The Potential Influence of Uremic Toxins on the Homeostasis of Bones and Muscles in Chronic Kidney Disease

Abstract

Patients with chronic kidney disease (CKD) often experience a high accumulation of protein-bound uremic toxins (PBUTs), specifically indoxyl sulfate (IS) and p-cresyl sulfate (pCS). In the early stages of CKD, the buildup of PBUTs inhibits bone and muscle function. As CKD progresses, elevated PBUT levels further hinder bone turnover and exacerbate muscle wasting. In the late stage of CKD, hyperparathyroidism worsens PBUT-induced muscle damage but can improve low bone turnover. PBUTs play a significant role in reducing both the quantity and quality of bone by affecting osteoblast and osteoclast lineage. IS, in particular, interferes with osteoblastogenesis by activating aryl hydrocarbon receptor (AhR) signaling, which reduces the expression of Runx2 and impedes osteoblast differentiation. High PBUT levels can also reduce calcitriol production, increase the expression of Wnt antagonists (SOST, DKK1), and decrease klotho expression, all of which contribute to low bone turnover disorders. Furthermore, PBUT accumulation leads to continuous muscle protein breakdown through the excessive production of reactive oxygen species (ROS) and inflammatory cytokines. Interactions between muscles and bones, mediated by various factors released from individual tissues, play a crucial role in the mutual modulation of bone and muscle in CKD. Exercise and nutritional therapy have the potential to yield favorable outcomes. Understanding the underlying mechanisms of bone and muscle loss in CKD can aid in developing new therapies for musculoskeletal diseases, particularly those related to bone loss and muscle wasting.

Keywords: bone loss; chronic kidney disease; indoxyl sulfate; sarcopenia; uremic toxins.

Figure 1

PBUTs and PTH affect bone metabolism at different stages of CKD. ① In the early stages of CKD (stages 2–3), the release of Wnt signaling inhibitors (DKK1, SOST, and sFRP) from the kidney or bone cells reduces the viability of osteoblasts. Additionally, PBUTs, such as IS and pCS, impair the function of osteoblasts and osteoclasts. CKD affects the gut microbiome, leading to the accumulation of uremic toxins in the blood, particularly IS, which is associated with low bone turnover, suppressed bone formation, and apoptosis in osteoblasts. This condition is known as “uremic osteoporosis”. Further bone loss occurs due to the progressive deterioration of renal function, metabolic acidosis, and hyponatremia. ② In CKD stages 4–5, the dysregulation of calcium, phosphate, vitamin D, and PTH can result in varying levels of PTH. High-turnover bone disease develops when elevated serum PTH levels override bone formation inhibitors, leading to increased osteoclast and osteoblast activity. ③ However, treating SHPT can restore bone cells to their original low viability status and low bone turnover status.

Figure 2

Mechanism of PBUTs and PTH-mediated skeletal muscle atrophy. Redox signaling changes in CKD, caused by uremic toxins, inflammation, and metabolic/hormonal shifts, resulting in oxidative stress, leading to muscle wasting and bone loss. ① Mild accumulation of PBUTs significantly contributes to muscle wasting in early-stage CKD (stages 2–3). Molecular mechanisms involved include imbalanced protein degradation and synthesis, increased reactive ROS and inflammatory cytokines, activation of myostatin and atrogene expression, impaired mitochondrial function, and negative effects from uremic toxins, parathyroid hormone, glucocorticoids, and angiotensin II. IS enters muscle cells using an OAT, where IS stimulates the pathway of AhR and NADPH oxidase to induce the production of ROS. Excessive production of ROS will produce inflammatory cytokines when myostatin and atrogin-1 are overexpressed, and this will be linked to muscle atrophy. The production of ROS has an impact on mitochondrial function. pCS induces insulin resistance in muscles due to decreased insulin or IGF-1-IRS-AKT capacity triggered by ERK1/2 activity. In late CKD (stages 4–5D), cachexia is a syndrome characterized by further increased energy expenditure and loss of muscle and adipose tissues. In addition to the further increase in PBUT levels, the excessive levels of PTH have detrimental effects on skeletal muscle metabolism, leading to aggravated muscle weakness and atrophy. ② High PTH levels are associated with sarcopenia and contribute to muscle loss. PTH and PTHrP drive adipose tissue browning and muscle wasting in cachexia. Elevated PTH indirectly leads to decreased muscle protein synthesis by acting on PTH receptors expressed in adipose tissue, thereby activating the expression of thermogenic genes, and finally causing muscle hypermetabolism and atrophy.