Abstract
Background
The phospholipase A2 receptor (PLA2R) associated with membranous nephropathy (MN) is an organ-specific autoimmune disease associated with PLA2R and human leukocyte antigen (HLA) genes. Familial PLA2R-related MN is rarely reported. The combination of anti-GBM disease and MN has been well documented, though the mechanism behind it remains unclear.
Case presentation
We describe two siblings diagnosed with pathology-confirmed PLA2R-related MN 1 year apart. And one of the two siblings developed an anti-GBM disease. The high-resolution HLA ty** showed identical alleles in both siblings, specifically heterozygotes of DRB1*15:01/*03:01.
Conclusion
We describe a familial case of PLA2R-related MN 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 the 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.
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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 [ 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. 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.Discussion and conclusion
Patient perspective
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All data generated or analyzed during this study are included in this published article.
Abbreviations
- pMN:
-
Primary membranous nephropathy
- PLA2R:
-
Phospholipase A2 receptor
- MN:
-
Membranous nephropathy
- HLA:
-
Human leukocyte antigen
- THSD7A:
-
Thrombospondin type-1 domain-containing 7A
- NELL-1:
-
Neural epidermal growth factor-like 1
- GBM:
-
Glomerular basement membrane
- α3(IV)NC1:
-
The noncollagenous domain of α3 chain of type IV collagen
- Scr:
-
Serum creatinine
- ANCA:
-
Neutrophil cytoplasmic antibodies
- Ig:
-
Immunoglobulin
References
Beck LH, Bonegio RGB, Lambeau G, Beck DM, Powell DW, Cummins TD, et al. M-type phospholipase a(sub 2) receptor as target antigen in idiopathic membranous nephropathy. N Engl J Med. 2009;361:11–21.
Tomas NM, Beck LH, Meyer-Schwesinger C, Seitz-Polski B, Ma H, Zahner G, et al. Thrombospondin Type-1 domain-containing 7A in idiopathic membranous nephropathy. N Engl J Med. 2014;371:2277–87.
Sethi S, Madden BJ, Debiec H, Charlesworth MC, Gross L, Ravindran A, et al. Exostosin 1/Exostosin 2-associated membranous nephropathy. J Am Soc Nephrol. 2019;30:1123–36.
Sethi S, Debiec H, Madden B, Charlesworth MC, Morelle J, Gross L, et al. Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. Kidney Int. 2020;97:163–74.
Radice A, Pieruzzi F, Trezzi B, Ghiggeri G, Napodano P, D’Amico M, et al. Diagnostic specificity of autoantibodies to M-type phospholipase A2 receptor (PLA2R) in differentiating idiopathic membranous nephropathy (IMN) from secondary forms and other glomerular diseases. J Nephrol. 2018;31:271–8.
Jia X, Hu S, Chen J, Qu Z, Liu G, Cui Z, et al. The clinical and immunological features of patients with combined anti-glomerular basement membrane disease and membranous nephropathy. Kidney Int. 2014;85:945–52.
Ahmad SB, Santoriello D, Canetta P, Bomback AS, D’Agati VD, Markowitz G, et al. Concurrent anti-glomerular basement membrane antibody disease and membranous nephropathy: a case series. Am J Kidney Dis. 2021;78:219–225.e1.
**e J, Liu L, Mladkova N, Li Y, Ren H, Wang W, et al. The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis. Nat Commun. 2020;11:1600.
Cui Z, **e L, Chen F, Pei Z, Zhang L, Qu Z, et al. MHC class II risk alleles and amino acid residues in idiopathic membranous nephropathy. JASN. 2017;28:1651–64.
Le WB, Shi JS, Zhang T, Liu L, Qin HZ, Liang S, et al. HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-related membranous nephropathy. J Am Soc Nephrol. 2017;28:1642–50.
**e L-J, Cui Z, Chen F-J, Pei Z-Y, Hu S-Y, Gu Q-H, et al. The susceptible HLA class II alleles and their presenting epitope(s) in Goodpasture’s disease. Immunology. 2017;151:395–404.
Stanescu HC, Arcos-Burgos M, Medlar A, Bockenhauer D, Kottgen A, Dragomirescu L, et al. Risk HLA-DQA1 and PLA(2)R1 alleles in idiopathic membranous nephropathy. N Engl J Med. 2011;364:616–26.
Vasmant D, Murnaghan K, Bensman A, Muller JY, Mougenot B. Familial idiopathic membranous glomerulonephritis. Int J Pediatr Nephrol. 1984;5:193–6.
Vangelista A, Tazzari R, Bonomini V. Idiopathic membranous nephropathy in 2 twin brothers. Nephron. 1988;50:79–80.
Mezzano S, Rojas G, Ardiles L, Caorsi I, Bertoglio JC, Lopez MI, et al. Idiopathic membranous nephropathy, associated with HLA-DRw3 and not related to monocyte-phagocyte system fc receptor dysfunction, in father and son. Nephron. 1991;58:320–4.
Maccario M, Segagni S, Efficace E, Piazza V, Poggio F, Villa G, et al. Idiopathic membranous nephropathy in two siblings. Nephrol Dial Transplant. 1995;10:108–10.
Tao T, Wang J, Lei S, Hu Z. Identical twins with idiopathic membranous nephropathy. J Nephrol. 2021;34:597–601.
Wang H, Cui Z, **e L, Zhang L, Pei Z-Y, Chen F, et al. HLA class II alleles differing by a single amino acid associate with clinical phenotype and outcome in patients with primary membranous nephropathy. Kidney Int. 2018;94:974–82.
Nikolopoulou A, Huang-Doran I, McAdoo SP, Griffith ME, Cook HT, Pusey CD. Membranous glomerulonephritis with crescents. Kidney International Reports. 2019;4:1577–84.
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The pathological figure provided by the renal pathology division of Peking university first hospital were greatly appreciated.
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Study idea: XYJ and ZC; Data acquisition: YJC, HRC, XYJ, and XYZ; data analysis/ experiments: YJC; drafted the manuscript: YJC; pathological figure: XJY, suggestions for gene test: XJZ; supervision and mentorship: ZC and MHZ. Each author contributed important intellectual content during the drafting and revision of the manuscript and has accepted responsibility for the overall work by ensuring that any questions about the accuracy or integrity of any portion of the work are appropriately investigated and resolved. XYJ and XYZ take responsibility that this study has been reported honestly, accurately, and transparently; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. The author(s) read and approved the final manuscript.
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Cheng, Yj., Jia, Xy., Cao, Hr. et al. Primary membranous nephropathy in two siblings with one combined with anti-glomerular basement membrane disease: a case report. BMC Nephrol 24, 183 (2023). https://doi.org/10.1186/s12882-023-03132-2
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DOI: https://doi.org/10.1186/s12882-023-03132-2