Urine Uromodulin as a Biomarker of Kidney Tubulointerstitial Fibrosis

Abstract

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; P<0.001), bicarbonate (0.20; P<0.001), and hemoglobin (0.11; P=0.03) at the time of biopsy but not with urine albumin (-0.07; P=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.

Keywords: biomarker; cross-sectional analysis; glomerulosclerosis; interstitial fibrosis; kidney biopsy; uromodulin.

Graphical abstract

Figure 1.

Association of urine uromodulin level and kidney histology. Nonparametric trend test. IF/TA, interstitial fibrosis and tubular atrophy.

Figure 2.

Correlation of interstitial fibrosis and urine uromodulin. Nonparametric (Spearman) correlation coefficient. Lines and shaded areas are the quadratic fit prediction and its 95% confidence interval, respectively.

Figure 3.

Fibrotic kidneys show decreased uromodulin expression in animal models. (A) Representative images of the whole-kidney sections immunostained for UMOD from fibrotic (n=8), repaired (n=8), and normal uninjured (n=7) mouse kidneys. Wild-type mice were subjected to 27 minutes of unilateral ischemia/reperfusion injury with contralateral kidney intact (fibrotic model) or unilateral ischemia/reperfusion injury with contralateral nephrectomy (repaired model) and harvested at 30 days after injury. Normal uninjured mice were age matched to fibrotic and repaired mice. Scale bar, 1 mm. (B) Uromodulin-positive areas of the entire kidney sections were quantified. n=7–8 kidneys per group. *P=0.05; ****P<0.001. (C) Scatterplot and best fit line showing the correlation between collagen and UMOD staining.