Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Assessment of catabolic state in infants with the use of urinary titin N-fragment

Abstract

Background

Urinary titin N-fragment levels have been used to assess the catabolic state, and we used this biomarker to evaluate the catabolic state of infants.

Methods

We retrospectively measured urinary titin N-fragment levels of urinary samples. The primary outcome was its changes according to postmenstrual age. The secondary outcomes included differences between gestational age, longitudinal change after birth, influence on growth, and relationship with blood tests.

Results

This study included 219 patients with 414 measurements. Urinary titin N-fragment exponentially declined with postmenstrual age. These values were 12.5 (7.1–19.6), 8.1 (5.1–13.0), 12.8 (6.0–21.3), 26.4 (16.4–52.0), and 81.9 (63.3–106.4) pmol/mg creatinine in full, late, moderate, very, and extremely preterm infants, respectively (p < 0.01). After birth, urinary levels of titin N-fragment exponentially declined, and the maximum level within a week was associated with the time to return to birth weight in preterm infants (ρ = 0.39, p < 0.01). This was correlated with creatine kinase in full-term infants (ρ = 0.58, p < 0.01) and with blood urea nitrogen in preterm infants (ρ = 0.50, p < 0.01).

Conclusions

The catabolic state was increased during the early course of the postmenstrual age and early preterm infants.

Impact

  • Catabolic state in infants, especially in preterm infants, was expected to be increased, but no study has clearly verified this.

  • In this retrospective study of 219 patients with 414 urinary titin measurements, the catabolic state was exponentially elevated during the early postmenstrual age.

  • The use of the urinary titin N-fragment clarified catabolic state was prominently increased in very and extremely preterm infants.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Urinary levels of titin N-fragment during postmenstrual age.
Fig. 2: Urinary levels of titin N-fragment in full-term and preterm infants.
Fig. 3: Longitudinal change in urinary levels of titin N-fragment after birth.
Fig. 4: Relationship between urinary titin N-fragment and the time to return to birth weight.

References

  1. 1.

    Hug, L., Alexander, M., You, D. & Alkema, L. National, regional, and global levels and trends in neonatal mortality between 1990 and 2017, with scenario-based projections to 2030: a systematic analysis. Lancet Glob. Health 7, e710–e720 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Patel, R. M. et al. Causes and timing of death in extremely premature infants from 2000 through 2011. N. Engl. J. Med. 372, 331–340 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Pierrat, V. et al. Neurodevelopmental outcome at 2 years for preterm children born at 22 to 34 weeks’ gestation in France in 2011: EPIPAGE-2 cohort study. BMJ 358, j3448 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Ancel, P.-Y. & Goffinet, F. Group at E-W survival and morbidity of preterm children born at 22 through 34 weeks’ gestation in France in 2011: results of the EPIPAGE-2 cohort study. JAMA Pediatr. 169, 230–238 (2015).

    PubMed  Article  Google Scholar 

  5. 5.

    Marlow, N., Wolke, D., Bracewell, M. A. & Samara, M. Neurologic and developmental disability at six years of age after extremely preterm birth. N. Engl. J. Med. 352, 9–19 (2005).

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Clark, R. H., Thomas, P. & Peabody, J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 111, 986–990 (2003).

    PubMed  Article  Google Scholar 

  7. 7.

    Fuchs, F. et al. Effect of maternal age on the risk of preterm birth: a large cohort study. PLoS ONE 13, e0191002 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  8. 8.

    Vogel, J. P. et al. The global epidemiology of preterm birth. Best Pr. Res. Clin. Obstet. Gynaecol. 52, 3–12 (2018).

    Article  Google Scholar 

  9. 9.

    McCormick, M. C. & Litt, J. S. The outcomes of very preterm infants: is it time to ask different questions? Pediatrics 139, e20161694 (2017).

  10. 10.

    Pencharz, P. B., Masson, M., Desgranges, F. & Papageorgiou, A. Total-body protein turnover in human premature neonates: Effects of birth weight, intra-uterine nutritional status and diet. Clin. Sci. 61, 207–215 (1981).

    CAS  Article  Google Scholar 

  11. 11.

    Ward Platt, M. & Deshpande, S. Metabolic adaptation at birth. Semin. Fetal Neonatal Med. 10, 341–350 (2005).

    PubMed  Article  Google Scholar 

  12. 12.

    de Boo, H. A. & Harding, J. E. Protein metabolism in preterm infants with particular reference to intrauterine growth restriction. Arch. Dis. Child Fetal Neonatal Ed. 92, F315–F319 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Tudehope, D., Vento, M., Bhutta, Z. & Pachi, P. Nutritional requirements and feeding recommendations for small for gestational age infants. J. Pediatr. 162, S81–S89 (2013).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Thureen, P. J. Early aggressive nutrition in the neonate. Pediatr. Rev. 20, e45–e55 (1999).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  15. 15.

    Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatrics 75, 976–986 (1985).

    Google Scholar 

  16. 16.

    Pereira-da-Silva, L., Virella, D. & Fusch, C. Nutritional assessment in preterm infants: a practical approach in the NICU. Nutrients 11, 1999 (2019).

    CAS  PubMed Central  Article  Google Scholar 

  17. 17.

    Maruyama, N. et al. Establishment of a highly sensitive sandwich ELISA for the N-terminal fragment of titin in urine. Sci. Rep. 6, 39375 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Matsuo, M., Awano, H., Maruyama, N. & Nishio, H. Titin fragment in urine: a noninvasive biomarker of muscle degradation. Adv. Clin. Chem. 90, 1–23 (2019).

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Nakanishi, N. et al. Urinary titin N-fragment as a biomarker of muscle atrophy, intensive care unit-acquired weakness, and possible application for post-intensive care syndrome. J. Clin. Med. 10, 614 (2021).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Awano, H. et al. Diagnostic and clinical significance of the titin fragment in urine of Duchenne muscular dystrophy patients. Clin. Chim. Acta 476, 111–116 (2018).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Nakanishi, N. et al. Urinary titin is a novel biomarker for muscle atrophy in nonsurgical critically ill patients: A two-center, prospective observational study. Crit. Care Med. 48, 1327–1333 (2020).

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Ishihara, M. et al. Elevated urinary titin and its associated clinical outcomes after acute stroke. J. Stroke Cerebrovasc. Dis. 30, 1–6 (2020).

    Google Scholar 

  23. 23.

    Whitehead, N. S. et al. Interventions to prevent iatrogenic anemia: a laboratory medicine best practices systematic review. Crit. Care 23, 278 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Matsuo, M., Shirakawa, T., Awano, H. & Nishio, H. Receiver operating curve analyses of urinary titin of healthy 3-y-old children may be a noninvasive screening method for Duchenne muscular dystrophy. Clin. Chim. Acta 486, 110–114 (2018).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Fukushima, S. et al. Prediction of poor neurological development in patients with symptomatic congenital cytomegalovirus diseases after oral valganciclovir treatment. Brain Dev. 41, 743–750 (2019).

    PubMed  Article  Google Scholar 

  26. 26.

    Shono, M. et al. Enhanced angiotensinogen expression in neonates during kidney development. Clin. Exp. Nephrol. 23, 537–543 (2019).

    CAS  PubMed  Article  Google Scholar 

  27. 27.

    Gao, C. et al. Time to regain birth weight predicts neonatal growth velocity: a single-center experience. Clin. Nutr. ESPEN 38, 165–171 (2020).

    PubMed  Article  Google Scholar 

  28. 28.

    Morton, S. U. & Brodsky, D. Fetal physiology and the transition to extrauterine life. Clin. Perinatol. 43, 395–407 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Taylor, A., Fisk, N. M. & Glover, V. Mode of delivery and subsequent stress response. Lancet 355, 120 (2000).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Niklasson, A. et al. Growth in very preterm children: a longitudinal study. Pediatr. Res. 54, 899–905 (2003).

    PubMed  Article  Google Scholar 

  31. 31.

    Cuestas, R. A. Jr. Creatine kinase isoenzymes in high-risk infants. Pediatr. Res. 14, 935–938 (1980).

    PubMed  Article  Google Scholar 

  32. 32.

    Bertini, G., Elia, S. & Dani, C. Using ultrasound to examine muscle mass in preterm infants at term-equivalent age. Eur. J. Pediatr. 180, 461–468 (2021).

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Yamaguchi, S., Suzuki, K., Kanda, K. & Okada, J. N-terminal fragments of titin in urine as a biomarker for eccentric exercise-induced muscle damage. J. Phys. Fit. Sports Med. 9, 21–29 (2020).

    Article  Google Scholar 

  34. 34.

    Nakano, H. et al. Urine titin N-fragment as a biomarker of muscle injury for critical illness myopathy. Am. J. Respir. Crit. Care Med. 203, 515–518 (2021).

    PubMed  Article  Google Scholar 

  35. 35.

    Moyer-Mileur, L. J. Anthropometric and laboratory assessment of very low birth weight infants: The most helpful measurements and why. Semin. Perinatol. 31, 96–103 (2007).

    PubMed  Article  Google Scholar 

  36. 36.

    Mathes, M. et al. Effect of increased enteral protein intake on plasma and urinary urea concentrations in preterm infants born at <32 weeks gestation and <1500 g birth weight enrolled in a randomized controlled trial—a secondary analysis. BMC Pediatr. 18, 154 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  37. 37.

    Ridout, E., Melara, D., Rottinghaus, S. & Thureen, P. J. Blood urea nitrogen concentration as a marker of amino-acid intolerance in neonates with birthweight less than 1250 g. J. Perinatol. 25, 130–133 (2005).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  38. 38.

    Roggero, P. et al. Blood urea nitrogen concentrations in low-birth-weight preterm infants during parenteral and enteral nutrition. J. Pediatr. Gastroenterol. Nutr. 51, 213–215 (2010).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  39. 39.

    Elustondo, P. A. et al. Physical and functional association of lactate dehydrogenase (LDH) with skeletal muscle mitochondria. J. Biol. Chem. 288, 25309–25317 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Baxmann, A. C. et al. Influence of muscle mass and physical activity on serum and urinary creatinine and serum cystatin C. Clin. J. Am. Soc. Nephrol. 3, 348–354 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Gluckman, P. D. & Hanson, M. A. Living with the past: evolution, development, and patterns of disease. Science 305, 1733–1736 (2004).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Stephens, B. E. et al. First-week protein and energy intakes are associated with 18-month developmental outcomes in extremely low birth weight infants. Pediatrics 123, 1337–1343 (2009).

    PubMed  Article  Google Scholar 

  43. 43.

    Thureen, P. J., Melara, D., Fennessey, P. V. & Hay, W. W. Jr. Effect of low versus high intravenous amino acid intake on very low birth weight infants in the early neonatal period. Pediatr. Res 53, 24–32 (2003).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    Vlaardingerbroek, H. et al. Safety and efficacy of early parenteral lipid and high-dose amino acid administration to very low birth weight infants. J. Pediatr. 163, 638–644 (2013). e631-635.

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    Ramel, S. E., Brown, L. D. & Georgieff, M. K. The impact of neonatal illness on nutritional requirements-one size does not fit all. Curr. Pediatr. Rep. 2, 248–254 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Lucas, A. et al. Randomized trial of nutrient-enriched formula versus standard formula for postdischarge preterm infants. Pediatrics 108, 703–711 (2001).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Bhatia, J., Mena, P., Denne, S. & García, C. Evaluation of adequacy of protein and energy. J. Pediatr. 162, S31–S36 (2013).

    PubMed  Article  Google Scholar 

  48. 48.

    Power, V. A. et al. Nutrition, growth, brain volume, and neurodevelopment in very preterm children. J. Pediatr. 215, 50–55 (2019).

    PubMed  Article  Google Scholar 

Download references

Acknowledgements

We would like to thank Yoshihiro Okayama (Clinical Research Center for Development Therapeutics, Tokushima University Hospital) for his support in the statistical aspect. We would also like to thank those who supported the muscle atrophy zero-project, which aims to prevent muscle atrophy in patients.

Author information

Affiliations

Authors

Contributions

S.F. and N.N. equally contributed to conception and design, acquisition of data, analysis, interpretation of data, and drafting of the manuscript as first authors. K.F. and K.S. equally contributed to all aspects of this study as second authors. T.S., K.O., K.H., and R.T. performed laboratory testing and analysis of data. M.U., R.N., and H.A. were involved in the acquisition of the data and drafting of the manuscript. J.O., H.S., and K.I. supervised all aspects of this study. M.M. supervised and contributed equally to all aspects of this study including drafting the article and revising it critically for important intellectual content as a corresponding author. All authors read and approved the final version to be published.

Corresponding author

Correspondence to Nobuto Nakanishi.

Ethics declarations

Funding

Titin N-Fragment Assay Kit was partly provided from Immuno-Biological Laboratories Co. Ltd. (Gunma, Japan). This study was partly supported by a crowdfunding project entitled the Muscle Atrophy Zero Project, using the platform “Otsucle” https://otsucle.jp/cf/project/2553.html. This study was partially supported by JSPS KAKENHI Grant Number JP20K17899.

Competing interests

M.M. discloses being employed by Kobe Gakuin University, which received funding from KNC Laboratories Inc., Kobe, Japan. M.M. further discloses being a scientific adviser for the Daiichi-Sankyo Co., Tokyo, Japan, and JCR Pharma Co., Ashiya, Japan. The remaining authors declare no competing interests.

Consent statement

Ethics approval was obtained from the Institutional Review Board of Kobe University (#B200211) and Tokushima University (#1425). Opt-out and opt-in informed consent at the Kobe University and Tokushima University, respectively, was obtained for this study. Written informed consent was obtained from all parents for the use of their personal medical data in research.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Fukushima, S., Nakanishi, N., Fujioka, K. et al. Assessment of catabolic state in infants with the use of urinary titin N-fragment. Pediatr Res (2021). https://doi.org/10.1038/s41390-021-01658-5

Download citation

Search

Quick links