Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes

Skander Mulder, Paul Perco, Christina Oxlund, Uzma F. Mehdi, Thomas Hankemeier, Ib A. Jacobsen, Robert Toto, Hiddo J.L. Heerspink, Michelle J. Pena

Research output: Contribution to journalArticle

Abstract

The mineralocorticoid receptor antagonist spironolactone significantly reduces albuminuria in subjects with diabetic kidney disease, albeit with a large variability between individuals. Identifying novel biomarkers that predict response to therapy may help to tailor spironolactone therapy. We aimed to identify a set of metabolites for prediction of albuminuria response to spironolactone in subjects with type 2 diabetes. Systems biology molecular process analysis was performed a priori to identify metabolites linked to molecular disease processes and drug mechanism of action. Individual subject data and urine samples were used from 2 randomized placebo controlled double blind clinical trials (NCT01062763, NCT00381134). A urinary metabolite score was developed to predict albuminuria response to spironolactone therapy using penalized ridge regression with leave-one-out cross validation. Bioinformatic analysis identified a set of 18 metabolites linked to a diabetic kidney disease molecular model and potentially affected by spironolactone mechanism of action. Spironolactone reduced UACR relative to placebo by median −42% (25th to 75% percentile −65 to 6) and −29% (25th to 75% percentile −37 to −1) in the test and replication cohorts, respectively. In the test cohort, UACR reduction was higher in the lowest tertile of the baseline urinary metabolite score compared with middle and upper tertiles −58% (25th to 75% percentile −78 to 33), −28% (25th to 75% percentile −46 to 8), −40% (25th to 75% percentile −52% to 31), respectively, P = 0.001 for trend). In the replication cohort, UACR reduction was −54% (25th to 75% percentile −65 to −50), −41 (25th to 75% percentile −46% to 30), and −17% (25th to 75% percentile −36 to 5), respectively, P = 0.010 for trend). We identified a set of 18 urinary metabolites through systems biology to predict albuminuria response to spironolactone in type 2 diabetes. These data suggest that urinary metabolites may be used as a tool to tailor optimal therapy and move in the direction of personalized medicine.

Original languageEnglish (US)
Pages (from-to)17-27
Number of pages11
JournalTranslational Research
Volume222
DOIs
StatePublished - Aug 2020

Keywords

  • Albuminuria
  • Metabolomics
  • Response
  • Spironolactone

ASJC Scopus subject areas

  • Public Health, Environmental and Occupational Health
  • Biochemistry, medical
  • Physiology (medical)

Fingerprint Dive into the research topics of 'Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes'. Together they form a unique fingerprint.

  • Cite this

    Mulder, S., Perco, P., Oxlund, C., Mehdi, U. F., Hankemeier, T., Jacobsen, I. A., Toto, R., Heerspink, H. J. L., & Pena, M. J. (2020). Baseline urinary metabolites predict albuminuria response to spironolactone in type 2 diabetes. Translational Research, 222, 17-27. https://doi.org/10.1016/j.trsl.2020.04.010