HLA Alleles and Prognosis of PLA2R-Related Membranous Nephropathy

2021 ◽  
pp. CJN.18021120
Author(s):  
Wei-Bo Le ◽  
Jingsong Shi ◽  
Fan Yang ◽  
Si-Wen Gong
Keyword(s):  
Membranous Nephropathy ◽  
Prospective Cohort ◽  
Poor Prognosis ◽  
Significant Risk ◽  
Chinese Patients ◽  
Hla Alleles ◽  
Cox Analysis ◽  
Antibody Levels ◽  
Egfr Decline

Background and objectives Associations between HLA alleles and susceptibility to PLA2R-related membranous nephropathy have been well defined previously in Chinese patients. However, the relationships between HLA alleles and kidney outcome remain unclear. Design, setting, participants, & measurements Five HLA genes (DRB1, DQA1, DQB1, DRB3, and DRB5) were genotyped in a prospective cohort of 392 patients with PLA2R-related membranous nephropathy. The associations between HLA alleles and kidney outcomes were studied. Results A total of 79 HLA alleles were identified in this study. Four HLA alleles, DRB1*13:01 (n=12, HR 3.7, 95% CI 1.8 - 7.8, P < 0.001) , DQB1*06:03 (n=12, HR 3.7, 95% CI 1.8 - 7.8, P < 0.001), DRB1*04:05 (n=12, HR 3.8，95% CI 1.5 - 9.5, P = 0.004) and DQB1*03:02 (n=21, HR 3.1，95% CI 1.4 - 6.7, P = 0.005), were associated with a ≥ 40% eGFR decline during follow-up. DRB1*13:01 and DQB1*06:03 were tightly linked with each other. Forty-four of the 392 patients (11%) carried at least one of the four identified risk HLA alleles in this study. Compared with patients who were negative for all risk HLA alleles, those carrying at least one risk HLA allele had a significant risk of a ≥ 40% eGFR decline during follow-up (HR 3.9, 95% CI 2.3 - 6.7, P < 0.001). After adjusting for age, sex, proteinuria, albumin, eGFR, and anti-PLA2R antibody levels, multivariable Cox analysis showed that patients carrying any of the four risk HLA alleles remained associated with a higher risk of a ≥40% decline in eGFR (HR 4.1, 95% CI 2.3 - 7.1, P < 0.001). Conclusions Carrying any of the HLA alleles, DRB1*13:01/DQB1*06:03, DRB1*04:05 and DQB1*03:02, was independently associated with poor prognosis in Chinese patients with PLA2R-related membranous nephropathy.

scholarly journals P0083HLA-DRB1*1301-DQB*0603-DRB3*0202 HAPLOTYPE IS INDEPENDENTLY ASSOCIATES WIHT POOR PROGNOSIS IN PLA2R-RELATED MEMBRANOUS NEPHROPAHTY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Weibo Le ◽  
JingSong Shi ◽  
Qin Hou
Keyword(s):  
Linkage Disequilibrium ◽  
Poor Prognosis ◽  
High Linkage Disequilibrium ◽  
Renal Outcome ◽  
Hla Alleles ◽  
Risk Alleles ◽  
Lower Egfr ◽  
Almost All ◽  
Egfr Decline

Abstract Background and Aims The susceptibility of Idiopathic membranous nephropathy (MN) is associated with HLA alleles. We previously found almost all (98.7%) patients with PLA2R-related MN carry either or both of the HLA-DRB1*1501 and DRB3*0202 risk alleles. However, the associations of HLA alleles and renal outcome is not known. Method we investigated the associations between HLA alleles and renal outcome in 392 PLA2R-related MN patients. Results We found that HLA-DRB1*1301 and DQB1*0603, which are in high linkage disequilibrium (R2 = 1.0, D’=1.0), are associated with at least 30% eGFR decline during follow-up (HR 2.2, p&lt;0.001). HLA-DRB1*1301 and DQB1*0603 are not a susceptible HLA allele for PLA2R-related MN. Neither HLA-DRB1*1501 nor DRB3*0202 is associated with renal outcome. After adjusting age, gender and the two susceptible HLA alleles, DRB1*1301 haplotype remains significant associated with renal outcome. Compared those patients with negative DRB1*1301, patients with positive DRB1*1301 showed a similar eGFR level at baseline, but a significant lower eGFR at the last follow up. There were 12 PLA2R-related MN patients with positive DRB1*1301, eight of them (66.7%) showed more than 30% eGFR decline during follow-up. Among the 12 patients carrying DRB1*1301, all (100%) had DRB3*0202, four (33.3%) had DRB1*1501, and none (0%) had DRB1*0301. Linkage disequilibrium analysis showed the susceptible allele DRB3*0202 was highly linked with DRB1*0301 and DRB1*1301, while HLA-DRB1*0301 was not associated with renal outcome. Conclusion HLA-DRB1*1301-DQB*0603-DRB3*0202 haplotype is independently associated with Poor Prognosis in PLA2R-related Membranous.

Abstract 16117: Nonresponders to Cardiac Rehabilitation and Outcomes

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Alban De Schutter ◽  
Carl Lavie ◽  
Eiman Jahangir ◽  
Arthur Menezes ◽  
Homeyar Dinshaw ◽  
...  
Keyword(s):  
Ejection Fraction ◽  
Cardiac Rehabilitation ◽  
Exercise Capacity ◽  
Poor Prognosis ◽  
Cardiopulmonary Exercise Testing ◽  
Significant Risk ◽  
Metabolic Equivalent ◽  
Cardiopulmonary Exercise ◽  
Before And After

Introduction: Studies of coronary heart disease (CHD) and cardiac rehabilitation (CR) have traditionally focused on increasing enrollment in CR. We examine here the prognosis of patients who enrolled and completed CR, but saw no significant improvement in exercise capacity [nonresponders (NR)]. Hypothesis: Nonresponders have a poor prognosis. Methods: 780 CHD patients who completed CR with cardiopulmonary exercise testing (CPX) before and after the intervention were divided according to improvement in exercise tolerance (ET; no change or decline vs improvement in metabolic equivalent). Mortality was tracked post CR for all patients; 1 to 161 months of follow-up (mean 6.4 years). Results: 243 (31%) subjects were NR. After adjustment for body mass index, age, gender, ejection fraction and baseline ET, lack of improvement in exercise capacity was associated with a statistically significant 55% increase in mortality (p=0.03; Figure 1). Higher age (OR 1.02; p 0.05) and baseline ET (OR 1.07; p 0.001) was significantly associated with being a NR, but depression, gender and ejection fraction were not significant risk factors. Conclusions: A substantial proportion of subjects referred to CR have no improvement in ET and comparatively demonstrate a poor prognosis. Further investigation into the identifying characteristics of this population is needed to examine if their prognosis can be altered.

scholarly journals Antibodies against Malondialdehyde in Haemodialysis Patients and Its Association with Clinical Outcomes: Differences between Subclasses and Isotypes

2020 ◽  
Vol 9 (3) ◽  
pp. 753
Author(s):  
Shailesh Kumar Samal ◽  
Abdul Rashid Qureshi ◽  
Mizanur Rahman ◽  
Peter Stenvinkel ◽  
Johan Frostegård
Keyword(s):  
Significant Risk ◽  
Premature Death ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Multivariate Risk ◽  
Increased Risk ◽  
All Cause Mortality ◽  
Low Levels ◽  
Antibody Levels

Patients on haemodialysis (HD-patients) have an increased risk of premature death. Low levels of IgM antibodies against malondialdehyde (anti-MDA) are associated with increased risk of cardiovascular disease (CVD) with underlying potential mechanisms described. Here, we studied subclasses and isotypes of anti-MDA in 210 HD-patients with mortality as outcome (56% men, median age 66, Interquartile range (IQR) 51–74 years, vintage time 29 (15–58) months, mean follow up period of 41 (20–60)months). Patients were also divided into inflamed c-reactive protein (CRP >5.6 mg/mL) and non-inflamed. Antibody levels were measured by ELISA. In multivariate risk analysis, patients in low tertile of IgM anti-MDA sub-distribution hazard ratio (sHR 0.54); 95% confidence interval (CI: 0.34–0.89) inversely and significantly associated with all-cause mortality after five years, after adjusting for confounders. Low tertile of IgG (sHR 0.48, 95%CI: 0.25–0.90, p = 0.02) and IgG1 (sHR 0.50, CI: 0.24–1.04, p = 0.06) was associated low mortality among non-inflamed patients. In contrast, anti-MDA IgG2 among inflamed patients was significantly associated with increased mortality, IgG2(sHR 2.33, CI: 1.16–4.68, p = 0.01). IgM anti-MDA was a novel biomarker among HD-patients with low levels being associated with mortality, while low levels of IgG and IgG1 but not IgA anti-MDA were associated with mortality only among non-inflamed patients. IgG2 anti-MDA was a significant risk marker among inflamed patients, which could be related to infection.

scholarly journals Renal Function during Hospitalization and Outcome in Chinese Patients with Acute Decompensated Heart Failure

2021 ◽  
Author(s):  
Hao-Wei Lee ◽  
Chin-Chou Huang ◽  
Chih-Yu Yang ◽  
Hsin-Bang Leu ◽  
Po-Hsun Huang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Renal Function ◽  
Clinical Outcomes ◽  
Acute Decompensated Heart Failure ◽  
Significant Risk ◽  
Decompensated Heart Failure ◽  
Chinese Patients ◽  
Cox Regression Analysis ◽  
The Impact

Abstract It is well known that the heart and kidney have a bi-directional correlation, in which organ dysfunction results in maladaptive changes in the other. We aimed to investigate the impact of renal function and its decline during hospitalization on clinical outcomes in patients with acute decompensated heart failure (ADHF). A total of 119 consecutive Chinese patients admitted for ADHF were prospectively enrolled. The course of renal function was presented with estimated glomerular filtration rate (eGFR), calculated by the four-variable equation proposed by the Modification of Diet in Renal Disease (MDRD) Study. Worsening renal function (WRF), defined as eGFR decline between admission (eGFRadmission) and pre-discharge (eGFRpredischarge), occurred in 41 patients. Clinical outcomes during the follow-up period were defined as 4P-major adverse cardiovascular events (4P-MACE), including the composition of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and nonfatal HF hospitalization. During an average follow-up period of 2.6±3.2 years, 66 patients experienced 4P-MACE. Cox regression analysis revealed that impaired eGFRpredischarge, but not eGFRadmission or WRF, was significantly correlated with the development of 4P-MACE (HR, 2.003; 95% CI, 1.072–3.744; P=0.029). In conclusion, impaired renal function before discharge, but not WRF, is a significant risk factor for poor outcomes in patients with ADHF.

scholarly journals The Most N-Terminal Region of THSD7A Is the Predominant Target for Autoimmunity in THSD7A-Associated Membranous Nephropathy

2018 ◽  
Vol 29 (5) ◽  
pp. 1536-1548 ◽  
Author(s):  
Larissa Seifert ◽  
Elion Hoxha ◽  
Anna M. Eichhoff ◽  
Gunther Zahner ◽  
Silke Dehde ◽  
...  
Keyword(s):  
Membranous Nephropathy ◽  
Epitope Mapping ◽  
Hek293 Cells ◽  
Serum Samples ◽  
Epitope Recognition ◽  
Multidomain Structure ◽  
Antibody Levels ◽  
Terminal Domains

Background Thrombospondin type 1 domain–containing 7A (THSD7A) has been identified as a pathogenic autoantigen in membranous nephropathy (MN). However, the THSD7A epitopes targeted by patient autoantibodies are unknown.Methods We performed an in silico analysis of the THSD7A multidomain structure, expressed the folded domains in HEK293 cells, and tested for domain reactivity with 31 serum samples from patients with THSD7A-associated MN using Western and native blotting. Immunogenicity of the antigen domains was further investigated by cDNA immunization of rabbits and mice.Results We characterized the extracellular topology of THSD7A as a tandem string of 21 thrombospondin type 1 domains. Overall, 28 serum samples (90%) recognized multiple epitope domains along the molecule. Detailed epitope mapping revealed that the complex consisting of the first and second N-terminal domains (amino acids 48–192) was recognized by 27 of 31 patient serum samples (87%). Serum recognizing one or two epitope domains showed lower anti-THSD7A antibody levels than serum recognizing three or more epitope domains. During follow-up, a loss of epitope recognition was observed in seven of 16 patients, and it was accompanied by decreasing antibody levels and remission of proteinuria. In four of 16 patients, epitope recognition patterns changed during follow-up. Notably, immunization experiments in rabbits and mice revealed that induced antibodies, like patient autoantibodies, preferentially bound to the most N-terminal domains of THSD7A.Conclusions Our data show that the immune response in THSD7A-associated MN is polyreactive and that autoantibodies predominantly target the most N-terminal part of THSD7A.

scholarly journals Poor prognosis of child and adolescent musculoskeletal pain: a systematic literature review

BMJ Open ◽  
2019 ◽  
Vol 9 (7) ◽  
pp. e024921 ◽  
Author(s):  
Negar Pourbordbari ◽  
Allan Riis ◽  
Martin Bach Jensen ◽  
Jens Lykkegaard Olesen ◽  
Michael Skovdal Rathleff
Keyword(s):  
Prognostic Factors ◽  
Literature Review ◽  
Cohort Studies ◽  
Children And Adolescents ◽  
Musculoskeletal Pain ◽  
Treatment Effect ◽  
Prospective Cohort ◽  
Poor Prognosis ◽  
Prospective Cohort Studies

ObjectivesTo identify baseline patient characteristics that are (1) associated with a poor outcome on follow-up regardless of which treatment was provided (prognosis) or (2) associated with a successful outcome to a specific treatment (treatment effect modifiers).DesignSystematic literature review according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines.Data sourcesMedline, Embase, Cinahl, Web of Science, Cochrane, SportDiscus, OT Seeker and PsychInfo were searched for prospective cohort studies up to February 2019 without limitation in publication date.Eligibility criteriaProspective cohort studies reporting either prognostic factors or treatment effect modifiers on persistent musculoskeletal pain in 0-year-old to 19-year-old children and adolescents. Pain caused by tumours, fractures, infections, systemic and neurological conditions were excluded.Outcome measuresOur primary outcome was musculoskeletal pain at follow-up and identification of any baseline characteristics that were associated with this outcome (prognostic factors). No secondary outcomes were declared.MethodTwo reviewers independently screened abstracts and titles. We included prospective cohort studies investigating the prognosis or treatment effect modifiers of 0-year-old to 19-year-old children and adolescents with self-reported musculoskeletal pain. Risk of bias assessment was conducted with the Quality in Prognostic Studies tool.ResultsTwenty-six studies yielding a total of 111 unique prognostic factors were included. Female sex and psychological symptoms were the most frequent investigated prognostic factors. Increasing age, generalised pain, longer pain duration and smoking were other identified prognostic factors. No treatment effect modifiers were identified.ConclusionSeveral prognostic factors are associated with a poor prognosis in children and adolescents with musculoskeletal pain. These prognostic factors may help guide clinical practice and shared decision-making. None of the included studies was conducted within a general practice setting which highlights an area in need of research.PROSPERO registration numberCRD42016041378.

scholarly journals Presence of Hepatic Steatosis Does Not Increase the Risk of Hepatocellular Carcinoma in Patients With Chronic Hepatitis B Over Long Follow-Up

2020 ◽  
Vol 13 ◽  
pp. 117863612091887
Author(s):  
Chong Teik Lim ◽  
George Boon Bee Goh ◽  
Huihua Li ◽  
Tony Kiat-Hon Lim ◽  
Wei Qiang Leow ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Chronic Hepatitis ◽  
Hepatitis B ◽  
Hepatic Steatosis ◽  
Chronic Hepatitis B ◽  
Significant Risk ◽  
Conclusive Evidence ◽  
Nonalcoholic Fatty Liver ◽  
Cox Analysis

Background: Chronic hepatitis B (CHB) infection and nonalcoholic fatty liver disease (NAFLD) are liver diseases which may lead to hepatocellular carcinoma (HCC) formation. Both disease entities have been attributed independently to increase risk of HCC development. While concomitant hepatic steatosis in patients with CHB are becoming more frequent in view of increasing NAFLD prevalence, there is no conclusive evidence linking presence of hepatic steatosis and increased HCC risk in patients with CHB infection. This study explores the association of hepatic steatosis among CHB-infected individuals in HCC development. Methods: This is a retrospective study on a cohort of patients with CHB who underwent liver biopsy between January 2000 and December 2014. They were stratified according to presence and severity of histologically proven hepatic steatosis and subsequently followed up to evaluate the association between hepatic steatosis and HCC development. Results: Among 289 patients with a median follow-up of 111.1 months, hepatic steatosis was present in 185 patients (64.0%). In all, 27 patients developed HCC on follow-up and 21 of them had hepatic steatosis. Univariate Cox analysis showed that age (hazard ratio [HR] = 1.08, 95% CI = 1.042-1.12), type 2 diabetes mellitus (T2DM) (HR = 4.00, 95% CI = 1.622-9.863), and Ishak score (HR = 1.221, 95% CI = 1.014-1.472) were associated with HCC development, whereas multivariate Cox analysis demonstrated that age and T2DM (HR = 2.69, 95% CI = 1.072-6.759) were significant risk factors for development of HCC. Conclusions: Concurrent hepatic steatosis in patients with CHB infection is not a risk factor for hepatocellular carcinoma formation.

scholarly journals CDX2 methylation may predict the prognosis of patients with lung cancer

2021 ◽  
Author(s):  
Hongxue Cui ◽  
Zhenliang Zhang ◽  
Xueli Sun ◽  
Ling Fu ◽  
Xiaohua Zhao ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Lung Cancer ◽  
Poor Prognosis ◽  
Cpg Island ◽  
Methylation Status ◽  
Prognostic Predictor ◽  
Specific Pcr ◽  
Kaplan Meier ◽  
Cox Analysis

IntroductionCDX2 methylation predicts poor prognosis in gastric cancer, squamous esophageal cancer and colorectal cancer. The present study was performed to investigate the roles of CDX2 methylation in lung cancer.Material and methodsOne hundred and sixty-seven patients with lung cancer were enrolled. Methylation-specific PCR (MSP) was performed to investigate the methylation status of CDX2. Sequencing of the CDX2 5’ CpG island was conducted as well. A 5-year follow-up was performed by a research nurse or dedicated physician. The primary endpoint was death related with lung cancer. Kaplan-Meier curve was used to analyze the survival situation of patients. Univariate and multivariate Cox analysis was performed to investigate the potential predictors for prognosis of patients with lung cancer.ResultsThe patients were classified into two groups according to CDX2 status: methylation (n=75) and unmethylation (n=92). After the 5-year follow-up, we found that the survival rate of patients with methylation of CDX2 was much lower than those with unmethylation of CDX2 (56% vs. 84.8%, P=0.000). Among the smoking patients, methylation of CDX2 was related with poorer prognosis of patients with lung cancer (P=0.000). DFS of patients with CDX2 methylation was lower than those without CDX2 methylation (56.0% vs. 73.9%, P=0.009). Univariate and multivariate Cox analysis demonstrated that CDX2 methylation served as independent prognostic predictor of patients with lung cancer (univariate: HR=3.705, 95%CI=1.922-7.139; multivariate: HR=3.418, 95%CI=1.826-6.397).ConclusionsCDX2 methylation may serve as independent prognostic predictor for patients with lung cancer.

MO321THE USE OF INTRAVENOUS CYCLOPHOSPHAMIDE AND ORAL STEROIDS IN PRIMARY MEMBRANOUS NEPHROPATHY WITH ADVANCED KIDNEY DISEASE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Omar Ragy ◽  
Patrick Hamilton ◽  
Durga Kanigicherla
Keyword(s):  
Kidney Disease ◽  
Hospital Admission ◽  
Membranous Nephropathy ◽  
Partial Remission ◽  
Female Ratio ◽  
Pulse Cyclophosphamide ◽  
Intravenous Pulse Cyclophosphamide ◽  
Oral Steroids ◽  
Antibody Levels

Abstract Background and Aims International guidelines do not recommend specific use of immunosuppression treatment in membranous nephropathy patients presenting with an estimated glomerular filtration rate of &lt;30ml/min/1.73m2. This is due to the scant published evidence of effectiveness and uncertainty around toxic effects at this stage. In this study, we sought to examine the safety and effectiveness of combined cyclophosphamide and steroids in primary membranous nephropathy with advanced kidney disease. Method This is a retrospective study of 18 patients with a biopsy confirmed membranous nephropathy who received combination therapy between 2004 and 2019. The mean age was 66.5 with a 5:1 male: female ratio. The immunosuppression regime included monthly intravenous pulse cyclophosphamide and daily oral steroids. All patients had an initial eGFR of &lt; or = 30 ml/min/1.73 m2 at time of treatment. Clinical parameters are serially monitored as part of clinical care and anti-PLA2R antibody levels were measured at the time of and 1-year post immunosuppression treatment where available. The primary outcome was the achievement of partial remission as per standard criteria. Secondary outcomes were immunological response defined by following the anti-PLA2R antibody levels at the time of presentation and 1-year post, need for renal replacement therapy, outcomes including hospital admission, infections, malignancy, and death. Results Partial Remission was achieved in 16 out of 18 (88%) patients.7 patients (39%) reached complete remission, with none of them requiring dialysis over an average follow-up of 5 years. The average increase in eGFR was 12.5 ml/min/1.73m2 from the time of immunosuppression till the latest follow up. 2 out of 18 (11%) patients were refractory to treatment and required initiation of dialysis 1 and 8 years post immunosuppression. Results for the anti-PLA2R antibody test were available for 12 (66.6%) patients at presentation all shown to be positive. Of these, 7 (58%) achieved both immunological and clinical remission. 4 patients developed 4 different cancers (Bladder, mesothelioma, skin SCC and sigmoid) during follow-up; 2 patients required hospital admission for episodes of infections. Both were managed with antibiotics, and patients were discharged home safely. 5 patients died at the end of the follow-up period (27.7%). Conclusion Here we show that the combination of intravenous pulse cyclophosphamide and steroid is well tolerated and effective in achieving remission in primary membranous nephropathy with advanced renal disease. Both immunological and clinical responses could be achieved in this cohort. Longer-term risk in such patients includes malignancy and infections. This study provides reassurance that this cohort of patients can be considered for immunosuppressive treatment, although prospective studies are required to provide further robust evidence.

Sign in / Sign up

Export Citation Format

Share Document