Association of Uremic Solutes With Cardiovascular Death in Diabetic Kidney Disease

CKD Biomarkers Consortium

doi:10.1053/j.ajkd.2022.02.016

Association of Uremic Solutes With Cardiovascular Death in Diabetic Kidney Disease

CKD Biomarkers Consortium

Laboratory Medicine and Pathology

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

18 Scopus citations

Abstract

RATIONALE & OBJECTIVE: Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease.

STUDY DESIGN: Observational cohort.

SETTINGS & PARTICIPANTS: Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at study entry.

EXPOSURE: ADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine.

OUTCOME: Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes).

ANALYTICAL APPROACH: Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons.

RESULTS: The mean baseline eGFR was 44 mL/min/1.73 m 2. Cardiovascular death, overall mortality, and KFRT occurred in 120, 285, and 89 participants, respectively, during a mean 6.2 years of follow-up. Higher plasma ADMA and SDMA (HRs of 1.20 and 1.28 per 1-SD greater concentration), and lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO (HRs per halving of 1.53, 1.69, and 1.38) were associated with cardiovascular mortality. Higher plasma concentrations of ADMA, SDMA, and TMAO (HRs of 1.31, 1.42, and 1.13 per 1-SD greater concentration) and lower urine to plasma ratios of ADMA, SDMA, and TMAO (HRs per halving of 1.34, 1.37, and 1.26) were associated with all-cause mortality. Higher plasma ADMA and SDMA were associated with incident KFRT by categorical comparisons (HRs of 2.75 and 2.96, comparing quartile 4 to quartile 1), but not in continuous analyses.

LIMITATIONS: Single cohort, restricted to patients with diabetes and eGFR < 60 mL/min/1.73 m 2, potential residual confounding by GFR, no dietary information.

CONCLUSIONS: Higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.

Original language	English (US)
Pages (from-to)	502-512.e1
Journal	American Journal of Kidney Diseases
Volume	80
Issue number	4
DOIs	https://doi.org/10.1053/j.ajkd.2022.02.016
State	Published - Oct 2022

Bibliographical note

Funding Information:
This study was supported by the CKD BioCon Consortium through NIDDK grant U01 DK106965 (to HS, HB, THH, and JRS). This research project is also supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), NIH , Department of Health and Human Services. NIH officials (PLK) participated in the study design, but otherwise the funders did not have a role in data collection, analysis, reporting, or the decision to submit for publication.

Funding Information:
The collaborators in phase II of the CKD Biomarkers Consortium are (asterisk indicates principal investigator): Joseph Massaro, PhD (Boston University School of Medicine); Clary Clish, PhD (Broad Institute); Michelle Denburg, MD, MSCE,∗ Susan Furth, MD, PhD∗ (The Children's Hospital of Philadelphia); Bradley Warady, MD (Children's Mercy Hospital); Joseph Bonventre, MD, PhD,∗ Sushrut Waikar, MD, MPH,∗ Gearoid McMahon, MB, BCH, Venkata Sabbisetti, PhD (Brigham and Women's Hospital, Harvard University); Josef Coresh, MD, PhD,∗ Morgan Grams, MD, Casey Rebholz, PhD, Alison Abraham, PhD, Adriene Tin, PhD, Chirag Parikh, MD, PhD∗ (Johns Hopkins University); Jon Klein, MD, PhD (University of Louisville); Steven Coca, DO, MS,∗ Bart S. Ferket, MD, PhD, Girish N. Nadkarni, MD, MPH, CPH (Icahn School of Medicine at Mount Sinai); Daniel Gossett, PhD (National Institute of Diabetes, Digestive and Kidney Diseases/National Institutes of Healh [NIDDK/NIH]); Brad Rovin, MD∗ (Ohio State University); Andrew S. Levey, MD, Lesley A. Inker, MD, MS, Meredith Foster, PhD (Tufts Medical Center); Ruth Dubin, MD∗ (University of California–San Francisco); Rajat Deo, MD∗ (University of Pennsylvania); Amanda Anderson, PhD, Theodore Mifflin, PhD, DABCC, Dawei Xie, PhD, Haochang Shou, PhD, Shawn Ballard, MS, Krista Whitehead, MS, Heather Collins, PhD (University of Pennsylvania Coordinating Center); Jason Greenberg, MD (Yale School of Medicine); Peter Ganz, MD∗ (Zuckerberg San Francisco General Hospital). Hima Sapa, PhD, Orlando M. Gutiérrez, MD, MMSc, Michael G. Shlipak, MD, MPH, Ronit Katz, DPhil, Joachim H. Ix, MD, MAS, Mark J. Sarnak, MD, MS, Mary Cushman, MD, Eugene P. Rhee, MD, Paul L. Kimmel, MD, Ramachandran S. Vasan, MD, Sarah J. Schrauben, MD, MSCE, Harold I. Feldman, MD, MSCE, Jesse C. Seegmiller, PhD, Henri Brunengraber, MD, PhD, Thomas H. Hostetter, MD, and Jeffrey R. Schelling, MD. OMG,∗ MGS,∗ JHI,∗ MJS,∗ EPR,∗ PLK, RSV, HIF,∗ JCS, THH,∗ and JRS,∗ are collaborators in phase II of the CKD Biomarkers Consortium (asterisk indicates principal investigator). RSV is chair of the Steering Committee. Designed study: OMG, MGS, MJS, MC, EPR, SJS, HIF, PLK, RSV, THH, JRS; conducted assays: HS, JCS, HB, THH, JRS; analyzed data: RK, MGS, JHI, MJS. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This study was supported by the CKD BioCon Consortium through NIDDK grant U01 DK106965 (to HS, HB, THH, and JRS). This research project is also supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), NIH, Department of Health and Human Services. NIH officials (PLK) participated in the study design, but otherwise the funders did not have a role in data collection, analysis, reporting, or the decision to submit for publication. Dr Gutierrez has received grant funding and honoraria from Akebia and GSK; honoraria from AstraZeneca, Ardelyx, and Reata; grant funding from GSK; and serves on the Data Monitoring Committee for a clinical trial from QED. The remaining authors declare that they have no relevant financial interests. The authors thank the staff and the participants of the REGARDS Study for their valuable contributions. Aspects of this work were presented in abstract form on November 6, 2021, at the American Society of Nephrology's Kidney Week 2021, held virtually. KFRT data used in this analysis were supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government. The content is solely the responsibility of the authors and does not necessarily represent the official views or opinion of NINDS, NIA, NIDDK, NIH, the Department of Health and Human Services, or the government of the United States. Received September 17, 2021. Evaluated by 3 external peer reviewers and a statistician, with editorial input from an Acting Editor-in-Chief (Editorial Board Member Ifeoma Ulasi, FWACP). Accepted in revised form February 6, 2022. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.

Funding Information:
Dr Gutierrez has received grant funding and honoraria from Akebia and GSK; honoraria from AstraZeneca, Ardelyx, and Reata; grant funding from GSK; and serves on the Data Monitoring Committee for a clinical trial from QED. The remaining authors declare that they have no relevant financial interests.

Publisher Copyright:
© 2022 The Authors

Keywords

Asymmetric dimethylarginine (ADMA)
biomarkers
cardiovascular disease (CVD)
diabetic kidney disease (DKD)
end-stage kidney disease (ESKD)
estimated glomerular filtration rate (eGFR)
kidney function
renal clearance
risk stratification
symmetric dimethylarginine (SDMA)
trimethylamine-N-oxide (TMAO)
uremic solute
Cardiovascular Diseases
Humans
Diabetic Nephropathies/complications
Oxides
Diabetes Mellitus
Arginine
Biomarkers
Methylamines

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural

UN SDGs

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

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10.1053/j.ajkd.2022.02.016

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Cite this

@article{3ac31cffb62743be9860f54ef4a3d2c7,

title = "Association of Uremic Solutes With Cardiovascular Death in Diabetic Kidney Disease",

abstract = "RATIONALE & OBJECTIVE: Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease.STUDY DESIGN: Observational cohort.SETTINGS & PARTICIPANTS: Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at study entry. EXPOSURE: ADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine.OUTCOME: Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes).ANALYTICAL APPROACH: Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons.RESULTS: The mean baseline eGFR was 44 mL/min/1.73 m 2. Cardiovascular death, overall mortality, and KFRT occurred in 120, 285, and 89 participants, respectively, during a mean 6.2 years of follow-up. Higher plasma ADMA and SDMA (HRs of 1.20 and 1.28 per 1-SD greater concentration), and lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO (HRs per halving of 1.53, 1.69, and 1.38) were associated with cardiovascular mortality. Higher plasma concentrations of ADMA, SDMA, and TMAO (HRs of 1.31, 1.42, and 1.13 per 1-SD greater concentration) and lower urine to plasma ratios of ADMA, SDMA, and TMAO (HRs per halving of 1.34, 1.37, and 1.26) were associated with all-cause mortality. Higher plasma ADMA and SDMA were associated with incident KFRT by categorical comparisons (HRs of 2.75 and 2.96, comparing quartile 4 to quartile 1), but not in continuous analyses. LIMITATIONS: Single cohort, restricted to patients with diabetes and eGFR < 60 mL/min/1.73 m 2, potential residual confounding by GFR, no dietary information. CONCLUSIONS: Higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.",

keywords = "Asymmetric dimethylarginine (ADMA), biomarkers, cardiovascular disease (CVD), diabetic kidney disease (DKD), end-stage kidney disease (ESKD), estimated glomerular filtration rate (eGFR), kidney function, renal clearance, risk stratification, symmetric dimethylarginine (SDMA), trimethylamine-N-oxide (TMAO), uremic solute, Cardiovascular Diseases, Humans, Diabetic Nephropathies/complications, Oxides, Diabetes Mellitus, Arginine, Biomarkers, Methylamines",

author = "{CKD Biomarkers Consortium} and Hima Sapa and Guti{\'e}rrez, {Orlando M.} and Shlipak, {Michael G.} and Ronit Katz and Ix, {Joachim H.} and Sarnak, {Mark J.} and Mary Cushman and Rhee, {Eugene P.} and Kimmel, {Paul L.} and Vasan, {Ramachandran S.} and Schrauben, {Sarah J.} and Feldman, {Harold I.} and Seegmiller, {Jesse C.} and Henri Brunengraber and Hostetter, {Thomas H.} and Schelling, {Jeffrey R.} and Joseph Massaro and Clary Clish and Michelle Denburg and Susan Furth and Bradley Warady and Joseph Bonventre and Sushrut Waikar and Gearoid McMahon and Venkata Sabbisetti and Josef Coresh and Morgan Grams and Casey Rebholz and Alison Abraham and Adriene Tin and Chirag Parikh and Jon Klein and Steven Coca and Ferket, {Bart S.} and Nadkarni, {Girish N.} and Daniel Gossett and Brad Rovin and Levey, {Andrew S.} and Inker, {Lesley A.} and Meredith Foster and Ruth Dubin and Rajat Deo and Amanda Anderson and Theodore Mifflin and Dawei Xie and Haochang Shou and Shawn Ballard and Krista Whitehead and Heather Collins and Jason Greenberg",

note = "Funding Information: This study was supported by the CKD BioCon Consortium through NIDDK grant U01 DK106965 (to HS, HB, THH, and JRS). This research project is also supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), NIH , Department of Health and Human Services. NIH officials (PLK) participated in the study design, but otherwise the funders did not have a role in data collection, analysis, reporting, or the decision to submit for publication. Funding Information: The collaborators in phase II of the CKD Biomarkers Consortium are (asterisk indicates principal investigator): Joseph Massaro, PhD (Boston University School of Medicine); Clary Clish, PhD (Broad Institute); Michelle Denburg, MD, MSCE,∗ Susan Furth, MD, PhD∗ (The Children's Hospital of Philadelphia); Bradley Warady, MD (Children's Mercy Hospital); Joseph Bonventre, MD, PhD,∗ Sushrut Waikar, MD, MPH,∗ Gearoid McMahon, MB, BCH, Venkata Sabbisetti, PhD (Brigham and Women's Hospital, Harvard University); Josef Coresh, MD, PhD,∗ Morgan Grams, MD, Casey Rebholz, PhD, Alison Abraham, PhD, Adriene Tin, PhD, Chirag Parikh, MD, PhD∗ (Johns Hopkins University); Jon Klein, MD, PhD (University of Louisville); Steven Coca, DO, MS,∗ Bart S. Ferket, MD, PhD, Girish N. Nadkarni, MD, MPH, CPH (Icahn School of Medicine at Mount Sinai); Daniel Gossett, PhD (National Institute of Diabetes, Digestive and Kidney Diseases/National Institutes of Healh [NIDDK/NIH]); Brad Rovin, MD∗ (Ohio State University); Andrew S. Levey, MD, Lesley A. Inker, MD, MS, Meredith Foster, PhD (Tufts Medical Center); Ruth Dubin, MD∗ (University of California–San Francisco); Rajat Deo, MD∗ (University of Pennsylvania); Amanda Anderson, PhD, Theodore Mifflin, PhD, DABCC, Dawei Xie, PhD, Haochang Shou, PhD, Shawn Ballard, MS, Krista Whitehead, MS, Heather Collins, PhD (University of Pennsylvania Coordinating Center); Jason Greenberg, MD (Yale School of Medicine); Peter Ganz, MD∗ (Zuckerberg San Francisco General Hospital). Hima Sapa, PhD, Orlando M. Guti{\'e}rrez, MD, MMSc, Michael G. Shlipak, MD, MPH, Ronit Katz, DPhil, Joachim H. Ix, MD, MAS, Mark J. Sarnak, MD, MS, Mary Cushman, MD, Eugene P. Rhee, MD, Paul L. Kimmel, MD, Ramachandran S. Vasan, MD, Sarah J. Schrauben, MD, MSCE, Harold I. Feldman, MD, MSCE, Jesse C. Seegmiller, PhD, Henri Brunengraber, MD, PhD, Thomas H. Hostetter, MD, and Jeffrey R. Schelling, MD. OMG,∗ MGS,∗ JHI,∗ MJS,∗ EPR,∗ PLK, RSV, HIF,∗ JCS, THH,∗ and JRS,∗ are collaborators in phase II of the CKD Biomarkers Consortium (asterisk indicates principal investigator). RSV is chair of the Steering Committee. Designed study: OMG, MGS, MJS, MC, EPR, SJS, HIF, PLK, RSV, THH, JRS; conducted assays: HS, JCS, HB, THH, JRS; analyzed data: RK, MGS, JHI, MJS. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This study was supported by the CKD BioCon Consortium through NIDDK grant U01 DK106965 (to HS, HB, THH, and JRS). This research project is also supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), NIH, Department of Health and Human Services. NIH officials (PLK) participated in the study design, but otherwise the funders did not have a role in data collection, analysis, reporting, or the decision to submit for publication. Dr Gutierrez has received grant funding and honoraria from Akebia and GSK; honoraria from AstraZeneca, Ardelyx, and Reata; grant funding from GSK; and serves on the Data Monitoring Committee for a clinical trial from QED. The remaining authors declare that they have no relevant financial interests. The authors thank the staff and the participants of the REGARDS Study for their valuable contributions. Aspects of this work were presented in abstract form on November 6, 2021, at the American Society of Nephrology's Kidney Week 2021, held virtually. KFRT data used in this analysis were supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government. The content is solely the responsibility of the authors and does not necessarily represent the official views or opinion of NINDS, NIA, NIDDK, NIH, the Department of Health and Human Services, or the government of the United States. Received September 17, 2021. Evaluated by 3 external peer reviewers and a statistician, with editorial input from an Acting Editor-in-Chief (Editorial Board Member Ifeoma Ulasi, FWACP). Accepted in revised form February 6, 2022. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies. Funding Information: Dr Gutierrez has received grant funding and honoraria from Akebia and GSK; honoraria from AstraZeneca, Ardelyx, and Reata; grant funding from GSK; and serves on the Data Monitoring Committee for a clinical trial from QED. The remaining authors declare that they have no relevant financial interests. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = oct,

doi = "10.1053/j.ajkd.2022.02.016",

language = "English (US)",

volume = "80",

pages = "502--512.e1",

journal = "American Journal of Kidney Diseases",

issn = "0272-6386",

publisher = "W.B. Saunders",

number = "4",

}

TY - JOUR

T1 - Association of Uremic Solutes With Cardiovascular Death in Diabetic Kidney Disease

AU - CKD Biomarkers Consortium

AU - Sapa, Hima

AU - Gutiérrez, Orlando M.

AU - Shlipak, Michael G.

AU - Katz, Ronit

AU - Ix, Joachim H.

AU - Sarnak, Mark J.

AU - Cushman, Mary

AU - Rhee, Eugene P.

AU - Kimmel, Paul L.

AU - Vasan, Ramachandran S.

AU - Schrauben, Sarah J.

AU - Feldman, Harold I.

AU - Seegmiller, Jesse C.

AU - Brunengraber, Henri

AU - Hostetter, Thomas H.

AU - Schelling, Jeffrey R.

AU - Massaro, Joseph

AU - Clish, Clary

AU - Denburg, Michelle

AU - Furth, Susan

AU - Warady, Bradley

AU - Bonventre, Joseph

AU - Waikar, Sushrut

AU - McMahon, Gearoid

AU - Sabbisetti, Venkata

AU - Coresh, Josef

AU - Grams, Morgan

AU - Rebholz, Casey

AU - Abraham, Alison

AU - Tin, Adriene

AU - Parikh, Chirag

AU - Klein, Jon

AU - Coca, Steven

AU - Ferket, Bart S.

AU - Nadkarni, Girish N.

AU - Gossett, Daniel

AU - Rovin, Brad

AU - Levey, Andrew S.

AU - Inker, Lesley A.

AU - Foster, Meredith

AU - Dubin, Ruth

AU - Deo, Rajat

AU - Anderson, Amanda

AU - Mifflin, Theodore

AU - Xie, Dawei

AU - Shou, Haochang

AU - Ballard, Shawn

AU - Whitehead, Krista

AU - Collins, Heather

AU - Greenberg, Jason

N1 - Funding Information: This study was supported by the CKD BioCon Consortium through NIDDK grant U01 DK106965 (to HS, HB, THH, and JRS). This research project is also supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), NIH , Department of Health and Human Services. NIH officials (PLK) participated in the study design, but otherwise the funders did not have a role in data collection, analysis, reporting, or the decision to submit for publication. Funding Information: The collaborators in phase II of the CKD Biomarkers Consortium are (asterisk indicates principal investigator): Joseph Massaro, PhD (Boston University School of Medicine); Clary Clish, PhD (Broad Institute); Michelle Denburg, MD, MSCE,∗ Susan Furth, MD, PhD∗ (The Children's Hospital of Philadelphia); Bradley Warady, MD (Children's Mercy Hospital); Joseph Bonventre, MD, PhD,∗ Sushrut Waikar, MD, MPH,∗ Gearoid McMahon, MB, BCH, Venkata Sabbisetti, PhD (Brigham and Women's Hospital, Harvard University); Josef Coresh, MD, PhD,∗ Morgan Grams, MD, Casey Rebholz, PhD, Alison Abraham, PhD, Adriene Tin, PhD, Chirag Parikh, MD, PhD∗ (Johns Hopkins University); Jon Klein, MD, PhD (University of Louisville); Steven Coca, DO, MS,∗ Bart S. Ferket, MD, PhD, Girish N. Nadkarni, MD, MPH, CPH (Icahn School of Medicine at Mount Sinai); Daniel Gossett, PhD (National Institute of Diabetes, Digestive and Kidney Diseases/National Institutes of Healh [NIDDK/NIH]); Brad Rovin, MD∗ (Ohio State University); Andrew S. Levey, MD, Lesley A. Inker, MD, MS, Meredith Foster, PhD (Tufts Medical Center); Ruth Dubin, MD∗ (University of California–San Francisco); Rajat Deo, MD∗ (University of Pennsylvania); Amanda Anderson, PhD, Theodore Mifflin, PhD, DABCC, Dawei Xie, PhD, Haochang Shou, PhD, Shawn Ballard, MS, Krista Whitehead, MS, Heather Collins, PhD (University of Pennsylvania Coordinating Center); Jason Greenberg, MD (Yale School of Medicine); Peter Ganz, MD∗ (Zuckerberg San Francisco General Hospital). Hima Sapa, PhD, Orlando M. Gutiérrez, MD, MMSc, Michael G. Shlipak, MD, MPH, Ronit Katz, DPhil, Joachim H. Ix, MD, MAS, Mark J. Sarnak, MD, MS, Mary Cushman, MD, Eugene P. Rhee, MD, Paul L. Kimmel, MD, Ramachandran S. Vasan, MD, Sarah J. Schrauben, MD, MSCE, Harold I. Feldman, MD, MSCE, Jesse C. Seegmiller, PhD, Henri Brunengraber, MD, PhD, Thomas H. Hostetter, MD, and Jeffrey R. Schelling, MD. OMG,∗ MGS,∗ JHI,∗ MJS,∗ EPR,∗ PLK, RSV, HIF,∗ JCS, THH,∗ and JRS,∗ are collaborators in phase II of the CKD Biomarkers Consortium (asterisk indicates principal investigator). RSV is chair of the Steering Committee. Designed study: OMG, MGS, MJS, MC, EPR, SJS, HIF, PLK, RSV, THH, JRS; conducted assays: HS, JCS, HB, THH, JRS; analyzed data: RK, MGS, JHI, MJS. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved. This study was supported by the CKD BioCon Consortium through NIDDK grant U01 DK106965 (to HS, HB, THH, and JRS). This research project is also supported by cooperative agreement U01 NS041588 co-funded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), NIH, Department of Health and Human Services. NIH officials (PLK) participated in the study design, but otherwise the funders did not have a role in data collection, analysis, reporting, or the decision to submit for publication. Dr Gutierrez has received grant funding and honoraria from Akebia and GSK; honoraria from AstraZeneca, Ardelyx, and Reata; grant funding from GSK; and serves on the Data Monitoring Committee for a clinical trial from QED. The remaining authors declare that they have no relevant financial interests. The authors thank the staff and the participants of the REGARDS Study for their valuable contributions. Aspects of this work were presented in abstract form on November 6, 2021, at the American Society of Nephrology's Kidney Week 2021, held virtually. KFRT data used in this analysis were supplied by the USRDS. The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government. The content is solely the responsibility of the authors and does not necessarily represent the official views or opinion of NINDS, NIA, NIDDK, NIH, the Department of Health and Human Services, or the government of the United States. Received September 17, 2021. Evaluated by 3 external peer reviewers and a statistician, with editorial input from an Acting Editor-in-Chief (Editorial Board Member Ifeoma Ulasi, FWACP). Accepted in revised form February 6, 2022. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies. Funding Information: Dr Gutierrez has received grant funding and honoraria from Akebia and GSK; honoraria from AstraZeneca, Ardelyx, and Reata; grant funding from GSK; and serves on the Data Monitoring Committee for a clinical trial from QED. The remaining authors declare that they have no relevant financial interests. Publisher Copyright: © 2022 The Authors

PY - 2022/10

Y1 - 2022/10

N2 - RATIONALE & OBJECTIVE: Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease.STUDY DESIGN: Observational cohort.SETTINGS & PARTICIPANTS: Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at study entry. EXPOSURE: ADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine.OUTCOME: Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes).ANALYTICAL APPROACH: Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons.RESULTS: The mean baseline eGFR was 44 mL/min/1.73 m 2. Cardiovascular death, overall mortality, and KFRT occurred in 120, 285, and 89 participants, respectively, during a mean 6.2 years of follow-up. Higher plasma ADMA and SDMA (HRs of 1.20 and 1.28 per 1-SD greater concentration), and lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO (HRs per halving of 1.53, 1.69, and 1.38) were associated with cardiovascular mortality. Higher plasma concentrations of ADMA, SDMA, and TMAO (HRs of 1.31, 1.42, and 1.13 per 1-SD greater concentration) and lower urine to plasma ratios of ADMA, SDMA, and TMAO (HRs per halving of 1.34, 1.37, and 1.26) were associated with all-cause mortality. Higher plasma ADMA and SDMA were associated with incident KFRT by categorical comparisons (HRs of 2.75 and 2.96, comparing quartile 4 to quartile 1), but not in continuous analyses. LIMITATIONS: Single cohort, restricted to patients with diabetes and eGFR < 60 mL/min/1.73 m 2, potential residual confounding by GFR, no dietary information. CONCLUSIONS: Higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.

AB - RATIONALE & OBJECTIVE: Cardiovascular disease (CVD) is a major cause of mortality among people with diabetic kidney disease (DKD). The pathophysiology is inadequately explained by traditional CVD risk factors. The uremic solutes trimethylamine-N-oxide (TMAO) and asymmetric and symmetric dimethylarginine (ADMA, SDMA) have been linked to CVD in kidney failure with replacement therapy (KFRT), but data are limited in populations with diabetes and less severe kidney disease.STUDY DESIGN: Observational cohort.SETTINGS & PARTICIPANTS: Random subcohort of 555 REGARDS (Reasons for Geographic and Racial Differences in Stroke) study participants with diabetes and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m 2 at study entry. EXPOSURE: ADMA, SDMA, and TMAO assayed by liquid chromatography-mass spectrometry in plasma and urine.OUTCOME: Cardiovascular mortality (primary outcome); all-cause mortality and incident KFRT (secondary outcomes).ANALYTICAL APPROACH: Plasma concentrations and ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO were tested for association with outcomes. Adjusted Cox regression models were fitted and hazard ratios of outcomes calculated per standard deviation and per doubling, and as interquartile comparisons.RESULTS: The mean baseline eGFR was 44 mL/min/1.73 m 2. Cardiovascular death, overall mortality, and KFRT occurred in 120, 285, and 89 participants, respectively, during a mean 6.2 years of follow-up. Higher plasma ADMA and SDMA (HRs of 1.20 and 1.28 per 1-SD greater concentration), and lower ratios of urine to plasma concentrations of ADMA, SDMA, and TMAO (HRs per halving of 1.53, 1.69, and 1.38) were associated with cardiovascular mortality. Higher plasma concentrations of ADMA, SDMA, and TMAO (HRs of 1.31, 1.42, and 1.13 per 1-SD greater concentration) and lower urine to plasma ratios of ADMA, SDMA, and TMAO (HRs per halving of 1.34, 1.37, and 1.26) were associated with all-cause mortality. Higher plasma ADMA and SDMA were associated with incident KFRT by categorical comparisons (HRs of 2.75 and 2.96, comparing quartile 4 to quartile 1), but not in continuous analyses. LIMITATIONS: Single cohort, restricted to patients with diabetes and eGFR < 60 mL/min/1.73 m 2, potential residual confounding by GFR, no dietary information. CONCLUSIONS: Higher plasma concentrations and lower ratios of urine to plasma concentrations of uremic solutes were independently associated with cardiovascular and all-cause mortality in DKD. Associations of ratios of urine to plasma concentrations with mortality suggest a connection between renal uremic solute clearance and CVD pathogenesis.

KW - Asymmetric dimethylarginine (ADMA)

KW - biomarkers

KW - cardiovascular disease (CVD)

KW - diabetic kidney disease (DKD)

KW - end-stage kidney disease (ESKD)

KW - estimated glomerular filtration rate (eGFR)

KW - kidney function

KW - renal clearance

KW - risk stratification

KW - symmetric dimethylarginine (SDMA)

KW - trimethylamine-N-oxide (TMAO)

KW - uremic solute

KW - Cardiovascular Diseases

KW - Humans

KW - Diabetic Nephropathies/complications

KW - Oxides

KW - Diabetes Mellitus

KW - Arginine

KW - Biomarkers

KW - Methylamines

UR - http://www.scopus.com/inward/record.url?scp=85132812814&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85132812814&partnerID=8YFLogxK

U2 - 10.1053/j.ajkd.2022.02.016

DO - 10.1053/j.ajkd.2022.02.016

M3 - Article

C2 - 35351578

AN - SCOPUS:85132812814

SN - 0272-6386

VL - 80

SP - 502-512.e1

JO - American Journal of Kidney Diseases

JF - American Journal of Kidney Diseases

IS - 4

ER -

Association of Uremic Solutes With Cardiovascular Death in Diabetic Kidney Disease

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