INTRODUCTION

Outcomes of kidney, liver and pancreas transplantation have improved progressively over time. Currently, 90% one-year survival and nearly 75% five-year survival have been achieved by several transplant programs worldwide. The main initial obstacles to success of transplantation were ethical, technical and immunological.

HISTORICAL AND CURRENT BARRIERS TO LIVER TRANSPLANTATION

Dr. Thomas E. Starzl, the father of modern liver transplantation and also a great contributor to kidney, pancreas, intestinal and multivisceral transplantation, has passed away recently. Dr. Starzl has overcome ethical barriers to establish the concept of brain death. Starting in 1963, Dr. Starzl performed the first series on successful liver transplantation at the University of Colorado in Denver, USA.¹

In the 1960’s and 70’s, outcomes of liver transplantation were dismal and only few liver transplants were performed worldwide. Immunologic obstacles to long-term success of liver transplantation were immense until 1979, when Sir. Roy Calne, a British surgeon largely involved in the establishment on the concept of brain death, pioneered utilization cyclosporine in kidney, pancreas and liver transplantation..² Starzl et al. have combined cyclosporine to steroids, improving the results of liver and kidney transplantation..^3-4 During the 1980’s, US Food and Drug administration (FDA) approved the use cyclosporine in the USA, and number of liver transplant programs increased. Liver transplantation also was disseminated outside the USA and England, with opening of programs in other European Countries and also in South America.

Dr. Starzl’s group at the University of Pittsburgh also was responsible for introducing the calcineurin inhibitor tacrolimus (FK506) in liver transplantation.⁴ FK506 enabled improvement on the outcomes of liver transplantation in patients suffering from cholestatic diseases. Driven by its successful outcomes, liver transplantation was disseminated as the standard of care for the treatment of patients with end-stage liver disease worldwide.
In 1988, Raia, Nery and Mies from University of Sao Paulo performed the first two successful living donor liver transplants (LDLTs) in the World.⁵ Broelsch et al. pioneered this practice in the United States.⁶ LDLT remains as the main modality of liver transplantation for small infants suffering from end-stage liver disease in the Western World.⁷ Due to cultural reasons, deceased donation is scarce in the Eastern World. LDLT also is the most common modality of liver transplantation in Asia. Currently, donor partial hepatectomy has been performed laparoscopically in few institutions.⁸

Liver preservation was another barrier to the progress of liver transplantation until late 1980’s. In 1988, Belzer’s group reported on liver transplantation utilizing the University of Wisconsin preservation solution (UW).⁹ UW replaced EuroCollins solution, thus enabling longer and safer preservation of liver, kidney and pancreas allografts, and contributing to improvement of outcomes of transplantation. Although UW is still considered the standard of care in the United States and in several countries worldwide, Adam et al. recently reported that liver transplantation using Institutes Georges Lopez-1 preservation solution (IGL-1) provided liver transplantation outcomes that were similar to those obtained with UW.¹⁰ This study, a report from the European Liver Transplant Registry, compared results of liver transplantation using four different preservation solutions: UW, IGL-1, Celsior and Histidine-tryptophan-ketoglutarate (HTK). Outcomes of liver transplantation using UW and IGL-1 were slightly superior to those obtained with HTK, especially in the setting of prolonged cold ischemia times.¹⁰ IGL-1 also was employed successfully for human pancreas transplantation, and provided outcomes that were similar to those obtained with UW for kidney transplantation.^11-12

Static cold storage has been the standard of care for liver, kidney and pancreas transplantation worldwide. High-risk lung allografts have been reconditioned by dynamic preservation (ex-vivo normothermic lung perfusion). Recently, dynamic preservation has been employed for preservation of liver and kidney allografts. There are two different methods of dynamic preservation: hypothermic machine preservation and normothermic machine preservation. Although related to increased costs, normothermic perfusion of liver allografts has been demonstrated as clinically feasible.¹³ Normothermic liver perfusion has been capable of improving laboratory perfusion parameters of marginal organs.¹⁴ It is yet to be proven whether normothermic perfusion will be able to recondition high-risk livers to the point of enabling successful transplantation using such suboptimal allografts.

Although liver allocation was largely improved by adoption of Model for End-Stage Liver Disease (MELD) score in early 2000’s, the disparity between donor demand and supply always has been a concern in abdominal solid organ transplantation.¹⁵ Besides partial liver grafts from live donors, livers removed from patients with familial amyloid polyneuropathy undergoing liver transplantation (domino liver transplants) promoted a small increase in the donor pool. Utilization of liver allografts procured from non-heart beating donors [deceased after cardiac death donors (DCD donors)] has contributed to a considerable increase the donor pool in the United States and in some European Countries, currently providing outcomes that are nearly as good as those obtained by the use of livers from brain dead donors.^16-17

Liver transplantation is an expensive medical practice. Reducing the costs related to liver transplantation is largely desired. The Mayo Clinic Florida Liver Transplant team has established a score that predicts the need for Intensive Care Unit (ICU) stay immediately following liver transplantation. Impressively, over half of all liver transplant recipients at Mayo Clinic Florida currently are extubated in the operating room and discharged directly to ward, eliminating the need for ICU stay.¹⁸

Extensive portal vein (PV) thrombosis (Grade 3, complete thrombosis of both PV and proximal superior mesenteric (SMV) vein with open distal SMV; Grade 4, complete thrombosis of PV and proximal and distal SMV) is a relative contraindication to liver transplantation. For grade 3 PV thrombosis, whenever eversion thromboendovenectomy is not accomplished, interposition of a venous graft between SMV and PV of the liver allograft may be a feasible solution. For Grade 4 PV thrombosis, utilization of portomesenteric venous system of the recipient usually is not feasible. Anastomose PV to a collateral shunt, construct a renoportal bypass.¹⁹ arterialize PV,²⁰ perform cavoportal hemitransposition²¹ and multivisceral transplantation²² are potential therapeutic options. Complications of renoportal bypass may include thrombosis, renal failure, and transient ascites. PV arteralization may be complicated by PV pseudoaneurysm. Among the available options for liver transplantation in the setting of Grade 4 PV thrombosis, multivisceral transplantation is the only procedure that completely reverses portal hypertension while addresses primary disease.²²

CURRENT BARRIERS TO KIDNEY TRANSPLANTATION

Renal transplantation in the setting of complete inferior vena cava thrombosis also can be problematic. In such instances, a collateral venous branch utilized as the site of the renal vein venous anastomosis.²³ Other suitable options for establishing venous outflow to renal allograft may include mesenteric veins and IVC.

Renal retransplantation is a standard of practice worldwide. Iliac vessels contralateral to the ones utilized on the first renal transplant are generally employed for renal retransplantation, providing results that are superior to ipsilateral renal transplantation.²⁴ However, in the setting of a third renal transplant or in the setting of renal retransplantation after prior simultaneous kidney and pancreas transplants, both iliac fossae have been used for prior transplants, and the placement of the new allograft can be problematic. A feasible solution to address this problem may be using an alternative technique in which nephrectomy of the failed allograft is performed, and the renal vessels of the failed allograft are preserved and utilized for transplantation of the new allograft.²⁵ The same technique may be employed in the setting of renal retransplantation in the setting of severe bilateral aortoiliac atherosclerosis.

Highly HLA-sensitized end-stage renal failure patients comprise a challenge to successful kidney transplantation. Such dialysis patient population faces immense difficulties searching a compatible donor. Paired donation has been increasingly performed in the United States. However, paired donation is not possible in several countries. ABO-incompatible and positive-crossmatch kidney transplantation may be suitable options for successful kidney transplantation in highly sensitized patients. Desenstization by plasma exchange and/or intravenous immunoglobulin usually is performed prior to positive-crossmatch kidney transplantation. Utilization of Eculizumab, a humanized monoclonal antibody directed against complement component C5, may be performed in conjunction with pre-transplant plasma exchange in recipients of living-donor kidney allografts who have high levels of donor specific antibodies (DSAs).²⁶ A recent multicenter US study has associated positive-crossmatch kidney transplantation to an improvement in patient survival as compared to being waitlisted for a compatible deceased dono.²⁷ Although being generally successful, positive crossmatch kidney transplantation is associated to a high incidence of acute humoral rejection. Plasma exchange, Rituximab, Eculizumab, and the preoteosome-inhibitor Bortezomib are suitable medical options for the treatment of antibody-mediated rejection. Medical treatment rarely fails to control rejection. In such instances, either splenectomy or spleen irradiation may provide control for antibody-mediated rejection because the spleen is a large plasma cell reservoir.^28-29

Nowadays, renal transplantation commonly has been performed simultaneously to other solid organ transplants (ex. simultaneous liver-kidney transplantation, simultaneous pancreas-kidney transplantation, simultaneous heart-kidney transplantation). Performance of crossmatch is not necessary before liver transplantation. However, crossmatch should be performed in the setting of simultaneous liver and kidney transplantation. Although performance of liver transplantation simultaneously to kidney transplantation usually confers protection to kidney allograft against rejection,³⁰ hyperacute antibody-mediated rejection with loss of the kidney allograft still may occur in rare instances.³¹

(references are located at the bottom of this article)

About our guest editor

Marcio F. Chedid, MD, PhD

Attending Transplant and Oncological Surgeon,
Hospital de Clinicas de Porto Alegre,
Federal University of Rio Grande do Sul (UFRGS),
Porto Alegre, Brazil

DR. Marcio F. Chedid obtained his Medical Doctor degree by the Federal University of Rio Grande do Sul (UFRGS) in Porto Alegre, Brazil in 2004. DR. CHEDID concluded a five-year General Surgery and Surgical Oncology Residency at Hospital de Clínicas de Porto Alegre - UFRGS in 2010. He obtained ECFMG certification and worked as a Clinical Fellow at the Division of Abdominal Transplantation Surgery of Mayo Clinic in Rochester, Minnesota USA, from 2011 to 2013. DR. Chedid also was a Visiting Scholar at the Department of Surgery of the Washington University in Saint Louis 2014.

DR. Chedid then returned to his home country Brazil to work as Attending Surgeon at the Division of Gastrointestinal Surgery and Liver and Pancreas Transplantation of Hospital de Clinicas de Porto Alegre (UFRGS), at his hometown Porto Alegre 2014. His current main activities are to perform transplants and hepatobiliary operations. He was the first surgeon to report on successful performance of human pancreas transplantation utilizing IGL-1 preservation solution (https://www.ncbi.nlm.nih.gov/pubmed/27163542).
As a former Professor of Human Anatomy, DR. Chedid co-edited a textbook about human anatomy of the abdomen - Anatomia Clínica e Cirúrgica do Abdome - that was published by the UFRGS university press. He has obtained a Ph.D. degree in Surgical Sciences and has authored/co-authored over 35 scientific articles in surgery and medicine. His main interest is researching ways of improving the outcomes of pancreas, liver and kidney transplantation. DR. CHEDID has worked as a reviewer for Transplantation journal, American Journal of Transplantation and also for Clinical Transplantation journal.

Link to Dr. Marcio F. Chedid’s CV: http://lattes.cnpq.br/7710366700138702

Call for nominations

The Thomas E. Starzl Transplantation Institute is accepting nominations for the 2018 Thomas E. Starzl Prize in Surgery and Immunology, awarded annually to a national or international leader in the field of organ transplantation and immunology.
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ISODP 2017 - APRIL 21
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INTERNATIONAL SOCIETY FOR ORGAN DONATION AND PROCUREMENT (WWW.ISODP2017.ORG) - September 6-9 - Geneva, Switzerland

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13TH CONGRESS OF THE INTERNATIONAL SOCIETY OF VASCULARIZED COMPOSITE ALLOTRANSPLANTATION (WWW.ISVCA2017.ORG)
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