Evolution of pediatric liver transplant: from inception to modern practice

This article explores the historical development of pediatric liver transplantation (LT), tracing its evolution from the first experimental procedures to modern high‑tech approaches. Throughout its history, LT in children has been a catalyst for innovation and novel surgical techniques. The earliest attempts at pediatric LT faced numerous technical and immunological challenges and were associated with extremely high mortality rates. A major breakthrough occurred in the 1980s with the introduction of cyclosporine A. During this period, pioneering advances such as reduced-size grafts, split-liver transplantation, and the first successful living-related donor procedures marked a new era. The 1990s witnessed further progress in surgical techniques, introduction of tacrolimus, and the development of right-lobe living donor transplantation. These innovations not only expanded the donor pool significantly but also improved surgical outcomes. Entering the 21st century, the field experienced further breakthroughs with the implementation of ABO-incompatible transplantation and the adoption of MELD and PELD scoring systems for organ allocation. In addition, the integration of minimally invasive laparoscopic and robot-assisted approaches reduced donor morbidity and improved postoperative recovery. Today, pediatric LT is recognized not only as a life-saving treatment for end-stage liver failure in children but also as a driving force of innovation in modern transplant practice. The article underscores the importance of continuous refinement of surgical techniques and personalization of immunosuppressive regimens as key strategies to improve long-term survival and enhance the quality of life in pediatric LT recipients.

1. Starzl TE, Marchioro TL, Von Kaulla KN, Hermann G, Brittain RS, Waddell WR. Homotransplantation of the liver in humans. Surg Gynecol Obstet. 1963 Dec; 117: 659–676.

2. Starzl TE, Groth CG, Brettschneider L, Penn I, Fulginiti VA, Moon JB et al. Orthotopic homotransplantation of the human liver. Ann Surg. 1968 Sep; 168 (3): 392–415.

3. Otte JB. History of pediatric liver transplantation. Where are we coming from? Where do we stand? Pediatr Transplant. 2002; 6 (4): 312–320.

4. Bismuth H, Houssin D. Reduced-sized orthotopic liver graft in hepatic transplantation in children. Surgery. 1984; 96 (3): 367–370.

5. Broelsch CE, Emond JC, Thistlethwaite JR, Whitington PF, Zucker AR, Baker AL et al. Liver transplantation, including the concept of reduced-size liver transplants in children. Ann Surg. 1988; 208 (4): 410–420.

6. Pichlmayr R, Ringe B, Gubernatis G, Hauss J, Bunzendahl H. Transplantation of a donor liver to 2 recipients (splitting transplantation) – a new method in the further development of segmental liver transplantation. Langenbecks Arch Chir. 1988; 373 (2): 127–130.

7. Strong RW, Lynch SV, Ong TH, Matsunami H, Koido Y, Balderson GA. Successful liver transplantation from a living donor to her son. N Engl J Med. 1990; 322 (21): 1505–1507.

8. Alexandre GP, Squiffiet JP, De Bruyere M, Latinne D, Reding R, Gianello P et al. Present experiences in a series of 26 АВ0-incompatible living donor renal allografts. Transplant Proc. 1987; 19 (1 Pt 1): 748–750.

9. Tokunaga Y, Tanaka K, Fujita S et al. Living donor liver transplantation across АВ0 incompatibility. Transplant Proc. 1999; 31 (1–2): 450–452.

10. Mazza G, De Coppi P, Gissen P et al. The history of liver transplantation. Pediatr Surg Int. 2020; 36 (10): 1137–1145.

11. Bishop GA, Bowen DG, Bertolino P. The liver: a special case for transplantation tolerance. Nat Rev Immunol. 2007; 7 (6): 440–451.

12. Starzl TE. The saga of liver transplantation, with particular reference to children. J Pediatr Surg. 1993; 28 (11): 1469–1478.

13. Demikhov VP. Peresadka zhiznenno vazhnykh organov v eksperimente. M.: Medgiz, 1960; 260.

14. Glyantsev SP. Vladimir Petrovich Demikhov (k 100-letiyu so dnya rozhdeniya). Vestnik transplantologii i iskusstvennykh organov. 2016; (3): 66–77.

15. Starzl TE, Iwatsuki S, Todo S et al. Historical perspective of liver transplantation at Children’s Hospital of Pittsburgh. J Japan Surg Soc. 1990; 91 (10): 1759–1765.

16. Fung JJ, Abu-Elmagd K, Jain A et al. A long-term analysis of 3000 liver transplantations at the University of Pittsburgh: a triumph of clinical and basic science. Ann Surg. 1997; 226 (4): 429–440.

17. Calne RY. A new lease on life: the history of transplantation. Transpl Immunol. 2004; 13 (4): 259–263.

18. Esquivel CO, Iwatsuki S, Gordon RD, Marsh WW Jr, Koneru B, Makowka L et al. Liver transplantation for biliary atresia. Long-term follow-up of 85 patients. Gastroenterology. 1987; 93 (5): 1117–1120.

19. Borel JF. Ciclosporin and its future. Clin Transplant. 1990: 1–8.

20. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC et al. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet. 1978; 2 (8104-5): 1323–1327.

21. Starzl TE, Klintmalm GB, Porter KA, Iwatsuki S, Schröter GP. Liver transplantation with use of cyclosporin A and prednisone. N Engl J Med. 1981; 305 (5): 266–269.

22. National Institutes of Health Consensus Development Conference Statement: liver transplantation – June 20– 23, 1983. Hepatology. 1984; 4 (1 Suppl): 107S–110S.

23. Starzl TE, Iwatsuki S, Shaw BW Jr, Gordon RD, Esquivel CO. Immunosuppression and other nonsurgical factors in the improved results of liver transplantation. Semin Liver Dis. 1985; 5 (4): 334–343.

24. Goss JA, Shackleton CR, McDiarmid SV et al. Long-term results of pediatric liver transplantation: an analysis of 569 transplants. Ann Surg. 1998; 228 (3): 411–420.

25. Broelsch CE, Emond JC, Whitington PF, Thistlethwaite JR, Baker AL, Lichtor JL. Application of reducedsize liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg. 1990; 212 (3): 368–375.

26. Broelsch CE, Whitington PF, Emond JC, Heffron TG, Thistlethwaite JR, Stevens L et al. Liver transplantation in children from living related donors. Surgical techniques and results. Ann Surg. 1991; 214 (4): 428–437.

27. Tanaka K, Uemoto S, Tokunaga Y, Fujita S, Sano K, Nishizawa T et al. Surgical techniques and innovations in living related liver transplantation. Ann Surg. 1993; 217 (1): 82–91.

28. Makuuchi M, Kawarazaki H, Iwanaka T, Kamada N, Takayama T, Kumon M. Living related liver transplantation. Surg Today. 1992; 22 (4): 297–300.

29. Hashikura Y, Makuuchi M, Kawasaki S, Matsunami H, Ikegami T, Nakazawa Y et al. Successful living-related partial liver transplantation to an adult patient. Lancet. 1994; 343 (8907): 1233–1234.

30. Yamaoka Y, Washida M, Honda K, Tanaka K, Mori K, Shimahara Y et al. Liver transplantation using a right lobe graft from a living related donor. Transplantation. 1994; 57 (7): 1127–1130.

31. Lo CM, Fan ST, Liu CL, Wei WI, Lo RJ, Lai CL et al. Adult-to-adult living donor liver transplantation using extended right lobe grafts. Ann Surg. 1997; 226 (3): 261–269.

32. Rogiers X, Malago M, Gawad K, Jauch KW, Olausson M, Knoefel WT et al. In situ splitting of cadaveric livers. The ultimate expansion of a limited donor pool. Ann Surg. 1996; 224 (3): 331–339.

33. Azoulay D, Astarcioglu I, Bismuth H, Castaing D, Majno P, Adam R, Johann M. Split-liver transplantation. The Paul Brousse policy. Ann Surg. 1996; 224 (6): 737–746.

34. Busuttil RW, Goss JA. Split liver transplantation. Ann Surg. 1999; 229 (3): 313–321.

35. Raia S, Nery JR, Mies S. Liver transplantation from live donors. Lancet. 1989; 2 (8661): 497.

36. Ozawa K, Uemoto S, Tanaka K, Kumada K, Yamaoka Y, Kobayashi N et al. An appraisal of pediatric liver transplantation from living relatives. Initial clinical experiences in 20 pediatric liver transplantations from living relatives as donors. Ann Surg. 1992; 216 (5): 547–553.

37. Inomata Y, Tanaka K, Uemoto S, Ozaki N, Okajima H, Yamaoka Y. Living donor liver transplantation: an 8-year experience with 379 consecutive cases. Transplant Proc. 1999; 31 (1–2): 381.

38. Emond JC, Whitington PF, Thistlethwaite JR, Cherqui D, Alonso EA, Woodle IS et al. Transplantation of two patients with one liver. Analysis of a preliminary experience with ‘split-liver’ grafting. Ann Surg. 1990; 212 (1): 14–22.

39. Bismuth H, Morino M, Castaing D, Gillon MC, Descorps Declere A, Saliba F, Samuel D. Emergency orthotopic liver transplantation in two patients using one donor liver. Br J Surg. 1989; 76 (7): 722–724.

40. Otte JB, de Ville de Goyet J, Alberti D, Balladur P, de Hemptinne B. The concept and technique of the split liver in clinical transplantation. Surgery. 1990; 107 (6): 605–612.

41. Broelsch CE, Emond JC, Whitington PF, Thistlethwaite JR, Baker AL, Lichtor JL. Application of reduced-size liver transplants as split grafts, auxiliary orthotopic grafts, and living related segmental transplants. Ann Surg. 1990; 212 (3): 368–375.

42. Otte JB, de Ville de Goyet J, Sokal E, Alberti D, Moulin D, de Hemptinne B et al. Size reduction of the donor liver is a safe way to alleviate the shortage of size-matched organs in pediatric liver transplantation. Ann Surg. 1990; 211 (2): 146–157.

43. Kawasaki S, Makuuchi M, Matsunami H, Hashikura Y, Ikegami T, Nakazawa Y et al. Living related liver transplantation in adults. Ann Surg. 1998; 227 (2): 269–274.

44. Marcos A, Fisher RA, Ham JM, Shiffman ML, Sanyal AJ, Luketic VA et al. Right lobe living donor liver transplantation. Transplantation. 1999; 68 (6): 798–803.

45. 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 (7): 567–580.

46. McDiarmid SV, Anand R, Lindblad AS; Principal Investigators and Institutions of the Studies of Pediatric Liver Transplantation (SPLIT) Research Group. Development of a pediatric end-stage liver disease score to predict poor outcome in children awaiting liver transplantation. Transplantation. 2002; 74 (2): 173–181.

47. Freeman RB Jr, Wiesner RH, Harper A, McDiarmid SV, Lake J, Edwards E et al. UNOS/OPTN Liver Disease Severity Score, UNOS/OPTN Liver and Intestine, and UNOS/OPTN Pediatric Transplantation Committees. The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl. 2002; 8 (9): 851–858.

48. Merion RM, Schaubel DE, Dykstra DM, Freeman RB, Port FK, Wolfe RA. The survival benefit of liver transplantation. Am J Transplant. 2005; 5 (2): 307–313.

49. Feng S, Goodrich NP, Bragg-Gresham JL, Dykstra DM, Punch JD, DebRoy MA et al. Characteristics associated with liver graft failure: the concept of a donor risk index. Am J Transplant. 2006; 6 (4): 783–790.

50. Schaubel DE, Sima CS, Goodrich NP, Feng S, Merion RM. The survival benefit of deceased donor liver transplantation as a function of candidate disease severity and donor quality. Am J Transplant. 2008; 8 (2): 419–425.

51. Rana A, Pallister ZS, Halazun K, Cotton RT, Guiteau JJ, Nalty CC et al. Pediatric liver transplant center volume and the likelihood of transplantation. Pediatrics. 2015; 136 (1): e99–e107.

52. Kasahara M, Umeshita K, Inomata Y, Uemoto S; Japanese Liver Transplantation Society Long-term outcomes of pediatric living donor liver transplantation in Japan: an analysis of more than 2200 cases listed in the registry of the Japanese Liver Transplantation Society. Am J Transplant. 2013; 13 (7): 1830–1839.

53. Otte JB, Reding R, de Ville de Goyet J, Sokal E, Lerut J, Janssen M et al. Experience with living related liver transplantation in 63 children. Acta Gastroenterol Belg. 1999; 62 (3): 355–362.

54. Spada M, Riva S, Maggiore G, Cintorino D, Gridelli B. Pediatric liver transplantation. World J Gastroenterol. 2009; 15 (6): 648–674.

55. Hackl C, Schlitt HJ, Melter M, Knoppke B, Loss M. Current developments in pediatric liver transplantation. World J Hepatol. 2015; 7 (11): 1509–1520.

56. Emre S, Umman V. Split liver transplantation: an over-view. Transplant Proc. 2011; 43 (3): 884–887.

57. Lauterio A, Di Sandro S, Concone G, De Carlis R, Giacomoni A, De Carlis L. Current status and perspectives in split liver transplantation. World J Gastroenterol. 2015; 21 (39): 11003–11015.

58. Cardillo M, De Fazio N, Pedotti P, De Feo T, Fassati LR, Mazzaferro V et al. NITp Liver Transplantation Working Group. Split and whole liver transplantation outcomes: a comparative cohort study. Liver Transpl. 2006; 12 (3): 402–410.

59. Renz JF, Emond JC, Yersiz H, Ascher NL, Busuttil RW. Split-liver transplantation in the United States: outcomes of a national survey. Ann Surg. 2004; 239 (2): 172–181.

60. 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 (9): 1052–1059.

61. Doyle MB, Maynard E, Lin Y, Vachharajani N, Shenoy S, Anderson C et al. Outcomes with split liver transplantation are equivalent to those with whole organ transplantation. J Am Coll Surg. 2013; 217 (1): 102–112.

62. Cauley RP, Vakili K, Fullington N, Potanos K, Graham DA, Finkelstein JA, Kim HB. Deceased-donor splitliver transplantation in adult recipients: is the learning curve over? J Am Coll Surg. 2013; 217 (4): 672–684.e1.

63. Maggi U, De Feo TM, Andorno E, Cillo U, De Carlis L, Colledan M et al. Liver Transplantation Nord Italia Transplant program (NITp) Working Group. Fifteen years and 382 extended right grafts from deceased donors: a multicenter study on donor and recipient outcomes. Liver Transpl. 2015; 21 (4): 500–508.

64. Lauterio A, Di Sandro S, De Carlis R, Ferla F, Buscemi V, De Carlis L. Current status and perspectives in split liver transplantation. World J Gastroenterol. 2019; 25 (43): 6347–6355.

65. Eurotransplant Manual. Chapter 5: ET Liver Allocation System (ELAS). Version 9.0. 2021. URL: https://www. eurotransplant.org/wp-content/uploads/2021/03/H5-Liver.pdf (дата обращения/date of access: 14.05.2025).

66. Organ Procurement and Transplantation Network (OPTN) Policies. Policy 9: Allocation of Livers and Liver-Intestines. 2022. URL: https://optn.transplant.hrsa.gov/media/eavh5bf3/optn_policies.pdf (дата обращения/date of access: 14.05.2025).

67. Lauterio A, Di Sandro S, Gruttadauria S, Spada M, Di Benedetto F, Baccarani U et al. Donor pool expansion in liver transplantation. Transplant Proc. 2019; 51 (1): 9–16.

68. Kasahara M, Sakamoto S, Umeshita K. Current status of living donor liver transplantation in Asia. Transplantation. 2024; 108 (1): 35–43.

69. Lee SG. A complete survey of living donor liver transplantation in Korea. J Korean Med Sci. 2015; 30 (12): 1731–1738.

70. Toida C, Mogushi K, Hoshino K et al. Current status and future prospects of pediatric organ transplantation in Japan. Pediatr Transplant. 2016; 20 (6): 756–765.

71. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). OPTN/SRTR 2022 Annual Data Report: Liver. Am J Transplant. 2024; 24 (2S): S1–S74.

72. Silva HT Jr, Felipe CR, Ferreira GF. Organ donation and transplantation: a global perspective. Nephrol Dial Transplant. 2025; 40 (1): 21–29.

73. Cohen J, Stolk E, Wouters O et al. The impact of presumed consent legislation on deceased organ donation: a systematic review and meta-analysis of controlled studies. BMJ Open. 2016; 6 (5): e010229.

74. Alexandre GP, Squiffiet JP, De Bruyere M et al. Present experiences in a series of 26 АВ0-incompatible living donor renal allografts. Transplant Proc. 1987; 19 (1 Pt 1): 700–702.

75. Tanabe M, Kawachi S, Obara H et al. Current progress in АВ0-incompatible liver transplantation. Eur J Clin Invest. 2010; 40 (5): 457–464.

76. Egawa H, Teramukai S, Haga H et al. Impact of rituximab on immunity in АВ0-incompatible living donor liver transplantation. Transplantation. 2014; 97 (1): 65–72.

77. Song GW, Lee SG, Hwang S et al. АВ0-incompatible adult living donor liver transplantation: a new era. Liver Transpl. 2016; 22 (2): 179–196.

78. Lee CF, Cheng CH, Wang YC et al. Outcomes of АВ0-incompatible pediatric living donor liver transplantation: A systematic review and meta-analysis. Pediatr Transplant. 2020; 24 (3): e13683.

79. Gelbart M, Hawthorne K, Wright M et al. АВ0-incompatible deceased donor pediatric liver transplantation: Novel titer-based management protocol and outcomes. Pediatr Transplant. 2018; 22 (5): e13216.

80. Gautier SV, Monakhov AR, Tsirulnikova OM et al. АВ0-Incompatible Liver Transplantation in Children: Single Center Experience. Transplantation. 2020; 104 (S3): S550.

81. Emre S, Umman V. Large-for-size syndrome in pediatric liver transplantation: A comprehensive review. Pediatr Transplant. 2019; 23 (7): e13561.

82. Kiuchi T, Kasahara M, Uryuhara K et al. Impact of graft-size mismatching on pediatric living-donor liver transplantation. Transplantation. 2000; 69 (1): 127–132.

83. Miller CM, Nakaji K, Molmenti EP et al. The reduced-size liver transplant. Techniques and applications. Transplantation. 1993; 56 (3): 561–566.

84. Hwang S, Lee SG, Kim KH et al. Surgical reconstruction of portal vein hypoplasia in pediatric living donor liver transplantation. Liver Transpl. 2013; 19 (5): 534–541.

85. Namgoong JM, Hwang S, Park GC et al. Portal vein reconstruction techniques in pediatric living donor liver transplantation for biliary atresia with portal vein hypoplasia: A pictorial essay. Korean J Radiol. 2021; 22 (1): 85–95.

86. Azoulay D, Linhares MM, Huguet E et al. Decision for retransplantation of the liver: an experienced-based approach. Ann Surg. 2002; 236 (6): 713–721.

87. Mehrabi A, Fonouni H, Schemmer P et al. Retransplantation of the liver: a single-center experience of 150 patients. Clin Transplant. 2008; 22 (3): 347–359.

88. MacConmara M, Hobeika L, Vachharajani N et al. Normothermic machine perfusion: The future of liver preservation. Curr Transplant Rep. 2020; 7 (1): 38–46.

89. Boteon YL, Laing RW, Schlegel A et al. Combined Hypothermic and Normothermic Machine Perfusion for Enhanced Organ Preservation in Liver Transplantation. Liver Transpl. 2022; 28 (3): 518–529.

90. Watson CJE, Kosmoliaptsis V, Randle LV et al. Normothermic machine perfusion in liver transplantation: a randomized clinical trial. JAMA Surg. 2019; 154 (6): 481–489.

91. Cherqui D, Soubrane O, Husson E et al. Laparoscopic living donor hepatectomy for liver transplantation in children. Lancet. 2002; 359 (9304): 392–396.

92. Soubrane O, Perdigao F, Goumard C et al. Laparoscopic living donor left lateral sectionectomy: a new standard practice for pediatric transplantation. Ann Surg. 2015; 261 (6): 1071–1076.

93. Kim KH, Kang SH, Jung DH et al. Initial experiences with 100 cases of purely laparoscopic living-donor hepatectomy. Br J Surg. 2017; 104 (12): 1648–1657.

94. Broering DC, Elsheikh Y, Nagy K et al. Robotic-assisted versus laparoscopic live donor hepatectomy: a systematic review and meta-analysis. Updates Surg. 2021; 73 (6): 2035–2045.

95. Rhu J, Choi GS, Kim JM et al. Feasibility of totally laparoscopic living donor hepatectomy for adult-to-adult living donor liver transplantation: A prospective pilot study. Am J Transplant. 2018; 18 (5): 1249–1255.

96. Suh KS, Hong SK, Yi NJ et al. Pure laparoscopic living donor hepatectomy and recipient hepatectomy for pediatric liver transplantation. Liver Transpl. 2018; 24 (10): 1443–1448.

97. Rela M, Kaliamoorthy I, Reddy MS. Robotic-assisted pediatric liver transplantation: The next frontier? Pediatr Transplant. 2021; 25 (1): e13871.

98. Giulianotti PC, Addeo P, Bianco FM. Robotic liver surgery: a systematic review. J Hepatobiliary Pancreat Sci. 2011; 18 (1): 1–10.

99. Fredericks EM, Bucuvalas JC, Alonso EM et al. Patient-reported outcomes in pediatric liver transplant recipients: A systematic review. Liver Transpl. 2016; 22 (8): 1149–1169.

100. Annunziato RA, Bucuvalas JC, Stuber ML. Health-related quality of life in pediatric liver transplant recipients: a meta-analysis. Pediatr Transplant. 2008; 12 (1): 70–77.