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.
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.
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).
The catabolic state was increased during the early course of the postmenstrual age and early preterm infants.
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.
Subscribe to Journal
Get full journal access for 1 year
only $9.15 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
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).
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).
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).
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).
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).
Clark, R. H., Thomas, P. & Peabody, J. Extrauterine growth restriction remains a serious problem in prematurely born neonates. Pediatrics 111, 986–990 (2003).
Fuchs, F. et al. Effect of maternal age on the risk of preterm birth: a large cohort study. PLoS ONE 13, e0191002 (2018).
Vogel, J. P. et al. The global epidemiology of preterm birth. Best Pr. Res. Clin. Obstet. Gynaecol. 52, 3–12 (2018).
McCormick, M. C. & Litt, J. S. The outcomes of very preterm infants: is it time to ask different questions? Pediatrics 139, e20161694 (2017).
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).
Ward Platt, M. & Deshpande, S. Metabolic adaptation at birth. Semin. Fetal Neonatal Med. 10, 341–350 (2005).
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).
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).
Thureen, P. J. Early aggressive nutrition in the neonate. Pediatr. Rev. 20, e45–e55 (1999).
Committee on Nutrition. Nutritional needs of low-birth-weight infants. Pediatrics 75, 976–986 (1985).
Pereira-da-Silva, L., Virella, D. & Fusch, C. Nutritional assessment in preterm infants: a practical approach in the NICU. Nutrients 11, 1999 (2019).
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).
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).
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).
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).
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).
Ishihara, M. et al. Elevated urinary titin and its associated clinical outcomes after acute stroke. J. Stroke Cerebrovasc. Dis. 30, 1–6 (2020).
Whitehead, N. S. et al. Interventions to prevent iatrogenic anemia: a laboratory medicine best practices systematic review. Crit. Care 23, 278 (2019).
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).
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).
Shono, M. et al. Enhanced angiotensinogen expression in neonates during kidney development. Clin. Exp. Nephrol. 23, 537–543 (2019).
Gao, C. et al. Time to regain birth weight predicts neonatal growth velocity: a single-center experience. Clin. Nutr. ESPEN 38, 165–171 (2020).
Morton, S. U. & Brodsky, D. Fetal physiology and the transition to extrauterine life. Clin. Perinatol. 43, 395–407 (2016).
Taylor, A., Fisk, N. M. & Glover, V. Mode of delivery and subsequent stress response. Lancet 355, 120 (2000).
Niklasson, A. et al. Growth in very preterm children: a longitudinal study. Pediatr. Res. 54, 899–905 (2003).
Cuestas, R. A. Jr. Creatine kinase isoenzymes in high-risk infants. Pediatr. Res. 14, 935–938 (1980).
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).
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).
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).
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).
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).
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).
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).
Elustondo, P. A. et al. Physical and functional association of lactate dehydrogenase (LDH) with skeletal muscle mitochondria. J. Biol. Chem. 288, 25309–25317 (2013).
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).
Gluckman, P. D. & Hanson, M. A. Living with the past: evolution, development, and patterns of disease. Science 305, 1733–1736 (2004).
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).
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).
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.
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).
Lucas, A. et al. Randomized trial of nutrient-enriched formula versus standard formula for postdischarge preterm infants. Pediatrics 108, 703–711 (2001).
Bhatia, J., Mena, P., Denne, S. & García, C. Evaluation of adequacy of protein and energy. J. Pediatr. 162, S31–S36 (2013).
Power, V. A. et al. Nutrition, growth, brain volume, and neurodevelopment in very preterm children. J. Pediatr. 215, 50–55 (2019).
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.
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.
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.
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.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
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