Porcine Kidney Xenotransplantation in Patients With End-Stage Kidney Disease
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 试验地点
- 2
- 主要终点
- Patient Survival After Porcine Transplant
研究概览
简要总结
The mismatch between organ supply and demand results in the deaths of thousands of Americans each year. Our research group aims to solve this unmitigated health care crisis by translating advances in xenotransplantation to humans and expanding organ supply in a sustainable fashion using genetically modified pigs as a source of organs. We propose here a phase I clinical trial of porcine kidney xenotransplantation into 20 people with end-stage kidney disease. Source donor animals are pigs with 10 gene edits (10-GE) which attenuate immunologic harm to the kidney xenograft. 10-GE pigs are housed in a designated pathogen-free facility within 30 minutes of the transplantation center. Xenotransplantation procedures follow conventional practices currently employed in allotransplantation and comply with multiple regulatory standards to ensure ethical treatment of research subjects and source animals. Recruitment and xenotransplantation will occur over 5 years with study follow-up extending 1 year after xenotransplantation. Primary outcome variables surround patient safety, such as patient survival and the rate of zoonotic disease transmission. Secondary outcome variables include commonly used metrics of graft survival and function.
详细描述
Twenty patients with ESKD listed for kidney allotransplantation at UAB will be enrolled to receive either one or two porcine kidney xenotransplants from a 10-GE pig donor, contingent on the pig's overall size at the time of procurement.
Recruitment and xenotransplantation will occur over a five-year time period. Patients will undergo follow-up of one year post-xenotransplant with study extension if graft survival exceeds one year.
Participants will undergo prospective crossmatching with a 10-GE pig to determine histocompatibility prior to xenotransplant. After performance of a negative crossmatch, procurement of the donor pig will occur in a surgical suite at the designated pathogen-free facility near the UAB campus where the donor herd is maintained.
Porcine kidney(s) will be transported under sterile and hypothermic conditions to the main UAB hospital. The porcine kidney(s) will be transplanted into the research subject in standard surgical fashion within the abdomen and immunosuppression will be administered. The induction immunosuppression regimen utilized will mirror that used in human-to-human allotransplantation; this regimen represents current standard-of-care. After transplantation, kidney health will be assessed biochemically, histologically, and radiographically. Subjects will be monitored for potential zoonotic disease transmission and blood-based chimerism as well as thrombocytopenia or indicators of consumptive coagulopathy, development of anti-human leukocyte antigen antibody/alloantibody sensitization.
FOLLOW-UP PHASE
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Ages 18-75 years
- •Body mass index (BMI) 18-40 kg/m2
- •Waitlisted for kidney allotransplantation at UAB
- •Dialysis dependent
- •Proficient in the English language
- •Presence of risk factors for
- •high wait list mortality, AND/OR
- •anticipated or actual prolonged wait time on the wait list, AND/OR
- •inability to access a suitable organ offer.
- •Note: Examples of risk factors include high cPRA, frequent incompatible crossmatches leading to prolonged wait times, listing at an advanced age, and impending loss of dialysis access, recurrent disease in previous transplants.
- •Crossmatch compatible with porcine donor
- •SARS-CoV-2 vaccination in accordance with most recent CDC guidance
- •Willingness to obtain other standard-of-care vaccinations for kidney transplant recipients (MMR, HBV, Herpes Zoster, etc.) and for patients receiving eculizumab (Menactra® and Bexsero®)
- •Reside within a 60-minute radius of the UAB hospital (by ground transport)
排除标准
- •Age <18y or ≥ 76y
- •BMI ≤ 18 or ≥ 41 kg/m2
- •Current pregnancy
- •Presence of severe comorbid disease, including but not limited to uncontrolled HTN or DM (hemoglobin A1C (HgA1C) >10%), advanced cardiovascular disease, absent surgical targets for implantation, etc.
- •Presence of hypercoagulable disorder
- •Inability to accept a blood transfusion
- •Intolerance of immunosuppression
- •History of medical non-compliance
- •Presence of untreated psychiatric disease
- •Significant psychosocial vulnerability and/or poor social support
- •Current use/abuse of illicit drugs and/or abuse of alcohol
- •History of psychiatric hospitalization
- •Inability to provide informed consent
- •Pre-emptive transplant
- •Inability to comply with study protocols and procedures
结局指标
主要结局
Patient Survival After Porcine Transplant
时间窗: 12 months
These time points align with both biologic events that occur after transplantation (i.e., immune reconstitution after T cell depletion) as well as conventional transplant outcome metrics used by regulatory authorities (i.e., Organ Procurement and Transplantation Network, United Network for Organ Sharing)
Prevalence of thrombocytopenia or indicators of consumptive coagulopathy after transplant with porcine kidney
时间窗: Month 12
Consumptive coagulopathy has been observed in some non-human primate models of transplant with a pig kidney. Thrombocytopenia was also observed in the UAB brain-dead recipient but could not be attributed to the porcine kidney given the altered physiology of brain death.
Prevalence of blood based chimerism after transplantation
时间窗: Month 12
The presence of donor-derived cells in the blood stream of a transplant recipient can either portend graft versus host disease (GVHD) or be diagnostic of the disease
Development of anti-human leukocyte antigen (HLA) antibody/alloantibody sensitization after transplant with a porcine kidney
时间窗: Month 12
It is currently unknown whether porcine kidney xenografts will ever function sufficiently to become a destination therapy for patients with ESKD. However, if porcine kidney xenografts have modest longevity, there may be benefit to temporary rescue from dialysis. Porcine kidney xenografts may then act as a bridge to human allotransplantation. Thus, there is the need to determine whether porcine kidney xenografts provoke the development of anti-HLA antibody and sensitize recipients against human allografts. Such sensitization may prevent xenograft recipients from ever receiving a human allotransplant, and the frequency of this event must be determined in order to counsel patients effectively about the risks of participating in additional trials of xenotransplantation.
次要结局
- Histologic outcomes including:(Through study completion, an average of one year)
- Infectious outcomes including:(Through study completion, an average of one year)
- Immunologic outcomes:(Through study completion, an average of one year)
- Kidney outcomes including:(Through study completion, an average of 1 year)
- Cardiovascular outcomes including:(Through study completion, an average of one year)
研究者
Jayme E Locke
Professor
University of Alabama at Birmingham