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Kidney Week

Abstract: FR-PO477

Inflammation Contributes to Anemia of CKD Through Both Iron and HIF/EPO-R Pathways

Session Information

Category: Anemia and Iron Metabolism

  • 201 Anemia and Iron Metabolism: Basic

Authors

  • Landau, Daniel, Tel Aviv University, Petach Tikva, Israel
  • Bandach, Inbar, Ben Gurion University, Beer Sheva, Israel
  • Segev, Yael, Ben Gurion University, Beer-Sheva, Israel
Background

Anemia of chronic kidney disease (CKD), originally thought to be due to impaired renal erythropoietin (EPO) synthesis as well as iron malabsorption, may also be due to EPO resistance, clinically associated with inflammation. The key pro-inflammatory cytokine Interleukin (IL-1) is normally controlled by a receptor antagonist (IL1Ra). IL1Ra-KO (RaKO) mice show arthritis and excessive inflammation. The aim of this study was to characterize the anemic state of RaKO mice with adenine induced-CKD.

Methods

Wild-type (WT) and RaKO mice were fed with 0.2% adenine or control diets, leading to 4 groups: WT, WT-CKD, RaKO, RaKO-CKD. Mice were sacrificed after 10 weeks. For a control model of anemia (CA), WT mice were bled every two days for a week.

Results

Higher levels of S-creat and histologic kidney inflammation were seen in RAKO-CKD Vs WT-CKD. Kidney IL-6 and phospho-STAT3 were increased in both CKD groups, especially in RAKO-CKD. Arthritis, associated with increased liver CRP, was more accentuated in RAKO-CKD Vs RaKO. Hct levels were decreased in CKD groups, especially in RAKO-CKD. The response to bleeding induced anemia (CA) included: no evidence for inflammation, low liver hepcidin, elevated renal HIF2 and increased EPO controlled bone marrow (BM) EPO-R and transferrin receptor (TFR). Serum iron and MCV levels were significantly reduced in both CKD groups and were even lower in RAKO-CKD Vs WT-CKD. Liver hepcidin mRNA levels were increased in RAKO-CKD in comparison to all other groups. Serum EPO levels were not increased. Renal HIF2 and BM EPO-R mRNA levels were significantly decreased in both CKD groups, especially in RAKO-CKD.

Conclusion

Exaggerated arthritis and inflammation were associated with higher degree of renal insufficiency and anemia in RAKO-CKD Vs WT-CKD. In addition to the well-known hepcidin mediated decreased iron absorption, the normal response to anemia induced hypoxia is deranged in CKD and even more accentuated when inflammation is increased in CKD-RaKO: renal HIF2 and EPO, BM EPO-R and TFR are not upregulated, which further exacerbate anemic tendency. Altogether, this supports the key role of inflammation in CKD-associated anemia. Novel treatments to reduce inflammation may attenuate the anemic state or increase the response to exogenous EPO.