Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
Nephrol Dial Transplant. 2021 Dec 31;37(1):72-84. doi: 10.1093/ndt/gfaa331.
Idiopathic nodular mesangial sclerosis, also called idiopathic nodular glomerulosclerosis (ING), is a rare clinical entity with an unclear pathogenesis. The hallmark of this disease is the presence of nodular mesangial sclerosis on histology without clinical evidence of diabetes mellitus or other predisposing diagnoses. To achieve insights into its pathogenesis, we queried the clinical, histopathologic and transcriptomic features of ING and nodular diabetic nephropathy (DN).
All renal biopsy reports accessioned at Indiana University Health from 2001 to 2016 were reviewed to identify 48 ING cases. Clinical and histopathologic features were compared between individuals with ING and DN (n = 751). Glomeruli of ING (n = 5), DN (n = 18) and reference (REF) nephrectomy (n = 9) samples were isolated by laser microdissection and RNA was sequenced. Immunohistochemistry of proline-rich 36 (PRR36) protein was performed.
ING subjects were frequently hypertensive (95.8%) with a smoking history (66.7%). ING subjects were older, had lower proteinuria and had less hyaline arteriolosclerosis than DN subjects. Butanoate metabolism was an enriched pathway in ING samples compared with either REF or DN samples. The top differentially expressed gene, PRR36, had increased expression in glomeruli 248-fold [false discovery rate (FDR) P = 5.93 × 10-6] compared with the REF and increased 109-fold (FDR P = 1.85 × 10-6) compared with DN samples. Immunohistochemistry revealed a reduced proportion of cells with perinuclear reaction in ING samples as compared to DN.
Despite similar clinical and histopathologic characteristics in ING and DN, the uncovered transcriptomic signature suggests that ING has distinct molecular features from nodular DN. Further study is warranted to understand these relationships.
特发性结节性系膜硬化症，也称为特发性结节性肾小球硬化症（ING），是一种罕见的临床实体，其发病机制尚不清楚。这种疾病的标志是组织学上存在结节性系膜硬化，而无糖尿病或其他易患诊断的临床证据。为了深入了解其发病机制，我们研究了 ING 和结节性糖尿病肾病（DN）的临床、组织病理学和转录组学特征。
回顾 2001 年至 2016 年在印第安纳大学健康中心进行的所有肾活检报告，以确定 48 例 ING 病例。比较 ING 患者和 DN 患者（n=751）的临床和组织病理学特征。通过激光微切割分离 ING（n=5）、DN（n=18）和参考（REF）肾切除术（n=9）样本的肾小球，并对其进行 RNA 测序。进行脯氨酸丰富蛋白 36（PRR36）蛋白的免疫组化。
ING 患者常伴有高血压（95.8%）和吸烟史（66.7%）。ING 患者年龄较大，蛋白尿较少，透明小动脉玻璃样变较少。与 REF 或 DN 样本相比，ING 样本中丁酸盐代谢是一种富集途径。差异表达基因 PRR36 的表达水平在肾小球中增加了 248 倍（错误发现率 FDR P=5.93×10-6），与 REF 相比增加了 109 倍（FDR P=1.85×10-6）与 DN 样本相比。免疫组化显示 ING 样本中核周反应的细胞比例较 DN 样本减少。
尽管 ING 和 DN 在临床和组织病理学特征上相似，但所揭示的转录组学特征表明 ING 具有与结节性 DN 不同的分子特征。需要进一步研究以了解这些关系。
