Role of uremic toxins in erythropoiesis-stimulating agent resistance in chronic kidney disease and dialysis patients

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

Research output: Contribution to journalReview articlepeer-review

25 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)160-163
Number of pages4
JournalJournal of Renal Nutrition
Issue number2
Publication statusPublished - 2015 Mar 1

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Nutrition and Dietetics
  • Nephrology


Dive into the research topics of 'Role of uremic toxins in erythropoiesis-stimulating agent resistance in chronic kidney disease and dialysis patients'. Together they form a unique fingerprint.

Cite this