A case report of NELL-1 positive membranous nephropathy associated with thymoma

It is widely recognized that malignant neoplasms can induce paraneoplastic glomerulonephropathy, including membranous nephropathy (MN). While instances of thymoma-associated nephritis are relatively rare, it has been documented that type B1 and B2 thymomas are predominantly linked with minimal change nephrotic syndrome, whereas type B3 thymoma is associated with MN. New antigens associated with MN such as neural epidermal growth factor-like 1 (NELL-1), Semaphorin3B, and Extosin1/2 have been discovered in the past few years. However, there is currently no existing reports regarding the relationship between these novel antigens and thymus-associated MN. Here, we present the first report of NELL-1 positive MN associated with thymoma.

A 73-year-old male had proteinuria during a physical exam but received no treatment. Five months later, he visited our hospital with complaints of weight loss. A CT scan revealed a thymoma, and he underwent a thymectomy. Pathological diagnosis was type B2 thymoma containing component of type B3 thymoma. Three months post-surgery, pleural effusion persisted, alongside the development of severe proteinuria (10.0 g/gCr, selectivity index: 0.2) and hypoalbuminemia (1.5 g/dL). The kidney biopsy results indicated thickening and duplication of the glomerular basement membrane (GBM). Immunofluorescence staining revealed a predominant deposition of IgG1 and IgG2 along GBM. Staining for PLA2R, Semaphorin3B, Extosin1/2, and THSD7A was negative, whereas NELL1 staining exhibited segmental positivity in GBM. These findings led to a diagnosis of thymoma-associated membranous nephropathy. Three months have passed since the thymectomy, yet the nephrotic syndrome remains unimproved. Consequently, treatment with prednisolone at 55 mg/day was initiated. Six months following the treatment, proteinuria improved to 0.3 g/gCr. Currently, proteinuria is successfully maintained below 0.5 g/gCr with a low dose of prednisolone.

In this case, nephrotic syndrome manifested several months prior to the onset of thymoma. Notably, the nephrotic syndrome persisted following thymectomy but responded well to treatment with prednisolone. Our literature review indicates that the temporal association between thymoma and nephrotic syndrome varies: thymoma may precede nephrotic syndrome, follow it after several months or years, or occur simultaneously. The prognosis of MN associated with thymoma exhibits variability across cases; however, in the majority of instances, the prognosis is favorable. Complete or partial remission was achieved in 89% (8/9) of patients following treatment with thymoma and corticosteroid therapy. The failure of surgical thymoma resection to achieve nephrotic syndrome remission, as seen in this case, may be attributed to abnormal autoantibodies produced by a highly epithelial thymoma and its prolonged persistence. The pathogenesis of MN associated with thymoma remains unclear, but type B3 component in a thymoma may have played a major role in development of MN in this case. Further, the NELL-1 staining in a thymoma was negative; therefore, no direct association between thymoma and MN has been demonstrated. To elucidate the pathogenesis of NELL-1 positive MN associated with thymoma, it is essential to accumulate more cases.