Although sarcopenia was originally described as an age-related structural and functional decline in skeletal muscle, recent investigations have consistently acknowledged that decreased kidney function is also involved in sustained muscle wasting and the subsequent development of sarcopenia. Compared to the elderly population, in which the prevalence of sarcopenia is 11% [32], CKD patients are likely to be much more prone to its occurrence, with an estimated prevalence of 30 - 60% [20, 21, 24, 33-35]. The two main components of sarcopenia, muscle strength and mass, are dissociated in the setting of ESRD, and the muscle strength is more important than muscle mass in terms of patient outcomes [20, 34]. In this context, we extensively investigated the effects of skeletal muscle dysfunction on major adverse events in hemodialysis patients. Our findings suggest that GS and HS represent different aspects of patient characteristics and that their combination could identify those at the highest risk for mortality and cardiovascular events. Of note, MAMC showed a tendency to be relatively lower in patients with poor physical performance but was not related to either clinical outcome (data not shown). Together, our data support the idea that the functional assessment of skeletal muscle is more important than its quantitative assessment and that measuring GS and HS is a suitable method for the evaluation of skeletal muscle function in hemodialysis patients.
Based on the significant correlation between poor physical performance and high mortality in dialysis patients, several prospective trials have assessed whether intradialytic exercise could improve patient outcomes [36-41]. Although physical training significantly improved patient quality of life in most studies, these benefits were not translated into better patient survival. One of the reasons for this discrepancy might be that patients enrolled in these studies were highly heterogeneous in their baseline clinical characteristics, underlying comorbidities, and laboratory findings. Moreover, there is no consensus on the definition of adequate exercise for hemodialysis patients, thereby limiting the application of intradialytic exercise in routine clinical practice. Therefore, well-designed randomized controlled trials are needed to clarify the clinical significance of intradialytic exercise, especially in terms of improving patient mortality.
We noticed that spKt/V, currently used as a standard method for the assessment of dialysis adequacy, was highest in patients with low GS and HS and lowest in patients with normal GS and HS (Table 1). The inverse relationship between Kt/V and physical performance was consistently shown in other studies, suggesting that this relationship is likely to be a universal phenomenon [24, 33, 35, 42]. We speculate that the low muscle mass and subsequent decreased volume of distribution of urea in the body (V) in patients with low GS and HS resulted in a relative increase in the value of Kt/V without affecting the true dialysis efficacy [43]. Therefore, sarcopenic patients may be underdialyzed if their dialysis time and dialyzer filter are selected solely based on the levels of Kt/V. Further study is warranted to define the optimal target of Kt/V in dialysis patients based on the severity of sarcopenia.
Although GS and HS are the two representative tests used to assess physical performance, direct comparisons of these parameters have rarely been made, especially in dialysis patients. Here, we examined their relationship and found that a substantial portion of patients exhibited low performance on one test while demonstrating normal performance on the other (114/277, 41.2%). Moreover, the correlation coefficient between GS and HS was very weak despite its statistical significance, suggesting that the factors contributing to these two conditions might be different. We consider that this finding is at least in part due to the differences in the muscles and neurologic systems involved during the execution of the HS and GS tests. In accordance with our data, Roshanravan et al. showed a discrepancy in upper and lower muscle strength in a nondialysis CKD cohort study [19]. Thus, these data provide a rationale that the combination of the GS and HS tests could integrate the different patient components, thereby allowing us to predict future outcomes better.
Despite the fact that the clinical relevance of GS and HS as predictors of mortality and cardiovascular outcomes was documented in previous studies, direct comparisons between these two tests have not been performed so far. Interestingly, patients with isolated low GS had a tendency to exhibit worse comorbidity indexes and physical functions than those with isolated low HS (Table 2). Furthermore, GS was significantly superior than HS for the prediction of all-cause mortality in the analysis of our cohort, implying that the muscle function of the lower extremities might be more important than that of the upper extremities in terms of patient outcomes. Several recent studies also revealed that skeletal muscle function in the lower extremities but not in the upper extremities was associated with overall physical performance and the hospitalization rate [44, 45], emphasizing the clinical importance of lower extremity performance. Moreover, the GS test is still valuable because low GS is associated with increased HRs for death and cardiovascular mortality regardless of HS (Figure 3 and Table 4). Johansen et al. investigated longitudinal trends in the physical performance of hemodialysis patients and found that GS frequently declined while HS did not change over time [46]. GS was the strongest individual predictor of future frailty and mortality among various physical activity assessment tools, including HS, which is in line with our findings. Therefore, we consider that monitoring gait functions has the potential to serve as a valuable tool for continuous risk stratification of dialysis patients.
We found that the levels of endocan and MMP-7 were elevated in patients with low GS and HS. Endocan is a water-soluble proteoglycan consisting of amino acid polymers and a single dermatan sulfate chain [47]. Plasma endocan is known to exclusively originate from the vascular endothelium, and its levels reflect endothelial activation and systemic inflammation. Several previous studies have demonstrated the clinical value of plasma endocan in the prediction of cardiovascular mortality as well as the progression of kidney diseases [48-51]. It should be confirmed whether elevated levels of plasma endocan result from sarcopenia itself or from other confounding factors, such as vascular injuries or infection [52, 53]. MMP-7 is an endopeptidase that belongs to the MMP family. In addition to its basic functions in cleaving extracellular matrix substrates, MMP-7 is also involved in the development of local and systemic inflammation [54-56]. Although MMP-2 and MMP-9 seem to play major roles in the degradation of the extracellular matrix that leads to muscle wasting, the pathophysiological relevance of MMP-7 in the development and progression of sarcopenia is still mostly unknown. Increased MMP-7 activity is observed in a hereditary form of muscular dystrophy [57], suggesting that upregulated MMP-7 might have detrimental effects on skeletal muscle. In contrast with a previous report [20], the levels of hs-CRP, IL-6, and TNF-α were not elevated in sarcopenic patients in our study. We speculate that these inconsistent findings are attributable to the differences in the degree of overall inflammation; the absolute concentrations of hs-CRP and IL-6 were lower and the levels of serum albumin were higher in patients in our study than in those in the previous study [20].
Although low GS or HS alone was not predictive of patient outcomes in our cohort (Table 4), several other studies showed that isolated low GS or low HS was an independent predictor of all-cause mortality in patients with CKD [19-22]. This discrepancy is, at least in part, because the number of cardiovascular events in this study during follow-up was low. Thus, the statistical power of multivariable analysis with respect to separately analyzing the prognostic impacts of GS and HS was reduced. Moreover, the appropriate cutoff values for low GS and HS are still controversial, even though guidelines had already been established for Asian populations [27]. More vigorous validations are needed to determine the clinical relevance of these criteria as predictors of patient outcomes.
The limitations of this study should be mentioned. There is a concern about selection bias because patients who were incapable of performing the GS and/or HS tests were excluded from our study. Indeed, a previous study reported that dialysis patients who could not complete a walking test had the highest comorbidity index and worst survival rate, even when compared to those who could walk very slowly (< 0.6 m/s) [21]. Plasma inflammatory markers were not adjusted for other clinical parameters. Thus, the impacts of these markers on patient outcomes were substantially limited. Nonetheless, we believe that these results may help clinicians assess the overall status of hemodialysis patients since their levels could reflect physical performance. Finally, we could not determine the possible mechanisms underlying the association between low physical performance and high mortality. We speculate that chronic sustained inflammation might be an essential mediator that contributes to both phenomena (Figure 3). This hypothesis should be explored in further studies.