The primary findings of this study were as follows: (1) the median urinary N-titin/Cr was 7.0 pmol/mg/dL in patients with ILD; (2) significant negative correlations were observed between urinary N-titin/Cr and changes in the PMCSA and ESMCSA. This is the first report investigating urinary N-titin/Cr in patients with ILD.

The median urinary N-titin/Cr was 7.0 pmol/mg/dL and 2.0 pmol/mg/dL in patients with ILD and healthy adult volunteers25. Titin, a giant sarcomere protein, is cleaved by calpain-3 in damaged muscles, and the resulting N-terminal fragments are excreted into the urine via glomerular filtration. Maruyama et al.25 established a highly sensitive, simple, and non-invasive sandwich ELISA system for evaluating muscle injury. Thus, research on muscle damage using the ELISA system has been active in recent years.

Although the elevation of urinary N-titin/Cr did not reach at a higher level as acute inflammatory condition such as nonsurgical critically ill patients on 7 day of intensive care unit admission (49.3 pmol/mg/dL)16 and patients who underwent cardiac surgery on the day of operation (43.3 pmol/mg/dL)26, that was at a similar level as chronic diseases such nonalcoholic fatty liver disease (NAFLD) and dilated cardiomyopathy18. They have an important clinical implication on the elevation of urinary N-titin/Cr: the urinary N-titin/Cr in patients with NAFLD reflected skeletal muscle deterioration and functional decline, and was associated with hepatic pathological conditions. Urinary N-titin/Cr in patients with dilated cardiomyopathy acted as a predictor of cardiac and all-cause mortality27.

Urinary N-titin/Cr in patients with ILD was not associated with their baseline information (including KL-6 level), disease severity (assessed using the ILD-GAP score), lung function, PMCSA, or ESMCSA during evaluation (Table 2). This may be explained by the failure of urinary N-titin/Cr, a marker of sarcomere damage, to directly reflect muscle mass rather muscle atrophy28.

Interestingly, the reduction in the PMCSA after 1 year and ESMCSA after 6 months and 1 year were significantly associated with urinary N-titin/Cr. The ESMCSA was reportedly correlated with the physiological parameters, symptoms, and disease prognosis29 in patients with COPD, besides being an independent mortality risk factor in elderly patients with pneumonia30. In addition, the ESMCSA was a poor prognostic factor in patients with ILD9,11,12. Particularly, Suzuki et al. reported that low ESMCSA was an independent prognostic factor associated with worse survival rates even in patients with IPF receiving antifibrotic therapy. In addition, it is essential to prevent sarcopenia for IPF management9. Furthermore, the PMCSA was correlated with mortality in ever smokers31 and the total energy expenditure and physical activity level in patients with COPD32. In patients with ILD, lower PMCSA was associated with the skeletal mass index, quadriceps isometric maximal voluntary contraction, and the indicators of ILD severity8,14,33, besides being a poor prognostic factor14.

Recently, the loss of skeletal muscle mass represented by sarcopenia has been considered important for evaluating the predictors of mortality in patients with various diseases, including ILD. However, it is difficult to predict the muscle mass in patients with ILD in the future. Considering significant negative correlations between urinary N-titin/Cr and muscle mass, our findings suggested that urinary N-titin/Cr in chronic patients with ILD could predict the future reduction in the PMCSA and ESMCSA associated with the skeletal muscle mass, strength, and prognosis in patients with ILD. In our study, the amount of reduction in the PMCSA and ESMCSA was not sufficient to predict mortality. In addition, because the number of patients who died during the investigation period was small, multiple comparisons would reduce statistical power to detect significance and further consideration was not possible.

Moreover, our cut-off values of urinary N-titin/Cr (5.2 pmol/mg/dL and 10.4 pmol/mg/dL) based on the ROC curve analysis could deduce the greater reduction of the PMCSA and ESMCSA compared with the median value after 1 year. Therefore, upon anticipating the reduction in muscle mass by simple measurements of urinary N-titin/Cr levels, we could implement an aggressive intervention, such as pulmonary rehabilitation program and nutritional support, in patients with ILD. This in turn may improve the disease prognosis.

This study had several limitations. First, the sample size was small, and we did not consider missing values in this study. Second, the study was based on a retrospective design. Third, it was conducted at a single institute. Lastly, most of our patients were mild cases (ILD-GAP score; 1 [0–2]). Therefore, our results were subject to selection bias and should be interpreted with caution. Larger multicenter studies are required to consider the detailed efficacy of urinary N-titin/Cr as a biomarker reflecting muscle damages. Moreover, we did not evaluate all patients for their physical function and performance (e.g., handgrip and quadriceps force and 6-min walking test); therefore, we could not investigate the relationship between physical performance and urinary N-titin/Cr. Despite the limitations, the strength of our study was that it clarified the usefulness of urinary N-titin/Cr in patients with ILD. Our findings will facilitate the development of novel prevention strategies for patients with ILD, thereby reducing the long-term effects of physical dysfunction and health care costs.

In conclusion, urinary N-titin/Cr of patients with ILD was high value similar other diseases, and urinary N-titin/Cr may be predictive of the skeletal muscle loss in the future. Particularly, clinicians should adopt earlier countermeasures, such as pulmonary rehabilitation, to maintain the muscle mass in patients with ILD and abnormalities in urinary N-titin/Cr level. This necessitates verifying the effectiveness of urinary N-titin/Cr in internal and external validity.

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