To the Editor:
Miyazaki et al.1 recently suggested in Kidney International Reports that neural epidermal growth factor-like1 (NELL1) is a causative antigen in bucillamine-associated membranous nephropathy (MN), and they described 4 Japanese patients with NELL1-positve MN complicated by rheumatoid arthritis (RA). Among 221 patients with MN who underwent NELL1 staining, 10 (4.5%) were positive for NELL1. Among them, 6 patients (60%) had NELL1-positive MN with RA, including 4 with suspected bucillamine-induced MN.
The rate of NELL1-positive MN with RA at our institutions is far lower, emphasizing the importance of the accumulation of more cases. Among 88 patients who underwent NELL1-staining at our institutions, 8 (9.1%) were diagnosed with NELL1-positive MN from 2013 to 2022, including 1 (12.5%) patient with MN associated with bucillamine-treated RA, 1 (12.5%) with immunoglobulin G4-related disease, and 6 (75%) with a nonspecific cause, suspected to be primary MN. Focusing on RA, 7 of our 88 patients (8.0%) were diagnosed with MN in a patient with RA, and 4 patients were treated with bucillamine. Only the bucillamine-treated patient (25%) mentioned above was NELL1-positive. None of the non-bucillamine patients were NELL1-positive; however, 1 patient was positive for thrombospondin type-1 domain-containing 7A.
Our NELL1-positive MN patient with RA was a 64-year-old male who was diagnosed with RA 10 months before the renal biopsy and treated with bucillamine plus prednisolone. His laboratory tests showed urinary protein 5 months after bucillamine induction. His eGFR at the renal biopsy was 80 ml/min per 1.73 m2, with 9.2 g/gCr urinary protein. Immunofluorescence microscopy revealed granular 1+ IgG, 2+ IgG1, 1+ IgG2, 1+ IgG3, 1+ IgG4, and 1+ NELL1, and negativity for IgA, IgM, C3, C1q, phospholipase A2 receptors, and thrombospondin type-1 domain-containing 7A. The NELL1 staining showed segmental distribution, which is consistent with electron-dense deposits (Figure 1). Even though the results obtained by both Miyazaki et al.1 and us suggested that NELL1 can be a causative antigen in bucillamine-associated MN and shared the features of relatively short treatment duration and segmental distribution of deposits, further investigation with a greater number of cases is necessary to conclude the positive rate of NELL1 in MN with RA. Moreover, unknown antigens may still exist.
Figure 1.
(a) NELL1 was positive in a patient with MN associated with bucillamine-treated RA. (b) Electron-dense microscopy showed segmental deposits, indicated by arrows.
Disclosure
All the authors have no competing interests.
Acknowledgment
We are deeply grateful to Ms. Mikie Daigo and Ms. Mami Kobayashi (University of Tsukuba, Tsukuba, Japan) for their technical support. This work was supported by grants from the Japan Society for the Promotion of Science KAKENHI (nos. JP22J20394, JP21H02822).
References
- 1.Miyazaki R., Ueda H., Hayashi A., et al. Neural epidermal growth factor-like 1-positive membranous nephropathy with rheumatoid arthritis. Kidney Int Rep. 2023;8:921–924. doi: 10.1016/j.ekir.2022.12.026. [DOI] [PMC free article] [PubMed] [Google Scholar]