Metabolomic Markers of Kidney Function Decline in Patients With Diabetes:
Evidence From the Chronic Renal Insufficiency Cohort (CRIC) Study.
Authors Kwan B, Fuhrer T, Zhang J, Darshi M, Van Espen B, Montemayor D, de Boer IH,
Dobre M, Hsu CY, Kelly TN, Raj DS, Rao PS, Saraf SL, Scialla J, Waikar SS,
Sharma K, Natarajan L,
Submitted By Submitted Externally on 10/12/2020
Status Published
Journal American journal of kidney diseases : the official journal of the National Kidney Foundation
Year 2020
Date Published 10/1/2020
Volume : Pages 76 : 511 - 520
PubMed Reference 32387023
Abstract Biomarkers that provide reliable evidence of future diabetic kidney disease
(DKD) are needed to improve disease management. In a cross-sectional study, we
previously identified 13 urine metabolites that had levels reduced in DKD
compared with healthy controls. We evaluated associations of these 13
metabolites with future DKD progression., Prospective cohort., 1,001 Chronic
Renal Insufficiency Cohort (CRIC) participants with diabetes with estimated
glomerular filtration rates (eGFRs) between 20 and 70mL/min/1.73m2 were followed
up prospectively for a median of 8 (range, 2-10) years., 13 urine metabolites,
age, race, sex, smoked more than 100 cigarettes in lifetime, body mass index,
hemoglobin A1c level, blood pressure, urinary albumin, and eGFR., Annual eGFR
slope and time to incident kidney failure with replacement therapy (KFRT; ie,
initiation of dialysis or receipt of transplant)., Several clinical metabolite
models were developed for eGFR slope as the outcome using stepwise selection and
penalized regression, and further tested on the time-to-KFRT outcome. A best
cross-validated (final) prognostic model was selected based on high prediction
accuracy for eGFR slope and high concordance statistic for incident KFRT.,
During follow-up, mean eGFR slope was-1.83±1.92 (SD) mL/min/1.73m2 per year; 359
(36%) participants experienced KFRT. Median time to KFRT was 7.45 years from the
time of entry to the CRIC Study. In our final model, after adjusting for
clinical variables, levels of metabolites 3-hydroxyisobutyrate (3-HIBA) and
3-methylcrotonyglycine had a significant negative association with eGFR slope,
whereas citric and aconitic acid were positively associated. Further, 3-HIBA and
aconitic acid levels were associated with higher and lower risk for KFRT,
respectively (HRs of 2.34 [95% CI, 1.51-3.62] and 0.70 [95% CI, 0.51-0.95]).,
Subgroups for whom metabolite signatures may not be optimal, nontargeted
metabolomics by flow-injection analysis, and 2-stage modeling approaches., Urine
metabolites may offer insights into DKD progression. If replicated in future
studies, aconitic acid and 3-HIBA could identify individuals with diabetes at
high risk for GFR decline, potentially leading to improved clinical care and
targeted therapies.

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