Single-cell RNA sequencing of kidney from idiopathic membranous nephropathy patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241302 | GEO | 2023/09/27
REPOSITORIES: GEO
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Project description:Background and objectivesThe impact of acute kidney injury (AKI) on the progression of renal function in idiopathic membranous nephropathy (iMN) with nephrotic syndrome (NS) patients have not yet been reported, we sought to investigate the incidence, clinical features and prognosis of AKI in iMN with NS patients and determine clinical predictors for progression from AKI to advanced chronic kidney disease (CKD) stage.MethodsWe analyzed clinical and pathological data of iMN with NS patients retrospectively collected from Jan 2012 to Dec 2018. The primary renal endpoint was defined as persistent eGFR <45ml/min per 1.73 m2 more than 3 months. Comparisons of survival without primary renal endpoint were performed by Kaplan-Meier curves and log-rank test. Univariate and multivariate Cox proportional hazard models were constructed to determine independent variables associated with primary renal endpoint .Results434 iMN with NS patients were enrolled. The incidence of AKI 1 stage, AKI 2 stage and AKI 3 stage was 23.1, 4.8 and 0.7% respectively. 66 (53.2%) patients with AKI had complete renal function recovery and 42 (33.9%) patients with AKI reached primary renal endpoint. Survival without primary renal endpoint was worse in AKI patients than No AKI patients (67.1 ± 5.3 and 43.7 ± 7.3% vs 99.5 ± 0.5 and 92.5 ± 4.2% at 2 and 4 years,p < 0.001). AKI was independently associated with primary renal endpoint, with an adjusted hazard ratio(HR) of 25.1 (95%CI 7.7-82.1, p < 0.001).ConclusionsAKI was usually mild and overlooked in iMN patients with NS, but it had a strong association with poor clinical outcomes and was an independent risk factor for CKD progression.
| S-EPMC8231360 | 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: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: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: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: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
Project description:Our understanding of the pathogenesis of idiopathic membranous nephropathy is limited by an incomplete molecular characterization of the cell types in the kidney and interaction between the cells. Besides, the reason for the heterogeneity of these patients as well as the variety of clinical outcomes remains elusive. Therefore, we applied scRNA-seq to kidney biopsies of patients with IMN to identify gene expression at the single-cell level, elucidate cells involved in the progression of IMN, and uncover intercellular interactions.
2021-05-30 | GSE171458 | GEO