**2. PEW and Frailty in MHD patients**

As MHD patients get older, they are affected more severely by age-related problems as compared to their counterparts in the general population. Two of the most significant problem are frailty and protein energy wasting (PEW) [2]. This phenomenon is clinically relevant because many manifestations of frailty and PEW are strong risk factors that affect quality of life, morbidity, and mortality. Frailty can be defined as a biological syndrome of decreased resistance to stressors caused by cumulative declines across multiple physiological systems which, ultimately, results in vulnerability to adverse outcomes. Frailty implies decreased body energy, protein reserves and reduced strength. Frailty is a common occurrence in CKD as well as MHD patients. A simple criterion for frailty can be the presence of three or more of the following abnormalities; unintentional weight loss, self-reported exhaustion, measured weakness, slow walking speed, and low physical activity. On the other hand, PEW is defined as the loss of somatic and circulating body protein and energy reserves. The comorbidity of infectious disease is also subject to the influence of these conditions. For instance, sarcopenia and osteopenia puts the patient at risk for falls as well as contracting pneumonia. In regards to aspiration pneumonia (AP), sarcopenia often causes difficulty in swallowing, which leads to unrecognized aspiration. Coordinated muscle movement and optimal muscle strength play an important role in the well-organized swallowing movement. Aspiration status was partly dependent on the lower anterior and posterior esophageal muscle and tongue strength [3]. These muscle strength was imparired by the decline in the global physical status. In ESRD patients under MHD, muscle and energy wasting are prominent, which influences the mortality and morbidity [2]. The tissue changes in muscle varies from morphological, electro‐ physiological and metabolic alterations. These malign changes of muscles lead to muscle weakness and finally to myopathy [4]. Additionally, atrophy of type II fibers was observed in the patients with MHD in several studies. These functional and structural muscle impairments in both systemic and/or oropharyngeal muscle strength are derived from the PEW state in MHD patients. Impaired immune function is associated with PEW in MHD [5]. In addition to an increased susceptibility to infections and poor wound healing, PEW leads to an impaired immune function which affects the gastrointestinal tract malfunction and aberrant microbiota population. These intestinal changes cause malabsorption and malnutrition [6], accelerating further the immune dysfunction. Deterioration in intestinal structure also leads to the en‐ hancement of bacterial translocation in the intestine, leading to systemic inflammation and PEW state.

PEW involves several mechanisms, including the activation of oxidative stress, the inflamma‐ tory response, and the dialysis measure itself. Several markers of PEW and the resultant malnutrition have been associated with the incidence and death rates in patients with MHD [2]. Biochemical markers like lower serum albumin, prealbumin and cholesterol levels [7] are linked to malnutrition with higher fatality in dialysis patients. Serum transferrin, creatinine and bicarbonates [8] as well as hemoglobin levels, lymphocytes counts and white blood cell counts are also shown to be associated with malnutrition. We previously reported that serum creatatinine, albumin and total cholesterol levels are independent risk factors for contracting AP and its corresponding mortality rate. We also identified serum inorganic phosphorus (IP) as the main predictors of dietary intake in MHD patients [9]. Since 24-hour creatinine excretion and serum creatinine levels are associated with muscle mass [10], creatinine decline over time are related to the level of malnutrition as well as sarcopenic changes after admission [10]. It was reported that, in a cohort of 121,762 MHD patients, serum creatinine decline, and lower body mass, lower muscle mass and weight loss are associated with higher mortality in MHD patients [11]. It was also reported that among these clinical parameters, a decline in serum creatinine is suggested to be a stronger predictor of fatality than weight loss in MHD patients [12]. Our study is in consistent with the results of this large cohort study in that creatinine decline rate as well as albumin decline rate are good predictive indicator for morbidity and mortality of AP [9].
