Frequent, Low-Dose Erythropoietin A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin

Frequent, Low-Dose Erythropoietin: A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin Therapy in Patients With Chronic Kidney Disease

Although several large well designed clinical trials have shown that erythropoietin which is commonly used to treat anemia associated with kidney disease, increases the risk of stroke and heart disease, the mechanism for this increased risk is unknown. The investigators' preliminary studies show that the adverse effects of erythropoietin are from activation of the heterodimeric erythropoietin/ beta common receptor which only occurs with high doses of erythropoietin. The investigators propose a clinical trial of 120 patients assigned to low doses of erythropoietin given more frequently or the same cumulative dose of erythropoietin administered as a high dose once every two weeks and assess effects on the beta common receptor activation, inflammation and vascular disease as evidence by MRI of the carotid arteries.

Erythropoietin (EPO) is the most widely prescribed cytokine, yet the benefits and potential side effects of different dosing regimens are poorly understood. It is now recognized that erythropoietin administered at high doses to patients with chronic kidney disease, results in an increased risk of morbidity and mortality from heart disease and stroke. However, the mechanisms that mediate this increased risk of cardiovascular disease is not known. There are two receptors for erythropoietin the homodimeric EPO receptor (EPOR) and the heterodimeric beta common receptor ( CR)/EPOR. The investigators have demonstrated that activation of the heterodimeric CR/EPOR only occurs with high doses of EPO. Our exciting, published, preliminary data also demonstrates that the CR is in a complex with vascular endothelial growth factor receptor-2 (VEGFR-2) and that high doses of EPO activate VEGFR-2 through the CR, resulting in the deleterious effects of VEGFR-2 activation on the cardiovascular system. This is particularly important in patients with kidney disease since they are already at a high risk of cardiovascular disease. Moreover in advanced kidney disease cyanate derived from the high urea levels can non-enzymatically form an amide bond with EPO. This carbamylated EPO (cEPO) has no effect on hemoglobin, but still activates the heterodimeric CR/EPOR. To date there have been no studies that have directly measured levels of cEPO or activation of the CR/EPOR in patients with kidney disease. Our hypothesis is that the administration of low-doses of EPO more frequently will result in lower levels of total and carbamylated erythropoietin decreased activation of VEGFR-2 via the heterodimeric CR/EPOR and consequently decreased inflammation and atherosclerosis. The investigators will directly test this hypothesis by randomly allocating 120 patients with chronic kidney disease to either low- dose EPO given thrice weekly or the same cumulative dose, a high-dose, administered once every 2 weeks. Our hypothesis predicts that low-dose EPO will be as effective at correcting anemia, but will demonstrate less progression of carotid artery plaque, as assessed by non-contrast magnetic resonance imaging, as compared to the high-dose, EPO given every 2 weeks. To delineate how EPO affects blood vessels, the investigators will isolate endothelial cells from blood vessels in 20 patients who are assigned to low-dose EPO and 20 allocated to high-dose EPO. Within these cells the investigators will investigate the signaling pathways that are triggered by activation of CR/EPOR. In a substudy of 20 subjects with kidney disease randomized to low-dose EPO or to high-dose EPO, as well as 20 healthy controls receiving a single dose of high- or low-dose EPO, the investigators will determine how kidney function and dosing affects levels of total and carbamylated erythropoietin. The investigators' study will not only provide us with a thorough understanding of the mechanism by which EPO mediates the increased risk of atherosclerosis, but a clinical strategy to avoid the side effects of EPO therapy and a tool to quantify the cardiovascular risk of EPO and newer erythropoiesis stimulating agents by assessing activation of the heterodimeric CR/EPOR.

Inclusion Criteria:

The investigators will enroll Veterans who fulfill the following criteria:

• stage 3, 4, or 5 CKD (estimated glomerular filtration rate of less than 60 ml/min/1.73 m2) on at least two separate occasions greater than 3 months apart; and
• candidates for EPO therapy as per the National Kidney Foundation's Kidney Disease Outcomes Quality Initiative guidelines (hemoglobin < 10 gm/dL and anemia of CKD).

Exclusion Criteria:

The investigators will exclude any Veteran who meets any of the following criteria:

1. pregnant, planning to become pregnant in the next year, or breast feeding;
2. uncontrolled hypertension (blood pressure > 180/100 mm Hg despite optimal antihypertensive medications);
3. active gastrointestinal bleeding (visible blood or positive tests for stool occult blood accompanied by a decrease in hemoglobin);
4. likely to have EPO resistance;
5. an adverse cardiovascular event in the prior three months;
6. active or recent (within the last 3 months) severe, systemic infection;
7. active inflammatory disease such as lupus, rheumatoid arthritis, or vasculitis requiring immunosuppressive or immunomodulatory medications;
8. history of solid organ transplantation;
9. expected off-dialysis survival of less than one year (as determined by the estimated glomerular filtration slope and the treating physician;
10. active cancer (undergoing chemotherapy or radiation within the last 3 months) or primary bone marrow disease such as myelofibrosis; or
11. a contraindication for an MRI or individuals who cannot comply with the study protocol. The investigators will exclude healthy subjects that meet a, b, f, g, h, or j.