Urinary uromodulin, kidney function, and cardiovascular disease in elderly adults

Abstract

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.

Figure 1

Population Sampling from within the Cardiovascular Health Study Rectangle: All CHS participants at 1996–1997 visit Large circle: Random sub-cohort Black circle: Participants included as controls in the case-control study for the CKD progression outcome. Light grey area: Participants included as cases in the case-control study for the CKD progression Dark Grey area: Participants included in the case-cohort study for the incident ESRD outcome.

Figure 2

Distribution of urine uromodulin levels in 958 community-living elderly participants in the Cardiovascular Health Study None.

Figure 3

Spline regression plots of urinary uromodulin and clinical outcomes. Left to right and top to bottom: Progressive GFR decline, incident CVD, HF and mortality. Each model was fitted using a restricted cubic spline function for uUMOD. In each plot, the solid line represents the point estimate and the dotted lines represent 95% confidence intervals. Observations in the highest 2.5% of the distribution were excluded to minimize the influence of extreme values.