02888nas a2200481 4500008004100000022001400041245008700055210006900142260001300211300001200224490000700236520154100243653000901784653002201793653001601815653001501831653002801846653002501874653001501899653002401914653001101938653003101949653001801980653001101998653001402009653002802023653000902051653003202060653001502092100002502107700001902132700001602151700001902167700002402186700002202210700002502232700002402257700002202281700002402303700002302327700002002350856003602370 2015 eng d a1523-175500aUrinary uromodulin, kidney function, and cardiovascular disease in elderly adults.0 aUrinary uromodulin kidney function and cardiovascular disease in c2015 Nov a1126-340 v883 a

Urinary uromodulin (uUMOD) is the most common secreted tubular protein in healthy adults. However, the relationship between uUMOD and clinical outcomes is still unclear. Here we measured uUMOD in 192 participants of the Cardiovascular Health Study with over a 30% decline in estimated glomerular filtration rate (eGFR) over 9 years, 54 with incident end-stage renal disease (ESRD), and in a random subcohort of 958 participants. The association of uUMOD with eGFR decline was evaluated using logistic regression and with incident ESRD, cardiovascular disease, heart failure, and mortality using Cox proportional regression. Mean age was 78 years and median uUMOD was 25.8 μg/ml. In a case-control study evaluating eGFR decline (192 cases and 231 controls), each 1-s.d. higher uUMOD was associated with a 23% lower odds of eGFR decline (odds ratio 0.77 (95% CI 0.62-0.96)) and a 10% lower risk of mortality (hazard ratio 0.90 (95% CI 0.83-0.98)) after adjusting for demographics, eGFR, albumin/creatinine ratio, and other risk factors. There was no risk association of uUMOD with ESRD, cardiovascular disease, or heart failure after multivariable adjustment. Thus, low uUMOD levels may identify persons at risk of progressive kidney disease and mortality above and beyond established markers of kidney disease, namely eGFR and the albumin/creatinine ratio. Future studies need to confirm these results and evaluate whether uUMOD is a marker of tubular health and/or whether it plays a causal role in preserving kidney function.

10aAged10aAged, 80 and over10aAlbuminuria10aBiomarkers10aCardiovascular Diseases10aCase-Control Studies10aCreatinine10aDisease Progression10aFemale10aGlomerular Filtration Rate10aHeart Failure10aHumans10aIncidence10aKidney Failure, Chronic10aMale10aProportional Hazards Models10aUromodulin1 aGarimella, Pranav, S1 aBiggs, Mary, L1 aKatz, Ronit1 aIx, Joachim, H1 aBennett, Michael, R1 aDevarajan, Prasad1 aKestenbaum, Bryan, R1 aSiscovick, David, S1 aJensen, Majken, K1 aShlipak, Michael, G1 aChaves, Paulo, H M1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/677002938nas a2200205 4500008004100000022001400041245009500055210006900150260001600219520228600235100002502521700002002546700001902566700002102585700002402606700002202630700002402652700002002676856003602696 2016 eng d a1523-683800aUrinary Uromodulin and Risk of Urinary Tract Infections: The Cardiovascular Health Study.0 aUrinary Uromodulin and Risk of Urinary Tract Infections The Card c2016 Oct 283 a

BACKGROUND: Laboratory studies suggest that urinary uromodulin, the most common protein in the urine of healthy adults, may protect against urinary tract infection (UTI). Epidemiologic studies evaluating this relationship in humans are lacking.

STUDY DESIGN: Prospective longitudinal cohort study.

SETTING & PARTICIPANTS: 953 participants enrolled in the Cardiovascular Health Study.

PREDICTOR: Uromodulin assayed using enzyme-linked immunosorbent assay in spot urine samples.

OUTCOMES: Composite of outpatient UTI events or UTI-related hospitalizations and each of them individually identified using International Classification of Diseases, Ninth Revision (ICD-9) codes using negative binomial regression with robust standard errors adjusted for age, race, sex, body mass index, diabetes, estimated glomerular filtration rate, and urinary albumin and urinary creatinine excretion.

RESULTS: Median uromodulin level was 25.9 (IQR, 17.3-38.9) μg/mL, mean age of participants was 78 years, 61% were women, and 15% were black. There were 331 outpatient UTI events and 87 UTI-related hospitalizations among 186 participants during a median 9.9 years of follow-up. Persons in the highest quartile (>38.93μg/mL) of uromodulin concentration had a significantly lower risk for the composite outcome (incidence rate ratio [IRR], 0.47; 95% CI, 0.29-0.79) compared with those in the lowest quartile (≤17.26μg/mL). This association remained significant for outpatient UTI events (highest vs lowest quartile even after excluding those with prior UTI: IRR, 0.42; 95% CI, 0.23-0.77). The direction of association with UTI hospitalization was similar, but not statistically significant (IRR, 0.78; 95% CI, 0.39-1.58).

LIMITATIONS: Use of ICD-9 codes to identify outcomes and lack of generalizability to younger populations.

CONCLUSIONS: High urinary uromodulin levels are associated with lower risk for UTI in older community-dwelling adults independent of traditional UTI risk factors. This finding supports prior laboratory data indicating a protective role of uromodulin against UTI. Further research is needed to understand if this may lead to new treatments to prevent or treat UTI.

1 aGarimella, Pranav, S1 aBartz, Traci, M1 aIx, Joachim, H1 aChonchol, Michel1 aShlipak, Michael, G1 aDevarajan, Prasad1 aBennett, Michael, R1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/736902544nas a2200229 4500008004100000022001400041245011800055210006900173260001600242520180400258100002002062700002102082700001902103700002202122700002402144700002302168700002402191700001802215700002002233700002502253856003602278 2019 eng d a1440-179700aAssociation of serum and urinary uromodulin and their correlates in older adults-The Cardiovascular Health Study.0 aAssociation of serum and urinary uromodulin and their correlates c2019 Dec 173 a

Uromodulin is released into serum (sUMOD) and urine (uUMOD) exclusively by renal tubular cells. Both sUMOD and uUMOD are correlated with estimated glomerular filtration rate (eGFR), and associated with mortality and cardiovascular disease (CVD). However, no study to our knowledge has measured both sUMOD and uUMOD in the same population, thus the relationship of sUMOD with uUMOD with one another, and their respective correlates have not been evaluated simultaneously. We evaluated the correlations of sUMOD, uUMOD with eGFR in a random sub-cohort (n = 933) of the Cardiovascular Health Study and their associations with demographic and laboratory parameters and CVD risk factors using multi-variable linear regression analysis. The mean age of the cohort was 78 years, 40% were male and 15% were Black. The mean sUMOD level was 127 ng/mL, uUMOD was 30 500 ng/mL and eGFR was 63 mL/min/1.73 m . Correlation between sUMOD and uUMOD, adjusted for eGFR was moderate (r = 0.27 [95% confidence interval = 0.21-0.33]). The correlation of eGFR with sUMOD (r = 0.44 [0.39-0.49]) was stronger than with uUMOD (r = 0.21 [0.15-0.27]). In multi-variable analysis adjusting sUMOD for uUMOD and vice versa, sUMOD was independently associated with eGFR (β = 1.3 [1.1-1.6]), log2 C-reactive protein (β = -4.2 [-6.8 to -1.6]) and male sex (β = -13.6 [-22.7 to -4.5]). In contrast, male sex was associated with higher uUMOD (β = 3700 [400-7000]), while diabetes (β = -6400 [-10 600 to -2100]) and hypertension (-4300 [-7500 to -1100]) were associated with lower uUMOD levels. We conclude that sUMOD is more strongly associated with eGFR compared with uUMOD. Correlates of sUMOD and uUMOD differ substantially, suggesting that apical and basolateral secretion may be differentially regulated.

1 aSteubl, Dominik1 aBůzková, Petra1 aIx, Joachim, H1 aDevarajan, Prasad1 aBennett, Michael, R1 aChaves, Paolo, H M1 aShlipak, Michael, G1 aBansal, Nisha1 aSarnak, Mark, J1 aGarimella, Pranav, S uhttps://chs-nhlbi.org/node/827902803nas a2200229 4500008004100000022001400041245012600055210006900181260001600250520205500266100002002321700002102341700002502362700001902387700002202406700002402428700002302452700002402475700001802499700002002517856003602537 2019 eng d a1460-238500aAssociation of serum uromodulin with mortality and cardiovascular disease in the elderly-the Cardiovascular Health Study.0 aAssociation of serum uromodulin with mortality and cardiovascula c2019 Mar 213 a

BACKGROUND: Uromodulin (UMOD) is released by renal tubular cells into the serum (sUMOD) and urine. Lower urine UMOD has been linked to mortality and cardiovascular disease but much less is known about sUMOD. We evaluated the association of sUMOD with these outcomes in community-dwelling older adults.

METHODS: We measured sUMOD in a random subcohort of 933 participants enrolled in the Cardiovascular Health Study. The associations of sUMOD with all-cause mortality, incident heart failure (HF) and incident cardiovascular disease (CVD; myocardial infarction, stroke and mortality due to coronary disease or stroke) were evaluated using multivariable Cox regression, adjusting for study participants' demographics, estimated glomerular filtration rate (eGFR), albuminuria and CVD risk factors. Generalized additive models with splines were used to address the functional form of sUMOD with outcomes. Due to nonlinear associations of sUMOD with all outcomes, 2.5% of the values on either end of the sUMOD distribution were excluded from the analyses, limiting the range of sUMOD to 34.3-267.1 ng/mL.

RESULTS: The mean age was 78 ± 5 years, 40% were male, sUMOD level was 127 ± 64 ng/mL, eGFR was 63 mL/min/1.73 m2 and 42% had CKD defined as eGFR <60 mL/min/1.73 m2. Patients in the lower sUMOD quartiles had lower eGFR and higher albuminuria (P < 0.01, respectively). During a median follow-up of 9.9 years, 805 patients died, 283 developed HF and 274 developed CVD. In multivariable analysis, higher sUMOD was significantly associated with a lower hazard for mortality {hazard ratio [HR] 0.89 [95% confidence interval (CI) 0.80-0.99] per 1 standard deviation (SD) higher sUMOD}, CVD [HR 0.80 (95% CI 0.67-0.96)] and the composite endpoint [HR 0.88 (95% CI 0.78-0.99)]; the association with HF was not statistically significant [HR 0.84 (95% CI 0.70-1.01)].

CONCLUSION: Higher sUMOD is independently associated with a lower risk for mortality and CVD in older adults.

1 aSteubl, Dominik1 aBůzková, Petra1 aGarimella, Pranav, S1 aIx, Joachim, H1 aDevarajan, Prasad1 aBennett, Michael, R1 aChaves, Paulo, H M1 aShlipak, Michael, G1 aBansal, Nisha1 aSarnak, Mark, J uhttps://chs-nhlbi.org/node/8007