Usefulness of computed tomography-measured psoas muscle thickness per height for predicting mortality in patients undergoing hemodialysis

Computed tomography (CT)-measured psoas muscle thickness standardized for height (PMTH) has emerged as a promising predictor of mortality. The study aimed to investigate whether PMTH could accurately predict mortality in patients undergoing hemodialysis. We examined 207 patients (mean age: 63.1 years; men: 66.2%) undergoing hemodialysis for more than 6 months in hospital affiliated clinic. PMTH was calculated at the L3 vertebra level using CT. Patients were divided according to the PMTH cut-off points: 8.44 mm/m in women and 8.85 mm/m in men; thereafter, they were combined into low and high PMTH groups. PMTH was independently correlated with the simplified creatinine index (β = 0.213, P = 0.021) and geriatric nutritional risk index (β = 0.295, P < 0.0001) in multivariate regression analysis. During a median follow-up of 3.7 (1.8–6.4) years, 76 patients died, including 41 from cardiovascular causes. In the multivariate Cox regression analysis, low PMTH (adjusted hazard ratio, 2.48; 95% confidence interval, 1.36–4.70) was independently associated with an increased risk of all-cause mortality. The addition of binary PMTH groups to the baseline risk model tended to improve net reclassification improvement (0.460, p = 0.060). In conclusion, PMTH may be an indicator of protein energy wasting and a useful tool for predicting mortality in patients undergoing hemodialysis.

. Baseline characteristics of the study participants. PMTH psoas muscle thickness per height, CVD cardiovascular disease, iPTH intact parathyroid hormone, CRP C-reactive protein, SCI simplified creatinine index, GNRI geriatric nutritional risk index, PMT psoas muscle thickness.  www.nature.com/scientificreports/ Associations between PMTH and baseline variables. In the univariate linear regression analysis, the PMTH was significantly and negatively associated with age and log CRP. Conversely, the PMTH was significantly and positively associated with sex (male), GNRI, and SCI. The correlation coefficients among all explanatory variables were less than 0.66. The VIFs were less than 2.56. Multivariate regression analysis revealed that PMTH was independently associated with sex (male; β = 0.202, P = 0.0025), SCI (β = 0.213, P = 0.021), and GNRI (β = 0.295, P < 0.0001) (

Discussion
The main findings of the present study were that CT-measured PMTH was independently associated with SCI and GNRI, which were markers of protein energy wasting, and that a low PMTH was independently associated with an increased risk of all-cause and cardiovascular mortality in patients undergoing hemodialysis. Therefore, PMTH may be an indicator of protein energy wasting and, consequently, a simple and useful tool for accurately predicting mortality in this population. In patients undergoing hemodialysis, muscle wasting may be partially explained by protein energy wasting 2 , a malnourished state of negative protein balance, characterized by the loss of body protein (muscle) and fuel reserves (fat) due to catabolic inflammation, which is prevalent and associated with an increased risk of mortality in this population 3,23 . We previously reported that high muscle mass and/or fat mass measured by bioelectrical impedance analysis are significantly associated with a decreased risk of all-cause mortality 28 . As a marker of protein energy wasting, GNRI, a simple objective nutritional assessment index that is calculated using only the serum albumin and actual/ideal body weight ratio, is widely used for patients undergoing hemodialysis [24][25][26][27][28] . The SCI, determined by age, sex, single pool Kt/V for urea, and pre-dialysis serum creatinine level, is used as a surrogate marker of muscle mass or as a valuable tool for observation of nutritional status in hemodialysis patients [29][30][31] . Tsai et al. 32 recently reported that SCI was an independent predictor of the presence of protein energy wasting. Moreover, Yamada et al. 33 demonstrated that GNRI and SCI equally predicted all-cause mortality in hemodialysis patients. In the present study, CT-measured PMTH was independently and positively associated with both SCI and GNRI, suggesting that PMTH may be an indicator of protein energy wasting.
Recently, CT-measured PMTH has emerged as a marker of muscle wasting as well as a prognostic indicator of mortality in patients with liver disease [15][16][17][18][19] . Compared with conventional CT-based sarcopenic indices measured at the L3 level, this novel method has advantages such as no requirement of specific software or technical skills. However, it also has some issues that need to be addressed before it is standardized for use. Durand et al. 15 and Huguet et al. 16 reported that CT-measured PMTH at the umbilicus level predicts mortality in patients with liver cirrhosis. Considering sex-related differences in muscle distribution and structure, Gu et al. 17 and Praktiknjo et al. 18 proposed sex-specific cut-off points for PMTH at the umbilicus level. They demonstrated that the use of Table 3. Cox proportional hazards analysis of the psoas muscle thickness per height for prediction of allcause and cardiovascular mortality. HR hazard ratio, CI confidence interval, PMTH psoas muscle thickness per height. a Adjusted for sex, age, history of cardiovascular disease, simplified creatinine index, geriatric nutritional risk index, and log C-reactive protein concentration, which were found to be significant in the univariate analysis. www.nature.com/scientificreports/ sex-specific cut-off points improves the prognostic value of PMTH in patients with cirrhosis. However, the level of the umbilicus is heterogeneously located from L3 to L5. Thus, Paternostro et al. 19 recently proposed a sexspecific standardized measurement of PMTH at the L3 level, where conventional CT-based sarcopenic indices are measured, and showed that PMTH is superior to conventional CT-measured sarcopenic indices in predicting mortality of patients with cirrhosis. CT may be the gold standard for the assessment of muscle mass 4, 11 even in patients undergoing hemodialysis because CT is not affected by the patient's hydration status. Several studies in Japan evaluated the association between CT-measured sarcopenic indices and prognosis in patients undergoing hemodialysis. Fukasawa et al. 20 reported that the dry weight-adjusted thigh muscle area, but not the abdominal muscle area, is a predictor of mortality. Kurumisawa et al. 21 demonstrated that the CT-measured psoas muscle index, assessed before cardiovascular surgery, is a predictor of long-term survival after cardiac surgery. Similarly, Takata et al. 22 reported that the CT-measured psoas muscle index is correlated with the bioelectrical impedance analysis-measured skeletal muscle mass index, where a low psoas muscle index is associated with an increased risk of mortality. Moreover, they suggested that the psoas muscle index assessed using CT can be an alternative to bioelectrical impedance analysis in patients undergoing hemodialysis. However, the relationship between CT-measured PMTH, a new CT-measured sarcopenic index, and mortality remains unknown. To our knowledge, our study is the first to analyze the relationship between CT-measured PMTH and mortality in patients undergoing hemodialysis. In the present study, a lower PMTH was independently associated with an increased risk of all-cause and cardiovascular mortality, even after adjusting for SCI and GNRI. In addition, the addition of PMTH on predicting model with established risk factors tended to improve the NRI and IDI, however, did not reach at statistical significance, probably due to small number of patients. These should be re-evaluated in larger population.
Our study has several limitations. First, the present retrospective, single-center study included a relatively small number of patients undergoing hemodialysis. Second, all enrolled patients were Japanese, who reportedly have a better prognosis that hemodialysis patients in the United States of America and Europe 34 . Thus, the results might not be generalizable to patients from other countries undergoing hemodialysis. Third, only PMTH data measured at enrolment were used for the analysis; therefore, any changes in these values during the longterm follow-up period were not considered. Further prospective, large-scale, multicenter studies are needed to validate our results.
In conclusion, CT-measured PMTH at the L3 level was independently associated with SCI and GNRI, and a low PMTH was independently associated with an increased risk of all-cause and cardiovascular mortality in patients undergoing hemodialysis. Therefore, PMTH may be an indicator of protein energy wasting and could be considered a simple and useful tool for accurately predicting mortality in this population.

Methods
Study participants. A total of 231 patients undergoing hemodialysis for longer than 6 months and who had undergone abdominal CT to detect early-stage renal cell carcinoma between January 2008 and December 2018 at the outpatient clinic of Matsunami General Hospital were screened. Twenty-four patients with a history of cancer were excluded; thus, 207 patients were ultimately enrolled in the present study. In our hospital, abdominal CT was performed as a screening test to detect early-stage renal cell carcinoma within 1 year after either the initiation of hemodialysis or transfer to our hospital. For this retrospective study, the requirement for informed consent was waived by the ethics committee of Matsunami General Hospital because patient data were anonymized. This study adhered to the principles of the Declaration of Helsinki, and the study protocol was approved by the ethics committee of Matsunami General Hospital (No. 484). Data collection. The following data were collected from the medical charts of the study participants: age; sex; underlying kidney disease; hemodialysis vintage; history of alcohol use, smoking, hypertension, diabetes, and CVD; dry weight; and height. In this study, CVD included angina pectoris, myocardial infarction, heart failure, stroke, and peripheral artery disease. Hypertension was defined as the use of antihypertensive drugs or a systolic blood pressure ≥ 140 mm Hg and/or a diastolic blood pressure ≥ 90 mm Hg prior to hemodialysis. Diabetes was defined as the use of glucose-lowering medication or a history of diabetes. Blood samples were obtained prior to the initiation of a hemodialysis session with the patient in the supine position, and the laboratory data that were extracted for data analysis were from the month when the CT was performed.
The GNRI was calculated from serum albumin level, dry weight, and height as follows: GNRI = 14.89 × serum albumin (g/dL) + 41.7 × (dry weight/ideal body weight) 25,35 . Ideal body weight (kg) was calculated as 22 × [height (m)] 2 . When dry weight was equal to or exceeded the ideal body weight, the ratio of dry weight to ideal body weight (dry weight/ideal body weight) was set to 1. The SCI was calculated from sex, age, single pool Kt/V for urea, and serum creatinine level as follows: SCI (mg/kg/day) = 16.21 + 1.12 × [0 for woman; 1 for man] -0.06 × age (years) -0.08 × single pool Kt/V for urea + 0.009 × serum creatinine (μmol/L) 29 .

Measurement of PMTH.
The PMT was determined using abdominal CT that was performed after a hemodialysis session using a wide-bore, 16-slice multidetector CT scanner (LightSpeed RT16; GE Healthcare, Waukesha, WI, USA), yielding 5-mm-thick slices. A cross-sectional CT image at the level of L3 was selected, and the transverse thickness of the right psoas muscle was measured using XTREK View (J-Mac System Inc., Sapporo, Japan). The transverse PMT was defined as the diameter of the psoas muscle perpendicular to the axial diameter, as previously reported [15][16][17][18][19] . The PMT was standardized for height to obtain the PMTH: PMTH (mm/m) = PMT (mm)/height (m). www.nature.com/scientificreports/ Follow-up study. The primary endpoint was all-cause mortality, and the secondary endpoint was cardiovascular mortality. Patients were followed up until December 2019. In this study, follow-up period was defined as the interval from the date when CT was performed to the date of death or the date when transferred to another hemodialysis unit. Patients who were alive were censored in December 2019.

Statistical analysis.
Normally distributed variables were expressed as means ± standard deviations, while non-normally distributed variables were expressed as medians and interquartile ranges. The Shapiro-Wilk test and visual inspection were used to examine whether a variable is normally distributed. ROC analysis was performed to assess the sensitivity and specificity of PMTH for predicting 10-year all-cause mortality in each sex. The optimal sex-specific cut-off values of PMTH were determined at the point to maximize Youden's J statistic. Thereafter, patients were combined into low and high PMTH groups. The differences between the low and high PMTH groups were compared using Student's t-test or the Wilcoxon rank sum test for continuous variables and the chi-squared test for categorical variables. Intra-and interobserver reproducibility for the measurement of PMT using CT were evaluated using the ICC and 95% CIs. Univariate linear regression analysis was performed to examine the baseline factors associated with PMTH. Subsequently, multivariate regression analysis was performed using the factors found to be significant (P < 0.05) in the univariate analysis. As assumptions for multivariate linear regression analysis, continuous variables which were non-normally distributed were log-transformed. To confirm the multi-collinearity, correlation coefficients were calculated among all explanatory variables. Variance Inflation Factors (VIFs) were also calculated. The Kaplan-Meier method was used to estimate survival, and the difference of the survival was compared using the log-rank test. HRs and 95% CIs for all-cause and cardiovascular mortality were examined using Cox proportional hazard regression analysis. Since the distribution of the PMTH values differed according to sex, interaction between PMTH and sex was examined, and sex was included in the multivariate analysis.
To determine whether the prediction of all-cause and cardiovascular mortality improved after the addition of PMTH to the baseline model with sex and the covariates that were found to be significant in the univariate analysis, Harrell's C-index for Cox regression model 36,37 , time dependent net reclassification improvement (NRI) 38 and time dependent integrated discrimination improvement (IDI) 39 were calculated with likelihoodratio tests using R version 4.04. The NRI is a relative indicator of the number of patients for whom the predicted probability of mortality improves, whereas the IDI represents the average improvement in predicted probabilities for mortality after the addition of variables to the baseline model. All statistical analyses were performed using SPSS version 21 (IBM Corp., Armonk, NY, USA) and R version 4.04. Statistical significance was set at P < 0.05.

Ethics declarations.
This study adhered to the principles of the Declaration of Helsinki, and the study protocol was approved by the ethics committee of Matsunami General Hospital (No. 484). The requirement for informed consent was waived because patient data were anonymized.

Data availability
The dataset analyzed in the present study is available from corresponding author on reasonable request.