Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) study

Sarah J. Schrauben; Hima Sapa; Dawei Xie; Xiaoming Zhang; Amanda Hyre Anderson; Michael G. Shlipak; Chi Yuan Hsu; Tariq Shafi; Rupal Mehta; Zeenat Bhat; Julie Brown; Jeanne Charleston; Jing Chen; Jiang He; Joachim H. Ix; Pandurango Rao; Ray Townsend; Paul L. Kimmel; Ramachandran S. Vasan; Harold I. Feldman; Jesse C. Seegmiller; Henri Brunengraber; Thomas H. Hostetter; Jeffrey R. Schelling

doi:10.1093/ndt/gfad103

Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) study

Sarah J. Schrauben^*, Hima Sapa, Dawei Xie, Xiaoming Zhang, Amanda Hyre Anderson, Michael G. Shlipak, Chi Yuan Hsu, Tariq Shafi, Rupal Mehta, Zeenat Bhat, Julie Brown, Jeanne Charleston, Jing Chen, Jiang He, Joachim H. Ix, Pandurango Rao, Ray Townsend, Paul L. Kimmel, Ramachandran S. Vasan, Harold I. FeldmanJesse C. Seegmiller, Henri Brunengraber, Thomas H. Hostetter, Jeffrey R. Schelling

^*Corresponding author for this work

Medicine, Nephrology Division

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Background: Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. Methods: This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography-tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. Results: Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01-1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07-1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08-4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. Conclusion: These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.

Original language	English (US)
Pages (from-to)	2809-2815
Number of pages	7
Journal	Nephrology Dialysis Transplantation
Volume	38
Issue number	12
DOIs	https://doi.org/10.1093/ndt/gfad103
State	Published - Dec 1 2023

Funding

R.M. owns stock in Abbvie and has received consultant fees/honoraria from AstraZeneca and is on the Speaker's Bureau for AstraZeneca. H.I.F. reports being Editor-in-Chief of the American Journal of Kidney Diseases (member of advisory board). M.G.S. has served on advisory boards for Boehringer Ingelheim and AstraZeneca, and receives research support from Bayer. J.H.I. is the principal investigator of an investigator-initiated research grant supported by Baxter International. P.L.K. reports being a Co-Editor of Chronic Renal Disease and Psychosocial Aspects of Chronic Kidney Disease, and a member of the Board of Directors of Washington Academy of Medicine. All remaining authors have nothing to disclose. S.J.S. is supported by the NIH career development grant K23DK118198 and R.M. is supported by K23HL150236. S.J.S. and A.H.A. have received support from the Chronic Kidney Disease Biomarker Consortium (U01DK103225). H.S., H.B., T.H.H. and J.R.S. have received funding from U01DK106965. C.-y.H. has received funding from K24DK092291. A.H.A. has received support from U01DK103225 and U01DK060990 and R01DK104730 related to this project.

Keywords

biomarker
cardiovascular disease
chronic kidney disease
diabetes
uremic solutes

ASJC Scopus subject areas

Nephrology
Transplantation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/ndt/gfad103

Cite this

Schrauben, S. J., Sapa, H., Xie, D., Zhang, X., Anderson, A. H., Shlipak, M. G., Hsu, C. Y., Shafi, T., Mehta, R., Bhat, Z., Brown, J., Charleston, J., Chen, J., He, J., Ix, J. H., Rao, P., Townsend, R., Kimmel, P. L., Vasan, R. S., ... Schelling, J. R. (2023). Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) study. Nephrology Dialysis Transplantation, 38(12), 2809-2815. https://doi.org/10.1093/ndt/gfad103

@article{59769e6b781e44cc8be52c1ba7727e1b,

title = "Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) study",

abstract = "Background: Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. Methods: This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography-tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. Results: Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01-1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07-1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08-4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. Conclusion: These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.",

keywords = "biomarker, cardiovascular disease, chronic kidney disease, diabetes, uremic solutes",

author = "Schrauben, {Sarah J.} and Hima Sapa and Dawei Xie and Xiaoming Zhang and Anderson, {Amanda Hyre} and Shlipak, {Michael G.} and Hsu, {Chi Yuan} and Tariq Shafi and Rupal Mehta and Zeenat Bhat and Julie Brown and Jeanne Charleston and Jing Chen and Jiang He and Ix, {Joachim H.} and Pandurango Rao and Ray Townsend and Kimmel, {Paul L.} and Vasan, {Ramachandran S.} and Feldman, {Harold I.} and Seegmiller, {Jesse C.} and Henri Brunengraber and Hostetter, {Thomas H.} and Schelling, {Jeffrey R.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s). Published by Oxford University Press on behalf of the ERA.",

year = "2023",

month = dec,

day = "1",

doi = "10.1093/ndt/gfad103",

language = "English (US)",

volume = "38",

pages = "2809--2815",

journal = "Nephrology Dialysis Transplantation",

issn = "0931-0509",

publisher = "Oxford University Press",

number = "12",

}

Schrauben, SJ, Sapa, H, Xie, D, Zhang, X, Anderson, AH, Shlipak, MG, Hsu, CY, Shafi, T, Mehta, R, Bhat, Z, Brown, J, Charleston, J, Chen, J, He, J, Ix, JH, Rao, P, Townsend, R, Kimmel, PL, Vasan, RS, Feldman, HI, Seegmiller, JC, Brunengraber, H, Hostetter, TH & Schelling, JR 2023, 'Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) study', Nephrology Dialysis Transplantation, vol. 38, no. 12, pp. 2809-2815. https://doi.org/10.1093/ndt/gfad103

Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) study. / Schrauben, Sarah J.; Sapa, Hima; Xie, Dawei et al.
In: Nephrology Dialysis Transplantation, Vol. 38, No. 12, 01.12.2023, p. 2809-2815.

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease

T2 - Findings from the Chronic Renal Insufficiency Cohort (CRIC) study

AU - Schrauben, Sarah J.

AU - Sapa, Hima

AU - Xie, Dawei

AU - Zhang, Xiaoming

AU - Anderson, Amanda Hyre

AU - Shlipak, Michael G.

AU - Hsu, Chi Yuan

AU - Shafi, Tariq

AU - Mehta, Rupal

AU - Bhat, Zeenat

AU - Brown, Julie

AU - Charleston, Jeanne

AU - Chen, Jing

AU - He, Jiang

AU - Ix, Joachim H.

AU - Rao, Pandurango

AU - Townsend, Ray

AU - Kimmel, Paul L.

AU - Vasan, Ramachandran S.

AU - Feldman, Harold I.

AU - Seegmiller, Jesse C.

AU - Brunengraber, Henri

AU - Hostetter, Thomas H.

AU - Schelling, Jeffrey R.

PY - 2023/12/1

Y1 - 2023/12/1

N2 - Background: Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. Methods: This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography-tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. Results: Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01-1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07-1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08-4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. Conclusion: These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.

AB - Background: Chronic kidney disease (CKD) is associated with atherosclerotic cardiovascular disease (ASCVD) risk, especially among those with diabetes. Altered metabolism of solutes that accumulate in CKD [asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and trimethylamine N-oxide (TMAO)] may reflect pathways linking CKD with ASCVD. Methods: This case-cohort study included Chronic Renal Insufficiency Cohort participants with baseline diabetes, estimated glomerular filtration rate <60 mL/min/1.73 m2, and without prior history for each outcome. The primary outcome was incident ASCVD (time to first myocardial infarction, stroke or peripheral artery disease event) and secondary outcome was incident heart failure. The subcohort comprised randomly selected participants meeting entry criteria. Plasma and urine ADMA, SDMA and TMAO concentrations were determined by liquid chromatography-tandem mass spectrometry. Associations of uremic solute plasma concentrations and urinary fractional excretions with outcomes were evaluated by weighted multivariable Cox regression models, adjusted for confounding covariables. Results: Higher plasma ADMA concentrations (per standard deviation) were associated with ASCVD risk [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.01-1.68]. Lower fractional excretion of ADMA (per standard deviation) was associated with ASCVD risk (HR 1.42, 95% CI 1.07-1.89). The lowest quartile of ADMA fractional excretion was associated with greater ASCVD risk (HR 2.25, 95% CI 1.08-4.69) compared with the highest quartile. Plasma SDMA and TMAO concentration and fractional excretion were not associated with ASCVD. Neither plasma nor fractional excretion of ADMA, SDMA and TMAO were associated with incident heart failure. Conclusion: These data suggest that decreased kidney excretion of ADMA leads to increased plasma concentrations and ASCVD risk.

KW - biomarker

KW - cardiovascular disease

KW - chronic kidney disease

KW - diabetes

KW - uremic solutes

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UR - http://www.scopus.com/inward/citedby.url?scp=85178649032&partnerID=8YFLogxK

U2 - 10.1093/ndt/gfad103

DO - 10.1093/ndt/gfad103

M3 - Article

C2 - 37230949

AN - SCOPUS:85178649032

SN - 0931-0509

VL - 38

SP - 2809

EP - 2815

JO - Nephrology Dialysis Transplantation

JF - Nephrology Dialysis Transplantation

IS - 12

ER -

Association of urine and plasma ADMA with atherosclerotic risk in DKD cardiovascular disease risk in diabetic kidney disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) study

Abstract

Funding

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ASJC Scopus subject areas

UN SDGs

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