Associations between m-type phospholipase A2 receptor,human leukocyte antigen gene polymorphisms and idiopathic membranous nephropathy.
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SUBMITTER: Liu X
PROVIDER: S-EPMC8806941 | biostudies-literature | 2021 Dec
REPOSITORIES: biostudies-literature
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Associations between m-type phospholipase A2 receptor,human leukocyte antigen gene polymorphisms and idiopathic membranous nephropathy.
Liu Xiaogang X Xu Weixi W Yu Chengyuan C Wang Mingao M Liu Ruichan R Xie Rujuan R
Bioengineered 20211201 1
Primary membranous nephropathy, also known as idiopathic membranous nephropathy, is an autoimmune disease. As an autoimmune disease, genetic factors are essential in the pathogenesis of IMN. People pay more and more attention to genetics and bioinformatics. With the continuous improvement and development of high-throughput gene sequencing and genotyping technology, it has been confirmed that many genes and their single nucleotide polymorphisms are strongly correlated with IMN disease susceptibil ...[more]
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Project description:BackgroundIdiopathic membranous nephropathy, a common form of the nephrotic syndrome, is an antibody-mediated autoimmune glomerular disease. Serologic diagnosis has been elusive because the target antigen is unknown.MethodsWe performed Western blotting of protein extracts from normal human glomeruli with serum samples from patients with idiopathic or secondary membranous nephropathy or other proteinuric or autoimmune diseases and from normal controls. We used mass spectrometry to analyze the reactive protein bands and confirmed the identity and location of the target antigen with a monospecific antibody.ResultsSerum samples from 26 of 37 patients (70%) with idiopathic but not secondary membranous nephropathy specifically identified a 185-kD glycoprotein in nonreduced glomerular extract. Mass spectrometry of the reactive protein band detected the M-type phospholipase A(2) receptor (PLA(2)R). Reactive serum specimens recognized recombinant PLA(2)R and bound the same 185-kD glomerular protein as did the monospecific anti-PLA(2)R antibody. Anti-PLA(2)R autoantibodies in serum samples from patients with membranous nephropathy were mainly IgG4, the predominant immunoglobulin subclass in glomerular deposits. PLA(2)R was expressed in podocytes in normal human glomeruli and colocalized with IgG4 in immune deposits in glomeruli of patients with membranous nephropathy. IgG eluted from such deposits in patients with idiopathic membranous nephropathy, but not in those with lupus membranous or IgA nephropathy, recognized PLA(2)R.ConclusionsA majority of patients with idiopathic membranous nephropathy have antibodies against a conformation-dependent epitope in PLA(2)R. PLA(2)R is present in normal podocytes and in immune deposits in patients with idiopathic membranous nephropathy, indicating that PLA(2)R is a major antigen in this disease.
| S-EPMC2762083 | biostudies-literature
Project description:The M-type receptor for phospholipase A2 (PLA2R1) is the major target antigen in idiopathic membranous nephropathy (iMN). Our recent genome-wide association study showed that genetic variants in an HLA-DQA1 and phospholipase A2 receptor (PLA2R1) allele associate most significantly with biopsy-proven iMN, suggesting that rare genetic variants within the coding region of the PLA2R1 gene may contribute to antibody formation. Here, we sequenced PLA2R1 in a cohort of 95 white patients with biopsy-proven iMN and assessed all 30 exons of PLA2R1, including canonical (GT-AG) splice sites, by Sanger sequencing. Sixty patients had anti-PLA2R1 in serum or detectable PLA2R1 antigen in kidney tissue. We identified 18 sequence variants, comprising 2 not previously described, 7 reported as rare variants (<1%) in the Single Nucleotide Polymorphism Database or the 1000 Genomes project, and 9 known to be common polymorphisms. Although we confirmed significant associations among 6 of the identified common variants and iMN, only 9 patients had the private or rare variants, and only 4 of these patients were among the 60 who were PLA2R positive. In conclusion, rare variants in the coding sequence of PLA2R1, including splice sites, are unlikely to explain the pathogenesis of iMN.
| S-EPMC3609136 | 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:BackgroundThe anti-phospholipase A2 receptor (PLA2R) antibody is a non-invasive diagnostic tool and prognosis predictor of idiopathic membranous nephropathy (IMN). Baseline hypercholesterolemia independently predicts proteinuria outcomes in IMN patients. Thus, we investigated whether hyperlipidemia is correlated with anti-PLA2R and pathological indicators.MethodsA total of 495 IMN patients identified by kidney biopsy in Wuhan Tongji Hospital, China, from January 2016 through December 2020 were enrolled in this study. Data on clinical features, pathology findings, and outcomes were collected.ResultsTotal cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) were positively related to proteinuria, indicating damage to the renal glomerulus [Spearman's rank correlation coefficient = 0.432, 0.462, 0.315, and 0.289, respectively, P < 0.001 for all]. In univariate logistic regression, low HDL-C [odds ratio (OR): 0.856; 95% CI: 0.778-0.939; P = 0.001] and high TG [OR: 1.025; 95% CI: 1.006-1.044; P = 0.011] were correlated with tubular atrophy, suggesting lesions on tubules. Increased TC [adjusted OR: 1.285; 95% CI: 1.119-1.475; P < 0.001], non-HDL-C [adjusted OR: 1.284; 95% CI: 1.113-1.482; P = 0.001], and LDL-C [adjusted OR: 1.178; 95% CI: 1.009-1.376; P = 0.039] independently predicted glomerular PLA2R deposit; similar results were observed for lipids in predicting the seropositivity of anti-PLA2R antibodies. After treatment, increased HDL-C [adjusted hazard ratio (HR): 1.764; 95% CI: 1.241-2.507; P = 0.002] and decreased non-HDL-C [adjusted HR: 0.884; 95% CI: 0.795-0.983; P = 0.022] independently predicted proteinuria remission.ConclusionHypercholesterolemia is a potentially useful biomarker for disease severity, serum anti-PLA2R antibody, glomerular PLA2R deposit, and proteinuria outcome of IMN.
| S-EPMC9248763 | biostudies-literature
Project description:IntroductionA 6-month course of cyclophosphamide (CP) and steroids is effective in primary membranous nephropathy (MN), but unappealing because of long-term side effects. We evaluated efficacy of an "antibody-guided" treatment schedule.MethodsPatients with phospholipase A2 receptor (PLA2R)-related MN and high risk of progression were treated with CP 1.5 mg/kg/d and steroids in cycles of 8 weeks. Anti-PLA2R antibodies were measured by indirect immunofluorescence (IIFT) at 8, 16, and 24 weeks, and a negative test resulted in withdrawal of CP, and rapid tapering of prednisone. In patients with persistent anti-PLA2R antibodies at 24 weeks, CP was switched to mycophenolate mofetil. Treatment was repeated in patients with a relapse.ResultsOur analysis included 65 patients (48 males, 17 females), age 61 ± 12 years, estimated glomerular filtration rate (eGFR) 46 ml/min per 1.73 m2 (35-68), urine protein-to-creatinine ratio 7.7 grams/10 mmol creatinine (5.4-11.1) and serum albumin 20 g/l (16-26). Immunologic remission rate was 71% after 8 weeks, 86% after 16 weeks, 88% after 24 weeks, and 94% after 3 years. Twenty-seven patients (42%) had persistent clinical remission after only 8 weeks of therapy. Sixteen patients needed a second course of therapy because of immunologic or clinical relapse. Follow-up was 37 (26-58) months. Overall partial remission rate was 92%. One patient developed end-stage kidney disease. Antibody-guided therapy (ABG) was as effective as the standard 6-month course, whereas providing a lower cumulative dose of CP (11.1 [8.0-18.5] vs. 18.9 [14.2-23.6] grams).ConclusionABG is effective, and allows individualized therapy, with many patients responding to 8 weeks of CP-based therapy.
| S-EPMC10014436 | biostudies-literature
Project description:IntroductionPrimary membranous nephropathy (PMN) is associated with the anti-phospholipase A2 receptor (anti-PLA2R) antibody in 70% of cases. Some anti-PLA2R-negative patients have the PLA2R antigen in renal tissue. This study examined the prognosis of patients with PMN according to their serum anti-PLA2R antibody (SAb) and glomerular PLA2R antigen (GAg) status.MethodsPatients diagnosed with PMN were included retrospectively. Patients were grouped according to their PLA2R status into the SAb-/GAg-, SAb-/GAg+, and SAb+/GAg + groups. Baseline data, renal biopsy results, treatment, and clinical data were compared among the groups. Cox univariable and multivariable analyses examined the factors related to complete remission (CR).ResultsA total of 114 patients were enrolled; 10 (9%) in the SAb-/GAg-, 23 (20%) in the SAb-/GAg+, and 81 (71%) in the SAb+/GAg+ groups. Cumulative CR rate showed a significant difference between the SAb-/GAg - and SAb+/GAg+ groups (log-rank p = 0.003). The multivariable Cox proportional hazard analysis showed that age (HR = 0.968; 95%CI = 0.946-0.990; p = 0.005), SAb+/GAg+ versus SAb-/GAg- (HR = 0.387; 95%CI = 0.190-0.788; p = 0.009), SAb-/GAg+ versus SAb-/GAg- (HR = 0.398; 95%CI = 0.169, 0.939; p = 0.035), total renal chronicity score ≥2 (HR = 0.461, 95%CI: 0.277-0.766, p = 0.003), and IgA deposition (HR = 2.596; 95%CI = 1.227-5.492; p = 0.013) were all independently related (p < 0.05) to CR.ConclusionsThe SAb and GAg status was an indicator of PMN prognosis. The patients with SAb-/GAg - had an increased likelihood of achieving CR than those with SAb-/GAg+ and SAb+/GAg+.
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Project description:BackgroundTo discuss the clinicopathological features and prognosis of patients with idiopathic membranous nephropathy (IMN) who are serum-negative for the anti-PLA2R antibody.MethodOverall, 229 IMN patients were retrospectively collected in this study and classified into anti-PLA2R antibody-negative (PLA2R-, 59 cases) and antibody-positive (PLA2R+, 170 cases) groups. The clinical and pathological features of the PLA2R- group were analyzed; 162 patients in both groups were followed up, and the PLA2R antigen was detected in renal biopsies from the PLA2R- group. Kaplan-Meier and survival analyses were used to compare differences in prognosis.ResultsSerum albumin levels were higher and 24-hour urine protein, creatinine, and beta 2-microglobulin (BMG) levels were lower in the PLA2R- group than in the PLA2R+ group; the proportion of acute and chronic tubular lesions was also significantly lower in the PLA2R- group than in in the PLA2R+ group. After treatment, the remission rate was significantly higher in the negative group than in the positive group (93.02% vs 74.78%,), especially the rate of complete remission (51.16% vs 23.47%). Furthermore, the PLA2R antigen-positive staining rate of 43 patients in the PLA2R- group was 62.79%. Although not significant, the survival rate was higher in the PLA2R- group than in the PLA2R+ group. BMG, 24-hour urine protein and acute and chronic tubular lesions were risk factors for kidney death, and 24-hour urine protein was an independent risk factor for kidney death.ConclusionsCompared with the PLA2R+ group, the PLA2R- group had mild clinical manifestations and pathological damage and a higher clinical treatment remission rate. Renal tissue PLA2R antigen testing can be considered for patients with seronegative IMN to increase the diagnostic rate.
| S-EPMC7039122 | biostudies-literature
Project description:Most patients with idiopathic membranous nephropathy (IMN) have IgG4 autoantibodies against phospholipase A2 receptor (PLA2R). C3 and C5b-9 are found in immune deposits of IMN kidney biopsy specimens, but the pathway of complement activation in IMN remains elusive. We report the case of a patient who developed IMN with intense staining for PLA2R, IgG4, C3, C5b-9, factor B, and properdin and very weak staining for C1q, C4d, and IgG1. Measurement of mannan binding lectin (MBL) antigenic level and activity revealed MBL deficiency. Genotyping revealed a heterozygous (A/C) polymorphism in codon 57 of MBL2 exon 1 associated with homozygous and heterozygous variations in the promoter region at -550 (L/L) and -221 (X/Y), respectively, suggesting that the patient harbored the LXA/LYC haplotypes linked to MBL deficiency. Genetic sequencing in 77 consecutive patients with IMN identified four patients with MBL2 promoter and coding region variations associated with MBL deficiency and the same complement pattern in immune deposits as the index patient. In contrast, patients with wild-type MBL2 had immune deposits with intense Cd4 staining. Thus, IMN can develop in patients with complete MBL deficiency, with complement activated mainly by the alternative pathway, whereas the lectin pathway is also activated in those with wild-type MBL2.
| S-EPMC5118485 | biostudies-literature
Project description:Background:M-type phospholipase A2 receptor (PLA2R) is the first autoantigen responsible for idiopathic membranous nephropathy (IMN). However, serum PLA2R antibody (PLA2R-Ab) can be inaccurate in distinguishing between IMN and secondary membranous nephropathy, while renal PLA2R antigen (PLA2R-Ag) emerges as an ancillary diagnostic. The present study is aimed at examining the associations between PLA2R-Ab in sera and PLA2R-Ag in kidneys in IMN patients. Methods:A total of 93 patients with IMN were retrospectively identified. Their serum PLA2R-Ab and renal PLA2R-Ag expression levels were determined, and the clinical correlations between these parameters and clinical features were examined. Results:The sensitivities of serum PLA2R-Ab and renal PLA2R-Ag for diagnosing IMN were 74.2% and 88.2%, respectively (P < 0.001), with poor consistency. Higher serum PLA2R-Ab levels were correlated to stronger renal PLA2R-Ag expression (P = 0.048). Patients with positive PLA2R-Ab significantly differed from those with negative levels, in terms of proteinuric levels over 24 hours (4.54 vs. 3.46?g/day, P = 0.015) and serum albumin (23.28 vs. 27.95?g/L, P = 0.038). Among patients with positive renal PLA2R-Ag, patients with positive PLA2R-Ab had significantly higher 24-hour proteinuria, when compared to patients with negative PLA2R-Ab (4.57 vs. 3.08?g/day, P = 0.005). Among those with positive PLA2R-Ab in sera, their PLA2R-Ab levels were correlated with the estimated glomerular filtration and serum creatinine. Conclusion:Serum PLA2R-Ab exhibits a closer correlation with proteinuric severity and renal function, when compared to renal PLA2R-Ag.
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Project description: Not available
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