Phospholipase A2 Receptor Autoantibodies, IgG

Membranous nephropathy (MN) belongs to a family of kidney diseases characterized by inflammation and hypersensitivity of the glomeruli (glomerulitis) and/or interstitium (nephritis) of the kidney.^2-4 The reported annual incident of MN amounts to 5 to 10 cases per million people in northern Europe.⁵ MN is an immunologically mediated disease characterized by the deposition of immune complexes at the glomerular basement membrane accompanied by a progressive reduction in kidney function in the majority of patients.^2,4 As the disease progresses, thickening of the glomerular basement membrane can be seen by light microscopy, and thus the disease was initially referred to as "membranous glomerulonephritis."^2,6 Immune deposits compromise the permeability of the capillary loops, leading to proteinuria and frequently to a nephrotic syndrome characterized by proteinuria, hypoalbuminemia, hyperlipidemia, and edema.⁷ MN accounts for approximately 20% of cases of nephrotic syndrome in adults.² Approximately one-third of patients with MN will go on to develop end-stage renal failure within ten years.⁸ Another third will endure chronic proteinuria and symptoms of nephrotic syndrome while another third will experience spontaneous remission.⁸

MN can occur secondary to a number of clinical conditions, including infections (ie, hepatitis B and syphilis), systemic lupus erythematosus, cancer, and drug toxicity.² MN that occurs independent of other known clinical syndromes is referred to as primary membranous nephropathy (pMN). This condition has historically been referred to as "idiopathic" MN because the etiology was unknown. Clinicians now realize that MN is an organ-specific autoimmune disease in which circulating autoantibodies bind to an intrinsic antigen on glomerular podocytes and form deposits of immune complexes on the glomerular capillary walls. Recent clinical studies have revealed that circulating autoantibodies to the podocyte M-type receptor for secretory phospholipase A2 (PLA2R) can be measured in 70% to 80% of patients with pMN.⁹ While the therapeutic approach to patients with secondary MN focuses on treating the underlying disease, patients with pMN are generally treated with an immunosuppressive strategy.¹⁰ It should be noted that a small fraction of individuals with secondary MN can been shown to be positive for anti-PLA2R.^1-13 The clinical significance of this finding is unclear. The occurrence of anti-PLA2R autoantibodies in secondary forms of MN may simply be coincidental or may have some role in the development and progression of disease.

Levels of circulating anti-PLA2R have been shown to correlate with clinical disease activity, as measured by level of proteinuria.¹⁴ Anti-PLA2R levels have been shown to be of value for predicting the course of the disease in that a correlation was reported between the anti-PLA2R level and the clinical outcome.^15,16 Renal failure has been reported to occur less frequently in patients with low anti-PLA2R levels,¹⁴ while spontaneous remissions are less common in patients with high levels.^12,16 Gunnarsson and coworkers also found that patients with high antibody levels required an immunosuppressive therapy more often than those lower titers.¹⁶ This group also observed that antibody correlated with response to immunosuppressive therapy, defined as time from the start of therapy until remission.¹⁶ Several studies have reported that patients undergoing immunosuppressive therapy show a decline of anti-PLA2R levels and that autoantibodies levels rise during a relapse.^{6,10,15,17-20} Recent data suggest that in PLA2R-ab-positive patients, measuring PLA2R-abs at the end of therapy predicts the subsequent course.²¹

El-Zoghby and coworkers reported that pMN recurs in up to 40% of patients after renal transplantation.²² The risk for recurrence is higher when anti-PLA2R autoantibodies are detected prior to the transplantation.¹⁹

1. Dähnrich C, Komorowski L, Probst C, et al. Development of a standardized ELISA for the determination of autoantibodies against human M-type phospholipase A2 receptor membranous nephropathy. Clin Chim Acta. 2013 Jun 5; 421:213-218. PubMed 23541686

2. Ronco P, Debiec H. Pathogenesis of membranous nephropathy: Recent advances and future challenges. Nat Rev Nephrol. 2012 Feb 28; 8(4):203-213. PubMed 22371247

3. Glassock RJ. Pathogenesis of membranous nephropathy: A new paradigm in evolution. Contrib Nephrol. 2013; 181:131-142. PubMed 23689575

4. Debiec H, Ronco P. Immunopathogenesis of membranous nephropathy: An update. Semin Immunopathol. 2014 Jul; 36(4):381-397. PubMed 24715030

5. McQuarrie EP, Mackinnon B, Stewart GA, Geddes CC, Scottish Renal Biopsy Registry. Membranous nephropathy remains the commonest primary cause of nephrotic syndrome in a northern European Caucasian population. Nephrol Dial Transplant. 2010 Mar; 25(3):1009-1010. PubMed 20037184

6. Beck LH Jr, Salant DJ. Membranous nephropathy: Recent travels and new roads ahead. Kidney Int. 2010 May; 77(9):765-770. PubMed 20182413

7. Scheidat S, Stahl RA. Membranous glomerulonephritis. Internist (Berl). 2003 Sep; 44(9):1120-1130. PubMed 14566465

8. Steinman TI, Nissenson AR, Glassock RJ, et al. L-carnitine use in dialysis patients: Is national coverage for supplementation justified? What were CMS regulators thinking—or were they? Nephrol News Issues. 2003 Apr; 17(5):28-36. PubMed 12715624

9. Beck Jr LH, Bonegio RG, Lambeau G, et al. M-type phospholipase A2 receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009 Jul 2; 361(1):11-21. PubMed 19571279

10. Kidney Disease: Improving Global Outcomes (KDIGO) Glomerulonephritis work group. KDIGO clinical practice guideline for glomerulonephritis. Kidney Int Suppl. 2012; 2:186-197.

11. Beck LH Jr, Salant DJ. Membranous nephropathy: From models to man. J Clin Invest. 2014 Jun; 124(6): 23.7-2314. PubMed 24892704

12. Gunnarsson I, Schlumberger W, Rönnelid J. Antibodies to M-type phospholipase A2 receptor (PLA2R) and membranous lupus nephritis. Am J Kidney Dis. 2012 Apr; 59(4):585-586. PubMed 22177657

13. Qin W, Beck LH Jr, Zeng C, et al. Anti-phospholipase A2 receptor antibody in membranous nephropathy. J Am Soc Nephrol. 2011 Jun; 22(6):1137-1143. P