Stephen Russ Price

The worldwide prevalence of chronic kidney disease (CKD) is high and growing, making CKD a leading cause of mortality. Skeletal muscle wasting, sometimes called sarcopenia or protein-energy wasting, is a frequent, serious consequence of CKD that reduces muscle strength and function, diminishes the quality of life of patients, and raises their risk of comorbidities and death. Muscle atrophy results from a disturbance in muscle protein balance that results from some combination of an increased rate of protein degradation, a decreased rate of protein synthesis, and dysfunctional muscle regeneration. Development of therapeutic strategies to ameliorate muscle loss, or maintain muscle mass, is challenging because of the multifactorial nature of the signals that alter protein homeostasis. This review discusses the cellular signals and mechanisms that negatively alter protein turnover in skeletal muscle during CKD.

Protein intake is crucial to maintain human health, and an adequate quantity and quality of dietary protein intake (DPI) is particularly important in patients with CKD. Both an insufficient amount of DPI (i.e., 1.3 g/kg body wt/d) pose potential health hazards in patients with CKD stages 3–5. Therefore, to optimize patient outcomes, healthcare providers should be familiar with the effects of both inadequate and excessive DPI in this population. The Kidney Disease Outcome Quality Initiative guidelines on DPI are rooted in detailed analyses of available scientific evidence and provide detailed recommendations regarding different dietary interventions strategies to achieve optimal quantity and quality of DPI. The more recent Kidney Disease Improving Global Outcomes guidelines on CKD management have a substantially broader scope and include a relatively brief section on diet, recommending a DPI of 0.8 g/kg body wt/d, emphasizing the need to avoid a DPI of >1.3 g/kg body wt/d. Besides aiming for a DPI of approximately 0.6–0.8 g/kg body wt/d in patients with CKD stages 3–5, successful practical implementation of dietary interventions requires an individualized approach which considers patient characteristics, such as sociocultural norms, habitual dietary habits, and nutrition literacy as well as systemic factors such as feasibility and availability of interventions.

Background: Diverse racial/ethnic representation in scientific studies is crucial for generalizability of results and development of potentially effective treatments. Racially diverse registries with research ready individuals have the potential to fill this gap. However, despite having signed up as part of a research registry and being invited to participate in clinical trials, many do not participate. To better understand research participation, the NC Registry for Brain Health surveyed its members to identify the characteristics of those likely to participate in research studies, their views on research, expectations when joining the group, and impediments to participation.Method: The NC Registry for Brain Health has been state‐funded since 2018 with goals of increasing access for all to information and research opportunities in brain health. Focused recruitment to under‐served and under‐represented groups across the State occurs through community outreach events sponsored by a five member university network. An email survey was sent to the 5,946 Registry members enrolled as of October 15, 2021.Result: Approximately 10% (n = 576) responded to this anonymized survey. Most were older women with high levels of formal education (Table 1). Despite the Registry’s demographics of 28% African American enrollees, only 8% of the survey respondents self‐identified as African Americans. Most individuals joined the Registry for the joint purpose of getting involved in research and receiving information about brain health (75%). When asked to describe what “brain health research” means, most reported studies involving dementia risk factors and memory testing. All participants had been approached to get involved in studies, but only 60% recalled getting an email invitation. The biggest impediment noted for participating in studies was inconvenient appointment times. The participants also wanted more available studies and more information about the opportunities.Conclusion: This study suggests that most participants in the Registry are seeking to be informed about brain health and have access to research opportunities at times convenient with their schedules. There was an observed gap between African Americans enrolled in the research registry and those who participated in the survey. Addressing gaps in research involvement of under‐represented groups in research is necessary to achieve inclusive representative science.

Loss of muscle proteins is a deleterious consequence of chronic kidney disease (CKD) that causes a decrease in muscle strength and function, and can lead to a reduction in quality of life and increased risk of morbidity and mortality. The effectiveness of current treatment strategies in preventing or reversing muscle protein losses is limited. The limitations largely stem from the systemic nature of diseases such as CKD, which stimulate skeletal muscle protein degradation pathways while simultaneously activating mechanisms that impair muscle protein synthesis and repair. Stimuli that initiate muscle protein loss include metabolic acidosis, insulin and IGF1 resistance, changes in hormones, cytokines, inflammatory processes and decreased appetite. A growing body of evidence suggests that signalling molecules secreted from muscle can enter the circulation and subsequently interact with recipient organs, including the kidneys, while conversely, pathological events in the kidney can adversely influence protein metabolism in skeletal muscle, demonstrating the existence of crosstalk between kidney and muscle. Together, these signals, whether direct or indirect, induce changes in the levels of regulatory and effector proteins via alterations in mRNAs, microRNAs and chromatin epigenetic responses. Advances in our understanding of the signals and processes that mediate muscle loss in CKD and other muscle wasting conditions will support the future development of therapeutic strategies to reduce muscle loss.

Muscle wasting in chronic kidney diseases (CKDs), sometimes referred to as protein energy wasting or cachexia, has been widely studied, yet much remains to be understood about the underlying pathophysiology. CKD-related changes in cell signaling disrupt proteostasis by activating muscle proteolysis [e.g. ubiquitin–proteasome system (UPS), autophagy and caspase-3] and negatively impacting protein synthesis and muscle regeneration. Muscle mass is controlled by a variety of signaling pathways, the most prominent being the insulin-GF-1)/Phosphatidylinositide 3-kinase (PI3K)/Protein Kinase B (Akt) pathway, which provides a point of intersection for protein synthesis, protein degradation and myogenesis. Akt phosphorylates and activates mTOR, which in turn stimulates key components of the protein synthesis and myoblast differentiation machineries. In contrast, Akt phosphorylates and inhibits the Forkhead box class O (FOXO) transcription factors, which increase the expression of several atrophy-inducing proteins including atrogin-1/MAFbx and Muscle RING finger 1 (MURF1) [ 1]. Other important signaling pathways include the Janus kinase/signal transducers and activators of transcription (JAK/STAT) and Activin receptor-IIB (ActRIIB)/SMAD pathways, which mediate the effects of cytokines [e.g. interleukin-6 (IL-6)] and the muscle-specific autocrine factor, myostatin (also called GDF-8), respectively [ 2].