Erythropoietin (EPO) and Ischemia-reperfusion After Kidney Transplantation

This study has been completed.
Sponsor:
Information provided by:
Hannover Medical School
ClinicalTrials.gov Identifier:
NCT00425698
First received: January 22, 2007
Last updated: September 23, 2010
Last verified: September 2010
  Purpose

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.


Condition Intervention Phase
Kidney Transplantation
Drug: Recombinant erythropoietin alpha (rHuEPO alpha)
Drug: Placebo
Phase 2
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Effect of Erythropoietin on Renal Function After Kidney Transplantation

Resource links provided by NLM:


Further study details as provided by Hannover Medical School:

Primary Outcome Measures:
  • Kidney Graft Function by Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: 42 days after transplantation ] [ Designated as safety issue: No ]
    Estimated glomerular filtration rate (eGFR) was assessed using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)equation


Secondary Outcome Measures:
  • Kidney Graft Function by Estimated Glomerular Filtration Rate (eGFR) [ Time Frame: 6 month after transplantation ] [ Designated as safety issue: No ]
    Estimated glomerular filtration rate (eGFR) was assessed using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)equation


Enrollment: 88
Study Start Date: February 2007
Study Completion Date: November 2009
Primary Completion Date: May 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: intravenous erythropoietin
Erythropoietin alpha 3 x 40.000 IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation
Drug: Recombinant erythropoietin alpha (rHuEPO alpha)
Erythropoietin alpha 3 x 40.000 IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation
Other Name: Erypo
Drug: Placebo
Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation
Other Name: Placebo
Placebo Comparator: intravenous placebo
Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation
Drug: Placebo
Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation
Other Name: Placebo

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.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00425698

Locations
Germany
Hannover Medical School
Hannover, Germany, 30625
Sponsors and Collaborators
Hannover Medical School
Investigators
Principal Investigator: Danilo Fliser, MD Saarland University Medical Centre
  More Information

No publications provided

Responsible Party: Danilo Fliser, MD, Professor of Medicine, Saarland University Medical Centre
ClinicalTrials.gov Identifier: NCT00425698     History of Changes
Other Study ID Numbers: MHH - EPONTX - 01/06
Study First Received: January 22, 2007
Results First Received: August 4, 2010
Last Updated: September 23, 2010
Health Authority: Germany: Federal Institute for Drugs and Medical Devices

Additional relevant MeSH terms:
Epoetin alfa
Hematinics
Hematologic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 31, 2014