Target Antigens in Membranous Nephropathy: An Ever Growing Portfolio

Membranous nephropathy(MN) is a renal limited autoimmune glomerular disorder and is the most common cause of nondiabetic nephrotic syndrome in adults worldwide. It accounts for approximately 30% of all cases of idiopathic nephrotic syndrome among adults in the USA and is histologically characterized by glomerular basement membrane (GBM) thickening on light microscopy, granular IgG staining around the capillary wall on immunofluorescence microscopy, and immune complex deposits in the subepithelial space outside the GBM on electron microscopy (1). The immune complex deposits consist of IgG antibodies against the target podocyte antigens and components of the complement system, including membrane attack complex (C5b-9) that disrupt the glomerular filtration barrier and manifest with nephrotic range proteinuria. Approximately, 30 to 40% patients with untreated membranous nephropathy may progress to ESRD in 5-10 years.

In patients diagnosed with MN, a secondary cause such as malignancy, infection, drugs, and autoimmune disease may be identified in up to 20% of cases. Although the clinical presentation and histologic findings cannot reliably distinguish idiopathic MN from secondary MN, the presence of mesangial or endocapillary proliferation on light microscopy, IgA, C1q, or full house IF staining on IF microscopy, or the presence of tubuloreticular inclusions, and subendothelial/mesangial deposits on EM may suggest a secondary cause of MN (2). 

The vast majority, approximately 80% of cases, were previously labeled as idiopathic, but the groundbreaking discovery of the target podocyte antigen, M-type phospholipase A2 receptor (PLA2R) on immunohistochemical staining (IHC) along the glomerular basement membrane in 2009 led to a paradigm shift in the diagnosis, management, and prognostication of MN. IgG antibodies to the PLA2R antigen (predominantly IgG4 subclass) now account for approximately 50%-70% of all cases of idiopathic (now primary) MN. The sensitivity of PLA2R antigen staining on kidney biopsy is 70-85%, but the specificity of PLA2R antibodies is almost 100%; therefore, a positive test is diagnostic of membranous nephropathy and may obviate the need for kidney biopsy in a subset of patients with isolated proteinuria with preserved kidney function and no associated diabetes or other autoimmune disease (3). PLA2R, together with the discovery of another podocyte antigen 5 years later, thrombospondin type 1 domain 7A (THSD7A) now accounts for around 60-80% of cases of primary MN. 

In the last five years, further technological advances involving the identification of podocyte antigens have led to a new portfolio of target podocyte antigens in the diagnosis and management of primary MN. These include the neural epidermal growth factor like 1 protein (NELL1), exostosin 1 and 2 (EXT1 and EXT2), semaphorin 3B (SEMA3B), neural cell adhesion molecule 1 (NCAM1), protocadherin 7 (PCDH7) and serine protease HTRA1 (4). In a recently published case series of 142 biopsy samples of PLA2R, NELL-1, THSD7A, and EXT1/2 negative MN, an additional seven podocyte antigens were discovered within immune complexes, including FCN3, CD206, EEA1, SEZ6L2, NPR3, MST1, and VASN (5). These together account for an additional 5% of all cases of MN, leaving only ~10% of cases where the target podocyte antigen is unknown (figure1).

Figure 1. Target podocyte antigens associated with primary and secondary membranous nephropathy.

Among these newly discovered target podocyte antigens, NELL-1 is the most common target antigen and accounts for 10% of cases of MN. In most cases, NELL1 positivity is associated with primary MN, but in one-third of cases, an association with malignancy has been identified, thereby warranting age-appropriate cancer workup before a diagnosis of NELL-1-positive primary MN is confirmed (6). Also, reports of alpha lipoic acid use and heavy metal toxicity in traditional Indian and Chinese medicines have been linked to NELL-1-positive MN(7).

On the contrary, EXT 1/2 positive MN are commonly associated with autoimmune disorders, such as SLE, MCTD and Sjogren's syndrome. The circulating antibodies are predominantly IgG1 subclass and tubuloreticular inclusions and mesangial deposits are often noted in the kidney biopsy. Several such causal antigens have been linked with various disease conditions (figure 2 and table 1).

Figure 2. Podocyte antigens and their associated conditions in membranous nephropathy

The ever growing portfolio of causal podocyte antigens and the circulating anti podocyte antibodies is transforming the understanding of the etiology of membranous nephropathy besides leading to accurate diagnosis, risk stratification, monitoring disease activity and determining renal prognosis. This has led to a proposal to reclassify membranous nephropathy based on the podocyte antigen type and a secondary cause, if present. In the future, this method of classification can be leveraged to develop targeted therapies that can be tailored based on antigen and antibody profiles, and to address any underlying secondary cause, if present. These targeted therapies have the potential to be more effective and safer than current treatments, marking a significant advancement in the management of membranous nephropathy.

References

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1. P. Ronco et al., “Membranous nephropathy,” Nat Rev Dis Primers, vol. 7, no. 1, p. 69, Sep. 2021

2. L. Alsharhan and L. H. Beck Jr, “Membranous Nephropathy: Core Curriculum 2021,” Am. J. Kidney Dis., vol. 77, no. 3, pp. 440–453, Mar. 2021

3. S. A. Bobart et al., “Noninvasive diagnosis of primary membranous nephropathy using phospholipase A2 receptor antibodies,” Kidney Int., vol. 95, no. 2, pp. 429–438, Feb. 2019.

4. S. Sethi, “New ‘Antigens’ in Membranous Nephropathy,” J. Am. Soc. Nephrol., vol. 32, no. 2, p. 268, Feb. 2021.

5. T. N. Caza et al., “Discovery of seven novel putative antigens in membranous nephropathy and membranous lupus nephritis identified by mass spectrometry,” Kidney Int., vol. 103, no. 3, pp. 593–606, Mar. 2023.

6. S. Sethi et al., “Mayo Clinic consensus report on membranous nephropathy: proposal for a novel classification,” Kidney Int., vol. 104, no. 6, pp. 1092–1102, Dec. 2023.

7. O. Efe, P. N. H. So, U. Anandh, E. V. Lerma, and N. Wiegley, “An Updated Review of Membranous Nephropathy,” Indian J. Nephrol., vol. 34, no. 2, pp. 105–118, Apr. 2024.