Solid-organ Transplants From Living Donors: Cumulative United States Experience on 140,156 Living Donor Transplants Over 28 Years.

BACKGROUND: Transplantation of organs from living donors helps to decrease the organ shortage and shortens waiting times. Living donor (LD) transplantation is also generally associated with better outcomes. Unfortunately, there has been no comprehensive analysis and comparison of all types of solid-organ transplantation from living donors since the inception of the United Network for Organ Sharing (UNOS). METHODS: Using the UNOS/Organ Procurement and Transplantation Network (OPTN) database, all LD transplants from October 1, 1987, to December 31, 2015, were studied with univariate and multivariate analyses. RESULTS: A total of 140,090 organs were transplanted from LDs, accounting for 21% of all transplants in the United States. Over 95% were kidney; 4% were liver; and <1% intestine, lung, and pancreas LDs. Only LD kidney transplant patient and graft survival rates were significantly higher compared deceased donor transplants over the period of analysis. The best long-term LD transplant results were achieved in pediatric liver recipients. Significantly more women than men donated organs and significantly more men than women received solid-organ transplants. A regional disparity was observed for LD kidney as well as for LD liver transplants. Despite improvements in outcomes and increased use of nonbiologic donors, the number of LD transplants in the United States has declined. This decline was greater in children than adults and was noted for all types of organ transplants. CONCLUSION: Further efforts are needed to educate the public, health professionals, and transplant candidates on the advantages of living vs deceased donor organ transplantation. Compared with other countries, LD transplantation has yet to reach its full potential in the United States.

Pancreas Transplantation: An Alarming Crisis in Confidence.

In the past decade, the annual number of pancreas transplantations performed in the United States has steadily declined. From 2004 to 2011, the overall number of simultaneous pancreas-kidney (SPK) transplantations in the United States declined by 10%, whereas the decreases in pancreas after kidney (PAK) and pancreas transplant alone (PTA) procedures were 55% and 34%, respectively. Paradoxically, this has occurred in the setting of improvements in graft and patient survival outcomes and transplanting higher-risk patients. Only 11 centers in the United States currently perform ≥20 pancreas transplantations per year, and most centers perform <5 pancreas transplantations annually; many do not perform PAKs or PTAs. This national trend in decreasing numbers of pancreas transplantations is related to a number of factors including lack of a primary referral source, improvements in diabetes care and management, changing donor and recipient considerations, inadequate training opportunities, and increasing risk aversion because of regulatory scrutiny. A national initiative is needed to "reinvigorate" SPK and PAK procedures as preferred transplantation options for appropriately selected uremic patients taking insulin regardless of C-peptide levels or "type" of diabetes. Moreover, many patients may benefit from PTAs because all categories of pancreas transplantation are not only life enhancing but also life extending procedures.

Pancreas After Islet Transplantation: A First Report of the International Pancreas Transplant Registry.

Pancreas after islet (PAI) transplantation is a treatment option for patients seeking insulin independence through a whole-organ transplant after a failed cellular transplant. This report from the International Pancreas Transplant Registry (IPTR) and the United Network for Organ Sharing (UNOS) studied PAI transplant outcomes over a 10-year time period. Forty recipients of a failed alloislet transplant subsequently underwent pancreas transplant alone (50%), pancreas after previous kidney transplant (22.5%), or simultaneous pancreas and kidney (SPK) transplant (27.5%). Graft and patient survival rates were not statistically significantly different compared with matched primary pancreas transplants. Regardless of the recipient category, overall 1- and 5-year PAI patient survival rates for all 40 cases were 97% and 83%, respectively; graft survival rates were 84% and 65%, respectively. A failed previous islet transplant had no negative impact on kidney graft survival in the SPK category: It was the same as for primary SPK transplants. According to this IPTR/UNOS analysis, a PAI transplant is a safe procedure with low recipient mortality, high graft-function rates in both the short and long term and excellent kidney graft outcomes. Patients with a failed islet transplant should know about this alternative in their quest for insulin independence through transplantation.

What defines success in pancreas and islet transplantation-insulin independence or prevention of hypoglycemia? A review.

Pancreas transplantation is considered to be the treatment of choice for selected uremic and diabetic patients, and insurance coverage is widely provided. In the USA, islet transplantation is considered to be an experimental procedure that awaits formal results of ongoing phase III trials to justify biologic licensure and transition to standard of care. Pancreas and islet registry analyses focus on different functional endpoints: insulin independence (pancreas transplants) versus avoidance of hypoglycemia (islet transplants). Although the results of islet transplants have significantly improved, the frequent use of multiple donor organs, suboptimal islet yields, and difficulties in monitoring successful engraftment or in diagnosing rejection remain major barriers that need to be overcome. Although pancreas and islet transplantations are frequently considered to be competing procedures, they are actually complementary treatment options for patients with type 1 diabetes mellitus. Because the results of pancreas transplants are superior to those for islet transplants, diabetic patients with a low surgical risk should undergo a pancreas transplantation. Type 1 diabetics with a high surgical risk (eg, serious comorbidities) should undergo an islet transplantation. Only an integrated approach to pancreas and islet transplantation, tailored to the need of the individual patient, will maximize the benefit of a scarce resource. Both procedures, if successful, have in common that they represent the only biologic treatment option to date for type 1 diabetic patients that prevents hypoglycemia long term.

Excellent outcomes can be achieved in young pancreas transplant alone recipients by addition of sirolimus to maintenance immunosuppression regimen.

BACKGROUND: Pancreas transplant alone (PTA) has evolved into a viable treatment option for nonuremic patients with labile diabetes mellitus. Historically, PTA outcomes were inferior to simultaneous pancreas-kidney transplant outcomes, because of the higher rate of graft loss due to rejection in PTA recipients. But with advances in immunosuppression, PTA outcomes have improved significantly--except in young PTA recipients. The more potent immune system in young recipients appears to play a key role. In this study, our objective was to investigate outcomes of PTA, by recipient age, with the use of different immunosuppressive maintenance regimens. METHODS: Using information from the International Pancreas Transplant Registry and from the United Network for Organ Sharing, we analyzed outcomes of 393 technically successful enteric-drained transplants in the PTA category that were performed from January 2003 through December 2012. All PTA recipients underwent induction immunosuppression with thymoglobulin and pulse steroids and were then maintained on long-term low-dose prednisone. Excluded from our study group were patients who experienced surgical graft loss. We divided the 393 recipients into 2 age groups: <42 years (187 patients) versus ≥42 years (206 patients). For both the younger group and the older group, we compared 2 maintenance immunosuppressive regimens: (1) tacrolimus (Tac) and mycophenolate mofetil (MMF) versus (2) Tac/MMF and sirolimus (Srl). We refer to immunosuppression with Tac and MMF as the non-Srl regimen. RESULTS: The overall 3-year graft survival rate, across both age groups, was significantly better with the Srl regimen (P = .03). Regardless of the immunosuppressive regimen used, outcomes were significantly better in the older group than in the younger group (P = .05). In the older group, with both regimens, outcomes were similar (P = .55). But in the younger group, outcomes with the Srl regimen were significantly better (P = .009) than with the non-Srl regimen and, in fact, were similar to outcomes in the older group. CONCLUSIONS: Our study shows that adding Srl to the standard maintenance immunosuppressive regimen of Tac and MMF provides the best outcomes in young PTA recipients, the most immunologically robust and therefore the most immunologically challenging age group. To achieve excellent outcomes, more potent immunosuppression is required in this cohort. We think that PTA should be offered to young patients with labile diabetes before secondary complications develop.

Declining numbers of pancreas transplantations but significant improvements in outcome.

In the United States, over the past 8 years, the number of pancreas transplantations has steadily declined. This decline comes as a surprise, because patient and graft outcomes have substantially improved during the same period of time. Patient survival rates at 1 year in all 3 recipient categories are >96%; graft survival rates are 82%-89%. Changes in immunosuppressive therapy have had a positive impact on outcome, as have better pancreas donor and recipient selection criteria and refined post-transplantation patient care. Although different factors may have contributed to the declining pancreas transplantation numbers, a more effective process of publicly promoting and widely communicating the improved results of pancreas transplantation is warranted.

Results of open and robot-assisted pancreatectomies with autologous islet transplantations: treating chronic pancreatitis and preventing surgically induced diabetes.

For patients with chronic pancreatitis (CP), standard surgical procedures (eg, partial or total resections, drainage procedures) are inadequate treatment options, because they do not confer pain relief and they leave patients prone to brittle diabetes and hypoglycemia. The combination of total pancreatectomy and islet autotransplantation (TP-IAT), however, can create insulin-independent and pain-free states. At our center, from August 2009 through August 2013, 61 patients with CP underwent either open or robot-assisted TP-IAT. The 30-day mortality rate was 0%. The transplanted islet equivalents per body weight ranged from 10,000 to 17,770. In all, 19% of the patients became insulin independent (after a range of 1-24 months); 27% of patients required <10 units of insulin. Moreover, at 12 months after surgery, 71% of the patients were pain free and no longer required analgesics. Our metabolic outcomes could have been even better if most patients had been referred at an earlier disease stage; instead, ∼80% had already undergone surgical procedures, and 91% had abnormal results on preoperative continuous glucose monitoring tests. Only if patients with CP are referred early for a TP-IAT-rather than being subjected to additional inadequate endoscopic and surgical procedures-can insulin-independent and pain-free states be accomplished in most.

The history of pancreas transplantation: past, present and future.

The first attempt to cure type 1 diabetes by pancreas transplantation was done at the University of Minnesota, in Minneapolis, on December 17, 1966, followed by a series of whole pancreas transplantation. Due to the lack of potent immunosuppressive drugs, rejections and infections, it was concluded that pancreas was less antigenic than the kidney which was less antigenic than the duodenum. It opened the door to a period, between the mid 70's to mid 80's where only segmental pancreatic grafts were used in the recipient. Numerous techniques for diverting or dealing with the pancreas juice secretion were described, none of them being satisfactory. In the late 70's - early 80's, three major events happened and boosted the development of pancreas transplantation: firstly the introduction of Cyclosporine A in the clinical field, secondly the organization on March 1980, of the first international meeting on Pancreas Transplantation with the first report of the International Pancreas Transplantation Registry (IPTR) and finally in 1982, the organization of the first informal so-called Spitzingsee meetings where pancreas transplantation successes but mainly failures were discussed which precluded the onset of IPITA (International Pancreas and Islet Transplantation Association), EuroSPK (European Study Group for simultaneous Pancreas and Kidney Transplantation) and EPITA (European Pancreas and Islet Transplantation Association). During one of the Spitzingsee meetings, participants had the idea to renew the urinary drainage technique of the exocrine secretion of the pancreatic graft with segmental graft and eventually with whole pancreaticoduodenal transplant. That was clinically achieved during the mid 80's and remained the mainstay technique during the next decade. In parallel, the Swedish group developed the whole pancreas transplantation technique with enteric diversion. It was the onset of the whole pancreas reign. The enthusiasm for the technique was rather moderated in its early phase due to the rapid development of liver transplantation and the need for sharing vascular structures between both organs, liver and pancreas. During the modern era of immunosuppression, the whole pancreas transplantation technique with enteric diversion became the gold standard for simultaneous pancreas and kidney transplantation (SPK), with portal drainage of the venous effluent of the pancreas, even for pancreas after kidney (PAK) or pancreas transplantation alone (PTA). Today, there remains room for improvement: safety of using the duodeno-duodenal anastomosis technique must be confirmed by prospective analysis while preventing ischemic reperfusion injuries, using specific drugs; that must be assessed in new trials.

Immunosuppression: evolution in practice and trends, 1994-2004.

Over the last 10 years, there have been important changes in immunosuppression management and strategies for solid-organ transplantation, characterized by the use of new immunosuppressive agents and regimens. An organ-by-organ review of OPTN/SRTR data showed several important trends in immunosuppression practice. There is an increasing trend toward the use of induction therapy with antibodies, which was used for most kidney, pancreas after kidney (PAK), simultaneous pancreas-kidney (SPK) and pancreas transplant alone (PTA) recipients in 2004 (72-81%) and for approximately half of all intestine, heart and lung recipients. The highest usage of the tacrolimus/mycophenolate mofetil combination as discharge regimen was reported for SPK (72%) and PAK (64%) recipients. Maintenance of the original discharge regimen through the first 3 years following transplantation varied significantly by organ and drug. The usage of calcineurin inhibitors for maintenance therapy was characterized by a clear transition from cyclosporine to tacrolimus. Corticosteroids were administered to the majority of patients; however, steroid-avoidance and steroid-withdrawal protocols have become increasingly common. The percentage of patients treated for acute rejection during the first year following transplantation has continued to decline, reaching 13% for those who received a kidney in 2003, 48% of which cases were treated with antibodies.

Intestinal graft versus native liver cytokine expression in a rat model of intestinal transplantation: effect of donor-specific cell augmentation.

INTRODUCTION: Immunomodulation by portal vein delivery of donor antigen reduces intestinal graft rejection. We investigated the impact of portal venous donor-specific cell augmentation (blood versus bone marrow) on cytokine expression in intestinal grafts versus native livers. METHODS: Ten groups of intestinal transplants (brown Norway male to Lewis female rats) varied by (1). the type of donor-specific cell augmentation and (2). the use and dose of tacrolimus-based immunosuppression. Tissue samples for histologic analysis and cytokine mRNA analysis were obtained at designated time points. RESULTS: Without immunosuppression, no type of cell augmentation reduced the rate of rejection. With immunosuppression, outcome was significantly better after portal donor-specific blood transfusion (versus bone marrow infusion). Irrespective of the type of cell augmentation, severe rejection caused strong intragraft expression of IL-1alpha, IL-1beta, IFN-gamma, and TNF-alpha; liver expression mainly involved TNF-alpha. Of note, nonimmunosuppressed, cell-augmented rats showed hardly any differences in cytokine expression in their grafts versus significant increases in their native livers. With immunosuppression, bone marrow infusion (versus blood transfusion) increased intragraft cytokine expression of IL-1alpha, IL-1beta, IFN-gamma, as well as TNF-alpha, and liver expression of IL-1beta. CONCLUSIONS: (1). Rejection and donor-specific cell augmentation independently caused differences in intragraft versus native liver cytokine expression after intestinal transplants. (2). Portal donor-specific blood transfusion (versus bone marrow infusion) lowered the incidence of rejection and diminished intragraft cytokine up-regulation. (3). In our study, TNF-alpha appeared to be the cytokine most strongly associated with rejection.