Hypoxia-inducible Factor Prolyl Hydroxylase Inhibitors on Sarcopenia in Hemodialysis Patients

Overview

Sarcopenia, abbreviated as muscle loss, is a prevalent complication among patients with chronic kidney disease (CKD), particularly those with end - stage renal disease (ESRD). It significantly impacts patients' quality of life. The prevalence of sarcopenia in patients receiving maintenance hemodialysis (MHD) ranges from 32.7% to 73.5%, which is substantially higher than that in the general population (5% - 13%). Sarcopenia significantly elevates the mortality risk in MHD patients. Specifically, sarcopenia patients experience an increased all - cause mortality rate, a heightened risk of cardiovascular events, a decline in quality of life, and an augmented risk of falls and fractures. A close pathophysiological relationship exists between the hypoxia - inducible factor - 1 (HIF - 1) pathway and sarcopenia. HIF - 1α serves as a key transcription factor for cells to respond to hypoxic conditions. Under normoxic conditions, HIF - 1α is hydroxylated by prolyl hydroxylase (PHD) and subsequently undergoes ubiquitination - mediated degradation. Conversely, under hypoxic circumstances, HIF - 1α is stably expressed, translocates into the nucleus, and activates downstream target genes. HIF - 1α promotes the expression of genes associated with glycolysis, such as GLUT1 and LDHA, while inhibiting mitochondrial oxidative phosphorylation. This results in a shift of skeletal muscle energy metabolism from aerobic to anaerobic pathways. Research has revealed that the protein level of HIF - 1α is significantly decreased in sarcopenia patients. Roxadustat capsules, an oral medication, represent the world's first small - molecule hypoxia - inducible factor prolyl hydroxylase inhibitor (HIF - PHI) developed for the treatment of renal anemia. The physiological function of HIF - 1α not only enhances the expression of erythropoietin but also upregulates the expression of erythropoietin receptors and proteins involved in promoting iron absorption and circulation. Theoretically, roxadustat has the potential to improve sarcopenia. However, due to its prominent effect on anemia correction, it is currently only clinically applicable to anemic patients. This study aims to use ESA as a control to investigate the effect of roxadustat on sarcopenia in hemodialysis patients during the treatment of renal anemia.

Sarcopenia, commonly abbreviated as age-related muscle loss, represents a highly prevalent and serious complication among patients suffering from chronic kidney disease (CKD), particularly those advancing to end-stage renal disease (ESRD). It profoundly undermines multiple aspects of patients' lives, leading to markedly reduced mobility, increased dependency, and overall diminished quality of life. Defined as a progressive and generalized skeletal muscle disorder, sarcopenia involves the accelerated loss of muscle mass and function, which goes beyond normal aging. Clinically, it is diagnosed through measurements showing declines in three key areas: muscle mass, muscle strength, and physical performance. Although initially recognized and characterized in the elderly, it is now evident that sarcopenia disproportionately affects individuals with chronic conditions such as CKD. The prevalence of sarcopenia is strikingly elevated in patients undergoing maintenance hemodialysis (MHD). Studies report that between 32.7% and 73.5% of MHD patients are affected, a rate substantially higher than the 5% to 13% observed in the general population. This condition is not merely a comorbidity; it significantly increases the risk of mortality. Specifically, MHD patients with sarcopenia face higher all-cause mortality, greater susceptibility to cardiovascular events, reduced quality of life, and elevated risks of falls and fractures. Consequently, the development of effective treatments for sarcopenia is of major clinical importance for this vulnerable population. The pathogenesis of sarcopenia in MHD patients is multifactorial. Major contributing factors include nutritional and metabolic imbalances. During hemodialysis, significant quantities of amino acids are lost, and many patients experience poor appetite, leading to chronically inadequate protein intake. Additionally, a state of chronic micro-inflammation promotes muscle protein breakdown via activation of proteolytic pathways, thereby accelerating muscle wasting. Other metabolic abnormalities-such as metabolic acidosis, insulin resistance, and vitamin D deficiency-further exacerbate the loss of muscle mass and function. Although current management strategies focus on addressing these factors through nutritional support, exercise interventions, and metabolic corrections, the overall outcomes remain suboptimal for a significant proportion of patients. Hence, there is a pressing need to explore targeted pharmacological therapies. Recent research has shed light on the hypoxia-inducible factor-1 (HIF-1) pathway, which appears to have a close pathophysiological relationship with muscle homeostasis. HIF-1α, a central transcription factor that mediates cellular adaptation to hypoxia, is regulated by oxygen-dependent degradation. Under normal oxygen conditions, prolyl hydroxylase domain (PHD) enzymes hydroxylate HIF-1α, marking it for ubiquitination and proteasomal degradation. Under hypoxic conditions, however, HIF-1α accumulates, translocates to the nucleus, dimerizes with HIF-1β, and activates the transcription of numerous target genes. Interestingly, HIF-1α drives the expression of genes related to glycolysis (e.g., GLUT1 and LDHA) and suppresses mitochondrial oxidative phosphorylation, shifting energy production in skeletal muscle from aerobic to anaerobic metabolism. Notably, research has shown that protein levels of HIF-1α are significantly reduced in individuals with sarcopenia, suggesting an impaired hypoxic response mechanism that may be essential for activating muscle regeneration. Therefore, therapeutic activation of HIF-1α and its target genes has emerged as a promising strategy to ameliorate skeletal muscle atrophy. Roxadustat, an orally administered capsule, is the world's first hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI) approved for the treatment of renal anemia. Its mechanism of action involves mimicking α-ketoglutarate, thereby inhibiting PHD enzymes and stabilizing HIF-1α. This not only enhances erythropoietin (EPO) expression but also upregulates erythropoietin receptors and proteins that facilitate iron absorption and recycling. By restoring iron homeostasis and promoting erythropoiesis, roxadustat effectively corrects anemia. Beyond its primary use in renal anemia, roxadustat is now being investigated and applied in other anemia types. Theoretical and preclinical evidence suggests that roxadustat may also confer benefits in sarcopenia. However, given its primary indication for anemia, current clinical use is restricted to anemic patients. Renal anemia is exceedingly common in hemodialysis patients, historically managed with injectable recombinant erythropoietin (erythropoiesis-stimulating agents, ESAs). While ESAs effectively raise hemoglobin levels, they are not expected to directly influence muscle mass or function. In contrast, roxadustat has demonstrated superior efficacy in correcting renal anemia compared to ESA therapy. Nonetheless, no direct comparative studies have yet evaluated the effects of roxadustat versus ESA on sarcopenia in the hemodialysis population. Therefore, this study is designed to address the existing gap by utilizing ESA as a control to evaluate the potential benefits of roxadustat on sarcopenia in hemodialysis patients, while concurrently targeting its intended treatment for renal anemia. The findings may offer valuable insights into a novel therapeutic approach that transcends mere anemia management and aims to enhance musculoskeletal health within this high-risk population.