ICURT ProceedingsRole of Uremic Toxins in Erythropoiesis-Stimulating Agent Resistance in Chronic Kidney Disease and Dialysis Patients
Section snippets
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.