Antibodies to M-Type Phospholipase A2 Receptor (PLA2R) and Membranous Lupus Nephritis
Article Outline
To the Editor:
The diagnosis of glomerulonephritis generally is based on kidney biopsy; to date, only a few diagnostic serologic markers have been described. To discriminate between different forms of nephritis without having to perform a kidney biopsy, new serologic biomarkers are needed. In systemic lupus erythematosus (SLE), the most common and severe forms of lupus nephritis are classified as either proliferative (ISN/RPS [International Society of Nephrology/Renal Pathology Society] class III/IV) or membranous (ISN/RPS class V) forms.1
Antibodies against double-stranded DNA represent a well-established marker of active disease in SLE, including exacerbations of renal involvement.2, 3 Autoantibodies against C1q,4 nucleosomes,5 and C-reactive protein6 have been found to associate with active kidney disease in SLE, mainly as markers of proliferative lupus nephritis. Specific serologic markers for membranous lupus nephritis are very limited, and to discriminate between different forms of lupus nephritis as well as other types of kidney disorders, a biopsy is required.
M-Type phospholipase A2 receptor (PLA2R) is a type I transmembrane protein abundantly expressed on glomerular podocytes. Antibodies against PLA2R were described by Beck et al7 as serum markers for idiopathic membranous nephritis and also shown in renal tissue. However, currently, the role of PLA2R and anti-PLA2R antibodies in glomerulonephritis pathology is largely unknown.
Recently, anti-PLA2R antibodies were found to correlate with clinical disease activity and proteinuria in idiopathic membranous nephritis.8 In serial investigations, Beck et al7 showed that anti-PLA2R antibody levels decrease or disappear upon treatment-induced or spontaneous remission in patients with idiopathic membranous nephritis. In their study, 6 patients with membranous lupus nephritis without anti-PLA2R antibodies were included as controls, only one of them without treatment. However, no samples were obtained in conjunction with kidney biopsy; the mean interval between biopsy and sampling was 9 months. Thus, because of immunosuppressive therapy, any initially existing anti-PLA2R antibodies might have disappeared by the time of sampling. In a recent study from a Chinese cohort, anti-PLA2R antibodies were detected in 1 of 20 patients with membranous lupus nephritis, as well as in a minor number of patients with membranous nephritis secondary to hepatitis B or cancer,9 which indicates that PLA2R antibodies may be present in sporadic cases with secondary forms of membranous nephritis or that there may be differences between ethnic groups.
To investigate whether anti-PLA2R antibodies are present at early stages of membranous nephritis in SLE, we studied patients at the time of membranous nephritis diagnosis by biopsy, before the onset of or increase in immunosuppressive therapy. Twenty-five patients (21 women, 4 men; mean age, 40 [range, 18-58] years) with SLE and biopsy-proven membranous lupus nephritis were included. All except 4 patients were of European origin. Controls were 10 European-origin female patients with proliferative lupus nephritis, mean age of 39 (range, 19-62) years, and 3 samples from patients with idiopathic membranous nephritis known to have increased levels of anti-PLA2R antibodies. All patients with SLE fulfilled the 1982 American College of Rheumatology classification criteria.
All patients with SLE had active kidney disease, confirmed by a kidney biopsy at the time of blood sampling. In 5 cases with low-grade or no albuminuria, biopsy was performed due to deteriorating kidney function or high overall disease activity with signs of renal involvement. In all patients except one, blood sampling was performed before the onset of or increase in immunosuppressive therapy. In one patient, treatment with high-dose oral prednisolone had been initiated 5 days earlier. Laboratory variables and prednisolone doses are listed in Table 1 (detailed information for patient demographics is provided in Table S1, available as online supplementary material).
Table 1. Clinical Characteristics of Lupus Nephritis Patients
| Membranous (n = 25) | Proliferative (n = 10) | |
|---|---|---|
| Serum creatinine (mg/dL) | 1.02 ±0.47(0.52-2.47) | 0.86±0.47(0.52-2.04) |
| Urine albumin (g/d) | 3.5±3.2(0-10.7) | 1.7±1.8(0.1-6.2) |
| eGFR (mL/min/1.73 m2) | 77±30(21-132) | 88±28(25-122) |
| Prednisolone (mg/d) | 9.1±7.5(0-30) | 6.0±4.6(0-12.5) |
Anti-PLA2R antibodies were investigated with indirect immune fluorescence on PLA2R-transfected HEK293 cells and nontransfected control cells (Euroimmun, www.euroimmun.de) with a screening dilution of 1:10 according to the manufacturer's instructions. Sera positive for anti-PLA2R were titrated to end point. None of the patients with SLE had detectable anti-PLA2R antibody, whereas all 3 patients with idiopathic membranous nephritis showed detectable antibodies, with titers of 100-1,000 (Fig 1).
Figure 1.
Anti–phospholipase A2 receptor (anti-PLA2R) antibody titers in patients with lupus nephritis classified as membranous (MLN), proliferative (PLN), or idiopathic (IMN).
To date, specific markers of membranous lupus nephritis are very limited and only antibodies to ribosomal P proteins, in the absence of anti–double-stranded DNA antibodies, have been found to associate with pure membranous lupus nephritis.10 We show that anti-PLA2R antibodies, even if found in 70% of idiopathic membranous nephritis sera,7 are absent in European-origin patients with SLE with membranous nephritis, as well as in patients with proliferative lupus nephritis in the active phase of nephritis. Although idiopathic membranous nephritis and membranous lupus nephritis have clinical and histopathologic similarities, the different autoantibody profiles suggest that different pathogenic mechanisms exist. Our study confirms and extends previous findings of the absence of PLA2R antibodies in membranous and proliferative lupus nephritis in patients of European origin. Thus, determination of anti-PLA2R may be of importance as a noninvasive tool in discriminating between subsets of kidney disorders in clinical practice.
Acknowledgements
Support: The study was supported by a grant from the King Gustaf V 80th Birthday Fund, the Swedish Association Against Rheumatism, and the Swedish Medical Research Council.
Financial Disclosure: The authors declare that they have no relevant financial interests.
Supplementary Material
Supplementary Table S1 (PDF) Patient Demographics.
References
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- Anti-dsDNA and complement profiles as prognostic guides in systemic lupus erythematosus . Arthritis Rheum. . 1979;22(3):226–235
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- Serum levels of autoantibodies against C-reactive protein correlate with renal disease activity and response to therapy in lupus nephritis . Arthritis Res Ther. . 2009;11(6):R188
- M-Type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy . N Engl J Med. . 2009;361(1):11–21
- Anti-phospholipase A2 receptor antibodies correlate with clinical status in idiopathic membranous nephropathy . Clin J Am Soc Nephrol. . 2011;6(6):1286–1291
- Anti-phospholipase A2 receptor antibody in membranous nephropathy . J Am Soc Nephrol. . 2011;22(6):1137–1143
- Antibodies to ribosomal P proteins: a potential serologic marker for lupus membranous glomerulonephritis . Arthritis Rheum. . 2006;54(5):1568–1572
Originally published online December 19, 2011.
PII: S0272-6386(11)01651-9
doi:10.1053/j.ajkd.2011.10.044
© 2012 National Kidney Foundation, Inc. Published by Elsevier Inc All rights reserved.
