Liver transplantation in Romania: present and future.

1. Center of General Surgery and Liver Transplantation Fundeni Clinical Institute BUCHAREST ROMANIA Liver transplantation in Romania: present and future. IrinelPopescu, MD, FACS, FEBS Professor of Surgery

2. INTRODUCTION Possible solutions • Liver transplantation (LT) has become an established treatment for end-stage liver disease, with more than 20.000 procedure annualy worldwide. • The request for LT continues to increase while the donor pool size remains inadequate. Kim WR, Stock PG, Smith JM, Heimbach JK, Skeans MA, Edwards EB, et al. OPTN/SRTR 2011 annual data report: liver. Am J Transplant 2013;13(suppl 1):73-102.

3. EPIDEMIOLOGICAL DATA Death rates per 100,000population from liver cirrhosis in European countries; WHO MortalityDatabase 2000-2002

4. Prevalence (%) of liver diseases in Europe

5. Inter-country comparison of the number of deaths per year; WHO, 2008

6. DONOR POOL SIZE ORGAN DONATION GLOBALLY Source: Global Observatory on Donation & Transplantation (WHO/ONT)

7. Deceased donation rates per million population Source: 2014 Transplant Newsletter (2013 data)

8. The rates of organ donation varies due to social, cultural or legal factors: • 30 organ donor per million in Spain – highest in Europe, • 20 in US, • 16 in UK, • <10 in New Zealand, • <6 in Romania. • About 75-80% of donors provide a liver for LT.

9. WAITING LIST • The liver transplantation waiting list has grown continuously over the past decade in the context of a profound organ shortage Increased mortality rate on the WL Prolonged time on the WL Lack of emergency LT supply • In US – ~10 000 new pts added each year on the WL, with ~15000 still on the WL by the end of the given year. Thuluvath PJ et al.Am J Transplant 2010; 10: 1003–1019; Busuttil RW, Tanaka K. Liver Transplant 2003; 9: 651–663; Rodrigue JR. American Journal of Transplantation 2011; 11: 1705–1711 Organ Procurement and Transplantation Network.Liver Transplantation Waiting List. 2000-2011.

10. By the end of 2013: • 6700 pts on WL in EU (508,000,000 population)  13.2 / 1,000,000 • 454 pts on WL in Romania (19,960,000 population)  22.7 / 1,000,000 • Necessity to significantly increase the overall number of LTs

11. Waiting List in Romania

12. Overall mortality on waiting list Fundeni Clinical Institute 2004- Dec. 2011 2012 – June 2016 N=856 pts N=919pts Median overall survival -30.84 months 1-yr mortality rate - 31.4% 3-yr mortality rate - 54.1% 5-yr mortality rate - 63.5% – not reached – 4.4% - 13.9% - 23.6% Gheorghe L, Iacob S, Popescu I (not published data) Gheorghe L, Iacob S…..Popescu I, J Gastrointestin Liver Dis 2014

13. Waiting time until LT Median waiting time OI – 19 months AII – 37.5 months BIII – 23.8 months ABIV – 28.4 months

14. LIVER TRANSPLANTATION Liver transplants per million population Source: 2014 Transplant Newsletter (2013 data)

15. First LT (15th of April 2015) 46-yr old man, HBV cirrhosis (MELD 19) Whole liver LT (April 2000) - 33-yr old compatible donor Alive at 16 yrsafterLT 17.05.2015

16. Stages of development Early stage of development Low-volume center (up to 20 pts/yr) 2000 – 2006 Group 1: 96 pts Intermediate stage Mid-volume center (20 to 50 pts/yr) 2007 – 2010 Group 2: 148 pts Advanced stage High-volume center (over 50 pts/yr) 2011 – 2016 Group 3: pts

17. April 2000 – September 2016 LT in pts ( re-LT) Performed inRomania M/F ratio: / ; mean age 45 yrs (median 50, range 7 mo - 68 yrs) LT/year 122 96 73 Center of General Surgery andLiver Transplantation - Fundeni Clinical Institute, Bucharest Center of General Surgery and Liver Transplantation - Clinical Hospital “Sf. Maria’’, Bucharest

18. Indications for LT

19. Indications in adults( LTsRetx)

20. Indications in children( LTsRetx)

21. Type of LT

22. Deceased donor LT Organ procurement in Romania No of Donors

23. Whole liver LT ( LTs) Use of extended criteria donors (ECD)– 346 donors (52.7%) Spitzer AL, Lao OB, Dick AA, Bakthavatsalam R, Halldorson JB, Yeh MM, et al. The biopsied donor liver: incorporating macrosteatosis into high-risk donor assessment. Liver Transpl 2010; 16: 874-884. Jiménez-Castro1 MB, Elias-Miró1 M, Peralta C. Expanding the Donor Pool in Liver Transplantation: Influence of Ischemia-Reperfusion. In: Organ Donation and Organ Donors. Nova Science Publishers, Inc. ISBN: 978-1-62618-853-2, 2013

24. Hypothermic oxygenated perfusionof marginal grafts with LiverAssist device • ↓ the ischemia-reperfusion injuries of the graft • ↓ the risk of postoperative primary non-function or dysfunction • ↓ the risk of postoperative complications Dutkowski P, Odermatt B, Heinrich T, et al. Hypothermic oscillating liver perfusion stimulates ATP synthesis prior to transplantation. J Surg Res 1998; 80(2):365-72. DutkowskiP, Schonfeld S, Heinrich T, et al. Reduced oxidative stress during acellular reperfusion of the rat liver after hypothermic oscillating perfusion. Transplantation 1999; 68(1):44-50.

25. First case with LiverAssist in Romania • Donor - 22-yr old female with polytrauma after car incident (including liver hematoma in segment 7). • Marginal graft: • resuscitated cardiac arrest, • high doses of noradrenaline (1 microg/kgc/min the first 12 hours, followed by 0.5 microg/kgc/min until prelevation) associated in the last 24 hours with adrenaline (1 microg/kgc/min), • hypernatremia (172 mEq/L).

27. Recipient - a 64-yr old male with HCC outside Milan Criteria (2 nodules – one of 5cm with previous TACE, and one of 2cm) on liver cirrhosis. • The postoperative course was uneventful, with normal liver function. • Discharged in POD 14 • Regular follow-up at 6 months

28. Other sources for liver grafts 12 pts (1.8%) Zota V, Popescu I, Ciurea S, Copaciu E, Predescu O, Costandache F, Turcu R, Herlea V, Tulbure D. Successful use of the liver of a methanol-poisoned, brain-dead organ donor. Transpl Int. 2003 Jun;16(6):444-6.

29. Liver graft trauma Liver graft hematoma POD 19: Complete resolution of haematoma. • 51-year old recipient; • transplanted for HCC on VHC cirrhosis. POD 5: Haematoma in S7 of liver graft.

30. Liver graft laceration • Donor: 19-yr old woman, • Politrauma after car accident (head and abdominal injuries – spleen rupture, right kidney hematoma and liver laceration in S6-7); • Operated for abdominal trauma (splenectomy, hemostasis for liver laceration); • Cause of death severe head trauma; • Atypical resection of the hepatic laceration on back table; • In situ hemostasis of the cut surface. • Recipient: 53-yr old male • Alcoholic cirrhosis, MELD 11 Follow-up: alive and well at 4 months.

31. Benign tumors in liver graft Donor: 23-yr old female, severe head trauma graft with adenoma S5-6 (resected on back-table). Recipient: 41-yr old male Alcoholic cirrhosis, MELD 21. Follow-up: alive and well at 12 months.

32. Particular cases of whole organ LT • 39-yr old man • Polycystic liver disease - highly symptomatic due to liver volume (23,200 cm3), whith severe physical and social handicaps • LT in April 2011 • Currently alive, with no complications.

33. 24-yr old man • Budd-Chiari syndrome, with complete thrombosis of retrohepatic IVC. • Idiopathic thrombophilia. Thrombosis of retrohepatic IVC. Thrombosis of hepatocaval confluence

34. Cavo-caval anastomosis (inferior). • LT in April 2014 • Currently alive with no complications. Cavo-atrial anastomosis (superior).

35. Split liver LT (10 procedures) • Needs donors with normal liver anatomy and no risk factors for compromised graft function; • Currently Split LT accounts for ~ 5% of total LTs, but ~20% of donors are potential candidates → they have to be properly identified; • Comparable survival results after in-situ split LT with those for conventional LT; • ↑incidence of biliary and vascular complications. deLemos AS, Vagefi PA. Expanding the Donor Pool in Liver Transplantation: Extended Criteria Donors. Clinical Liver Disease, Vol 2, No 4, 2013, 156-159. Goss JA, Yersiz H, Shackleton CR, et al.:In situ splitting of the cadaveric liver for transplantation. Transplantation 1997, 64:871–877. Rogiers X, Malago M, Gawad K, et al. In situ splitting of cadaveric livers. Ann Surg 1996, 224:331–341. Vagefi PA, Parekh J, Ascher NL, Roberts JP, Freise CE. Outcomes with split liver transplantation in 106 recipients: the University of California, San Francisco, experience from 1993 to 2010. Arch Surg 2011;146:1052-1059

36. SURGICAL TECHNIQUE

37. Drawbacks: • Lengthy procedure with prolonged cold ischemic time; • Increased inflammatory response on reperfusion; • Poor function of the graft; SURGICAL TECHNIQUE EX-VIVO • Prolonged procurement time; • More experienced surgeon. IN-SITU

38. Split Liver Procedures 10 Split LTs – 20 recipients * 1 Split LT – Domino LT (adult) Adult + adult Adult + child Adult + child Adult * + child Adult + child Adult + child Adult + child

39. Adult-child split LT Donor: 38-yr old male, severe head trauma in car crash. • Recipient 1: • 21-yr old male; • Cryptogenic cirrhosis; • Extended right lobe LT (1350ml). • Recipient 2: • 9-yr old female; • Cryptogenic cirrhosis; • Left lateral section LT (350ml). Follow-up: No complications at 10 months.

40. Adult-adult split LT Donor: 21-yr old male, severe head trauma in car crash. • Recipient 1: • 18-yr old male; • Acute liver failure (Wilson’s disease); • Right lobe LT (890ml). • Recipient 2: • 24-yr old female; • Cryptogenic cirrhosis; • Left lobe LT (496ml). Follow-up: No complications at 44 months.

41. Domino LT (1 LT) Donor Recipient & Marginal donor with hereditary metabolic disease: • familial amyloidotic polyneuropathy; • familial hypercholesterolemia. Marginal recipient (i.e. with cirrhosis + HCC) Popescu I, Simionescu M, Tulbure D, Sima A, Catana C, Niculescu L, Hancu N, Gheorghe L, Mihaila M, Ciurea S, Vidu V. Homozygous familial hypercholesterolemia: specific indication for domino liver transplantation. Transplantation. 2003 Nov 15;76(9):1345-50 Popescu I, Habib N, Dima S, Hancu N, Gheorghe L, Iacob S, Mihaila M, Dorobantu B, Matei E, Botea F. Domino liver transplantation using a graft from a donor with familial hypercholesterolemia: seven-yr follow-up. Clin Transplant. 2009 Aug-Sep;23(4):565-70. Popescu I, Dima SO. Domino liver transplantation: how far can we push the paradigm? Liver Transpl. 2012 Jan;18(1):22-8. Liu C, Niu DM, Loong CC, Hsia CY, Tsou MY, Tsai HL, Wei C . Domino liver graft from a patient with homozygous familial hypercholesterolemia Pediatr Transplant. 2010 May;14(3):E30-3.

42. Domino LT (combined with Split LT) 1 Deceased Donor – 3 LTs Child with glycogenosis split Adult with familial Hypercholesterolemia domino Adult with HCC on cirrhosis Popescu I, Simionescu M, Tulbure D, Sima A, Catana C, Niculescu L, Hancu N, Gheorghe L, Mihaila M, Ciurea S, Vidu V. Homozygous familial hypercholesterolemia: specific indication for domino liver transplantation. Transplantation. 2003 Nov 15;76(9):1345-50 Popescu I, Habib N, Dima S, Hancu N, Gheorghe L, Iacob S, Mihaila M, Dorobantu B, Matei E, Botea F. Domino liver transplantation using a graft from a donor with familial hypercholesterolemia: seven-yr follow-up. Clin Transplant. 2009 Aug-Sep;23(4):565-70. Popescu I, Dima SO. Domino liver transplantation: how far can we push the paradigm? Liver Transpl. 2012 Jan;18(1):22-8.

43. Living donor LT • One of the most remarkable steps in the field of LT. • Unique source of grafts because the liver is directed to only one specified candidate, with no the need for an allocation system; • For pediatric patients – main source of donors • For adults – good indication in selected cases. Schiano T.D., Kim-Schluger L., Gondolesi G., Miller C.M. Adult living donor liver transplantation: the hepatologist’s perspective. Hepatology 2001;33(1):3-9. Middleton P., Duffield M., Lynch S., Padbury R.T., House T., Stanton P., et al. Living donor liver transplantation-Adult donor outcomes: A systematic review. Liver Transplantation 2005;12(1):24-30

45. LDLT – 128 procedures in 126 pts ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( )

46. Advantages: • can be performed on an elective basis, with optimal timing and no waiting time for the recipient; • graft in excellent condition (preselected graft, healthy donor); • short ischemic time; • extended indications (i.e. HCC beyond Milan criteria). Disadvantages: • mortality in donors, even though <1%; • higher rate of vascular (5-15%) and biliary (10-30%) complications for both donor and recipient; • risk of small-for-size syndrome. Schiano T.D., Kim-Schluger L., Gondolesi G., Miller C.M. Adult living donor liver transplantation: the hepatologist’s perspective. Hepatology 2001;33(1):3-9. Middleton P., Duffield M., Lynch S., Padbury R.T., House T., Stanton P., et al. Living donor liver transplantation-Adult donor outcomes: A systematic review. Liver Transplantation 2005;12(1):24-30

47. Surgical technique RIGHT HEMILIVERLDLT with MHV RHV+MHV RHV IVC MHV

48. RIGHT HEMILIVERLDLT without MHV with venous reconstruction S5 S8

49. Dual LDLT (2 LTs) • Dual graft LDLT proved to be an efficient method to increase the pool donor, avoiding in the same time small-for-size grafts. • Since the first case was published in 2001 by Lee SG et al, to date a total of 243 cases are reported worldwide. • 2 indications for dual graft LDLT: • when 2 donors are rejected for RL donation (due to anatomical variations of the liver hilum or insufficient remnant liver volume), but they can donate their left lobe or left lateral section for dual graft LDLT; • when a right lobe graft is available but considered insufficient (as volume or have significant liver steatosis), is supplemented with a left lobe or a left lateral section from a second donor. Lee SG, Hwang S, Park KM, et al. An adult-to-adult living donor liver transplant using dual left lobe grafts. Surgery 2001;129:647-50. Lee SG, Hwang S, Park KM, et al. Seventeen adult-to-adult living donor liver transplantations using dual grafts. Transplant Proc 2001;33:3461-3. Lee SG. Living-donor liver transplantation in adults . Br Med Bull. 2010;94:33-48.

50. 2nd Donor 19-year old female (sister) right hemiliver GV/SLV = 40.9% GRWR = 0.76 Recipient 15-year old female with acute liver failure due to Wilson’s disease Combined GV/SLV = 56.4% GRWR = 1.10 • First case of dual LDLT in Romania. 1st Donor 38-year old female (mother) left lateral section GV/SLV =15.5% GRWR = 0.33 Botea F, Braşoveanu V, Constantinescu A, Ionescu M, Matei E, Popescu I. Living donor liver transplantation with dual grafts -- a case report. Chirurgia (Bucur). 2013 Jul-Aug;108(4):547-52