Association of endothelial dysfunction with sarcopenia and muscle function in a relatively young cohort of kidney transplant recipients

Introduction

Sarcopenia, characterized by a progressive decline of skeletal muscle mass, strength, and physical performance, is highly prevalent in patients undergoing dialysis, which leads to poor clinical outcomes (Domanski & Ciechanowski, 2012; Fahal, 2014; Moorthi & Avin, 2017). While kidney transplantation (KT) serves as the optimal treatment for end-stage renal disease, which improves the quality of life and lowers the mortality rate, the prevalence of sarcopenia remains higher than the general population (Limirio et al., 2019; Kosoku et al., 2020). Chronic inflammation, reduced energy and protein intake, nutrient loss, oxidative stress, insulin resistance, and pre-existing comorbidities are well-established risk factors associated with sarcopenia (Fahal, 2014; Stenvinkel et al., 2016). Beyond these factors, vascular dysfunction is postulated to play a crucial role in the pathogenesis of sarcopenia in the rationale of high vascularization of skeletal muscle (Larsson et al., 2019).

As a key regulator of vascular homeostasis, endothelial function may be implicated in the skeletal muscle health. In chronic heart failure patients, impaired endothelial function was more frequently observed in those with sarcopenia (Dos Santos et al., 2017). In community-dwelling older women, there was a significant relationship between endothelial function and skeletal muscle strength (Yoo et al., 2018). While abnormality in endothelial function is highly prevalent in KT recipients (Yildirim et al., 2015), research over the past decade has mainly focused its role on kidney graft survival and cardiovascular outcomes ( Shoskes & Halloran, 1996; Abedini et al., 2010; Frenay et al., 2015); there are no previous studies addressing the association of endothelial dysfunction and sarcopenia in KT recipients.

As a hallmark of endothelial dysfunction, impaired endothelial-dependent dilatation could be assessed by digital thermal monitoring (DTM), a reliable noninvasive method to measure vascular reactivity index (VRI). Poor VRI is well-documented to be correlated with atherosclerosis and predict cardiovascular risks (Naghavi et al., 2016). Thus, the objective of the present study was to explore, in KT recipients, the association of VRI with sarcopenia and its individual components.

Materials & Methods

Results

A total of 95 patients were enrolled in the study, which consisted of 46 males (48.4%) and 49 females (51.6%). The mean age of the patients was 45.2 ± 10.9 years, and the median time from transplantation was 72.0 months (interquartile range 27.0–111.0). The prevalences of DM, HTN, hyperlipidemia, and CV disease were 45.3%, 38.9%, 41.1%, and 17.9%, respectively. Among them, 48 (50.5%), 34 (35.8%), and 13 (13.7%) of them were classified as having good, intermediate, and poor vascular reactivity, respectively.

The distribution of low SMI, low HGS, slow GS, and sarcopenia overall and by different VRI categories are depicted in Fig. 1. Overall, the prevalence of low SMI, low HGS, and slow GS was 33.7%, 22.1%, and 36.8% in our KT recipients. Sarcopenia was identified in 11.6% of all patients. Notably, among the three VRI groups, the prevalence of low SMI, low HGS, slow GS, and sarcopenia were all higher in patients with VRI < 1.0.

The baseline characteristics of all patients, with and without sarcopenia, are showed in Table 1. Patients with sarcopenia were lower in BMI (p = 0.001) and VRI (p = 0.041), and have a higher proportion of low muscle mass (p < 0.001), low HGS (p < 0.001), and slow GS (p = 0.001). There were no differences between patients with and without sarcopenia in terms of age, gender, time from transplantation, smoking status, blood pressure, laboratory data, the presence of comorbidities, and the use of medications.

The clinical characteristics of the 95 KT recipients with good, intermediate, or poor vascular reactivity are presented in Table 2. Patients with poor vascular reactivity have a higher proportion of sarcopenia (p = 0.005), low HGS (p = 0.006), and slow GS (p = 0.029). There was no significant difference in age, gender, time from transplantation, smoking status, blood pressure, laboratory data among the three groups. There were also no differences in the distribution of comorbidities or the use of medications.

Table 3 demonstrated the univariate and multivariate logistic regression of sarcopenia among KT recipients. In addition to BMI, patients in the poor VRI group were significantly associated with sarcopenia (odds ratio, OR = 6.88; 95% confidence interval CI [1.51–31.29]; p = 0.013), comparing to those with good VRI. This association remained unchanged after adjustment (OR = 6.17; 95% CI [1.06–36.04]; p = 0.043). However, while treating VRI as a continuous variable, the association between VRI and sarcopenia didn’t achieve significance after adjustment (OR = 0.46; 95% CI [0.20–1.04]; p = 0.062).

Table 4 depicted the associations of VRI with low SMI, HGS, and slow GS individually. After full adjustment, VRI entered as a continuous variable independently predicted slow GS significantly (OR = 0.41; 95% CI [0.21–0.79]; p = 0.007), but not low HGS (OR = 0.59; 95% CI [0.31–1.16]; p = 0.125) and SMI (OR = 1.15; 95% CI [0.53–2.49]; p = 0.718). Similar results were achieved when VRI was entered as a categorical variable.

Discussion

The primary findings of the present study are that lower BMI and poor VRI were two independent factors associated with sarcopenia in our KT recipients. Furthermore, among the three components of sarcopenia, VRI appeared to predict GS, but no SMI and HGS.

Few previous studies investigated the link between endothelial dysfunction and sarcopenia and its individual components. In chronic heart failure patients, those with sarcopenia had a lower baseline and peak reactive hyperemia blood flow in the forearm and leg than those without sarcopenia. This reactive hyperemia was closely associated with physical performance, included peak VO2 and 6-min walk distance (Dos Santos et al., 2017). In community-dwelling older women, endothelial dysfunction independently predicted handgrip strength weakness (Yoo et al., 2018). Elevated serum levels of asymmetric dimethylarginine, a surrogate biomarker of endothelial dysfunction, were not only associated with lower muscle strengths and slower GS among elderly individuals (Obayashi et al., 2016) but also with reduced physical performance in the 10-repetition sit-to-stand test in prevalent hemodialysis patients (Pajek et al., 2018). In accordance with aforementioned findings, our study, for the first time, showed a significant association between endothelial dysfunction and sarcopenia in KT recipients.

Skeletal muscle mass, HGS, and GS, the three components of sarcopenia, may have different clinical relevance. Among our KT recipients, we interestingly found that VRI was more closely related to GS than HGS and SMI. This finding indicated that endothelial dysfunction may have more adverse impacts on physical performance than on muscle mass and strength. Physiologically, the performance of gait speed test is more dependent upon enhanced local blood flow, compared to the production of maximal handgrip strength. Consistent with our finding, in elderly and patients with pre-dialysis chronic kidney disease, endothelial dysfunction is associated with frailty, a clinical syndrome characterized by a decline in physiological reserve and poor physical performance (Alonso-Bouzón et al., 2014; Mansur et al., 2015).

Several possible mechanisms explained the crosslink between endothelial dysfunction and sarcopenia in KT recipients. First, skeletal muscle microcirculation plays a vital role in skeletal muscle health (Hendrickse & Degens, 2019). Endothelial dysfunction was shown to impair microcirculation of skeletal muscle and downregulate vascular endothelial growth factor expression, which compromises angiogenesis and hampers muscle regeneration (Latroche et al., 2015). In vitro study, treatment of asymmetric dimethylarginine, an endothelial inhibitor of nitric oxide synthesis, results in increased protein degradation in cultured C2C12 myotubes (Zhou et al., 2009). Second, impaired endothelial function in skeletal muscle may reduce the delivery of dietary amino acids to skeletal muscle fibers and impair skeletal muscle protein synthesis (Moro et al., 2016). Third, emerging evidence showed myokines, which are hundreds of cytokines and proteins secreted by skeletal muscle in response to muscle contraction, exert autocrine, paracrine, and endocrine effects on various systems, including the vascular system (Severinsen & Pedersen, 2020). For example, follistatin-related protein one, a muscle-secreted glycoprotein, has been shown to regulate endothelial cell function and blood vessel growth in skeletal muscle through a nitric-oxide synthase-dependent mechanism (Ouchi et al., 2008). Fourth, endothelial dysfunction compromises cardiovascular health, which may manifest as muscle weakness and poor physical performance. Finally, endothelial dysfunction and sarcopenia shared some common pathogenic mechanisms, such as inflammation, insulin resistance, and oxidative stress, which could explain the close link to each other (Fahal, 2014; Goligorsky, 2015).

Apart from endothelial dysfunction, BMI was another relevant factor strongly associated with sarcopenia in our KT recipients. Consistent with our findings, Kosoku et al. showed that BMI is a reliable nutritional marker for predicting sarcopenia in KT recipients, which has a good discrimination performance (Kosoku et al., 2020).

Surprisingly, aging is recognized as an irrefutable predictor for sarcopenia in the geriatric population (Yamada et al., 2013; Han et al., 2016), but not in our study. This discrepancy may be explained by the relatively young age of our enrolled participants.

This is the first study to report the association between endothelial dysfunction and sarcopenia in KT recipients. However, several significant limitations need to be considered. First, the total sample size was relatively small, and a small proportion was categorized as having sarcopenia and poor VRI, which could affect the precision of estimation. Second, we directly measured vascular reactivity but didn’t measure some biomarkers of endothelium dysfunction, such as asymmetric dimethylarginine and Soluble Vascular Cell Adhesion Molecule-1. Third, a bioimpedance device was used for the measurement of skeletal muscle mass. Computed tomography and magnetic resonance imaging, the gold standard for the assessment of skeletal muscle mass, were not used. Fourth, inflammatory markers, such as C-reactive protein and interleukin-6, were not available in this study. Fifth, the causal relationships between endothelial function and sarcopenia couldn’t be established by the cross-sectional design. Finally, the participants in this study were relatively young, and our results may not be generalizable to elderly KT recipients.

Conclusions

Our study showed a significant association between endothelial dysfunction and sarcopenia in KT recipients, which implicated that endothelial dysfunction may be involved in the pathogenesis of sarcopenia. Furthermore, endothelial dysfunction is more closely related to physical performance than muscle mass and strength. Further longitudinal studies investigating the changes among endothelial function, skeletal muscle mass, and function are warranted to establish the causal relationship.

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