TY - JOUR
T1 - Plasma levels of carboxylic acids are markers of early kidney dysfunction in young people with type 1 diabetes
AU - Vigers, Timothy
AU - Vinovskis, Carissa
AU - Li, Lu-Ping
AU - Prasad, Pottumarthi
AU - Heerspink, Hiddo
AU - D’Alessandro, Angelo
AU - Reisz, Julie A.
AU - Piani, Federica
AU - Cherney, David Z.
AU - van Raalte, Daniel H.
AU - Nadeau, Kristen J.
AU - Pavkov, Meda E.
AU - Nelson, Robert G.
AU - Pyle, Laura
AU - Bjornstad, Petter
N1 - Funding Information: Financial support for this work provided by the NIDDK Diabetic Complications Consortium (RRID:SCR_001415, www.diacomp.org ), grants DK076169 and DK115255 (18AU3871 [P.B.]), JDRF grant number 2-SRA-2018-627-M-B (P.B.), and NIH/NIDDK grant number K23-DK116720 (P.B.), K24-HL145076 (K.J.N.), and UL1-RR025780 (University of Colorado Denver), support from the Center for Women’s Health Research at University of Colorado, the Department of Pediatrics, Section of Endocrinology and Barbara Davis Center for Diabetes at University of Colorado School of Medicine, by Interagency Agreement 16FED1604631 with the Centers for Disease Control and Prevention (R.G.N.), and by the Intramural Research Program of the NIDDK. Publisher Copyright: © 2022, The Author(s), under exclusive licence to International Pediatric Nephrology Association.
PY - 2023/1
Y1 - 2023/1
N2 - Background: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. Methods: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. Results: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:−0.33, q = 0.01), histidine (r:−0.45, q < 0.001), methionine (r: −0.29, q = 0.02), phenylalanine (r: −0.29, q = 0.01), serine (r: −0.42, q < 0.001), threonine (r: −0.28, q = 0.02), citrate (r: −0.35, q = 0.003), fumarate (r: −0.24, q = 0.04), and malate (r: −0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: −0.28, q = 0.04), phenylalanine (r:−0.3, q = 0.03), fumarate (r: −0.29, q = 0.04), and malate (r: −0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: −0.28, q = 0.02) was correlated with higher mean ACR. Conclusions: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. Trial registration: ClinicalTrials.gov NCT03618420 and NCT03584217 Graphical abstract: A higher resolution version of the Graphical abstract is available as Supplementary information [Figure not available: see fulltext.]
AB - Background: We compared plasma metabolites of amino acid oxidation and the tricarboxylic acid (TCA) cycle in youth with and without type 1 diabetes mellitus (T1DM) and related the metabolites to glomerular filtration rate (GFR), renal plasma flow (RPF), and albuminuria. Metabolites associated with impaired kidney function may warrant future study as potential biomarkers or even future interventions to improve kidney bioenergetics. Methods: Metabolomic profiling of fasting plasma samples using a targeted panel of 644 metabolites and an untargeted panel of 19,777 metabolites was performed in 50 youth with T1DM ≤ 10 years and 20 controls. GFR and RPF were ascertained by iohexol and p-aminohippurate clearance, and albuminuria calculated as urine albumin to creatinine ratio. Sparse partial least squares discriminant analysis and moderated t tests were used to identify metabolites associated with GFR and RPF. Results: Adolescents with and without T1DM were similar in age (16.1 ± 3.0 vs. 16.1 ± 2.9 years) and BMI (23.4 ± 5.1 vs. 22.7 ± 3.7 kg/m2), but those with T1DM had higher GFR (189 ± 40 vs. 136 ± 22 ml/min) and RPF (820 ± 125 vs. 615 ± 65 ml/min). Metabolites of amino acid oxidation and the TCA cycle were significantly lower in adolescents with T1DM vs. controls, and the measured metabolites were able to discriminate diabetes status with an AUC of 0.82 (95% CI: 0.71, 0.93) and error rate of 0.21. Lower glycine (r:−0.33, q = 0.01), histidine (r:−0.45, q < 0.001), methionine (r: −0.29, q = 0.02), phenylalanine (r: −0.29, q = 0.01), serine (r: −0.42, q < 0.001), threonine (r: −0.28, q = 0.02), citrate (r: −0.35, q = 0.003), fumarate (r: −0.24, q = 0.04), and malate (r: −0.29, q = 0.02) correlated with higher GFR. Lower glycine (r: −0.28, q = 0.04), phenylalanine (r:−0.3, q = 0.03), fumarate (r: −0.29, q = 0.04), and malate (r: −0.5, q < 0.001) correlated with higher RPF. Lower histidine (r: −0.28, q = 0.02) was correlated with higher mean ACR. Conclusions: In conclusion, adolescents with relatively short T1DM duration exhibited lower plasma levels of carboxylic acids that associated with hyperfiltration and hyperperfusion. Trial registration: ClinicalTrials.gov NCT03618420 and NCT03584217 Graphical abstract: A higher resolution version of the Graphical abstract is available as Supplementary information [Figure not available: see fulltext.]
KW - Blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI)
KW - Elevated albumin excretion
KW - Hyperfiltration
KW - Kidney oxygenation
KW - Plasma metabolomics
KW - Type 1 diabetes
UR - http://www.scopus.com/inward/record.url?scp=85129545939&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00467-022-05531-3
DO - https://doi.org/10.1007/s00467-022-05531-3
M3 - Article
C2 - 35507146
SN - 0931-041X
VL - 38
SP - 193
EP - 202
JO - Pediatric nephrology (Berlin, Germany)
JF - Pediatric nephrology (Berlin, Germany)
IS - 1
ER -