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【論文摘要】Investigated the Safety of Intra-Renal Arterial Transfusion of Autologous CD34+ Cells and Time Courses of creatinine Levels, Endothelial Dysfunction Biomarkers and Micro-RNAs in Chronic Kidney Disease Patients---Phase I Clinical Trial
摘要
Chronic kidney disease (CKD) with vast known and unknown causal etiologies clearly established remains the major and growing contributor to health care burden worldwide. Abundant data from clinical observational studies have revealed that CKD contributed high morbidity and mortality in hospitalized patients, especially in those CKD patients with co-existing cardiovascular disease (i.e., cardiorenal syndrome). Surprisingly, despite the state-of-the-art therapeutic and advanced pharmaceutical strategies, such as the uses of angiotensin converting enzyme inhibitor (ACEI), angiotensin II type I receptor blockade (ARB), and direct renin inhibitor (DRI), as well as good education, and renewed guideline for CKD precise management, progressive deterioration of renal function is frequently observed, subsequently leading to the adverse development of end-stage renal disease (ESRD) in CKD patients. Through more than several-decade keen investigation, the aetiology of CKD has been clearly shown to be divergent and the mechanisms involved are complicated. Endothelial cell dysfunction in the arterioles, followed by propagation and the development of obstructive atherosclerosis, has been implicated as one of the major aetiologies in the pathogenesis of the CKD disease. In particular, inflammatory reactions, fibrosis formation and generations of oxidative stress and reactive oxygen species (ROS) have been reported as the principal mechanisms involved in the disease. Taken into account the variety of aetiologies and the intricate mechanisms involved, satisfactory treatment of the disease with a single therapeutic strategy would be impossible. Therefore, finding an innovative therapeutic strategy with relatively broad-spectrum effect for preservation and improvement of renal microvasculature/endothelial function and renal function is a topic of utmost importance. Results from clinical observational studies, including our recent clinical study, have shown that the number and function of endothelial progenitor cells (EPCs) decreased significantly in patients with CKD. On the other hand, numerous experimental studies have shown that stem cell therapy improves ischemia-induced organ dysfunction through angiogenesis and restoring blood flow in the ischemic area. Additionally, growing data from clinical trials, including our recent study, have shown that both circulatory derived and bone marrow derived CD34+ stem cell therapy remarkably improved angina and ischemia-related left ventricular dysfunction, and restored the microvascular blood flow. Recently, our experimental study demonstrated that peripheral blood-derived EPC therapy could impede the deterioration of CKD induced by 5/6 nephrectomy in rats. The results of our animal model study and clinical trial encouraged the use of circulatory-derived autologous stem cell therapy for patients with CKD. Accordingly, a phase I clinical trial employing autologous CD34+ cell to treated patients with CKD stages III and IV was performed with two essential purposes as: (1) to investigate the safety of autologous administration of peripheral blood-derived CD34+ cells to CKD patients, and (2) to analyze endothelial dysfunction elements, focusing on the angiogenesis and circulating anti-apoptotic micro-RNAs.