RESUMO
OBJECTIVE: High serum levels of B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL) have been observed in patients with idiopathic membranous nephropathy (iMN); however, their relationships with disease severity and progression remain unclear. METHODS: Patients with iMN diagnosed via renal biopsy were enrolled in this study. The concentrations of BAFF and APRIL were determined using ELISA kits. Proteinuria remission, including complete remission (CR) and partial remission (PR), and renal function deterioration were defined as clinical events. The Cox proportional hazards method was used to analyze the relationship between cytokine levels and disease progression. RESULTS: Seventy iMN patients were enrolled in this study, with a median follow-up time of 24 months (range 6-72 months). The serum levels of BAFF and APRIL were higher in iMN patients than in healthy controls but lower than those in minimal change disease (MCD) patients. The serum BAFF level was positively correlated with the serum APRIL level, serum anti-phospholipase A2 receptor (anti-PLA2R) antibody level, and 24-h proteinuria and negatively correlated with the serum albumin (ALB) level. However, no significant correlation was observed between the serum APRIL level and clinical parameters. According to the multivariate Cox proportional hazards regression model adjusted for sex, age, systolic blood pressure (SBP), estimated glomerular filtration rate (eGFR), immunosuppressive agent use, 24-h proteinuria, APRIL level, and anti-PLA2R antibody, only the serum BAFF level was identified as an independent predictor of PR (HR, 0.613; 95% CI, 0.405-0.927; p = 0.021) and CR of proteinuria (HR, 0.362; 95% CI, 0.202-0.648; p < 0.001). CONCLUSIONS: A high serum BAFF level is associated with severe clinical manifestations and poor disease progression in patients with iMN.
Assuntos
Fator Ativador de Células B , Progressão da Doença , Glomerulonefrite Membranosa , Proteinúria , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral , Humanos , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Fator Ativador de Células B/sangue , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Prognóstico , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Proteinúria/sangue , Proteinúria/etiologia , Modelos de Riscos Proporcionais , Receptores da Fosfolipase A2/imunologia , Receptores da Fosfolipase A2/sangue , Estudos de Casos e Controles , Idoso , Taxa de Filtração Glomerular , Rim/fisiopatologia , Rim/patologiaRESUMO
Secretory phospholipase A2 group IB (sPLA2-IB) and M-type phospholipase A2 receptor (PLA2R) are closely associated with proteinuria in idiopathic membranous nephropathy (IMN). Podocytes constitute an important component of glomerular filtration, and high basal autophagy is indispensable for podocyte function. The current study aimed to analyze the relationship between sPLA2-IB and podocyte autophagy in IMN and determine whether sPLA2-IB mediates abnormal autophagy regulation in podocytes. The serum sPLA2-IB level and podocyte autophagy were detected, and clinical data were collected from IMN patients with different proteinuria levels. Then, the effects of sPLA2-IB on autophagy signaling pathways were evaluated in cultured human podocytes treated with sPLA2-IB, rapamycin, p38 inhibition, and PLA2R-siRNA in vitro. We found that IMN patients with nephrotic-range proteinuria have a significantly higher level of sPLA2-IB and fewer autophagosomes than those with non-nephrotic-range proteinuria. In vitro sPLA2-IB-induced insufficient autophagy in podocytes and promoted podocyte injury via activation of the mTOR/ULK1ser757 signaling pathway. Moreover, inhibition of p38 MAPK evidently abrogated sPLA2-IB-induced autophagy and the activation of mTOR/ULK1ser757 . Additionally, PLA2R silencing demonstrated that sPLA2-IB-induced abnormal autophagy was also PLA2R-dependent. In conclusion, the results revealed that sPLA2-IB downregulated autophagy and contributed to podocyte injury via PLA2R though activation of the p38MAPK/mTOR/ULK1ser757 signaling pathway.
Assuntos
Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Autofagia/genética , Glomerulonefrite Membranosa/sangue , Fosfolipases A2 do Grupo IB/sangue , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Sistema de Sinalização das MAP Quinases/genética , Podócitos/metabolismo , Receptores da Fosfolipase A2/sangue , Serina-Treonina Quinases TOR/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Idoso , Adesão Celular/genética , Movimento Celular/genética , Células Cultivadas , Feminino , Glomerulonefrite Membranosa/genética , Glomerulonefrite Membranosa/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Receptores da Fosfolipase A2/genética , TransfecçãoRESUMO
BACKGROUND: Antibodies to M-type phospholipase A2 receptor (a-PLA2R) have been identified in most patients with idiopathic membranous nephropathy, but the prevalence in membranous lupus nephritis (MLN) is still unclear. The objective of this study was to assess the prevalence of a-PLA2R antibodies in a large cohort of patients with lupus nephritis. METHODS: a-PLA2R antibodies were measured by ELISA in serum from patients with systemic lupus erythematosus ( n = 190), of whom 37 had a biopsy-proven MLN. Positive samples were confirmed by commercial ELISA kit, Western blot and immunohistochemistry in renal tissue. RESULTS: A total of 10 from 190 patients (5.3%) with systemic lupus erythematosus had circulating a-PLA2R measured by in-house ELISA assay. The antibodies were detected in 7 patients with MLN (18.9%) and 3 patients with non-renal lupus disease (3.2%). PLA2R staining was detected in the kidney biopsy of 5 of the 7 (71.4%) patients with MLN. a-PLA2R levels were associated with active disease but not proteinuria levels. Presence of a-PLA2R antibodies at baseline was associated with worse remission rates and longer time to remission compared to those patients serologically negative. CONCLUSIONS: a-PLA2R antibodies can be detected with low prevalence in MLN patients, but their detection is associated with a worse renal prognosis.
Assuntos
Autoanticorpos/imunologia , Nefrite Lúpica/imunologia , Receptores da Fosfolipase A2/imunologia , Adulto , Autoanticorpos/sangue , Biomarcadores/sangue , Western Blotting , Estudos de Casos e Controles , Progressão da Doença , Ensaio de Imunoadsorção Enzimática , Feminino , Glomerulonefrite Membranosa/diagnóstico , Humanos , Rim/imunologia , Estudos Longitudinais , Nefrite Lúpica/classificação , Nefrite Lúpica/diagnóstico , Masculino , Valor Preditivo dos Testes , Proteinúria , Receptores da Fosfolipase A2/sangue , Estudos RetrospectivosRESUMO
BACKGROUND: The diagnostic value of serum M-type phospholipase A2 receptor antibody (sPLA2R-ab) expression in patients with primary membranous nephropathy (PMN) has been established. However, the association between sPLA2R-ab and clinical remission remains uncertain. METHODS: We systematically searched the literature for clinical trials regarding the correlation between sPLA2R-ab expression and clinical remission of PMN patients. Meta-analysis was performed to determine this association. Subgroup analysis, funnel plots, and sensitivity analysis were also performed to investigate heterogeneity or bias. RESULTS: A total of 11 trials involving 824 patients were included. Patients with positive sPLA2R-ab had a poor clinical remission rate (RR = 0.76, 95%CI 0.68-0.86, P < 0.0001; I2 = 39%), a higher titer of sPLA2R-ab had a lower chance of clinical remission (RR = 0.72, 95%CI 0.59-0.87, P = 0.0006; I2 = 42%),and a higher risk of renal failure (RR = 4.85, 95% CI, 1.83-12.85, P = 0.002; I2 = 0%), without affecting relapse (RR = 0.97, 95% CI, 0.55-1.70; P = 0.92, I2 = 0%). Subgroup analysis by treatment strategies, assay methods, ethnicity, gender, renal function, the approach of ruling out SMN, and the ratio of patients with nephrotic-range proteinuria at baseline showed no significant association between these factors with the prognostic value of sPLA2R-ab for PMN patients. No significant publication bias was found. CONCLUSION: This meta-analysis adds to the evidence for current guidelines that sPLA2R-ab acts as not only a diagnostic marker but also a pivotal predictor for clinical remission. Therefore, sPLA2R-ab can be considered as a prognostic factor for stratifying PMN patients.
Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Receptores da Fosfolipase A2/sangue , Biomarcadores/sangue , Estudos de Coortes , Humanos , Prognóstico , Estudos Prospectivos , Indução de RemissãoRESUMO
BACKGROUND: Complement activation plays a substantial role in the pathogenesis of primary membranous nephropathy (pMN). C5b-9, C3c, MBL, and factor B have been documented in the subepithelial immune deposits. However, the changing of complement activation products in circulation and urine is not clear. METHODS: We measured the circulating and urinary levels of C1q, MBL, C4d, Bb, properdin, C3a, C5a, and sC5b-9, in 134 patients with biopsy-proven pMN, by enzyme-linked immunosorbent assay. All the plasma values were corrected by eGFR and all the urinary values were corrected by urinary creatinine and urinary protein excretion. Anti-PLA2R antibodies were measured in all patients. RESULTS: The plasma complement activation products were elevated both in the patients with and without anti-PLA2R antibodies. C3a levels were remarkably increased in the circulation and urine, much higher than the elevated levels of C5a. C5b-9 was in normal range in plasma, but significantly higher in urine. The urinary C5a had a positive correlation with anti-PLA2R antibody levels and urinary protein. The plasma level of C4d was elevated, but C1q and MBL were comparable to healthy controls. Positive correlations were observed between plasma C4d/MBL and urinary protein, only in the patients with positive anti-PLA2R antibodies but not in those without. The plasma level of Bb was elevated and had positive correlation with urinary protein only in the patients without anti-PLA2R antibodies. CONCLUSION: Complement activation products were remarkable increased in pMN and may serve as sensitive biomarkers of disease activity. The complement may be activated through lectin pathway with the existence of anti-PLA2R antibodies, while through alternative pathway in the absence of antibody.
Assuntos
Ativação do Complemento , Proteínas do Sistema Complemento/análise , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/urina , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Complemento C1q/análise , Complemento C1q/urina , Complemento C3a/análise , Complemento C3a/urina , Complemento C4/análise , Complemento C4/urina , Complemento C5a/análise , Complemento C5a/urina , Fator B do Complemento/análise , Fator B do Complemento/urina , Complexo de Ataque à Membrana do Sistema Complemento/análise , Complexo de Ataque à Membrana do Sistema Complemento/urina , Proteínas do Sistema Complemento/urina , Creatinina/sangue , Creatinina/urina , Feminino , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/terapia , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/urina , Pessoa de Meia-Idade , Properdina/análise , Properdina/urina , Receptores da Fosfolipase A2/análise , Receptores da Fosfolipase A2/sangue , Receptores da Fosfolipase A2/imunologia , Análise de Regressão , Estatísticas não Paramétricas , Adulto JovemRESUMO
BACKGROUND: Idiopathic membranous nephropathy is an autoimmune disease. In approximately 70% of patients, it is associated with autoantibodies against the phospholipase A2 receptor 1 (PLA2R1). Antigenic targets in the remaining patients are unknown. METHODS: Using Western blotting, we screened serum samples from patients with idiopathic membranous nephropathy, patients with other glomerular diseases, and healthy controls for antibodies against human native glomerular proteins. We partially purified a putative new antigen, identified this protein by means of mass spectrometry of digested peptides, and validated the results by analysis of recombinant protein expression, immunoprecipitation, and immunohistochemical analysis. RESULTS: Serum samples from 6 of 44 patients in a European cohort and 9 of 110 patients in a Boston cohort with anti-PLA2R1-negative idiopathic membranous nephropathy recognized a glomerular protein that was 250 kD in size. None of the serum samples from the 74 patients with idiopathic membranous nephropathy who were seropositive for anti-PLA2R1 antibodies, from the 76 patients with other glomerular diseases, and from the 44 healthy controls reacted against this antigen. Although this newly identified antigen is clearly different from PLA2R1, it shares some biochemical features, such as N-glycosylation, membranous location, and reactivity with serum only under nonreducing conditions. Mass spectrometry identified this antigen as thrombospondin type-1 domain-containing 7A (THSD7A). All reactive serum samples recognized recombinant THSD7A and immunoprecipitated THSD7A from glomerular lysates. Moreover, immunohistochemical analyses of biopsy samples from patients revealed localization of THSD7A to podocytes, and IgG eluted from one of these samples was specific for THSD7A. CONCLUSIONS: In our cohort, 15 of 154 patients with idiopathic membranous nephropathy had circulating autoantibodies to THSD7A but not to PLA2R1, a finding that suggests a distinct subgroup of patients with this condition. (Funded by the French National Center for Scientific Research and others.).
Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/imunologia , Receptores da Fosfolipase A2/imunologia , Trombospondinas/imunologia , Western Blotting , Estudos de Casos e Controles , Glomerulonefrite Membranosa/sangue , Humanos , Glomérulos Renais/metabolismo , Receptores da Fosfolipase A2/sangue , Receptores da Fosfolipase A2/metabolismo , Trombospondinas/sangue , Trombospondinas/metabolismoRESUMO
BACKGROUND: The optimal dosing and the efficacy of rituximab for primary membranous nephropathy (PMN) has not been established. This multicentric prospective study evaluates the efficacy and safety of low-dose rituximab (RTX) therapy in patients with PMN in clinical practice. METHODS: Thirty-four consecutive patients with PMN and nephrotic syndrome were included and received RTX (375 mg/m2) once (18 patients) or twice (16 patients). RTX was the first-line therapy for 19 (56%) and the second line for 15 (44%) patients. All patients were followed for 12 months after RTX and 24 for at least 18 months (mean 23.9 ± 18.6 months). RESULTS: At 12 months, 5 patients (14.7%) achieved complete response, 10 (29.4%) partial and 19 (55.8%) no response. Response occurred â¼6 months after RTX. At 24 months, the clinical situation was unchanged: two non-responders achieved partial response and two responders relapsed. Responders had significantly higher baseline GFR and lower anti-PLA2R antibodies compared with non-responders. Outcome was similar between one or two doses of RTX (non-responders 55.5 versus 56%, respectively) and between patients who had received previous therapy versus those receiving RTX as first-line therapy (non-responders 40 versus 68%, respectively). In the 15 patients already treated, the response to RTX was comparable to that of previous therapies. CONCLUSION: Low-dose RTX obtains remission in <50% of PMN patients. Probably, higher doses and longer treatments are needed to induce and maintain a response. The balance between the costs and benefits should guide the selection of the patient and the optimal dosage.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Síndrome Nefrótica/tratamento farmacológico , Rituximab/uso terapêutico , Adulto , Idoso , Biomarcadores/sangue , Feminino , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Síndrome Nefrótica/sangue , Síndrome Nefrótica/patologia , Estudos Prospectivos , Receptores da Fosfolipase A2/sangue , Indução de Remissão , Resultado do Tratamento , Adulto JovemRESUMO
BACKROUND ~This study used two standardized methods to evaluate anti-PLA2R antibody in serum of primary membranous nephropathy (PMN) among Chinese patients to determine Anti-PLA2R antibody distribution and whether immunological reactivity reflected by antibody titer correlates with kidney function parameters. MATERIAL AND METHOD ~Overall, 82 subjects with biopsy-proven primary membranous nephropathy (PMN) , 22 cases with secondary membranous nephropathy (SMN), 40 non-MN patients with established glomerulonephritis, 20 healthy volunteers were recruited from the Division of Nephrology, Nanfang Hospital, China. Anti-PLA2R antibody in the serum of each patient was evaluated by both recombinant cell-based indirect immunofluorescence assay (RC-IFA) and enzyme linked immunosorbent assay (ELISA). Kidney function was assessed by proteinuria for 24 hours, serum albumin, blood urea nitrogen (BUN), serum creatine, serum cystatin C. We assessed the correlation between anti-PLA2R antibody levels and clinical parameter in the PMN patients. RESULTS ~ Fifty-three patients with PMN (64.6%) were positive for anti-PLA2R antibody. The level of antibody determined by RC-IFA ranged from 1:10 to 1:1000 and 0 to 1423 RU/ml by ELISA. The two anti-PLA2R test systems correlated very well with each other and reached an agreement of 95.7% for PMN patients. The level of antibody detected by ELISA in patients with PMN also significantly correlated with proteinuria and nephritic-range proteinuria (> 3.5g/day) . CONCLUSIONS ~Anti-PLA2R antibody is sensitive and extremely specific for diagnosis of Chinese patients with primary membranous nephropathy. Concentration of autoantibody against PLA2R is an ideal marker for monitoring the activity of immunological disease.
Assuntos
Autoanticorpos/imunologia , Glomerulonefrite Membranosa/imunologia , Receptores da Fosfolipase A2/imunologia , Adulto , Anticorpos Anti-Idiotípicos/sangue , Anticorpos Anti-Idiotípicos/imunologia , Povo Asiático , Autoanticorpos/sangue , Biomarcadores/sangue , China , Ensaio de Imunoadsorção Enzimática , Feminino , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/genética , Humanos , Masculino , Pessoa de Meia-Idade , Proteinúria/sangue , Receptores da Fosfolipase A2/sangue , Receptores da Fosfolipase A2/genéticaRESUMO
OBJECTIVE: To examine levels of M-type phospholipase A2 receptor (PLA2R) and its antibody in the patients with hepatitis B virus-associated membranous nephropathy (HBV-MN), and to explore the correlation of PLA2R with laboratory parameters and pathological characteristics.â© Methods: A total of 49 adult patients with biopsy-proved HBV-MN were enrolled in this study. Levels of anti-PLA2R antibody in serum and PLA2R in renal tissue were detected. Patients were assigned into two groups: a positive PLA2R group and a negative PLA2R group. Differences in laboratory parameters and pathological characteristics were compared between the two groups.â© Results: Of 49 patients with HBV-MN, 17 had positive PLA2R expression in renal tissues. In the positive PLA2R group, 10 patients were positive for serum anti-PLA2R antibody. Patients with positive PLA2R expression in renal tissues showed higher levels of 24 hour urinary protein [(4.6±3.9) g/d], serum HbsAg (70.5%) and renal HbsAg expression (71%), while lower level of serum albumin [(24.1±7.5) g/L] than those of the negative group.â© Conclusion: PLA2R is expressed in the renal tissues and serum anti-PLA2R antibody can be detected in some HBV-MN patients. Positive PLA2R expression in renal tissue might be related to HbsAg deposition in serum and renal tissues. Patients with positive PLA2R expression in renal tissue have more severe glomerular sclerosis.
Assuntos
Glomerulonefrite Membranosa/genética , Antígenos de Superfície da Hepatite B/efeitos adversos , Hepatite B/complicações , Nefropatias/etiologia , Nefropatias/genética , Nefropatias/fisiopatologia , Receptores da Fosfolipase A2/fisiologia , Adulto , Anticorpos , Autoanticorpos/genética , Autoanticorpos/fisiologia , Biópsia , Glomerulonefrite Membranosa/complicações , Glomerulonefrite Membranosa/etiologia , Vírus da Hepatite B , Humanos , Rim/irrigação sanguínea , Rim/química , Rim/fisiopatologia , Masculino , Prognóstico , Proteinúria/epidemiologia , Proteinúria/genética , Receptores da Fosfolipase A2/sangue , Albumina Sérica/genéticaRESUMO
Of the glomerulonephritis associated with sarcoidosis, membranous nephropathy (MN) is the most prevalent. Coincidence or a causal relationship between these two diseases is unclear. Here, we present for the first time a high prevalence of PLA2R-related MN among patients with MN associated with active sarcoidosis. Our results suggest some causal link between sarcoidosis and PLA2R-related MN. Detection of anti-PLA2R antibodies in serum or PLA2R antigen in biopsy should not be taken as evidence against a secondary cause, particularly sarcoidosis. This important observation can affect treatment decision in these patients.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/epidemiologia , Receptores da Fosfolipase A2/imunologia , Sarcoidose/fisiopatologia , Adulto , Feminino , França/epidemiologia , Glomerulonefrite Membranosa/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Prognóstico , Receptores da Fosfolipase A2/sangue , Estudos Retrospectivos , Adulto JovemRESUMO
OBJECTIVE: To explore the value of anti-phospholipase A2 receptor (PLA2R) antibody in the diagnosis and disease activity monitoring of idiopathic membranous nephropathy (IMN). METHODS: A total of 233 patients with IMN proven by kidney biopsy at Peking Union Medical College Hospital from January 2012 to March 2014 were enrolled in this study. Another 46 patients with non-IMN kidney diseases at the same period were selected as control group. Serum titer of anti-PLA2R antibody was measured by quantitative enzyme-linked immuno sorbent assay (ELISA) at the time of renal biopsy. Clinical data were reviewed and retrospectively analyzed. The diagnostic accuracy of anti-PLA2R antibody in IMN was estimated by ROC curve. RESULTS: The total sensitivity of anti-PLA2R antibody was 60.0% in IMN. However, the sensitivity increased to 71.3% in patients who did not receive immuno-suppression therapies. The specificity of anti-PLA2R antibody was 100.0%, of which was not detected in any of the 25 control patients with lupus nephritis. The area under ROC curve of anti-PLA2R antibody for IMN diagnosis was 0.800. The prevalence of positive anti-PLA2R antibody in nephrotic range proteinuria group and non-nephrotic range proteinuria group were 68.3% and 41.7% (P < 0.05), respectively. The positive rates in patients with serum albumin level less than 30 g/L and more than 30 g/L were 67.3% and 44.6% (P < 0.05), respectively. Hypoalbuminemia became worse (P < 0.05) and the proportion of nephrotic arrange proteinuria rose significantly (P < 0.05) according to the elevation of antibody level. CONCLUSIONS: Anti-PLA2R antibody has high sensitivity and notable specificity for the diagnosis of IMN, which reveals good diagnostic accuracy. The antibody positive rate is affected by immunosuppression therapy, disease activity and other clinical status. Moreover, the antibody could reflect the disease activity.
Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/patologia , Proteinúria/sangue , Receptores da Fosfolipase A2/sangue , Pequim/epidemiologia , Biomarcadores/sangue , Biópsia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/imunologia , Humanos , Fosfolipases , Prevalência , Proteinúria/epidemiologia , Curva ROC , Receptores da Fosfolipase A2/imunologia , Estudos Retrospectivos , Sensibilidade e EspecificidadeRESUMO
Aim of the study - assessment of the presence of M-type phospholipase A2 receptor antibodies in Georgian patients with biopsy proven IMN and their correlation with the disease activity for the appliance and monitoring of immunosuppressive therapy. A total 37 patients, after exclusion of the possible secondary factors, with biopsy proven IMN entered the study. All patients received standard immunosuppressive therapy: cyclosporine combined with methylprednisolone. There were 28 (76%) patients with PLA2R-AB positive and 9 (24%) negative (assessed as 1:<10) at baseline. Among the 28 patients under immunosuppressive therapy at month 6 in 11 of them PLA2R-AB turned negative, in 14 decreased quantitatively but were persistent positive and in 3 of them PLA2R-AB once turned negative then relapsed after withdrawn of immunosuppressive therapy. Among 11 PLA2R-AB negative patients, 9 patients got complete remission of proteinuria and the other 2 patients only partial remission. At month 12 the range of proteinuria was significantly lower in PLA2R-AB negative group than in PLA2R-AB positive group. The level of circulating PLA2R-AB in IMN patients showed correlation with disease activity. The indicators of good prognosis of IMN were negative PLA2R-AB titer at baseline and progressive decreasing of titer under the immunosuppressive therapy in PLA2R-AB positive patients. The detection and measurement of PLA2R-AB in INM patients may be important tool in monitoring of the disease and efficacy of the treatment.
Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/sangue , Receptores da Fosfolipase A2/sangue , Adulto , Idoso , Autoanticorpos/imunologia , Biópsia , Feminino , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/patologia , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Receptores da Fosfolipase A2/imunologia , Fatores de RiscoRESUMO
Glomerulopathy is an uncommon but increasingly recognized complication of hematopoietic cell transplantation. It typically manifests as membranous nephropathy, less commonly as minimal change disease, and rarely as proliferative glomerulonephritis. There is evidence to suggest that these glomerulopathies might represent manifestations of chronic graft-versus-host disease. In this report, we focus on membranous nephropathy as the most common form of glomerulopathy after hematopoietic cell transplantation. We present a case of membranous nephropathy that developed 483 days post-allogeneic hematopoietic stem cell transplantation in a patient with a history of acute graft-versus-host disease. We also share our experience with 4 other cases of membranous nephropathy occurring after allogeneic hematopoietic stem cell transplantation. Clinicopathologic correlates, including the association with graft-versus-host-disease, HLA antigen typing, glomerular deposition of immunoglobulin G (IgG) subclasses, subepithelial colocalization of IgG deposits with phospholipase A2 receptor staining, C4d deposition along the peritubular capillaries, and treatment, are discussed with references to the literature.
Assuntos
Complemento C4b , Glomerulonefrite Membranosa/diagnóstico , Doença Enxerto-Hospedeiro/diagnóstico , Antígenos HLA , Fragmentos de Peptídeos , Receptores da Fosfolipase A2 , Adulto , Diagnóstico Diferencial , Seguimentos , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/complicações , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/complicações , Antígenos HLA/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/química , Masculino , Fragmentos de Peptídeos/sangue , Estrutura Secundária de Proteína , Receptores da Fosfolipase A2/sangueRESUMO
Idiopathic membranous nephropathy (IMN) is an antibody-mediated and kidney-specific autoimmune disease, with the antigen phospholipase A2 receptor 1 (PLA2R1) accounting for approximately 70% of IMN cases. Although a variety of new podocyte target antigens and their autoantibodies have been identified, they are still of limited diagnostic and therapeutic value due to lack of high specificity and sensitivity. N-glycans play vital roles in renal system and their pathobiological relevance has become increasingly recognized in many kidney diseases, but not fully explored in IMN. To find possible glyco-signatures for PLA2R1-related IMN diagnosis, we herein established a comprehensive workflow for total serum N-glycome analysis based on our recently developed mass spectrometry (MS)-based N-glycan purification method, named Ultrafast Glycoprotein Immobilization for Glycan extraction (UltraGIG). A total of 191 N-glycans were identified from IMN patients, representing the largest N-glycome dataset in IMN. Compared to healthy controls, up-regulation of sialylation and core-fucosylation as well as down-regulation of galactosylation were observed in PLA2R1-positive IMN patients, and up-regulation of hyper-galactosylation was specific for PLA2R1-negative IMN patients. A six-glycan marker panel consisting of H4N3S1, H4N3F1, H6N4S2, H6H5F1S2, H6N5 and H6N6F1S1, was proposed to aid in the accurate diagnosis of PLA2R1-related IMN, which provided new insights into IMN biomarker study. SIGNIFICANCE: PLA2R1-related IMN is a kidney-specific autoimmune disease with a high risk of developing end-stage renal disease (ESRD) and even kidney failure. Current biomarkers are still of limited diagnostic and therapeutic value due to lack of high specificity and sensitivity. An in-depth MS analysis of total serum N-glycome of PLA2R1-related IMN patients was conducted for the first time. We generated the largest dataset of serum N-glycome for IMN to date, and proposed a novel six-glycan marker panel that may help the accurate diagnosis of PLA2R1-related IMN.
Assuntos
Glomerulonefrite Membranosa , Polissacarídeos , Receptores da Fosfolipase A2 , Humanos , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Receptores da Fosfolipase A2/sangue , Polissacarídeos/sangue , Polissacarídeos/análise , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores/sangue , Adulto , Glicômica/métodosAssuntos
Anticorpos Anti-Idiotípicos/sangue , Glomerulonefrite Membranosa/sangue , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Imunoglobulina M/sangue , Mielite Transversa/sangue , Receptores da Fosfolipase A2/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/etiologia , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/etiologia , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Masculino , Pessoa de Meia-Idade , Mielite Transversa/diagnóstico , Mielite Transversa/etiologia , Transplante Homólogo/efeitos adversos , Transplante Homólogo/tendênciasRESUMO
BACKGROUND: The renal biopsy is an accurate and reliable gold standard for membranous nephropathy (MN) diagnosis. However, it is an invasive procedure involving the risk of hemorrhage or infection. Thus, an alternative approach that can facilitate the effective diagnosis and treatment monitoring of idiopathic membranous nephropathy (IMN) is urgently needed. METHODS: We established a dual-labeled time-resolved fluoroimmunoassay (TRFIA) to simultaneously detect phospholipase A2 receptor (PLA2R)-IgG4 and PLA2R-IgG antibodies. Utilizing this assay, we determined the ratio of autoantibodies in the serum of patients with different kidney diseases and normal controls. RESULTS: The sensitivity of TRFIA for detecting anti-PLA2R-IgG and anti-PLA2R-IgG4 was 0.12 µg/mL and 0.001 µg/mL, respectively. Human IgA did not interfere with the assay. Compared to anti-PLA2R-IgG alone, the positive rate of IMN could be increased from 86.5 % to 91.7 % through the combined use of anti-PLA2R-IgG4 and the PLA2R-IgG4/IgG ratio. In contrast, the false-positive rates for the detection of IgA nephropathy, lupus nephropathy, diabetic nephropathy, and minimal change nephropathy decreased from 25 to 50 % to 0 %. CONCLUSIONS: The dual-labeled PLA2R-IgG4/IgG-TRFIA for simultaneous detection of anti-PLA2R-IgG4 and anti-PLA2R-IgG will contribute to improved accuracy of IMN diagnosis.
Assuntos
Autoanticorpos/sangue , Glomerulonefrite Membranosa/sangue , Imunoglobulina G/sangue , Receptores da Fosfolipase A2/sangue , Fluorimunoensaio , Glomerulonefrite Membranosa/diagnóstico , Humanos , Sensibilidade e EspecificidadeRESUMO
Background: The concurrence of anti-contactin 1 (CNTN1) antibody-associated chronic inflammatory demyelinating polyneuropathy (CIDP) and membranous nephropathy (MN) has previously been reported in the literature. CIDP with autoantibodies against paranodal proteins are defined as autoimmune nodopathies (AN) in the latest research. In view of the unclear relationship between CIDP and MN, we performed a case study and literature review to investigate the clinical characteristics of anti-CNTN antibody-associated AN with MN. Methods: We detected antibodies against NF155, NF186, CNTN1, CNTN2, CASPR1 and PLA2R in blood samples of a patient with clinically manifested MN and concomitant peripheral neuropathy via double immunofluorescence staining and conducted a quantitative measurement of anti-PLA2R IgG antibodies via enzyme-linked immunosorbent assay (ELISA). Case reports of anti-CNTN1 antibody-associated AN, anti-CNTN1 antibody-associated AN with MN, and CIDP with MN were retrieved through a literature search for a comparative analysis of clinical characteristics. The cases were grouped according to the chronological order of CIDP and MN onset for the comparison of clinical characteristics. Results: A 57-year-old man with anti-PLA2R positive MN was admitted to the hospital due to limb numbness, weakness, and proprioceptive sensory disorder. He was diagnosed with anti-CNTN1 antibody-associated AN and recovered well after immunotherapy. Our literature search returned 22 cases of CIDP with MN that occurred before, after, or concurrently with CIDP. Good responses were achieved with early single-agent or combination immunotherapy, but eight out of the 22 patients with CIDP and concomitant MN ultimately developed different motor sequelae. Five patients had anti-CNTN1 antibody-associated AN with MN. Among these patients, males accounted for the majority of cases (male:female=4:1), the mean age at onset was late (60.2 ± 15.7 years, range 43-78 years), and 40% had acute to subacute onset. Clinical manifestations included sensory-motor neuropathy, sensory ataxia caused by proprioceptive impairment, and elevated cerebrospinal fluid protein levels. Conclusion: The age at onset of CIDP with MN was earlier than that of anti-CNTN1 antibody-associated AN. MN may occur before, after or concurrently with CIDP. The early detection and isotyping of anti-CNTN1 and anti-PLA2R antibodies and the monitoring of isotype switching may be essential for suspected CIDP patients.
Assuntos
Contactina 1/imunologia , Glomerulonefrite Membranosa/imunologia , Imunoglobulina G/imunologia , Contactina 1/sangue , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Humanos , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Receptores da Fosfolipase A2/sangue , Receptores da Fosfolipase A2/imunologiaRESUMO
ABSTRACT: To compare the efficacy and safety of calcineurin inhibitor (CNI) and Tripterygium wilfordii polyglycoside tablets (TWPs) in treating idiopathic membranous nephropathy (IMN) with CNI and glucocorticoids (GCs).Data of patients with IMN who were treated with CNI+TWPs (TWP group) or CNI+GCs (GC group) and followed up for more than 12âmonths at the Affiliated Hospital of Shandong University of Traditional Chinese Medicine from 2017 to 2020 were retrospectively analyzed. The 24-h urine protein (24hUP), serum albumin (ALB), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), serum creatinine, alanine aminotransferase, and aspartate transaminase levels on the third, sixth, ninth, and twelfth months of treatment and phospholipase A2 receptor (PLA2R) level before and after treatment were compared in both groups.We recruited 64 patients who were assigned to either the GC group (nâ=â31) or TWP group (nâ=â33). No difference in baseline indicators between the two groups were observed (Pâ>â.05). After 12âmonths, the 24hUP levels of both groups significantly decreased compared with that at baseline (Pâ<â.01). At the end of the sixth month, 24hUP of the TWP group were less and reduced more quickly than those in the GC group (Pâ<â.05), but there is no difference at the other time point (Pâ>â.05). After treatment, the number of patients who up to the standard of TG and the ALB levels in both groups increased (Pâ<â.05), the LDL-C levels and the number of patients positive for PLA2R in both groups were reduced (Pâ<â.05), and no significant difference was observed in the overall changes of 24hUP, ALB and LDL-C levels, TG compliance rate, and PLA2R positive rate between both groups (Pâ>â.05). During treatment, no patient in either group had hepatorenal dysfunction, one case in the TWP group and two cases in the GC group experienced side effects, but no apparent difference in the side effects were observed between both groups (Pâ>â.05).Two therapeutic schemes have the advantage of reducing urinary protein excretion in patients with IMN. Compared with CNI+GCs, CNI+TWPs have high efficiency and is widely applied, which might be considered as an optimum therapy in the future.
Assuntos
Inibidores de Calcineurina/uso terapêutico , Glomerulonefrite Membranosa/tratamento farmacológico , Tripterygium/química , Adolescente , Adulto , Idoso , Albuminas , LDL-Colesterol/sangue , Creatinina/sangue , Feminino , Humanos , Imunossupressores , Masculino , Pessoa de Meia-Idade , Receptores da Fosfolipase A2/sangue , Estudos Retrospectivos , Comprimidos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Sjögren's syndrome (SS) has been a well-documented cause of secondary membranous nephropathy (MN); however, the prevalence is quite low. Since primary MN is also a common disease in middle age, whether MN is secondary to SS or just coincidence remains uncertain. The detection of phospholipase A2 receptor (PLA2R), which is most often positive in idiopathic MN, has been rarely reported in such cases. METHODS: We retrospectively studied 13 cases diagnosed with MN and SS in Huashan Hospital between 2009 and 2020, and performed PLA2R detection. We also review the literature by searching in the PubMed database. RESULTS: Among the 13 patients, 8 were found to be PLA2R-positive and 5 were negative. Nine patients were female. All but 1 patients had normal renal function at the time of biopsy. All patients showed positive anti-nuclear antibody and anti-SSA. Two of the 8 PLA2R-positive patients showed positive anti-SSB and 1/8 had mild hypocomplementemia, while all 5 PLA2R-negative patients had positive anti-SSB and 3 showed hypocomplementemia. Renal biopsy revealed focal MN and markedly mesangial hyperplasia in PLA2R-negative patients. Mesangial electron deposits were observed in 1 PLA2R-positive patient in small amounts, and in 3 PLA2R-negative patients with 2 in large amounts. During follow-up, 2 patients in the PLA2R-negative group presented with progressively decreasing serum complement levels, and another one was diagnosed with systemic lupus erythematosus (SLE). CONCLUSIONS: In patients with both MN and SS, PLA2R-negative MN should be considered as a secondary form. Careful screen for SLE is necessary in these patients during follow-up.
Assuntos
Glomerulonefrite Membranosa/etiologia , Receptores da Fosfolipase A2/sangue , Síndrome de Sjogren/complicações , Adulto , Idoso , Autoanticorpos/sangue , Biomarcadores/sangue , Feminino , Glomerulonefrite Membranosa/sangue , Glomerulonefrite Membranosa/diagnóstico , Glomerulonefrite Membranosa/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Receptores da Fosfolipase A2/imunologia , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Síndrome de Sjogren/sangue , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologiaRESUMO
Membranous nephropathy represents the most frequent cause of nephrotic syndrome in the adult, leading to end-stage renal disease in one third of all the patients. In the last years, the discovery of circulating autoantibodies against phospholipase A2 receptor 1 (PLA2R) and thrombospondin type-1 containing 7A domain (THSD7A), shed light on the pathogenesis of idiopathic forms, being responsible for 70% and 3% of all the cases, respectively. These identifications allowed the development of serological and histologic tests to detect autoantibodies and relative targets for diagnostic and prognostic purposes. Rising evidences suggest that serum titer correlates with disease activity and response to therapy. For these reasons, for patients with nephrotic syndrome, a serum-based approach has been proposed, reserving renal biopsy only in cases with doubtful/negative serology. However, the recent introduction of useful criteria for the interpretation of PLA2R/THSD7A immunohistochemistry could lead to high values of sensitivity and specificity for the in situ detection of target antigens. The present multicentric study on a series of membranous nephropathy cases with available serum/histologic correlation will show the importance of the crosstalk among the different techniques, recovering the possible role of electron microscopy in challenging situations.