Abstract: TH-PO404

Erythropoietin Pathway Dysregulation in Anemia of CKD

Session Information

Category: Nutrition, Inflammation, and Metabolism

  • 1401 Nutrition, Inflammation, Metabolism

Authors

  • Landau, Daniel, Ben Gurion University of the Negev, Beer Sheva, Israel
  • London, Lital, Ben Gurion University of the Negev, Beer-Sheva, Israel
  • Bandach, Inbar, Ben Gurion University of the Negev, Beer Sheva, Israel
  • Segev, Yael, Ben Gurion University of the Negev, Beer Sheva, Israel
Background

Anemia is a known driver for hypoxia inducible factor (HIF) which leads to increased renal erythropoietin (EPO) synthesis. Bone marrow (BM) EPO receptor (EPOR) signals are transduced through a JAK2-STAT5 pathway. Anemia of CKD is considered to be of multifactorial origin, including impaired renal EPO synthesis and intestinal iron absorption. EPO resistance in CKD may be an additional factor but its mechanisms are poorly understood. We investigated the HIF- EPO- EPOR axis in kidney, BM and proximal tibia in anemic juvenile CKD rats.

Methods

CKD was induced by 5/6 nephrectomy in young (20 days old) Sprague-Dawley rats while C group was sham operated. An additional control anemic (C-A) group was daily bled for 7 days. Rats were sacrificed 4 weeks after CKD induction and 5 minutes after a single bolus of IV rhEPO (25 U/kg).

Results

Hemoglobin levels were similarly reduced in CKD and C-A (11.7 ± 0.4 and 10.8±0.2 Vs 14.3±0.2 g/dL in C, p<0.0001). Liver hepcidin mRNA was decreased in CA but increased in CKD. Serum iron and transferrin levels were unchanged in CKD. Kidney HIF2α was elevated in C-A but unchanged in CKD. Remnant kidney EPO protein and mRNA levels were unchanged between groups. However, BM EPO protein (which reflects circulating EPO) was increased in C-A but remained unchanged in CKD. BM and proximal tibia EPOR were unchanged in C-A but decreased in CKD. Proximal tibial phsopho-STAT5 increased in C but not in CKD.

Conclusion

Compared to chronic blood loss, anemia in young CKD rats is associated with inappropriate responses: kidney HIF2α and BM EPO are not increased, BM and bone EPOR levels, as well as bone pSTAT5 response to EPO are reduced. This may allow the introduction of additional therapeutic avenues for CKD related anemia beyond iron and EPO supplementation.