Background

Primary membranous nephropathy (MN) is an organ-specific autoimmune disease characterized by the formation of subepithelial immune deposits, with the identification of underlying antigen, such as M-type phospholipase A2 receptor (PLA2R) [1], thrombospondin type-1 domain-containing 7A (THSD7A) [2], Exostosin 1/Exostosin 2 [3], and neural epidermal growth factor-like 1 (NELL-1) [4], etc. PLA2R-related MN accounted for 70–80% of primary MN [5]. Anti-glomerular basement membrane (GBM) disease is also an autoimmune disorder with target antigen as the noncollagenous (NC1) domain of α3 chain of type IV collagen [α3(IV)NC1] and manifests as crescentic nephritis with rapid progression of kidney dysfunction. The combination of anti-GBM disease and MN has been well documented [6, 7], though the mechanism behind it remains unclear.

Genetic susceptibility especially human leukocyte antigen (HLA) genes are essential for the mechanism of autoimmune diseases. There was evidence of associations between HLA class II and both primary MN and anti-GBM disease [

Discussion and conclusion

This report described two siblings who presented with non-nephrotic range proteinuria and were diagnosed with pathology-confirmed PLA2R-related MN 1 year apart. One of them developed anti-GBM disease after the onset of MN. The high-resolution HLA ty** showed identical alleles in both siblings, specific heterozygote of DRB1*15:01/*03:01. Both alleles are reported as independent risk alleles for PLA2R-related MN and DRB1*15:01 is associated with anti-GBM disease [13,14,15,16,17]. There was one report having done high-resolution HLA ty** only for DRB1 and DQB1 in a familial MN [17]. But only one of the twins was PLA2R-related MN [17]. To our knowledge, this was the first study using high-resolution HLA ty** in siblings develo** PLA2R-related MN.

DRB1*03:01 allele was reported to be susceptible for primary MN in the Chinese population, strongly associated with anti-PLA2R antibody positive patients [9] and higher levels of anti-PLA2R antibodies [18]. Another study from China found DRB3*02:02 was an independent risk allele for both PLA2R-related MN and higher levels of anti-PLA2R antibodies, which allele was strongly linked to DRB1*03:01 [10]. Our results supported that the haplotype DRB1*03:01 plays an important role in the development of PLA2R-related MN. HLA-DRB1*15:01 was another risk allele found in PLA2R-related MN in the Chinese population [10]. It has been reported consistently with the haplotypes DRB1*15:01-DQB1*06:02. The siblings carry no DQB1*06:02 and supported DRB1*15:01 as the risk allele in PLA2R-related MN.

Our second patient developed GBM disease several months after the diagnosis of MN, suggesting the possibility of conversion to GBM disease followed MN. Previous studies have reported anti-GBM disease occurring with or secondary to membranous nephropathy [6, 19]. MN secondary to GBM disease may be associated with a local immune response to MN leading to GBM abnormalities that favor stimulation of anti-GBM antibody production by α3 (IV) NC1 conformational changes. DRB1*15:01 is a risk allele for both anti-GBM disease and membranous nephropathy [8, 11], suggesting the mechanism of the combination of MN and anti-GBM disease may be associated with the same HLA susceptibility genotype. The siblings had the same HLA type and only one of them developed anti-GBM disease. Given they lived separately after childhood, this supported the contribution of the environment to disease pathogenesis.

Although, it is difficult to exclude anti-GBM disease in this patient developed secondary to IgA nephropathy. Since the patient’s kidney biopsy showed very mild pathological changes of IgA nephropathy under light microscopy, and there was no obvious clinical manifestation of nephritis syndrome. Moreover, it has been reported patients with combined MN and anti-GBM disease have higher levels of urinary protein, a lower proportion of glomerular crescents, and higher rates of kidney function recovery, after the treatments of plasma exchange combined with glucocorticoid and cyclophosphamide [6]. The clinical manifestations of case 2 were consistent with these characteristics. We prefer that the patient’s anti-GBM disease was secondary to membrane nephropathy rather than IgA nephropathy. But, indeed, we cannot exclude the possibility of secondary to IgA nephropathy.

The proposed mechanism of better kidney outcome includes a narrower antigen spectrum of anti-GBM antibodies, lower reactivity against NC1 domains, and less anti-α3(IV)NC1 IgG1 and IgG3 in these patients [6]. Early identification and intensive treatments for such patients are very important to improve the prognosis.

In summary, we describe a familial case of PLA2R-related MN sharing a strong genetic concordance, supporting the role of genetic factors that HLA-DRB1*15:01 and DRB1*03:01 predispose patients in the development of PLA2R-related MN in Han Chinese population. The combination of MN and anti-GBM disease may also partially be associated with the same susceptible HLA allele DRB1*15:01.

Patient perspective

Regular follow-up visits allowed me to detect the problem of kidney function early and receive timely examination and treatment. I never thought that plasma replacement and glucocorticoids and other medications could help me get off dialysis, which was so lucky.