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.

Islet oxygen consumption rate dose predicts insulin independence for first clinical islet allotransplants.

BACKGROUND: Human islet allotransplantation for the treatment of type 1 diabetes is in phase III clinical trials in the U.S. and is the standard of care in several other countries. Current islet product release criteria include viability based on cell membrane integrity stains, glucose-stimulated insulin release, and islet equivalent (IE) dose based on counts. However, only a fraction of patients transplanted with islets that meet or exceed these release criteria become insulin independent following 1 transplant. Measurements of islet oxygen consumption rate (OCR) have been reported as highly predictive of transplant outcome in many models. METHOD: In this article we report on the assessment of clinical islet allograft preparations using OCR dose (or viable IE dose) and current product release assays in a series of 13 first transplant recipients. The predictive capability of each assay was examined and successful graft function was defined as 100% insulin independence within 45 days post-transplant. RESULTS: OCR dose was most predictive of CTO. IE dose was also highly predictive, while glucoses stimulated insulin release and membrane integrity stains were not. CONCLUSION: OCR dose can predict CTO with high specificity and sensitivity and is a useful tool for evaluating islet preparations prior to clinical human islet allotransplantation.

Age-based disparity in outcomes of intestinal transplants in pediatric patients.

Outcomes of intestinal transplants (ITx; n = 977) for pediatric patients are examined using the United Network for Organ Sharing data from 1987 to 2009. Recipients were divided into four age groups: (1) <2 years of age (n = 569), (2) 2-6 years (n = 219), (3) 6-12 years (n = 121) and (4) 12-18 years (n = 68). Of 977 ITx, 287 (29.4%) were isolated ITx and 690 (70.6%) were liver and ITx (L-ITx). Patient survival for isolated ITx at 1, 3 and 5 years, 85.3%, 71.3% and 65.0%, respectively, was significantly better than L-ITx, 68.4%, 57.0% and 51.4%, respectively, (p = 0.0001); this was true for all age groups, except for patients <2 years of age. The difference in graft survival between isolated ITx and L-ITx was significant at 1 and 3 years (Wilcoxon test, p = 0.0012). After attrition analysis of graft survival of patients who survived past first year, 3 and 5 years, graft survival for L-ITx patient was significantly better than those for isolated ITx. Isolated ITx should be considered early before the onset of liver disease in children >2 with intestinal failure but is not advantageous in patients <2 years.

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.

Kidney and pancreas transplantation without a crossmatch in select circumstances--it can be done.

Given the constant flux in caseload and the number of personnel available in the OR, waiting for a final XM often prolongs organ preservation time (a room available at the time a XM is started is not available when the XM is completed). Longer preservation is associated with increased DGF and decreased graft survival. We have shown in a retrospective analysis that final XMs on 0% PRA recipients were always negative (Transplantation, 1999). We now describe a policy of: a) not doing screening XM and b) proceeding to the OR without a XM, in situations where the recipients's PRA has been documented to be 0% and when there have not been any interim transfusions (and the OR is ready before XM completion). Final XM is completed after the transplant. All patients send sera every 6 weeks for PRA (antiglobulin technique). If > o r=3 consecutive PRAs are 0%, no donor-specific screening XM is done prior to calling the patient in for tx (UNOS allocation algorithm used). If there have not been any interim transfusions, we have proceeded to tx prior to completion of the final XM. Between 1/1/98-12/31/99, we did 109 CAD kidney (K) and 79 simultaneous kidney pancreas (SPK) tx; 67 (61%) K and 56 (71%) SPK had 0% PRA. Of the 0% PRA, 25/67 (37%) K and 28/56 (50%) SPK had no pre-tx XM. For K with no XM, cold ischemia was shorter (13.2+/-0.2 vs. 18+/-0.9 hrs, p=0.01) and DGF less (12% vs. 24%, p=0.3); for SPK with no XM, cold ischemia was shorter (15.2+/-2 vs. 18+/-0.9 hrs, p=0.1); no diff in DGF. All post-XM were negative and there were no hyperacute rejections; there was no diff in acute rejection episodes. Actuarial 1 yr graft survival: no XM-K=87.5%, SKP=82%; Yes XM-K=88%, SKP=86% (NS). Our data suggests it is safe, in select circumstances, to proceed to the OR without a XM. Elimination of the screening XM for 0% PRA candidates saves money. Proceeding of the OR (if available) without a final XM shortens cold ischemia time.

Pancreas after kidney transplants.

BACKGROUND: For certain uremic diabetic patients, a sequential transplant of a kidney (usually from a living donor) followed by a cadaver pancreas has become an attractive alternative to a simultaneous transplant of both organs. The purpose of this study was to compare outcomes with simultaneous pancreas-kidney (SPK) versus pancreas after kidney (PAK) transplants to determine advantages and disadvantages of the two procedures. METHODS: Between January 1, 1994, and June 30, 2000, we performed 398 cadaver pancreas transplants at our center. Of these, 193 were SPK transplants and 205 were PAK transplants. We compared these two groups with regard to several endpoints, including patient and graft survival rates, surgical complications, acute rejection rates, waiting times, length of hospital stay, and quality of life. RESULTS: Overall, surgical complications were more common for SPK recipients. The total relaparotomy rate was 25.9% for SPK recipients versus 15.1% for PAK recipients (P = 0.006). Leaks, intraabdominal infections, and wound infections were all significantly more common in SPK recipients (P = 0.009, P = 0.05, and P = 0.01, respectively, versus PAK recipients). Short-term pancreas graft survival rates were similar between the two groups: at 1 year posttransplant, 78.0% for SPK recipients and 77.9% for PAK recipients (P = not significant). By 3 years, however, pancreas graft survival differed between the two groups (74.1% for SPK and 61.7% for PAK recipients), although this did not quite reach statistical significance (P = 0.15). This difference in graft survival seemed to be due to increased immunologic losses for PAK recipients: at 3 years posttransplant, the incidence of immunologic graft loss was 16.2% for PAK versus 5.2% for SPK recipients (P = 0.01). Kidney graft survival rates were, however, better for PAK recipients. At 3 years after their kidney transplant, kidney graft survival rates were 83.6% for SPK and 94.6% for PAK recipients (P = 0.001). The mean waiting time to receive the pancreas transplant was 244 days for SPK and 167 days for PAK recipients (P = 0.001). CONCLUSIONS: PAK transplants are a viable option for uremic diabetics. While long-term pancreas graft results are slightly inferior to SPK transplants, the advantages of PAK transplants include the possibility of a preemptive living donor kidney transplant, better long-term kidney graft survival, significantly decreased waiting times, and decreased surgical complication rates. Use of a living donor for the kidney transplant expands the donor pool. Improvements in immunosuppressive regimens will hopefully eliminate some of the difference in long-term pancreas graft survival between SPK and PAK transplants.

2,500 living donor kidney transplants: a single-center experience.

OBJECTIVE: To review a single center's experience and outcome with living donor transplants. SUMMARY BACKGROUND DATA: Outcome after living donor transplants is better than after cadaver donor transplants. Since the inception of the authors' program, they have performed 2,540 living donor transplants. For the most recent cohort of recipients, improvements in patient care and immunosuppressive protocols have improved outcome. In this review, the authors analyzed outcome in relation to protocol. METHODS: The authors studied patient and graft survival by decade. For those transplanted in the 1990s, the impact of immunosuppressive protocol, donor source, diabetes, and preemptive transplantation was analyzed. The incidence of rejection, posttransplant steroid-related complications, and return to work was determined. Finally, multivariate analysis was used to study risk factors for worse 1-year graft survival and, for those with graft function at 1 year, to study risk factors for worse long-term survival. RESULTS: For each decade since 1960, outcome has improved after living donor transplants. Compared with patients transplanted in the 1960s, those transplanted in the 1990s have better 8-year actuarial patient and graft survival rates. Death with function and chronic rejection have continued to be a major cause of graft loss, whereas acute rejection has become a rare cause of graft loss. Cardiovascular deaths have become a more predominant cause of patient death; infection has decreased. Donor source (e.g., ideally HLA-identical sibling) continues to be important. For living donor transplants, rejection and graft survival rates are related to donor source. The authors show that patients who had preemptive transplants or less than 1 year of dialysis have better 5-year graft survival and more frequently return to full-time employment. Readmission and complications remain problems; of patients transplanted in the 1990s, only 36% never required readmission. Similarly, steroid-related complications remain common. The authors' multivariate analysis shows that the major risk factor for worse 1-year graft survival was delayed graft function. For recipients with 1-year graft survival, risk factors for worse long-term outcome were pretransplant smoking, pretransplant peripheral vascular disease, pretransplant dialysis for more than 1 year, one or more acute rejection episodes, and donor age older than 55. CONCLUSIONS: These data show that the outcome of living donor transplants has continued to improve. However, for living donors, donor source affects outcome. The authors also identify other major risk factors affecting both short- and long-term outcome.