The prevalence of malignancy in patients with membranous nephropathy (MN) ranges from 4% to 10% (1, 2). In adults, MN is the most common cause of nephrotic syndrome outside of diabetes and is well described but not well studied in patients with cancer.
In a recent article by Thet and colleagues (3) in Translational Oncology, the authors impart on an update on cancer risks in patients with a glomerular diseases. Thet et al. (3) used MN as a prototype to understand malignancy-related glomerular disease. Malignancy-related MN is a disease of the elderly, predominantly in the 7th decade (4). The diagnosis of cancer preceded the diagnosis of MN in one-fifth of the cases, and in 80%, neoplasm detection is within the first year of MN diagnosis (5). Patients with malignancy-related MN are older with a lower estimated glomerular filtration rate and serum albumin than those without neoplasms (6, 7).
The most common malignancy-related [membranous nephropathies] include lung and breast cancer, followed by prostate and hematological malignancy.
The most common malignancy-related MNs include lung and breast cancer, followed by prostate and hematological malignancy (4). In the article by Thet et al. (3), various strategies for screening cancers in patients with glomerular diseases are discussed. First, the authors highlight the lack of consensus among clinicians concerning cancer screening in glomerular diseases. Second, the practice ranges from a selective screening of older patients (8) with glomerular diseases to a risk-based, three-step approach (9), where the first two steps are limited to general screening, and the third step involves evaluating high-risk cases. Finally, after deliberating various strategies for screening cancers in patients with MN, the authors suggest adapting cancer-screening recommendations in the United States for solid organ cancers. Recently, 8F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) emerged helpful in detecting primary tumors in patients with cancer of an unknown primary site (10). However, before routinely adapting FDG-PET/CT to diagnose cancer in patients with MN, the tool will mandate cost-effectiveness and benefit-harm assessment.
Numerous reports describe anti-M-type phospholipase A2 receptor (PLA2R) and anti-thrombospondin type-I domain-containing 7A (THSD7A) in secondary MN, including malignancy-related MN (11). In addition, the recent discovery of neural epidermal growth factor-like 1 (NELL-1) as a culprit antigen in 33% of malignancy-related MN may dictate active surveillance for cancer (11).
The Translational Oncology (3) article also highlights the association of NELL-1-positive and seven septuple-negative status with malignancy-related MN. Importantly, the debate of malignancy causing secondary MN or a coincidental detection of MN (and anti-PLA2R anti-THSD7A antibodies) and cancer remains unresolved. The presence of non-immunoglobulin G4 (IgG4) dominance may help identify malignancy-related MN (7, 11). The other crucial aspect is deciding further therapy. A few reports suggest resolution of proteinuria with successful cancer treatment (12, 13), and hence, early detection and treatment of the cancer are paramount to treating MN per se.
To summarize, IgG subtyping and staining for NELL-1 and other antigens would identify the cohort of patients deserving extensive workup for malignancy. However, limited availability and lack of standardization (of the technique for antigen detection) remain a critical deterrent to differentiate primary and secondary MN successfully. Therefore, future research must develop and validate biomarkers to distinguish between primary and malignancy-related MN.
Row PG, et al. Membranous nephropathy. Long-term follow-up and association with neoplasia. Q J Med 1975; 44:207–239. https://doi.org/10.1093/oxfordjournals.qjmed.a067422
Cahen R, et al. Aetiology of membranous glomerulonephritis: A prospective study of 82 adult patients. Nephrol Dial Transplant 1989; 4:172–180. doi: 10.1093/oxfordjournals.ndt.a091852
Thet Z, et al. Critical evaluation of cancer risks in glomerular disease. Transl Oncol [published online ahead of print February 24, 2022]. doi: 10.1016/j.tranon.2022.101376; https://www.sciencedirect.com/science/article/pii/S1936523322000389?via%3Dihub
Leeaphorn N, et al. Prevalence of cancer in membranous nephropathy: A systematic review and meta-analysis of observational studies. Am J Nephrol 2014; 40:29–35. doi: 10.1159/000364782
Bjørneklett R, et al. Long-term risk of cancer in membranous nephropathy patients. Am J Kidney Dis 2007; 50:396–403. doi: 10.1053/j.ajkd.2007.06.003
Zhang D, et al. Clinicopathological features in membranous nephropathy with cancer: A retrospective single-center study and literature review. Int J Biol Markers 2019; 34:406–413. doi: 10.1177/1724600819882698
Qu Z, et al. Absence of glomerular IgG4 deposition in patients with membranous nephropathy may indicate malignancy. Nephrol Dial Transplant 2012; 27:1931–1937. doi: 10.1093/ndt/gfr534
Pani A, et al. Glomerular diseases and cancer: Evaluation of underlying malignancy. J Nephrol 2016; 29:143–152. doi: 10.1007/s40620-015-0234-9
Nissan E, et al. The usefulness of [18F]FDG-PET/CT in detecting and managing cancers with unknown primary site depends on histological subtype. Sci Rep 2021; 11:17732. doi: 10.1038/s41598-021-96451-z
Caza TN, et al. NELL1 is a target antigen in malignancy-associated membranous nephropathy. Kidney Int 2021; 99:967–976. doi: 10.1016/j.kint.2020.07.039
Khan MB, et al. Complete resolution of paraneoplastic membranous nephropathy following curative therapy of triple-negative breast cancer. Cureus 2021; 13:e18125. doi: 10.7759/cureus.18125
Adlington D, et al. Remission of membranous nephropathy after treatment of localised prostate cancer. Case Rep Nephrol Dial 2019; 9:79–84. doi: 10.1159/000500948; https://core.ac.uk/download/pdf/237441013.pdf