The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

Hepatocellular Carcinoma in Transplantable Child-Pugh A Cirrhotics: Should Cost Affect Resection vs Transplantation?

BACKGROUND: There is no consensus regarding the optimal surgical treatment for transplantable hepatocellular carcinoma (HCC) patients with well-compensated cirrhosis. Our aim was to compare outcomes between Child-Pugh A (CPA) cirrhotics who underwent liver resection or transplantation for HCC. METHODS: Clinicopathologic data were retrospectively collected for all surgically treated HCC patients between 7/1992 and 12/2015. Disease-free survival (DFS) and overall survival (OS) were calculated from the time of operation or diagnosis (intention-to-treat analysis including patients removed from the transplant list). The average overall cost including pre-operative and post-operative procedures was calculated for each group. RESULTS: Of the 513 surgically treated HCC patients, 184 had CPA cirrhosis and fulfilled the Milan criteria (MC). Of those, 95 (52%) were resected and 89 (48%) were transplanted. Twenty-two patients were removed from the transplant list. Transplanted patients were younger (p < 0.001), had a higher MELD score (p < 0.001) and a higher frequency of hepatitis C (p < 0.001). Length of stay and postoperative complication rates were similar between groups. DFS was longer for transplanted patients (3-, 5-, and 10-year DFS rates 48, 44, 31% vs 96, 94, 94%, respectively, p < 0.001). OS was similar between groups (3-, 5-, and 10-year OS rates 76, 62, 41% vs 82, 77, 53%, respectively, p = 0.07). Only size of greatest lesion and T stage were independent predictors of OS. The cost was much higher for the transplant group, even when accounting for the treatment of recurrences ($37,391 vs $137,996). CONCLUSIONS: Since OS is similar between CPA cirrhotics within the MC undergoing resection or transplantation for HCC, but cost is significantly higher for transplantation. Resection should be considered for first-line treatment.

Reframing the approach to patients with hepatocellular carcinoma: Longitudinal assessment with hazard associated with liver transplantation for HCC (HALTHCC) improves ablate and wait strategy.

Patients with hepatocellular carcinoma (HCC) are screened at presentation for appropriateness of liver transplantation (LT) using morphometric criteria, which poorly specifies risk. Morphology is the crux of measuring tumor response to locoregional therapy (LRT) using modified Response Evaluation Criteria in Solid Tumors (mRECIST). This study investigated the utility of following a continuous risk score (hazard associated with liver transplantation in hepatocellular carcinoma; HALTHCC) to longitudinally assess risk. This multicenter, retrospective study from 2002 to 2014 enrolled 419 patients listed for LT for HCC. One cohort had LRT while waiting (n = 351), compared to the control group (n = 68) without LRT. Imaging studies (n = 2,085) were collated to laboratory data to calculate HALTHCC, MORAL, Metroticket 2.0, and alpha fetoprotein (AFP) score longitudinally. Cox proportional hazards evaluated associations of HALTHCC and peri-LRT changes with intention-to-treat (ITT) survival (considering dropout or post-LT mortality), and utility was assessed with Harrell's C-index. HALTHCC better predicted ITT outcome (LT = 309; dropout = 110) when assessed closer to delisting (P < 0.0001), maximally just before delisting (C-index, 0.742 [0.643-0.790]). Delta-HALTHCC post-LRT was more sensitive to changes in risk than mRECIST. HALTHCC score and peri-LRT percentage change were independently associated with ITT mortality (hazard ratio = 1.105 [1.045-1.169] per point and 1.014 [1.004-1.024] per percent, respectively). CONCLUSIONS: HALTHCC is superior in assessing tumor risk in candidates awaiting LT, and its utility increases over time. Peri-LRT relative change in HALTHCC outperforms mRECIST in stratifying risk of dropout, mortality, and recurrence post-LT. With improving estimates of post-LT outcomes, it is reasonable to consider allocation using HALTHCC and not just waiting time. Furthermore, this study supports a shift in perspective, from listing to allocation, to better utilize precious donor organs. (Hepatology 2018).

National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities.

Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

A reliable scoring system after major liver resection in mice.

BACKGROUND: Posthepatectomy liver failure and its transplant counterpart, small-for-size syndrome, remain significant limitations for liver resections and segmental liver transplantation. Partial hepatectomy in mice is one of the most commonly used models to study liver regeneration, but blood and tissue sampling necessary to collect data can affect outcomes or even require euthanasia. We therefore developed a quantitative observational system to predict death from hepatectomy during the first 24 postoperative hours. MATERIALS AND METHODS: A total of 100 female, 10 to 12-week-old C57BL/6 mice underwent two-thirds hepatectomy and were monitored for up to 7 d. Our scoring system was based on five categories, each assigned 0-2 points: activity level, body posture, fur condition, respiratory status, and eye appearance. Seventy-five mice were scored 6 h, 12 h, 24 h, 2 d, 3 d, 5 d, and 7 d after surgery. The remaining 25 mice were scored similarly, but underwent, in addition, blood sampling for serum alanine aminotransferase, total bilirubin, interleukin-6, tumor necrosis factor-alpha, or euthanasia with liver sampling for conventional hematoxylin-eosin and Ki-67 staining. RESULTS: Retrospective analysis indicated that body condition scores ≤5 on two consecutive time points within the first 24 postoperative hours accurately predicted eventual death. Animals in the low scoring group also had significantly higher serum alanine aminotransferase, total bilirubin, interleukin-6, tumor necrosis factor-alpha, more hepatocyte necrosis in hematoxylin-eosin, and fewer Ki-67 positive hepatocytes. CONCLUSIONS: Our scoring system accurately predicts survival, hepatocyte damage, liver regeneration, and systemic inflammation in a mouse hepatectomy model, within the first 24 hours of surgery. This could be useful in evaluating posthepatectomy interventions for their effect on survival and liver regeneration.

Temporal Analysis of Market Competition and Density in Renal Transplantation Volume and Outcome.

BACKGROUND: Kidney transplant centers are distributed unevenly throughout 58 donor service areas (DSAs) in the United States. Market competition and transplant center density may affect transplantation access and outcomes. We evaluated the role of spatial organization of transplant centers in conjunction with market competition in the conduct of kidney transplantation. METHODS: The Scientific Registry of Transplant Recipients was queried for market characteristics associated with kidney transplantation between 2003 and 2012. Market competition was calculated using the Herfindahl Hirschman Index. Kidney transplant centers were geocoded to measure spatial organization by the average nearest neighbor (ANN) method. Kidney quality was assessed by kidney donor risk index. A hierarchical negative binomial mixed effects model tested the relationship between market characteristics and annual kidney transplants by DSA. RESULTS: About 152,071 kidney transplants were performed at 229 adult kidney transplant centers in 58 DSAs. Greater market competition was associated with kidney transplant center spatial clustering (P < 0.001). In multivariable analysis, more kidney transplant centers (incidence rate ratio [IRR], 1.04; P = 0.005), 100 more new listings (IRR, 1.02; P = 0.003), 100 more deceased donors (IRR, 1.23; P < 0.001), 100 more new dialysis registrants (IRR, 1.01; P < 0.001), and higher kidney donor risk index (IRR, 1.98; P < 0.001) were associated with increased kidney transplants. CONCLUSIONS: After controlling for market characteristics, larger numbers of kidney transplant centers were associated with more kidney transplants and increased utilization of deceased donor kidneys. This underlines the importance of understanding geography as well as competition in improving access to kidney transplantation.

Market Competition and Density in Liver Transplantation: Relationship to Volume and Outcomes.

BACKGROUND: Liver transplantation centers are unevenly distributed within the Donor Service Areas (DSAs) of the United States. This study assessed how market competition and liver transplantation center density are associated with liver transplantation volume within individual DSAs. STUDY DESIGN: We conducted a retrospective cohort study of 53,156 adult liver transplants in 45 DSAs with 110 transplantation centers identified from the Scientific Registry of Transplant Recipients between 2003 and 2012. The following measures were derived annually for each DSA: market competition using the Herfindahl Hirschman Index, transplantation center density by the Average Nearest Neighbor method, liver quality by the Liver Donor Risk Index, and patient risk by the Model for End-Stage Liver Disease. A hierarchical mixed effects negative binomial regression model of the relationship between liver transplants and market factors was created annually. Patient and graft survival were investigated with a Cox proportional hazards model. RESULTS: Transplantation center density was associated with market competition (p < 0.0001), listings for organ transplantation (p < 0.0001), and Model for End-Stage Liver Disease at transplantation (p = 0.0005). More liver transplantation centers (incidence rate ratio [IRR] = 1.03; p = 0.04), greater market competition (IRR = 1.36; p = 0.02), increased listings (IRR = 1.14; p < 0.0001), more donors (IRR = 1.24; p < 0.0001), and higher Liver Donor Risk Index (IRR = 3.35; p < 0.0001) were associated with more transplants. No market variables were associated with increased mortality after transplantation. CONCLUSIONS: After controlling for demographic and market factors, a greater concentration of centers was associated with more liver transplants without impacting overall survival. These results warrant additional investigation into the relationship between geospatial factors and liver transplantation volume with consideration for the optimization of scarce resources.

Market competition influences renal transplantation risk and outcomes.

OBJECTIVE: To evaluate the impact of market competition on patient mortality and graft failure after kidney transplantation. BACKGROUND: Kidneys are initially allocated within 58 donation service areas (DSAs), which have varying numbers of transplant centers. Market competition is generally considered beneficial. METHODS: The Scientific Registry of Transplant Recipients database was queried and the Herfindahl-Hirschman index (HHI), a measure of market competition, was calculated for each DSA from 2003 to 2012. Receipt of low-quality kidneys (Kidney Donor Profile Index ≥ 85) was modeled with multivariable logistic regression, and Cox proportional hazards models were created for graft failure and patient mortality. RESULTS: A total of 127,355 adult renal transplants were performed. DSAs were categorized as 7 no (HHI = 1), 17 low (HHI = 0.52-0.97), 17 medium (HHI = 0.33-0.51), or 17 high (HHI = 0.09-0.32) competition. For deceased donor kidney transplantation, increasing market competition was significantly associated with mortality [hazard ratio (HR): 1.11, P = 0.01], graft failure (HR: 1.18, P = 0.0001), and greater use of low-quality kidneys (odds ratio = 1.39, P < 0.0001). This was not true for living donor kidney transplantation (mortality HR: 0.94, P = 0.48; graft failure HR: 0.99, P = 0.89). Competition was associated with longer waitlists (P = 0.04) but not with the number of transplants per capita in a DSA (P = 0.21). CONCLUSIONS: Increasing market competition is associated with increased patient mortality and graft failure and the use of riskier kidneys. These results may represent more aggressive transplantation and tolerance of greater risk for patients who otherwise have poor alternatives. Market competition should be better studied to ensure optimal outcomes.

The migrated liver transplantation candidate: insight into geographic disparities in liver distribution.

BACKGROUND: A minority of liver transplantation (LT) candidates pursue listing at multiple centers to achieve transplantation. The purpose of this study was to assess the characteristics and outcomes of the migrated LT candidates, that is, those who travel to secondary centers seeking LT. STUDY DESIGN: Single-center retrospective study from January 1, 2005 to January 1, 2013 at a tertiary care center within United Network for Organ Sharing Region 1. Adult recipients who were listed at the primary center of interest, but subsequently achieved transplantation at a secondary center (Massachusetts General Hospital [MGH]-migrated; n = 44) were compared with recipients who achieved LT at the primary center (MGH-transplanted; n = 279). RESULTS: The MGH-migrated recipients most frequently traveled to United Network for Organ Sharing Region 3 (70.5%), with a mean (±SD) distance traveled of 1,134 (±392) miles. The MGH-migrated patients, when compared with MGH-transplanted recipients, spent more time on the waitlist (907.6 ± 930.1 days vs 354.9 ± 533.2 days; p < 0.00001), were more likely to have cholestatic liver disease (22.7% vs 6.8%; p = 0.0006) and private insurance (80.0% vs 51.6%; p = 0.0005), but were less likely to have alcoholic liver disease (2.3% vs 18.6%; p = 0.006) and Model for End-Stage Liver Disease exception points (6.8% vs 50.9%; p < 0.00001). On multivariable analysis, candidates with private insurance who lacked both alcoholic liver disease and Model for End-Stage Liver Disease exception point listing were significantly associated with the odds of pursuing migration. Despite achieving LT, MGH-migrated patients had inferior 5-year patient survival rates (63% vs 80%; p = 0.03). CONCLUSIONS: A small and distinctive cohort of LT recipients pursue migration to achieve transplantation. Travel patterns of migrated LT recipients appear to reflect the ongoing geographic disparities in liver distribution and underscore the need for alterations in policy to allow for equitable distribution.

Geographic inequity in access to livers for transplantation.

BACKGROUND: Liver transplantation offers life-saving therapy for patients with decompensated liver disease or T2 hepatocellular carcinomas. In the United States, deceased donor livers are primarily allocated by Model for End-Stage Liver Disease (MELD) score within each of the country's more than 50 donation service areas (DSAs). Variation in DSA size, population, and organ availability have engendered concern that unequal access to deceased donor livers across DSAs contributes to geographic variability in outcome. METHODS: To determine the extent to which DSA variability in organ availability correlated with combined waitlist and posttransplant mortality, we analyzed retrospectively national waitlist and posttransplant data for a 7-year period after implementation of the current MELD-based allocation system. RESULTS: Marked variation among DSAs was evident in death rate (3.3-fold), transplant rate (20-fold), and mean transplant MELD (>10 points). Death rate correlated with organ availability was assessed by transplant rate and transplant MELD. DSAs with low organ availability included the country's largest cities, had more new listings per capita, larger waitlists, more transplant centers per DSA, and a higher proportion of black and Asian patients. DSAs of organ shortage were also characterized by more frequent dual listing at another transplant center, more living donor liver transplants, and increased average length of the transplant admission. CONCLUSIONS: Geographic differences in deceased donor organ availability contribute to variation in overall death rate of liver transplant patients, shape the clinical practice of transplant, and influence the resources consumed per transplant. Geographic variation in organ access results primarily from rates of listing rather than donation. Our findings highlight the need to restructure organ distribution areas to achieve equal access to deceased donor livers for transplantation in the United States.

Kidney transplantation at the University of Pennsylvania: 1998-2008.

Kidney transplantation at the University of Pennsylvania has grown substantially over the past 11 years. Although our transplant volume has increased primarily as a consequence of multiorgan transplants as well as the utilization of historically "marginal" allografts, our post-transplantation outcomes remain excellent in both children and adults. We attribute these outcomes to technical improvements in tissue typing and donor-recipient crossmatching, modification of immunosuppression protocols, and rigorous donor and recipient selection. In the next decade, we hope to substantially expand our living donor program and refine our overall donor and recipient selection process such that we maintain excellent post-transplant outcomes in the face of aging and increasingly comorbid donors and recipients. We further predict significant changes in post-transplant management of kidney recipients with respect to immunosuppression regimens. In particular, we anticipate the modulation of immunosuppression regimens in recipients with high titers of donor-specific antibody and the integration of B-cell specific immunosuppression into post-transplant patient care. Only time will tell whether such therapies will 1) improve long-term outcomes, 2) allow us to diminish the degree of non-specific pharmacologic immunosuppression currently in use, 3) or even promote donor-specific tolerance in kidney transplant recipients.

Expanded-criteria donor kidneys: a single-center clinical and short-term financial analysis--cause for concern in retransplantation.

BACKGROUND: Expanded-criteria donor (ECD) kidneys are associated with a higher risk of posttransplant failure, but they remain a favorable alternative to dialysis. Now that a uniform definition of "expanded criteria" exists, it is more appropriate than ever to evaluate their utility compared with that seen with non-ECD kidneys. METHODS: The authors analyzed 202 cadaveric kidney-only recipients that underwent transplantation from January 1999 to September 2001, including 45 (22%) recipients whose donors met current ECD criteria. RESULTS: ECD and non-ECD kidney recipients had similar pretransplant characteristics except for older age and increased duration of renal failure in the ECD group. Patient, graft, and death-censored graft survival in both groups were similar in primary recipients but significantly worse in retransplant recipients of ECD kidneys. The relative risk of death-censored graft loss was 1.58 in the ECD group (P = 0.45). Overall inpatient charges (minus organ acquisition charge) for 1 year posttransplant were 76,962 US dollars (ECD) versus 71,026 US dollars (non-ECD) (P = 0.53); the same charges in retransplant recipients were 136,596 US dollars (ECD) versus 91,296 US dollars (non-ECD) (P = 0.25). ECD recipients, especially retransplant recipients, had consistently higher creatinine concentrations, although the average current value of all functioning ECD grafts remains less than 2 mg/dL. ECD recipients had a higher incidence of ureteral stricture (4.4% vs. 0%), but this never resulted in graft loss. CONCLUSIONS: Considering the widening disparity between renal allograft availability and need and the fact that ECD kidneys provide superior outcomes compared with dialysis, the authors' data encourage the continued use of ECD kidneys in primary recipients but justify caution in the retransplant setting.

Transplantation for type I diabetes: comparison of vascularized whole-organ pancreas with isolated pancreatic islets.

OBJECTIVE: We sought to compare the efficacy, risks, and costs of whole-organ pancreas transplantation (WOP) with the costs of isolated islet transplantation (IIT) in the treatment of patients with type I diabetes mellitus. SUMMARY BACKGROUND DATA: A striking improvement has taken place in the results of IIT with regard to attaining normoglycemia and insulin independence of type I diabetic recipients. Theoretically, this minimally invasive therapy should replace WOP because its risks and expense should be less. To date, however, no systematic comparisons of these 2 options have been reported. METHODS: We conducted a retrospective analysis of a consecutive series of WOP and IIT performed at the University of Pennsylvania between September 2001 and February 2004. We compared a variety of parameters, including patient and graft survival, degree and duration of glucose homeostasis, procedural and immunosuppressive complications, and resources utilization. RESULTS: Both WOP and IIT proved highly successful at establishing insulin independence in type I diabetic patients. Whole-organ pancreas recipients experienced longer lengths of stay, more readmissions, and more complications, but they exhibited a more durable state of normoglycemia with greater insulin reserves. Achieving insulin independence by IIT proved surprisingly more expensive, despite shorter initial hospital and readmission stays. CONCLUSION: Despite recent improvement in the success of IIT, WOP provides a more reliable and durable restoration of normoglycemia. Although IIT was associated with less procedure-related morbidity and shorter hospital stays, we unexpectedly found IIT to be more costly than WOP. This was largely due to IIT requiring islets from multiple donors to gain insulin independence. Because donor pancreata that are unsuitable for WOP can often be used successfully for IIT, we suggest that as IIT evolves, it should continue to be evaluated as a complementary alternative to rather than as a replacement for the better-established method of WOP.

Survival following liver transplantation from non-heart-beating donors.

OBJECTIVE: To determine whether patient and graft survival following transplantation with non-heart-beating donor (NHBD) hepatic allografts is equivalent to heart-beating-donor (HBD) allografts. SUMMARY BACKGROUND DATA: With the growing disparity between the number of patients awaiting liver transplantation and a limited supply of cadaveric organs, there is renewed interest in the use of hepatic allografts from NHBDs. Limited outcome data addressing this issue exist. METHODS: Retrospective evaluation of graft and patient survival among adult recipients of NHBD hepatic allografts compared with recipients of HBD livers between 1993 and 2001 using the United Network of Organ Sharing database. RESULTS: NHBD (N = 144) graft survival was significantly shorter than HBD grafts (N = 26856). One- and 3-year graft survival was 70.2% and 63.3% for NHBD recipients versus 80.4% and 72.1% (P = 0.003 and P = 0.012) for HBD recipients. Recipients of an NHBD graft had a greater incidence of primary nonfunction (11.8 vs. 6.4%, P = 0.008) and retransplantation (13.9% vs. 8.3%, P = 0.04) compared with HBD recipients. Prolonged cold ischemic time and recipient life support were predictors of early graft failure among recipients of NHBD livers. Although differences in patient survival following NHBD versus HBD transplant did not meet statistical significance, a strong trend was evident that likely has relevant clinical implications. CONCLUSIONS: Graft and patient survival is inferior among recipients of NHBD livers. NHBD donors remain an important source of hepatic grafts; however, judicious use is warranted, including minimization of cold ischemia and use in stable recipients.

Operative parameters that predict the outcomes of hepatic transplantation.

BACKGROUND: A growing discrepancy between the number of patients awaiting liver transplantation and the number of organs available mandates the use of even marginal organ donors in whom there is major risk of suboptimal graft function. A comprehensive analysis of operative parameters on the outcomes of liver transplantation has not been reported. STUDY DESIGN: We analyzed the impact of 24 operative variables on the survival of 942 consecutive primary liver allografts performed at a single center from June 1992 through December 1997. Univariate and Cox proportional hazards analysis was used to identify those variables with independent prognostic significance in graft survival. Resource utilization for variables with multivariate significance was also analyzed. RESULTS: Of 12 intraoperative variables found to have significance in univariate analysis, three were significant by Cox multivariate analysis: 1) lack of immediate bile production by the graft intraoperatively, 2) platelet transfusion > or = 20 U, and 3) recipient urine output < or =2.0 mL/kg/h intraoperatively. Each of the three variables was associated with marked increases in hospital and Intensive Care Unit length of stay and hospital charges accrued during the admission for transplantation. CONCLUSION: We identified three operative parameters that predict a poor outcome after liver transplantation. The presence of these indicators suggests that early retransplantation should be considered. Early identification of grafts likely to have poor function might also provide an opportunity for therapeutic intervention to salvage graft function.