Erythropoietin (EPO) and Ischemia-reperfusion After Kidney Transplantation

NCT ID: NCT00425698

Last Updated: 2010-09-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2/PHASE3
• Total Enrollment: 88 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2007-02-28
• Study Completion Date: 2009-11-30

Brief 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.

Conditions

Kidney Transplantation

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: DOUBLE

Study Groups

intravenous erythropoietin

Erythropoietin alpha 3 x 40.000 IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation

Group Type: ACTIVE_COMPARATOR

Recombinant erythropoietin alpha (rHuEPO alpha)

Intervention Type: DRUG

Erythropoietin alpha 3 x 40.000 IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation

Placebo

Intervention Type: DRUG

Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation

intravenous placebo

Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation

Interventions

Recombinant erythropoietin alpha (rHuEPO alpha)

Erythropoietin alpha 3 x 40.000 IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation

Intervention Type: DRUG

Placebo

Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation

Intervention Type: DRUG

Other Intervention Names

Erypo

Eligibility Criteria

Inclusion Criteria

1. Signed written informed consent

2. Male or female aged 18 to 70 years without restricted legal competence and being able to follow the trial instructions

3. Cadaveric renal transplant, cold ischemia time below 24 h, and standard immunosuppressive regimen

4. A haemoglobin level > 8 and < 14 g/dl

5. Treatment with standard immunosuppression (steroids, cyclosporine A, tacrolimus, MMF or azathioprine)

6. In patient with diabetes mellitus HbA1c < 9%

Exclusion Criteria

1. Previous or current myelodysplastic or -proliferative disorders

2. History of cancer within the last 5 years.

3. Systemic chemotherapy or radiotherapy

4. Higher degree renal anemia or persistent Hb > 14 g/dl

5. Treatment with other stem cell growth factors cells like GM-CSF, VEGF

6. Bleeding episodes within 3 month prior transplantation

7. Sitting diastolic BP > 110 mmHg or sitting systolic BP > 170 mmHg

8. Known intolerance of rHuEpo or analogs

9. Cardiovascular event within 6 months prior transplantation

10. Thromboembolic event within 6 months prior transplantation

11. Relevant stenosis of extra- and intracranial, and peripheral arteries

12. Systemic diseases (SLE or vasculitis)

13. Acute or chronic infection and/or CRP > 10 mg/l prior transplantation

14. Hemolysis or disorders of blood formation (e.g., thalassemia)

15. Further organ transplants or combined organ transplantation

16. Pregnancy or inadequate contraception

17. Psychiatric or emotional problems, or chronic seizures

18. Unwillingness to participate satisfactorily for the entire trial period

19. Participation in a clinical trial within 30 days prior to study inclusion

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hannover Medical School

OTHER

Sponsor Role: lead

Responsible Party

Saarland University Medical Centre

Principal Investigators

Danilo Fliser, MD

Role: PRINCIPAL_INVESTIGATOR

Saarland University Medical Centre

Locations

Hannover Medical School

Hanover, , Germany

Countries

Germany

Other Identifiers

MHH - EPONTX - 01/06

Identifier Type: -

Identifier Source: org_study_id