儿童起病系统性红斑狼疮中慢性肾脏损伤和肾功能下降的尿液生物标志物。
Urine biomarkers of chronic kidney damage and renal functional decline in childhood-onset systemic lupus erythematosus.
机构信息
Division of Rheumatology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, 3333 Burnet Avenue, MC 4010, Cincinnati, OH, 45229, USA.
Division of Allergy and Rheumatology, Department of Medicine, University of Cincinnati, Cincinnati, USA.
出版信息
Pediatr Nephrol. 2019 Jan;34(1):117-128. doi: 10.1007/s00467-018-4049-5. Epub 2018 Aug 29.
OBJECTIVES
To delineate urine biomarkers that reflect kidney structural damage and predict renal functional decline in pediatric lupus nephritis (LN).
METHODS
In this prospective study, we evaluated kidney biopsies and urine samples of 89 patients with pediatric LN. Urinary levels of 10 biomarkers [adiponectin, ceruloplasmin, kidney injury molecule-1, monocyte chemotactic protein-1, neutrophil gelatinase-associated lipocalin, osteopontin, transforming growth factor-ß (TGFß), vitamin-D binding protein, liver fatty acid binding protein (LFABP), and transferrin] were measured. Regression analysis was used to identify individual and combinations of biomarkers that determine LN damage status [NIH-chronicity index (NIH-CI) score ≤ 1 vs. ≥ 2] both individually and in combination, and biomarker levels were compared for patients with vs. without renal functional decline, i.e., a 20% reduction of the glomerular filtration rate (GFR) within 12 months of a kidney biopsy.
RESULTS
Adiponectin, LFABP, and osteopontin levels differed significantly with select histological damage features considered in the NIH-CI. The GFR was associated with NIH-CI scores [Pearson correlation coefficient (r) = - 0.49; p < 0.0001] but not proteinuria (r = 0.20; p > 0.05). Similar to the GFR [area under the ROC curve (AUC) = 0.72; p < 0.01], combinations of osteopontin and adiponectin levels showed moderate accuracy [AUC = 0.75; p = 0.003] in discriminating patients by LN damage status. Renal functional decline occurred more commonly with continuously higher levels of the biomarkers, especially of TGFß, transferrin, and LFABP.
CONCLUSION
In combination, urinary levels of adiponectin and osteopontin predict chronic LN damage with similar accuracy as the GFR. Ongoing LN activity as reflected by high levels of LN activity biomarkers heralds renal functional decline.
KEY MESSAGES
• Levels of osteopontin and adiponectin measured at the time of kidney biopsy are good predictors of histological damage with lupus nephritis. • Only about 20% of children with substantial kidney damage from lupus nephritis will have an abnormally low urine creatinine clearance. • Continuously high levels of biomarkers reflecting lupus nephritis activity are risk factors of declining renal function.
目的
确定反映肾脏结构损伤并预测儿童狼疮性肾炎（LN）肾功能下降的尿液生物标志物。
方法
在这项前瞻性研究中，我们评估了 89 例儿童 LN 患者的肾脏活检和尿液样本。测定了 10 种生物标志物[脂联素、铜蓝蛋白、肾损伤分子-1、单核细胞趋化蛋白-1、中性粒细胞明胶酶相关脂质运载蛋白、骨桥蛋白、转化生长因子-β（TGFβ）、维生素-D 结合蛋白、肝脂肪酸结合蛋白（LFABP）和转铁蛋白]的尿液水平。采用回归分析确定了单独和联合确定 LN 损伤状态的个体和生物标志物组合（NIH-慢性指数（NIH-CI）评分≤1 与≥2），并比较了有和无肾功能下降患者的生物标志物水平，即肾小球滤过率（GFR）在肾脏活检后 12 个月内下降 20%。
结果
脂联素、LFABP 和骨桥蛋白的水平与 NIH-CI 中考虑的某些组织学损伤特征显著不同。GFR 与 NIH-CI 评分相关（Pearson 相关系数（r）=-0.49；p<0.0001），但与蛋白尿无关（r=0.20；p>0.05）。与 GFR 相似[ROC 曲线下面积（AUC）=0.72；p<0.01]，骨桥蛋白和脂联素水平的组合在区分 LN 损伤状态方面具有中等准确性[AUC=0.75；p=0.003]。生物标志物水平持续升高时，肾功能下降更为常见，尤其是 LN 活性生物标志物 TGFβ、转铁蛋白和 LFABP。
结论
联合检测脂联素和骨桥蛋白的尿液水平可准确预测 LN 慢性损伤，与 GFR 相似。反映 LN 活性的生物标志物水平升高预示着肾功能下降。
关键信息
在进行肾脏活检时测量的骨桥蛋白和脂联素水平是狼疮性肾炎组织学损伤的良好预测指标。
只有约 20%的狼疮性肾炎患者肾脏损伤严重，肾小球滤过率会异常降低。
持续高水平的反映狼疮性肾炎活动的生物标志物是肾功能下降的危险因素。
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