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Neuromuscular
Original research
Ratio of urinary N-terminal titin fragment to urinary creatinine is a novel biomarker for amyotrophic lateral sclerosis
  1. Shinichiro Yamada1,
  2. Atsushi Hashizume1,
  3. Yasuhiro Hijikata1,
  4. Daisuke Ito1,
  5. Yoshiyuki Kishimoto1,
  6. Madoka Iida1,
  7. Haruki Koike1,
  8. Akihiro Hirakawa2,
  9. Masahisa Katsuno1
  1. 1 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan
  2. 2 Department of Clinical Biostatistics, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan
  1. Correspondence to Dr Masahisa Katsuno, Neurology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan; ka2no{at}med.nagoya-u.ac.jp

Abstract

Objective We aimed to investigate the validity of urinary N-terminal titin fragment as a biomarker for amyotrophic lateral sclerosis (ALS).

Methods We consecutively enrolled patients with ALS (n=70) and healthy controls (HC) (n=43). We assessed the urinary titin N-terminal fragment, urinary neurotrophin receptor p75 extracellular domain, serum neurofilament light chain (NfL), motor functional measurements and prognosis. We used urinary creatinine (Cr) levels to normalise the urinary levels of titin fragment.

Results Compared with HC, patients with ALS had significantly increased urinary levels of titin N-terminal fragment normalised with Cr (titin/Cr) (ALS, 27.2 pmol/mg/dL; HC, 5.8 pmol/mg/dL; p<0.001), which were correlated with the scores of the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (r=−0.422, p<0.001). A Cox proportional hazards model demonstrated that the high urinary level of titin/Cr was a survival predictor in patients with ALS. Multivariate analysis of prognostic factors showed that the urinary titin/Cr and serum NfL were independent factors for poor prognosis.

Conclusions Our findings indicate that urinary N-terminal titin fragment is a non-invasive measure of muscle damage in ALS, which could be applied in disease monitoring and prediction of disease progression, in combination with serum NfL.

Data availability statement

Data are available on reasonable request. Anonymised data of this study will be shared by request from any qualified investigator.

https://doi.org/10.1136/jnnp-2020-324615

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    Data availability statement

    Data are available on reasonable request. Anonymised data of this study will be shared by request from any qualified investigator.

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    Footnotes

    • Contributors SY: designed and conceptualised study; acquired clinical data; performed statistical analysis; analysed the data; interpreted the data and drafted the manuscript. AHa: designed and conceptualised study; acquired clinical data; performed statistical analysis; analysed the data; interpreted the data and revised the manuscript for intellectual content. YH, DI, YK, MI and HK: acquired clinical data. AHi: performed statistical analysis. MK: designed and conceptualised study; analysed the data; interpreted the data and revised the manuscript for intellectual content.

    • Funding This work was funded by JSPS KAKENHI (Grant Numbers JP17H04195 and JP20H00527); grants from the Japan Agency for Medical Research and Development (Nos. 19ek0109221 and 19ek0109359); a grant from the Naito Foundation and a grant from the Hori Sciences and Arts Foundation. SY is supported by JSPS KAKENHI (Grant Number JP19K17060). AH is supported by KAKENHI (Grant Number JP18K07523). YH is supported by JSPS KAKENHI (Grant Number JP18K07497). MI is supported by JSPS KAKENHI (Grant Number JP18K15361). HK is supported by JSPS KAKENHI (Grant Number JP17K09777). He received honoraria from Takeda Pharmaceutical Co. Ltd., Pfizer Japan Co. Ltd., Alnylam Japan, Japan Blood Products Organization, CSL Behring Co. Ltd., Daiichi Sankyo Co. Ltd. and Teijin Parma Co. Ltd. MK is supported by JSPS KAKENHI (Grant Numbers JP17H04195 and JP20H00527), grants from the Japan Agency for Medical Research and Development (Nos. 19ek0109221, 19ek0109359, 19dk0207027, 19lk0201101 and 19dm0107155) and a grant from the Hori Sciences and Arts Foundation. He received honoraria from Takeda Pharmaceutical Co. Ltd., Alnylam Japan, Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co. Ltd., Novartis Pharma Co. Ltd., Biogen Japan and UCB Japan as well as grants from Zenyaku Kogyo Co. Ltd., Japan Blood Products Organization, Mitsubishi-Tanabe Pharma, CSL Behring Co. Ltd., Dainippon Sumitomo Pharma Co. Ltd., Otsuka Pharmaceutical Co. Ltd. and Daiichi Sankyo Co. Ltd.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.