A Report of the Vancouver Forum on the Care of the Live Organ Donor: Lung, Liver, Pancreas, and Intestine Data and Medical Guidelines

Abstract

An international conference of transplant physicians, surgeons, and allied health professionals was held in Vancouver, Canada, on September 15 and 16, 2005 to address the care of the live lung, liver, pancreas, and intestine organ donor. The Vancouver Forum was convened under the auspices of the Ethics Committee of The Transplantation Society. Forum participants included over 100 leaders in organ transplantation, representing many countries from around the world, including participants from the following continents: Africa, Asia, Australia, Europe, North and South America. The objective of the Vancouver Forum was to develop an international standard of care for the live lung, liver, pancreas and intestinal organ donor. This Vancouver Forum followed a conference convened in Amsterdam on the care of the live kidney donor (1, 2). There were four organ specific work groups at the Vancouver Forum: lung, liver, pancreas and intestine. Each organ work group addressed the following topics in concert and reported their findings in a plenary presentation to all participants: The evaluation of the potential live donor Criteria of live donor medical suitability Operative events, donor morbidity and mortality Responsibility and duration of donor follow up. The Vancouver Forum also provided an opportunity for the Ethics Committee of The Transplantation Society to address issues of informed consent, the responsibilities of the transplant team, live donor selection, autonomy and satisfaction, and procedural safeguards. An ethics statement of the Vancouver Forum pertaining to these issues will be published separately by the Ethics Committee of The Transplantation Society. The transplant community has a responsibility for the care of the live organ donor. The death of a live donor is a tragedy of immeasurable proportion that brings an ethical dimension distinct from the complications that might be experienced in a recipient. Report from the Thoracic Group Live donor lung transplantation generally involves three simultaneous operations: two donor lobectomies and a recipient bilateral pneumonectomy and lobar implantation. The use of live donors is occurring in cases in which the potential recipient mortality is high while awaiting for lung allografts from a deceased donor. With increasing experience however, the practice may expand to include elective patients (3, 4). I. Donor Evaluation The goals of donor selection are to identify donors with excellent health, adequate pulmonary reserve for lobar donation and a willingness to accept the risks of donation without coercion (5, 6). A preference is given for family members or unrelated individuals with emotional attachment to recipient and/or family. A preference is also given for a spouse or donor with “significant other” relationship to the potential recipient. The necessity of two live lung donors for a single recipient also brings a consideration of both parents as donors for the potential recipient. An element of coercion can always exist between any potential donor and the recipient and/or the recipient's other siblings. “Stranger” or “Good Samaritan” donation remains controversial with caution required in the screening process to exclude active or uncontrolled psychiatric disorders or inappropriate motivation, and ensure the altruistic nature of the donation. The donor evaluation is a multi-phased process that begins with the potential recipient and family providing the names of potential donors with basic health information and height, weight, age, relationship, and smoking history. A preliminary psychosocial evaluation of selected donors is performed to assess the desire to donate. This evaluation includes a determination of the donor motivation, pain tolerance, feelings regarding the possible death of the potential recipient (and the donor) and the ability of the potential donor to be separated from family responsibilities and career obligations. Consultation with appropriate authorities regarding postlobectomy employability and insurability (life, disability insurance) is required. Prospective donors should be informed of the morbidity associated with lobectomy and the potential for mortality, as well as for potential negative recipient outcomes in regard to life expectancy and quality of life after transplantation. II. Criteria of Live Donor Medical Suitability The following are the eligibility criteria for living lobar lung donation: Age 18–60 years and able to give informed consent No active tobacco smoking or a significant smoking history No active lung disease/previous ipsilateral thoracic surgery No identifiable risk for familial lung disease (i.e. familial forms of idiopathic lung disease or pulmonary artery hypertension) No cachexia (BMI <18 kg/m2) or obesity (BMI ≥30 kg/m2) ABO blood type compatibility with recipient Donor lobe size compatible with recipient hemithorax Normal pulmonary function and arterial blood gas results No conditions that significantly increase the risk of general anesthesia, surgery, and postoperative recovery No psychosocial, ethical issues, or concerns about donor motivation Not pregnant No active malignancy No active significant infection (HIV, hepatitis, acute CMV) III. Operative Events, Donor Morbidity and Mortality The standard operative live donor lung transplant procedure is for the recipient to undergo a bilateral pneumonectomy and for two live lung donors to provide the left lower lobe and the right lower lobe simultaneously to the recipient (7, 8). Approximately 550 live lung donors constitute 98% of the global experience. The mean age was 38±10 years (range 18–60 years). Sixty percent of the live lung donors have been male, 76% have been related to the recipient and 24% were unrelated. Of the related donors, 40% were parents, 29% siblings, and 15% uncle/aunt. The remainder were cousins 9%, 5% son/daughter, 1% nephew/niece, <1% grandparent, and 1% miscellaneous. Of the live donors that were unrelated to the recipients 74% were friends, 20% spouses, and 6% strangers. To date there has been no reported peri-operative mortality of a lung donor. There have been life-threatening complications in 3 donors (0.5%) with an intra-operative ventricular fibrillation arrest (1) and two with a postoperative pulmonary artery thrombosis. The mean length of the initial hospitalization following the lung lobectomy has been 8.5 days (range 3–36). Approximately 4% of live lung donors have experienced an intraoperative complication that included ventricular fibrillation arrest (1), the necessity of a right middle lobe sacrifice 7 (1.3%), the necessity of a right middle lobe re-implantation 6 (1.1%), the necessity of a non-autologous transfusion PRBC's 5 (0.9%) and a permanent phrenic nerve injury (1). Approximately 5% (27) of donors experienced complications requiring surgical or bronchoscopic intervention. These complications included bleeding (6), bronchopleural fistula (5), pleural effusion (5), empyema (2) bronchial stricture (2), pericarditis requiring pericardiectomy (2), arrhythmias requiring ablation (2) and a chylothorax (1). There were 14 (2.6%) live lung donors that were readmitted to the hospital because of a pneumothorax, an arrhythmia, empyema, pericarditis, dyspnea, pleural effusion, bronchial stricture, bronchopleural fistula, pneumonia, hemoptysis, and dehydration. The long term (> one year) donor complaints of live lung donors include chronic incisional pain, dyspnea, pericarditis, and non-productive cough. IV. Responsibility and Duration of Donor Follow Up A constant awareness of the risk to the living donors must be maintained with any live donor organ transplantation program, and comprehensive short term follow-up should be mandatory. The Vancouver Forum Lung Group recommended that long term follow-up be strongly encouraged and funded by government/insurance authorities. While the outcomes are well known in the recipient population, long-term consequences of live donor lobectomy have proven difficult to ascertain. Factors impeding long term follow-up include expense, distance from the transplant center, willingness of donors to participate, work load to the transplant center, and a general assumption that they are healthy. Many donors live far away from the transplant center and are reluctant to return for follow-up evaluation. The death of the recipient further exacerbates this situation. Whether all donors have returned to their activities of daily living without restrictions is unknown. Responsibility for the care of the donor if complications occur varied widely among the centers represented within the Lung Group based on institution, country, and insurance system. In addition to the normal postoperative surgical clinic visit, recommended follow-up by the transplant center or the medical system in general ranged from one visit sometime between 3 months to one year, to multiple visits starting as early as three months and continuing generally through 1 to 3 years. Recommended testing in the follow-up also varied and included pulmonary function testing, 6-minute walk, chest radiography, quality of life surveys, and psychiatric evaluation. Report from the Liver Group A potential recipient should be determined to be a suitable candidate for liver transplantation prior to the assessment of the potential donor. A set of practice principles was developed for live donor liver transplantation (but these principles could also be considered appropriate for organ transplants from lung, pancreas and intestine donors). Principles of Live Liver Donation Live liver donation should only be performed if the risk to the donor is justified by the expectation of an acceptable outcome in the recipient. The patient and graft survival of a live donor transplant should approximate the expected outcome for a recipient with the same disease etiology undergoing a deceased donor transplant. The indications for live donor liver transplantation should be the same as those established for deceased donor transplantation with the exception of institutionally-approved protocol studies that consider live donor transplantation preferential to liver transplantation from a deceased donor. Live donor liver transplantation should offer an overall advantage to the recipient when compared to waiting for an acceptable deceased donor organ to become available for transplantation. The decision to proceed with a live donor liver transplant should be made after a careful analysis of the recipient risk to benefit ratio as it relates to severity of liver failure, quality of life and expected wait list time for a deceased donor. The estimated risk of mortality and morbidity currently associated with live donor right hepatectomy is 0.4% and 35% respectively. Since the risk to the donor is considerable, programs performing live donor liver transplantation should institute procedures and protocols that insure that donor mortality and morbidity is minimized. Concerning a pediatric recipient of a live liver donor (mostly parental), the patient and graft survival should be superior to the outcome for a recipient of the same disease etiology undergoing a deceased donor transplant. Special Disease Indications for Live Donor Transplantation Special disease entity considerations were addressed that have been considered controversial: hepatocellular carcinoma (HCC), hepatitis C virus infection (HCV), and fulminant hepatic failure (FHF). Hepatocellular Carcinoma HCC fulfilling the Milan criteria (classified as a single tumor less than 5 cm or 3 or fewer tumors, each no more than 3 cm) is an acceptable indication for live donor liver transplantation (9). Until further data are available on improved preoperative staging and long-term follow up, the contraindications for live donor liver transplantation in patients with tumors exceeding the Milan criteria should be the same as that for deceased donor transplantation. Hepatitis C Virus Infection HCV cirrhosis is an acceptable indication for live donor liver transplantation. Early transplantation for hepatitis C with either a live donor or deceased donor may not be beneficial because of the risk of disease recurrence and unpredictable outcome. Thus, the appropriate timing for transplantation in hepatitis C requires further investigation, even though a liver may be more readily available from a live liver donor. Fulminant Hepatic Failure FHF is an acceptable indication for emergency live donor liver transplantation. Centers performing live donor liver transplantation for FHF should have the capacity to expeditiously complete the donor evaluation and education process. The ability to perform a rapid evaluation of the potential donor including blood tests, electrocardiogram, chest x-ray, pulmonary function test, echocardiography, imaging studies of the liver, psychological assessment and evaluation by the ethical board in a 24 to 48 hr time period is considered optimal. I. Donor Evaluation The donor evaluation should be accomplished in a staged protocol that includes an independent donor advocate and a separate assessment of the recipient as a suitable candidate for a partial liver graft. The content of the donor evaluation should include: Initial screening of potential donors Complete history and physical examination Body weight and height (to calculate BMI) Laboratory testing No psychosocial, ethical issues, or concerns about the motivations of the donor. No active or uncontrolled psychiatric disorder. Imaging studies Possible preoperative donor liver biopsy A complete history and physical examination including body weight and height should be obtained to exclude co-morbidities that would significantly increase the donor risk. Biochemical donor evaluation should include: routine blood tests, serologies, a comprehensive coagulation profile and etiologic markers of liver disease. The donor should be screened for relevant endemic diseases that may have a detrimental effect on the donor (and possibly the recipient), e.g. asymptomatic schistomiasis and brucellosis. The psychosocial/psychiatric evaluation should be conducted by a mental health care professional such as a psychiatrist, psychologist or social worker. Appropriate radiologic imaging should be obtained preoperatively to assess liver volume and vascular anatomy. Biliary anatomy may be assessed either preoperatively or intraoperatively based upon the judgment of the surgical team. Donor Liver Biopsy A routine preoperative donor liver biopsy remains controversial (10, 11). The use of the body mass index as a predictor of hepatic steatosis, and thus the need for a donor liver biopsy is not absolute. Accurate quantification of hepatic fat as a contraindication to donation may not be afforded by BMI and imaging studies alone. The recommendation of the Vancouver Forum participants was to suggest that a donor liver biopsy be performed if blood specimen liver tests are abnormal and steatosis or other abnormalities are noted on imaging studies. A liver biopsy may be considered if the BMI >30 or in potential donors genetically related to a potential recipient with autoimmune hepatitis, primary sclerosing cholangitis or primary biliary cirrhosis. II. Criteria of Live Donor Medical Suitability The following are the eligibility criteria for live liver donation: • Age There is insufficient data to define the upper age limit for living liver donation. Based upon reported general surgery data and experimental regeneration data, a limit of 60 years has been considered appropriate. However, live donor liver transplantation has been performed successfully with donors aged >60 years. Minimal age is determined by ability to give legal consent. • Relationship Dr. Christoph Broelsch reported that German transplantation law requires living donors to be first or second degree relatives of recipients or have close emotional ties with them. This condition and the absence of any financial interest for donation are evaluated by an ethical board. The Ethics Board in Germany is completely independent of the hospital evaluation team. A similar process exists in France. In Hong Kong, Doctors ST Fan and CM Lo reported that an application must be submitted to the Human Organ Transplant Board by the potential donor if the donor is not genetically related to the recipient (i.e. friends, in-laws), is a spouse of <3 years, or if the donor is genetically related but without proof of official documents (i.e. birth certificate or marriage certificate) to establish that relationship. For many of Vancouver participants a genetic identity alone is not an essential criterion of suitability (versus sharing an emotional relationship). Otherwise, the use of a non-directed donor likely unknown to the potential recipient (now common in live donor kidney transplantation) was reported to be an unusual circumstance of live liver donation. Body Mass Index General surgical experience indicates that a high BMI (>30 kg/m2) may increase the risk of surgical complications. However, a BMI of >30 may not affect graft quality and it is not an absolute contraindication to live liver donation. Imaging Volumetric imaging analysis may overestimate the actual liver volume by 10%. Donor safety requires a calculated remnant liver of at least 30% of the original liver volume with complete venous drainage. Vancouver Forum participants concluded that in the interest of recipient safety an estimated graft liver volume to recipient body weight ratio (GWBWR) of >0.8% should be achieved. ABO Blood Type Compatible ABO blood type is recommended; however, ABO incompatible blood type live donor transplants may be undertaken in special instances such as infants <1 year of age without the presence of isoagglutinins, and in emergency situations where no deceased donor allograft is available. Liver Biopsy Results that Preclude Donation Histological findings that should preclude living liver donation are: Portal or sinusoidal fibrosis Non alcoholic steatohepatitis (NASH) Steatosis >20% (only for right liver) Portal inflammation and necrotic-inflammatory changes. Dieting is recommended for donors with steatosis. A repeated liver biopsy should be obtained after weight reduction. • Laboratory Blood Tests Blood tests results that confirm donor infection with HIV, HCV or HBV (HBsAg+) are a contraindication for living liver donation. Testing for serum HBV DNA is recommended in donors with detectable anti-HBc with or without anti-HBs. Laboratory testing for a preexisting hypercoaguable condition should be performed especially if the potential donor has a history of venous thrombosis. III. Operative Events, Donor Morbidity and Mortality • Thromboembolism Thromboembolism prevention following live donor liver transplantation is strongly recommended. Further, the presence of any unexplained postoperative cardio-pulmonary symptoms requires a radiologic investigation to exclude pulmonary emboli. • Autologous Blood Storage of autologous blood is utilized by several institutions in the setting of right lobe donation. Technical progress has resulted in very low donor blood loss. Recorded Complications The following definition of a complication was developed by the Vancouver Forum liver work group for a live liver donor: The result of a procedure performed on the donor A deviation from the ideal course Induces changes in management of patients (diagnostic/therapeutic) Occurs during surgical performance or recovery from the procedure. The incidence of complications associated with live liver donation varies widely since a uniform definition of what constitutes a complication has been lacking. The Vancouver Forum participants recommended the international use of the Clavien system to record and grade live donor complications by severity (Table 1) (12), as previously used to assess morbidity of donor (13) and recipient (14) liver transplantation patients. Recently, a revised version of this classification, using a similar therapy based system to grade complications, was proposed, which may also serve to evaluate the outcome of live donors (15).TABLE 1: Clavien classification of surgical complications adapted for live liver donors: gradeA list of donor complications reported in the United States, European and Asian experiences is listed in Table 2 (16, 17). Right lobe liver donation is associated with an increased morbidity (ranging from 20–60%, overall approximately 35%) and more severe complications than that associated with left lobectomy or left lateral segmentectomy.TABLE 2: Survey of liver donor complicationsThe overall incidence of complications in the recently reported NIH sponsored Adult-to-Adult Live Donor Liver Transplant (A2ALL) cohort study is provided in Table 3 (13). At the time of the Vancouver Forum, 1008 donor candidates have been evaluated, 402 went to operating room with the intent of being a live liver donor however only 385 donated. There were 606 not accepted for live donation based upon either donor or recipient reasons.TABLE 3: A list of complications recorded in the Adult-to-Adult Live Donor Liver Transplant (A2ALL) studyEstimated Worldwide Operative Donor Mortality To date, approximately 6000–7000 live donor hepatic resections have been performed worldwide for the purpose of transplantation and the rate of catastrophic complications is estimated to be 0.4–0.6% (Table 4). There have been 14 live donor deaths, 2 donors have undergone liver transplantation secondary to operative complications from right lobe donation and 1 donor is in a persistent vegetative state after donation. Mortality approaches 0.5% for the right lobe donor in contrast to approximately 0.1% for left lobe donation.TABLE 4: Estimated worldwide operative donor mortalityIV. Responsibility and Duration of Donor Follow Up Live donors should be followed postoperatively for at least 1 year after the hepatectomy. Thereafter, follow-up may be desired but may not be always feasible because the residence of the donor is remote to the transplant center. Donor health insurance may influence the feasibility of long-term follow up. The Vancouver Forum participants recommended that a registry of live donor complications be established and that donor deaths be reported to that registry. In the United States, the Organ Procurement and Transplant Network (OPTN) that is run by the United Network for Organ Sharing (UNOS) has recently made a live donor death or the necessity of a liver transplant following a donor hepatic resection a reportable event to the OPTN (18). Several centers offering live donor adult liver transplantation are investigating the impact of donation on the donor's health and quality of life. Results from a survey sent to all individuals undergoing live liver donation in Japan through 2003 was presented at the Vancouver Forum by the Japanese Liver Transplantation Society. Of the 2667 live liver donors, 62% completed the survey with only half of the donors reporting complete recovery by 4 months postoperatively. Another 45% of donors reported near complete recovery with 90% of those individuals back to work or school. Only 3% of donors considered their recovery to be poor. A significant number of donors (40%) expressed anxiety regarding their future health. This anxiety was independent of the extent of liver resection since left lateral segment donors were equally concerned when compared with right lobe donors. Overall recipient mortality in this cohort was 17%. Of the recipients that died, 87% of their donor's were lost to follow-up. The participants of the Vancouver Forum agreed that the transplantation community must continue to monitor the health and long-term outcome of the live liver donor. Financial disincentives to donation and the donor's ability to obtain and maintain health and life insurance must continue to be examined. The participants also considered an outcome that penalizes living donors for the act of donation to be unacceptable. Report from The Pancreas Group Patients with type 1 diabetes who are appropriate candidates for pancreas transplantation may be simultaneously evaluated for suitable living segmental pancreas donors. Potential donors may undergo either segmental pancreas donation alone (for nonuremic or posturemic recipients) or simultaneous segmental pancreas and unilateral kidney donation (for uremic recipients). Once identified, potential donors will be subject to a thorough medical, metabolic and psychosocial screening. ABO and HLA cross-match compatibility is preferred but not mandatory. A segmental donor pancreatectomy can also be applied for islet isolation and allotransplantation (19, 20). I. Donor Evaluation An initial screen will exclude donor candidates with a history of diabetes (including gestational), pancreatic disease, active or chronic infectious or malignant diseases. If a crossmatch between the potential donor and recipient is negative, then a psychosocial evaluation would follow in the form of a screening interview by a social worker, with follow-up consultation with a staff psychiatrist/psychologist if deemed necessary. Caution is required in the screening process to exclude active or uncontrolled psychiatric disorders, and ensure the altruistic nature of the donation. Endocrinology consultation is done by a designated staff endocrinologist and a surgical consult by a designated donor surgeon. Preoperative medical screening includes a detailed history and physical exam and the following laboratory investigations: complete blood count, serum electrolytes, blood coagulation profile, liver function tests, amylase, lipase, uric acid, hepatitis B and C profile, HIV testing, RPR, CMV IgG, EBV IgG, urine analysis; and a 12 lead EKG. Radiologic donor work-up includes chest x-ray and abdominal ultrasound, and after passing the metabolic and immunological tests (see below), an MRA/CTA to assess the anatomy of the pancreas and its vascular supply (19). Additional tests specific for the live pancreas donor include preoperative metabolic screening of the live donor via the following: Fasting glucose level (post 10- to 16-hr fast) Hemoglobin A1c level 3. Oral glucose tolerance test (OGTT) A >150 g carbohydrate diet is given for 3 days prior to the test and usual physical activity. After a 10 to 16 hr fast (water is permitted, smoking is not), a 75 g oral glucose load in 250–300 cc of water is given over 10 min. The end of the drink is time zero. Measurement of glucose and insulin is performed at the following intervals: –10,−5, 0, 15, 30, 60, 90, 120, 150, 180, 240 and 300 min. 4. Intravenous glucose tolerance test (IVGTT) A >150 g carbohydrate diet is given for 3 days prior to the test and usual physical activity. After a 10 to 16 hr fasting period (water is permitted, smoking is not), the test is commenced between 0730 and 1000 hr. A 0.5 g/kg dose (max. 35 g) of glucose is given IV over 3 minutes and 15 seconds. The end of the infusion is time zero. Glucose, insulin, glucagon and C-peptide are measured at the following intervals: –10, −5, 0, 1, 3, 4, 5, 10, 15, 20, 25 and 30 min. Acute Insulin Response (AIR) to glucose is defined as the mean of the 3, 4 and 5 min insulin values following the glucose injection with the basal value subtracted. Glucose disposal rate (Kg) is defined as the slope of the natural log of glucose values between 10 and 30 min. after injection. First phase insulin release (FPIR) is defined as sum of insulin levels at 1 and 3 min. 5. Arginine stimulation test (AST) At the 35 min mark of the above test, 5 g of arginine (arginine HCl 10%) IV push is given over 30 seconds. Zero time is at the end of the bolus. Measurement of glucose, insulin, glucagon and C-peptide is performed at the following intervals: 0, 2, 3, 4, 5, 7, 10, 25 and 30 min. Acute insulin response (AIR) to arginine is defined as the mean of the peak three insulin values between 2 and 5 min following the arginine injection with the basal value subtracted. 6. Glucose potentiation of arginine-induced insulin secretion (GPAIS) About 60 min after the last blood draw in the above test, a glucose infusion (D20W) at 900 mg/min is started through an IV pump. The infusion is maintained for 70 min. At minute 60, 5 g of arginine (10% arginine HCL) IV is given over 30 seconds. The end of the bolus is time zero. Measurement of glucose, insulin, glucagon and C-peptide is performed at the following intervals: 2, 3, 4, 5, 7 and 10 min. Acute insulin response at 900 mg/min glucose potentiation (AIR-900) is defined as the mean of the three peak insulin values between 2 and 5 min. with the basal value subtracted. 7. Insulin auto-antibodies (IAA) Measured by fluid phase radio-assay incorporating competition with cold insulin and precipitation with polyethylene glycol. 8. GAD 65 auto-antibodies (GAA) Measured in triplicate by radio-assay, using in vitro transcribed and translated recombinant human GAD (65-kDa isoform) and precipitation with protein A-sepharose. 9. Islet cell antigen 512 auto-antibodies (ICA512) ICA512 is measured by radio-immunoassay in duplicate using a 96-well plate format using a recombinant ICA512 protein. Based on the history and physical exam in combination with the screening tests the following criteria will have to be met, in order to be considered a potential live segmental pancreas donor. II. Criteria of Live Donor Medical Suitability General Inclusion Criteria Male and female segmental pancreas donor volunteers should be between the ages of 18 and 60. However, some parental donors greater than 60 years of age would be acceptable in Japan. The difference regarding the age criterion in Asian countries may be necessitated because of the current lack of deceased donor alternatives. The potential donor should be capable to provide written, informed consent; be mentally competent and be able to comply with the procedures and postoperative follow-up. Donor participatio