학술연구용역과제최종결과보고서

학술연구용역과제최종결과보고서

연구결과점검보고서요약문 간장응급도기준개선방안연구 - 한국형 MELD(Model for End stage Liver disease) 모형의개발 1

Summary 2

학술연구용역과제연구결과 3

4

5

6

2000년 2월장기등이식에관한법률 ( 장기법 ) 이발효되면서국내뇌사자간장의배분은 CTP 점수 (Child-Turcott-Pugh score) 를근간으로한 Status 개념으로배분되었다. 그러나 UNOS(the United Network o Organ Sharing) 에서는 2002년부터간장의배분을 MELD 점수 (Model for End Stage Liver Disease score) 를근간으로변경하였으며 (MELD era), 이러한 MELD system은여러국가에서뇌사자간장분배의원칙으로사용되고있는것이현재의상황이다. 본연구는한국형 MELD System 을개발하기위한작업의일환으로, 향후개발하고자 하는간이식대기자의위급도의척도를국내실정에맞게검증함으로서예측이가능한 7

척도를개발하는기본자료로사용될수있다. 이는국내간이식대기자의예후예측및 간이식의요구도를측정하는유용한척도로향후연구과제의기본자료로사용된다. 8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

MELD점수체계상의기준점 결과물 전체 MELD >= 30 Fig. 6 Status 2A MELD >= 25 Fig. 7 Status 2B MELD >= 30 Fig. 8 Status 3 MELD >= 25 Fig. 9 소아간이식대기자 PELD >= 20 Fig. 16 급성간부전 MELD >= 35 Fig. 19 35

36

37

38

Issues in Liver allocation system for deceased donor liver transplantation 39

40

41

1. Kim MS, Kim SI, Kim YS. Current Status of Deceased Donor Organ Recovery and Sharing in Korea. J Korean Med Assoc 2008;51:685-91 2. Wiesner RH, McDiarmid SV, Kamath PS, Edwards EB, Malinchoc M, Kremers WK, et al. MELD and PELD: application of survival models to liver allocation. Liver Transpl 2001;7:567-80. 3. Malinchoc M, Kamath PS, Gordon FD, Peine CJ, Rank J, ter Borg PC. A model to predict poor survival in patients undergoing transjugular intrahepatic portosystemic shunts. Hepatology 2000;31:864-71. 4. Santori G, Andorno E, Morelli N, Antonucci A, Bottino G, Mondello R, et al. MELD score versus conventional UNOS status in predicting short-term mortality after liver transplantation. Transpl Int 2005;18:65-72. 5. Dutkowski P, Oberkofler C, Bechir M, Mullhaupt B, Geier A, Raptis DA et al. The model of end-stage liver disesase allocation system for liver 42

ytansplantation saves lives, but increase morbidity and cost: A prospective outcome analysis. Liver Transpl 2011;17:674-684 6. Cywinski JB, Mascha EJ, You J, Sessler DI, Kapural L, Argalious M, Parker BM. Pre-transplant MELD and sodium MELD score are poor predictors of graft failure and mortality after liver transplantation. Hepatol Int 2011;5:841-849 7. KONOS. 2010 Annual Data Report [Internet]. Seoul: KONOS. 2011;[cited 2012 May 5]:Available from: http://www.konos.go.kr 8. Kim MS, Kim SI, Kim YS. Current Status of Deceased Donor Organ Recovery and Sharing in Korea. J Korean Med Assoc 2008;51:685-91 9. Joo DJ, Kim MS, Kim SI, Jeon KO, Huh KH, Choi GH et al. Severity of end-stage liver disease in liver transplant candidate; Comparison of KONOS status with MELD score. J Korean Soc Transplant 2012;26:112-119 10. Hong G, Lee KW, Suh SW, Yoo T, Kim H, Park MS, Choi Y, Yi NJ, Suh KS. The Model for End-Stage Liver Disease score-based system predicts short term mortality better than the current Child-Turcotte-Pugh score-based allocation system durinh waiting for decesed liver transplantation. J Korean Med Sci 2013; 28: 1207-1212 11. KONOS. 2012 Annual Data Report [Internet]. Seoul: KONOS. 2012;[cited 2013 Nov.5]:Available from: http://www.konos.go.kr 43

44

45

46

47

48

CRF : 한국형 MELD System 개발 : 간이식대기자의생존분석의작성요령 1. 등록군 2009 년 1 월 1 일부터 2011 년 12 월 31 일까지간이식대기자로새로이등록한환자 2. 제외군다장기이식대기자 연구군등록대상 연구군추적조사기간 2009-01-01 2010-01-01 2011-01-01 2012-01-01 2013-01-01 등록병원의이름을적으시면됩니다. 관리번호는각등록병원마다일련번호로작성하여주십시요. 관리번호에해당되는환자의신상정보는별도로관리합니다. 대규모연구이다보니간질환의구분을간략하게하였습니다. Others 밑칸에질환을적어주어도됩니다.( 선택사항 ) 동반질환이있는경우에는 V 표시를해주십시요. 표시가없는경우에는동반질환없는것으로간주합니다. None: Liver cancer-free HCC: Hepatocellular carcinoma Non-HCC: HCC 이외의 liver cancer HCC+cholangiocarcinoma 인경우에는 non-hcc 로표기바람 49

Date 1 = KONOS 등록일이원칙이나간기능정도의변동이없는범위내에서 1 달이내로기록하세요 성인과소아를구분하기위한조치로 V 로표시 등록당시의 HCC 의상태를표시한다. Stable: 기존의 HCC 가그대로유지된경우 New HCC: 등록시점 1 개월이내에새로이확인된경우 Recurred, Local: 등록시점 1 개월이내에재발이된경우 KONOS 등록일 = Date 1 을기준으로이전에시행한 HCC 처치를요약한다 Local ablation : TACE, RFA, RTx on Liver Resection: only surgical resection Others: CCRT, systemic chemotherapy 시행한경우에는횟수에관계없이 V 표시를하여주십시요. 중복투여가능 CTP/MELD 점수는다른검사결과와임상증상이작성된경우에는빈칸으로두어도됨소아인경우에는 PELD 값은 MELD 값에기록한다. Date 2 의자료는 Date 1 부터 Date 2 사이의변화를기록한다. Date 3 의자료는 Date 2 부터 Date 4 사이의변화를기록한다. Date 2, Date 3 는유의한수준의간기능의변화혹은 HCC 의변화가있는경우작성한다. Date 2/Date 3 시점의 HCC 상태를표시한다. Stable: 기존의 HCC 가그대로유지된경우 New HCC: 중간기간중에새로이확인된경우 Recurred, Local: 중간기간중에재발이된경우 중간기간중에시행한 HCC 처치를요약한다 Local ablation : TACE, RFA, RTx on Liver Resection: only surgical resection Others: CCRT, systemic chemotherapy 시행한경우에는횟수에관계없이 V 표시를하여주십시요. 중복투여가능 50

Date 4 는마지막추적조사결과를기록한다. 4 가지중에하나만을선택한다 이식을시행한경우에는이식직전의임상상태를, 사망혹은탈락한경우에는사망혹은탈락직전의임상상태를, 추적조사누락인경우에는마지막추적조사시기의일상상태를, 대기상태인경우에는마지막추적조사시기의임상상태를기록한다. 관리장부작성요령 아랫부분의인정사항이기입되면자동으로계산이됩니다. 이부분에피험자의인적사항을작성하여주십시요. 관리번호는일련번호로, 병원번호는각병원의인식번호로, 성별은남 :1, 여 :2 로기입합니다. 51

KONOS Era from 2000.02 to 2011.11 대한이식학회 2013년춘계학술대회대한이식학회정책과제중간보고 2013년 4월 27일 ( 토 ), 경주현대호텔 13 Jan. 1979, First deceased donor and kidney transplantation à pre-konos Era 9 Feb. 2000, Law for Brain death and Organ Transplantation à KONOS Era 16 Feb. 2000, First deceased donor and organ allocation in KONOS Era After 2006, Increment of deceased donor - 20010 Dec, 2,091 deceased donor and 6,290 solid organ allocation were performed KONOS KODA 간장응급도기준개선방안연구 ( 한국형 MELD 모형의개발 ) I. 간이식대기자생존분석 No. per year 1200 1000 800 600 400 No. of Allocation organ No. of Recovery donor 1,169 867 409 368 268 200 0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 Year Last update: 2013.01.10 Living donor versus Deceased donor in Liver transplantation 국내간이식대기자선정기준 Living donor liver transplantation is still major portion of liver transplantation in Korea Proportion of deceased donor liver transplantation was slightly increased (18.4% à 25.9%) Yearly census (No.) Liver Transplantation 1000 800 600 400 200 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 42 37 28 50 64 66 118 127 233 236 242 313 Deceased Living 186 286 335 364 480 530 560 620 873 995 835 896 % DD 18.4% 11.5% 7.7% 12.1% 11.8% 11.1% 17.4% 17.0% 21.1% 19.1% 22.5% 25.9% 기증자체중에따른대기자응급도동일권역항목별점수 2. 간장가. 장기기증자체중의 0.5배부터 2.0배까지에해당하는이식대기자중에서이식대상자선정나. 위에해당하는이식대기자 2인이상인경우응급도가가장높은순위로선정. 동일응급도에 2인이상인경우 (1) 1순위 : 기증자와동일권역안에있는대기자 (2) 2순위 : 기증자와다른권역에있는대기자다. 나항목의규정에따라대기자가선정되지않는경우동일권역안에있는대기자중에서응급도가높은순위로선정라. 나또는다항목의규정에해당하는대기자가 2인이상인경우에다음의항목에부여된점수의합계가가장높은자선정 (1) 이식대기자의나이 (2) 이식대기자의대기시간 (3) 장기기증과거력여부및배우자, 직계존비속, 형제자매또는 4촌이내의친족중뇌사자장기기증을한과거력여부 (4) 장기기증자와의혈액형동일여부 (5) 장기기증자와이식대기자의지리적근접도마. 기증자와의간의크기와대상자의크기를고려할때간장을분할하여이식할수있는경우국립장기이식관리기관의장은이식대상자의이식수술을담당하는장기이식의료기관의장과협의하여분할이식대상자를추가로선정가능 Last update: 2012.10.10 간장이식대기자의응급도 Emergency Allocation of Liver 50~60% Organ/Status 2008 2009 2010 2011 2012.10 Total Status 3 Status 2B Status 2A Status 1 Chronic liver disease with compensations (CTP score 7) Hepatocellular carcinoma Stage III/IV Chronic liver disease with compensations (CTP score 7) Hepatocellular carcinoma Stage I/II Chronic liver disease with decompensation : CTP score 10 + bleeding / Hepatorenal SD / Hepatic encephalopathy / uncontrolled ascites Need Retransplantation Fulminant hepatic failure Liver status 1 25 27 17 29 17 115 status 1,Retransplant 2 5 4 8 10 29 status 2A 118 124 131 193 177 743 status 2B 84 74 86 78 89 411 status 3 4 6 4 5 6 25 계 233 236 242 313 299 1,323 Intestine status 1 2 0 0 1 0 3 status 2 0 1 1 1 0 3 계 2 1 1 2 0 6 Heart status 0 11 10 8 15 13 57 status 1 47 28 29 30 26 160 status 2 23 25 13 26 28 115 status 3 3 2 23 27 20 75 계 84 65 73 98 87 407 Lung status 0 19 15 34 status 1 5 6 11 status 2 6 8 13 10 2 39 8.7% 2.2% 56.2% 67.0% 31.1% 33.0% 1.9% need Re-evaluation of allocation system status 3 1 0 3 1 8 13 status 7 2 2 계 7 8 18 35 31 99 Last update: 2012.11.30 52

MELD/PELD System, from 2002 MELD / PELD = Model for End stage Liver Disease Prognosis prediction in End stage liver disease Difference versus conventional parameter : Based on Objective data MELD score as a Risk on Waiting List Serial change of MELD score 3 month mortality Morality risk during waiting : Linear correlation Child-Pugh score= Ascites + Bilirubin + Albumin + PT + Encephalopathy Clinical Application of MELD in Liver Allocation Effect of MELD in Liver Allocation Follow-up Schedule by MELD score MELD Interval Laboratory Less than 6 months Clinic visits should be used not only to update the condition of the patients 10 or 1 year with assessment of clinical or subclinical portosystemic encephalopathy, 11~18 3 months ascites, and edema, but also to obtain the parameters used for MELD 19~24 Monthly scoring along with a full battery of liver tests, creatinine, electrolytes, complete blood count, and prothrombin time. >=25 Weekly Periodic ultrasound and computed tomography (CT) / magnetic resonance imaging of the liver is appropriate to rule out the development of HCC. Waiting time Mortality during waiting Effect of MELD in Liver Allocation (II) 간장대기자선정기준의검토를위한 TFT ( 간장 TFT) Medical Severity Morbidity and Cost 2011 년 12 월 27 일질병관리본부로부터공문접수됨. 성명 직위 KONOS 간장분과위원 학교 / 병원 지역 2011년 12월 29일대한이식학회 / 대한간이식연구회 TFT 구성 2012년 1월 5일 KONOS 간장분과위원회개최및 TFT 위원확정 2012년 1월 14일 TFT 1차회의 2012년 1월 26일 TFT 2차회의 2012년 2월 2일 KONOS, 장기이식코디네이터와의면담결과 2012년 2월 11일추가회신정리 2012년 2월 21일 KONOS 제출보고서 ( 안 ) 질병관리본부에회신함 김순일 위원장 연세대세브란스 1권역 병원 김명수 위원 / 간 KONOS 간장 연세대세브란스 1권역 사 분과위원 병원 서울대병원 이광웅 위원 KONOS 간장 1권역 분과위원 유희철 위원 KONOS 간장 전북대병원 2권역 분과위원 최동락 위원 KONOS 간장 대구가톨릭대병원 3권역 분과위원 황신 위원 KONOS 간장 울산대아산병원 1권역 분과위원 권준혁 위원 KONOS 간장 성균관대서울삼 1권역 분과위원 ( 예 성병원 정 ) 김동식 위원 고려대안암병원 1권역 나양원 위원 울산대병원 3권역 유영경 위원 가톨릭대서울성 1권역 모병원 최인석위원건양대병원 2 권역 53

간장대기자선정기준의검토를위한 TFT ( 간장 TFT) Re-Evaluation of Allocation Principles 1. 과연장기배분의원칙이대기시간이나대기중 대기자사망률을줄일수있는가? 2. 과연장기배분의원칙이보다의학적으로응급 한환자에게유리한가? 3. 과연장기배분의원칙이장기이식관련된의학적인자즉이송시간의증가, 냉허헐시간의증가, 다른장기와의동반적출의장애등의부정 National-based analysis Multi-center analysis Single-center analysis 적인인자를증가시키지않는지? 4. 과연장기배분의결과로이식후성적이호전될 것인지아니면나빠질것인지? 5. 과연장기배분의원칙이지역적인배분에서적 재평가및해결 절한지? 2013 년도정책과제및학술용역과제 - 연구대상군 2013 년도정책과제및학술용역과제 추진일정및참여병원 N=3,000 New Registration from 2009 to 2011 (3 years) Minimal F/W= 1 year 참여병원 : 전국 11 개장기이식센터 + 추가모집중 김명수 연세대교수 권준혁 성균관의대교수 이광웅 서울의대교수 김동식 고려의대교수 최동락 가톨릭의대교수 나양원 울산대병원교수 최인석 건양의대교수 유영경 가톨릭의대교수 왕희정 아주대의대교수 유희철 전북의대교수 황신 울산의대교수 2013 년도정책과제및학술용역과제 - 연구내용 2013 년도정책과제및학술용역과제 - 연구내용 CTP score + Status versus MELD 추적조사 : (1) Transplantation 시행여부 (2) 대기기간중질환의진행여부 (3) 대기기간중환자사망여부 MELD score CTP score Status 54

2013 년도정책과제및학술용역과제 기여도및활용방안 2013 년도정책과제및학술용역과제 중간보고 Data Collection : Until March 31, 2013 Study population : from 11 transplantation Center, 2,719 candidates were enrolled. N= 2,719 Liver transplant registration N=58 Exclude due to incomplete data N=954 (35.9%) Transplantation N=716 (26.9%) Drop out or Mortality N=253 (9.5%) Follow-up Loss 간장이식대기자선정기준을재설정함에있어서기초자료로활용할수있다 N=738 (27.7%) On Waiting 2013 년도정책과제및학술용역과제 중간보고 2013 년도정책과제및학술용역과제 중간보고 Prognosis by Status at registration Transplantation Probability by Status at registration 100% 9.6 2.4 80% 60% 40% 20% 0% 24.4 47.3 46.5 43.3 27.8 17.5 47.3 42.1 38 27.2 1 2A 2B 3 Loss Waiting Death Tx Transplantation Probability 60.3% 52.0%* 46.5%* 30.9% 13.0%* 18.2% 7.2%* 65.5% 40.7% 25.3% Status 1 Status 2A Status 2B Status 3 Status at registration * : means transplantation rate within 14 days Post-registration days 2013 년도정책과제및학술용역과제 중간보고 2013 년도정책과제및학술용역과제 중간보고 Deceased /Living Donor Transplantation Probability by Status at registration Patient Survival Rate by Status at registration Deceased donor Living donor 94.3% 85.4% Transplantation Probability 44.4% 29.5% Status 1 Status 2A Status 2B Transplantation Probability Survival rate 82.2% 38.3% 68.3% 35.7% 71.9% 54.6% Status 3 Status 2B Status 3 Status 1 Post-registration days Post-registration days 22.6% 19.4% Status 2A % means transplantation rate within 14 days Status 1: Transplantation Probability = 46.5% = 29.5% (Deceased) + 23.2% (Living) Status 2A: Transplantation Probability = 52.0% = 44.5% (deceased) + 13.3% (Living) Post-registration days 55

2013 년도정책과제및학술용역과제 중간보고 2013 년도정책과제및학술용역과제 중간보고 Patient Survival Rate by MELD/PELD score at registration Patient Survival Rate by MELD/PELD score at registration in Status 2A 97.1% 91.9% 93.5% 78.0% 75.3% MELD<10 68.6% Survival rate 30.8% 60.2% 49.3% 59.3% MELD, 10-19 MELD, 20-29 Survival rate 44.7% 34.3% MELD, 10-19 19.6% 17.0% MELD 30 22.4% MELD, 20-29 15.2% 10.1% MELD 30 Post-registration days Post-registration days 56

57

58

Introduction Allocation Issue in Deceased Donor Liver Transplantation CAST 2013, State of Art September 4, 2013 Kyoto International Convention Center, Kyoto, Japan Allocation Issue in Deceased Donor Liver Transplantation Comparison between Status with CTP score and MELD score in allocation of deceased donor liver ; Korean National-based survey??? Poor data for Liver allocation in Asian country Liver Transplantation 2002;8:851-858 Summary of Transplantation Situation in Korea Recent Situation in Korea; KONOS Era from 2000.02 Since 2008, 13 Jan. 1979, First Deceased donor and kidney transplantation à pre-konos Era 9 Feb. 2000, Law for Brain death and Organ Transplantation à KONOS Era 16 Feb. 2000, First Deceased donor and organ allocation in KONOS Era After 2008, Increment of deceased donor - 2012 Dec, 2,868 deceased donor and 8,768 solid organ allocation were performed Explosive increasing of DD Proportion of DD transplantation But, Waiting list also increased in higher ratio 1400 1200 No. of Allocation organ No. of Recovery donor KONOS KODA 1,309 1,169 Organ Shortage!!!! Debate about Liver Allocation No. per year 1000 800 600 400 867 409 368 268 200 Japanese Journal of Transplantation 2008; 43(6):416-422 0 1979 1981 1983 1985 1987 1989 1991 1993 1995 1997 1999 2001 2003 2005 2007 2009 2011 Year Deceased Donor Recovery Rate, year 2012 Living donor versus Deceased donor in Liver transplantation in Korea Donor recovery rate per million population of Korea was 8.40 in 2012 Rate Country No. 1,643 34.80 Spain 8,143 26.01 USA 1,589 24.90 France 252 24.02 Portugal 117 23.49 Norway 190 22.50 Austria 1,332 22.40 Italy 108 19.92 Finland 1,056 17.00 UK 354 15.60 Australia 531 15.14 Canada 143 15.03 Sweden 1,046 12.80 Germany 409 8.40 Korea 57 7.30 Israel 528 6.90 Iran Estimated Recovery Rate 51 7.20 Hong Kong Est. No. Est. Rate 134 5.77 Taiwan 343 4.54 Turkey 400 8.40 413 3.53 Mexico 500 10.50 65 3.42 Romania 600 12.60 83 3.07 Saudi Arabia 800 17.00 110 0.86 Japan 18 0.64 Malaysia 0 5 10 15 20 25 30 35 Recovery rate (per million population) Living donor liver transplantation is still major portion of liver transplantation in Korea Proportion of deceased donor liver transplantation was increased (18.4% à 28.8%) Liver Transplantation 1000 800 Yearly census (No.) 600 400 200 0 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 42 37 28 50 64 66 118 127 233 236 242 313 363 Deceased Living 186 286 335 364 480 530 560 620 873 995 835 896 897 % DD 18.4% 11.5% 7.7% 12.1% 11.8% 11.1% 17.4% 17.0% 21.1% 19.1% 22.5% 25.9% 28.8% International Registry of Organ Donation and Transplantation (IDROaT), http://www.irodat.org 59

Allocation Rule in Korea, Liver Definition of Emergency Status by Law The Allocation rule is provided in the transplantation law which is established at 2000. The Allocation rule is provided in the transplantation law which is established at 2000. Size Matching Candidate weight is ranged in 0.5 ~ 2.0 of donor weight Status 3 Chronic liver disease with compensation (CTP score 7) Hepatocellular carcinoma Stage III/IV Disease Severity 1 st Regional Emergency status Status 2B Chronic liver disease with compensation (CTP score 7) Hepatocellular carcinoma Stage I/II Regional Priority 2 nd National Emergency status 3 rd Regional Non-emergency status 4rd National Non-emergency status Status 2A Status 1 Chronic liver disease with decompensation : CTP score 10 + Varices bleeding / Hepatorenal SD / Hepatic encephalopathy / uncontrolled ascites Score for Waiting List Age, Waiting time, Previous donation history, Matching degree of ABO blood type, Nearness from donor Fulminant hepatic failure Need Retransplantation Provide priority for 2 weeks Emergency Allocation of Liver, Recent 5 years in Korea Organ/Status 2008 2009 2010 2011 2012.10 Total Liver status 1 25 27 17 29 17 115 8.7% status 1,Retransplant 2 5 4 8 10 29 2.2% 67.0% status 2A 118 124 131 193 177 743 56.2% 31.1% status 2B 84 74 86 78 89 411 33.0% 1.9% status 3 4 6 4 5 6 25 233 236 242 313 299 1,323 계 Intestine status 1 2 0 0 1 0 3 status 2 0 1 1 1 0 3 Heart 계 2 1 1 2 0 6 Above 2/3 of deceased donor liver was allocated in Emergency status status 0 11 10 8 15 13 57 status 1 47 28 29 30 26 160 status 2 23 25 13 26 28 115 status 3 3 2 23 27 20 75 84 65 73 98 87 407 계 Lung status 0 19 15 34 status 1 5 6 11 status 2 6 8 13 10 2 39 status 3 1 0 3 1 8 13 status 7 2 2 7 8 18 35 31 99 계 Exclusive Allocation of Liver MELD/PELD System, from 2002 MELD / PELD = Model for End stage Liver Disease Prognosis prediction in End stage liver disease Difference versus conventional parameter : Based on Objective data 3 month mortality Child-Pugh score= Ascites + Bilirubin + Albumin + PT + Encephalopathy MELD score as a Risk on Waiting List Effect of MELD system in Liver Allocation (I) Serial change of MELD score Waiting time Mortality during waiting Morality risk during waiting : Linear correlation 60

Effect of MELD system in Liver Allocation (II) Considerations before Application of MELD system in Korean Situation Medical Severity Morbidity and Cost Is Acceptable MELD System in Korean Situation? Korean Transplantation Situation ; Differences from Western Korean Situation UNOS/OPTN 2011 HBV-induced cirrhosis, more than 60% HCV, 23.5% Frequent Hepatocellular carcinoma, about 40% 20.9% Too Late registration, MELD 25, more than 20% 1.8% Living donor transplantation, above 60% DD:LD=96.8% : 3.2% National-based Survey for Waiting List Study design of Waiting List Survey Overview New Registration for isolated liver transplant from 2009 to 2011 (for 3 years) Minimal follow-up = 1 year 11 Transplant Centers are participate in this survey Data Collection : Until March 31, 2013 Study population : from 11 transplantation Center, 2,702 candidates were enrolled. Mean Follow-up duration : 349 ± 412 days (~1,526 days) New Registration N= 2,702 Liver transplant registration N=967 (35.8%) Transplantation N=349 (36.1%) Deceased donor N=601 (62.2%) Living donor 2009 2010 2011 2012 2013 Clinical data Registration Data Waiting Data Demographics Follow-up duration CTP score + status Prognosis MELD score Transplant Data Liver disease Drop out/mortality Data Combined HCC Recurrence of HCC N=719 (26.6%) On Waiting N=750 (27.8%) Drop out or Mortality N=266 (9.8%) Follow-up Loss N=17 (1.8%) Overseas transplant N=724 (96.5%) Drop out or Mortality N=26 (3.5%) Recovery N=69 (25.9%) <14 days N=197 (74.1%) 14 days consider as survival exclude in survival analysis Overall Prognosis Data Collection : Until March 31, 2013 Study population : from 11 transplantation Center, 2,702 candidates were enrolled. Mean Follow-up duration : 349 ± 412 days (~1,526 days) Transplant Rate by Status at registration Overall Transplant Status 2A N=488 (67.4%) Liver failure N=100 (13.8%) New & Advanced HCC Transplant Rate Status 1 Status 2B Status 3 N=136 (18.8%) others Post-registration days N 14 D 30 D 3 Mo 1 Y 2 Y 3 Y 117 45.2 Status 1 Status 2A 174 52.4 60.4 65.4 68.5 80.3 80.3 Status 2B 1592 13.0 21.2 31.1 41.1 47.7 51.0 Status 3 750 7.1 12.7 18.4 25.2 31.4 34.1 61

Transplant Rate by Status at registration Deceased donor Transplant Transplant Rate by Status at registration Living donor Transplant Transplant Rate Status 2A Status 1 Transplant Rate Status 2A Status 1 Status 2B Status 2B Status 3 Status 3 Post-registration days 30 D 3 Mo 1 Y N 14 D 2 Y 3 Y 117 27.6 Status 1 Status 2A 174 45.0 48.6 53.1 57.4 64.5 73.3 Status 2B 1592 3.0 5.3 9.4 17.1 24.7 27.8 Status 3 750 0.1 1.0 1.7 3.2 7.9 9.2 Post-registration days 30 D 3 Mo 1 Y N 14 D 2 Y 3 Y 117 23.5 Status 1 Status 2A 174 13.0 22.5 25.7 Status 2B 1592 10.3 16.7 23.5 27.9 29.4 31.1 Status 3 750 7.3 11.8 16.8 22.0 24.8 26.7 Deceased /Living Donor Transplant Rate by Status at registration Learning from Transplant Rate Analysis Overall Transplant rate = Deceased donor + Living donor (around 20%) in Korea Deceased donor Living donor + % transplant cases in waiting interval 50 40 30 Living donor Deceased donor 20 10 0 14 D 30 D 3 Mo 6 Mo 1 Y after 1 Y I. Living donor Liver Transplantation Living donor transplantation was decided in early period(3 months) after registration. After then, transplant rate by living donor is deceased. II. Deceased donor Liver Transplantation Exclusive allocation of deceased donor liver to Status 2A within 14 days Transplant rate is increasing after 1 year after registration Exclusive allocation of liver to Status 1 or 2A Transplantation Rate within 14 days Deceased Living Status 1 27.6% 23.5% Status 2A 45.0% 13.0% Status 2B 3.0% 10.3% Status 3 0.1% 7.3% Remarkable difference of transplant rate by Status causes allocation issue Arising Issue from Transplant Rate Analysis Survival Rate of waiting list by Status at registration Transplant Rate by deceased donor within 14 days Status 2A Status 2B 45.0% 3.0% Is all Status 2A urgent? Is all Status 2B stable? Allocation rule must be verified by mortality rate of waiting list Survival rate Status 3 Status 2B Status 1 Status 2A Post-registration days N 14 D 30 D 3 Mo 1 Y 2 Y 3 Y 70 43.6 38.9 33.7 31.6 Status 1 Status 2A 91 34.1 20.9 11.4 9.1 6.8 Status 2B 968 90.0 83.1 75.1 60.2 50.4 44.7 Status 3 537 98.1 95.7 92.6 83.3 74.4 68.5 62

Survival Rate of waiting list by MELD score at registration Survival Rate of Waiting list by MELD score at registration, in Status 2A <15 15~19 20~24 Survival rate 25~29 Status 2A Survival rate <25 30~34 35 25~29 30~34 35 Post-registration days 30 D 3 Mo 1 Y N 14 D 2 Y 3 Y MELD <15 747 99.9 99.3 97.1 88.3 76.8 68.3 MELD,15-19 325 96.9 94.7 88.6 66.5 56.0 51.6 MELD, 20-24 166 90.3 79.8 70.2 49.3 36.8 33.5 MELD, 25-29 154 77.8 61.8 45.7 34.5 32.5 31.1 MELD, 30-34 114 57.0 39.0 25.4 19.7 17.5 MELD 35 160 40.0 23.7 15.8 13.5 13%(12/91), superior survival Post-registration days 30 D 3 Mo 1 Y N 14 D 2 Y 3 Y 12 75.0% 58.3% 33.3% 22.2% 11.1% MELD <25 MELD, 25-29 18 55.6% 33.3% 16.7% MELD, 30-34 22 27.3% 18.2% 12.1% MELD 35 39 15.4% 5.1% 2.6% Survival Rate of Waiting list by MELD score at registration, in Status 2B Survival Rate of Waiting list by MELD score at registration, in Status 3 Status 3 Status 2B <15 <15 15~19 15~19 Survival rate 30~34 20~24 25~29 Survival rate 20~24 35 25 15%(148/968), inferior survival Post-registration days 30 D 3 Mo 1 Y N 14 D 2 Y 3 Y MELD <15 360 99.7% 99.2% 96.0% 85.2% 70.9% 61.3% MELD,15-19 230 96.5% 93.9% 87.1% 62.4% 50.2% 43.4% MELD, 20-24 123 92.7% 81.2% 73.8% 51.2% 40.0% 35.4% MELD, 25-29 107 84.1% 68.1% 52.3% 40.5% 37.9% 36.1% MELD, 30-34 67 64.2% 42.7% 23.9% MELD 35 81 56.8% 29.6% 20.7% Post-registration days 30 D 3 Mo 1 Y N 14 D 2 Y 3 Y MELD <15 385 100.0% 99.5% 98.4% 91.4% 82.6% 74.7% MELD, 15-19 86 98.8% 98.8% 95.2% 79.3% 72.4% 72.4% MELD, 20-24 33 90.9% 84.2% 65.9% 46.5% 25.9% MELD 25 33 81.8% 53.3% 38.5% 25.0% 20.0% Learning from Survival Analysis of Waiting List Hepatocellular Carcinoma, Effect on Liver Transplant Rate & Allocation Living donor transplantation P=0.006 Deceased donor transplantation P=0.002 versus Compared to Status with CTP score, the MELD system provide accurate correlation with liver disease severity and better prediction of mortality during waiting time Transplantation rate Post-registration days HCC HCC-free Transplantation rate Post-registration days HCC-free HCC This data provide the rationale for change of allocation rule in Korea N 30 D 3 Mo 6 Mo 1 Y 2 Y HCC-free 1,272 12.0% 17.3% 20.7% 22.9% 24.9% HCC 1,077 16.6% 23.3% 26.1% 27.4% 29.4% N 30 D 3 Mo 6 Mo 1 Y 2 Y HCC-free 1,272 7.6% 11.2% 13.0% 15.8% 22.1% HCC 1,077 4.2% 5.5% 9.1% 10.8% 17.3% 63

Hepatocellular carcinoma, Prognosis during Waiting time Hepatocellular carcinoma, Prognosis during Waiting time 1/3 of mortality or drop out was caused by aggravation of HCC More than 40% of HCC was aggravated during waiting time Aggravation of HCC occurred between 1 and 2 years after registrarion Recurrent rate of HCC after registration N=121 (46.7%) Liver failure N=94 (36.3%) Advanced HCC N=44 (17.0%) others N=275 (51.1%) Stable HCC N=22 (4.1%) unclear N=241 (44.8%) Advanced HCC HCC Recurrent rate Post-registration days N 30 D 3 Mo 6 Mo 1 Y 2 Y 3 Y Recurrent 538* 0.4% 2.3% 5.0% 14.2% 48.1% 69.9% * exclude Center No.=2 due to incomplete data Hepatocellular Carcinoma, Effect on Survival rate of Waiting list Pediatric Transplantation, Prognosis Presence of HCC did not affect survival rate in MELD 20 Presence of HCC affect long-term survival after 1 year in MELE < 20 This study provide the restrictive information about pediatric transplant MELD < 20 LELD 20 HCC-free P=0.347 N= 106 Liver transplant registration N=23 (32.4%) Deceased donor Survival rate P=0.003 HCC Survival rate HCC HCC-free N=71 (67.0%) Transplantation N=14 (13.2%) Drop out or Mortality N=48 (67.6%) Living donor N=0 Overseas transplant N=13 (92.9%) Drop out or Mortality N=1 (7.1%) Recovery consider as survival Post-registration days 30 D 3 Mo 6 Mo N 1 Y 2 Y 474 97.2% 92.9% 88.3% 82.9% 76.9% HCC-free HCC 573 98.6% 95.9% 89.9% 80.9% 65.2% Post-registration days 30 D 3 Mo 6 Mo N 1 Y 2 Y 379 50.3% 39.2% 31.9% 27.3% 22.3% HCC-free HCC 90 64.4% 42.3% 34.9% 30.1% 23.3% N=17 (16.0%) On Waiting N=4 (3.8%) Follow-up Loss N=0 (0%) <14 days N=4 (100.0%) 14 days exclude in survival analysis given MELD score =20 point in HCC patients Pediatric Transplantation, Transplantation Rate & Waiting Survival rate Pediatric Transplantation, Waiting Survival rate Early transplant by Living donorm Late transplant by deceased donor In spite of limited numbers, survival of waiting list was correlated with PELD score. Deceased donor Deceased Transplantation rate PELD<10 PELD,10-19 Transplantation rate Living + Post-registration days Living donor Survival rate Survival rate PELD,20-29 PELD 30 Post-registration days Transplantation rate Post-registration days N 14 D 30 D 3 Mo 6 Mo 1 Y Post-registration days N 14 D 30 D 3 Mo 6 Mo 1 Y N 14 D 30 D 3 Mo 1 Y 2 Y 106 28.0% 42.4% 58.4% 68.8% 76.4% All Transplant Deceased 106 2.4% 6.8% 25.7% 39.0 48.7% Living 106 26.02% 38.1% 45.3% 48.8% 53.9% Post-registration days All Pediatrics 35 85.7% 74.3% 71.4% 68.4% 62.7% PELD <10 11 100.0% 100.0% 100.0% 90.9% PELD,10-19 6 100.0% 100.0% 83.3% PELD, 20-29 12 75.0% 58.3% 58.3% 41.7% PELD 30 6 66.7% 33.3% 64

Acute Liver Failure, Prognosis Acute Liver Failure, Transplantation Rate Registration with Acute liver failure shows 1/4 recovery from acute liver disease Transplant was performed by both living and deceased donor. Almost transplantation performed within 30 days. N= 179 Liver transplant registration N=63 (35.2%) Transplantation N=84 (46.9%) Drop out or Mortality N=2 (1.1%) Follow-up Loss N=30 (16.8%) On Waiting N=28 (44.4%) Deceased donor N=35 (55.6%) Living donor N=0 Overseas transplant N=62 (73.8%) Drop out or Mortality N=22 (26.2%) Recovery N=1 (50.0%) <14 days N=1 (50.0%) 14 days consider as survival exclude in survival analysis Transplantation rate Living+Deceased Post-registration days N 14 D 30 D 3 Mo 1 Y 2 Y 178 36.4% 41.4% 41.4% All Transplant Deceased 178 19.6% 21.8% 21.8% Living 178 20.4% 24.2% 25.6% + Transplantation rate Transplantation rate Deceased donor Post-registration days Living donor Post-registration days Acute Liver Failure, Survival rate Summary; Learning from National based Survey In spite of limited numbers, survival of waiting list was correlated with MELD score. Is Acceptable MELD System in Korean Situation? may be Yes MELD<20 Korean Transplantation Situation ; Differences from Western MELD,20-24 Korean Situation UNOS/OPTN 2011 Survival rate Survival rate MELD,25-29 MELD,30-34 HBV-induced cirrhosis, more than 60% HCV, 23.5% Frequent Hepatocellular carcinoma, about 40% 20.9% Minor effect MELD 35 Too Late registration, MELD 25, more than 20% 1.8% Living donor transplantation, above 60% DD:LD=96.8% : 3.2% Major effect Post-registration days 14 D 30 D 3 Mo N 6 Mo 1 Y 115 58.0% 53.3% 47.1% 43.7% All ALF * ALF: Acute liver failure Post-registration days 14 D 30 D 3 Mo N 6 Mo 1 Y 8 100.0% 100.0% 100.0% 83.3% MELD <20 MELD,20-24 10 80.0% MELD,25-30 24 70.8% 70.8% 56.3% MELD,30-34 26 65.4% 57.4% 52.6% 46.8% MELD 35 47 36.2% 29.8% 25.4% 23.0% Modification of allocation rule must performed after precise evaluation of transplant situation 65