Indoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in young adult rats

Hirata, Junya; Hirai, Kazuya; Asai, Hirobumi; Matsumoto, Chiho; Inada, Masaki; Miyaura, Chisato; Yamato, Hideyuki; Watanabe-Akanuma, Mie

doi:10.1016/j.bone.2015.06.010

Cited by 29 publications

(27 citation statements)

References 35 publications

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“…This may predispose clinically to adynamic bone disease, as suggested by studies in rats after parathyroidectomy where dietary supplementation with indole (a precursor of indoxyl sulphate) raised blood c 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society levels of indoxyl sulphate and decreased bone remodeling [113]. In CKD patients, there is a positive correlation between serum fibroblast growth factor-23 with indoxyl sulphate levels, supporting an association between gut-derived uremic toxins and metabolic bone disease [114].…”

Section: Bone Diseasementioning

confidence: 87%

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

et al. 2018

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In chronic kidney disease (CKD), influx of urea and other retained toxins exerts a change in the gut microbiome. There is decreased number of beneficial bacteria that produce short-chain fatty acids, an essential nutrient for the colonic epithelium, concurrent with an increase in bacteria that produce uremic toxins such as indoxyl sulphate, p-cresyl sulphate, and trimethylamine-N-oxide (TMAO). Due to intestinal wall inflammation and degradation of intercellular tight junctions, gut-derived uremic toxins translocate into the bloodstream and exert systemic effects. In this review, we discuss the evidence supporting a role for gut-derived uremic toxins in promoting multiorgan dysfunction via inflammatory, oxidative stress, and apoptosis pathways. End-organ effects include vascular calcification, kidney fibrosis, anemia, impaired immune system, adipocyte dysfunction with insulin resistance, and low turnover bone disease. Higher blood levels of gut-derived uremic toxins are associated with increased cardiovascular events and mortality in the CKD population. Clinical trials that have examined interventions to trap toxic products or reverse gut microbial dysbiosis via oral activated charcoal AST-120, prebiotics and probiotics have not shown impact on cardiovascular or survival outcomes but were limited by sample size and short trials. In summary, the gut microbiome is a major contributor to adverse cardiovascular outcomes and progression of CKD.

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Section: Bone Diseasementioning

confidence: 87%

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

et al. 2018

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“…Thus, the intestine produces uraemic toxins and this generation increases as kidney disease progresses. High levels of p-cresol and indoxyl sulfate have well-recognized effects on several organs, such as osteoblast dysfunction and low turnover in the bone 175,176 and proinflammatory effects in the vascular system as a result of increased leucocyte adhesion and rolling 177 . Furthermore, both molecules have been linked to cardiovascular diseases and death in ESRD 178 .…”

Section: Ckd Alters the Gut-kidney Linkmentioning

confidence: 99%

The systemic nature of CKD

et al. 2017

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The accurate definition and staging of chronic kidney disease (CKD) is one of the major achievements of modern nephrology. Intensive research is now being undertaken to unravel the risk factors and pathophysiologic underpinnings of this disease. In particular, the relationships between the kidney and other organs have been comprehensively investigated in experimental and clinical studies in the last two decades. Owing to technological and analytical limitations, these links have been studied with a reductionist approach focusing on two organs at a time, such as the heart and the kidney or the bone and the kidney. Here, we discuss studies that highlight the complex and systemic nature of CKD. Energy balance, innate immunity and neuroendocrine signalling are highly integrated biological phenomena. The diseased kidney disrupts such integration and generates a high-risk phenotype with a clinical profile encompassing inflammation, protein-energy wasting, altered function of the autonomic and central nervous systems and cardiopulmonary, vascular and bone diseases. A systems biology approach to CKD using omics techniques will hopefully enable in-depth study of the pathophysiology of this systemic disease, and has the potential to unravel critical pathways that can be targeted for CKD prevention and therapy.

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“…However, the suppression of PTH was observed at higher indoxyl sulfate levels than seen in dialysis patients. Hirata et al [58] studied the condition of low bone turnover in renal failure with reduced production of new bone in setting of low PTH levels. They induced low bone turnover by performing parathyroidectomy in rats.…”

Section: Evidence For Toxicitymentioning

confidence: 99%

Indoxyl Sulfate—Review of Toxicity and Therapeutic Strategies

Leong

Sirich

2016

Toxins

213

178

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Indoxyl sulfate is an extensively studied uremic solute. It is a small molecule that is more than 90% bound to plasma proteins. Indoxyl sulfate is derived from the breakdown of tryptophan by colon microbes. The kidneys achieve high clearances of indoxyl sulfate by tubular secretion, a function not replicated by hemodialysis. Clearance by hemodialysis is limited by protein binding since only the free, unbound solute can diffuse across the membrane. Since the dialytic clearance is much lower than the kidney clearance, indoxyl sulfate accumulates to relatively high plasma levels in hemodialysis patients. Indoxyl sulfate has been most frequently implicated as a contributor to renal disease progression and vascular disease. Studies have suggested that indoxyl sulfate also has adverse effects on bones and the central nervous system. The majority of studies have assessed toxicity in cultured cells and animal models. The toxicity in humans has not yet been proven, as most data have been from association studies. Such toxicity data, albeit inconclusive, have prompted efforts to lower the plasma levels of indoxyl sulfate through dialytic and non-dialytic means. The largest randomized trial showed no benefit in renal disease progression with AST-120. No trials have yet tested cardiovascular or mortality benefit. Without such trials, the toxicity of indoxyl sulfate cannot be firmly established.

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Indoxyl sulfate exacerbates low bone turnover induced by parathyroidectomy in young adult rats

Cited by 29 publications

References 35 publications

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

Altered microbiome in chronic kidney disease: systemic effects of gut-derived uremic toxins

The systemic nature of CKD

Indoxyl Sulfate—Review of Toxicity and Therapeutic Strategies

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