Mechanisms of Erythropoietin Action in the Cardiorenal Syndrome
Condition: Heart Failure, Congestive; Renal Insufficiency, Chronic
MeSH terms: Renal Insufficiency; Renal Insufficiency, Chronic; Cardio-Renal Syndrome; Heart Failure
Study type: Interventional
Phase: Phase 3

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.
    

Intervention name(s): Erythropoietin administration
Intervention type(s): Drug
Intervention description(s): 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)
Intervention MeSH terms: Epoetin Alfa
Allocation: Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: cardiorenal syndrome; erythropoietin; Heart Failure, Congestive; Renal Insufficiency, Chronic