Steven Paraskevas

Reduced dose Thymoglobulin, tacrolimus, and mofetil mycophenolate results in excellent solitary pancreas transplantation outcomes.

Abstract:u2002 Background:u2002 Graft survival following solitary pancreas transplantation has traditionally lagged behind that of simultaneous pancreas–kidney transplants. Thymoglobulin® (TMG), a polyclonal rabbit‐derived antilymphocyte antibody was originally introduced as treatment for acute rejection of renal allografts. However, data regarding the efficacy of TMG induction in solitary pancreas transplants is lacking. We present the 1‐yr graft survival and acute rejection rate of 22 solitary pancreas transplants performed at the McGill University Health Centre using reduced dose TMG induction with lower dose tacrolimus and mophetil mycophenolate.

Positive cultures of organ preservation fluid predict postoperative infections in solid organ transplantation recipients.

OBJECTIVEnThe significance of positive cultures of organ preservation fluid (OPF) in solid organ transplantation is not known. We sought to describe the microbiology and define the clinical impact of positive OPF cultures.nnnDESIGNnRetrospective cohort study.nnnSETTINGnTertiary care hospital.nnnPATIENTSnA consecutive sample of all solid organ transplantations at our center between July 2006 and January 2009 was reviewed. A total of 331 allografts (185 kidneys, 104 livers, 31 pancreases, and 11 hearts) met the inclusion criterion of having OPF cultures taken from the transplanted allograft.nnnMETHODSnOrganisms recovered from OPF were classified as high or low risk according to their virulence. Clinical outcomes were compared between recipients of organs with positive OPF cultures and recipients of organs with negative OPF cultures.nnnRESULTSnu2003OPF cultures were positive in 62.2% of allografts and yielded high-risk organisms in 17.8%. Normal skin flora constituted the majority of positive OPF cultures, while Enterobacteriaceae spp. and Staphylococcus aureus made up the majority of high-risk organisms. Recipients of allografts with positive OPF cultures developed more frequent bacterial infections, regardless of allograft type (relative risk, 2.39; 95% confidence interval [CI], 1.61-3.54). Moreover, isolation of a given organism in OPF samples was associated with the development of a clinical infection with the same organism, regardless of allograft type.nnnCONCLUSIONSnPositive cultures of OPF are common events in solid organ transplantation, frequently involve high-risk organisms, and are associated with the development of postoperative clinical bacterial infections. Further study is required to determine the optimal strategies for their prevention and management.

Differential expression pattern of ZAC in developing mouse and human pancreas

ZAC is a transcription factor and cofactor, a strong candidate for transient neonatal diabetes mellitus (TNDM). TNDM involves impaired beta-cell development and is probably due to a double dose of ZAC, which is normally expressed only from the paternal copy. ZAC and Zac1 (its mouse orthologue) are strongly expressed in the proliferating progenitor/stem cells in many systems and also in some differentiated sites in human and mouse, suggesting a dual role in cell proliferation and differentiation control. Little is known about its expression in developing pancreas, the organ affected in TNDM. In this study, we examined ZAC/Zac1 expression in developing mouse and human pancreas by real-time PCR and dual in situ hybridization and immunofluorescence. Overall pancreatic expression drastically declined during gestation and early post-natal life in the mouse, and between the second trimester and adult in the human. Zac1 was predominantly expressed in mesenchyme in the mouse embryo, while ZAC was specifically expressed in islets of the human fetus. Thus, ZAC/Zac1 may play different roles in mouse and human pancreas development. The specific expression of ZAC in the human fetal beta-cells supports it as the gene involved in TNDM and the different expression pattern of Zac1 in mice from human may explain the much milder phenotype in the mouse model of ZAC double dose.

Early renal function recovery and long‐term graft survival in kidney transplantation

Following kidney transplantation (KTx), renal function improves gradually until a baseline eGFR is achieved. Whether or not a recipient achieves the best‐predicted eGFR after KTx may have important implications for immediate patient management, as well as for long‐term graft survival. The aim of this cohort study was to calculate the renal function recovery (RFR) based on recipient and donor eGFR and to evaluate the association between RFR and long‐term death‐censored graft failure (DCGF). We studied 790 KTx recipients between January 1990 and August 2014. The last donor SCr prior to organ procurement was used to estimate donor GFR. Recipient eGFR was calculated using the average of the best three SCr values observed during the first 3 months post‐KTx. RFR was defined as the ratio of recipient eGFR to half the donor eGFR. 53% of recipients had an RFR ≥1. There were 127 death‐censored graft failures (16%). Recipients with an RFR ≥1 had less DCGF compared with those with an RFR <1 (HR 0.56; 95% CI 0.37–0.85; P = 0.006). Transplant era, acute rejection, ECD and DGF were also significant determinants of graft failure. Early recovery of predicted eGFR based on donor eGFR is associated with less DCGF after KTx.

Machine perfusion and long-term kidney transplant recipient outcomes across allograft risk strata

BackgroundnThe use of machine perfusion (MP) in kidney transplantation lowers delayed graft function (DGF) and improves 1-year graft survival in some, but not all, grafts. These associations have not been explored in grafts stratified by the Kidney Donor Profile index (KDPI).nnnMethodsnWe analyzed 78xa0207 deceased-donor recipients using the Scientific Registry of Transplant Recipients data from 2006 to 2013. The cohort was stratified using the standard criteria donor/expanded criteria donor (ECD)/donation after cardiac death (DCD)/donation after brain death (DBD) classification and the KDPI scores. In each subgroup, MP use was compared with cold storage.nnnResultsnThe overall DGF rate was 25.4% and MP use was associated with significantly lower DGF in all but the ECD-DCD donor subgroup. Using the donor source classification, the use of MP did not decrease death-censored graft failure (DCGF), except in the ECD-DCD subgroup from 0 to 1 year {adjusted hazard ratio [aHR]u20090.56 [95% confidence interval (CI) 0.32-0.98]}. In the ECD-DBD subgroup, higher DCGF from 1 to 5 years was noted [aHRu20091.15 (95% CI 1.01-1.31)]. Also, MP did not lower all-cause graft failure except in the ECD-DCD subgroup from 0 to 1 year [aHRu2009=u20090.59 (95% CI 0.38-0.91)]. Using the KDPI classification, MP did not lower DCGF or all-cause graft failure, but in the ≤70 subgroup, higher DCGF [aHRu20091.16 (95% CI 1.05-1.27)] and higher all-cause graft failure [aHRu20091.10 (95% CI 1.02-1.18)] was noted. Lastly, MP was not associated with mortality in any subgroup.nnnConclusionsnOverall, MP did not lower DCGF. Neither classification better risk-stratified kidneys that have superior graft survival with MP. We question their widespread use in all allografts as an ideal approach to organ preservation.

Presence of diabetes autoantigens in extracellular vesicles derived from human islets

Beta-cell (β-cell) injury is the hallmark of autoimmune diabetes. However, the mechanisms by which autoreactive responses are generated in susceptible individuals are not well understood. Extracellular vesicles (EV) are produced by mammalian cells under normal and stressed physiological states. They are an important part of cellular communication, and may serve a role in antigen processing and presentation. We hypothesized that isolated human islets in culture produce EV that contain diabetes autoantigens (DAA) from these otherwise normal, non-diabetic donors. Here we report the caspase-independent production of EV by human islets in culture, and the characterization of DAA glutamic acid decarboxylase 65 (GAD65) and zinc transporter 8 (ZnT8), as well as the β-cell resident glucose transporter 2 (Glut2), present within the EV.

Renal resistance thresholds during hypothermic machine perfusion and transplantation outcomes - a retrospective cohort study

Renal resistance (RR), of allografts undergoing hypothermic machine perfusion (HMP), is considered a measure of organ quality. We conducted a retrospective cohort study of adult deceased donor kidney transplant (KT) recipients whose grafts underwent HMP. Our aim was to evaluate whether RR is predictive of death‐censored graft failure (DCGF). Of 274 KT eligible for analysis, 59% were from expanded criteria donor. RR was modeled as a categorical variable, using a previously identified terminal threshold of 0.4, and 0.2 mmHg/ml/min (median in our cohort). Hazard ratios (HR) of DCGF were 3.23 [95% confidence interval (CI): 1.12–9.34, P = 0.03] and 2.67 [95% CI: 1.14–6.31, P = 0.02] in univariable models, and 2.67 [95% CI: 0.91–7.86, P = 0.07] and 2.42 [95% CI: 1.02–5.72, P = 0.04] in multivariable models, when RR threshold was 0.4 and 0.2, respectively. Increasing risk of DCGF was observed when RR over the course of HMP was modeled using mixed linear regression models: HR of 1.31 [95% CI: 1.07–1.59, P < 0.01] and 1.25 [95% CI: 1.00–1.55, P = 0.05], in univariable and multivariable models, respectively. This suggests that RR during HMP is a predictor of long‐term KT outcomes. Prospective studies are needed to assess the survival benefit of patients receiving KT with higher RR in comparison with staying wait‐listed.