Erythropoietin (EPO) and Ischemia-reperfusion After Kidney Transplantation
Condition: Kidney Transplantation
Study type: Interventional
Phase: Phase 2/Phase 3

Summary: 
      The hematopoetic cytokine erythropoietin (EPO) has been shown to reduce programmed cell death
      and tissue destruction in experimental models of acute kidney ischemia-reperfusion injury.
      Thus, treatment with high dose recombinant human EPO (rHuEPO) may prevent kidney tissue
      damage and loss of renal function after successful kidney transplantation in humans.
    

Detailed description: 
      Erythropoietin (EPO) has pleiotropic effects well beyond the maintenance of red blood cell
      mass. In the embryo, EPO is a major regulator of vascular formation and organ growth, and EPO
      receptors are found in almost every embryonic tissue. EPO receptors also exist in many adult
      tissues including renal tissue, and even the notion of autocrine or paracrine EPO systems has
      been raised. Although the peritubular fibroblasts are the major adult site for EPO
      production, EPO receptors have been demonstrated in many kidney cell types, e.g. proximal
      tubule epithelial cells, mesangial cells, and the glomerulus. Moreover, EPO has important
      cytoprotective effects on various cell lines and organs, and protection from ischemic injury
      and inhibition of apoptotic death-related pathways has been reported in brain, heart and
      renal tissue. The intracellular pathways involved in these favourable EPO effects may involve
      nuclear translocation of the transcription factor NF- B, JAK2 phosphorylation and
      phosphorylation of Akt (protein kinase B).

      A recent experimental study revealed that cobalt administration to rats caused up-regulation
      of EPO, and diminished the degree of renal injury caused by ischemia-reperfusion (I/R),
      suggesting that EPO may also play an important role in renal ischemic preconditioning.
      Indeed, subsequent studies from different laboratories demonstrated that preconditioning with
      recombinant human EPO (rHuEPO) is protective against I/R injury in rodents. In this respect
      data on specific protective effects of rHuEPO and its analogues on endothelial cells of
      glomeruli are of particular interest. Furthermore, administration of rHuEPO may not have only
      protective effects on the vascular level, but also potential of regeneration, since EPO also
      stimulates proliferation and differentiation of regenerative cells such as endothelial
      progenitor cells (EPCs).

      Renal ischemia, whether caused by shock or after surgery, is a major cause of acute renal
      failure (ARF) in man. In this respect kidney transplantation is a classical model of ARF due
      to I/R injury, since the transplanted organ is connected to the recipients blood supply
      usually after several hours of "cold ischemia". Although reperfusion is essential for the
      survival of ischemic tissue, it also initiates a complex and interrelated sequence of events
      that results in injury and the eventual death of renal cells as a result of a combination of
      both apoptosis and necrosis. Apoptotic cell death has been documented in human biopsies after
      renal I/R, and inhibition of apoptotic signalling and cell death ameliorates the associated
      injury and inflammation in an experimental model of ischemic ARF. Similarly, I/R damage of
      transplanted kidney is thought to be a major factor limiting renal function after successful
      transplantation.
    

Intervention name(s): Recombinant erythropoietin alpha (rHuEPO alpha); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Erythropoietin alpha 3 x 40.000 IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation; Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation
Other intervention name(s): Erypo
Intervention MeSH terms: Epoetin Alfa
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Prevention