1 Allocation of Donor Livers in the People’s Republic of China Wenshi JIANG1, Wen LI1, Haibo WANG2, Sheung Tat FAN2 1 2 China Liver Transplant Registry, Shenzhen, China and Department of Surgery, The University of Hong Kong, Queen Mary Hospital, Hong Kong, China Keywords: Allocation, Liver transplantation Word count: 2280 Number of tables: 2 Number of figures: 2 2 Footnotes Corresponding author: Professor Sheung Tat FAN Department of Surgery The University of Hong Kong Queen Mary Hospital 102 Pok Fu Lam Road Hong Kong China Tel: (852) 2255 4703 Fax: (852) 2986 5262 E-mail: stfan@hku.hk Abbreviations: PRC, People’s Republic of China; OPO, organ procurement organization; MELD, Model for End-stage Liver Disease; PELD, Pediatric End-stage Liver Disease; HCC, hepatocellular carcinoma; COTRS, China Organ Transplant Response System Declaration: All authors participated in the study design; data analysis, and interpretation of data; drafting and critical review of the manuscript; and they have all seen and approved the final version. There is no conflict of interests in this article. 3 Abstract Liver transplantation is the mainstream treatment for patients with end-stage liver diseases saving thousands of lives each year in the People’s Republic of China (PRC). Since the first clinical liver transplantation in 1978, new techniques and strategies to improve patient survival have evolved in China. While patient survival after liver transplantation has greatly improved in recent years, the shortage of donor organs has become the major issue limiting the development of liver transplantation. Similar to the early experience in the United States and the United Kingdom, the shortfall between the demand for and supply of donor organs has given rise to an equitable organ allocation system. The Human Organ Transplant Regulation promulgated by the State Council of the PRC in 2007 called for the development of a fair and transparent organ allocation and sharing system in China. In December 2010, the first national liver and kidney allocation policy of the PRC was officially initiated by the Ministry of Health. The purpose wasto maximize the utilization of organs for patients in need of transplantation and enhance public trust on the equitable and transparent organ allocation and sharing system in China. The China Organ Transplant Response System (COTRS) was launched nationwide in April 2011 to identify the best match between donors and recipients, and to ensure the traceability of each donor organ. The first successful organ allocation by the COTRS for controlled donation after cardiac death was accomplished one week after the system launched and symbolized the establishment of a national organ allocation and sharing network in China. 4 Background Liver transplantation is one of the greatest successes in medicine and is now saving thousands of lives each year in the People’s Republic of China (PRC). The first clinical liver transplantation in China was performed in 1978 (1). However, China then had a moratorium period with total suspension of liver transplantation for more than 10 years until 1993, when there was a remarkable growth in the number of liver transplants (1). As of December 2009, the cumulative number of liver transplants in the PRC was 16089, which was the second largest number of liver transplantations performed worldwide (Figure 1). Similar to the US and the UK, the disparity between donor organ demand and supply has widened as organ transplantation has evolved from a high-risk experimental procedure to an effective therapeutic modality for patients with end-stage liver diseases (2, 3). Such imbalance has made an equitable organ allocation system inevitable and imperative (4, 5). The Legal Framework “The Human Organ Transplant Regulation” promulgated by the State Council of the PRC in 2007 assigns the Ministry of Health and provincial public health authorities governance over clinical organ transplantation and initiation of an equitable organ allocation system in China(6). Having gone through a research phase conducted by the China Liver Transplant Registry and an open comment period conducted by the national Organ Transplant Committee, the first national liver and kidney allocation policy of the PRC was enacted and announced by the Ministry of Health in December 2010. The specific aims were: optimize the availability of organs for patients in need of 5 transplant and ensure that the allocation procedures are in compliance with the principles of fairness, equality and transparency. The policy clearly states the objectives to be achieved and the principle to be followed in the construction of an organ allocation and sharing framework. It also provides guidelines for determining organ allocation to patients on the liver and kidney transplant waiting list and the criteria of organ matching. Allocation of Deceased Donor Livers Principles of justice, fairness, equity and transparency have been acknowledged as the golden criteria in allocating organ by the international transplant community (7, 8). Under these rules, all allocation policies are evaluated by organ utility/wastage, waitlist mortality, recipient post-transplant survival, transplant benefit, allocation efficiency and the extent to which they can be achieved. What complicates the rationale in policy making are the tradeoffs between these measures. To reach an approach in keeping with the national criteria for organ allocation, the OTC reached a consensus on the following principles and objectives: Ranking of organ transplant candidates should be based upon sound medical need that adheres with the principles of fairness, equity and transparency. Allocation and sharing of organs should serve medical purposes. The transplant team has the rights to decline an unsuitable organ for a specific candidate based upon rational medical judgments. The allocation policy should minimize waiting list mortality as its first priority. On the premise that waiting list mortality is kept to the lowest level, the best patient and graft survival is considered the second priority of the allocation policy . 6 As far as organ utility is concerned, the allocation policy should minimize organ wastage and maximize the efficiency of organ allocation. To promote equity, the allocation policy should take into account the disparity in medical/demographic characteristics among candidates. Those with biological or medical disadvantages should be given an equitable opportunity to receive a transplantable organ. The allocation policy should be periodically reviewed and revised. Geographic Distribution of Donor Organs The organ distribution area is expanded using the following approach until a suitable candidate is found. Distribution within a transplant center: When the donor’s host hospital is one of the certified liver transplant centers in the PRC, the waiting list of the donor’s host hospital is considered first. Distribution within transplant centers serviced by the host organ procurement organization (OPO) of the donor liver: The distribution area includes the waiting lists of all transplant hospitals within the service area of a specific OPO (this is also the minimal distribution area when the host hospital of the donor is not one of the certified transplant centers in the PRC). Distribution within a region where the donor’s host hospital is located: The distribution area includes the waiting lists of all the transplant hospitals within the province where the host hospital is located. 7 Distribution within the country: The distribution area refers to the national waiting list. Organ Allocation Ranking Criteria Disease Severity The ranking system is designed to accommodate three groups of patients under three main diagnosis categories. Ranking priorities are given to candidates in the same geographic distribution area based primarily on their urgency for a transplant with little regard to the waiting time. Candidates with fulminant hepatic failure are granted the first priority on the waitlist and are labeled as super urgent candidates (Table1). The definitions of super urgent candidates are similar to those for 1A candidates currently adopted by the United Network for Organ Sharing(9). The Model for End-stage Liver Disease (MELD) and Pediatric End-stage Liver Disease (PELD) scoring systems have been adopted for allocation of deceased donor livers to those with chronic liver disease(10). An exception system promoted by Wiesner,et al is incorporated into the MELD scoring system for candidates diagnosed with hepatocellular carcinoma (HCC)(11). However, the T1 tumor(12) will not earn additional points when applying the HCC exception under the current policy. The issue will be reconsidered afterl sufficient data has been collected to address its necessity. The status of active candidates on the waiting list requires timely updating according to their current MELD/PELD scores. HCC Candidates The effect of the MELD scoring system in predicting the 3-month waitlist mortality has 8 been reported in several previous studies (13-15). Nevertheless, the MELD exception scoring system is imperfect. It places HCC candidates with lower MELD scores to preferentially receive a donor organ (Figure 2) yet, does not consider the risk of drop-out due to progression of HCC. Data from the US suggested similar results (11, 16). HCC recipients accounted for almost 50% of the liver transplant recipients pool in the PRC(17). This finding urges the need to incorporate an exception system for HCC candidates into the MELD-based system in order to eliminate the inequality. The Milan criteria (18)(a single lesion 5 cm in diameter or three lesions 3 cm diameter each) was employed although the expansion of this criteria is under debate. HCC candidates meeting the Milan criteria but exceeding T1 stage (Table 2) will be assigned a mortality risk of 30% if their MELD score computed from the laboratory data is less than this. Application of the HCC exception system should be accompanied by a report of the alpha-fetoprotein level. Re-certification is required every 3 months. An increase of 10% in the mortality score will be assigned to those who have been successfully granted extension upon each re-certification. ABO Blood Type Compatibility Candidates with blood type incompatible to the donor are not considered in the donor-recipient matching unless they are of the super urgent status or have MELD/PELD scores equal or higher than 30. Waiting Time 9 Calculation of waiting time for a liver candidate is initiated at the time of listing. In principle, the waiting time for a candidate is calculated as the sum of the waiting time accrued at the current MELD/PELD score and the waiting time accrued at any previous higher scores. For a super urgent candidate, the waiting time is the cumulative length of time he/she is/was currently and previously at this status registered on the liver waiting list. For a candidate with a particular MELD/PELD score, his/her time of waiting is the length of time he/she remains at the current level plus those days he/she accrued at any previous higher (or equal) scores except the super urgent status. Within a distribution area, candidates under the same MELD score level are ranked based upon their waiting time and blood compatibility. Other Priorities Candidates below 12 years old have a priority to receive livers recovered from donors under 12 years old. To encourage organ donation, ranking priority is also granted to those who were living donors or any of the immediate family members was a deceased donor. The Allocation Program A computer program named the China Organ Transplant Response System (COTRS) was launched in April 2011 for implementation of organ allocation. Patient MELD/PELD scoring, donor-recipient matching and organ allocation and sharing are processed automatically by the computer system in compliance with the national organ allocation policy. This ensures the equality of the organ allocation process and the traceability of each donor organ. One week after the launch of COTRS, with a growing national waiting list, the first 10 successful organ allocation and sharing of a controlled donation after cardiac death utilizing COTRS was accomplished in the General Hospital of Guangzhou Military Command PLA and the First Affiliated Hospital of Sun Yat-Sen University, China. The liver and kidneys recovered from a 29-year-old blood type O donor were transplanted into three recipients on the waiting list. This milestone transplant marked the initiation of the national organ allocation and sharing network in the hope of promoting effective and efficient national organ allocation and sharing in China. For supervision purpose, the Ministry of Health and provincial public health authorities can monitor each allocation procedure effectively by logging into the monitoring platform of the system. Cases that do not follow the allocation rules will be captured and recorded in a real-time fashion by the system. COTRS also serves to collect scientific data for evaluation of the current policies. The Road Map of COTRS Establishment of Donor/Transplant Candidates Screening Modules No uniform definition for donor acceptance criteria or the patient selection criteria for listing/removal from waiting list has been reached at the national level. In order to understand the clinical behavior of these selection and listing/delisting procedures, two corresponding screening modules will be established in COTRS to capture detailed raw data bundled with the process of screening. The donor screening module will serve as a decision making support system to facilitate OPO navigation through the complex process of donor screening, 11 as well as an evaluation tool to assess the performance of the OPO system in China. The patient screening module introduces convenience in patient listing and removal from waiting list. The impact of these selection procedures on the donation rate and waiting list mortality can be analyzed through the scientific data collected in the processes. Minimum Standards for OPO Recently, the national Organ Transplant Committee announced the first hospital-based OPO to be founded in the 163 certified transplant centers around the country. As far as the organ allocation and sharing is concerned, the service area of each OPO should be defined in order to optimize the availability of organs and eliminate inequities in geographical organ distribution. For the purpose of regulating practices of the OPO, minimum standards need to be established for improving the quality and protecting the safety of both donors and recipients. What followed is the establishment of the certificate authority and performance assessment system for OPO based on empirical evidence and measurement indexes. Periodical Scientific Review on Allocation Policies The lack of historical waitlist data in the planning phase of the allocation schema may result in an imperfect solution for liver allocation in China. In the early research phase of policy development, the research team from the China Liver Transplant Registry extensively reviewed allocation policies of 15 countries worldwide. Due to the similarity of geographic distribution and population census, many organ allocation polices and algorithms developed in the US were considered suitable for adoption by the China organ allocation system. 12 Although the ranking criteria in use are widely recognized by the international transplant community, the suitability of these criteria for use in a different population of patients remains unclear. Issues such as the effect of HCC patient selection criteria on the scoring system, incorporation of donor factor or post-transplant benefit, and the extent to which organ sharing is compulsory for the super urgent candidates should be addressed and brought to further investigation. Independent and multidisciplinary scientific reviews of the allocation policy will be scheduled regularly for ensuring that the allocation system is as equitable as possible. Conclusion Organ shortage is one of the main hindrances to the healthy development of liver transplantation in the PRC(1). Although different surgical strategies, such as living donor liver transplantation and split-liver transplantation, have been promoted to expand the organ pool(19), an allocation system that distributes organs in a fair, unbiased way is highly desirable. The organ allocation and sharing network in the PRC is built upon a firm legal framework that is derived from evidence-based practices. The Ministry of Health of the PRC is responsible for governing the clinical application of organ transplantation including organ allocation. The allocation policy for deceased livers and kidneys has been developed to promote equality and efficiency in organ distribution. Ranking guidelines have been devised for those with fulminant hepatic failure, HCC and other chronic liver diseases. The system has been designed in a way to assure that organs are equitably allocated to patients with the most urgent medical need with little regard to the waiting time. The current 13 allocation system is imperfect. Nevertheless, it is believed that the establishment of the organ allocation and sharing network will lead organ transplantation in China towards its healthy development. 14 References 1. Huang J. Ethical and legislative perspectives on liver transplantation in the People's Republic of China. Liver Transpl. 2007;13(2):193-6. 2. Malago M, Rogiers X, Broelsch CE. Liver splitting and living donor techniques. Br Med Bull. 1997;53(4):860-7. 3. Taylor MJ, Baicu SC. Current state of hypothermic machine perfusion preservation of organs: The clinical perspective. Cryobiology. 2010;60(3 Suppl):S20-35. 4. Merion RM, Sharma P, Mathur AK, Schaubel DE. Evidence-based development of liver allocation: a review. Transpl Int. 2011. 5. Cherkassky L. Rational rejection? The ethical complications of assessing organ transplant candidates in the United Kingdom and the United States. J Law Med. 2010;18(1):156-68. 6. Regulation on Human Transplantation: Order of the State Council of the People’s Republic of China No. 491. 2007 [cited 2011-07-14]; Available from: http://www.moh.gov.cn/publicfiles/business/htmlfiles/mohylfwjgs/s3576/200804/29213. htm 7. UNOS Rationale for Objectives of Equitable Organ Allocation. 1996 [cited 2011-07-18]; Available from: http://www.unos.org/about/index.php?topic=newsroom&article_id=1503 8. Neuberger J, Gimson A, Davies M, Akyol M, O'Grady J, Burroughs A, et al. Selection of patients for liver transplantation and allocation of donated livers in the UK. Gut. 2008;57(2):252-7. 15 9. UNOS. UNOS Policy 3.6:Organ Distribution: Allocation of Livers. Richmond, Virginia; 2010. 10. MELD/PELD Calculator Documentation. 1/28/2009 [cited 2011-07-18]; Available from: http://www.unos.org/docs/MELD_PELD_Calculator_Documentation.pdf 11. Wiesner RH, Freeman RB, Mulligan DC. Liver transplantation for hepatocellular cancer: the impact of the MELD allocation policy. Gastroenterology. 2004;127(5 Suppl 1):S261-7. 12. Group ALTS. A randomized prospective multi-institutional trial of orthotopic liver transplantation or partial hepatic resection with or without adjuvant chemotherapy for hepatocellular carcinoma. Richmond, Va: United Network for Organ Sharing; 1998. 13. Freeman RB, Jr., Wiesner RH, Harper A, McDiarmid SV, Lake J, Edwards E, et al. The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl. 2002;8(9):851-8. 14. Freeman RB, Wiesner RH, Edwards E, Harper A, Merion R, Wolfe R. Results of the first year of the new liver allocation plan. Liver Transpl. 2004;10(1):7-15. 15. Kamath PS, Wiesner RH, Malinchoc M, Kremers W, Therneau TM, Kosberg CL, et al. A model to predict survival in patients with end-stage liver disease. Hepatology. 2001;33(2):464-70. 16. Pomfret EA, Washburn K, Wald C, Nalesnik MA, Douglas D, Russo M, et al. Report of a national conference on liver allocation in patients with hepatocellular carcinoma in the United States. Liver Transpl. 2010;16(3):262-78. 17. CLTR 2009 Annual Scientific Report : Liver Transplantation for 16 HepatocellularCarcinoma. China Liver Transplant Registry; 2010. 18. Mazzaferro V, Regalia E, Doci R, Andreola S, Pulvirenti A, Bozzetti F, et al. Liver transplantation for the treatment of small hepatocellular carcinomas in patients with cirrhosis. N Engl J Med. 1996;334(11):693-9. 19. Chung HY, Chan SC, Lo CM, Fan ST. Strategies for widening liver donor pool. Asian J Surg. 2010;33(2):63-9. 17 Figure1. Numbers of liver transplantation in the world (2000-2009) U.S.A ( N=59600 )1 Australia&New Zealand ( N=1947 ) European ( N=14790 ) 2 Scandia ( N=2608 ) 4 5 China ( N=16089 ) 3 Number of Transplants 7,000 6,000 5,000 4,000 China 3,000 2,000 1,000 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Transplant Year Source: 1. Based on OPTN data as of July 06, 2011. http://optn.transplant.hrsa.gov/data/annualReport.asp 2. Anuanl Report 2010.Eurotransplant International Foundation. http://www.eurotransplant.org 3. Based on CLTR data of June 1, 2011. China Liver Transplant Registry. http://www.cltr.org 4. ANZLT Registry Report 2009. Australia & New Zealand Liver Transplant Registry. http://www.anzltr.org 5. NLTR 2010 Annual Report. The Nordic Liver Transplant Registry. http://www.scandiatransplant.org 18 Figure 2. Distribution of MELD scores at liver transplantation in China (1980-2010) Source: China Liver Transplant Registry analysis, June 2011 19 Table 1. Definition of super urgent status on the liver transplant waiting list in China An adult candidate (18 years old) in one of the following categories with a life expectancy without a liver transplant of less than 7 days can be listed as a super urgent candidate. Adult Category 1 Fulminant hepatic failure: Fulminant hepatic failure is defined as the onset of hepatic encephalopathy within 8 weeks of the first symptoms of liver disease. Besides staying in the intensive care unit, one of the three criteria below must be met: (i) ventilator dependence; (ii) requiring dialysis or continuous veno-venous hemofiltration or continuous veno-venous hemodialysis; (iii) international normalized ratio >2.0. Adult Category 2 Primary non-function of the transplanted liver graft: The diagnosis of primary non-function of a transplanted liver graft should be made within 7 days of transplantation, meeting one of the following: (i) aspartate aminotransferase ≥3,000 U/L as well as an international normalized ratio ≥2.5 and/or acidosis, defined as having an arterial pH≤7.30 or venous pH of 7.25 and/or lactate≥ 4mMol/L; or (ii) anhepatic candidate. All labs must be from the same blood drawn within 24 hours to 7 days following the transplant. Adult Category 3 Hepatic artery thrombosis in a transplanted liver graft within 7 days of transplantation, and meeting one of the conditions (i) (ii) in Adult Category 2. Adult Category 4 Acute decompensated Wilson disease A pediatric candidate (<18 years old) in one of the following categories with a life expectancy without a liver transplant of less than 7 days can be listed as a super urgent candidate. Pediatric Category 1 Fulminant hepatic failure: Fulminant liver failure is defined as the onset of hepatic encephalopathy within 8 weeks of the first symptoms of liver disease. Besides staying in the intensive care unit, one of three criteria below must be met: (i) ventilator dependence; (ii) requiring dialysis or continuous veno-venous hemofiltration or continuous veno-venous hemodialysis; (iii) international normalized ratio >2.0. Pediatric Category 2 Primary non-function of the transplanted graft: The diagnosis is made within 7 days of transplantation; additional criteria to be met for this indication must include two of the followings: (i) aspartate aminotransferase ≥2000 U/L; (ii) international normlized ratio ≥2.5; (iii) total bilirubin ≥10 mg/dl; (iv) acidosis, defined as having an arterial pH≤ 7.30, venous pH of 7.25 or lactate ≥4mMol/L. All labs must be from the same blood drawn within 24 hours to 7 days following the transplant. Pediatric Category 3 Hepatic artery thrombosis: The diagnosis must be made within 14 days of transplantation. Pediatric Category 4 Acute decompensated Wilson disease 20 Table 2. Hepatocellular carcinoma (HCC) exception for candidates on the liver transplant waiting list Hepatocellular carcinoma exception Candidates with HCC diagnosed on the basis of imaging results that meet both of the following conditions are eligible for the HCC exception: (i) a single lesion >=1.9 but <5 cm in diameter or three lesions <3 cm diameter each. (ii) no extrahepatic metastasis or macrovascular involvement (portal or hepatic vain) has been found. Application for an HCC exception should be accompanied by the alpha-fetoprotein level. Re-certification is required every 3 months. An increase of 10% in mortality score will be assigned to those who have been successfully granted extension upon each re-certification.