Abstract
Sarcopenia is common in CKD and associates with morbidity and mortality. A rapid and standardized MRI (Magnetic Resonance Imaging) scan protocol allows an accurate muscle composition analysis by quantification of skeletal muscle volume and muscle fat infiltration (MFI). The combined observation of low muscle volume and high muscle fat infiltration, i.e. adverse muscle composition (AMC), is a prevalent muscle composition phenotype within CKD and associates to poor function, high prevalence of comorbidity, and an increased risk for coronary heart disease (CHD). It has also been shown that AMC is an independent predictor of all-cause mortality in patients with non-alcoholic fatty liver disease and in general population.
In this study we aimed to investigate muscle composition as predictor of all-cause mortality within participants with CKD in the UK Biobank imaging study (UKB).
This is a prospective study including UKB participants with CKD defined as having an eGFR cystatin C < 60 ml/min/1, 73 m2. A control group was created by matching each participant with CKD for sex, age, and BMI to four participants with normal eGFR. Cystatin C was analyzed based on blood samples at time of study enrolment 7-9 years prior to the MRI. Fat-tissue free thigh muscle volume and MFI were quantified using a rapid neck-to-knee water and fat separated MRI protocol and automated image analysis (AMRA® Researcher). For each participant, a personalized muscle volume z-score (sex- and body size-specific) was calculated and combined with MFI to divide the participants into four muscle composition phenotype groups; 1) normal muscle composition, 2) only low muscle volume, 3) only high MFI and 4) AMC, using previously published thresholds based on the whole UKB cohort. The thresholds were the 25th percentile (< -0.68 SD) for muscle volume z-score and the 75th percentile (men >7.69%; women >8.82%) for MFI. The mortality data were obtained through the UKB´s linkage to national death registries.
All-cause mortality was investigated using Kaplan-Meier curves and Cox regression. Models within participants with CKD were crude and subsequently adjusted for sex, age, BMI, low hand grip strength (<16/27 kg for females/males), physical activity, smoking, alcohol, and previous diagnosis of cancer, prevalent CHD and type 2 diabetes, all assessed at the time of imaging.
894 participants with CKD and complete data were included (Table 1).
During a mean follow-up of 4.0 years, 50 out of the 894 participants with CKD (66% male, age 71.5 ± 4.2 years, BMI 29.6 ± 5.5 kg/m2, eGFR 51.9± 8.0 ml/min/1, 73 m2) and 69 out of the 3576 participants in the control group (65.2% male, age 72.8 ± 4.7 years, BMI 29.0 ± 5.2, eGFR 83.1 ± 13.7 ml/min/1, 73 m2) died. The hazard ratio (HR) for mortality within the CKD group was 2.41 (95% CI 1.67-3.48, P<.001) compared with the control group (Fig. 1A).
In the crude model, AMC, only low muscle volume, and only high MFI were significantly associated with all-cause mortality risk in participants with CKD compared with the control group (HR: 6.17; 95% CI: 2.36-16.15, P<.001; HR: 3.43; 95% CI: 1.09-10.81, P = .036 and HR: 2.94, 95% CI: 1.05-8.25, P = .040 respectively).
After adjustment for sex, age and BMI, the association remained significant for AMC (HR: 5.98; 95% CI: 2.22-16.11, P<.001) and only low muscle volume (HR: 3.29;95% CI: 1.03-10.47, P = .044).
When additionally full adjustment for low hand grip strength, lifestyle variables (physical activity, smoking, alcohol consumption) and relevant comorbidities (cancer, CHD and T2D) only AMC remained significantly associated with mortality (HR: 4.34; 95% CI 1.55-12.17, P = .005).
AMC, determined by standardized MRI, was a strong predictor of all-cause mortality in CKD. The study results indicate that CKD patients with poor muscle health, identified as having both low muscle volume z-score and high MFI, have a significantly higher mortality risk. This vulnerable group would potentially benefit from targeted interventions and is also of specific interest when evaluating new treatments for CKD.
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