Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis

Hiroshi Mitsumoto; Diana C. Garofalo; Regina M. Santella; Eric J. Sorenson; Björn Oskarsson; J. americo M. Fernandes; Howard Andrews; Jonathan Hupf; Madison Gilmore; Daragh Heitzman; Richard S. Bedlack; Jonathan S. Katz; Richard J. Barohn; Edward J. Kasarskis; Catherine lomen-Hoerth; Tahseen Mozaffar; Sharon P. Nations; Andrea J. Swenson; Pam Factor-Litvak

doi:10.1080/21678421.2020.1746810

Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis

Hiroshi Mitsumoto
, Diana C. Garofalo
, Regina M. Santella
, Eric J. Sorenson
, Björn Oskarsson
, J. americo M. Fernandes
, Howard Andrews
, Jonathan Hupf
, Madison Gilmore
, Daragh Heitzman
, Richard S. Bedlack
, Jonathan S. Katz
, Richard J. Barohn
, Edward J. Kasarskis
, Catherine lomen-Hoerth
, Tahseen Mozaffar
, Sharon P. Nations
, Andrea J. Swenson
, Pam Factor-Litvak

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

34 Scopus citations

Abstract

Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355). Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F_2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival. Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = −0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time. Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.

Original language	English
Pages (from-to)	263-272
Number of pages	10
Journal	Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
Volume	21
Issue number	3-4
DOIs	https://doi.org/10.1080/21678421.2020.1746810
State	Published - Apr 2 2020

Bibliographical note

Publisher Copyright:
© 2020, © 2020 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.

Funding

The Study was funded by the ALS Ride for Life, Anthony Senerchia Family Foundation, Judith and Jean Pape Adams Charitable Foundation, William Spina Foundation, MDA Wings Over Wall Street, and the NIEHS [R01-ES016348]. We are deeply grateful to all the patients and their caregivers for their commitment and participation in this lengthy study. Dr. Annette Kirshner at NIEHS strongly supported us in our endeavor. We also thank Drs. Robert Miller, Jeremy Shefner, Jinsy Andrews, and Boguslawa A. Koczon-Jaremko and Yvonne Rollins, and Ms. Janet Bowen who participated in the early stages of the study. Serge Cramer, PhD, Irving Institute of Clinical Translational Research, Biomarkers Core Laboratory and Departments of Pathology, Cell Biology and Medicine, Columbia University, measured PCr and PUA. David Merle, BA, Coordinating Center (DCC), Mailman School of Public Health Biostatistics Department, Columbia University, developed and managed the clinical database for the project. Irina Gurvich, MS, managed the ALS COSMOS Biorepository. Jess Singleton, BA, Columbia ALS Center, contributed to the data acquisition, input, and analyses. Georgia Christodoulou, MA, University of Southern California, and Cassandra Talerico-Kaplin, PhD, Cleveland Clinic, reviewed the manuscript. Hiroshi Mitsumoto, MD, DSc: Grants – NINDS, NIEHS, MDA Wings, SPF, ALSA, MNDA, CDC/ATSDR, Cytokinetics, Tsumura; Advisory Board: Mitsubishi-Tanabe, Biohaven, and Dainippon-Sumitomo. Diana C. Garofalo, MPH: None. Regina M. Santella, PhD: Grants – NIEHS, NCI, Breast Cancer Research Foundation. Eric J. Sorenson, MD: None. Bjorn Oskarsson, MD: Grants-NINDS, MDA, ALSA, Cytokinetics, Biogen, Genentech; Advisory Board – Mitsubishi-Tanabe, Biohaven. J Americo M. Fernandes, Jr, MD: Clinical trials – Malliinckrodt Pharmaceuticals. Howard Andrews, PhD: None. Jonathan Hupf, BA: None. Madison Gilmore, BA: None. Daragh Heitzman, MD: Speaker/Consultant for Biohaven Pharmaceuticals; Research Grant Support: Cytokinetics, Malliinckrodt Pharmaceuticals, Orion Pharma, Amylyx Therapeutics, Revance Therapeutics, Muscular Dystrophy Association, ALS Association, and The Neurologix Foundation. Richard S. Bedlack, MD, PhD, MS: Research Grants – ALSA, Cytokinetics, MNDA, Orion, Ultragenyx. Consulting Support – ALSA, Biogen, Biohaven, Brainstorm, ITF Pharma, Mallinkrodt. Jonathan S. Katz, MD: Grants from Genentech, Biogen, Orion and Brainstorm. Medical advisory board – MT Pharma. Richard J. Barohn, MD, PhD: Advisory: NuFactor and Momenta Pharmaceutical and research support from PTC Therapeutics, Ra Pharma, Orphazyme, Sanofi Genzyme, FDA OOPD, NIH, and PCORI. Edward J. Kasarskis, MD, PhD: Clinical support from ALSA; serves on the Data Safety Monitoring Board for a Cytokinetics reldesemtiv study. Catherine Lomen-Hoerth, MD, PhD: None. Tahseen Mozaffar, MD: Grants – NIH, MDA, The Myositis Association, Alexion, Amicus, Argenx, aTyr, Bristol-Myers-Squib, Idera, Ionis, Grifols, Momenta, Ra Pharmaceuticals, Sanofi-Genzyme, Spark Therapeutics, UCB, Ultragenyx, Valerion. Advisory Board – Alexion, Amicus, Argenx, aTyr, Bristol-Myers-Squib, Idera, Ionis, Grifols, Momenta, Ra Pharmaceuticals, Sanofi-Genzyme, Spark Therapeutics, UCB, Ultragenyx, Valerion. Data Safety Monitoring Board – Acceleron and Avexis. Sharon P. Nations, MD: None. Andrea J. Swenson, MD: None. Pam Factor-Litvak, PhD: CDC, MDA, NIH (NIEHS, NICHD).

Funders	Funder number
Amylyx Therapeutics
Anthony Senerchia Family Foundation
Columbia ALS Center
Mailman School of Public Health Biostatistics Department
Neurologix Foundation
National Childhood Cancer Registry – National Cancer Institute
National Institutes of Health/National Institute of Environmental Health Sciences	R01ES016348
National Institutes of Health/National Institute of Environmental Health Sciences
Hennepin Faculty Associates Amyotrophic Lateral Sclerosis Association Certified ALS Center
Breast Cancer Research Foundation
Judith and Jean Pape Adams Charitable Foundation
Muscular Dystrophy Association
Missile Defense Agency
University of Southern California
Patient-Centered Outcomes Research Institute
Univ. of Northern British Columbia
Horizon Pharma
PTC Therapeutics
Mallinckrodt Pharmaceuticals
Cytokinetics Incorporated
Revance

Keywords

Amyotrophic lateral sclerosis
biomarker
creatinine
oxidative stress
uric acid

ASJC Scopus subject areas

Neurology
Clinical Neurology

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10.1080/21678421.2020.1746810

Cite this

Mitsumoto, H., Garofalo, D. C., Santella, R. M., Sorenson, E. J., Oskarsson, B., Fernandes, J. A. M., Andrews, H., Hupf, J., Gilmore, M., Heitzman, D., Bedlack, R. S., Katz, J. S., Barohn, R. J., Kasarskis, E. J., lomen-Hoerth, C., Mozaffar, T., Nations, S. P., Swenson, A. J., & Factor-Litvak, P. (2020). Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 21(3-4), 263-272. https://doi.org/10.1080/21678421.2020.1746810

@article{5e8d7f788dc74be3a2452b776ae49972,

title = "Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis",

abstract = "Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355). Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival. Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (\%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = −0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time. Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.",

keywords = "Amyotrophic lateral sclerosis, biomarker, creatinine, oxidative stress, uric acid",

author = "Hiroshi Mitsumoto and Garofalo, \{Diana C.\} and Santella, \{Regina M.\} and Sorenson, \{Eric J.\} and Bj{\"o}rn Oskarsson and Fernandes, \{J. americo M.\} and Howard Andrews and Jonathan Hupf and Madison Gilmore and Daragh Heitzman and Bedlack, \{Richard S.\} and Katz, \{Jonathan S.\} and Barohn, \{Richard J.\} and Kasarskis, \{Edward J.\} and Catherine lomen-Hoerth and Tahseen Mozaffar and Nations, \{Sharon P.\} and Swenson, \{Andrea J.\} and Pam Factor-Litvak",

note = "Publisher Copyright: {\textcopyright} 2020, {\textcopyright} 2020 World Federation of Neurology on behalf of the Research Group on Motor Neuron Diseases.",

year = "2020",

month = apr,

day = "2",

doi = "10.1080/21678421.2020.1746810",

language = "English",

volume = "21",

pages = "263--272",

number = "3-4",

}

Mitsumoto, H, Garofalo, DC, Santella, RM, Sorenson, EJ, Oskarsson, B, Fernandes, JAM, Andrews, H, Hupf, J, Gilmore, M, Heitzman, D, Bedlack, RS, Katz, JS, Barohn, RJ, Kasarskis, EJ, lomen-Hoerth, C, Mozaffar, T, Nations, SP, Swenson, AJ & Factor-Litvak, P 2020, 'Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis', Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, vol. 21, no. 3-4, pp. 263-272. https://doi.org/10.1080/21678421.2020.1746810

TY - JOUR

T1 - Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis

AU - Mitsumoto, Hiroshi

AU - Garofalo, Diana C.

AU - Santella, Regina M.

AU - Sorenson, Eric J.

AU - Oskarsson, Björn

AU - Fernandes, J. americo M.

AU - Andrews, Howard

AU - Hupf, Jonathan

AU - Gilmore, Madison

AU - Heitzman, Daragh

AU - Bedlack, Richard S.

AU - Katz, Jonathan S.

AU - Barohn, Richard J.

AU - Kasarskis, Edward J.

AU - lomen-Hoerth, Catherine

AU - Mozaffar, Tahseen

AU - Nations, Sharon P.

AU - Swenson, Andrea J.

AU - Factor-Litvak, Pam

PY - 2020/4/2

Y1 - 2020/4/2

N2 - Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355). Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival. Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = −0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time. Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.

AB - Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355). Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival. Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = −0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time. Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.

KW - Amyotrophic lateral sclerosis

KW - biomarker

KW - creatinine

KW - oxidative stress

KW - uric acid

UR - https://www.scopus.com/pages/publications/85083525839

UR - https://www.scopus.com/pages/publications/85083525839#tab=citedBy

U2 - 10.1080/21678421.2020.1746810

DO - 10.1080/21678421.2020.1746810

M3 - Article

C2 - 32276554

AN - SCOPUS:85083525839

SN - 2167-8421

VL - 21

SP - 263

EP - 272

JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration

IS - 3-4

ER -

Plasma creatinine and oxidative stress biomarkers in amyotrophic lateral sclerosis

Abstract

Bibliographical note

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ASJC Scopus subject areas

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