TY - JOUR
T1 - Metabolomic alterations associated with cause of CKD
AU - Grams, Morgan E.
AU - Tin, Adrienne
AU - Rebholz, Casey M.
AU - Shafi, Tariq
AU - Köttgen, Anna
AU - Perrone, Ronald D.
AU - Sarnak, Mark J.
AU - Inker, Lesley A.
AU - Levey, Andrew S.
AU - Coresh, Josef
N1 - Funding Information:
M.E.G. receives support from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (K08DK092287 and R01DK108803). A.T. receives support from R01 DK108803. J.C., L.A.I., A.S.L., M.E.G., and M.J.S. receive support from CKD Biomarkers Consortium (NIDDK U01 DK085689). J.C., L.A.I., and A.S.L. receive support from CKD-Epi panel eGFR (R01 DK097020). A.K. was supported by German Research Foundation grants KO 3598/3-1 and KO 3598/4-1. T.S. is supported by R03-DK-104012 and R01-HL-132372. C.M.R. is supported by a mentored research scientist development grant from the NIDDK (K01 DK107782).
Publisher Copyright:
© 2017 by the American Society of Nephrology.
PY - 2017/11/7
Y1 - 2017/11/7
N2 - Background and objectives Causes of CKD differ in prognosis and treatment. Metabolomic indicators of CKD cause may provide clues regarding the different physiologic processes underlying CKD development and progression. Design, setting, participants & measurements Metabolites were quantified from serum samples of participants in the Modification of Diet in Renal Disease (MDRD) Study, a randomized controlled trial of dietary protein restriction and BP control, using untargeted reverse phase ultraperformance liquid chromatography tandem mass spectrometry quantification. Known, nondrug metabolites (n=687) were log-transformed and analyzed to discover associations with CKD cause (polycystic kidney disease, glomerular disease, and other cause). Discovery was performed in Study B, a substudy of MDRD with low GFR (n=166), and replication was performed in Study A, a substudy of MDRD with higher GFR (n=423). Results Overall in MDRD, average participant age was 51 years and 61% were men. In the discovery study (Study B), 29% of participants had polycystic kidney disease, 28% had glomerular disease, and 43% had CKD of another cause; in the replication study (Study A), the percentages were 28%, 24%, and 48%, respectively. In the discovery analysis, adjusted for demographics, randomization group, body mass index, hypertensive medications, measured GFR, log-transformed proteinuria, and estimated protein intake, seven metabolites (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, hippurate, homocitrul-line, and 1,5-anhydroglucitol) were associated with CKD cause after correction for multiple comparisons (P<0.0008). Five of these metabolite associations (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2, N2-dimethylguanosine, and hippurate) were replicated in Study A (P<0.007), with all replicated metabolites exhibiting higher levels in polycystic kidney disease and lower levels in glomerular disease compared with CKD of other causes. Conclusions Metabolomic profiling identified several metabolites strongly associated with cause of CKD.
AB - Background and objectives Causes of CKD differ in prognosis and treatment. Metabolomic indicators of CKD cause may provide clues regarding the different physiologic processes underlying CKD development and progression. Design, setting, participants & measurements Metabolites were quantified from serum samples of participants in the Modification of Diet in Renal Disease (MDRD) Study, a randomized controlled trial of dietary protein restriction and BP control, using untargeted reverse phase ultraperformance liquid chromatography tandem mass spectrometry quantification. Known, nondrug metabolites (n=687) were log-transformed and analyzed to discover associations with CKD cause (polycystic kidney disease, glomerular disease, and other cause). Discovery was performed in Study B, a substudy of MDRD with low GFR (n=166), and replication was performed in Study A, a substudy of MDRD with higher GFR (n=423). Results Overall in MDRD, average participant age was 51 years and 61% were men. In the discovery study (Study B), 29% of participants had polycystic kidney disease, 28% had glomerular disease, and 43% had CKD of another cause; in the replication study (Study A), the percentages were 28%, 24%, and 48%, respectively. In the discovery analysis, adjusted for demographics, randomization group, body mass index, hypertensive medications, measured GFR, log-transformed proteinuria, and estimated protein intake, seven metabolites (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, hippurate, homocitrul-line, and 1,5-anhydroglucitol) were associated with CKD cause after correction for multiple comparisons (P<0.0008). Five of these metabolite associations (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2, N2-dimethylguanosine, and hippurate) were replicated in Study A (P<0.007), with all replicated metabolites exhibiting higher levels in polycystic kidney disease and lower levels in glomerular disease compared with CKD of other causes. Conclusions Metabolomic profiling identified several metabolites strongly associated with cause of CKD.
KW - Blood pressure
KW - Body mass index
KW - Chromatography, liquid
KW - Citrulline
KW - Demography
KW - Diet
KW - Dietary proteins
KW - Glomerular filtration rate
KW - Hippurates
KW - Homocitrulline
KW - Kidney
KW - Kynurenic acid
KW - MDRD study
KW - Male
KW - Metabolites
KW - Metabolomic profiling
KW - Polycystic kidney diseases
KW - Prognosis
KW - Proteinuria
KW - Random allocation
KW - Renal insufficiency, chronic
KW - Sulfates
KW - Tandem mass spectrometry
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U2 - 10.2215/CJN.02560317
DO - 10.2215/CJN.02560317
M3 - Article
C2 - 28971980
AN - SCOPUS:85033408702
SN - 1555-9041
VL - 12
SP - 1787
EP - 1794
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 11
ER -