Phospholipase A2 Receptor 1 Epitope Spreading at Baseline Predicts Reduced Likelihood of Remission of Membranous Nephropathy

The phospholipase A2 receptor (PLA2R1) is the major autoantigen in primary membranous nephropathy. Several PLA2R1 epitopes have been characterized, and a retrospective study identified PLA2R1 epitope spreading as a potential indicator of poor prognosis. Here, we analyzed the predictive value of anti-PLA2R1 antibody (PLA2R1-Ab) titers and epitope spreading in a prospective cohort of 58 patients positive for PLA2R1-Ab randomly allocated to rituximab (n=29) or antiproteinuric therapy alone (n=29). At baseline, the epitope profile (CysR, CysRC1, CysRC7, or CysRC1C7) did not correlate with age, sex, time from diagnosis, proteinuria, or serum albumin, but epitope spreading strongly correlated with PLA2R1-Ab titer (P<0.001). Ten (58.8%) of the 17 patients who had epitope spreading at baseline and were treated with rituximab showed reversal of epitope spreading at month 6. In adjusted analysis, epitope spreading at baseline was associated with a decreased remission rate at month 6 (odds ratio, 0.16; 95% confidence interval, 0.04 to 0.72; P=0.02) and last follow-up (median, 23 months; odds ratio, 0.14; 95% confidence interval, 0.03 to 0.64; P=0.01), independently from age, sex, baseline PLA2R1-Ab level, and treatment group. We propose that epitope spreading at baseline be considered in the decision for early therapeutic intervention in patients with primary membranous nephropathy.

Download Full-text

Anti-Phospholipase A2 Receptor Antibody as Prognostic Indicator in Idiopathic Membranous Nephropathy

American Journal of Nephrology ◽

10.1159/000440983 ◽

2015 ◽

Vol 42 (3) ◽

pp. 250-257 ◽

Cited By ~ 25

Author(s):

Yang Gyun Kim ◽

Young-Wook Choi ◽

Se-Yun Kim ◽

Ju Young Moon ◽

Chun-Gyoo Ihm ◽

...

Keyword(s):

Phospholipase A2 ◽

Membranous Nephropathy ◽

Remission Rate ◽

High Titer ◽

Severe Disease ◽

Idiopathic Membranous Nephropathy ◽

Enzyme Linked Immunosorbent Assay ◽

Healthy Controls ◽

Receptor Antibody ◽

Phospholipase A2 Receptor

Background: Anti-phospholipase A2 receptor antibody (PLA2R-Ab) is useful in diagnosing idiopathic membranous nephropathy (IMN). We investigated the clinical relevance of PLA2R-Ab enzyme-linked immunosorbent assay (ELISA) in patients with IMN. Methods: We measured PLA2R-Ab with an ELISA kit from the serum of 160 patients with IMN (n = 93), secondary MN (n = 14) and other glomerulonephritis (n = 41) as well as healthy controls (n = 12) at the time of renal biopsy and investigated the correlation of titers of PLA2R-Ab with clinical parameters. Results: PLA2R-Ab was positive in 41 of 93 patients (44.1%) with IMN. No samples from the patients with secondary MN and other glomerulonephritis or healthy controls were positive with the ELISA test. The PLA2R-Ab-positive patients showed severe disease activity and a low remission rate. The PLA2R-Ab titer positively correlated with proteinuria and was negatively associated with renal function and serum albumin. The patients with a high titer of PLA2R-Ab had significantly decreased remission rates. The cumulative probabilities of remission was significantly lower in patients with PLA2R-Ab (p = 0.01) and even so in patients with a high titer of PLA2R-Ab (p = 0.04). When we compared the ELISA titers with Western blot (WB) data of 43 patients who had been enrolled in our previous study, 18 and 30 patients were positive on ELISA (41.9%) and WB (69.8%), respectively. WB and ELISA had a concordance rate of 72.1% and were positively correlated (r = 0.590, p < 0.001). Conclusion: The presence, as well as a high titer, of PLA2R-Ab on ELISA was associated with poor prognosis of IMN. Assessment of PLA2R-Ab with ELISA is an easy and reliable tool for the diagnosis and guidance of therapeutic plans.

Download Full-text

Effect of belimumab on proteinuria and anti-phospholipase A2 receptor autoantibody in primary membranous nephropathy

Nephrology Dialysis Transplantation ◽

10.1093/ndt/gfz086 ◽

2019 ◽

Vol 35 (4) ◽

pp. 599-606 ◽

Cited By ~ 6

Author(s):

Christine Barrett ◽

Lisa C Willcocks ◽

Rachel B Jones ◽

Ruth M Tarzi ◽

Robert B Henderson ◽

...

Keyword(s):

Phospholipase A2 ◽

Membranous Nephropathy ◽

Remission Induction ◽

Experimental Medicine ◽

Open Label ◽

Intention To Treat ◽

Phospholipase A2 Receptor ◽

B Cell Subsets ◽

Treat Population

Abstract Background Immunosuppressant drugs reduce proteinuria and anti-phospholipase A2 receptor autoantibodies (PLA2R-Ab) in primary membranous nephropathy (PMN) with varying success and associated toxicities. This study aimed to evaluate the effect of belimumab on proteinuria and PLA2R-Ab in participants with PMN. Methods In this prospective, open-label, experimental medicine study, 14 participants with PMN and persistent nephrotic-range proteinuria received up to 2 years belimumab monotherapy (10 mg/kg, every 4 weeks). Changes in proteinuria (urinary protein:creatinine ratio), PLA2R-Ab, albumin, cholesterol, B-cell subsets and pharmacokinetics were analysed during treatment and up to 6 months after treatment. Results Eleven participants completed to the primary endpoint (Week 28) and nine participants completed the study. In the intention-to-treat population population, baseline proteinuria of 724 mg/mmol [95% confidence interval (CI) 579–906] decreased to 498 mg/mmol (95% CI 383–649) and 130 mg/mmol (95% CI 54–312) at Weeks 28 and 104, respectively, with changes statistically significant from Week 36 (n = 11, P = 0.047). PLA2R-Ab decreased from 174 RU/mL (95% CI 79–384) at baseline to 46 RU/mL (95% CI 16–132) and 4 RU/mL (95% CI 2–6) at Weeks 28 and 104, respectively, becoming statistically significant by Week 12 (n = 13, P = 0.02). Nine participants achieved partial (n = 8) or complete (n = 1) remission. Participants with abnormal albumin and/or cholesterol at baseline gained normal/near normal levels by the last follow-up. Adverse events were consistent with those expected in this population. Conclusions Belimumab treatment in participants with PMN can reduce PLA2R-Ab and subsequently proteinuria, important preludes to remission induction.

Download Full-text

Circulating anti-phospholipase A2 receptor antibodies as a diagnostic and prognostic marker in Greek patients with idiopathic membranous nephropathy – a retrospective cohort study

Romanian Journal of Internal Medicine ◽

10.2478/rjim-2018-0044 ◽

2019 ◽

Vol 57 (2) ◽

pp. 141-150

Author(s):

Simella Provatopoulou ◽

Dimitra Kalavrizioti ◽

Maria Stangou ◽

Maria-Nikoleta Kouri ◽

Pantellitsa Kalliakmani ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Complete Remission ◽

Phospholipase A2 ◽

Disease Activity ◽

Membranous Nephropathy ◽

Clinical Status ◽

Immunosuppressive Treatment ◽

Idiopathic Membranous Nephropathy ◽

Phospholipase A2 Receptor

Abstract Introduction. Circulating autoantibodies against phospholipase A2 receptor (anti-PLA2R) are recognized as key elements in the pathogenesis of idiopathic membranous nephropathy. In current clinical practice, they are increasingly gaining attention as novel tools for diagnosis and disease monitoring. We investigated the diagnostic and prognostic utility of anti-PLA2R antibody measurements in Greek patients with biopsy-proven membranous nephropathy. Methods. Anti-PLA2R levels were measured in serum samples from 33 patients at diagnosis using ELISA and were associated with treatment outcome. Moreover, serial anti-PLA2R measurements were performed in 15 patients under different clinical conditions and level alterations were correlated with disease activity. Results. Positive anti-PLA2R antibodies at diagnosis were found in 16 of 33 patients (48.5%). Anti-PLA2R levels were independently associated with the achievement of complete remission of nephrotic syndrome after immunosuppressive treatment compared to partial remission (p = 0.02, R2 = 0.265, 95%CI -0.019 to -0.0003). Higher detectable antibody levels at diagnosis were correlated with higher proteinuria levels (r = 0.813, p = 0.0001, 95%CI 0.532 to 0.933) and lower eGFR at the end of follow-up (r = -0.634, p = 0.0083, 95%CI -0.86 to -0.202). Serial antibody measurements during follow-up showed that anti-PLA2R titers were significantly reduced at the end of treatment after complete remission was achieved, remained low under sustained clinical remission, and increased during relapse. Conclusions. Our findings confirm the usefulness of anti-PLA2R measurements in the diagnosis of idiopathic membranous nephropathy. Low levels of anti-PLA2R antibodies at diagnosis are predictive of complete remission of nephrotic syndrome following immunosuppressive treatment. Serial anti-PLA2R measurements correlate well with clinical status throughout the follow-up period and could be used routinely for monitoring of disease activity and treatment planning.

Download Full-text

Serum anti-phospholipase A2 receptor (PLA2R) antibody detected at diagnosis as a predictor for clinical remission in patients with primary membranous nephropathy: a meta-analysis

BMC Nephrology ◽

10.1186/s12882-019-1544-2 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 5

Author(s):

Yufeng Liang ◽

Jianxin Wan ◽

Yongping Chen ◽

Yangbin Pan

Keyword(s):

Phospholipase A2 ◽

Subgroup Analysis ◽

Membranous Nephropathy ◽

Clinical Remission ◽

Remission Rate ◽

Meta Analysis ◽

Treatment Strategies ◽

Diagnostic Value ◽

Clinical Remission Rate ◽

Phospholipase A2 Receptor

Abstract 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.

Download Full-text

Predictive values of serum phospholipase A2 receptor antibody and urinary IgG, α1- macroglobulin in patients with idiopathic membranous nephropathy and nephrotic syndrome

10.21203/rs.3.rs-29945/v1 ◽

2020 ◽

Author(s):

Lili Liu ◽

Haitao Wang ◽

Ban Zhao ◽

Xin Liu ◽

Ying Sun ◽

...

Keyword(s):

Nephrotic Syndrome ◽

Phospholipase A2 ◽

Membranous Nephropathy ◽

Multivariate Regression ◽

Idiopathic Membranous Nephropathy ◽

Renal Outcome ◽

Predictive Values ◽

Receptor Antibody ◽

Phospholipase A2 Receptor

Abstract BackgroundThe biomarkers predicting long-term outcome of idiopathic membranous nephropathy (IMN) with nephrotic syndrome (NS) remains indeterminacy. We conducted this study to evaluate the different features between phospholipase A2 receptor (PLA2R)-associated and non-PLA2R-associated IMN, and to explore the association between serum PLA2R antibody (PLA2R-Ab), urinary immunoglobulin G (UIgG), urinary α1-macroglobulin (Uα1m) and renal outcomes in patients with idiopathic membranous nephropathy (IMN) and nephrotic syndrome (NS). MethodsIMN patients who were biopsy-proven and presenting NS were retrospectively recruited for the present study. Serum PLA2R-Ab levels were detected by enzyme-linked immunosorbent assay (ELISA) kits, and values over 20 RU/mL was considered positive. UIgG) and Uα1m were measured by immunonephelometry and corrected by urinary creatinine. The clinicopathologic features, remission and renal outcome were compared between the PLA2R-associated and non-PLA2R-associated IMN patients. Furthermore, the predictive values of biomarkers (PLA2R-Ab, UIgG/Cr and Uα1m/Cr) for remission and renal outcome were assessed by multivariate regression. The renal endpoint was defined as progression to end stage kidney disease (ESRD) or estimated glomerular filtration rate (eGFR) decline ≥50% of baseline. ResultsA total of 111 IMN patients were enrolled this study, and 81 (73.0%) of them were PLA2R-associated. The mean age, 24-hour proteinuria and eGFR showed no difference between PLA2R-associated and non-PLA2R-associated groups (p>0.05). However, PLA2R-associated IMN patients had significantly higher UIgG/Cr (17.78 vs. 9.82 mg/g; median, p=0.001) and Uα1m (0.339 vs 0.202 mg/g; median, p<0.001) when compared to non-PLA2R-associated patients. Histologically, the PLA2R-associated group represented more proportion of patients with acute tubular necrosis (ATN) (27.16% vs. 3.33%, P=0.006) and glomerular C3 deposits (88.89% vs. 70.00%, P=0.016) than the non-PLA2R-associated group. During a median follow-up of 40 months (range 9 to 92), non-PLA2R-associated patients had significantly higher remission rate at the 6th and 12th month and end of follow-up, even after adjusting for the use of immunosuppressor. Furthermore, 11 (13.6%) patients reaching renal endpoint were all PLA2R-associated IMN. Multivariate regression analysis represented that baseline serum PLA2R-Ab titer was an independent predictor of remission (OR, 1.002; 95% confidence interval [CI] 1.001 to 1.004; p=0.002) and renal outcome (HR, 1.002; 95% CI 1.001-1.003, p= 0.004). Receiver operating characteristic (ROC) showed that serum PLA2R-Ab titer >216.93 RU/ml (AUC=0.778, p=0.003), UIgG/Cr >15.76mg/g (AUC=0.758, p=0.005) and Uα1m/Cr >0.3042mg/g (AUC=0.738, p=0.010) predicted renal failure in patients with IMN and NS. Kaplan-Meier curves indicated that subjects with combination of all three high biomarkers had significantly shorter renal survival (log rank p=0.007) than subjects with ≤2 high biomarkers. ConclusionHigh PLA2R-Ab levels is poor prognosis predictor of IMN in addition to proteinuria. In addition, combination of multiple factors (PLA2R-Ab, UIgG and Uα1m) represents a stronger predictive power. These findings suggested the potential different pathogenesis and progression in IMN with NS. Keywords: idiopathic membranous nephropathy, phospholipase A2 receptor antibody, urinary IgG, urinary α1- macroglobulin, nephrotic syndrome.

Download Full-text

Antiphospholipase A2 Receptor Autoantibodies: A Step Forward in the Management of Primary Membranous Nephropathy

BioMed Research International ◽

10.1155/2015/249740 ◽

2015 ◽

Vol 2015 ◽

pp. 1-8 ◽

Cited By ~ 10

Author(s):

Bogdan Obrisca ◽

Gener Ismail ◽

Roxana Jurubita ◽

Catalin Baston ◽

Andreea Andronesi ◽

...

Keyword(s):

Animal Model ◽

Phospholipase A2 ◽

Disease Activity ◽

Membranous Nephropathy ◽

Pathogenic Role ◽

Promising Tool ◽

Phospholipase A2 Receptor ◽

Definition Of ◽

Made In

Since the identification of PLA2R (M-type phospholipase A2 receptor) as the first human antigenic target in primary membranous nephropathy (MN), perpetual progress has been made in understanding the pathogenesis of this disease. Accumulating clinical data support a pathogenic role for the anti-PLA2R antibodies (PLA2R ABs), but confirmation in an animal model is still lacking. However, PLA2R ABs were related to disease activity and outcome, as well as to response therapy. Accordingly, PLA2R ABs assay seems to be promising tool not only to diagnose MN but also to predict the course of the disease and could open the way to personalize therapy. Nevertheless, validation of a universal assay with high precision and definition of cut-off levels, followed by larger studies with a prolonged follow-up period, are needed to confirm these prospects.

Download Full-text