Keratoplasty is the primary treatment to cure blindness due to corneal opacification. However, immune-mediated rejection remains the leading cause of keratoplasty failure. Here, we utilize an in vivo imaging approach to monitor, track, and characterize in real-time the recruitment of GFP-labeled allo-specific activated (Bonzo) T cells during corneal allograft rejection. We show that the recruitment of effector T cells to the site of transplantation determined the fate of corneal allografts, and that local intra-graft production of CCL5 and CXCL9/10 regulated motility patterns of effector T cells in situ, and correlated with allograft rejection. We also show that different motility patterns associate with distinct in vivo phenotypes (round, elongated, and ruffled) of graft-infiltrating effector T cells with varying proportions during progression of rejection. The ruffled phenotype was characteristic of activated effectors T cells and predominated during ongoing rejection, which associated with significantly increased T cell dynamics within the allografts. Importantly, CCR5/CXCR3 blockade decreased the motility, size, and number of infiltrating T cells and significantly prolonged allograft survival. Our findings indicate that chemokines produced locally within corneal allografts play an important role in the in situ activation and dynamic behavior of infiltrating effector T cells, and may guide targeted interventions to promote graft survival.

Israel and Pakistan-two major participants in the global organ trade-enacted legislative prohibitions on the trade at roughly the same time. The article highlights three influences that brought about this change of policy in both countries: advocacy by local physicians coupled with media coverage and reinforced by the international medical community. The analysis also explains why the two countries have differed with respect to the enforcement of the organ-trade prohibition. The insights from the Israeli and Pakistani cases will be of use for the transplant community's efforts against organ trafficking.

Few studies have compared determinants of live donor kidney transplantation (LDKT) across all major US racial-ethnic groups. We compared determinants of racial-ethnic differences in LDKT among 208 736 patients who initiated treatment for end-stage kidney disease during 2005-2008. We performed proportional hazards and bootstrap analyses to estimate differences in LDKT attributable to sociodemographic and clinical factors. Mean LDKT rates were lowest among blacks (1.19 per 100 person-years [95% CI: 1.12-1.26]), American Indians/Alaska Natives-AI/ANs (1.40 [1.06-1.84]) and Pacific Islanders (1.10 [0.78-1.84]), intermediate among Hispanics (2.53 [2.39-2.67]) and Asians (3.89 [3.51-4.32]), and highest among whites (6.46 [6.31-6.61]). Compared with whites, the largest proportion of the disparity among blacks (20%) and AI/ANs (29%) was attributed to measures of predialysis care, while the largest proportion among Hispanics (14%) was attributed to health insurance coverage. Contextual poverty accounted for 16%, 4%, 18%, and 6% of the disparity among blacks, Hispanics, AI/ANs and Pacific Islanders but none of the disparity among Asians. In the United States, significant disparities in rates of LDKT persist, but determinants of these disparities vary by race-ethnicity. Efforts to expand preESKD insurance coverage, to improve access to high-quality predialysis care and to overcome socioeconomic barriers are important targets for addressing disparities in LDKT.

Few equations have been developed to predict end-stage renal disease (ESRD) after deceased donor liver transplant. This retrospective observational cohort study analyzed all adult deceased donor liver transplant recipients in the Scientific Registry of Transplant Recipients (SRTR) database, 1995-2010. The prediction equation for ESRD was developed using candidate predictor variables available in SRTR after implementation of the allocation policy based on the model for end-stage liver disease. ESRD was defined as initiation of maintenance dialysis therapy, kidney transplant or registration on the kidney transplant waiting list. We used Cox proportional hazard models to develop separate equations for assessing risk of ESRD by 6 months posttransplant and between 6 months and 5 years posttransplant. Variables in the 6-month equation included recipient age, history of diabetes, history of dialysis before liver transplant, history of malignancy, body mass index, serum creatinine and liver donor risk index. Variables in the 6-month to 5-year equation included recipient race, history of diabetes, hepatitis C status, serum albumin, serum bilirubin and serum creatinine. The prediction equations have good calibration and discrimination (C statistics 0.74-0.78). We have produced risk prediction equations that can be used to aid in understanding the risk of ESRD after liver transplant.

Sotrastaurin, a novel immunosuppressant, blocks early T cell activation through protein kinase C inhibition. Efficacy and safety of sotrastaurin with tacrolimus were assessed in a dose-ranging non-inferiority study in renal transplant recipients. A total of 298 patients were randomized 1:1:1:1 to receive sotrastaurin 100 (n = 77; discontinued in December 2011) or 200 mg (n = 73) b.i.d. plus standard tacrolimus (sTAC; 5-12 ng/mL), sotrastaurin 300 mg (n = 75) b.i.d. plus reduced tacrolimus (rTAC; 2-5 ng/mL) or enteric-coated mycophenolic acid (MPA) plus sTAC (n = 73); all patients received basiliximab and corticosteroids. Composite efficacy failure (treated biopsy-proven acute rejection ≥ grade IA, graft loss, death or loss to follow up) rates at Month 12 were 18.8%, 12.4%, 10.9% and 14.0% for the sotrastaurin 100, 200 and 300 mg, and MPA groups, respectively. The median estimated glomerular filtration rates were 55.7, 53.3, 64.9 and 59.2 mL/min, respectively. Mean heart rates were faster with higher sotrastaurin doses and discontinuations due to adverse events and gastrointestinal adverse events were more common. Fewer patients in the sotrastaurin groups experienced leukopenia than in the MPA group (1.3-5.5% vs. 16.5%). Sotrastaurin 200 and 300 mg had comparable efficacy to MPA in prevention of rejection with no significant difference in renal function between the groups.

Whilst initial rates of insulin independence following islet transplantation are encouraging, long-term function using the Edmonton Protocol remains a concern. The aim of this single-arm, multicenter study was to evaluate an immunosuppressive protocol of initial antithymocyte globulin (ATG), tacrolimus and mycophenolate mofetil (MMF) followed by switching to sirolimus and MMF. Islets were cultured for 24 h prior to transplantation. The primary end-point was an HbA1c of <7% and cessation of severe hypoglycemia. Seventeen recipients were followed for ≥12 months. Nine islet preparations were transported interstate for transplantation. Similar outcomes were achieved at all three centers. Fourteen of the 17 (82%) recipients achieved the primary end-point. Nine (53%) recipients achieved insulin independence for a median of 26 months (range 7-39 months) and 6 (35%) remain insulin independent. All recipients were C-peptide positive for at least 3 months. All subjects with unstimulated C-peptide >0.2 nmol/L had cessation of severe hypoglycemia. Nine of the 17 recipients tolerated switching from tacrolimus to sirolimus with similar graft outcomes. There was a small but significant reduction in renal function in the first 12 months. The combination of islet culture, ATG, tacrolimus and MMF is a viable alternative for islet transplantation.

Erythropoietin has a tissue-protective effect independent of its erythropoietic effect that may be enhanced by combining it with the nitric oxide donor glyceryl trinitrate (GTN) and the sodium-hydrogen exchange inhibitor zoniporide in rat hearts stored with an extracellular-based preservation solution (EBPS). We thus sought to test this combination of agents in a porcine model of orthotopic heart transplantation incorporating donor brain death and total ischaemic time of approximately 260 min. Pig hearts were stored in one of four storage solutions: unmodified EBPS (CON), EBPS supplemented with GTN and zoniporide (GZ), EBPS supplemented with erythropoietin and zoniporide (EZ), or EBPS supplemented with all three agents (EGZ). A total of 4/5 EGZ hearts were successfully weaned from cardiopulmonary bypass compared with only 2/5 GZ hearts, 0/5 CON hearts and 0/5 EG hearts (p = 0.017). Following weaning from bypass EGZ hearts demonstrated superior contractility and haemodynamics than GZ hearts. All weaned hearts displayed impaired diastolic function. Release of troponin I from EGZ hearts was lower than all other groups. In conclusion, supplementation of EBPS with erythropoietin, glyceryl trinitrate and zoniporide provided superior donor heart preservation than all other strategies tested.

Heart transplantation is the most effective therapy for children with end-stage heart disease; however, its use is limited by the number of donor organs available. This shortage may be further compounded by concerns about organ quality, leading to refusal of potential donor organ offers. We report on the successful transplantation and 5-year follow-up of a heart from a donor with Ullrich congenital muscular dystrophy (UCMD). The candidate was critically ill at the time of the transplant and the donor organ was declined repeatedly on the match run list due to concerns about organ quality, despite having normal cardiac function by echocardiography on minimal inotropic support. We believe the diagnosis of "muscular dystrophy" in the donor combined with a lack of understanding about the specifics of the diagnosis of UCMD enabled our candidate to receive a primary offer for this organ. We are unaware of any previous reports of the use of a heart from a donor with UCMD for orthotopic heart transplantation in adults or children.

We compared cold static with acellular normothermic ex vivo liver perfusion (NEVLP) as a novel preservation technique in a pig model of DCD liver injury. DCD livers (60 min warm ischemia) were cold stored for 4 h, or treated with 4 h cold storage plus 8 h NEVLP. First, the livers were reperfused with diluted blood as a model of transplantation. Liver injury was determined by ALT, oxygen extraction, histology, bile content analysis and hepatic artery (HA) angiography. Second, AST levels and bile production were assessed after DCD liver transplantation. Cold stored versus NEVLP grafts had higher ALT levels (350 ± 125 vs. 55 ± 35 U/L; p < 0.0001), decreased oxygen extraction (250 ± 65 mmHg vs. 410 ± 58 mmHg, p < 0.01) and increased hepatocyte necrosis (45% vs. 10%, p = 0.01). Levels of bilirubin, phospholipids and bile salts were fivefold decreased, while LDH was sixfold higher in cold stored versus NEVLP grafts. HA perfusion was decreased (twofold), and bile duct necrosis was increased (100% vs. 5%, p < 0.0001) in cold stored versus NEVLP livers. Following transplantation, mean serum AST level was higher in the cold stored versus NEVLP group (1809 ± 205 U/L vs. 524 ± 187 U/L, p < 0.05), with similar bile production (2.5 ± 1.2 cc/h vs. 2.8 ± 1.4 cc/h; p = 0.2). NEVLP improved HA perfusion and decreased markers of liver duct injury in DCD grafts.