A CAPTIVATING CASE OF NEURAL EPIDERMAL GROWTH FACTOR-LIKE 1 PROTEIN (NELL-1) ASSOCIATED MEMBRANOUS NEPHROPATHY

Introduction:

Membranous nephropathy (MN) is classified as primary or idiopathic MN and secondary MN. In 2020, in addition to PLA2R and THSD7A, Sethi et al. reported another pathogenic antigen of primary membranous nephropathy, known as neural epidermal growth factor-like 1 protein (NELL-1). Some studies have shown that, NELL1 MN may be found to be associated with various diseases like malignancy, drugs, autoimmune disease, infections, sarcoidosis, hematopoietic stem cell transplant, and de novo MN in a kidney transplant. Thus, there is marked diversity among the patients of NELL-1 associated membranous nephropathy and there is a conundrum for classifying these patients of membranous nephropathy as idiopathic versus secondary.

Methods:

A 68-year-old female presented with a 2 weeks history of swelling fully over the body. The patient’s laboratory profile was as follows: hemoglobin: 14.8 g/dL, total leukocyte count: 6750/mm3, platelet count: 2.4 × 10 5 /mm 3 , random blood sugar: 176 mg/dL serum albumin: 2.6 g/dL, blood urea: 26 mg/dL, serum creatinine: .8 mg/dL serum sodium: 134.4 mEq/L, serum potassium: 3.6 mEq/L, serum calcium: 8.2 mg/dL, serum phosphorus: 3.3 mg/dL, HBsAg: negative, HIV I and II: negative, , and anti-HCV: negative, Serum rheumatoid factor: <10 IU/ml (normal<14), serum antinuclear antibody (ANA): 6.52 units (normal <20), serum antithyroid peroxidase antibody titre: .30 IU/ml (normal <9). Serum protein electrophoresis: no ‘M’ band, and Phospholipase A2 receptor (PLA2R) antibody titre: <2.0 RU/ml (normal<14). Urinary albumin: 3+, urinary sugar: 0, urine microscopy: white blood cell count: 2–3/high-power field, red blood cell count: 0/high- power field, urinary pH: –6.4. A 24-hour urinary protein value was 5.8 grams/day. Urinary mercury level: <5.0μg/L (normal<20). Stool for occult blood was negative. Pap smear was negative for malignancy. A mammogram of breasts showed normal picture. Upper gastrointestinal endoscopy and colonoscopy did not show any evidence of malignancy.  Contrast enhanced computed tomography of chest and abdomen were with in normal limit. A renal biopsy, at light microscopy showed diffuse thickening of capillaries with intramembranous mottling in silver methenamine stained sections (Figure 1). Direct immunofluorescence (IF) showed the following immunostaining pattern: IgA, IgM, and C1q: negative, IgG:3+; segmental capillary wall granular, IgG1: 2+; segmental capillary wall granular, IgG4: 3+; segmental capillary wall granular, IgG2 & IgG3: negative, kappa light chains: 3+; segmental capillary wall granular, and Lambda light chains:3+; segmental capillary wall granular. Immunohistochemical (IHC) staining for neural epidermal growth factor-like 1 protein (NELL-1) showed granular positivity along glomerular capillary walls while anti PLA2R was negative (Figure 2). Renal electron microscopy showed subepithelial electron dense deposits and no substructure was identified in the deposits (Figure 3).

Results:

Based on these findings, the diagnosis of PLA2R negative NELL-1 associated idiopathic membranous nephropathy was made. Patient’s treatment was started with telmisartan 40 mg in morning and 20 mg in evening. After 6 months of telmisartan therapy, 24-hour urine protein was 1.1 grams/day. 

Conclusions:

In patients of membranous nephropathy, the NELL-1 antigen appears to be a distinctive target antigen. Although most cases of NELL-1 MN are idiopathic or primary, many secondary diseases have been found to be related to NELL-1 antigen. Thus, there is a need for extensive workup of patients with NELL-1 MN to rule out all secondary causes.

I have no potential conflict of interest to disclose.

I did not use generative AI and AI-assisted technologies in the writing process.