Frequent, Low-Dose Erythropoietin: A Mechanistic Approach to Mitigate Adverse Cardiovascular Effects of Erythropoietin Therapy in Patients With Chronic Kidney Disease
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 5
- 试验地点
- 1
- 主要终点
- Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Single (Outcomes Assessor)
盲法说明
The outcome is the progression of carotid plaque. John Forder, PhD, who will read the MRIs will be blinded to the subject and treatment group.
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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).
排除标准
- •The investigators will exclude any Veteran who meets any of the following criteria:
- •pregnant, planning to become pregnant in the next year, or breast feeding;
- •uncontrolled hypertension (blood pressure > 180/100 mm Hg despite optimal antihypertensive medications);
- •active gastrointestinal bleeding (visible blood or positive tests for stool occult blood accompanied by a decrease in hemoglobin);
- •likely to have EPO resistance;
- •an adverse cardiovascular event in the prior three months;
- •active or recent (within the last 3 months) severe, systemic infection;
- •active inflammatory disease such as lupus, rheumatoid arthritis, or vasculitis requiring immunosuppressive or immunomodulatory medications;
- •history of solid organ transplantation;
- •expected off-dialysis survival of less than one year (as determined by the estimated glomerular filtration slope and the treating physician;
- •active cancer (undergoing chemotherapy or radiation within the last 3 months) or primary bone marrow disease such as myelofibrosis; or
- •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.
研究组 & 干预措施
Low dose erythropoietin
Subjects randomized to this arm will receive low-dose of EPO administered thrice weekly
干预措施: Low dose erythropoietin (Drug)
High dose erythropoietin
Subjects randomized to this arm will receive the same cumulative dose of EPO administered as a high-dose of EPO every 2 weeks
干预措施: High dose erythropoietin (Drug)
结局指标
主要结局
Change in Carotid Total Plaque Volume From Baseline to Approximately 1 Year, as Assessed by Non-contrast MRI
时间窗: 1 year
The plaque characteristics will be analyzed by MRI-PlaqueViewTM (VP diagnostics Inc., WA). Planimetry will be performed on the image data sets, using histogram equalization to improve edge detection for plaque, arterial wall and lumen. Differences in image contrast between T1-weighted, T2-weighted, Time of Flight, and proton density will be used to characterize the plaque as fibrous, stable, or unstable.
次要结局
- Percentage of Total Plaque Area at Baseline and Upon Follow-up.(1 year)
- Characteristics of Plaques (Soft or Fibrous and Stable or Unstable) at Baseline and Upon Follow-up.(1 year)
- Severity of Maximal Stenosis at Baseline and Upon Follow-up.(1 year)