OPTN/SRTR 2017 Annual Data Report: Pancreas.

In 2017, 1492 patients were added to the pancreas transplant waiting list, 964 listed as active, a slight increase from 2016. This is significant because for the first time in the past decade, the steady downward trend in additions to the waiting list has been reversed. Proportions of pancreas donors with cerebrovascular accident as cause of death decreased, with a concomitant increase in proportions with anoxia and head trauma. This is partly a result of the national opioid crisis, and it reflects increasing use of younger donors for pancreas transplant. The 2017 outcome report remains compromised by previous variation in reporting graft failure. Although the OPTN Pancreas Transplantation Committee has approved more precise definitions of pancreas graft failure, implementation of these definitions took place recently, and the data are not reflected in this report.

Impact of ureteral stricture and treatment choice on long-term graft survival in kidney transplantation.

We aimed to evaluate the influence of urological complications occurring within the first year after kidney transplantation on long-term patient and graft outcomes, and sought to examine the impact of the management approach of ureteral strictures on long-term graft function. We collected data on urological complications occurring within the first year posttransplant. Graft survivals, patient survival, and rejection rates were compared between recipients with and without urological complications. Male gender of the recipient, delayed graft function, and donor age were found to be significant risk factors for urological complications after kidney transplantation (P < .05). Death censored graft survival analysis showed that only ureteral strictures had a negative impact on long-term graft survival (P = .0009) compared to other complications. Death censored graft survival was significantly shorter in kidney recipients managed initially with minimally invasive approach when compared to the recipients with no stricture (P = .001). However, graft survival was not statistically different in patients managed initially with open surgery (P = .47). Ureteral strictures following kidney transplantation appear to be strongly negatively correlated with long-term graft survival. Our analysis suggests that kidney recipients with ureteral stricture should be managed initially with open surgery, with better long-term graft survival.

Broadened Allocation of Pancreas Transplants Across Compatible ABO Blood Types.

BACKGROUND: Current Organ Procurement and Transplantation Network (OPTN) policy restricts certain blood type-compatible simultaneous pancreas and kidney (SPK) transplants. Using the Kidney Pancreas Simulated Allocation Model, we examined the effects of 5 alternative allocation sequences that allowed all clinically compatible ABO transplants. METHODS: The study cohort included kidney (KI), SPK, and pancreas alone (PA) candidates waiting for transplant for at least 1 day between January 1, 2010, and December 31, 2010 (full cohort), and kidneys and pancreata recovered for transplant during the same period. Additionally, because the waiting list has shrunk since 2010, the study population was reduced by random sampling to match the volume of the 2015 waiting list (reduced cohort). RESULTS: Compared with the current allocation sequence, R4 and R5 both showed an increase in SPK transplants, a nearly corresponding decrease in KI transplants, and virtually no change in PA transplants. Life-years from transplant and median years of benefit also increased. The distribution of transplants by blood type changed, with more ABO:A, B, and AB transplants performed, and fewer ABO:O across all transplant types (KI, SPK, PA), with the relative percent changes largest for SPK. DISCUSSION: Broadened ABO compatibility allowances primarily benefitted SPK ABO:A and AB candidates. ABO:O candidates saw potentially reduced access to transplant. The simulation results suggest that modifying the current allocation sequence to incorporate broadened ABO compatibility can result in an increase in annual SPK transplants.

Laparoscopic Biopsies in Pancreas Transplantation.

As there is no precise laboratory test or imaging study for detection of pancreas allograft rejection, there is increasing interest in obtaining pancreas tissue for diagnosis. Pancreas allograft biopsies are most commonly performed percutaneously, transcystoscopically, or endoscopically, yet pancreas transplant surgeons often lack the skills to perform these types of biopsies. We have performed 160 laparoscopic pancreas biopsies in 95 patients. There were 146 simultaneous kidney-pancreas biopsies and 14 pancreas-only biopsies due to pancreas alone, kidney loss, or extraperitoneal kidney. Biopsies were performed for graft dysfunction (89) or per protocol (71). In 13 cases, an additional laparoscopic procedure was performed at the same operation. The pancreas diagnostic tissue yield was 91.2%; however, the pancreas could not be visualized in eight cases (5%) and in 6 cases the tissue sample was nondiagnostic (3.8%). The kidney tissue yield was 98.6%. There were four patients with intraoperative complications requiring laparotomy (2.5%) with two additional postoperative complications. Half of all these complications were kidney related. There were no episodes of pancreatic enzyme leak and there were no graft losses related to the procedure. We conclude that laparoscopic kidney and pancreas allograft biopsies can be safely performed with very high tissue yields.

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.

Modulation of human allogeneic and syngeneic pluripotent stem cells and immunological implications for transplantation.

Tissues derived from induced pluripotent stem cells (iPSCs) are a promising source of cells for building various regenerative medicine therapies; from simply transplanting cells to reseeding decellularized organs to reconstructing multicellular tissues. Although reprogramming strategies for producing iPSCs have improved, the clinical use of iPSCs is limited by the presence of unique human leukocyte antigen (HLA) genes, the main immunologic barrier to transplantation. In order to overcome the immunological hurdles associated with allogeneic tissues and organs, the generation of patient-histocompatible iPSCs (autologous or HLA-matched cells) provides an attractive platform for personalized medicine. However, concerns have been raised as to the fitness, safety and immunogenicity of iPSC derivatives because of variable differentiation potential of different lines and the identification of genetic and epigenetic aberrations that can occur during the reprogramming process. In addition, significant cost and regulatory barriers may deter commercialization of patient specific therapies in the short-term. Nonetheless, recent studies provide some evidence of immunological benefit for using autologous iPSCs. Yet, more studies are needed to evaluate the immunogenicity of various autologous and allogeneic human iPSC-derived cell types as well as test various methods to abrogate rejection. Here, we present perspectives of using allogeneic vs. autologous iPSCs for transplantation therapies and the advantages and disadvantages of each related to differentiation potential, immunogenicity, genetic stability and tumorigenicity. We also review the current literature on the immunogenicity of syngeneic iPSCs and discuss evidence that questions the feasibility of HLA-matched iPSC banks. Finally, we will discuss emerging methods of abrogating or reducing host immune responses to PSC derivatives.

Diagnosis and Treatment of Pancreas Rejection.

Despite significant improvement in pancreas allograft survival, rejection of the pancreas remains a major clinical problem. In addition to cellular rejection of the pancreas, antibody-mediated rejection of the pancreas is now a well-described entity. The 2011 Banff update established comprehensive guidelines for the diagnosis of acute and chronic AMR. The pancreas biopsy is critical in order to accurately diagnose and treat pancreas rejection. Other modes of monitoring pancreas rejection we feel are neither sensitive nor specific enough. In this review, we examine recent advances in the diagnosis and treatment of pancreas rejection as well as describe practical diagnostic and treatment algorithms.

Acute cellular and antibody-mediated rejection of the pancreas allograft: incidence, risk factors and outcomes.

Antibody-mediated rejection (AMR) after pancreas transplantation is a recently identified entity. We describe the incidence of, risk factors for, and outcomes after AMR, and the correlation of C4d immunostaining and donor-specific antibody (DSA) in the diagnosis of AMR. We retrospectively analyzed 162 pancreas transplants in 159 patients who underwent 94 pancreas allograft biopsies between 2006 and 2009. Univariate and multivariate analyses were performed to evaluate risk factors for pancreas graft AMR. One-year rejection rates and survival after rejection were calculated by Kaplan-Meier methods. AMR occurred in 10% of patients by 1-year posttransplant. Multivariate risk factors identified for AMR include nonprimary simultaneous pancreas-kidney (SPK) transplant, primary solitary pancreas (PAN) transplant and race mismatch. After pancreas rejection, patient survival was 100% but 20% (8 of 41) of pancreas grafts failed within 1 year. Graft survival after acute cellular rejection (ACR), AMR and mixed rejection was similar. Of biopsies that stained >5% C4d, 80% were associated with increased Class I DSA. In summary, AMR occurs at a measurable rate after pancreas transplantation, and the diagnosis should be actively sought using C4d staining and DSA levels in patients with graft dysfunction, especially after nonprimary SPK and primary PAN transplantation.

A comparison of alemtuzumab with basiliximab induction in simultaneous pancreas-kidney transplantation.

Alemtuzumab is a humanized, rat monoclonal antibody directed against the CD52 antigen. After binding, alemtuzumab causes profound and durable depletion and has been successfully used as immune induction therapy for organ transplantation. This was a single center, retrospective review of patients who underwent simultaneous pancreas-kidney transplantation at the University of Wisconsin using alemtuzumab induction therapy compared with historical controls that received induction with basiliximab. There were no differences in donor or recipient demographics, rates of patient survival, renal or pancreas allograft survival, renal allograft delayed graft function, EBV infection, BKV infection, PTLD or sepsis. There was a statistically significant increase in the incidence of cytomegalovirus (CMV) infection in the alemtuzumab-treated group. Given the significantly higher incidence of CMV infections, we have since altered our induction protocol to consist of a single 30 mg dose of alemtuzumab instead of two doses. The long-term effects of this change remain to be seen. Due to the results seen in this study, the low initial cost of the drug and the absence of any severe, short-term side effects, alemtuzumab has been selected as the induction drug of choice at our center for patients undergoing SPK.

Kidney function after solitary pancreas transplantation.

Preserving kidney function in patients after solitary pancreas transplantation (SPTx) is an important consideration, yet various factors may negatively impact long-term function of the native kidneys or kidney allograft. To determine changes in kidney function over time in a series of patients receiving SPTx, we conducted a retrospective analysis and tracked changes in serum creatinine (SCr) and calculated glomerular filtration rate (GFR) from baseline to 6 months, 1 year, or 3 years after SPTx in a series of pancreas after kidney transplants PAK; (n = 61) and pancreas transplants alone PTA; (n = 27) performed at our institution. The mean follow-up for the PAK and PTA groups was 3.4 and 2.7 years, respectively. In this series, 8% of patients after SPTx developed significant kidney failure, defined by either initiation of dialysis or receiving a kidney transplant (PAK-6, PTA-1). Twenty seven percent of SPTx patients with a baseline GFR < 60 suffered either an elevated SCr > 2.2, dialysis, or kidney transplant, whereas no patients with a baseline GFR > 60 developed significant kidney dysfunction. In the PAK group, the GFR did not show significant deterioration over time. In contrast to relatively stable kidney function in PAK patients, PTA patients experienced overall significantly greater rates of decline over time. GFR in PTA patients decreased from 78 +/- 19 (40 to 114) mL/min/1.73 m2 at baseline to 65 +/- 20 at 1 year (P = .006), while SCr increased from 1.03 +/- 0.25 mg/dL to 1.28 +/- 0.43 over the same time period (P = .012). These data show that kidney function may deteriorate after SPTx and proper patient selection may reduce the frequency of this complication.

Simultaneous pancreas-kidney and pancreas transplantation.

The best available method currently for achieving steady normoglycemia in individuals with type 1 diabetes mellitus (DM) is replacing the pancreas, e.g. whole pancreas transplantation. Pancreatic transplantation, as either simultaneous pancreas-kidney (SPK) or solitary pancreas transplantation alone (PTA), has moved beyond simple metabolic or quality-of-life goals. It is now an effective treatment to reverse or minimize metabolic abnormalities and complications of type 1 DM as well as potentially extend the life span of those afflicted by type 1 DM and its many co-morbid complications. Candidates for SPK and PTA transplantation need to meet various criteria even to undergo the transplant procedure and receive a pancreatic allograft that is deemed suitable. SPK and PTA recipients, though free from insulin use, still may encounter common post-transplant medical complications, e.g. cardiovascular disease, high blood pressure, as well as complications unique to SPK and PTA transplantation. The advantages of PTA and SPK transplantation are frankly now more obvious as improvements in surgical technique and new immunosuppression have made an increasing number of PTA and SPK transplants viable and functional long-term. The idea of pancreas transplantation can be touted as a therapeutic advance for type 1 DM. It can improve survival and limit many diabetic-related complications, while improving quality of life, especially in those individuals also afflicted with diabetic-related kidney disease.

Multilineage differentiation from human embryonic stem cell lines.

Stem cells are unique cell populations with the ability to undergo both self-renewal and differentiation. A wide variety of adult mammalian tissues harbors stem cells, yet "adult" stem cells may be capable of developing into only a limited number of cell types. In contrast, embryonic stem (ES) cells, derived from blastocyst-stage early mammalian embryos, have the ability to form any fully differentiated cell of the body. Human ES cells have a normal karyotype, maintain high telomerase activity, and exhibit remarkable long-term proliferative potential, providing the possibility for unlimited expansion in culture. Furthermore, they can differentiate into derivatives of all three embryonic germ layers when transferred to an in vivo environment. Data are now emerging that demonstrate human ES cells can initiate lineage-specific differentiation programs of many tissue and cell types in vitro. Based on this property, it is likely that human ES cells will provide a useful differentiation culture system to study the mechanisms underlying many facets of human development. Because they have the dual ability to proliferate indefinitely and differentiate into multiple tissue types, human ES cells could potentially provide an unlimited supply of tissue for human transplantation. Though human ES cell-based transplantation therapy holds great promise to successfully treat a variety of diseases (e.g., Parkinson's disease, diabetes, and heart failure) many barriers remain in the way of successful clinical trials.

Living-unrelated renal transplantation at the University of Wisconsin.

Since 1984, we have performed 243 living-unrelated renal transplants at the University of Wisconsin. Rejection occurred in 47% of the patients. Graft loss occurred in 59 patients and 39 patients died. Graft survival in LURD transplants at 10 years is 54% and 43% at 15 years. Patient survival is 68% at 10 years and 54% at 15 years. These long-term results demonstrate that LURD is equivalent to haploidentical renal transplantation and superior to cadaveric transplantation. Husband-to-wife donation demonstrated improved graft survival when compared with wife-to-husband and nonspousal donation. Living-unrelated renal transplantation has been utilized successfully at the University of Wisconsin and may help to alleviate the donor shortage.

Liver transplantation from controlled non-heart-beating donors.

BACKGROUND: The use of organs from non-heart-beating donors (NHBDs) has been proposed as one way to increase the donor pool. However, few centers have transplanted livers from NHBDs. We report here the results of 19 liver transplants from controlled NHBDs. METHODS: From January 1993 through August 1999, 364 liver transplantations were performed from heart-beating donors (HBDs) and 19 liver transplantations were performed from NHBDs. Donor and recipient characteristics, posttransplant complications, and patient and allograft survival were compared. RESULTS: No differences in hepatic artery, portal vein, or biliary complications were noted between the groups. However, the rate of primary nonfunction was higher in recipients of livers from NHBDs (10.5% vs. 1.3%; P = .04). No difference in patient survival was seen between recipients of NHBDs or HBDs (72.6% vs. 84.8%; P =.36); however, allograft survival was lower in recipients who received livers from NHBDs (53.8% vs. 80.9%; P =.007). CONCLUSIONS: Liver transplantation from controlled NHBDs results in similar patient survival and post-transplant complications. However, primary nonfunction was higher and allograft survival was less in recipients of livers from NHBDs. The results of liver transplantation from controlled NHBDs are encouraging and should continue to be cautiously pursued as one way to help alleviate the current shortage of donor livers.

Long-term results of liver transplantation in older patients 60 years of age and older.

BACKGROUND: Advances in perioperative care and immunosuppression have enabled clinicians to broaden the indications for organ transplantation. Advanced age is no longer considered a contraindication to transplantation at most centers. Although short-term studies of elderly liver transplant recipients have demonstrated that the incidence of complications and overall patient survival are similar to those of younger adults, transplant center-specific, long-term data are not available. METHODS: From August of 1984 to September of 1997, 91 patients 60 years of age or older received primary liver transplants at the University of Wisconsin, Madison. This group of patients was compared with a group of younger adults (n=387) ranging in age from 18 to 59 years who received primary liver transplants during the same period. The most common indications for transplantation in both groups were Laennec's cirrhosis, hepatitis C, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis. There was no difference in the preoperative severity of illness between the groups. Results. The length of hospitalization was the same for both groups, and there were no significant differences in the incidence of rejection, infection (surgical or opportunistic), repeat operation, readmission, or repeat transplantation between the groups. The only significant difference identified between the groups was long-term survival. Five-year patient survival was 52% in the older group and 75% in the younger group (P<0.05). Ten-year patient survival was 35% in the older group and 60% in the younger group (P<0.05). The most common cause of late mortality in elderly liver recipients was malignancy (35.0%), whereas most of the young adult deaths were the result of infectious complications (24.2%). CONCLUSION: Although older recipients at this center did as well as younger recipients in the early years after liver transplantation, long-term survival results were not as encouraging.