Genetic susceptibility to idiopathic membranous nephropathy in high-prevalence Area, Taiwan.
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ABSTRACT:
SUBMITTER: Chen SY
PROVIDER: S-EPMC4265015 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Overlapping idiopathic membranous nephropathy (IMN) and immunoglobulin A nephropathy (IgAN) is rare. This study aims to investigate the unique prognostic, clinical, and renal histopathological characteristics of IMN+IgAN. This retrospective observational study included 73 consecutive cases of IMN+IgAN and 425 cases of IMN treated between September 2006 and November 2015. Prognostic and baseline clinical and histopathological data were compared between the two patient groups. Poor prognostic events included a permanent 50% reduction in eGFR, end-stage renal disease, and all-cause mortality. Renal histopathology demonstrated that the patients with IMN+IgAN presented with significantly increased mesangial cell proliferation and matrix expansion, increased inflammatory cell infiltration, and higher proportions of arteriole hyalinosis and lesions than the patients with IMN (all P?<?0.05). Kaplan-Meier analysis showed that the patients with IMN+IgAN had significantly higher cumulative incidence rates of partial or complete remission (PR or CR, P?=?0.0085). Multivariate Cox model analysis revealed that old age at biopsy and high baseline serum creatinine and uric acid levels were significantly associated with poor prognosis (all P?<?0.05), and increased IgA expression correlated significantly with PR or CR (P?<?0.05). The present study found that overlapping IMN and IgAN presents with unique renal histopathology and appears not to cause a poorer prognosis than IMN.
| S-EPMC5597578 | biostudies-literature
Project description:BACKGROUND: Idiopathic membranous nephropathy (IMN) is one of the most common forms of autoimmune nephritic syndrome in adults. The purpose of this study is to evaluate whether polymorphisms of PLA2R1 affect the development of IMN. METHODS: Taiwanese-Chinese individuals (129 patients with IMN and 106 healthy controls) were enrolled in this study. The selected single nucleotide polymorphisms (SNPs) in PLA2R1 were genotyped by real-time polymerase chain reaction using TaqMan fluorescent probes, and were further confirmed by polymerase chain reaction-restriction fragment length polymorphism. The roles of the SNPs in disease progression were analyzed. RESULTS: Genotype distribution was significantly different between patients with IMN and controls for PLA2R1 SNP rs35771982 (p = 0.015). The frequency of G allele at rs35771982 was significantly higher in patients with IMN as compared with controls (p = 0.005). In addition, haplotypes of PLA2R1 may be used to predict the risk of IMN (p = 0.004). Haplotype H1 plays a role in an increased risk of IMN while haplotype H3 plays a protective role against this disease. None of these polymorphisms showed a significant and independent influence on the progression of IMN and the risk of end-stage renal failure and death (ESRF/death). High disease progression in patients having C/T genotype at rs6757188 and C/G genotype at rs35771982 were associated with a low rate of remission. CONCLUSIONS: Our results provide new evidence that genetic polymorphisms of PLA2R1 may be the underlying cause of IMN, and the polymorphisms revealed by this study warrant further investigation.
| S-EPMC2959017 | biostudies-literature
Project description:BackgroundMembranous nephropathy (MN), a major cause of nephrotic syndrome, has attracted people's attention in recent years for its growing prevalence. It is the second or third leading cause of ESRD in patients with primary glomerulonephritis and is the leading glomerulopathy that recurs after kidney transplantation.SummaryMN can be classified as idiopathic membranous nephropathy (IMN) and secondary MN. The discovery of the M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) provides the new diagnostic methods and treatment strategies for IMN on the molecular level. The study on single nucleotide polymorphism of IMN genes, such as the single M-type phospholipase A2 receptor 1 (PLA2R1) gene and human leukocyte antigen (HLA) gene, explains the pathogenesis of the disease from the perspective of genetics and conforms to the trend of the era of precision medicine.Key messagesThis review focuses on advances in the pathogenesis of IMN, including molecular and genetic pathogenesis, as well as discussing the diagnostic and treatment guiding value brought by these new discoveries.
| S-EPMC7745661 | biostudies-literature
Project description:Introduction: Minimal change disease (MCD) is a major cause of nephrotic syndrome. With a substantial number of patients requiring long-term immunosuppression leading to significant morbidity, the study aim was to determine MCD glomerular transcriptome to serve as a basis for biomarker discovery and novel drug target identification. Animal work showed podocyte injury induced by IL-7/IL-7R signaling (Zhai S, BBRC, 2018). Methods: Renal biopsies from adult patients representing the following groups were selected from the Norwegian Kidney Biopsy Registry: MCD (n=14), as well as normal tissue (n=8) and primary membranous nephropathy (MN; n=12) as the two reference groups. RNA for 75 base-pair paired-end RNASeq was obtained by dissecting glomeruli via laser capture microdissection (LCM) from FFPE cross-sections. Systematic delineation of condition-specific alteration in transcriptional landscapes was achieved by combining pathway-centered analyses with methodologies derived from network science and integrating multiple bioinformatics resources. Results: Compared to normal glomeruli, glomeuli from MCD displayed an inflammatory signature that appeared to be predominantly governed by the IL1 and IL7 systems. While enrichment of IL1 production and secretion was a shared feature of MCD and MN compared to normal tissue, responses involving IL7 pathway activation were unique to MCD. Indeed, IL7R expressed by glomeruli was the most up-regulated gene of to the interleukin-family in MCD vs normal controls. IL7 pathway activation was paralleled by significant enrichment in adaptive immune system processes and transcriptional regulation and depletion in pathways related to energy metabolism and transcription. Downregulation of these organ function-related themes again occurred predominately in MDC and were significantly less pronounced in MN. Conclusion: Our results demonstrate that archival FFPE-biopsies can be used to generate glomeruli-specific gene expression profiles suitable for systematic delineation of kidney-associated diseases. Here the latter provides a data-driven rationale to experimentally address these MCD-specific features as biomarkers and as novel drug targets. In this context inhibiting activation of the IL7 pathway may be particularly promising.
2023-01-25 | GSE216841 | GEO
Project description:BackgroundBased on the etiology, membranous nephropathy (MN) can be categorized into idiopathic membranous nephropathy (IMN) and secondary membranous nephropathy. Malignancy-associated membranous nephropathy (MMN) is a common type of secondary MN. Its incidence is only second to that of lupus nephritis. As the treatment and prognosis of MMN differ significantly from those of other MNs, the identification of MMN is crucial for clinical practice. The purpose of this study was to develop a model that could efficiently discriminate MMN, to guide more precise selection of therapeutic strategies.MethodsA total of 385 with IMN and 62 patients with MMN, who were hospitalized at the First Affiliated Hospital of Zhengzhou University between January 2017 and December 2020 were included in this study. We constructed a discriminant model based on demographic information and laboratory parameters for distinguishing MMN and IMN. To avoid an increased false positivity rate resulting from the large difference in sample numbers between the two groups, we matched MMN and IMN in a 1:3 ratio according to gender. Regression analysis was subsequently performed and a discriminant model was constructed. The calibration ability and clinical utility of the model were assessed via calibration curve and decision curve analysis.ResultsWe constructed a discriminant model based on age, CD4+ T cell counts, levels of cystatin C, albumin, free triiodothyronine and body mass index, with a diagnostic power of 0.860 and 0.870 in the training and test groups, respectively. The model was validated to demonstrate good calibration capability and clinical utility.ConclusionIn clinical practice, patients demonstrating higher scores after screening with this model should be carefully monitored for the presence of tumors in order to improve their outcome.
| S-EPMC9329587 | biostudies-literature
Project description:BackgroundIdiopathic membranous nephropathy (IMN) is a noninflammatory autoimmune glomerulonephropathy. Based on the risk stratification for disease progression, conservative nonimmunosuppressive and immunosuppressive therapy strategies have been recommended. However, there remains challenges. Therefore, novel approaches to treat IMN are needed. We evaluated the efficacy of Astragalus membranaceus (A membranaceus) combined with supportive care or immunosuppressive therapy in the treatment of moderate-high risk IMN.MethodsWe comprehensively searched PubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure, the Database for Chinese Technical Periodicals, Wanfang Knowledge Service Platform, and SinoMed. We then performed a systematic review and cumulative meta-analysis of all randomized controlled trials assessing the two therapy methods.ResultsThe meta-analysis included 50 studies involving 3423 participants. The effect of A membranaceus combined with supportive care or immunosuppressive therapy is better than that of supportive care or immunosuppressive therapy along in regulating for improving 24 hours urinary total protein (MD = -1.05, 95% CI [-1.21, -0.89], P = .000), serum albumin (MD = 3.75, 95% CI [3.01, 4.49], P = .000), serum creatinine (MD = -6.24, 95% CI [-9.85, -2.63], P = .0007), complete remission rate (RR = 1.63, 95% CI [1.46, 1.81], P = .000), partial remission rate (RR = 1.13, 95% CI [1.05, 1.20], P = .0004).ConclusionsAdjunctive use of A membranaceus preparations combined with supportive care or immunosuppressive therapy have a promising treatment for improving complete response rate, partial response rate, serum albumin, and reducing proteinuria, serum creatinine levels compared to immunosuppressive therapy in people with MN being at moderate-high risk for disease progression. Given the inherent limitations of the included studies, future well-designed randomized controlled trials are required to confirm and update the findings of this analysis.
| S-EPMC9981402 | biostudies-literature
Project description:Idiopathic membranous nephropathy (iMN) is a single-organ autoimmune disease characterized by subepithelial deposition of immune complexes containing IgG4 resulting in proteinuria, nephrotic syndrome, and, in some, end-stage renal disease. The pathogenesis involves a chronic IgG4 response against specific podocyte antigens which have now been at least partially defined in the neonatal, early childhood, and adult varieties. More has recently been learned about the genetic predisposition as well. This review discusses the pathophysiology of iMN in light of these discoveries and what is known about the genesis and potential clinical ramifications of an antigen specific IgG4 response.
| S-EPMC4928035 | biostudies-literature
Project description:BACKGROUND: Idiopathic membranous nephropathy (IMN) is increasingly seen in older patients. However, differences in disease presentation and outcomes between older and younger IMN patients remain controversial. We compared patient characteristics between younger and older IMN patients. METHODS: We recruited 171 Japanese patients with IMN, including 90 (52.6%) patients <65 years old, 40 (23.4%) patients 65-70 years, and 41 (24.0%) patients ? 71 years. Clinical characteristics and outcomes were compared between younger and older IMN patients. RESULTS: During a median observation period of 37 months, 103 (60.2%) patients achieved complete proteinuria remission, which was not significantly associated with patient age (P = 0.831). However, 13 (7.6%) patients were hospitalized because of infection. Multivariate Cox proportional hazards models identified older age [adjusted hazard ratio (HR)?= 3.11, 95% confidence interval (CI): 1.45-7.49, per 10 years; P = 0.003], prednisolone use (adjusted HR = 11.8, 95% CI: 1.59-242.5; P = 0.014), and cyclosporine used in combination with prednisolone (adjusted HR = 10.3, 95% CI: 1.59-204.4; P = 0.012) as significant predictors of infection. A <25% decrease in proteinuria at 1 month after immunosuppressive therapy initiation also predicted infection (adjusted HR = 6.72, 95% CI: 1.51-37.8; P = 0.012). CONCLUSIONS: Younger and older IMN patients had similar renal outcomes. However, older patients were more likely to develop infection when using immunosuppressants. Patients with a poor response in the first month following the initiation of immunosuppressive therapy should be carefully monitored for infection and may require a faster prednisolone taper.
| S-EPMC4203783 | biostudies-literature
Project description:Background and objectivesCyclophosphamide treatment improves renal survival in patients with idiopathic membranous nephropathy. However, use of cyclophosphamide is associated with cancer. The incidence of malignancies in patients with idiopathic membranous nephropathy was evaluated, and the cancer risk associated with cyclophosphamide use was estimated.Design, setting, participants, & measurementsPatients who attended the clinic were included prospectively from 1995 on. A crude incidence ratio for the occurrence of malignancy was calculated. Incidence ratios were subsequently standardized to potential confounders. Latency between cyclophosphamide therapy and the occurrence of cancer was estimated by stratifying for time since the start of treatment. Finally, Poisson regression was used to obtain a multiple adjusted incidence ratio and investigate the dose-response relationship between cyclophosphamide and cancer.ResultsData were available for 272 patients; the mean age was 51 years, and 70% of the patients were men. Median follow-up was 6.0 years (interquartile range=3.6-9.5), and 127 patients were treated with cyclophosphamide. Cancer incidence was 21.2 per 1000 person-years in treated patients compared with 4.6 per 1000 person-years in patients who did not receive cyclophosphamide, resulting in crude and adjusted incidence ratios of 4.6 (95% confidence interval, 1.5 to 18.8) and 3.2 (95% confidence interval, 1.0 to 9.5), respectively.ConclusionCyclophosphamide therapy in idiopathic membranous nephropathy gives a threefold increase in cancer risk. For the average patient, this finding translates into an increase in annual risk from approximately 0.3% to 1.0%. The increased risk of malignancy must be balanced against the improved renal survival.
| S-EPMC4046727 | biostudies-literature
Project description:BackgroundIdiopathic membranous nephropathy (IMN) is a cause of nephrotic syndrome that is increasing in incidence but has unclear pathogenesis. Urinary peptidomics is a promising technology for elucidating molecular mechanisms underlying diseases. Dysregulation of the proteolytic system is implicated in various diseases. Here, we aimed to conduct urinary peptidomics to identify IMN-related proteases.ResultsPeptide fingerprints indicated differences in naturally produced urinary peptide components among 20 healthy individuals, 22 patients with IMN, and 15 patients with other kidney diseases. In total, 1,080 peptide-matched proteins were identified, 279 proteins differentially expressed in the urine of IMN patients were screened, and 32 proteases were predicted; 55 of the matched proteins were also differentially expressed in the kidney tissues of IMN patients, and these were mainly involved in the regulation of proteasome-, lysosome-, and actin cytoskeleton-related signaling pathways. The 32 predicted proteases showed abnormal expression in the glomeruli of IMN patients based on Gene Expression Omnibus databases. Western blot revealed abnormal expression of calpain, matrix metalloproteinase 14, and cathepsin S in kidney tissues of patients with IMN.ConclusionsThis work shown the calpain/matrix metalloproteinase/cathepsin axis might be dysregulated in IMN. Our study is the first to systematically explore the role of proteases in IMN by urinary peptidomics, which are expected to facilitate discovery of better biomarkers for IMN.
| S-EPMC8613922 | biostudies-literature