine protein, and serum albumin levels were significantly improved in pharmacogenetic testing group as compared with the control group (P < 0.05). CONCLUSION Individualized and precise administration of immunosuppressive drugs based on pharmacogenetic testing better controls proteinuria and serum antiphospholipase A2 receptor antibodies and increases serum albumin level in patients with PLA2R-related membranous nephropathy.
Humans ; Autoantibodies ; Cyclosporine/therapeutic use* ; Glomerulonephritis, Membranous/diagnosis* ; Homozygote ; Immunosuppressive Agents/therapeutic use* ; Pharmacogenomic Testing ; Receptors, Phospholipase A2 ; Sequence Deletion ; Serum Albumin ; Tacrolimus/therapeutic use*

BACKGROUND: Phospholipase A2 receptor (PLA2R) has been identified as a major autoantigen in primary membranous nephropathy (MN). We evaluated the association between anti-PLA2R antibodies and clinical outcome in Korean patients with primary MN. METHODS: A total of 66 patients with biopsy-proven MN were included. Serum level of anti-PLA2R antibodies was measured by enzyme-linked immunosorbent assay. Biochemical parameters were estimated initially and at follow-up. RESULTS: Anti-PLA2R antibodies were detected in 52.1% and 27.8% of patients with primary and secondary MN, respectively. Forty-eight patients with primary MN were grouped based on presence or absence of anti-PLA2R antibodies. Proteinuria was more severe in anti-PLA2R-positive patients than in anti-PLA2R-negative patients (urine protein/creatinine ratio 7.922 ± 3.985 g/g vs. 4.318 ± 3.304 g/g, P = 0.001), and anti-PLA2R antibody level was positively correlated with proteinuria. The incidence of chronic kidney disease stage ≥ 3 was higher in anti-PLA2R-positive patients compared with anti-PLA2R-negative patients (P = 0.004). The probabilities of spontaneous remission were higher in anti-PLA2R-negative patients compared with anti-PLA2R-positive patients (P < 0.001). Multivariate analysis demonstrated that anti-PLA2R antibodies are an independent risk factor for developing chronic kidney disease stage ≥ 3 and for not reaching spontaneous remission. CONCLUSION: Detection of anti-PLA2R antibodies at diagnosis in patients with primary MN can predict prognosis and guide treatment decisions.
Antibodies ; Diagnosis ; Enzyme-Linked Immunosorbent Assay ; Follow-Up Studies ; Glomerulonephritis, Membranous* ; Humans ; Incidence ; Multivariate Analysis ; Prognosis ; Proteinuria ; Receptors, Phospholipase A2 ; Remission, Spontaneous ; Renal Insufficiency, Chronic ; Risk Factors

Heavy proteinuria in the nephrotic range is an uncommon, often unrecognized manifestation of graft-versus-host disease (GVHD) following hematopoietic stem cell transplantation. A few isolated case reports have been published in the Korean literature involving a small number of patients who developed membranous nephropathy as GVHD after peripheral blood stem cell transplantation (PBSCT). A 17-year-old female was diagnosed with non-Hodgkin's lymphoma. Following remission, she underwent allogeneic PBSCT. Shortly thereafter, she developed acute GVHD, which was managed by medical therapy with prednisolone and cyclosporine. Approximately 13 months following PBSCT, the patient developed proteinuria without peripheral edema. Pulsed steroid therapy was initiated three times, but her condition did not improve. Twenty months after PBSCT, she developed nephrotic range proteinuria. A renal biopsy was performed, and the diagnosis was histologically consistent with membranous nephropathy. Because the response to steroids was not satisfactory, the dose of cyclosporine was increased. Approximately 3 months after renal biopsy, the proteinuria disappeared. Given the recent increase in the incidence of GVHD-mediated renal disease, in particular, renal biopsy is indispensable to the diagnosis of nephropathy and to the prevention of disease progression.
Adolescent ; Biopsy ; Cyclosporine ; Diagnosis ; Disease Progression ; Edema ; Female ; Glomerulonephritis, Membranous* ; Graft vs Host Disease* ; Hematopoietic Stem Cell Transplantation ; Humans ; Incidence ; Lymphoma, Non-Hodgkin ; Peripheral Blood Stem Cell Transplantation ; Prednisolone ; Proteinuria ; Stem Cells* ; Steroids

Tubulointerstitial nephritis (TIN) is the most common form of renal involvement in IgG4-related disease. It is characterized by a dominant infiltrate of IgG4-positive plasma cells in the interstitium and storiform fibrosis. Demonstration of IgG4-positive plasma cells is essential for diagnosis, but the number of IgG4-positive cells and the ratio of IgG4-positive/IgG-positive plasma cells may vary from case to case and depending on the methods of tissue sampling even in the same case. IgG4-positive plasma cells can be seen in TIN associated with systemic lupus erythematosus, Sjogren syndrome, or anti-neutrophil cytoplasmic antibody-associated vasculitis, which further add diagnostic confusion and difficulties. To have a more clear view of IgG4-TIN and to delineate differential points from other TIN with IgG4-positive plasma cell infiltrates, clinical and histological features of IgG4-TIN and its mimickers were reviewed. In the rear part, cases suggesting overlap of IgG4-TIN and its mimickers and glomerulonephritis associated with IgG4-TIN were briefly described.
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ; Diagnosis ; Fibrosis ; Glomerulonephritis ; Glomerulonephritis, Membranous ; Lupus Erythematosus, Systemic ; Lupus Nephritis ; Nephritis, Interstitial* ; Plasma Cells ; Sjogren's Syndrome ; Tin

Incidence of renal involvement in mixed connective tissue disease (MCTD) is low. In the presence of glomerulonephritis, membranous nephropathy (MN) in MCTD is common. A 47-year-old woman presented with hypothyroidism. She developed Raynaud's phenomenon, arthralgia, and incomplete lupus erythematosus, diagnosed with MCTD. One year after then, the patient developed persistent proteinuria (1+) without hematuria. Following diagnosis with MCTD, her renal function began to deteriorate. The renal biopsy showed late stage MN. For the treatment of MN with mild proteinuria and MCTD, we prescribed an angiotensin II receptor blocker and 7.5 mg of methotrexate per week and 300 mg of hydroxychloroquine daily. The patient had a reduced estimated glomerular filtration rate of 55% for the subsequent eight years. The MN in MCTD is known to show good renal prognosis. Here, we report on a rare case of MN in MCTD in Korea with a bad prognosis.
Arthralgia ; Biopsy ; Diagnosis ; Female ; Glomerular Filtration Rate ; Glomerulonephritis ; Glomerulonephritis, Membranous* ; Hematuria ; Humans ; Hydroxychloroquine ; Hypothyroidism ; Incidence ; Korea ; Methotrexate ; Middle Aged ; Mixed Connective Tissue Disease* ; Prognosis* ; Proteinuria ; Receptors, Angiotensin

Syphilis is a chronic systemic infectious disease caused by the bacterium Treponema pallidum. Gastric involvement and nephrotic syndrome are uncommon but well documented complications of syphilis, but the co-occurrence of these two complications in the same patient is extremely rare. Thus, because of their nonspecific presentation, suspicion of gastric syphilis (GS) and nephrotic syndrome is essential for diagnosis. Patients should be investigated thoroughly and a diagnosis made based on clinical, endoscopic, and histological findings, in order to initiate appropriate therapy. We report of a 34-year-old male patient with a history of epigastric pain and a diagnosis of GS and syphilis-associated membranous glomerulonephritis confirmed by gastroscopy and kidney biopsy, who was treated successfully with penicillin G benzathine. This case report provides information on the typical features of GS that should help raise awareness of this rare disease entity among clinicians, resulting in earlier diagnosis and administration of appropriate therapy.
Adult ; Biopsy ; Communicable Diseases ; Diagnosis ; Gastroscopy ; Glomerulonephritis, Membranous* ; Humans ; Kidney ; Male ; Nephrotic Syndrome ; Penicillin G Benzathine ; Rare Diseases ; Stomach ; Syphilis* ; Treponema pallidum

BACKGROUNDIn China, the prevalence of chronic kidney disease has increased significantly. Many studies shows that the spectrum of kidney disease had changed in recent years. We retrospectively analyzed the pathological types of renal biopsy and its spectrum change at the General Hospital of the Chinese People's Liberation Army from December 1987 to December 2012, in order to offer new supporting evidences for further specifying the distribution of renal pathological types in China.

METHODSAccording to the "Revised Protocol for the Histological Typing of Glomerulopathy" (WHO, 1995), pathological diagnosis of renal biopsy was classified, detection rate of each pathological type was summarized (i.e., percentage of total renal biopsy cases), study period was divided at an interval of 5 years, and age-stratified distribution change of main pathological types was analyzed.

RESULTSThe proportion of pathological types in 11 618 cases of renal biopsy was as follows: primary glomerulonephritis (PGN, 70.7%), secondary glomerulonephritis (SGN, 20.7%), tubular-interstitial nephropathy (4.0%), hereditary/rare nephropathy (0.3%), end-stage renal disease (0.9%), and unclassified renal disease (3.3%). Among PGN, there was IgA nephropathy (IgAN, 37.0%), membranous nephropathy (MN, 11.8%), mesangial proliferative glomerulonephritis (MsPGN, 8.9%), minimal change disease (MCD, 6.6%), and focal segmental glomerulosclerosis (3.9%). Among SGN there was lupus nephritis (LN, 5.5%), Henoch-Schönlein purpura glomerulonephritis (5.3%), hepatitis B virus-associated nephritis (HBVAN, 3.03%), diabetic nephropathy (2.2%), and hypertension/malignant hypertension-associated renal damage (1.9%). Pathological data were analyzed from 1987-1992 to 2008-2012 (after age adjustment). Detection rate of IgAN tended to rise (P < 0.001). Detection rates of MN and MCD rose significantly (P < 0.001), but detection rate of MsPGN dropped significantly (P < 0.001). Among SGN, detection rate of HBVAN tended to drop (P < 0.001).

CONCLUSIONIn China, PGN was the most common glomerulopathy (mostly IgAN), LN was the most common SGN, and detection rate of MN and MCD rose significantly.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Biopsy ; methods ; Child ; Child, Preschool ; China ; Female ; Glomerulonephritis, Membranous ; diagnosis ; Humans ; Kidney ; pathology ; Kidney Diseases ; diagnosis ; Male ; Middle Aged ; Young Adult

Membranous glomerulonephritis is one of the most common causes of nephrotic syndrome in adults. Pulmonary alveolar proteinosis (PAP) is a rare lung disease in which abnormal accumulation of surfactant occurs within the alveoli. We describe a 61-year-old man with concurrent membranous glomerulonephritis and PAP, which is very rare; both are pathophysiologically related to an abnormal immune response. A patient came to hospital with leg edema but no respiratory symptoms. Chest X-ray and CT showed classical PAP findings, which are ground-glass opacities with interlobular septal thickening, in both lung fields. A bubbly whitish secretion retrieved via broncho-alveolar lavage showed neutrophils and lymphocytes as well as Periodic acid-Schiff-positive proteinaceous materials. A kidney biopsy revealed findings of membranous glomerulonephritis with irregular subepithelial deposits by electron microscopy. At 1 year after diagnosis, the membranous glomerulonephritis was well under control with steroids and mycophenolate mofetil but PAP became aggravated gradually and whole-lung lavage was needed.
Adult ; Biopsy ; Diagnosis ; Edema ; Glomerulonephritis, Membranous* ; Humans ; Kidney ; Leg ; Lung ; Lung Diseases ; Lymphocytes ; Microscopy, Electron ; Middle Aged ; Nephrotic Syndrome ; Neutrophils ; Pulmonary Alveolar Proteinosis* ; Steroids ; Therapeutic Irrigation ; Thorax

BACKGROUND: All types of membranoproliferative glomerulonephritis (MPGN) are progressive diseases with poor prognoses. Recently, a newly proposed classification of these diseases separated them into immune complex- and complement- mediated diseases. We investigated the frequency of C3 glomerulonephritis among previously diagnosed MPGN patients. METHODS: We conducted a retrospective study of patients diagnosed with MPGN at three tertiary care institutions between 2001 and 2010. We investigated the incidence of complement-mediated disease among patients diagnosed with MPGN. Progressive renal dysfunction was defined as a 50% reduction in the glomerular filtration rate or the need for renal replacement therapy. RESULTS: Among the 3,294 renal biopsy patients, 77 (2.3%) were diagnosed with MPGN; 31 cases were excluded, of which seven were diagnosed with systemic lupus nephritis, and the others were not followed for a minimum of 12 months after biopsy. Based on the new classification, complement-mediated MPGN was diagnosed in two patients (4.3%); only one patient developed progressive renal dysfunction. Among the immune complex-mediated MPGN patients, 17 patients developed progressive renal dysfunction. Serum albumin and creatinine levels at the time of MPGN diagnosis were risk factors of renal deterioration, after adjusting for low C3 levels and nephrotic syndrome. CONCLUSION: Complement-mediated glomerulonephritis was present in 4.3% of patients previously diagnosed with MPGN.
Biopsy ; Classification* ; Complement C3 ; Creatinine ; Diagnosis ; Glomerular Filtration Rate ; Glomerulonephritis ; Glomerulonephritis, Membranoproliferative* ; Glomerulonephritis, Membranous ; Humans ; Incidence ; Lupus Nephritis ; Nephrotic Syndrome ; Prognosis ; Renal Replacement Therapy ; Retrospective Studies ; Risk Factors ; Serum Albumin ; Tertiary Healthcare