Insufficient Activation of the HIF Pathway is a Principal Cause of Anemia of CKD

CKD Disrupts HIF Signaling1,2,16,18

CKD Disrupts Normal HIF Signaling

CKD=chronic kidney disease; EPO=erythropoietin; HIF=hypoxia-inducible factor; Na+=sodium; O2=oxygen; REP=renal erythropoietin-producing.

  • In CKD, oxygen consumption in the kidneys is reduced due to disease-related changes16,18
  • This causes REP cells to sense pseudonormoxia in their immediate environment, which may not reflect the oxygen levels in the whole kidneys or the rest of the body2,16,18
  • Thus, normal HIF signaling is disrupted, which leads to reduced EPO production2,18
  • As a result, oxygen delivery to the rest of the body could be decreased1,16,18

Pseudonormoxia in CKD

  • Progression of CKD results in structural and functional changes that upset the normal oxygen balance18
  • These changes include:
    • Disproportionately lower oxygen consumption as a result of declining glomerular filtration rate (GFR) and sodium reabsorption16,18
  • As a result, regardless of oxygen levels elsewhere in the body, there is sufficient oxygen to satisfy the local needs of the REP cells, creating a pseudonormoxic environment for them2,16,18

Insufficient Activation of the HIF Pathway is a Principal Cause of Anemia of CKD

  • Currently recommended therapies—ESAs, iron, and transfusions—supplement EPO, iron, and red blood cell (RBC) deficiencies1,22,23
  • However, this supplemental approach may not fully address the impaired oxygen sensing or other pathophysiologic features of anemia of CKD1
Treatment Practices for Anemia of CKD

ESA=erythropoiesis-stimulating agent; Fe=iron.

Consequences of Anemia of CKD

  • In CKD, an impaired oxygen-sensing mechanism leads to insufficient HIF signaling1,18
  • This results in decreased RBC production and anemia1,18
  • Thus, oxygen delivery to the rest of the body is reduced, and critical organs may experience hypoxia, which, when severe, may lead to injury18,24-28
Mechanism of Disrupted Oxygen Sensing in CKD