Role of Uremic Toxins in Erythropoiesis-Stimulating Agent Resistance in Chronic Kidney Disease and Dialysis Patients

Nangaku, Masaomi; Mimura, Imari; Yamaguchi, Junna; Higashijima, Yoshiki; Wada, Takehiko; Tanaka, Tetsuhiro

doi:10.1053/j.jrn.2014.10.011

Cited by 37 publications

(22 citation statements)

References 22 publications

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“…Indoxyl sulphate interferes with the production of erythropoietin partly by impairing cellular oxygen-sensing mechanisms [106,107]. Treatment of HepG2 human hepatoma cells with indoxyl sulphate impaired nuclear accumulation of hypoxia-inducible transcription factors and decreased erythropoietin mRNA [106].…”

Section: Anemiamentioning

confidence: 99%

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: Anemiamentioning

confidence: 99%

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

et al. 2018

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“…Indoxyl sulfate increases oxygen consumption in proximal renal tubules, decreases renal oxygenation, and consequently aggravates hypoxia in the rat kidney, which is dependent on sodium-potassium adenosine triphosphatase and oxidative stress [34]. Indoxyl sulfate also impedes the recruitment of transcriptional coactivators by hypoxia-inducible factor (HIF) via upregulation of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (CITED2) through a mechanism of posttranscriptional messenger RNA stabilization [46]; this decreases nuclear accumulation of HIF-α proteins and thereby suppresses HIF target gene expression, such as erythropoietin (EPO) [47]. Via these processes, indoxyl sulfate induces tubulointerstitial fibrosis and glomerular sclerosis, which might lead to CKD progression.…”

Section: Amino Acid Metabolism and Ckdmentioning

confidence: 99%

Dietary Metabolites and Chronic Kidney Disease

2017

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Dietary contents and their metabolites are closely related to chronic kidney disease (CKD) progression. Advanced glycated end products (AGEs) are a type of uremic toxin produced by glycation. AGE accumulation is not only the result of elevated glucose levels or reduced renal clearance capacity, but it also promotes CKD progression. Indoxyl sulfate, another uremic toxin derived from amino acid metabolism, accumulates as CKD progresses and induces tubulointerstitial fibrosis and glomerular sclerosis. Specific types of amino acids (d-serine) or fatty acids (palmitate) are reported to be closely associated with CKD progression. Promising therapeutic targets associated with nutrition include uremic toxin absorbents and inhibitors of AGEs or the receptor for AGEs (RAGE). Probiotics and prebiotics maintain gut flora balance and also prevent CKD progression by enhancing gut barriers and reducing uremic toxin formation. Nrf2 signaling not only ameliorates oxidative stress but also reduces elevated AGE levels. Bardoxolone methyl, an Nrf2 activator and NF-κB suppressor, has been tested as a therapeutic agent, but the phase 3 clinical trial was terminated owing to the high rate of cardiovascular events. However, a phase 2 trial has been initiated in Japan, and the preliminary analysis reveals promising results without an increase in cardiovascular events.

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“…Uremic solutes, such as indoxyl sulfate (IS), also appear to contribute to ESA resistance. IS induces endoplasmic reticulum stress [21,22,23], suppresses Epo expression and leads to the progression of CKD. Recent studies by Wu et al [24] showed improvement of anemia in pre-dialysis CKD patients by treatment with AST-120, oral adsorbent to reduce serum IS levels.…”

Section: Contentmentioning

confidence: 99%

How the Target Hemoglobin of Renal Anemia Should Be?

Mimura

Tanaka

Nangaku³

2015

Nephron

Self Cite

301

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Renal anemia is caused by the deficiency of endogenous erythropoietin (Epo) due to renal dysfunction. We think that it is possible to slow the progression of chronic kidney disease (CKD) in case we initiate Epo early in pre-dialysis patients, especially in the non-diabetic population. Erythropoiesis stimulating agent (ESA) treatments targeting mild anemia (10-12 g/dl) can decrease the risk of occurrence of cardiovascular disease (CVD) in patients with hypertension, diabetes mellitus and congestive heart failure. As the large randomized controlled trials such as Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta, Correction of Hemoglobin and Outcomes in Renal Insufficiency and Trial to Reduce Cardiovascular Events with Aranesp Thearpy in the Western countries suggested, we do not recommend high doses of ESA to achieve the target hemoglobin (Hb) level. The target Hb of >13 g/dl might lead to increase in the risk of CVD although maintaining a high Hb of >12 g/dl without ESA is not harmful for CKD patients. It is desirable to determine the target Hb in dialysis patients depending on their ages. Renal anemia should be monitored constantly to start ESA and iron replacement therapy at an appropriate time, while avoiding their excess in order to minimize the occurrence of CVD and other complications. Taken all the international guidelines and our clinical experiences together, we should consider administration of ESA when the Hb level becomes <11 g/dl in pre-dialysis patients and <10 g/dl in dialysis patients.

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Role of Uremic Toxins in Erythropoiesis-Stimulating Agent Resistance in Chronic Kidney Disease and Dialysis Patients

Cited by 37 publications

References 22 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

Dietary Metabolites and Chronic Kidney Disease

How the Target Hemoglobin of Renal Anemia Should Be?

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