A PILOT STUDY OF ISLET TRANSPLANTATION IN NON-UREMIC DIABETIC PATIENTS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这项研究的主要目标是通过单一供体胰腺的胰岛细胞移植实现I型糖尿病患者长期(超过1年)的胰岛素独立。据估计，美国I型糖尿病的患病率为80万人，每年的发病率约为3万例新病例。目前还没有完全可用的预防或治疗措施。最接近的是糖尿病控制和并发症试验，该试验表明，强化治疗有效地延迟和减缓了糖尿病视网膜病变(眼睛问题)、神经病变(神经系统问题)和肾病(肾脏问题)的发病和进展。全胰腺移植是控制血糖最成功的方法。作为游离移植物的胰岛移植扩展了针对I型糖尿病患者的β细胞替代疗法的概念。与传统的胰腺移植相比，胰岛移植的吸引力在于其发病率最低，并且相对较少地使用医院资源。胰岛细胞移植的β细胞替代疗法，如果成功，可以逆转高血糖和外源性(从其他来源)胰岛素治疗的需要。绝大多数(95%)的胰岛移植是在同时接受肾移植或已经接受肾移植并因此致力于接受全身免疫抑制治疗的患者中进行的。因此，所有这些患者都已经患有糖尿病的晚期继发性并发症。胰岛移植的目标是能够在疾病过程中足够早地应用它，以便预防这些继发性血管并发症。要做到这一点，必须设计出抗排斥方案，将器官特有的副作用降至最低，同时提供实质性的排斥保护。根据这一线索，埃德蒙顿大学的研究小组对没有慢性肾功能衰竭证据的I型糖尿病患者进行了胰岛移植。如果患者的内生肌酐清除量低于60ml/分钟/m2或患者出现大量蛋白尿(每24小时排泄量大于300毫克)，则排除患者。最近的埃德蒙顿统计数据(2003年1月)指出，移植后一年，84%的患者保持无胰岛素状态，三年后，89%的患者仍在产生胰岛素。在抗白细胞介素1受体抗体诱导过程的窗口内，从第二个捐赠者进行了第二次胰岛移植，在每种情况下，患者都能够停止胰岛素治疗。这项研究建立在先前经验的基础上，并将把应计费用限制在8名患者，这些患者将在移植后至少一年内接受随访。患者将接受一次或多次胰岛细胞移植。将进行各种测试，以确定对外源性胰岛素的需求是否已经减少或完全停止。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The main goal of the study is to achieve long-term (greater than 1 year) insulin independence in patients with type I diabetes mellitus by means of islet cell transplantation from a single donor pancreas. The prevalence of type I diabetes in the United States is estimated to be 800,000 individuals, and the incidence is approximately 30,000 new cases each year. There are no thoroughly preventative or curative measures currently available. The closest has been the Diabetes Control and Complications Trial that demonstrated intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy (eye problems), neuropathy (nervous system problems), and nephropathy (kidney problems). The modality of beta-cell replacement by transplantation of the whole pancreas is the most successful method to control glycemia. Transplantationof the islets as free grafts extends the concept of beta-cell replacement therapy for patients with type I diabetes. The attraction of islet transplantation compared to conventional pancreas transplantation is its minimal morbidity and relative little use of hospital resources. Beta cell replacement therapy by means of islet cell transplantation, when successful, reverses hyperglycemia and the need for exogenous (from other sources) insulin therapy. The vast majority (95%) of islet transplants have been performed in patients who are either simultaneously receiving a kidney transplant or who have already received one and thus are committed to receiving systemic immunosuppressive therapy. Thus, all of these patients already suffered from advanced secondary complications of diabetes. The goal of islet transplantation is to be able to apply it early enough in the course of the disease so that these secondary vascular complications are prevented. For this to occur, anti-rejection regimens must be devised that minimize organ specific side effects while providing substantial protection from rejection. Following this lead, the University of Edmonton group have performed islet transplants in patients with type I diabetes and no evidence of chronic renal failure. Patients were excluded if their creatinine clearance was less than 60ml/minute/m2 or if the patient exhibited macroalbuminuria (greater than 300 mg excretion per 24 hours). Current Edmonton statistics (January 2003) state that one year after transplantation 84 % of patients remain insulin free and that after three years, 89 % of patients are still producing insulin. Within the window of the anti-interleukin-1 receptor antibody induction course, a second islet transplant was performed from a second donor and in each instance, the patient was able to discontinue insulin therapy. This study builds on the strengths of the previous experience and will limit accrual to eight patients that will be followed for at least one year post-transplantation. Patients will receive one or more islet cell transplants. Various tests will be performed to see if demand for exogenous insulin has been reduced or halted altogether.