Please select the eligibility criteria that correspond to the clinical trial below.
Title: 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?


Options:
A: Inclusion Criteria:

* Heart failure of at least 3 months duration and of New York Heart Association (NYHA) class II, III, or IV
* hemoglobin between 9.0 g/dL and 12.0 g/dL
* left ventricular ejection fraction equal to or less than 40%

Exclusion Criteria:

* Transferrin saturation (Tsat) \< 15%
* Blood pressure \> 160/100 mm Hg
* Heart failure primarily due to valvular heart disease or clinically significant valvular heart disease that might lead to surgical correction within 12 months of randomization
* Recipient of a major organ transplant or receiving renal replacement therapy
* Serum creatinine \> 3.0 mg/dL (\> 265 µmol/L)
B: Inclusion Criteria:

* End stage renal disease
* Regular dialysis treatment
* Renal anemia (hemoglobin\<9.0 g/dl)
* Age \> 18 years
* Adequate iron stores (TIBC saturation \> 20%, ferritin \>200)

Exclusion Criteria:

* Signs of bleeding
* Major surgery in previous 60 days
* Hemolysis
* Other causes of anemia
* Cancer
* Inflammatory diseases
C: 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
D: * Inclusion Criteria

  1. Patients with 19 years of age or older
  2. Patients with chronic renal failure of stage 3 or above who are not on dialysis
  3. Patients with the Hb levels of 8 to 10g/dl measured at screening
  4. Patients with enough body iron stores who meet the following item:

     -Serum ferritin ≥ 100ng/ml or Transferrin saturation ≥ 20%
  5. Patients who have provided written consent to participate in the clinical trial voluntarily
* Exclusion Criteria

  1. Patients who are expected to need dialysis within a year or patients with rapidly progressive chronic renal failure
  2. Patients who have received drug treatment such as erythropoiesis stimulating agent for the purpose of correcting anemia within 12 weeks prior to screening
  3. Patients who have received red blood cell transfusion within 12 weeks prior to screening
  4. Patients with uncontrolled hypertension
  5. Patients who had hypersensitivity to erythropoietin agents
  6. Patients who had known hypersensitivity to mammalian cell-derived products or additives
  7. Patients with history of severe cardiovascular diseases
  8. Patients whose anemia is not caused by chronic renal failure or may affect anemia correction including the following conditions:
  9. Patients whose AST/ALT test results performed at screening exceeds twice of normal upper limit
  10. Patients who have experience of positive result in anti-erythropoietin antibody in previous treatment with erythropoiesis stimulating agent

Answer: C