Uromodulin, as a protein and genetic biomarker, is not a reliable predictor of hypertension or hypertension-related outcomes, reveals a study. However, it may have potential use in the prediction of other cardiovascular outcomes.
Also called Tamm-Horsfall protein, uromodulin is the most abundant protein in mammalian urine produced by epithelial cells of the thick ascending limb of the loop of Henle and is secreted into the tubular lumen, with a smaller fraction entering the circulation through basolateral secretion. [Kidney Blood Press Res 2010;33:393-398; Biochem Biophys Res Commun 2001;280:110-114; Nat Rev Nephrol 2017;13:525-544; Am J Physiol Renal Physiol 2013;304:F1066-F1075]
In this systematic review and meta-analysis, human studies examining uromodulin protein levels or uromodulin-related genome-wide association study outcomes with respect to hypertension were included. The researchers analysed continuous outcomes using inverse variance weighted random effects models and assessed publication bias with Begg’s test, Egger’s test, and funnel plots.
Thirty-five studies met the eligibility criteria. A total of 10,726 individuals with hypertension (3,461 females) and 8,762 (3,605 females) normotensives were included across diagnostic, prognostic, and predictive biomarker studies. Genome-wide association studies included <450,000 hypertension and >150,000 normotensives. [Am J Med 2026;139:1160-1199.e10]
Uromodulin fell short of showing clinically meaningful utility as a biomarker for hypertension or hypertension-related outcomes across all analyses.
Furthermore, urinary uromodulin levels across single-nucleotide polymorphisms (SNPs) demonstrated only a very small difference between genotype groups (standardized mean difference, 0.19, 95 percent confidence interval, 0.00‒0.39; p=0.047). This borderline finding indicated no clinically meaningful or reliable difference.
“[C]omprehensive synthesis of human data indicates that uromodulin is not a clinically useful protein or genetic diagnostic, prognostic, or predictive biomarker for hypertension or hypertension-related outcomes,” the researchers said.
Mendelian studies
In two independent Mendelian randomization studies, genetically higher uromodulin levels correlated with higher systolic and diastolic blood pressure and increased hypertension risk. [Front Cardiovasc Med 2021;8:736001; Kidney Int 2021;100:1282-1291]
The same studies also reported the association of genetically predicted uromodulin with lower estimated glomerular filtration rate and higher risk of chronic kidney disease, suggesting a causal role in both hypertension and renal dysfunction.
“This discrepancy suggests that although uromodulin may be mechanistically involved in blood pressure regulation, its circulating or urinary levels do not reliably capture this biology at the clinical level, limiting its utility as a measurable biomarker,” the researchers said.
Furthermore, a large prospective study that measured serum uromodulin levels in a community-based cohort found associations between higher uromodulin quantiles and lower risks of all-cause mortality and incident cardiovascular disease. [Nephrol Dial Transplant 2020;35:1399-1405]
“These associations were observed in an older population and were not evaluated in individuals with hypertension,” the researchers said. “This suggests that uromodulin may still be relevant to cardiovascular and renal outcomes more broadly, including chronic kidney disease.” [Am J Kidney Dis 2012;59:452-461]
Previous studies have implicated circulating uromodulin in immune modulation and observed inverse associations with systemic illness, diabetes, and metabolic syndrome. [Am J Physiol Renal Physiol 2013;304:F1066-F1075; J Am Soc Nephrol 2015;26:2172-2182; J Clin Endocrinol Metab 2019;104:3795-3802; Med (Baltim) 2017;96:e5798; Endocr Connect 2019;8:1363-1371]
Notably, several genome-wide association studies and genetic analyses revealed associations between uromodulin SNPs and hypertension in both humans and mouse models across diverse populations. [PLoS One 2020;15:e0234547; J Hum Hypertens 2022;36:983-988; Hypertension 2014;63:551-558]