Excerpt from Clinical Transplants 2012

CHAPTER 7

Five -year Outcomes after a Change from a Cyclosporin -based to a 'Low -dose' Tacrolimus- based Primary Immunosuppression Regimen for Incident Kidney Transplants - The Glasgow Experience

Colin C. Geddes, Alan G. Jardine, David Kingsmore, Enric Murio, Laura Buist, Vlad Shumeyko, Neal Padmanabhan, Conal Daly, Elton McGregor, Margaret McMillan, Siobhan McManus, R. Stuart C. Rodger, and Marc Clancy Glasgow Renal and Transplant Unit, Western Infirmary, Glasgow, United Kingdom Corresponding

INTRODUCTION

The Glasgow Transplant unit is one of two kidney transplant units in Scotland. It has provided adult and paediatric kidney transplant services to the West of Scotland (a population of approximately 2.8 million) since the first transplant in 1968. Since then, more than 3000 kidney transplants have been performed. In the last three decades, minimisation of calcineurin inhibitor exposure has been an interest in our unit (1 -5). Calcineurin inhibitors (CNI) are effective at preventing immunological rejection of solid organ transplants, but in the standard doses used clinically, are associated with renal haemodynamic (6) and histological changes (7), which may represent nephrotoxicity. The introduction of mycophenolate mofetil (MMF) and monoclonal IL -2 receptor antagonists in the 1990s offered increased efficacy of immunosuppression without the renal toxicity of CNI. This created an opportunity to treat renal transplant patients with lower doses of CNI without increasing the risk of immunological rejection. The Symphony study published in 2007 demonstrated reduced acute rejection, superior renal function, and superior transplant survival at 1 year with a combination of IL -2 receptor antagonist induction and prednisolone (Pred), MMF, low -dose tacrolimus (Tac) maintenance compared with a conventional -dose cyclosporin (CyA), Pred, MMF regimen, a sirolimus based regimen and a low - dose CyA regimen (8). This low -dose Tac regimen was anticipated, therefore, to be associated with improved long -term transplant outcome. The 3 -year outcome data from the Symphony trial showed that the low -dose Tac cohort continued to perform best, albeit with fewer marked benefits at 3 years, explained perhaps by the large number of patients who had crossed over to the more effective regimen after the initial trial and the relative lack of predicted statistical power for detection of end- point differences at the later time point (9). Since this study's publication, the Tac (low - dose) /MMF /Pred has come to be adopted as primary immunosuppression protocol by many transplant units. Since that time, few publications have confirmed that the benefits demonstrated in the selected trial patient population have translated in to a "real world" unselected recipient population. Having previously used a CyA based regimen, our unit adopted this Tac (low- dose) /MMF /Pred regimen as our primary immunosuppression regimen for all kidney transplants at the beginning of 2007, following the first presentation of the study results. This now gives us an opportunity to report the 5 -year impact of such a change, outside the context of a clinical trial, by comparing the transplants performed 2 years before and 2 years after the change, taking in to account changes in baseline characteristics over this time period.

Excerpt from Clinical Transplants 2012

CHAPTER 6

An Analysis of Intestinal Transplant in the United States

Toshiyuki Sasaki Terasaki Foundation Laboratory, Los Angeles, California

INTRODUCTION

The results of intestinal transplantation have significantly improved over the past decade. In 1998, the 1 -year adjusted allograft survival was 69 %. In 2007, the 1 -year adjusted allograft survival improved to 79% (1). Nevertheless, the overall graft survival rate, early post - transplant graft survival, and number of patients are still lower than transplantation of other organs. In order to improve the prognosis, medical treatment based on more exact and detailed information is required. In this chapter, we analyze the reasons for allograft failure, the changes in intestinal transplant over the years, and the essential factors about each method of operation for intestinal transplantation [intestine alone versus intestine with other organ(s)]. The purpose of this analysis is to gain greater insight and ultimately to improve transplant outcomes.

Excerpt from Clinical Transplants 2012

CHAPTER 5

Factors Affecting Graft Survival Within 1 -Year Post - transplantation in Heart and Lung Transplant: An Analysis of the OPTN /UNOS Registry

Hidenori Ohe Terasaki Foundation Laboratory, Los Angeles, California 

INTRODUCTION

It has been over a half - century since the Shumway Team at Stanford performed the first successful heart transplant in the United States (1). That transplant patient lived just 15 days after the procedure. Since that time, more than 50,000 patients have received heart transplants, and heart transplant has become a valuable surgical treatment for patients with end -stage heart failure. Although the procedure is not as old as heart transplantation, orthotopic lung transplantation has been performed since the early 1980s (2). Prior to 1990, the number of lung transplants performed was less than 1,000 per year. However, the number of lung transplants performed has increased remarkably since 2005 when the lung allocation score was implemented (3). For both of these transplant procedures, graft survival has improved in both adults and pediatrics with the development of new surgical techniques, new immunosuppression therapy, and an increased understanding of the impact of humoral immunity on allograft outcome. Today, a main focus of the transplant community is on the long -term outcomes of lung and heart allograft recipients. However, even early post - transplant survival (within the first post - transplant year) needs improvement, as early graft failure still accounts for many allograft losses. In this chapter, we review the experience of heart and lung transplantation as reported to the Organ Procurement Transplant Network/United Network of Organ Sharing (UNOS) registry and investigate the factors responsible for causing failure in the first post - transplant year.

Excerpt from Clinical Transplants 2012

CHAPTER 4

Liver Transplantation in the MELD Era — Analysis of the OPTN /UNOS Registry

Michiko Taniguchi Terasaki Foundation Laboratory, Los Angeles, California Corresponding

INTRODUCTION

The standardization and refinement of operative techniques since the first human orthotopic liver transplantation (OLT) in 1963— combined with progress in immunosuppression and perioperative management —led to improvement in OLT outcomes, with OLT becoming standard treatment for end -stage liver disease. Although the number of OLTs naturally rose, the limited availability of donor livers limited the number of liver transplants possible. To counter that limit, physicians began to accept extended- criteria donor grafts. Yet the supply of organs would always remain inadequate to meet the need for OLTs, so reform of allocation policies was necessary to achieve a fair, transparent, and more recipient- orientated distribution, the then - extant allocation system being inefficient and failing to accurately stratify patients according to their level of sickness, instead basing the award of grafts mainly on waiting time. To overcome these deficiencies, the Model for End -stage Liver Disease (MELD) system was implemented in February 2002. The aim of MELD was to prioritize organ allocation based on the severity of the chronic liver diseases of patients on the waiting list by scoring the laboratory values of their serum bilirubin, serum creatinine, and the international normalized ratio (INR) of prothrombin time. The implementation of MELD resulted in a significant reduction of patient mortality, number of patients on the transplant waiting list, and their time on the list (1). However, MELD had a limitation in its ability to rate the urgency of need for transplantation: its scoring system does not truly reflect the severity of all liver diseases (2). So MELD was adjusted to offer priority MELD score exceptions for certain disease categories (3). Since the rationale for MELD was to reduce pre - transplant mortality by allocating livers to the sickest patients first, the resultant shift to a sicker transplantation population may have compromised post - transplant survival. This report investigates that question, exploring the dynamics in liver transplantation during the MELD era and the impact of MELD on graft survival based on the data of the Organ Procurement and Transplant Network (OPTN) / United Network for Organ Sharing (UNOS) Registry.