Erythropoietin (EPO) and Ischemia-reperfusion After Kidney Transplantation

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.

Inclusion criteria

• Signed written informed consent
• Male or female aged 18 to 70 years without restricted legal competence and being able to follow the trial instructions
• Cadaveric renal transplant, cold ischemia time below 24 h, and standard immunosuppressive regimen
• A haemoglobin level > 8 and < 14 g/dl
• Treatment with standard immunosuppression (steroids, cyclosporine A, tacrolimus, MMF or azathioprine)
• In patient with diabetes mellitus HbA1c < 9%

Exclusion criteria

• Previous or current myelodysplastic or -proliferative disorders
• History of cancer within the last 5 years.
• Systemic chemotherapy or radiotherapy
• Higher degree renal anemia or persistent Hb > 14 g/dl
• Treatment with other stem cell growth factors cells like GM-CSF, VEGF
• Bleeding episodes within 3 month prior transplantation
• Sitting diastolic BP > 110 mmHg or sitting systolic BP > 170 mmHg
• Known intolerance of rHuEpo or analogs
• Cardiovascular event within 6 months prior transplantation
• Thromboembolic event within 6 months prior transplantation
• Relevant stenosis of extra- and intracranial, and peripheral arteries
• Systemic diseases (SLE or vasculitis)
• Acute or chronic infection and/or CRP > 10 mg/l prior transplantation
• Hemolysis or disorders of blood formation (e.g., thalassemia)
• Further organ transplants or combined organ transplantation
• Pregnancy or inadequate contraception
• Psychiatric or emotional problems, or chronic seizures
• Unwillingness to participate satisfactorily for the entire trial period
• Participation in a clinical trial within 30 days prior to study inclusion