The Role of Anti-PLA2R in the Diagnosis, Monitoring and Treatment of Membranous Nephropathy: A Summary of Recent Guidelines
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Introduction to membranous nephropathy
Primary membranous nephropathy (MN) is a kidney-specific autoimmune disease that is a major cause of nephrotic syndrome. The autoimmune nature of adult MN was first discovered upon the identification of antibodies to the phospholipase A2 receptor (PLA2R), located within glomerular podocytes.1 Since the discovery of anti-PLA2R antibodies, several additional anti-podocyte antibodies have been identified in MN.2-4 For a more comprehensive discussion on MN and other MN-associated antibodies, click here.
Recent guidelines for the management of glomerular diseases have highlighted the importance of anti-PLA2R antibody detection for MN diagnosis, monitoring and transplant evaluation.5 A review of the key points of these guidelines will be discussed here.
The role of anti-PLA2R in MN diagnosis
Antibodies to PLA2R occur in 70% to 80% of patients with MN and have been shown to have a high diagnostic value.6 For patients with nephrotic syndrome (NS), confirmation of a diagnosis of MN is critical for guiding treatment decisions. Renal biopsies have long been used for the diagnosis of glomerular disease but have the disadvantage of being invasive, costly and risky.7 Risks of renal biopsies include bruising and pain, on-going bleeding, puncture of nearby organs and infection. Additionally, renal biopsies may not be possible in certain patients. On the other hand, serological testing for anti-PLA2R antibodies offers a non-invasive method for determination of PLA2R-associated MN. Anti-PLA2R are highly specific for MN (~100%) as they have not been detected in either patients with other kidney or systemic diseases or healthy individuals.8
Due to the high occurrence of anti-PLA2R antibodies in MN and a specificity close to 100%, the detection of PLA2R antibodies has been suggested to be sufficient to confirm a diagnosis of MN in patients with NS, without the need for a biopsy.9 Accordingly, in the recent 2021 KDIGO guidelines, a practice point states that “A kidney biopsy is not required to confirm the diagnosis of membranous nephropathy (MN) in patients with nephrotic syndrome and a positive anti-PLA2R antibody test.”5 This guidance is based off the findings from multiple studies. One meta-analysis of 9 studies found the sensitivity of a positive anti-PLA2R antibody test for the diagnosis of MN to be 0.78, with a specificity of 0.99.8 The 95% confidence interval for specificity is 0.96 to 1.0, which is comparable to the diagnostic performance of kidney biopsy. Another study strengthens the conclusion that in anti-PLA2R antibody-positive patients with normal estimated glomerular filtration rate (eGFR), a kidney biopsy does not alter the diagnosis of primary MN.10
In certain scenarios, a renal biopsy might still be needed. Some patients may exhibit very low titers of anti-PLA2R antibodies and may therefore test negative for anti-PLA2R by serological means. Low or absent titers might occur in early stages of the disease and not be detectable serologically until later.5 In such cases a kidney biopsy could be performed with staining of the biopsy for the PLA2R antigen. The testing algorithm for determining when to consider a kidney biopsy in a patient who is anti-PLA2R antibody-positive is shown in Figure 1. In a suspected case of MN, PLA2R antibodies should be tested for in serum using indirect immunofluorescence tests (IIFT) or ELISA. In the case where anti-PLA2R antibodies are present, and the patient has normal kidney function and does not receive immunosuppressive therapy, a positive diagnosis of PLA2R-associated MN can be confirmed without a biopsy.5 A kidney biopsy should be still considered in anti-PLA2R positive patients with reduced kidney function, receiving immunosuppressive therapy, having other serological abnormalities or deterioration of eGFR, and in patients who are negative of anti-PLA2R antibodies.
Figure 1. Diagnostic guideline for suspected primary MN. Modified from KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Disease. Kidney Int. 2021;100(4s):S1-s276. doi: 10.1016/j.kint.2021.05.021
Anti-PLA2R testing for MN monitoring
High titers of PLA2R are associated with lower likelihood of spontaneous remission and higher likelihood of nonresponse to low-dose rituximab.5,11 For those with PLA2R-associated MN, levels of PLA2Rab should be measured at three- to six-month intervals. Patients with high levels (>150 RU/ml) should be monitored at the shorter end of the range. Persistence of PLAR2ab after three to six months of observation is a sign of persistent disease activity, where disappearance of PLA2Rab is consistent with remission.5
Using PLA2R antibodies to assess MN disease severity and guide treatment decisions
In MN patients, it is important to assess the risk of progressive loss of kidney function before starting immunosuppressive treatment, so that a determination can be made as to whether treatment is necessary considering adverse side effects of the therapy. Several clinical criteria are used to assess the risk of progressive loss of kidney function including eGFR, proteinuria, serum albumin, urinary α1-microglobulin, urinary IgG, urinary β2-microglobulin and PLA2R antibodies.5 Levels of PLA2R antibodies >50 RU/ml are consistent with a “high” risk of progressive loss of kidney function.5 Further, changes in levels during follow-up likely add to risk estimation. The disappearance of anti-PLA2R antibodies precedes clinical remission and therefore can indicate that additional therapy can be avoided.5
The risk estimate guides treatment options. For patients with MN and at least one risk factor for disease progression, the KDIGO 2021 guidelines recommend rituximab or cyclophosphamide and alternate month glucocorticoids for six months, or CNI-based therapy for ≥ six months, with the choice of treatment depending on the risk estimate.5
Antibody detection for therapeutic monitoring of MN
The decrease in serum levels of anti-PLA2R in response to treatment serves as an indicator of later remission. Therefore, the monitoring of anti-PLA2R antibodies may enable treatment to be personalized for patients. The 2021 KDIGO Guidelines state that “longitudinal monitoring of antiPLA2R antibody levels at 6 months after start of therapy may be useful for evaluating treatment response in patients with MN, and can be used to guide adjustments to therapy.” It is noted that some centers will measure anti-PLA2R antibodies and adapt treatment at the three-month time point. In most patients, response occurs within three months after start of therapy.5
According to the 2021 KDIGO guidelines, in patients with PLA2R-associated MN, resistant disease can be defined by “the persistence of anti-PLA2R antibodies at high or unchanged levels after 1 line of immunosuppressive therapy (of sufficient dose and duration).” In patients who are anti-PLA2R negative, defining resistance is more difficult. In such seronegative patients, resistance may be considered if patients exhibit persistent NS.5
Evaluation of renal transplant recipients with MN
For many patients with MN, renal transplantation is needed. However, the presence of anti-PLA2R antibodies poses a unique problem to renal transplant recipients. Among patients awaiting renal transplantation, higher levels of anti-PLA2R could predict those more likely to have recurrence of the disease after transplantation. Studies have shown that the presence of high levels of anti-PLA2R antibodies (>45 RU/ml) is estimated to result in recurrence in 50% of cases. Although an exact cutoff has not yet been established. Due to this high correlation between antibody levels and disease recurrence, testing for anti-PLA2R antibodies pre-transplantation is critical. In contrast, the absence of PLA2R antibodies at the time of transplantation predicts a low risk of recurrence.5
Anti-PLA2R antibody detection is also useful for post-transplant evaluation. According to the KDIGO guidelines, in patients with PLA2R-associated MN, “regular measurement of anti-PLA2R antibodies after kidney transplantation is advised in the first 6–12 months after transplantation.” The frequency of testing may vary from one to three months depending on pretransplant antibody status. The risk of a relapse can be predicted if titers of anti-PLA2R persist or increase. The KDIGO guidelines advise that patients with recurrent MN should be treated with maximal conservative, antiproteinuric therapy and suggest treatment with rituximab if proteinuria >1 g/d.5
While there is not yet enough evidence to say definitively, the same algorithm for pre- and post-transplant evaluation is thought to also apply to THSD7A antibodies.
Conclusion
The 2009 discovery of anti-PLA2R antibodies and their association with adult MN has had a huge impact on how MN patients are diagnosed and managed. Over the last 10 years, new research has demonstrated the utility of measuring anti-PLA2R antibodies and contributed to having anti-PLA2R antibodies included in 2021 KDIGO guidelines for the diagnosis, prognosis and treatment of MN.
The KDIGO guidelines include several research recommendations for the future of MN management. These include studies to determine how long positive serology precedes the development of the disease with clinical symptoms, evaluate the accuracy of anti-PLA2R antibody levels in predicting outcome in patients with MN, evaluate the predictive value of changes on anti-PLA2R antibody levels over a three- to six-month period in patients with MN, and others. Other questions include “Should treatment be aimed at complete immunologic remission, or is a substantial reduction of anti-PLA2R–antibody level sufficient?”
Also needed are additional studies to evaluate the role of antibodies directed against newly discovered minor antigens such as THSD7A, NELL-1, semaphorin 3B and exostosin 1/2, as 20% of patients are double-negative for PLA2R and THSD7A.
References
1. Beck LH, Bonegio RGB, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361(1):11-21 doi: 10.1056/nejmoa0810457.
2. Tomas NM, Beck LH, Meyer-Schwesinger C, et al. Thrombospondin type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371(24):2277-2287 doi: 10.1056/NEJMoa1409354.
3. Sethi S, Debiec H, Madden B, et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int. 2020;97(1):163-174 doi: 10.1016/j.kint.2019.09.014.
4. Sethi S, Madden BJ, Debiec H, et al. Exostosin 1/exostosin 2–associated membranous nephropathy. J Am Soc Nephrol. 2019;30(6):1123-1136 doi: 10.1681/ASN.2018080852.
5. KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4s):S1-s276. doi: 10.1016/j.kint.2021.05.021
6. Couser WG. Primary membranous nephropathy. Clin J Am Soc Nephrol. 2017;12(6):983-997. doi: 10.2215/CJN.11761116.
7. Visconti L, Cernaro V, Ricciardi CA, et al. Renal biopsy: still a landmark for the nephrologist. World J Nephrol. 2016;5(4):321-327. doi: 10.5527/wjn.v5.i4.321
8. Du Y, Li J, He F, et al. The diagnosis accuracy of PLA2R-AB in the diagnosis of idiopathic membranous nephropathy: a meta-analysis. PloS one. 2014;9(8):e104936-e104936. doi: 10.1371/journal.pone.0104936
9. Bobart SA, De Vriese AS, Pawar AS, et al. Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies. Kidney Int. 2019;95(2):429-438. doi: 10.1016/j.kint.2018.10.021
10. Wiech T, Stahl RAK, Hoxha E. Diagnostic role of renal biopsy in PLA(2)R1-antibody-positive patients with nephrotic syndrome. Mod Pathol. 2019;32(9):1320-1328. doi: 10.1038/s41379-019-0267-z
11. Radice A, Trezzi B, Maggiore U, et al. Clinical usefulness of autoantibodies to M-type phospholipase A2 receptor (PLA2R) for monitoring disease activity in idiopathic membranous nephropathy (IMN). Autoimmun Rev. 2016;15(2):146-154. doi: 10.1016/j.autrev.2015.10.004
