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Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome

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ClinicalTrials.gov Identifier: NCT00356733
Recruitment Status : Completed
First Posted : July 26, 2006
Last Update Posted : December 2, 2011
Dutch Heart Foundation
Information provided by (Responsible Party):
G.B. Braam, University of Alberta

Tracking Information
First Submitted Date  ICMJE July 25, 2006
First Posted Date  ICMJE July 26, 2006
Last Update Posted Date December 2, 2011
Study Start Date  ICMJE January 2007
Actual Primary Completion Date July 2011   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 30, 2011)
changes in gene-arrays, EPC and biomarkers panels [ Time Frame: 14 days, 6 and 12 months ]
Original Primary Outcome Measures  ICMJE
 (submitted: July 25, 2006)
  • Cardiac function
  • Renal function
  • Morbidity
  • Mortality
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 30, 2011)
  • cardiac performance and renal function [ Time Frame: 6 and 12 months ]
  • QoL [ Time Frame: 6 and 12 months ]
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
Descriptive Information
Brief Title  ICMJE Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome
Official Title  ICMJE Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome
Brief Summary

Erythropoietin (EPO) treatment in patients with the severe cardiorenal syndrome increases cardiac performance and decreases progression of renal failure by dampening the main driving forces of the cardiorenal syndrome in part via non-erythropoietic pathways.

I. Does EPO administration to patients with the severe cardiorenal syndrome increase cardiac performance and decrease progression of renal disease?

II. Does EPO treatment affect the main driving forces of the cardiorenal connection, that is, dampen the activated renin-angiotensin system (RAS), attenuate increased reactive oxygen species (ROS), normalize increased sympathetic activity, and decrease inflammation?

III. Does EPO treatment positively affect the cell function of patients with the cardiorenal syndrome:

  1. are gene expression signatures of leukocytes positively influenced by EPO treatment,
  2. does EPO shift the Jak/STAT pathway to a less pro-inflammatory profile in monocytes, and
  3. are function and number of endothelial progenitor cells (EPCs) affected by treatment with EPO in the cardiorenal syndrome?

IV. Can the direct actions of EPO be differentiated from the effects on hemoglobin levels?

Detailed Description

The combination of renal and cardiac failure is associated with an extraordinary cardiovascular morbidity and mortality. We propose that the severe cardiorenal syndrome (SCRS), the pathophysiological condition in which there is combined cardiac and renal dysfunction, amplifies the progression of the failure of the individual organ. Central in the pathogenesis of the cardiorenal syndrome is enhanced oxidative stress, inflammation and enhanced activation of the renin-angiotensin and sympathetic nervous system. Chronic renal failure is further accompanied by anemia due to a gradual decline in erythropoietin (EPO) formation by the diseased kidneys and/or by EPO resistance. Recently, the interest in EPO is increasing since it serves not only as a hematopoietic factor, but also has been shown to increase the number of endothelial progenitor cells (EPCs) in end-stage renal disease (ESRD) patients. Moreover, EPO is involved in signaling via Akt to support NO release and may act as an anti-apoptotic. Some evidence supports the idea that EPO improves cardiac and renal function in the syndrome; however, no information is available about the mechanisms. The hypothesis of the present proposal is that EPO treatment in patients with the severe cardiorenal syndrome increases cardiac performance and decreases progression of renal failure in part via non-erythropoietic pathways. The questions are whether EPO administration to patients with the severe cardiorenal syndrome:

  1. increases cardiac performance and decreases progression of renal disease,
  2. dampens the activated RAS and sympathetic nervous system, attenuates increased ROS and decreases signs of inflammation and
  3. positively influences cell function of leukocytes (assessed by gene expression signatures), of monocytes (shifts to a less pro-inflammatory Jak/Stat signaling) and of EPC (number and function).

This will be addressed in a two-part clinical study in patients with combined moderate chronic renal failure and heart failure (New York Heart Association [NYHA] II-III). First, patients will be treated with EPO for 12 months, and hemoglobin levels will be kept constant at initial levels or will be allowed to increase; another group will be left untreated. Besides cardiac and renal function, the RAS, the SNS, and ROS/NOS balance and inflammatory parameters will be assessed. Furthermore, cell function of leukocytes (gene expression signatures), monocytes (Jak/STAT activation) and EPCs (number and function) will be studied. Taken together, central in the proposal is that combined heart-kidney failure is accompanied by relative or absolute EPO dysfunction, disproportional to the degree of renal failure and that treatment with EPO improves cardiac performance and renal function.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Heart Failure, Congestive
  • Renal Insufficiency, Chronic
Intervention  ICMJE Drug: Erythropoietin administration
50 IU/kg/week EPO to a target haemoglobin level of 13.7 g/dL for men and 13.4 g/dL for women (group A) or to a target comparable to starting hemoglobin level (group B)
Study Arms  ICMJE
  • Experimental: EPO rise
    EPO administration
    Intervention: Drug: Erythropoietin administration
  • Experimental: EPO stable
    EPO and stable Hemoglobin
    Intervention: Drug: Erythropoietin administration
  • No Intervention: control
    standard treatment
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 30, 2011)
Original Enrollment  ICMJE
 (submitted: July 25, 2006)
Actual Study Completion Date  ICMJE July 2011
Actual Primary Completion Date July 2011   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Patients with moderate renal failure (glomerular filtration rate [GFR] by Cockroft formula of 20-70 ml/min)
  • Patients with heart failure NYHA class II-III-IV
  • Hemoglobin (Hb) between 6.4 - 7.8 mmol/L in men and between 6.0 - 7.4 mmol/L in women
  • Age > 18 years, < 80 years
  • Written informed consent must be obtained from the subject or legally accepted representative before study-specific procedures, including screening procedures, are performed.

Exclusion Criteria:

  • Therapy within 1 year before randomisation or any planned erythropoietic therapy between randomisation and study day 1
  • Known intolerance to EPO administration
  • Previously suspected of or confirmed to have neutralizing antibodies to recombinant human erythropoietin (rHuEPO)
  • Uncontrolled hypertension (RR > 160 systolic, >100 diastolic)
  • Forms of secondary hypertension other than renal hypertension
  • Uncontrolled diabetes (HbA1c > 8.0 %)
  • Primary dyslipidemia
  • Kidney transplantation
  • Proteinuria > 3.5 g/L
  • Acute renal failure or rapidly progressive glomerulonephritis
  • Hyperparathyroidism (parathyroid hormone [PTH] > 40)
  • Bleeding or haemolysis as a cause of anaemia
  • Deficiency of iron, folate, and/or vitamin B12
  • Presence of chronic inflammatory disease or clinically significant infection
  • Haematologic malignancy or solid tumour < 5 years ago
  • Chronic liver disease
  • Haemoglobinopathies
  • Alcohol and/or drug abuse
  • Enrolment in another study
  • Child bearing potential (pre-menopausal woman who is not using adequate contraceptive precautions)
  • Any kind of disorder that compromises the ability of the subject to give written informed consent and/or to comply with study procedures
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
Administrative Information
NCT Number  ICMJE NCT00356733
Other Study ID Numbers  ICMJE NHS-2005B192
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Current Responsible Party G.B. Braam, University of Alberta
Original Responsible Party Not Provided
Current Study Sponsor  ICMJE UMC Utrecht
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Dutch Heart Foundation
Investigators  ICMJE
Principal Investigator: Branko Braam, MD, PhD UMC Utrecht, The Netherlands
Principal Investigator: Carlo AJ Gaillard, MD, PhD Meander Medical Center Amersfoort, The Netherlands
Study Director: Pieter AF Doevendans, MD, PhD UMC Utrecht, The Netherlands
PRS Account UMC Utrecht
Verification Date November 2011

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP