Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
The Ohio State University Wexner Medical Center, Columbus.
Arthritis Rheumatol. 2021 Feb;73(2):244-254. doi: 10.1002/art.41507. Epub 2021 Jan 12.
To evaluate the role of urinary epidermal growth factor (EGF) as a biomarker of chronic kidney damage in lupus nephritis (LN).
A proteomics approach was used to identify urinary EGF as a biomarker of interest in a discovery cohort of patients with LN. The expression of urinary EGF was characterized in 2 large multiethnic LN cohorts, and the association between urinary EGF levels at the time of flare and kidney outcomes was evaluated in a subset of 120 patients with long-term follow-up data. For longitudinal studies, the expression of urinary EGF over time was determined in 2 longitudinal cohorts of patients with LN from whom serial urine samples were collected.
Discovery analysis showed the urinary EGF levels as being low in patients with active LN (median peptide count 8.4, interquartile range [IQR] 2.8-12.3 in patients with active LN versus median 48.0, IQR 45.3-64.6 in healthy controls). The peptide sequence was consistent with that of proEGF, and this was confirmed by immunoblotting. The discovery findings were verified by enzyme-linked immunosorbent assay. Patients with active LN had a significantly lower level of urinary EGF compared to that in patients with active nonrenal systemic lupus erythematosus (SLE), patients with inactive SLE, and healthy kidney donors (each P < 0.05). The urinary EGF level was inversely correlated with the chronicity index of histologic features assessed in kidney biopsy tissue (Spearman's r = -0.67, P < 0.001). Multivariate survival analysis showed that the urinary EGF level was associated with time to doubling of the serum creatinine level (DSCr), a marker of future end-stage kidney disease (ESKD) (hazard ratio 0.88, 95% confidence interval 0.77-0.99, P = 0.045). Patients whose LN symptoms progressed to DSCr and those who experienced progression to ESKD had a lower urinary EGF level at the time of flare, and urinary EGF levels decreased over the 12 months following flare. All patients who experienced progression to ESKD were identified based on a urinary EGF cutoff level of <5.3 ng/mg.
Urinary EGF levels are correlated with histologic kidney damage in patients with LN. Low urinary EGF levels at the time of flare and decreasing urinary EGF levels over time are associated with adverse long-term kidney outcomes.
评估尿表皮生长因子 (EGF) 作为狼疮性肾炎 (LN) 慢性肾损伤生物标志物的作用。
采用蛋白质组学方法鉴定出 LN 患者发现队列中感兴趣的尿 EGF 作为生物标志物。在两个大型多民族 LN 队列中对尿 EGF 的表达进行了特征描述，并在具有长期随访数据的 120 名患者亚组中评估了 flare 时尿 EGF 水平与肾脏结局之间的关联。对于纵向研究，对来自 LN 患者的两个纵向队列进行了随时间的尿 EGF 表达测定，从这些患者中收集了系列尿液样本。
发现分析表明，活动期 LN 患者的尿 EGF 水平较低（活动期 LN 患者的中位肽计数为 8.4，四分位距 [IQR] 2.8-12.3，而健康对照组的中位值为 48.0，IQR 45.3-64.6）。肽序列与 proEGF 一致，这通过免疫印迹得到了证实。发现结果通过酶联免疫吸附试验得到了验证。与活动期非肾系统性红斑狼疮 (SLE)患者、非活动期 SLE 患者和健康肾脏供体相比，活动期 LN 患者的尿 EGF 水平显著降低（均 P <0.05）。尿 EGF 水平与肾活检组织中评估的组织学特征慢性指数呈负相关（Spearman r =-0.67，P <0.001）。多变量生存分析表明，尿 EGF 水平与血清肌酐水平翻倍的时间（DSCr）相关，DSCr 是未来终末期肾脏疾病 (ESKD)的标志物（风险比 0.88，95%置信区间 0.77-0.99，P = 0.045）。在 DScr 进展和进展为 ESKD 的 LN 症状患者中，在 flare 时尿 EGF 水平较低，并且在 flare 后 12 个月内尿 EGF 水平下降。所有进展为 ESKD 的患者均根据尿 EGF 截断值 <5.3 ng/mg 确定。
尿 EGF 水平与 LN 患者的组织学肾损伤相关。flare 时的低尿 EGF 水平和随时间的尿 EGF 水平降低与不良的长期肾脏结局相关。
