Can genetics risk-stratify patients with membranous nephropathy?
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ABSTRACT:
SUBMITTER: Bomback AS
PROVIDER: S-EPMC3736707 | biostudies-literature | 2013 Jul
REPOSITORIES: biostudies-literature
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Can genetics risk-stratify patients with membranous nephropathy?
Bomback Andrew S AS Gharavi Ali G AG
Journal of the American Society of Nephrology : JASN 20130705 8
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Project description:An HLA-DR3 association with membranous nephropathy (MN) was described in 1979 and additional evidence for a genetic component to MN was suggested in 1984 in reports of familial MN. In 2009, a pathogenic autoantibody was identified against the phospholipase A2 receptor 1 (PLA2R1). Here we discuss the genetic studies that have proven the association of human leucocyte antigen class II and PLA2R1 variants and disease in MN. The common variants in PLA2R1 form a haplotype that is associated with disease incidence. The combination of the variants in both genes significantly increases the risk of disease by 78.5-fold. There are important genetic ethnic differences in MN. Disease outcome is difficult to predict and attempts to correlate the genetic association to outcome have so far not been helpful in a reproducible manner. The role of genetic variants may not only extend beyond the risk of disease development, but can also help us understand the underlying molecular biology of the PLA2R1 and its resultant pathogenicity. The genetic variants identified thus far have an association with disease and could therefore become useful biomarkers to stratify disease risk, as well as possibly identifying novel drug targets in the near future.
| S-EPMC6113634 | biostudies-literature
Project description: Not available
| S-EPMC10403650 | biostudies-literature
Project description:Here we conducted a retrospective study to examine the risk of cardiovascular events (CVEs) relative to that of end-stage renal disease (ESRD) in patients with primary membranous nephropathy, in a discovery cohort of 404 patients. The cumulative incidence of CVEs was estimated in the setting of the competing risk of ESRD with risk factors for CVEs assessed by multivariable survival analysis. The observed cumulative incidences of CVEs were 4.4%, 5.4%, 8.2%, and 8.8% at 1, 2, 3, and 5 years respectively in the primary membranous nephropathy cohort. In the first 2 years after diagnosis, the risk for CVEs was similar to that of ESRD in the entire cohort, but exceeded it among patients with preserved renal function. Accounting for traditional risk factors and renal function, the severity of nephrosis at the time of the event (hazard ratio 2.1, 95% confidence interval 1.1 to 4.3) was a significant independent risk factor of CVEs. The incidence and risk factors of CVEs were affirmed in an external validation cohort of 557 patients with primary membranous nephropathy. Thus early in the course of disease, patients with primary membranous nephropathy have an increased risk of CVEs commensurate to, or exceeding that of ESRD. Hence, reduction of CVEs should be considered as a therapeutic outcome measure and focus of intervention in primary membranous nephropathy.
| S-EPMC6787915 | biostudies-literature
Project description:IntroductionThe majority of primary membranous nephropathy (MN) cases are no longer considered idiopathic with the discovery of the podocytic autoantigens: phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A). Limited data on PLA2R-related MN in Indians exist in literature, and THSD7A-related MN remains undocumented in this population. We aimed to characterize the baseline PLA2R and THSD7A profile of adult and pediatric membranous nephropathy (MN) in a large Indian single-institution cohort.MethodsA retrospective analysis of all cases of MN (primary and secondary) between 2014 and 2017 was performed with PLA2R direct immunofluorescence and THSD7A immunohistochemistry on the biopsies and anti-PLA2R enzyme-linked immunosorbent assay (ELISA) on baseline sera.ResultsMN constituted 10% of kidney biopsies received in the study period. A total of 216 cases with adequate tissue underwent PLA2R direct immunofluorescence, and 110 of them had available sera for PLA2R ELISA. Combining both testing methods, the prevalence of PLA2R-related primary MN was 72.8%, with moderate concordance between the 2 methods (kappa 0.61). PLA2R was also detected in 16.7% cases of secondary MN, most commonly lupus MN. THSD7A immunohistochemistry performed on 176 cases showed a prevalence of 3.4% in primary MN. One case of lupus MN was also positive for THSD7A. Dual positivity (PLA2R and THSD7A) was noted in 2 cases. The large pediatric cohort tested showed a prevalence of 44% of PLA2R based on tissue testing, whereas 1 case demonstrated THSD7A positivity.ConclusionThis study in a large cohort of Indian patients demonstrates prevalence rates of PLA2R- and THSD7A-related MN similar to world literature, including the substantial cohort of pediatric MN. It also confirms variation in MN in the form of outliers within PLA2R (related to tissue and serum testing), dual positivity for PLA2R and THSD7A, and PLA2R/THSD7A-positive secondary MN.
| S-EPMC7486174 | biostudies-literature
Project description:We characterized the renal parenchymal cell and immune cell profiles of IMN renal tissues and discovered the distinct expression signatures of myeloid cell, T cell and B cell subsets.
2023-09-27 | GSE241302 | GEO
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:BACKGROUND:Patients with Idiopathic membranous nephropathy (IMN) have various outcomes. The aim of this study is to construct a tool for clinicians to precisely predict outcome of IMN. METHODS:IMN patients diagnosed by renal biopsy from Shanghai Ruijin Hospital from 2009.01 to 2013.12 were enrolled in this study. Primary outcome was defined as a combination of renal function progression [defined as a reduction of estimated glomerular filtration rate (eGFR) equal to or over 30% comparing to baseline], ESRD or death. Risk models were established by Cox proportional hazard regression analysis and validated by bootstrap resampling analysis. ROC curve was applied to test the performance of risk score. RESULTS:Totally 439 patients were recruited in this study. The median follow-up time was 38.73 ± 19.35 months. The enrolled patients were 56 (15-83) years old with a male predominance (sex ratio: male vs female, 1:0.91). The median baseline serum albumin, eGFR-EPI and proteinuria were 23(8-43) g/l, 100.31(12.81-155.98) ml/min/1.73 m2 and 3.98(1.50-22.98) g/24 h, respectively. In total, there were 36 primary outcomes occurred. By Cox regression analysis, the best risk model included age [HR: 1.04(1.003-1.08), 95% CI from bootstrapping: 1.01-1.08), eGFR [HR: 0.97 (0.96-0.99), 95% CI from bootstrapping: 0.96-0.99) and proteinuria [HR: 1.09 (1.01-1.18), 95% CI from bootstrapping: 1.02-1.16). One unit increasing of the risk score based on the best model was associated with 2.57 (1.97-3.36) fold increased risk of combined outcome. The discrimination of this risk score was excellent in predicting combined outcome [C statistics: 0.83, 95% CI 0.76-0.90]. CONCLUSIONS:Our study indicated that older IMN patients with lower eGFR and heavier proteinuria at the time of renal biopsy were at a higher risk for adverse outcomes. A risk score based on these three variables provides clinicians with an effective tool for risk stratification.
| S-EPMC6368730 | biostudies-literature
Project description:To search for new markers of active lesions that might help better understand the molecular basis of MN and IgAN and aid in their diagnosis, DNA microarray analysis was performed with peripheral blood mononuclear cells (PBMCs)
2016-04-22 | GSE73953 | GEO
Project description:Anti-M-type phospholipase A2 receptor (anti-PLA2R) is a widely accepted biomarker for clinical idiopathic membranous neurophathy (IMN). However, its ability to differentiate between IMN and secondary MN (SMN) is controversial. The objective of this study was to assess clinical MN biomarkers in blood, tissue and urine samples from Chinese patients. In total, 195 MN patients and 70 patients with other glomerular diseases were prospectively enrolled in the study. Participants were followed up for average of 17 months (range 3-39 months). Anti-PLA2R and anti-THSD7A (thrombospondin type-1 domain-containing 7A) were detected only in MN patient sera and not in controls. Serum anti-THSD7A and THSD7A-positive biopsies were detected in 1/18 and 2/18 PLA2R-negative MN cases, respectively. PLA2R and THSD7A were detected in 72.27% and 40% of SMN cases, respectively. While serum positivity for both anti-PLA2R and anti-THSD7A at the time of renal biopsy was specific to MN patients, neither antigen could discriminate between primary and secondary MN. We also found that high urinary levels of retinol binding protein (RBP) predicted poor proteinuria outcomes in study participants. Patients with low or medium urinary RBP levels achieved remission more frequently than those with high RBP.
| S-EPMC5356526 | biostudies-literature
Project description:GWAS for Membranous Nephropathy
| PRJNA609184 | ENA