The role of indoxyl sulfate in renal anemia in patients with chronic kidney disease

Abstract

Renal anemia is a common complication in patients with advanced chronic kidney disease. In vitro studies have shown that indoxyl sulfate decreases erythropoietin production. Whether this effect is seen in vivo remains unclear. Our goal was to explore the role of indoxyl sulfate in renal anemia. We found serum indoxyl sulfate levels are significantly and negatively associated with erythropoietin levels in human. A multiple stepwise linear regression analyses after adjustment for other independent parameters revealed that free indoxyl sulfate, and total indoxyl sulfate were significantly associated with erythropoietin levels. In animal studies, erythropoietin gene and protein expression were markedly inhibited in rats with chronic kidney disease; however, this effect was significantly reversed by lowering serum indoxyl sulfate with AST-120. Indoxyl sulfate may also inhibit erythropoietin expression in animal models with chronic kidney disease. These findings further support the role of indoxyl sulfate in the development of renal anemia.

Keywords: chronic kidney disease; erythropoietin; indoxyl sulfate; renal anemia.

Figure 1. Agreement between EPO and IS analyzed by Pearson’s correlation

(A) ln EPO vs T-IS, r=-0.22, p=0.041 (B) ln EPO vs F-IS, r=-0.25, p=0.021.

Figure 2. The EPO expression status in an animal model

(A) Real-time quantitative PCR was performed to assess the change of EPO mRNA expression in control-sham, CKD and CKD+AST-120 group. EPO mRNA was suppressed in CKD rat. It was restored in rats with feeding AST-120 by lowering serum IS. (B) Western blot analysis. EPO protein expression was also decreased significantly in CKD rat. AST-120 could reverse the inhibition of EPO expression in CKD. n=5 for each, #, p<0.01 compared to control-sham group, *, p<0.05 compared CKD group.