Background and objectivesThe neural EGF-like 1 (NELL-1) protein is a novel antigen in primary membranous nephropathy. The prevalence and clinical characteristics of NELL-1–positive membranous nephropathy in Chinese individuals with primary membranous nephropathy are unclear.Design, setting, participants, & measurementsA total of 832 consecutive patients with biopsy-proven primary membranous nephropathy were enrolled. The glomerular expression of phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing 7A (THSD7A) was screened. Glomerular immunohistochemistry staining for NELL-1 was performed in 43 patients with PLA2R- and THSD7A-negative membranous nephropathy, 31 patients with PLA2R-positive membranous nephropathy, and two patients with PLA2R and THSD7A double positivity. The NELL-1 antibody was also detected in the sera of patients with NELL-1–positive membranous nephropathy by western blot. Clinical and pathologic features were comparable between patients with isolated NELL-1–positive, isolated PLA2R/THSD7A-positive, and triple antigen–negative membranous nephropathy.ResultsAmong the 832 patients with primary membranous nephropathy, 11 of 54 (20%) patients with PLA2R-negative membranous nephropathy had THSD7A-positive membranous nephropathy. NELL-1–positive membranous nephropathy accounted for 35% (15 of 43) of all patients with PLA2R- and THSD7A-negative membranous nephropathy. One patient was double positive for NELL-1 and PLA2R in glomerular deposits and positive for only the PLA2R antibody in the serum. Most patients with NELL-1–positive membranous nephropathy were women. No tumors were found. There were significant differences in the prevalence of IgG subtypes between patients with different antigen positivity. Among patients with isolated NELL-1–positive membranous nephropathy, although 80% (12 of 15) were IgG4 staining positive, the proportion of IgG4 dominance was only 67% (ten of 15).ConclusionsAbout one third of patients who were PLA2R and THSD7A negative were NELL-1 positive in Chinese patients with primary membranous nephropathy. NELL-1–positive membranous nephropathy was more common than THSD7A-positive membranous nephropathy in PLA2R-negative membranous nephropathy.

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We reported a large Chinese family diagnosed with autosomal dominant tubulointerstitial kidney disease caused by MUC1 mutation (ADTKD-MUC1). Cytosine duplication within a string of 7 cytosines in the variable-number tandem repeats (VNTR) region of the MUC1 gene was detected by long-read single-molecule real-time (SMRT) sequencing. MUC1 frameshift protein (MUC1fs) was found to be expressed in renal tubules and urinary exfoliated cells by pathological examination. The family, which consisted of 5 generations including 137 individuals, was followed for 5 years. Genetic testing was performed in thirty-four individuals, 17 of whom carried MUC1 mutations. The ADTKD-MUC1-affected individuals had an elevated incidence of hyperuricaemia without gout attack. Within five years, higher baseline levels of urinary α1-microglobulin were detected in affected individuals with rapidly progressing renal failure than in affected individuals with stable renal function, and the increases manifested even before increases in serum creatinine. This study demonstrates that SMRT sequencing is an effective method for the identification of MUC1 mutations. The pathological examination of MUC1fs expression in renal tissue and urinary exfoliated cells can contribute to early screening of family members suspected to be affected. It is suggested that affected individuals with elevated urinary α1microglobulin levels should be closely monitored for renal function. Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a hereditary disease characterized by progressive tubulointerstitial nephropathy that ultimately leads to end-stage renal disease (ESRD) 1-4. To date, four genes mutation which causes ADTKD have been identified: uromodulin (UMOD) 5 , mucin-1 (MUC1) 6 , renin (REN) 7 and hepatocyte nuclear factor 1β (HNF1B) 8. The disease forms caused by these mutations were named ADTKD-UMOD, ADTKD-MUC1, ADTKD-REN and ADTKD-HNF1B, respectively. Recently, a SEC. 61A1 mutation was identified as a novel cause of ADTKD 9. The manifestations of ADTKD are nonspecific, including autosomal dominant inheritance, bland urinary sediment with absent or mild proteinuria, progressive kidney failure, and, in some cases, multiple small renal cysts 1-3,10,11. Renal histology shows interstitial fibrosis and tubular atrophy, varying degree of nephrosclerosis and arteriolar thickening. Immunofluorescence or immunostaining on the renal tissue is negative. Electron microscopy usually showed irregular width and lamelation of the glomerular basement membrane and particular the tubular basement membrane 2,12-14. The diagnosis of ADTKD-MUC1 depends on genetic analysis. The MUC1 gene, located on chromosome 1q21, contains 20-125 copies of a repetitive sequence of 60 basepair in the variable-number tandem repeats (VNTR) domain 13. Most MUC1 mutations are caused by duplication of a cytosine within a seven-cytosine stretch in the VNTR region that produces a frameshift muatation, resulting in MUC1 frameshift protein (MUC1fs) 6,14-16. In addition, mutations in other areas of ...