Erythropoietin (EPO) and Ischemia-reperfusion After Kidney Transplantation

Kidney Transplantation Clinical Trial

Official title:

Effect of Erythropoietin on Renal Function After Kidney Transplantation

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00425698
• Other study ID #: MHH - EPONTX - 01/06
• Status: Completed
• Phase: Phase 2/Phase 3
• First received: January 22, 2007
• Last updated: September 23, 2010
• Start date: February 2007
• Est. completion date: November 2009

Study information

• Verified date: September 2010
• Source: Hannover Medical School
• Contact: n/a
• Is FDA regulated: No
• Health authority: Germany: Federal Institute for Drugs and Medical Devices
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 88
• Est. completion date: November 2009
• Est. primary completion date: May 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Kidney Transplantation

Intervention

Drug:
• Recombinant erythropoietin alpha (rHuEPO alpha)
Erythropoietin alpha 3 x 40.000 IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation
• Placebo
Placebo 3x IU intraarterial or intravenous within 7 days after cadaveric kidney transplantation

Locations

Country	Name	City	State
Germany	Hannover Medical School	Hannover

Sponsors (1)

Lead Sponsor	Collaborator
Hannover Medical School

Country where clinical trial is conducted

Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Kidney Graft Function by Estimated Glomerular Filtration Rate (eGFR)	Estimated glomerular filtration rate (eGFR) was assessed using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)equation	42 days after transplantation	No
Secondary	Kidney Graft Function by Estimated Glomerular Filtration Rate (eGFR)	Estimated glomerular filtration rate (eGFR) was assessed using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration)equation	6 month after transplantation	No