Membranous Nephropathy, Susceptibility To

Description

Membranous nephropathy, a major cause of the nephrotic syndrome in adults, is characterized by the presence of glomerular deposits that typically contain immunoglobulin and complement components. Two major antigens, both of which are membrane glycoproteins, have been identified in human membranous nephropathy. Neutral endopeptidase (MME; 120520) is the alloantigen involved in membranous nephropathy in neonates whose mothers have a deficiency of this enzyme. The second is the M-type phospholipase A2 receptor (PLA2R1; 604939), the first antigen identified in adults with idiopathic membranous nephropathy, which is generally considered to be an autoimmune disease. In addition, autoantibodies against aldose reductase (AKR1B1; 103880), mitochondrial superoxide dismutase-2 (SOD2; 147460), and THSD7A (612249) have been found in serum and glomeruli from patients with idiopathic membranous nephropathy. Familial occurrence has been noted by Short et al. (1984) and Bockenhauer et al. (2008) (summary by Stanescu et al., 2011 and Tomas et al., 2014).

Biochemical Features

Debiec et al. (2002) described a case in which anti-neutral endopeptidase antibodies produced by a pregnant woman were transferred to a fetus, in which a severe form of membranous glomerulonephritis developed prenatally. The mother had a deficiency of neutral endopeptidase and probably had become immunized against the antigen at the time of or after an earlier miscarriage. This was the first podocytic antigen that had been found to be involved in human membranous glomerulonephritis. Despite the absence of neutral endopeptidase, the mother was healthy, as were mice with a targeted disruption of the neutral endopeptidase gene, suggesting enzymatic redundancy.

Debiec and Ronco (2011) assessed the presence of PLA2R autoantibody in the serum and PLA2R in glomerular deposits in 42 consecutive patients with biopsy-proven membranous nephropathy without features of secondary disease. Serum samples were collected before treatment at the time of biopsy. The sensitivities of the serum and biopsy tests were 57% and 74%, respectively. Of the 42 patients, 21 with circulating PLA2R autoantibodies had PLA2R in glomerular deposits. However, Debiec and Ronco (2011) also found 3 patients who had a high circulating level of PLA2R autoantibodies at a serum dilution of 1:3000 and who did not have detectable PLA2R in glomerular deposits. The authors noted that these cases might suggest that antibodies were not nephritogenic or that epitopes were poorly accessible at the time of kidney biopsy. Eighteen patients had no detectable PLA2R autoantibodies even at a serum dilution of 1:10, although 10 of them had PLA2R in glomerular deposits. These discordant findings might be due to rapid clearance of antibodies from the blood and deposition in glomeruli or to the late referral of patients when proteinuria persisted because of irreversible ultrastructural changes. The authors concluded that the absence of circulating PLA2R autoantibody at the time of kidney biopsy does not rule out a diagnosis of PLA2R-related membranous nephropathy.

Tomas et al. (2014) screened 154 patients with idiopathic membranous nephropathy who did not have anti-PLA2R1 antibodies; serum samples from 15 patients reacted against THSD7A (612249). Before identification, the putative autoantigen was found to be present in normal human glomeruli and was N-glycosylated to a lesser extent than PLA2R1. IgG4 was the predominant anti-THSD7A autoantibody identified in these patients, although other subtypes were weakly present in most serum samples. Immunofluorescence staining of renal biopsy samples from healthy controls showed linear glomerular expression of THSD7A, and there was colocalization with podocyte foot processes, but not with the glomerular basement membrane or endothelial cells. Circulating soluble immune complexes were not detected in the patients. There were no significant clinical differences between patients with anti-THSD7A and anti-PLA2R autoantibodies. Tomas et al. (2014) concluded that patients with membranous nephropathy with autoantibodies against THSD7A account for 8 to 14% of those patients who are seronegative for anti-PLA2R1 autoantibodies.

Population Genetics

Stanescu et al. (2011) stated that membranous nephropathy has an incidence of approximately 1 case per 100,000 persons per year.

Mapping

Associations Pending Confirmation

Stanescu et al. (2011) performed independent genomewide association studies in patients with idiopathic membranous nephropathy from 3 populations of white ancestry (75 French, 146 Dutch, and 335 British patients). The patients were compared with racially matched control subjects; population stratification and quality controls were carried out. In a joint analysis of the data from 556 patients studied (398 men), Stanescu et al. (2011) identified significant alleles at 2 genomic loci associated with idiopathic membranous nephropathy. Chromosome 2q24 contains the PLA2R1 gene (rs4664308, p = 8.6 x 10(-29)), previously shown to be the target of an autoimmune response. Chromosome 6p21 contains the gene encoding HLA complex class II HLA-DQ alpha chain 1 (HLA-DQA1; 146880) (rs2187668, p = 8.0 x 10(-93)). The association with HLA-DQA1 was significant in all 3 populations (p = 1.8 x 10(-9), p = 5.6 x 10(-27), and p = 5.2 x 10(-36) in the French, Dutch, and British groups, respectively). The odds ratio for idiopathic membranous nephropathy with homozygosity for both risk alleles was 78.5 (95% confidence interval, 34.6 to 178.2). Stanescu et al. (2011) concluded that an HLA-DQA1 allele on chromosome 6p21 is most closely associated with idiopathic membranous nephropathy in persons of white ancestry. This allele may facilitate an autoimmune response against targets such as variants of PLA2R1.