尿调蛋白作为肾肾小管间质性纤维化的生物标志物。
Urine Uromodulin as a Biomarker of Kidney Tubulointerstitial Fibrosis.
机构信息
Section of Nephrology, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
Clinical and Translational Research Accelerator, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut.
出版信息
Clin J Am Soc Nephrol. 2022 Sep;17(9):1284-1292. doi: 10.2215/CJN.04360422. Epub 2022 Aug 10.
BACKGROUND AND OBJECTIVES
Uromodulin, produced exclusively in the kidney's thick ascending limb, is a biomarker of kidney tubular health. However, the relationship between urine uromodulin and histologic changes in the kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histologic findings in humans and mice.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histologic features in 364 participants at two academic medical centers from 2015 to 2018 using multivariable linear regression models. This relationship was further examined by comparison of uromodulin staining in murine models of kidney fibrosis and repair.
RESULTS
We found urine uromodulin to be correlated with serum creatinine (rho=-0.43; <0.001), bicarbonate (0.20; <0.001), and hemoglobin (0.11; =0.03) at the time of biopsy but not with urine albumin (-0.07; =0.34). Multivariable models controlling for prebiopsy GFR, serum creatinine at biopsy, and urine albumin showed higher uromodulin to be associated with lower severity of interstitial fibrosis/tubular atrophy and glomerulosclerosis (interstitial fibrosis/tubular atrophy: -3.5% [95% confidence intervals, -5.7% to -1.2%] and glomerulosclerosis: -3.3% [95% confidence intervals, -5.9% to -0.6%] per two-fold difference in uromodulin). However, when both interstitial fibrosis/tubular atrophy and glomerulosclerosis were included in multivariable analysis, only interstitial fibrosis/tubular atrophy was independently associated with uromodulin (interstitial fibrosis/tubular atrophy: -2.5% [95% confidence intervals, -4.6% to -0.4%] and glomerulosclerosis: -0.9% [95% confidence intervals, -3.4% to 1.5%] per two-fold difference in uromodulin). In mouse kidneys, uromodulin staining was found to be lower in the fibrotic model than in normal or repaired models.
CONCLUSIONS
Higher urine uromodulin is independently associated with lower tubulointerstitial fibrosis in both human kidney biopsies and a mouse model of fibrosis.
PODCAST
This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2022_08_10_CJN04360422.mp3.
背景和目的
尿调蛋白仅在肾脏的厚升支中产生，是肾脏管状健康的生物标志物。然而，尿液中尿调蛋白与肾小管间质性组织学变化之间的关系尚未被描述。在这项研究中，我们测试了尿液中尿调蛋白与人类和小鼠肾脏组织学发现之间的关联。
设计、设置、参与者和测量：我们使用多变量线性回归模型，调查了 2015 年至 2018 年间在两个学术医疗中心进行肾脏活检时测量的尿液尿调蛋白与 364 名参与者的组织学特征之间的独立关联。通过比较肾脏纤维化和修复的小鼠模型中的尿调蛋白染色，进一步研究了这种关系。
结果
我们发现，尿液尿调蛋白与血清肌酐（rho=-0.43；<0.001）、碳酸氢盐（0.20；<0.001）和血红蛋白（0.11；=0.03）相关，但与尿液白蛋白不相关（-0.07；=0.34）。在控制活检前 GFR、活检时的血清肌酐和尿液白蛋白的多变量模型中，发现较高的尿调蛋白与较低的间质纤维化/肾小管萎缩和肾小球硬化严重程度相关（间质纤维化/肾小管萎缩：-3.5%[95%置信区间，-5.7%至-1.2%]和肾小球硬化：-3.3%[95%置信区间，-5.9%至-0.6%]每两倍差异）。然而，当间质纤维化/肾小管萎缩和肾小球硬化都被纳入多变量分析时，只有间质纤维化/肾小管萎缩与尿调蛋白独立相关（间质纤维化/肾小管萎缩：-2.5%[95%置信区间，-4.6%至-0.4%]和肾小球硬化：-0.9%[95%置信区间，-3.4%至 1.5%]每两倍差异）。在小鼠肾脏中，与正常或修复模型相比，纤维化模型中的尿调蛋白染色较低。
结论
在人类肾脏活检和纤维化小鼠模型中，较高的尿液尿调蛋白与较低的肾小管间质纤维化独立相关。
播客
本文包含在 https://www.asn-online.org/media/podcast/CJASN/2022_08_10_CJN04360422.mp3 中的播客。
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