International comparison and time trends of first kidney transplant recipient characteristics across Europe: an ERA Registry study.

BACKGROUND: The aim of this study was to provide an overview of age, sex and primary renal disease (PRD) distribution among first kidney transplant recipients across Europe. METHOD: The European Renal Association (ERA) Registry database was used to obtain data on patients aged 20 years or older receiving their first kidney transplant between 2010 and 2019 from 12 European countries. The numbers and percentages of recipients in each age, sex and PRD group were calculated by country, donor type and year. RESULTS: In total, 99 543 adults received a first kidney transplant. Overall, 23% of the recipients were 65 years or older, 36% were female, and 21% had glomerulonephritis and 15% diabetes mellitus as PRD. Compared with deceased donor kidney transplant recipients, living donor kidney transplant recipients were less often 65 years or older (13% versus 26%), more often had glomerulonephritis (25% versus 20%) and less often diabetes mellitus (8% versus 17%) as PRD. We found large international differences, which were most prominent for age and PRD and less prominent for sex. Over time, the largest change in recipient characteristics was observed for the percentage of recipients aged 65 years or older, increasing from 18% in 2010 to 28% in 2019 for all countries combined with a similar trend in most countries. CONCLUSION: We observed large differences for age and PRD distribution between recipients of living and deceased donor kidneys and between European countries. Over time, the percentage of older first kidney transplant recipients increased.

Time trends in preemptive kidney transplantation in Europe: an era registry study.

BACKGROUND: Preemptive kidney transplantation has better outcomes when compared to transplantation after dialysis. We aimed to examine trends in preemptive kidney transplantation between 2000 and 2019 in Europe and to provide an overview of associated policies, barriers and initiatives. METHODS: Adult patients from 12 European countries who received a preemptive kidney transplant were included. The representatives of the registries providing these data were questioned on the policies, barriers and initiatives around preemptive kidney transplantation. RESULTS: Between 2000 and 2019, 20 251 adults underwent preemptive kidney transplantation (11 169 from living donors, 8937 from deceased donors). The proportion of first kidney transplantations that were preemptive more than doubled from 7% in 2000 to 18% in 2019, reflecting a similar relative increase for living donor kidney recipients (from 21% to 43%) and deceased donor kidney recipients (from 4% to 11%). Large international differences were found. The increase in preemptive kidney transplantation was observed across all age, sex and primary renal disease groups. Countries had similar criteria for preemptive waitlisting. Barriers mentioned included donor shortage, late referral to the transplant center and long donor or recipient work-up. Suggested initiatives included raising awareness on the possibility of preemptive kidney transplantation, earlier start and shorter work-up time for recipient and living donor. CONCLUSIONS: Over the last two decades the proportion of patients receiving a first kidney transplant preemptively has more than doubled, reflecting a similar relative increase for living and deceased donor kidney recipients.

Trends in kidney transplantation rate across Europe: study from the ERA Registry.

BACKGROUND: The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries. METHODS: The European Renal Association (ERA) Registry and the Global Observatory on Donation and Transplantation (GODT) databases were used to obtain the number of KTs in individual European countries between 2010 and 2018. General population counts were obtained from Eurostat or the national bureaus of statistics. The KT rate per million population (p.m.p.) and the average annual percentage change (APC) were calculated. RESULTS: The total KT rate in the 40 participating countries increased with 1.9% annually  [95%  confidence  interval  (CI) 1.5, 2.2] from 29.6 p.m.p. in 2010 to 34.7 p.m.p. in 2018, reflecting an increase of 3.4 p.m.p. in the DD-KT rate (from 21.6 p.m.p. to 25.0 p.m.p.; APC 1.9%; 95% CI 1.3, 2.4) and of 1.5 p.m.p. in the LD-KT rate (from 8.1 p.m.p. to 9.6 p.m.p.; APC 1.6%; 95% CI 1.0, 2.3). The trends in KT rate varied widely across European countries. An East-West gradient was observed for DD-KT rate, with Western European countries performing more KTs. In addition, most countries performed fewer LD-KTs. In 2018, Spain had the highest DD-KT rate (64.6 p.m.p.) and Turkey the highest LD-KT rate (37.0 p.m.p.). CONCLUSIONS: The total KT rate increased due to a rise in the KT rate from DDs and to a lesser extent from LDs, with large differences between individual European countries.

Scoring of medial arterial calcification predicts cardiovascular events and mortality after kidney transplantation.

BACKGROUND: Progression of vascular calcification causes cardiovascular disease, which is the most common cause of death in chronic kidney failure and after kidney transplantation (KT). The prognostic impact of the extent of medial vascular calcification at KT is unknown. METHODS: In this prospective cohort study, we investigated the impact of medial calcification compared to a mix of intimal and medial calcification represented by coronary artery calcification (CAC score) and aortic valve calcification in 342 patients starting on kidney failure replacement therapy. The primary outcomes were cardiovascular events (CVE) and death. The median follow-up time was 6.4 years (interquartile range 3.7-9.6 years). Exposure was CAC score and arteria epigastrica medial calcification scored as none, mild, moderate, or severe by a pathologist at time of KT (n = 200). We divided the patients according to kidney failure replacement therapy during follow-up, that is, living donor KT, deceased donor KT, or dialysis. RESULTS: Moderate to severe medial calcification in the arteria epigastrica was associated with higher mortality (p = 0.001), and the hazard ratio for CVE was 3.1 (95% confidence interval [CI] 1.12-9.02, p < 0.05) compared to no or mild medial calcification. The hazard ratio for 10-year mortality in the dialysis group was 33.6 (95% CI, 10.0-113.0, p < 0.001) compared to living donor recipients, independent of Framingham risk score and prevalent CAC. CONCLUSION: Scoring of medial calcification in the arteria epigastrica identified living donor recipients as having 3.1 times higher risk of CVE, independent of traditional risk factors. The medial calcification score could be a reliable method to identify patients with high and low risk of CVE and mortality following KT.

A Worldwide Survey of Activities and Practices in Clinical Islet of Langerhans Transplantation.

A global online survey was administered to 69 islet transplantation programs, covering 84 centers and 5 networks. The survey addressed questions on program organization and activity in the 2000-2020 period, including impact on activity of national health care coverage policies. We obtained full data from 55 institutions or networks worldwide and basic activity data from 6 centers. Additional data were obtained from alternative sources. A total of 94 institutions and 5 networks was identified as having performed islet allotransplantation. 4,365 islet allotransplants (2,608 in Europe, 1,475 in North America, 135 in Asia, 119 in Oceania, 28 in South America) were reported in 2,170 patients in the survey period. From 15 centers active at the start of the study period, the number of simultaneously active islet centers peaked at 54, to progressively decrease to 26 having performed islet allotransplants in 2020. Notably, only 16 centers/networks have done >100 islet allotransplants in the survey period. Types of transplants performed differed notably between North America and the rest of the world, in particular with respect to the near-absence of simultaneous islet-kidney transplantation. Absence of heath care coverage has significantly hampered transplant activity in the past years and the COVID-19 pandemic in 2020.

Outcomes at 3 years posttransplant in imlifidase-desensitized kidney transplant patients.

Imlifidase is a cysteine proteinase which specifically cleaves IgG, inhibiting Fc-mediated effector function within hours of administration. Imlifidase converts a positive crossmatch to a potential donor (T cell, B cell, or both), to negative, enabling transplantation to occur between previously HLA incompatible donor-recipient pairs. To date, 39 crossmatch positive patients received imlifidase prior to a kidney transplant in four single-arm, open-label, phase 2 studies. At 3 years, for patients who were AMR+ compared to AMR-, death-censored allograft survival was 93% vs 77%, patient survival was 85% vs 94%, and mean eGFR was 49 ml/min/1.73 m2 vs 61 ml/min/1.73 m2 , respectively. The incidence of AMR was 38% with most episodes occurring within the first month post-transplantation. Sub-analysis of patients deemed highly sensitized with cPRA ≥ 99.9%, and unlikely to be transplanted who received crossmatch-positive, deceased donor transplants had similar rates of patient survival, graft survival, and eGFR but a higher rate of AMR. These data demonstrate that outcomes and safety up to 3 years in recipients of imlifidase-enabled allografts is comparable to outcomes in other highly sensitized patients undergoing HLA-incompatible transplantation. Thus, imlifidase is a potent option to facilitate transplantation among patients who have a significant immunologic barrier to successful kidney transplantation. Clinical Trial: ClinicalTrials.gov (NCT02790437), EudraCT Number: 2016-002064-13.

Autologous regulatory T cells in clinical intraportal allogenic pancreatic islet transplantation.

Allogeneic islet transplantation in type 1 diabetes requires lifelong immunosuppression to prevent graft rejection. This medication can cause adverse effects and increases the susceptibility for infections and malignancies. Adoptive therapies with regulatory T cells (Tregs) have shown promise in reducing the need for immunosuppression in human transplantation settings but have previously not been evaluated in islet transplantation. In this study, five patients with type 1 diabetes undergoing intraportal allogeneic islet transplantation were co-infused with polyclonal autologous Tregs under a standard immunosuppressive regimen. Patients underwent leaukapheresis from which Tregs were purified by magnetic-activated cell sorting (MACS) and cryopreserved until transplantation. Dose ranges of 0.14-1.27 × 106 T cells per kilo bodyweight were transplanted. No negative effects were seen related to the Treg infusion, regardless of cell dose. Only minor complications related to the immunosuppressive drugs were reported. This first-in-man study of autologous Treg infusion in allogenic pancreatic islet transplantation shows that the treatment is safe and feasible. Based on these results, future efficacy studies will be developed under the label of advanced therapeutic medical products (ATMP), using modified or expanded Tregs with the aim of minimizing the need for chronic immunosuppressive medication in islet transplantation.

Observational study of risk factors associated with clinical outcome among elderly kidney transplant recipients in Sweden - a decade of follow-up.

Kidney transplantation (Ktx) in elderly has become increasingly accepted worldwide despite their higher burden of comorbidities. We investigated important risk factors affecting long-term patient and graft survival. We included all (n = 747) Ktx patients >60 years from 2000 to 2012 in Sweden. Patients were age-stratified, 60-64, 65-69 and >70 years. Follow-up time was up to 10 years (median 7.9 years, 75% percentile >10 years). Primary outcome was 10-year patient survival in age-stratified groups. Secondary outcomes were 5-year patient and graft survival in age-stratified groups and the impact of risk factors including Charlson comorbidity index (CCI) on patient and graft survival. Mortality was higher in patients >70 years, after 10 years (HR 1.94; 95% CI 1.24-3.04; P = 0.004). Males had a higher 10-year risk of death (HR 1.39; CI 95% 1.04-1.86; P = 0.024). Five-year patient survival did not differ between age groups. In multivariate Cox analysis (n = 500), hazard ratio for 10-year mortality was 4.6 in patients with CCI ≥7 vs. <4 (95% CI 2.42-8.62; P = 0.0001). Higher CCI identified ESKD patients with 4.6 times higher risk of death after Ktx. We suggest that this index should be used as a part of the preoperative evaluation in elderly.

US food and drug administration (FDA) panel endorses islet cell treatment for type 1 diabetes: A pyrrhic victory?

Allogeneic islet transplantation is a standard of care treatment for patients with labile type 1 diabetes in many countries around the world, including Japan, the United Kingdom, Australia, much of continental Europe, and parts of Canada. The United States is now endorsing islet cell treatment for type 1 diabetes, but the FDA has chosen to consider islets as a biologic that requires licensure, making the universal implementation of the procedure in the clinic very challenging and opening the manufacture of islet grafts to private companies. The commercialization of human tissues raises significant legal and ethical issues and ironically leads to a situation where treatments developed as a result of the scientific and economic efforts of academia over several decades become exploited exclusively by for-profit entities.

The association of living donor source with patient and graft survival among kidney transplant recipients in the ERA-EDTA Registry - a retrospective study.

In this study we aimed to compare patient and graft survival of kidney transplant recipients who received a kidney from a living-related donor (LRD) or living-unrelated donor (LUD). Adult patients in the ERA-EDTA Registry who received their first kidney transplant in 1998-2017 were included. Ten-year patient and graft survival were compared between LRD and LUD transplants using Cox regression analysis. In total, 14 370 patients received a kidney from a living donor. Of those, 9212 (64.1%) grafts were from a LRD, 5063 (35.2%) from a LUD and for 95 (0.7%), the donor type was unknown. Unadjusted five-year risks of death and graft failure (including death as event) were lower for LRD transplants than for LUD grafts: 4.2% (95% confidence interval [CI]: 3.7-4.6) and 10.8% (95% CI: 10.1-11.5) versus 6.5% (95% CI: 5.7-7.4) and 12.2% (95% CI: 11.2-13.3), respectively. However, after adjusting for potential confounders, associations disappeared with hazard ratios of 0.99 (95% CI: 0.87-1.13) for patient survival and 1.03 (95% CI: 0.94-1.14) for graft survival. Unadjusted risk of death-censored graft failure was similar, but after adjustment, it was higher for LUD transplants (1.19; 95% CI: 1.04-1.35). In conclusion, patient and graft survival of LRD and LUD kidney transplant recipients was similar, whereas death-censored graft failure was higher in LUD. These findings confirm the importance of both living kidney donor types.

IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.

BACKGROUND: Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab')2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1-2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor. METHODS: We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound. RESULTS: Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred. CONCLUSIONS: IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).

Cost and clinical outcome of islet transplantation in Norway 2010-2015.

Islet transplantation is a minimally invasive ß-cell replacement strategy. Islet transplantation is a reimbursed treatment in Norway. Here, we summarize the cost and clinical outcome of 31 islet transplantations performed at Oslo University Hospital (OUS) from January 2010 to June 2015. Patients were retrospectively divided into three groups. Thirteen patients received either one or two islet transplantation alone (ITA), while five patients received islet transplantation after previous solid organ transplantation. For the group receiving 2 ITA, Kaplan-Meier estimates show an insulin independence of 20% more than 4 years after their last transplantation. An estimated 70% maintain at least partial graft function, defined as fasting C-peptide >0.1 nmol L-1 , and 47% maintain a HbA1c below 6.5% or 2 percent points lower than before ITA. For all groups combined, we estimate that 44% of the patients have a 50% reduction in insulin requirement 4 years after the initial islet transplantation. The average cost for an islet transplantation procedure was 347 297±60 588 NOK, or 35 424±6182 EUR, of which isolation expenses represent 34%. We hereby add to the common pool of growing experience with islet transplantation and also describe the cost of the treatment at our center.

Outcome after total pancreatectomy with islet autotransplantation: A European single-center study.

BACKGROUND AND AIMS: Chronic pancreatitis may cause intractable abdominal pain, with total pancreatectomy sometimes being the last resort. To mitigate the subsequent diabetes, total pancreatectomy can be followed by islet autotransplantation (TP-IAT). The primary aim of this study was to assess the outcomes in patients undergoing TP-IAT at Karolinska University Hospital with respect to safety, postoperative complications, and islet graft function. A secondary aim was to compare liver to skeletal muscle as autotransplantation sites. METHODS: Single-center observational cohort study on patients undergoing TP-IAT. Islets were transplanted either into the liver or skeletal muscle. Data on baseline characteristics and pretransplantory conditions were collected. Outcome measures included mortality and major postoperative complications as well as the glycemic measures: insulin use, fasting C-peptide, and HbA1c. RESULTS: Between 2004 and 2020, 24 patients underwent TP-IAT. Islets were transplanted into the liver in 9 patients and into skeletal muscle in 15 patients. There was no 90-day mortality, and major complications (Clavien-Dindo ⩾IIIa) occurred in 26.7%, all related to the procedure of total pancreatectomy. Fasting C-peptide could be detected postoperatively, with higher levels in patients receiving islet autotransplantation into the liver (p = 0.006). Insulin independence was not achieved, although insulin doses at last follow-up were significantly lower in patients receiving islet autotransplantation into the liver compared to skeletal muscle (p = 0.036). CONCLUSION: TP-IAT is safe and associated with tolerable risk, the component of islet autotransplantation being seemingly harmless. Although islet grafts maintain some endocrine function, insulin independence should not be expected. Regarding islet autotransplantation sites, the liver seems superior to skeletal muscle. CLINICAL TRIAL REGISTRATION: Not applicable.

Evaluation of Methods to Obtain Peripheral Blood Mononuclear Cells From Deceased Donors for Tolerance-Induction Protocols.

Regulatory cell therapies have shown promise in tolerance-induction protocols in living donor organ transplantation. These protocols should be pursued in deceased donor transplantation. Donor peripheral mononuclear cells (PBMCs) are an optimal source of donor antigens for the induction of donor-specific regulatory cells. During the development of a regulatory cell tolerance-induction protocol with organs from deceased donors, we compared 3 methods of obtaining PBMCs from deceased donors focusing on cell yield, viability, and contamination of unwanted cell types. PBMC procurement methods: 1. During organ procurement at the time of cold perfusion, blood was collected from the vena cava and placed into a 10-liter blood collection bag, and thereafter transported to Karolinska University Hospital, where leukapheresis was performed (BCL). 2. Blood was collected via the vena cava into blood donation bags before cold perfusion. The bags underwent buffy coat separation and thereafter automated leukocyte isolation system (BCS). 3. To collect PBMCs, leukapheresis was performed via a central dialysis catheter on deceased donors in the intensive care unit (ICU) prior to the organ procurement procedure (LEU).All 3 methods to obtain PBMC from deceased donors were safe and did not affect the procurement of organs. BCL contained around 50% of NK cells in lymphocytes population. LEU had a highest yield of donor PBMC among 3 groups. LEU had the lower amount of granulocyte contamination, compared to BCS and BCL. Based on these results, we choose LEU as the preferred method to obtain donor PBMC in the development of our tolerance-induction protocol.

On the etiology of type 1 diabetes: a new animal model signifying a decisive role for bacteria eliciting an adverse innate immunity response.

The cause of type 1 diabetes (T1D) remains unknown; however, a decisive role for environmental factors is recognized. The increased incidence of T1D during the last decades, as well as regional differences, is paralleled by differences in the intestinal bacterial flora. A new animal model was established to test the hypothesis that bacteria entering the pancreatic ductal system could trigger ß-cell destruction and to provide new insights to the immunopathology of the disease. Obtained findings were compared with those present in two patients dying at onset of T1D. Different bacterial species, present in the human duodenum, instilled into the ductal system of the pancreas in healthy rats rapidly induced cellular infiltration, consisting of mainly neutrophil polymorphonuclear cells and monocytes/macrophages, centered around the pancreatic ducts. Also, the islets of Langerhans attracted polymorphonuclear cells, possibly via release of IL-6, IL-8, and monocyte chemotactic protein 1. Small bleedings or large dilatations of the capillaries were frequently found within the islets, and several ß-cells had severe hydropic degeneration (ie, swollen cytoplasm) but with preserved nuclei. A novel rat model for the initial events in T1D is presented, revealing marked similarities with the morphologic findings obtained in patients dying at onset of T1D and signifying a decisive role for bacteria in eliciting an adverse innate immunity response. The present findings support the hypothesis that T1D is an organ-specific inflammatory disease.

Healthcare costs after kidney transplantation compared to dialysis based on propensity score methods and real world longitudinal register data from Sweden.

This study aimed to estimate the healthcare costs of kidney transplantation compared with dialysis using a propensity score approach to handle potential treatment selection bias. We included 693 adult wait-listed patients who started renal replacement therapy between 1998 and 2012 in Region Skåne and Stockholm County Council in Sweden. Healthcare costs were measured as annual and monthly healthcare expenditures. In order to match the data structure of the kidney transplantation group, a hypothetical kidney transplant date of persons with dialysis were generated for each dialysis patient using the one-to-one nearest-neighbour propensity score matching method. Applying propensity score matching and inverse probability-weighted regression adjustment models, the potential outcome means and average treatment effect were estimated. The estimated healthcare costs in the first year after kidney transplantation were €57,278 (95% confidence interval (CI) €54,467-60,088) and €47,775 (95% CI €44,313-51,238) for kidney transplantation and dialysis, respectively. Thus, kidney transplantation leads to higher healthcare costs in the first year by €9,502 (p = 0.066) compared to dialysis. In the following two years, kidney transplantation is cost saving [€36,342 (p < 0.001) and €44,882 (p < 0.001)]. For patients with end-stage renal disease, kidney transplantation reduces healthcare costs compared with dialysis over three years after kidney transplantation, even though the healthcare costs are somewhat higher in the first year. Relating the results of existing estimates of costs and health benefits of kidney transplantation shows that kidney transplantation is clearly cost-effective compared to dialysis in Sweden.

Heparin Conjugate Pretreatment of Kidneys From Deceased Donors Before Transplantation: Results From the First-in-human Randomized Phase I Trial.

Pretreating porcine kidneys with Corline Heparin Conjugate (CHC) during hypothermic machine perfusion (HMP) has been shown to reduce preservation injury and improve early kidney function. In this first-in-human phase I study, the safety and tolerability of transplanting CHC-pretreated kidneys were evaluated. Methods: CHC or placebo was added to the preservation solution during HMP of donated kidneys from deceased donors for at least 3 h before transplantation into adult patients. The primary safety endpoint was the number and severity of adverse events (AEs) and serious AEs (SAEs) during the first 30 d after transplantation. Results: In the first 30 d, 66 AEs were reported in 8 patients who received CHC-pretreated kidneys with 39 AEs in 8 patients who received placebo-pretreated kidneys (P = 0.1 in post hoc analysis). The most common AEs were hypertension (CHC, n = 5; placebo, n = 2) and anemia (CHC, n = 5; placebo, n = 2). Most AEs were assessed as mild (58%) or moderate (39%) and not related to treatment (95%). There were 2 SAEs reported in each group. One SAE, considered possibly related to CHC treatment, was a case of severe postprocedural hemorrhage that required reoperation. No patients needed dialysis. There were no observed rejections and no patient deaths. Conclusions: Pretreatment of kidneys with CHC before transplantation was considered safe and tolerable. Efficacy studies are now planned to investigate if CHC can reduce early ischemia-reperfusion injury in humans.

Cibinetide Protects Isolated Human Islets in a Stressful Environment and Improves Engraftment in the Perspective of Intra Portal Islet Transplantation.

During intra-portal pancreatic islet transplantation (PITx), innate immune reactions such as the instant blood mediated inflammatory reaction (IBMIR) cause an immediate loss of islets. The non-hematopoietic erythropoietin analogue cibinetide has previously shown islet-protective effects in mouse PITx. Herein, we aimed to confirm cibinetide's efficacy on human islets, and to characterize its effect on IBMIR. We cultured human islets with pro-inflammatory cytokines for 18 hours with or without cibinetide. ATP content and caspase 3/7 activity were measured. Dynamic glucose perfusion assay was used to evaluate islet function. To evaluate cibinetides effect on IBMIR, human islets were incubated in heparinized polyvinyl chloride tubing system with ABO compatible blood and rotated for 60 minutes to mimic the portal vein system. Moreover, human islets were transplanted into athymic mice livers via the portal vein with or without perioperative cibinetide treatment. The mice were sacrificed six days following transplantation and the livers were analyzed for human insulin and serum for human C-peptide levels. Histological examination of recipient livers to evaluate islet graft infiltration by CD11b+ cells was performed. Our results show that cibinetide maintained human islet ATP levels and reduced the caspase 3/7 activity during culture with pro-inflammatory cytokines and improved their insulin secreting capacity. In the PVC loop system, administration of cibinetide reduced the IBMIR-induced platelet consumption. In human islet to athymic mice PITx, cibinetide treatment showed an increased amount of human insulin in the livers and higher serum human C-peptide, while histological examination of the livers showed reduced infiltration of pro-inflammatory CD11b+ cells around islets grafts compared to the controls. In summary, Cibinetide protected isolated human islets in a pro-inflammatory milieu and reduced IBMIR related platelet consumption. It improved engraftment of human islets in athymic mice. The study confirms that cibinetide is a promising agent to be used in clinical PITx.

Improvement of Islet Allograft Function Using Cibinetide, an Innate Repair Receptor Ligand.

BACKGROUND: During intraportal pancreatic islet transplantation (PITx), early inflammatory reactions cause an immediate loss of more than half of the transplanted graft and potentiate subsequent allograft rejection. Previous findings suggest that cibinetide, a selective innate repair receptor agonist, exerts islet protective and antiinflammatory properties and improved transplant efficacy in syngeneic mouse PITx model. In a stepwise approach toward a clinical application, we have here investigated the short- and long-term effects of cibinetide in an allogeneic mouse PITx model. METHODS: Streptozotocin-induced diabetic C57BL/6N (H-2) mice were transplanted with 320 (marginal) or 450 (standard) islets from BALB/c (H-2) mice via the portal vein. Recipients were treated perioperative and thereafter daily during 14 d with cibinetide (120 µg/kg), with or without tacrolimus injection (0.4 mg/kg/d) during days 4-14 after transplantation. Graft function was assessed using nonfasting glucose measurements. Relative gene expressions of proinflammatory cytokines and proinsulin of the graft-bearing liver were assessed by quantitative polymerase chain reaction. Cibinetide's effects on dendritic cell maturation were investigated in vitro. RESULTS: Cibinetide ameliorated the local inflammatory responses in the liver and improved glycemic control immediately after allogeneic PITx and significantly delayed the onset of allograft loss. Combination treatment with cibinetide and low-dose tacrolimus significantly improved long-term graft survival following allogeneic PITx. In vitro experiments indicated that cibinetide lowered bone-marrow-derived-immature-dendritic cell maturation and subsequently reduced allogeneic T-cell response. CONCLUSIONS: Cibinetide reduced the initial transplantation-related severe inflammation and delayed the subsequent alloreactivity. Cibinetide, in combination with low-dose tacrolimus, could significantly improve long-term graft survival in allogeneic PITx.

Targeting CXCR1/2 Does Not Improve Insulin Secretion After Pancreatic Islet Transplantation: A Phase 3, Double-Blind, Randomized, Placebo-Controlled Trial in Type 1 Diabetes.

OBJECTIVE: Reparixin is an inhibitor of CXCR1/2 chemokine receptor shown to be an effective anti-inflammatory adjuvant in a pilot clinical trial in allotransplant recipients. RESEARCH DESIGN AND METHODS: A phase 3, multicenter, randomized, double-blind, parallel-assignment study (NCT01817959) was conducted in recipients of islet allotransplants randomized (2:1) to reparixin or placebo in addition to immunosuppression. Primary outcome was the area under the curve (AUC) for C-peptide during the mixed-meal tolerance test at day 75 ± 5 after the first and day 365 ± 14 after the last transplant. Secondary end points included insulin independence and standard measures of glycemic control. RESULTS: The intention-to-treat analysis did not show a significant difference in C-peptide AUC at both day 75 (27 on reparixin vs. 18 on placebo, P = 0.99) and day 365 (24 on reparixin vs. 15 on placebo, P = 0.71). There was no statistically significant difference between treatment groups at any time point for any secondary variable. Analysis of patient subsets showed a trend for a higher percentage of subjects retaining insulin independence for 1 year after a single islet infusion in patients receiving reparixin as compared with patients receiving placebo (26.7% vs. 0%, P = 0.09) when antithymocyte globulin was used as induction immunosuppression. CONCLUSIONS: In this first double-blind randomized trial, islet transplantation data obtained with reparixin do not support a role of CXCR1/2 inhibition in preventing islet inflammation-mediated damage.