University of Michigan, Ann-Arbor, MI, USA.
University of Miami, Miami, FL, USA.
Nephrol Dial Transplant. 2018 Feb 1;33(2):310-318. doi: 10.1093/ndt/gfw443.
BACKGROUND: Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies. METHODS: We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria. RESULTS: IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis. CONCLUSIONS: The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression.
背景：间质纤维化（IF）、肾小管萎缩（TA）和间质炎症（II）是已知的决定肾脏疾病进展的因素。这些特征的标准化量化可能会为目前的肾小球病分类增加价值。
方法：我们研究了肾脏病研究网络（NEPTUNE）研究中的 315 名参与者，包括经活检证实的微小病变性肾病（MCD=98 例）、局灶节段性肾小球硬化症（FSGS=121 例）、膜性肾病（MN=59 例）和 IgA 肾病（IgAN=37 例）。通过五位具有高读者间一致性（组内相关系数>0.8）的病理学家，在数字化全切片活检图像上对 IF、TA 和 II 进行了定量（%）。在一部分患者中测量了肾小管间质信使 RNA 的表达。使用多变量 Cox 比例风险模型评估 IF 与 eGFR 下降 40%和终末期肾病（ESRD）的复合终点以及蛋白尿完全缓解（CR）的相关性。
结果：IF 与 TA（P<0.001）和 II（P<0.001）高度相关。IF 的中位数因诊断而异：FSGS 为 17%，IgAN 为 21%，MN 为 7%，MCD 为 1%（P<0.001）。IF 与基线 eGFR（P<0.001）和蛋白尿（P=0.002）密切相关。在调整临床病理诊断、年龄、种族、全球肾小球硬化、基线蛋白尿、eGFR 和药物后，IF 每增加 10%，ESRD/40%eGFR 下降的风险比为 1.29（P<0.03），但与 CR 无显著相关性。共有 981 个基因与 IF 显著相关（|r|>0.4，错误发现率（FDR）<0.01），包括肿瘤坏死因子、干扰素γ（IFN-γ）和转化生长因子β 1（TGF-B1）等上游调节剂，以及抗原呈递和肝纤维化的信号通路。
结论：IF 的程度与不同类型蛋白尿性肾小球病的 eGFR 下降风险相关，与炎症和纤维化基因表达相关，可能在评估进展风险方面具有预测价值。
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