Uromodulin (Tamm-Horsfall protein) is a renal specific glycoprotein produced by the epithelial cells of the thick ascending limb of the loop of Henle. Several important roles have been identified for uromodulin including ion transportation, water maintenance, electrolyte balance and innate immunity of the urinary tract (1,2). In addition, urine uromodulin levels are an important marker for renal tubular function (3) and mutations in the uromodulin (UMOD) gene result in autosomal dominant tubulointerstitial kidney disease (ADTKD), medullary cystic kidney disease or uromodulin-associated kidney disease (4,5). The renal abnormalities caused by UMOD mutations are characterized by tubulointerstitial dysfunction from aggregation of abnormal uromodulin protein and manifested by defective urinary concentration, hyperuricemia and lower urinary uromodulin levels culminating in early onset end stage renal disease among affected individuals (4-7). In addition, UMOD gene variants are also associated with the development of chronic kidney disease (3) and hypertension in the general population (8).
The publication by Delgado et al. (9) is an important development in moving forward the paradigm of uromodulin as a biomarker and expanding its clinical implications to beyond renal pathophysiology. In the study, serum uromodulin levels were determined for more than 3,000 patients undergoing coronary angiography and participating in the Ludwigshafen Risk and Cardiovascular Health study. The association between serum uromodulin at baseline and all-cause as well as cardiovascular mortality was assessed by Cox regression analysis over a 10-year period. The results showed that patients with higher serum uromodulin were younger, and more likely to have lower blood pressure, triglycerides, hemoglobin A1C, high-sensitivity C-reactive protein (hsCRP), N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high LDL levels. Serum uromodulin levels correlated positively with eGFR and inversely with serum creatinine levels. Higher serum uromodulin concentrations were found in patients without coronary artery disease, diabetes and hypertension. Higher quartiles of uromodulin were significantly associated with reduced all-cause mortality. The association between high uromodulin levels and decreased mortality remained significant after adjusting for age, sex, diabetes, body mass index, hypertension, smoking, eGFR as well as hsCRP, NT-proBNP and medications in a multivariate model. Serum uromodulin information when added to risk prediction models such as the European Society of Cardiology heart score and the Pooled Cohort Equation, improved the Harrell C statistics for all-cause mortality and cardiovascular death and lead to a net reclassification index for 9% of the population.
This study adds a new candidate to the list of renal specific biomarkers for predicting cardiovascular outcomes. Prior studies have demonstrated important role of serum creatinine (10), urinary albumin (11) and serum cystatin C levels (12,13) for predicting cardiovascular mortality among various populations. Although, Garimella et al. (14) have previously reported low urinary uromodulin levels to be associated with development of progressive renal disease and increased all-cause mortality in an elderly population. However, there are significant difficulties with measuring urine uromodulin levels (15) and serum uromodulin measurement remains the preferred assay (15,16). This is the first study to assess and determine the predictive value of serum uromodulin for cardiovascular mortality in patients being evaluated for the presence of coronary artery disease. The major strengths of the study include a large sample size; prospective and robust study design and long term clinical follow up.
However, additional studies for confirmation of observed findings in diverse populations and elucidate the biological mechanisms are needed before serum uromodulin measurements can be applied in routine clinical setting. The study by Delgado et al. (9) is likely to stimulate further interest in uromodulin as a biomarker for both renal dysfunction as well as cardiovascular outcomes.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Pak J, Pu Y, Zhang ZT, et al. Tamm-Horsfall protein binds to type 1 fimbriated Escherichia coli and prevents E. coli from binding to uroplakin Ia and Ib receptors. J Biol Chem 2001;276:9924-30. [Crossref] [PubMed]
- Torffvit O, Melander O, Hulten UL. Urinary excretion rate of Tamm-Horsfall protein is related to salt intake in humans. Nephron Physiol 2004;97:31-6. [Crossref] [PubMed]
- Pruijm M, Ponte B, Ackermann D, et al. Associations of Urinary Uromodulin with Clinical Characteristics and Markers of Tubular Function in the General Population. Clin J Am Soc Nephrol 2016;11:70-80. [Crossref] [PubMed]
- Köttgen A, Glazer NL, Dehghan A, et al. Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 2009;41:712-7. [Crossref] [PubMed]
- Köttgen A, Hwang SJ, Larson MG, et al. Uromodulin levels associate with a common UMOD variant and risk for incident CKD. J Am Soc Nephrol 2010;21:337-44. [Crossref] [PubMed]
- Olden M, Corre T, Hayward C, et al. Common variants in UMOD associate with urinary uromodulin levels: a meta-analysis. J Am Soc Nephrol 2014;25:1869-82. [Crossref] [PubMed]
- Rampoldi L, Caridi G, Santon D, et al. Allelism of MCKD, FJHN and GCKD caused by impairment of uromodulin export dynamics. Hum Mol Genet 2003;12:3369-84. [Crossref] [PubMed]
- Padmanabhan S, Melander O, Johnson T, et al. Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension. PLoS Genet 2010;6:e1001177. [Crossref] [PubMed]
- Delgado GE, Kleber ME, Scharnagl H, et al. Serum Uromodulin and Mortality Risk in Patients Undergoing Coronary Angiography. J Am Soc Nephrol 2017. [Epub ahead of print]. [Crossref] [PubMed]
- Mazza A, Pessina AC, Tikhonoff V, et al. Serum creatinine and coronary mortality in the elderly with normal renal function: the CArdiovascular STudy in the ELderly (CASTEL). J Nephrol 2005;18:606-12. [PubMed]
- Matsushita K, van der Velde M, Astor BC, et al. Association of estimated glomerular filtration rate and albuminuria with all-cause and cardiovascular mortality in general population cohorts: a collaborative meta-analysis. Lancet 2010;375:2073-81. [Crossref] [PubMed]
- Ix JH, Shlipak MG, Chertow GM, et al. Association of cystatin C with mortality, cardiovascular events, and incident heart failure among persons with coronary heart disease: data from the Heart and Soul Study. Circulation 2007;115:173-9. [Crossref] [PubMed]
- Keller T, Messow CM, Lubos E, et al. Cystatin C and cardiovascular mortality in patients with coronary artery disease and normal or mildly reduced kidney function: results from the AtheroGene study. Eur Heart J 2009;30:314-20. [Crossref] [PubMed]
- Garimella PS, Biggs ML, Katz R, et al. Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults. Kidney Int 2015;88:1126-34. [Crossref] [PubMed]
- Youhanna S, Weber J, Beaujean V, et al. Determination of uromodulin in human urine: influence of storage and processing. Nephrol Dial Transplant 2014;29:136-45. [Crossref] [PubMed]
- Jennings P, Aydin S, Kotanko P, et al. Membrane targeting and secretion of mutant uromodulin in familial juvenile hyperuricemic nephropathy. J Am Soc Nephrol 2007;18:264-73. [Crossref] [PubMed]
Cite this article as: Liu S, Cheema AN. Uromodulin, a novel biomarker for cardiovascular risk assessment? J Lab Precis Med 2017;2:39.