nutrients Review Maintenance of Skeletal Muscle to Counteract Sarcopenia in Patients with Advanced Chronic Kidney Disease and Especially Those Undergoing Hemodialysis Katsuhito Mori Department of Nephrology, Osaka City University Graduate School of Medicine 1-4-3, Asahi-Machi, Abeno-ku, Osaka 545-8585, Japan; [email protected]; Tel.: +81-6-6645-3806; Fax: +81-6-6645-3808 Abstract: Life extension in modern society has introduced new concepts regarding such disorders as frailty and sarcopenia, which has been recognized in various studies. At the same time, cutting-edge technology methods, e.g., renal replacement therapy for conditions such as hemodialysis (HD), have made it possible to protect patients from advanced lethal chronic kidney disease (CKD). Loss of muscle and fat mass, termed protein energy wasting (PEW), has been recognized as prognostic factor and, along with the increasing rate of HD introduction in elderly individuals in Japan, appropriate countermeasures are necessary. Although their origins differ, frailty, sarcopenia, and PEW share common components, among which skeletal muscle plays a central role in their etiologies. The nearest concept may be sarcopenia, for which diagnosis techniques have recently been reported. The focus of this review is on maintenance of skeletal muscle against aging and CKD/HD, based on muscle physiology and pathology. Clinically relevant and topical factors related to muscle wasting including sarcopenia, such as vitamin D, myostatin, insulin (related to diabetes), insulin-like growth factor I, mitochondria, and physical inactivity, are discussed. Findings presented thus far indicate Citation: Mori, K. Maintenance of that in addition to modulation of the aforementioned factors, exercise combined with nutritional Skeletal Muscle to Counteract supplementation may be a useful approach to overcome muscle wasting and sarcopenia in elderly Sarcopenia in Patients with Advanced patients undergoing HD treatments. Chronic Kidney Disease and Especially Those Undergoing Hemodialysis. Keywords: skeletal muscle; sarcopenia; hemodialysis; aging; chronic kidney disease; diabetes Nutrients 2021, 13, 1538. https://doi.org/10.3390/nu13051538 Academic Editor: R. Andrew Shanely 1. Introduction Most societies, especially those in developed countries, have shown increased longevity Received: 31 March 2021 over the past few generations and interest has now shifted to how to extend healthy life Accepted: 30 April 2021 Published: 2 May 2021 expectancy. Aging is profoundly associated with changes related to human organs and tissues, and recently ‘frailty’ has become recognized as a key term related to age-related Publisher’s Note: MDPI stays neutral decline [1]. A sedentary lifestyle, commonly seen in modern society settings, also accel- with regard to jurisdictional claims in erates deterioration of motor functions. Skeletal muscle, which constitutes the largest published maps and institutional affil- type of tissue mass and accounts for 40–45% of total body weight [2], has a core role in iations. maintenance of a healthy life. Its functional failure leads to physical impairment, resulting in poor outcomes, especially in elderly individuals. Thus, much attention has been given to ‘sarcopenia’, which is generally defined as loss of skeletal muscle mass and function [3]. In addition to aging, other chronic disorders are known to exacerbate frailty and/or sarcopenia, with advanced chronic kidney disease (CKD), especially end-stage kidney Copyright: © 2021 by the author. Licensee MDPI, Basel, Switzerland. disease including hemodialysis (HD), a representative condition [4]. ‘Protein-energy wast- This article is an open access article ing (PEW)’ is characterized by adverse changes in nutrition and body composition in distributed under the terms and advanced CKD/HD patients [5]. Historically, frailty and sarcopenia have been considered conditions of the Creative Commons to originate from aging-related derangement, and PEW has been proposed to express Attribution (CC BY) license (https:// the wasting that occurs in association with kidney dysfunction [6]. As a result, there is creativecommons.org/licenses/by/ considerable overlapping among frailty, sarcopenia, and PEW in elderly patients with 4.0/). advanced CKD/HD. Nutrients 2021, 13, 1538. https://doi.org/10.3390/nu13051538 https://www.mdpi.com/journal/nutrients Nutrients 2021, 13, x FOR PEER REVIEW 2 of 23 Nutrients 2021, 13, 1538 2 of 22 wasting that occurs in association with kidney dysfunction [6]. As a result, there is con- siderable overlapping among frailty, sarcopenia, and PEW in elderly patients with ad- vancedThe CKD/HD. aim of this report is not to provide a systematic review of sarcopenia in advanced CKD/HDThe aim cases, of this but report rather is tonot examine to provide the a widesystematic range review of related of sarcopenia fields in an in easilyadvanced un- CKD/HDderstood mannercases, but in rather order to to examine facilitate the research wide range regarding of related skeletal fields muscle in an maintenanceeasily under- stoodand healthy manne lifer in expectancy.order to facilitate Specifically, research the regarding author would skeletal like muscle to focus maintenance on the decline and healthyand dysfunction life expectancy. of skeletal Specifically, muscle, the along author with would countermeasures like to focus on from the the decline viewpoint and dys- of functionaging and of advanced skeletal muscle, CKD/HD along as commonwith countermeasures key components from of PEW,the viewpoint sarcopenia, of andaging frailty and (Figureadvanced1). CKD/HD as common key components of PEW, sarcopenia, and frailty (Figure 1). Figure 1. ConceptualConceptual overlapping overlapping among among frailty, frailty, sarcopenia, and PEW. Aging accelerates frailty and sarcopenia. Advanced CKD/HD is is profoundly profoundly associated associated with with PEW. PEW. Elderly HD patients have the highest riskrisk forfor these these pathological pathological conditions. conditions. Among Among these these conditions, conditions, skeletal skeletal muscle muscle derangement derange- is menta common is a common component. component. CKD, chronic CKD, kidney chronic disease; kidney HD, disease; hemodialysis; HD, hemodialysis; PEW, protein-energy PEW, protein wasting.-en- ergy wasting. 2. Conceptual Overlapping among Frailty, Sarcopenia, and PEW 2. ConceptualThe concept Overlapping of frailty is among considered Frailty acceptable, Sarcopenia to describe, and PEW the condition of an indi- vidual.The Generally, concept of it frailty is used is toconsidered explain the acceptable state resulting to describe from the an condition age-related of decrease an indi- vidual.in physiological Generally, reserve it is used and to increase explain inthe vulnerability state resulting to stressors,from an age resulting-related in decrease disability, in physiologicalhospitalization, reserve institutionalization, and increase in and vulnerability finally death to stressors, [4,7]. Fried resulting et al. defined in disability, frailty hos- as a pitalization,clinical syndrome institutionalization, in which three and or more finally of thedeath following [4,7]. Fried abnormalities et al. defined were frailty combined; as a unintentional weight loss, self-reported exhaustion, weakness (grip strength), slow walking clinical syndrome in which three or more of the following abnormalities were combined; speed, and low physical activity [1]. In contrast to that phenotype model, Rockwood et al. unintentional weight loss, self-reported exhaustion, weakness (grip strength), slow walk- proposed a frailty index based on accumulation of such deficits as age-associated diseases, ing speed, and low physical activity [1]. In contrast to that phenotype model, Rockwood non-specific vulnerability, and disabilities (accumulated deficit model) [8]. Nevertheless, et al. proposed a frailty index based on accumulation of such deficits as age-associated no universal standard for diagnosis of frailty has been established. diseases, non-specific vulnerability, and disabilities (accumulated deficit model) [8]. Nev- The term ‘sarcopenia’ was first proposed by Irwin Rosenberg to describe loss of ertheless, no universal standard for diagnosis of frailty has been established. muscle mass (i.e., sarx meaning flesh and penia loss in Greek) [9]. However, the concept of The term ‘sarcopenia’ was first proposed by Irwin Rosenberg to describe loss of mus- sarcopenia has changed over time and later included related dysfunctions, such as loss of cle mass (i.e., sarx meaning flesh and penia loss in Greek) [9]. However, the concept of muscle strength. The European Working Group on Sarcopenia in Older People (EWGSOP) sarcopenia has changed over time and later included related dysfunctions, such as loss of provided a definition along with diagnostic criteria [10], an objective assessment based on muscle strength. The European Working Group on Sarcopenia in Older People measurements of gait speed, grip strength, and muscle mass that has greatly contributed to progress(EWGSOP) in researchprovided of a sarcopenia. definition along Recently, with a reviseddiagnostic consensus criteria (EWGSOP2) [10], an objective was released assess- mentto promote based earlyon measurements detection and of treatmentgait speed, of grip affected strength, patients and [muscle3]. mass that has greatly In addition to age-related frailty and sarcopenia, the presence of advanced CKD is inde- pendently associated with malnutrition and inflammation.