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-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.

Keywords:

• Amyotrophic lateral sclerosis
• biomarker
• creatinine
• uric acid
• oxidative stress

Acknowledgements

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.

Declaration of interest

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).

Additional information

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].