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 histological changes in kidney tubulointerstitium has not been characterized. In this study, we test the association of urine uromodulin with kidney histological findings in humans and mice. 

Design, setting, participants, and measurements

We investigated the independent association of urine uromodulin measured at the time of kidney biopsy with histological features in 364 participants at two academic medical centers from 2015-2018 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 pre-biopsy glomerular filtration rate, serum creatinine at biopsy, and urine albumin showed higher uromodulin to be associated with lower severity of interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis [IF/TA -3.5 (-5.7, -1.2)% and glomerulosclerosis -3.3 (-5.9, -0.6)% per 2-fold difference in uromodulin]. However, when both IF/TA and glomerulosclerosis were included in multivariable analysis, only IF/TA was independently associated with uromodulin [IF/TA -2.5 (-4.6, -0.4)% and glomerulosclerosis -0.9 (-3.4, 1.5)% per 2-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.