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

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Patients with advanced chronic kidney disease are exposed to uremic toxins. In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. Indoxyl sulfate (IS) increases oxygen consumption in tubules, aggravating hypoxia of the kidney, and progression of the kidney disease. IS also induces endoplasmic reticulum stress and thereby contributes the progression of cellular damages in tubular epithelial cells. Hypoxia-inducible factor (HIF) is a master transcriptional regulator of adaptive responses against hypoxia and regulates expression of erythropoietin (EPO). IS suppresses EPO expression via HIF-dependent and HIF-independent manner. IS impedes the recruitment of transcriptional coactivators to HIF via upregulation of Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 through a mechanism of posttranscriptional messenger RNA stabilization. Furthermore, IS induces activating transcription factor 4 via endoplasmic reticulum stress, decreasing EPO expression. Although erythropoiesis-stimulating agent (ESA) resistance is generally defined as lack of responses to exogenous ESA administration, suppression of endogenous production of EPO under uremic conditions may aggravate ESA resistance. Uremia is associated with increased formation of advanced glycation end products (AGE). Studies of transgenic rats overexpressing glyoxalse 1 (GLO1), which detoxifies precursors of advanced glycation end products, demonstrated that glycative stress causes renal senescence and vascular endothelial dysfunction. Glycative stress also suppresses HIF activation making the kidney susceptible to hypoxia as a final common pathway to end-stage kidney disease.

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Uremia and Progression of CKD

Patients with advanced CKD patients are exposed to uremic toxins. To date, more than 90 molecules have been identified as uremic toxins, and indoxyl sulfate (IS) is a representative organic compound that has been proposed to contribute to the development of uremic symptoms.7

In addition to causing uremic symptoms, uremic toxins accelerate the progression of renal failure. IS increases oxygen consumption in freshly isolated rat and human proximal tubules, which is dependent on oxidative stress

Uremia and Renal Anemia: IS

Although mechanisms involved in the pathogenesis of renal anemia include chronic inflammation, iron deficiency, and shortened half-life of erythrocytes, the primary cause is deficiency of erythropoietin (EPO).10 As erythrocytes deliver oxygen to vital organs, anemia results in poor oxygenation of target organs. A retrospective analysis of a population of 71,802 subjects in Okinawa, Japan, showed that the odds ratio and 95% CI for the influence of hematocrit (percentage) on the development of

Uremia and Renal Anemia: Glycative Stress

Uremia is associated with increased formation of advanced glycation end products (AGEs). AGEs are formed by nonenzymatic glycative and oxidative reactions. The levels of AGE, such as pentosidine and carboxymethyllysine, are elevated in the plasma proteins of nondiabetic CKD patients. Although AGE formation is enhanced in diabetic patients, the AGE accumulation in uremia cannot be attributed to hyperglycemia. Glycative stress in CKD patients plays an important role in the pathogenesis of a

Future Perspectives

As observed in covalent modification of p300 by glycative stress under uremic conditions, epigenetic regulation of gene expression is a focus of intensive researches in CKD and dialysis patients.19 The recent and rapid advent of next-generation sequencing has made this technology broadly available. Using next-generation sequencing, we can perform ChIP-seq (chromatin immunoprecipitation with sequencing) and RNA-seq for sample preparation and interpretation of raw data in the investigation of

Conclusion

Uremia causes suppression of EPO expression in both HIF-dependent and HIF-independent manners (Fig. 1). Although ESA resistance is generally defined as lack of responses to exogenous ESA administration, suppression of endogenous production of EPO under uremic conditions may aggravate ESA resistance.

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    Financial Disclosure: M.N. received honoraria and research funding from Kyowa Hakko Kirin, Chugai, and Tanabe Mitsubishi. The other authors have nothing to declare.

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