A health economic analysis of clinical islet transplantation

Islet cell transplantation is in clinical development for type 1 diabetes. There are no data on the cost in relationship to its benefits. We performed a cost-effectiveness analysis and made a comparison with standard insulin therapy, using Markov modeling and Monte Carlo simulations. The patient population was adults aged 20 yr suffering from hypoglycemia unawareness. Data were estimates from literature and clinical trials: costs were based on the situation in the United States. For insulin therapy, cumulative cost per patient during a 20-yr follow-up was $663,000, and cumulative effectiveness was 9.3 quality-adjusted life years (QALY), the average cost-effectiveness ratio being $71,000 per QALY. Islet transplantation had a cumulative cost of $519,000, a cumulative effectiveness of 10.9 QALY, and an average cost-effectiveness ratio of $47,800. During the first 10 yr, costs for transplantation were higher, but cumulative effectiveness was higher from the start onwards. In sensitivity analyses, the need for one instead of two transplants during the first year did not affect the conclusions, and islet transplantation remained cost-saving up to an initial cost of the procedure of $240,000. This exploratory evaluation shows that islet cell transplantation is more effective than standard insulin treatment, and becomes cost-saving at about 9-10 yr after transplantation.     

Kidney transplantation in the elderly: a decision analysis

Transplantation offers superior life expectancy and quality of life compared with dialysis in young patients with end-stage renal failure. However, the initial risks of mortality and morbidity are high. This study used a decision analysis model to evaluate the costs and benefits of kidney transplantation versus continued dialysis for older patients with renal failure. A decision analytic model comparing cadaveric renal transplantation to continued hemodialysis treatment was developed. The base case considered a theoretical cohort of patients aged 65 yr without known comorbidity or contraindications to transplantation who would have to wait 2 yr for a cadaveric transplant. Separate models were constructed for patients with diabetes or cardiovascular disease and for patients receiving an organ after a variety of wait-list times. Probability, utility, and survival data were obtained from published reports and renal registries. For 65-yr-old patients, quality-adjusted life expectancy increased by 1.1 quality-adjusted life years (QALY) at an incremental cost of $67,778 per QALY. Assuming a 2-yr wait-listed time, transplantation remained economically attractive for 70-yr-old patients (incremental cost effectiveness [ICE], $79,359 per QALY) but was less economically attractive for those over 75 yr of age (ICE, $99,553) or for 70-yr-olds with either cardiovascular disease or diabetes (ICE, $126,751 and $161,090 per QALY, respectively). The analytic results were sensitive only to the time spent waiting for the graft. The cost-effectiveness reduced such that the costs associated with one QALY were in excess of $100,000/yr when the probability of a complication was > or = 50% per 3-mo cycle and when the utility of transplantation fell below 0.62. If available within a timely period, transplantation may offer substantial clinical benefits to older patients at a reasonable financial cost. Prolonged waiting times dramatically decrease the clinical benefits and economic attractiveness of transplantation, suggesting that living donor transplantation may be of particular benefit in this population.     

An economic assessment of contemporary kidney transplant practice

Kidney transplantation is the optimal therapy for end‐stage renal disease, prolonging survival and reducing spending. Prior economic analyses of kidney transplantation, using Markov models, have generally assumed compatible, low‐risk donors. The economic implications of transplantation with high Kidney Donor Profile Index (KDPI) deceased donors, ABO incompatible living donors, and HLA incompatible living donors have not been assessed. The costs of transplantation and dialysis were compared with the use of discrete event simulation over a 10‐year period, with data from the United States Renal Data System, University HealthSystem Consortium, and literature review. Graft failure rates and expenditures were adjusted for donor characteristics. All transplantation options were associated with improved survival compared with dialysis (transplantation: 5.20‐6.34 quality‐adjusted life‐years [QALYs] vs dialysis: 4.03 QALYs). Living donor and low‐KDPI deceased donor transplantations were cost‐saving compared with dialysis, while transplantations using high‐KDPI deceased donor, ABO‐incompatible or HLA‐incompatible living donors were cost‐effective (<$100 000 per QALY). Predicted costs per QALY range from $39 939 for HLA‐compatible living donor transplantation to $80 486 for HLA‐incompatible donors compared with $72 476 for dialysis. In conclusion, kidney transplantation is cost‐effective across all donor types despite higher costs for marginal organs and innovative living donor practices.     

Induction therapy with rabbit antithymocyte globulin versus basiliximab after kidney transplantation: a health economic analysis from a German perspective

A health economic analysis was undertaken based on the 1‐year database from a randomized study of rabbit anti‐human thymocyte immunoglobulin (rATG) versus basiliximab, in kidney transplantation using resource utilization data and cost estimates from three German hospitals. A three‐state Markov model was applied to estimate cost‐effectiveness to 10 years post‐transplant. Total mean treatment cost per patient to year 1 post‐transplant was €62 075 vs. €59 767 for rATG versus basiliximab (P < 0.01). rATG therapy was associated with similar treatment costs to basiliximab by year 2, and a predicted cumulative treatment cost saving of €4 259 under rATG versus basiliximab by year 10 post‐transplant. The mean number of quality‐adjusted life years (QALYs) per patient by year 1 was 0.809 vs. 0.802 in the rATG and basiliximab cohorts, respectively (P = 0.38), with cumulative QALYs of 6.161 and 6.065 per patient by year 10. By year 2, the cumulative cost per QALY was slightly lower under rATG (€35 378) than basiliximab (€35 885), progressing to a saving of €1 041 under rATG for the cumulative cost per QALY by year 10. In conclusion, this model indicates that rATG induction provides a modest increase in QALYs with lower long‐term costs than basiliximab in deceased‐donor high‐risk kidney transplant patients.     

Five‐layer border dressings as part of a quality improvement bundle to prevent pressure injuries in US skilled nursing facilities and Australian nursing homes: A cost‐effectiveness analysis

The BORDER III trial found that five‐layer silicone border dressings effectively prevented pressure injuries in long‐term care, but the value of this approach is unknown. Our objective was to analyse the cost‐effectiveness of preventing facility‐acquired pressure injuries with a quality improvement bundle, including prophylactic five‐layer dressings in US and Australian long‐term care. Markov models analysed the cost utility for pressure injuries acquired during long‐term care from US and Australian perspectives. Models calibrated outcomes for standard care compared with a dressing‐inclusive bundle over 18 monthly cycles or until death based on BORDER III outcomes. Patients who developed a pressure injury simulated advancement through stages 1 to 4. Univariate and multivariate probabilistic sensitivity analyses tested modelling uncertainty. Costs in 2017 USD and quality‐adjusted life years (QALYs) were used to calculate an incremental cost‐effectiveness ratio (ICER). Dressing use yielded greater QALYs at slightly higher costs from perspectives. The US ICER was $36 652/QALY, while the Australian ICER was $15 898/QALY, both of which fell below a willingness‐to‐pay threshold of $100 000/QALY. Probabilistic sensitivity analysis favoured dressings as cost‐effective for most simulations. A quality improvement bundle, including prophylactic five‐layer dressings, is a cost‐effective approach for pressure injury prevention in all US and Australia long‐term care residents.     

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes—Chapter 6: patient selection for pilot clinical trials of islet xenotransplantation

Patients in whom type 1 diabetes is complicated by impaired awareness of hypoglycemia and recurrent episodes of severe hypoglycemia are candidates for islet or pancreas transplantation if severe hypoglycemia persists after completion of a structured stepped care approach or a formalized medical optimization run‐in period that provides access to hypoglycemia‐specific education including behavioral therapies, insulin analogs, and diabetes technologies under the close supervision of a specialist hypoglycemia service. Patients with type 1 diabetes and end‐stage renal failure who cannot meet clinically appropriate glycemic goals or continue to experience severe hypoglycemia after completion of a formalized medical optimization program under the guidance of an expert diabetes care team are candidates for islet or pancreas transplantation either simultaneously with or after a previous kidney transplant. Similarly, patients with type 2 diabetes and problematic hypoglycemia or renal failure who meet these criteria are considered candidates for islet replacement. Likewise, patients with pancreatectomy‐induced diabetes in whom an islet autograft was not available or deemed inappropriate are candidates for islet or pancreas transplantation if extreme glycemic lability persists despite best medical therapy. To justify participation of these transplant candidates in early‐phase trials of porcine islet cell products, lack of timely access to islet or pancreas allotransplantation due to allosensitization, high islet dose requirements, or other factors, or alternatively, a more favorable benefit–risk determination associated with the xenoislet than the alloislet or allopancreas transplant must be demonstrated. Additionally, in non‐uremic xenoislet recipients, the risks associated with diabetes must be perceived to be more serious than the risks associated with the xenoislet product and the rejection prophylaxis, and in xenoislet recipients with renal failure, the xenoislet product and immunosuppression must not impact negatively on renal transplant outcomes. The most appropriate patient group for islet xenotransplantation trials will be defined by the specific characteristics of each investigational xenoislet product and related technologies applied for preventing rejection. Selecting recipients who are more likely to experience prolonged benefits associated with the islet xenograft will help these patients comply with lifelong monitoring and other public health measures.     

Islet cell xenotransplantation: a serious look toward the clinic

Type I diabetes remains a significant clinical problem in need of a reliable, generally applicable solution. Both whole organ pancreas and islet allotransplantation have been shown to grant patients insulin independence, but organ availability has restricted these procedures to an exceptionally small subset of the diabetic population. Porcine islet xenotransplantation has been pursued as a potential means of overcoming the limits of allotransplantation, and several preclinical studies have achieved near‐physiologic function and year‐long survival in clinically relevant pig‐to‐primate model systems. These proof‐of‐concept studies have suggested that xenogeneic islets may be poised for use in clinical trials. In this review, we examine recent progress in islet xenotransplantation, with a critical eye toward the gaps between the current state of the art and the state required for appropriate clinical investigation.     

Comparative effectiveness of donation after cardiac death versus donation after brain death liver transplantation: Recognizing who can benefit

Due to organ scarcity and wait-list mortality, transplantation of donation after cardiac death (DCD) livers has increased. However, the group of patients benefiting from DCD liver transplantation is unknown. We studied the comparative effectiveness of DCD versus donation after brain death (DBD) liver transplantation. A Markov model was constructed to compare undergoing DCD transplantation with remaining on the wait-list until death or DBD liver transplantation. Differences in life years, quality-adjusted life years (QALYs), and costs according to candidate Model for End-Stage Liver Disease (MELD) score were considered. A separate model for hepatocellular carcinoma (HCC) patients with and without MELD exception points was constructed. For patients with a MELD score <15, DCD transplantation resulted in greater costs and reduced effectiveness. Patients with a MELD score of 15 to 20 experienced an improvement in effectiveness (0.07 QALYs) with DCD liver transplantation, but the incremental cost-effectiveness ratio (ICER) was >$2,000,000/QALY. Patients with MELD scores of 21 to 30 (0.25 QALYs) and >30 (0.83 QALYs) also benefited from DCD transplantation with ICERs of $478,222/QALY and $120,144/QALY, respectively. Sensitivity analyses demonstrated stable results for MELD scores <15 and >20, but the preferred strategy for the MELD 15 to 20 category was uncertain. DCD transplantation was associated with increased costs and reduced survival for HCC patients with exception points but led to improved survival (0.26 QALYs) at a cost of $392,067/QALY for patients without exception points. In conclusion, DCD liver transplantation results in inferior survival for patients with a MELD score <15 and HCC patients receiving MELD exception points, but provides a survival benefit to patients with a MELD score >20 and to HCC patients without MELD exception points.     

Advantages of combined fetal and adult porcine islets as donor tissue for transplantation

Abstract: The molecular similarity between human and porcine insulin is the primary reason for selecting the pig as a donor for islet xenotransplantation in order to treat type I diabetes. Porcine islets can be prepared from adult, newborn, or fetal pigs. However, each of these islet types possesses advantages and disadvantages due to their anatomical, developmental, and physiological characteristics. We have evaluated both adult and fetal porcine islets for their ability to reverse diabetes using an allograft model. Based on our accumulated data, we recommend transplantation of combined adult and fetal porcine islets as a prospective approach for pig to man islet xenotransplantation. The advantages of combined adult and fetal islet transplantation are as follows: 1) Adult porcine islets can reverse hyperglycemia soon after transplantation; 2) well controlled blood glucose at the critical developmental stage of fetal islets will provide the time and environment necessary to achieve the optimal proliferation, growth and maturation of fetal β cells; 3) after 2 to 3 months, fetal islets will functionally mature and begin to share the insulin-producing load previously carried by adult islets, while new islets will continuously emerge and proliferate from stem cells; and 4) islets from fetal pigs will subsequently play a primary role in controlling hyperglycemia, and provide long-lasting insulin independence.     

Cost effectiveness of laparoscopic versus open mesh hernia operation: results of a Department of Veterans Affairs randomized clinical trial

BACKGROUND: Evidence comparing laparoscopic versus open hernia repair has varied with time and with changes in techniques used. Cost effectiveness is an important consideration when evidence for predominance of one surgical technique is lacking. Current cost estimates of hernia repair are not available. STUDY DESIGN: This study is a cost effectiveness analysis within a randomized controlled trial comparing open (OPEN) versus laparoscopic (LAP) hernia repair using mesh at 14 Department of Veterans Affairs medical centers, with 2-year followup for each patient. Between January 1999 and November 2001, 2,164 men with inguinal hernia were randomized and 1,983 had an operation; 1,395 patients (708 OPEN and 687 LAP) with outpatient hernia operations were included in the cost effectiveness analysis. Outcomes included surgical and postoperative costs, quality adjusted life years (QALY), and incremental cost per QALY gained or the incremental cost effectiveness ratio (ICER). RESULTS: Over 2 years, LAP cost an average of $638 more than OPEN. QALYs at 2 years were similar, resulting in $45,899 per QALY gained (95% CI: -$669,045, $722,457). The probability that LAP is cost effective at the $50,000 per QALY level (slightly more costly but more effective), was 51%. For unilateral primary and unilateral recurrent hernia repair, the probabilities that LAP is cost effective at the $50,000 per QALY level were 64% and 81%, respectively. For bilateral hernia repair, OPEN was less costly and more effective. CONCLUSIONS: Overall, laparoscopic hernia repair is not cost effective compared with open repair. For patients with unilateral (primary or recurrent) hernia, laparoscopic repair is a cost effective treatment option.     

Species incompatibilities in the pig-to-macaque islet xenotransplant model affect transplant outcome: a comparison with allotransplantation

Graham ML, Bellin MD, Papas KK, Hering BJ, Schuurman H‐J. Species incompatibilities in the pig‐to‐macaque islet xenotransplant model affect transplant outcome: a comparison with allotransplantation. Xenotransplantation 2011; 18: 328–342. © 2011 John Wiley & Sons A/S. Abstract: Background: Porcine islet transplantation into diabetic non‐human primates is considered most relevant in translational research supporting a clinical application. Most studies have focused on immunosuppressive protocols, while metabolic aspects have mainly been utilized in graft monitoring. We evaluated data from our group regarding human and non‐human primate (NHP) allotransplantation and pig‐to‐NHP xenotransplantation to identify incompatibilities in metabolic factors and their consequences for transplant outcomes. Methods: Basic gluco‐metabolic parameters (fasting blood glucose, C‐peptide, and response to stimulation with arginine or glucose) were derived from literature (humans), 72 macaques, and 47 adult Landrace pigs. Islet preparations from 15 human deceased donors, 61 macaques, and 23 adult pigs were compared with respect to yield, fractional viability assessed by oxygen consumption normalized for DNA, and in vitro glucose‐induced insulin release. Metabolic parameters at day 75 after a single islet transplantation in the liver were compared for 19 patients and 9 macaques receiving an allotransplant and 11 macaques receiving a porcine xenotransplant: recipients received chronic immunosuppression. Results: Pigs differ from NHPs and humans by a much lower C‐peptide level (0.42 vs. 1.3 to 2.0 ng/ml, respectively) and a 2‐ to 7‐fold lower C‐peptide response to arginine stimulation. In contrast, NHPs have the highest metabolic demand as evidenced by a high C‐peptide and high C‐peptide response to arginine stimulation; values are about twice higher than in humans. For manufactured islet preparations, these differences are reflected by glucose‐stimulated insulin release (the stimulation index for pigs is 1.5, for humans 3.8, and for macaques 7.7), but not by fractional viability, which was in the same range. The day 75 outcome after transplantation assessed by C‐peptide was similar for allotransplanted humans and NHPs (80 to 90% good graft function) and lower in xenografted NHPs (36% good graft function); gluco‐metabolic parameters were in accordance with graft function, albeit different between species because normoglycemia under exogenous insulin is maintained more aggressively in patients than in NHPs. In xenografted NHPs, the shift in glycemic control with respect to normal values, combined with low values of circulating porcine C‐peptide, resembled more the normal condition in a pig than that in a macaque. Conclusions: The substantially lower glucose‐induced insulin response in adult porcine islet preparations as opposed to islets manufactured from humans or macaques combined with the much higher need for insulin in macaques than in humans creates an imbalance between the metabolic demand and the engrafted islet mass in the pig‐to‐NHP xenograft recipient. Engrafted islet mass is affected by dose, suggesting that a much higher dose level of islets is necessary in the xenogeneic setting than in human or NHP allotransplantation, and pig islets need to be given at a higher dose in macaques than the anticipated effective dose in humans. To cope with differences in metabolic demand and presumably also metabolic dynamics, a liberal regime in supportive exogenous insulin might be essential to achieve long‐term survival. These intrinsic characteristics of the NHP model deserve consideration to optimally design experimental studies with the perspective of translational value of results.     

A decision-analytic economic evaluation of valaciclovir prophylaxis for the prevention of cytomegalovirus infection and disease in renal transplantation

OBJECTIVE: This analysis evaluates the cost-effectiveness of valaciclovir prophylaxis using clinically and economically important health outcomes including graft failure, life-years, and quality-adjusted life-years (QALYs). METHODS: A Markov model was developed using a randomized, placebo-controlled trial of valaciclovir prophylaxis, together with a published epidemiological study and national renal transplant registry data. The model's population was stratified into two risk groups by donor/recipient cytomegalovirus (CMV) serostatus at transplantation: donor-positive/recipient-negative (D+R-) and recipient-positive (R+) patients. The model estimated costs and health outcomes over a 30-yr period from the perspective of Australian health care providers. RESULTS: The total health care cost was $3619 lower for D+R- patients receiving valaciclovir prophylaxis compared with those not receiving prophylaxis. D+R- patients receiving valaciclovir gained an extra 0.33 yr of life and 0.27 QALYs. R+ patients receiving valaciclovir prophylaxis gained an extra 0.07 yr of life and 0.05 QALYs, with an incremental cost of $914. This equates to $17 127 per QALY gained, which is highly cost-effective compared with other drugs and health interventions. CONCLUSIONS: Valaciclovir for the prophylaxis of CMV disease in renal transplant recipients is a cost-effective intervention, significantly reducing the burden of CMV disease to patients and health care providers.     

Native pancreatic α-cell adaptation in streptozotocin-induced diabetic primates: importance for pig islet xenotransplantation

Abstract: Background: Metabolic compatibility between donor and recipient species is an important matter for pig islet xenotransplantation. Glucagon is a key hormone for the function of pig islets as well as control of hypoglycemia in the recipients of the islets. Because a discrepancy exists in the composition of glucagon cells of pig and human/primate islets, the present study was designed to determine the role of native recipient glucagon cells in the treatment of diabetes by islet transplantation in a “pig‐to‐primate” model. Methods: Streptozotocin‐treated (50 mg/kg) monkeys (n = 12, follow‐up of 6 to 231 days) were compared with non‐diabetic animals (n = 5; follow‐up, 180 days). Metabolic [fasting and intravenous glucose tolerance tests (IVGTTs) for serum levels of glucose, insulin, glucagon] and morphologic (endocrine volume density and cell mass for insulin and glucagon) were compared between non‐diabetic and diabetic animals. Six additional diabetic primates were given transplants of 15 000 adult pig islet equivalents without immunosuppression to monitor glucose, glucagon, insulin, and porcine C‐peptide levels until 48 h after transplantation. Results: Elevated fasting blood glucose, pathologic IVGTT, destruction of 95% of β‐cell mass, and glycosylated hemoglobin (>13%) were assessed in diabetic monkeys. The serum glucagon levels and glucagon cell mass correlated significantly with diabetes time course of diabetes (R = 0.940, p = 0.005; R = 0.663, p = 0.019, respectively). A mean increase of 89% in glucagon cell mass was observed for primates suffering from diabetes >53 days. No response of glucagon secretion was observed for diabetic animals during IVGTT, because no increase of serum insulin levels followed glucose loading. Blood glucose levels dropped after pig islet xenografts in diabetic primates. This reduction was maintained by an insulin level >20 μU/ml over the period of time of xenograft function (porcine C‐peptide >0.1 ng/ml). A total restoration of native primate glucagon sensitivity to insulin was found after pig islets xenotransplantation as revealed by a reduction of 80% of the glucagon level. When graft dysfunction (>24 h post‐transplantation), the insulin level dropped and glucagon levels rose again (>50 pg/ml). Conclusions: Native glucagon cells provide morphologic and functional plasticity to diabetes. Adult pig islet xenotransplantation can restore the sensitivity of primate glucagon to insulin but cannot protect the diabetic recipient against hypoglycemia.     

Cost‐effectiveness of using kidneys from hepatitis C nucleic acid test–positive donors for transplantation in hepatitis C–negative recipients

Kidneys from deceased donors who are hepatitis C virus (HCV) nucleic acid test positive are infrequently used for transplantation in HCV‐negative patients due to concerns about disease transmission. With the development of direct‐acting antivirals (DAAs) for HCV, there is now potential to use these kidneys in HCV‐negative candidates. However, the high cost of DAAs poses a challenge to adoption of this strategy. We created a Markov model to examine the cost‐effectiveness of using deceased donors infected with HCV for kidney transplantation in uninfected waitlist candidates. In the primary analysis, this strategy was cost saving and improved health outcomes compared to remaining on the waitlist for an additional 2 or more years to receive a HCV‐negative transplant. The strategy was also cost‐effective with an incremental cost‐effectiveness ratio of $56 018 per quality‐adjusted life year (QALY) from the payer perspective, and $4647 per QALY from the societal perspective, compared to remaining on the waitlist for 1 additional year. The results were consistent in 1‐way and probabilistic sensitivity analyses. We conclude that the use of kidneys from deceased donors with HCV infection is likely to lead to improved clinical outcomes at reduced cost for HCV‐negative transplant candidates.     

Can donors with high donor risk indices be used cost‐effectively in liver transplantation in US Transplant Centers?

In an effort to quantify the impact of donor risk factors on recipient outcomes, the donor risk index (DRI) was developed. A high DRI correlates with poorer post‐transplant survival. In this study, high‐DRI donors are classified as those having DRIs >2.0, while low‐DRI donors have DRIs <2.0. The aim of this study was to evaluate the cost‐effectiveness of high‐DRI donor use in US Transplant Centers. A Markov‐based decision analytic model was created to simulate outcomes for an allocation scheme using only low‐DRI donors versus a scheme using both low‐ and high‐DRI donors. Baseline values and ranges were determined from published data and Medicare cost data. Sensitivity analyses were conducted to test model strength and parameter variability. An allocation scheme in which only low‐DRI donors were used generated 5.2 quality‐adjusted life years (QALYs) at a cost of $83 000/QALY. An allocation scheme using both low‐ and high‐DRI donors generated 5.9 QALYs at a cost of $66 000/QALY. Sensitivity analyses supported the use of an allocation scheme using both low‐ and high‐DRI donors. The overall contribution of high‐DRI grafts to the donor pool and the resultant reduction in wait‐list mortality make them cost‐effective.     

Long-term control of diabetes in a nonhuman primate by two separate transplantations of porcine adult islets under immunosuppression

Porcine islet transplantation is an alternative to allo-islet transplantation. Retransplantation of islets is a routine clinical practice in islet allotransplantation in immunosuppressed recipients and will most likely be required in islet xenotransplantation in immunosuppressed recipients. We examined whether a second infusion of porcine islets could restore normoglycemia and further evaluated the efficacy of a clinically available immunosuppression regimen including anti-thymocyte globulin for induction; belimumab, sirolimus, and tofacitinib for maintenance and adalimumab, anakinra, IVIg, and tocilizumab for inflammation control in a pig to nonhuman primate transplantation setting. Of note, all nonhuman primates were normoglycemic after the retransplantation of porcine islets without induction therapy. Graft survival was >100 days for all 3 recipients, and 1 of the 3 monkeys showed insulin independence for >237 days. Serious lymphodepletion was not observed, and rhesus cytomegalovirus reactivation was controlled without any serious adverse effects throughout the observation period in all recipients. These results support the clinical applicability of additional infusions of porcine islets. The maintenance immunosuppression regimen we used could protect the reinfused islets from acute rejection.     

A review of piscine islet xenotransplantation using wild‐type tilapia donors and the production of transgenic tilapia expressing a “humanized” tilapia insulin

Most islet xenotransplantation laboratories have focused on porcine islets, which are both costly and difficult to isolate. Teleost (bony) fish, such as tilapia, possess macroscopically visible distinct islet organs called Brockmann bodies which can be inexpensively harvested. When transplanted into diabetic nude mice, tilapia islets maintain long‐term normoglycemia and provide human‐like glucose tolerance profiles. Like porcine islets, when transplanted into euthymic mice, they are rejected in a CD4 T‐cell‐dependent manner. However, unlike pigs, tilapia are so phylogenetically primitive that their cells do not express α(1,3)Gal and, because tilapia are highly evolved to live in warm stagnant waters nearly devoid of dissolved oxygen, their islet cells are exceedingly resistant to hypoxia, making them ideal for transplantation within encapsulation devices. Encapsulation, especially when combined with co‐stimulatory blockade, markedly prolongs tilapia islet xenograft survival in small animal recipients, and a collaborator has shown function in diabetic cynomolgus monkeys. In anticipation of preclinical xenotransplantation studies, we have extensively characterized tilapia islets (morphology, embryologic development, cell biology, peptides, etc.) and their regulation of glucose homeostasis. Because tilapia insulin differs structurally from human insulin by 17 amino acids, we have produced transgenic tilapia whose islets stably express physiological levels of humanized insulin and have now bred these to homozygosity. These transgenic fish can serve as a platform for further development into a cell therapy product for diabetes.     

Reducing Infection Transmission in Solid Organ Transplantation Through Donor Nucleic Acid Testing: A Cost‐Effectiveness Analysis

For solid organ transplant (SOT) donors, nucleic acid‐amplification testing (NAT) may reduce human immunodeficiency virus (HIV) and hepatitis C virus (HCV) transmission over antibody (Ab) testing given its shorter detection window period. We compared SOT donor NAT + Ab versus Ab alone using decision models to estimate incremental cost‐effectiveness ratios (ICERs; cost per quality‐adjusted life year [QALY] gained) from the societal perspective across a range of HIV/HCV prevalence values and NAT costs. The cost per QALY gained was calculated for two scenarios: (1) favorable: low cost ($150/donor)/high prevalence (HIV: 1.5%; HCV: 18.2%) and (2) unfavorable: high cost ($500/donor)/low prevalence (HIV: 0.1%; HCV: 1.5%). In the favorable scenario, adding NAT screening cost $161 013 per QALY gained for HIV was less costly) for HCV, and cost $86 653 per QALY gained for HIV/HCV combined. For the unfavorable scenario, the costs were $15 568 484, $221 006 and $10 077 599 per QALY gained, respectively. Universal HCV NAT + Ab for donors appears cost‐effective to reduce infection transmission from SOT donors, while HIV NAT + Ab is not, except where HIV NAT is ≤$150/donor and prevalence is ≥1.5%. Our analyses provide important data to facilitate the decision to implement HIV and HCV NAT for deceased SOT donors and shape national policy regarding how to reduce infection transmission in SOT.     

Enhanced effect of human mesenchymal stem cells expressing human TNF‐αR‐Fc and HO‐1 gene on porcine islet xenotransplantation in humanized mice

Background

Porcine islet xenotransplantation is considered an attractive alternative treatment for type 1 diabetes mellitus. However, it is largely limited because of initial rejection due to Instant Blood‐Mediated Inflammatory Reaction (IBMIR), oxidative stress, and inflammatory responses. Recently, soluble tumor necrosis factor‐ɑ receptor type I (sTNF‐αR) and heme oxygenase (HO)‐1 genes (HO‐1/sTNF‐αR) have been shown to improve the viability and functionality of porcine islets after transplantation.

Methods

In this study, genetically modified mesenchymal stem cells (MSCs) expressing the HO‐1/sTNF‐αR genes (HO‐1/sTNF‐αR‐MSC) were developed using an adenoviral system, and porcine islet viability and function were confirmed by in vitro tests such as GSIS, AO/PI, and the ADP/ATP ratio after coculturing with HO‐1/sTNF‐αR‐MSCs. Subsequently, isolated porcine islets were transplanted underneath the kidney capsule of diabetic humanized mice without MSCs, with MSCs or with HO‐1/sTNF‐αR‐MSCs.

Results

According to the results, the HO‐1/sTNF‐αR‐MSC‐treated group exhibited improved survival of porcine islets and could reverse hyperglycemia more than porcine islets not treated with MSCs or islets cotransplanted with MSCs. Moreover, the HO‐1/sTNF‐αR‐MSC group maintained its morphological characteristics and the insulin secretion pattern of transplanted porcine islets similar to endogenous islets in immunocompetent humanized mice.

Conclusions

Our results suggest that HO‐1/sTNF‐αR‐MSCs are efficient tools for porcine islet xenotransplantation, and this study may provide basic information for pre‐clinical animal models and future clinical trials of porcine islet xenotransplantation.     

Cost‐Effectiveness of Hypothermic Machine Preservation Versus Static Cold Storage in Renal Transplantation

Static cold storage (CS) is the most widely used organ preservation method for deceased donor kidney grafts but there is increasing evidence that hypothermic machine perfusion (MP) may result in better outcome after transplantation. We performed an economic evaluation of MP versus CS alongside a multicenter RCT investigating short‐ and long‐term cost‐effectiveness. Three hundred thirty‐six consecutive kidney pairs were included, one of which was assigned to MP and one to CS. The economic evaluation combined the short‐term results based on the empirical data from the study with a Markov model with a 10‐year time horizon. Direct medical costs of hospital stay, dialysis treatment, and complications were included. Data regarding long‐term survival, quality of life, and long‐term costs were derived from literature. The short‐term evaluation showed that MP reduced the risk of delayed graft function and graft failure at lower costs than CS. The Markov model revealed cost savings of $86 750 per life‐year gained in favor of MP. The corresponding incremental cost‐utility ratio was minus $496 223 per quality‐adjusted life‐year (QALY) gained. We conclude that life‐years and QALYs can be gained while reducing costs at the same time, when kidneys are preserved by MP instead of CS.