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Portuguese Journal of Nephrology & Hypertension

versão impressa ISSN 0872-0169

Port J Nephrol Hypert vol.34 no.2 Lisboa jun. 2020

https://doi.org/10.32932/pjnh.2020.07.072 

REVIEW ARTICLE

 

Anti-phospholipase A2 receptor antibodies: Current applications in primary membranous nephropathy

 

Miguel Relvas1,2, Rodrigo Batata3, Ana Teresa Nunes1,2, Luís Coentrão1,2,3

1 Nephrology Department, Centro Hospitalar e Universitário de São João, Oporto, Portugal

2 Nephrology & Infectious Diseases R&D, i3S - Instituto de Investigação e Inovação em Saúde da Universidade do Porto, Oporto, Portugal

3 Faculty of Medicine, University of Oporto, Oporto, Portugal

 

Correspondence to:

 

ABSTRACT

Background: Membranous nephropathy (MN) is among the most common causes of nephrotic syndrome in nondiabetic adults. The podocytic M‑type phospholipase A2 receptor (PLA2R) has been identified as the major antigenic target of the immune response that underlies primary membranous nephropathy (PMN). In the last decade, anti‑PLA2R antibodies have been seen as promising diagnostic biomarkers for PMN. Other potential uses include assessment of disease activity and prognosis, therapeutic monitoring and prediction of disease recurrence after renal transplant. Objective: To review clinical studies exploring the current role of anti‑PLA2R antibodies. Methods: This systematic review was conducted according to PRISMA guidelines. Two databases were searched for articles published between January 2010 and August 2019. Fifty‑one studies met the inclusion criteria. Results: Anti‑PLA2R antibodies constitute highly sensitive and specific markers for PMN. Antibody titers correlate positively with disease activity. Low levels or seronegativity correlate to higher remission rates. Relative reduction of antibody titers seems to correlate with the likelihood of response to therapy. The value of this antibody in the prediction of post‑transplant recurrence is uncertain, as is its use in the pediatric population. Conclusion: Anti‑PLA2R antibodies are assuming an increasingly important role in MN management. Anti‑PLA2R positivity in the context of nephrotic syndrome is very suggestive of PMN diagnosis. Nevertheless, further efforts are required to define optimal cut‑off values for seropositivity and risk stratification.

Keywords: Anti‑PLA2R; Biomarkers; Membranous nephropathy.

 

INTRODUCTION

Membranous nephropathy (MN) is the denomination of a specific glomerular disease induced by the deposition of immune complexes at the glomerular basement membrane (GBM), causing its thickening.1

This immunological process alters the permeability of the glomerular vasculature and is the most common etiology of nephrotic syndrome (NS) in Caucasian adults.2

MN's long‑term outcomes have been said to follow the "rule of thirds". According to this model, one third of diagnosed patients evolve towards spontaneous remission, one third maintain persistent proteinuria, while another third develop end‑stage renal failure in ten years.3

Currently, this depiction is considered excessively simplistic and most clinicians opt for a risk‑stratification approach when predicting a patient's prognosis and determining the optimal treatment strategy.4

MN is classically divided into two subgroups: primary MN (PMN) and secondary MN (SMN). SMN constitutes around 20% of all MN cases and occurs in the context of underlying conditions (malignancies, drugs, rheumatological diseases and infections).5 PMN refers to the remaining cases with no identifiable underlying cause. The pathological mechanism of PMN still remains to be clarified.6

In 1959, W. Heymann developed an experimental model in rats that identified megalin, a podocyte antigen, as the main target for circulating antibodies responsible for the formation of GBM deposits.

Despite the importance of this discovery, the mechanism described wasn't directly transposable to humans.7-11

In 2003, P. Ronco observed that pregnant women with neutral endopeptidase (NEP) deficiency developed IgG1 and IgG4 NEP‑binding antibodies capable of crossing the placenta, inducing neonatal MN.

This confirmed that podocyte antigens constitute potential targets for circulating antibodies that may lead to complement activation and subsequent deposition of glomerular immune complexes.12,13

In PMN specifically, M‑type phospholipase A2 receptor (PLA2R) has been identified as the main target antigen. Circulating anti‑PLA2R antibodies are present in approximately 70% of PMN patients.14 Other antigenic targets include thrombospondin type 1 domain-containing 7A (THSD7A), with anti‑THSD7A antibodies present in 3-5% of PMN patients.15,16 Recently, using laser microdissection of glomeruli and mass spectrometry analysis of renal biopsies, Sethi et al. discovered two novel antigens that also play a role in MN: exostosin (associated with autoimmune disorders) and NELL‑1.17-19

Recent studies suggest a strong correlation between the levels of circulating anti‑PLA2R antibodies and disease activity, typically estimated through proteinuria quantification. Special care is required in the interpretation of discordant antibody and proteinuria levels. Low or absent antibody levels may indicate remission or decreased disease activity, but simultaneously increased proteinuria levels may constitute an indirect sign of glomerular structural changes and tubular damage.20

Studies also suggest anti‑PLA2R quantification may be used to predict disease outcomes and to evaluate patient response to treatment.21,22 Other potential applications of this marker include the estimation of the risk of PMN recurrence after kidney transplant and immunosuppressive therapy optimization.23-25

In this paper, we analyzed data from recent clinical studies to understand the current role of anti‑PLA2R antibodies on several fronts: MN diagnosis, determination of disease activity, therapeutic monitoring, differential diagnosis with secondary forms and evaluation of the risk of disease recurrence.

METHODS

This systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta‑Analyses (PRISMA) guidelines. The article search for the present review was carried out from September 2018 to September 2019.

Two different electronic databases were used, PUBMED and SCOPUS. The authors agreed on a set of inclusion and exclusion criteria for automatic depuration. The search criteria were coded into queries specific to each database with "phospholipase a2" and "membranous nephropathy" as keywords.

The resulting papers had their abstracts screened following predefined criteria to select original articles with well‑defined assessment methodology relevant to the scope of this review. Figure 1 attempts to summarize the article search and depuration protocol for this paper.

The following information - study type, subject number, anti‑PLA2R positivity, PLA2R expression, assay used and clinical outcomes - was extracted for each selected paper (when applicable) and are shown on table I. Divergences over inclusion of studies and interpretatio  of data were resolved by consensus discussion. Due to significant heterogeneity in terms of methodology, participant selection, and reported outcome measures, the results of the included studies were not pooled but instead presented qualitatively.

RESULTS

In total, 51 articles were critically analyzed. Most of the selected studies were prospective in nature (n = 31, 60.8%). All patients with MN included in the clinical trials had pathological confirmation of their diagnosis. Anti‑PLA2R antibody detection was predominantly performed through conventional enzyme‑linked immunosorbent assay (ELISA) and indirect immunofluorescence testing (PLA2R IIFT, Euroimmun).

Anti‑PLA2R antibodies and PMN diagnosis

The consensus is that anti‑PLA2R antibodies constitute highly sensitive and specific biomarkers of PMN in the adult population. Reported sensitivity varied between 44.1 and 88.9%.26,27 Interstudy variability mainly relates to different cut‑off

values and quantification methods used. The inclusion of patients already under immunosuppressive treatment may have contributed to the emergence of false negatives.28-34

Regarding ELISA testing, commercially available kits have a manufacturer's recommended cut‑off value of 14 RU/mL, used by most of the included articles. Tampoia et al. adopted an adapted cut‑off value of 2.7 RU/mL with increased sensitivity (88,1%) and no impact on the test's specificity.33

Anti‑PLA2R titers, disease activity and response to therapy

Most included studies suggested a linear correlation between antibody titers and PMN activity.26,33,43-48,35-42

Isolated pre‑treatment values appear to be inaccurate predictors of response to treatment. Anti‑PLA2R seronegative individuals, however, were found to have higher likelihood of spontaneous remission.20,30,36-38,46,49-52

In these cases, Hoxha et al. reported that immunosuppression does not seem to increase the likelihood of remission when compared to supportive therapy.36

The rate of anti‑PLA2R decline seems to be a superior indicator of response to treatment. Two studies by Medrano et al. showed no association between isolated antibody titers prior and clinical response.

In the same trials, the relative reduction of antibodies after initiation of therapy had an apparent correlation with time elapsed until remission and the likelihood of achieving it.53,54

AntiPLA2R antibody titers versus antigen deposits

Various authors also investigated the role of PLA2R antigen glomerular deposits as biomarkers of MN - despite reports of higher sensitivity when compared to anti‑PLA2R antibodies, PLA2R antigen deposits seem to have a weaker correlation with disease status and prognosis. Dual positivity is correlated with higher disease activity and lower remission rates. Dual negativity, on the other hand, is highly suggestive of secondary MN.27,37,45,46,55-58

Anti‑PLA2R antibodies and renal transplantation

There is no consensus regarding the usefulness of anti‑PLA2R baseline quantification when it comes to stratifying the risk of disease recurrence after kidney transplant. Two of the reviewed articles dismiss a correlation between antibody titers at the time of transplantation and risk of disease recurrence.23,59 On the other hand, Gutpta et al.'s results suggest pre‑transplant titers above 29RU/mL are predictive of disease recurrence with high sensitivity (85%) and specificity (92%).60 SeitzPolski et al. suggest that positive IgG4 anti‑PLA2R activity during follow‑up is a significant risk factor for MN relapse.59

PLA2R studies in the pediatric population

Only three clinical trials regarding pediatric patients were included in this review. In children, serum anti‑PLA2R antibody and renal PLA2R antigen positivity is less frequent than in adult PMN patients. Adolescent patients with PMN, however, seem to exhibit similar rates of PLA2R+ staining to those found in adults.61-63

AntiPLA2R antibodies and noninvasive PMN diagnosis

Bobart et al. reviewed the potential of anti‑PLA2R testing for non‑invasive diagnosis of PMN. In this study, anti‑PLA2R quantification was prompted in most cases due to the presence of nephrotic range proteinuria or nephrotic syndrome. 143 patients tested positively. Of these, 132 were subjected to kidney biopsy (KB) that confirmed MN diagnosis. After exclusion of secondary causes, KB provided little or no management‑altering information.15

DISCUSSION

This systematic review shows the persistently increasing value of PLA2R studies in MN patients, particularly when it comes to diagnosis and disease management. Despite our expanding grasp of the significance of anti‑PLA2R antibodies, several areas still require further investigation.

One of these relates to ELISA cut‑off values. As previously mentioned, reported sensitivity for anti‑PLA2R ELISA testing had significant interstudy variability (44.1 to 88.9%). Reducing the threshold for positivity might push results higher up the sensitivity spectrum with no prejudice to test specificity as suggested by Tampoia et al.33. Further studies are required to validate these findings, but if results are consistent, the recommended cut‑off value should be significantly reduced.

In recent years, several studies have confirmed that different immunoglobulin IgG subtypes relate to distinct MN etiologies - IgG4 is predominant in PMN, while IgG1 and IgG3 occur mainly in SMN.27,34,58,64,65 Yang et al. suggest anti‑PLA2R IgG4 monitoring might constitute a more effective technique than total antibody quantification.35 Further research is necessary to better understand immunological interactions in PMN patients and to determine how IgG characterization would be better applied in our clinical practice.

As previously mentioned, anti‑PLA2R baseline quantification in transplant recipients is of uncertain value. Of the three included articles on this topic, two dismiss a correlation between antibody titers at the time of transplantation and risk of disease recurrence.23,59 The third suggests titers above 29RU/mL are highly sensitive and specific predictive markers of disease relapse.60 SeitzPolski et al. suggest however that persistently positive anti‑PLA2R activity six months after kidney transplant is significantly associated with MN recurrence.59 As such, PLA2R antibody testing should be considered prior to kidney transplantation in patients with history of PMN. Patients with significant PLA2R titers should be monitored closely post‑transplant for proteinuria and graft disfunction. Repeated testing should be considered to document persistent PLA2R activity, when possible. Both SeitzPolski and Gupta et al. suggest the use of stronger immunosuppressive regimens might constitute a protective factor for disease recurrence.59,60

Preemptive rituximab therapy is another potential strategy.60 Prospective studies with larger samples are needed to validate these findings and confirm the legitimacy of these approaches.

PLA2R studies are also of dubious value in children. Again, only three clinical trials regarding this population were included in this review. All showed serum anti‑PLA2R antibody and renal PLA2R antigen positivity to be less frequent than in adult PMN patients, which suggests a different underlying etiology. Further studies are required in this area, preferably with greater and more ethnically diverse samples to avoid potential confounding factors.61-63

The identification of PLA2R's immunodominant epitope (a protein complex consisting of cysteine‑rich, fibronectin‑like type II, and C‑type lectin‑like domains) was an important breakthrough in this biomarker's relatively short lifespan.66 SeitzPolski et al. state that epitope spreading at baseline is an independent risk factor for non‑remission and should be included in the therapeutic decision, depending on further confirmatory studies.67

To conclude, despite KB still being considered the gold standard for MN diagnosis, a noninvasive approach through anti‑PLA2R antibody quantification is an increasingly pertinent alternative. Considering the high positive predictive value of anti‑PLA2R testing for tissue diagnosis of PMN, KB may soon be considered a superfluous and invasive procedure in patients with stable renal function.15 Sidelining KB in the diagnostic approach could imply a revision of the nomenclature associated with this disease, as a membranous histopathologic presentation would no longer be the hallmark feature of MN. However, most authors support a continued role for KB in patients presenting with severe azotemia, in spite of PLA2R positivity. Figure 2 shows a potential algorithm for noninvasive MN diagnosis applying current knowledge on PLA2R‑associated biomarkers.

CONCLUSION

Anti‑PLA2R antibody positivity in the context of nephrotic syndrome is very suggestive of MN. Despite occurring more frequently in primary forms, exclusion of neoplasia and autoimmune disorders is still indispensable, as anti‑PLA2R may also be present in secondary cases.

This biomarker is assuming an increasingly important role in the assessment of PMN activity, risk of recurrence and therapeutic monitoring.

However, its interpretation must always be integrated with other markers of renal function. Immunoglobulin subtype characterization and PLA2R antigen staining can be useful to further characterize MN patients. IgG4 predominance supports PMN diagnosis, while dual positivity for PLA2R antigen deposits and anti‑PLA2R antibodies might indicate increased disease severity and serve as supportive evidence for more aggressive therapeutic measures.

In the future, to increase this marker's clinical applicability, standardized cut‑off values for seropositivity and for risk stratification must be set, taking into account the different detection methods used.

 

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Correspondence to:

Miguel Relvas, MD

Nephrology Department, Centro Hospitalar e Universitário de São João,

Oporto, Portugal

Email: mic21892@gmail.com

 

Disclosure of potential conflicts of interest: none declared

 

Received for publication: Dec 9, 2019

Accepted in revised form: Mar 25, 2020

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