Outcomes of kidney transplant recipients who underwent pre-transplant bariatric surgery for severe obesity: a long-term follow-up study.

BACKGROUND: Kidney transplantation (KT) is the preferred therapy for end-stage renal disease (ESRD). While a major cause for ESRD, obesity is also a key obstacle to candidacy for KT. Bariatric surgery, particularly sleeve gastrectomy (SG), is increasingly used to improve access to KT in patients with obesity, but the literature especially on outcomes post-KT remains lacking. We aimed to provide a long-term follow-up analysis of efficacy and outcomes of a previously described cohort of patients with obesity, who had SG as a means for access to KT. METHODS: This is a single-center retrospective follow-up study of 32 patients with advanced chronic kidney disease or ESRD, who were referred and underwent SG between 2013 and 2018 as an access strategy to KT. The primary outcome was successful KT. Ninety-day outcomes, long-term graft function, and changes in weight and obesity-related comorbidities after KT were assessed. Descriptive statistics are presented as count (percentage) or median (interquartile range). RESULTS: At baseline, 18 (56%) were male with a median age and BMI of 51 (11) years and 42.3 (5.2) kg/m2, respectively. Median follow-up time post-SG was 53 (58) months. At last follow-up, 23 (72%) patients received KT. Median time to KT was 16 (20) months and BMI was 34.0 (5.1) kg/m2 at time of transplant. At KT, 13 (57%) and 20 (87%) had diabetes and hypertension, respectively. Median follow-up post-KT was 16 (47) months. There was one graft loss requiring return to dialysis. At 5-year post-KT, median serum creatinine was 136 (66) µmol/l. At last follow-up post-KT, median BMI remained at 33.7 (7.6) kg/m2. Among patients with diabetes and hypertension, 7/13 (54%) and 5/20 (25%) had either improvement or remission of their comorbidities, respectively. CONCLUSION: SG is an effective strategy to improve access to KT in patients with severe obesity. Transplant recipients also continue to benefit from sustained weight loss and improved related comorbidities that may positively impact their graft function after KT.

The impact of COVID-19 on the Canadian Kidney Paired Donation program: an opportunity for universal implementation of kidney shipping.

SUMMARY: "Never let a good crisis go to waste." - Sir Winston Churchill.The value of Canada's Kidney Paired Donation program to the population cannot be overstated. Its greatest challenge as a national program, however, is the geographic separation of recipient and matched donor. Representatives from every transplant program in the country have been working toward increased use of kidney shipping in order to diminish the disincentive of donor travel. With transplantation program and travel restrictions in place to minimize the risk of coronavirus disease 2019 (COVID-19), the time to make a full transition from donor travel to the shipment of donor kidneys has clearly arrived.

Extracellular Vesicles in Type 1 Diabetes: Messengers and Regulators.

PURPOSE OF REVIEW: Theories about the pathogenesis of type 1 diabetes (T1D) refer to the potential of primary islet inflammatory signaling as a trigger for the loss of self-tolerance leading to disease onset. Emerging evidence suggests that extracellular vesicles (EV) may represent the missing link between inflammation and autoimmunity. Here, we review the evidence for a role of EV in the pathogenesis of T1D, as well as discuss their potential value in the clinical sphere, as biomarkers and therapeutic agents. RECENT FINDINGS: EV derived from ß cells are enriched in diabetogenic autoantigens and miRNAs that are selectively sorted and packaged. These EV play a pivotal role in antigen presentation and cell to cell communication leading to activation of autoimmune responses. Furthermore, recent evidence suggests the potential of EV as novel tools in clinical diagnostics and therapeutic interventions. In-depth analysis of EV cargo using modern multi-parametric technologies may be useful in enhancing our understanding of EV-mediated immune mechanisms and in identifying robust biomarkers and therapeutic strategies for T1D.

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

Background: The 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). Methods: We analyzed 78 207 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. Results: The 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] 0.56 [95% confidence interval (CI) 0.32-0.98]}. In the ECD-DBD subgroup, higher DCGF from 1 to 5 years was noted [aHR 1.15 (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 [aHR = 0.59 (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 [aHR 1.16 (95% CI 1.05-1.27)] and higher all-cause graft failure [aHR 1.10 (95% CI 1.02-1.18)] was noted. Lastly, MP was not associated with mortality in any subgroup. Conclusions: Overall, 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.

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.

Kidney paired donation and the unique challenges of kidney shipment in Canada.

SUMMARY: Kidney paired donation (KPD) programs are an effort to bridge the disparity between kidney supply and demand. These programs combine several incompatible donor-recipient pairs in a national paired exchange database, thereby increasing the number of compatible matches. But KPD programs face unique challenges, particularly the large distances that often separate donors and recipients. Here we discuss key factors to consider when transitioning from a donor travelling model to a kidney shipment model in the Canadian context.

Lysine deacetylase inhibition prevents diabetes by chromatin-independent immunoregulation and ß-cell protection.

Type 1 diabetes is due to destruction of pancreatic ß-cells. Lysine deacetylase inhibitors (KDACi) protect ß-cells from inflammatory destruction in vitro and are promising immunomodulators. Here we demonstrate that the clinically well-tolerated KDACi vorinostat and givinostat revert diabetes in the nonobese diabetic (NOD) mouse model of type 1 diabetes and counteract inflammatory target cell damage by a mechanism of action consistent with transcription factor--rather than global chromatin--hyperacetylation. Weaning NOD mice received low doses of vorinostat and givinostat in their drinking water until 100-120 d of age. Diabetes incidence was reduced by 38% and 45%, respectively, there was a 15% increase in the percentage of islets without infiltration, and pancreatic insulin content increased by 200%. Vorinostat treatment increased the frequency of functional regulatory T-cell subsets and their transcription factors Gata3 and FoxP3 in parallel to a decrease in inflammatory dendritic cell subsets and their cytokines IL-6, IL-12, and TNF-α. KDACi also inhibited LPS-induced Cox-2 expression in peritoneal macrophages from C57BL/6 and NOD mice. In insulin-producing ß-cells, givinostat did not upregulate expression of the anti-inflammatory genes Socs1-3 or sirtuin-1 but reduced levels of IL-1ß + IFN-γ-induced proinflammatory Il1a, Il1b, Tnfα, Fas, Cxcl2, and reduced cytokine-induced ERK phosphorylation. Further, NF-κB genomic iNos promoter binding was reduced by 50%, and NF-κB-dependent mRNA expression was blocked. These effects were associated with NF-κB subunit p65 hyperacetylation. Taken together, these data provide a rationale for clinical trials of safety and efficacy of KDACi in patients with autoimmune disease such as type 1 diabetes.

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.

GABA protects pancreatic beta cells against apoptosis by increasing SIRT1 expression and activity.

We have previously shown that GABA protects pancreatic islet cells against apoptosis and exerts anti-inflammatory effects. Notably, GABA inhibited the activation of NF-κB in both islet cells and lymphocytes. NF-κB activation is detrimental to beta cells by promoting apoptosis. However, the mechanisms by which GABA mediates these effects are unknown. Because the above-mentioned effects mimic the activity of sirtuin 1 (SIRT1) in beta cells, we investigated whether it is involved. SIRT1 is an NAD(+)-dependent deacetylase that enhances insulin secretion, and counteracts inflammatory signals in beta cells. We found that the incubation of a clonal beta-cell line (rat INS-1) with GABA increased the expression of SIRT1, as did GABA receptor agonists acting on either type A or B receptors. NAD(+) (an essential cofactor of SIRT1) was also increased. GABA augmented SIRT1 enzymatic activity, which resulted in deacetylation of the p65 component of NF-κB, and this is known to interfere with the activation this pathway. GABA increased insulin production and reduced drug-induced apoptosis, and these actions were reversed by SIRT1 inhibitors. We examined whether SIRT1 is similarly induced in newly isolated human islet cells. Indeed, GABA increased both NAD(+) and SIRT1 (but not sirtuins 2, 3 and 6). It protected human islet cells against spontaneous apoptosis in culture, and this was negated by a SIRT1 inhibitor. Thus, our findings suggest that major beneficial effects of GABA on beta cells are due to increased SIRT1 and NAD(+), and point to a new pathway for diabetes therapy.

Pretransplant, Th17 dominant alloreactivity in highly sensitized kidney transplant candidates.

Introduction: Sensitization to donor human leukocyte antigen (HLA) molecules prior to transplantation is a significant risk factor for delayed access to transplantation and to long-term outcomes. Memory T cells and their cytokines play a pivotal role in shaping immune responses, thereby increasing the risk of allograft rejection among highly sensitized patients. This study aims to elucidate the precise contribution of different CD4+ memory T cell subsets to alloreactivity in highly sensitized (HS) kidney transplant recipients. Methods and results: Stimulation of peripheral blood mononuclear cells (PBMC) with various polyclonal stimulating agents to assess non-specific immune responses revealed that HS patients exhibit elevated immune reactivity even before kidney transplantation, compared to non-sensitized (NS) patients. HS patients' PBMC displayed higher frequencies of CD4+ T cells expressing IFNγ, IL4, IL6, IL17A, and TNFα and secreted relatively higher levels of IL17A and IL21 upon stimulation with PMA/ionomycin. Additionally, PBMC from HS patients stimulated with T cell stimulating agent phytohemagglutinin (PHA) exhibited elevated expression levels of IFNγ, IL4 and, IL21. On the other hand, stimulation with a combination of resiquimod (R848) and IL2 for the activation of memory B cells demonstrated higher expression of IL17A, TNFα and IL21, as determined by quantitative real-time PCR. A mixed leukocyte reaction (MLR) assay, employing third-party donor antigen presenting cells (APCs), was implemented to evaluate the direct alloreactive response. HS patients demonstrated notably higher frequencies of CD4+ T cells expressing IL4, IL6 and IL17A. Interestingly, APCs expressing recall HLA antigens triggered a stronger Th17 response compared to APCs lacking recall HLA antigens in sensitized patients. Furthermore, donor APCs induced higher activation of effector memory T cells in HS patients as compared to NS patients. Conclusion: These results provide an assessment of pretransplant alloreactive T cell subsets in highly sensitized patients and emphasize the significance of Th17 cells in alloimmune responses. These findings hold promise for the development of treatment strategies tailored to sensitized kidney transplant recipients, with potential clinical implications.

An investigation of functionalized chitosan and alginate multilayer conformal nanocoating on mouse beta cell spheroids as a model for pancreatic islet transplantation.

Multilayer conformal coatings have been shown to provide a nanoscale barrier between cells and their environment with adequate stability, while regulating the diffusion of nutrition and waste across the cell membrane. The coating method aims to minimize capsule thickness and implant volume while reducing the need for immunosuppressive drugs, making it a promising approach for islet cell encapsulation in clinical islet transplantation for the treatment of Type 1 diabetes. This study introduces an immunoprotective nanocoating obtained through electrostatic interaction between quaternized phosphocholine-chitosan (PC-QCH) and tetrahydropyran triazole phenyl-alginate (TZ-AL) onto mouse ß-cell spheroids. First, successful synthesis of the proposed polyelectrolytes was confirmed with physico-chemical characterization. A coating with an average thickness of 540 nm was obtained with self-assembly of 4-bilayers of PC-QCH/TZ-AL onto MIN6 ß-cell spheroids. Surface coating of spheroids did not affect cell viability, metabolic activity, or insulin secretion, when compared to non-coated spheroids. The exposure of the polyelectrolytes to THP-1 monocyte-derived macrophages lead to a reduced level of TNF-α secretion and exposure of coated spheroids to RAW264.7 macrophages showed a decreasing trend in the secretion of TNF-α and IL-6. In addition, coated spheroids were able to establish normoglycemia when implanted into diabetic NOD-SCID mice, demonstrating in vivo biocompatibility and cellular function. These results demonstrate the ability of the PC-QCH/TZ-AL conformal coating to mitigate pro-inflammatory responses from macrophages, and thus can be a promising candidate towards nanoencapsulation for cell-based therapy, particularly in type 1 diabetes, where the insulin secreting ß-cells are subjected to inflammation and immune cell attack.

RORγt inverse agonist TF-S14 inhibits Th17 cytokines and prolongs skin allograft survival in sensitized mice.

Chronic antibody mediated rejection (AMR) is the major cause of solid organ graft rejection. Th17 contributes to AMR through the secretion of IL17A, IL21 and IL22. These cytokines promote neutrophilic infiltration, B cell proliferation and donor specific antibodies (DSAs) production. In the current study we investigated the role of Th17 in transplant sensitization. Additionally, we investigated the therapeutic potential of novel inverse agonists of the retinoic acid receptor-related orphan receptor gamma t (RORγt) in the treatment of skin allograft rejection in sensitized mice. Our results show that RORγt inverse agonists reduce cytokine production in human Th17 cells in vitro. In mice, we demonstrate that the RORγt inverse agonist TF-S14 reduces Th17 signature cytokines in vitro and in vivo and leads to blocking neutrophilic infiltration to skin allografts, inhibition of the B-cell differentiation, and the reduction of de novo IgG3 DSAs production. Finally, we show that TF-S14 prolongs the survival of a total mismatch grafts in sensitized mice. In conclusion, RORγt inverse agonists offer a therapeutic intervention through a novel mechanism to treat rejection in highly sensitized patients.

Postoperative delirium in the intensive care unit predicts worse outcomes in liver transplant recipients.

BACKGROUND: Delirium is common in intensive care unit patients and is associated with worse outcome. OBJECTIVE: To identify early risk factors for delirium in patients admitted to the intensive care unit following orthotopic liver transplantation (OLT). METHODS: An observational study of patients admitted to the intensive care unit from January 2000 to May 2010 for elective or semi-elective OLT was conducted. The primary end point was delirium in the intensive care unit. Pre- and post-transplantation and intraoperative factors potentially associated with this outcome were examined. RESULTS: Of the 281 patients included in the study, 28 (10.03%) developed delirium in the intensive care unit at a median of two days (interquartile range one to seven days) after OLT. According to multivariate analysis, independent risk factors for delirium were intraoperative transfusion of packed red blood cells (OR 1.15 [95% CI 1.01 to 1.18]), renal replacement therapy during the pretransplantation period (OR 13.12 [95% CI 2.82 to 72.12]) and Acute Physiologic and Health Evaluation (APACHE) II score (OR per unit increase 1.10 [95% CI 1.03 to 1.29]). Using Cox proportional hazards models adjusted for baseline covariates, delirium was associated with an almost twofold risk of remaining in hospital, a fourfold increased risk of dying in hospital and an almost threefold increased rate of death by one year. CONCLUSION: Intraoperative transfusion of packed red blood cells, pretransplantation renal replacement therapy and APACHE II score are predictors for the development of delirium in intensive care unit patients post-OLT and are associated with increased hospital lengths of stay and mortality.

Hepatitis C infection and hepatocellular carcinoma in liver transplantation: a 20-year experience.

BACKGROUND: Hepatitis C infection (HCV) and hepatocellular carcinoma (HCC), the two main causes of liver transplantation (LT), have reduced survival post-LT. The impact of HCV, HCC and their coexistence on post-LT survival were assessed. METHODOLOGY: All 601 LT patients from 1992 to 2011 were reviewed. Those deceased within 30 days (n = 69) and re-transplants (n = 49) were excluded. Recipients were divided into four groups: (a) HCC-/HCV-(n = 252) (b) HCC+/HCV- (n = 58), (c) HCC-/HCV+ (n = 106) and (d) HCC+/HCV+ (n = 67). Demographics, the donor risk index (DRI), Model for End-Stage Liver Disease (MELD) score, survival, complications and tumour characteristics were collected. Statistical analysis included anova, chi-square, Fisher's exact tests and Cox and Kaplan-Meier for overall survival. RESULTS: Groups were comparable with regards to baseline characteristics, but HCC patients were older. After adjusting for age, MELD, gender and the donor risk index (DRI), survival was lower in the HCC+/HCV+ group (59.5% at 5 yrs) and the hazard ratio (HR) was 1.90 [95% confidence interval (CI),1.24-2.95, P = 0.003] and 1.45 (95% CI, 0.99-2.12, P = 0.054) for HCC-/HCV+. HCC survival was similar to controls (HR 1.18, 95% CI, 0.71-1.93, P = 0.508). HCC+/HCV- patients exceeded the Milan criteria (50% versus 31%, P < 0.04) and had more micro-vascular invasion (37.5% versus 20.6%, P = 0.042). HCC+/HCV+ versus HCC+/HCV- survival remained lower (HR 1.94, 95% CI, 1.06-3.81, P = 0.041) after correcting for tumour characteristics and treatment. CONCLUSION: HCV patients had lower survival post-LT. HCC alone had no impact on survival. Patient survival decreased in the HCC+/HCV+ group and this appears to be as a consequence of HCV recurrence.

Discovery, Synthesis, and In Vitro Characterization of 2,3 Derivatives of 4,5,6,7-Tetrahydro-Benzothiophene as Potent Modulators of Retinoic Acid Receptor-Related Orphan Receptor γt.

Retinoic acid receptor-related orphan receptor γt (RORγt) is a nuclear receptor that is expressed in a variety of tissues and is a potential drug target for the treatment of inflammatory and auto-immune diseases, metabolic diseases, and resistant cancer types. We herein report the discovery of 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene modulators of RORγt. We also report the solubility in acidic/neutral pH, mouse/human/dog/rat microsomal stability, Caco-2, and MDR1-MDCKII permeabilities of a set of these derivatives. For this group of modulators, inverse agonism by steric clashes and push-pull mechanisms induce greater instability to protein conformation compared to agonist lock hydration. Independent of the two mechanisms, we observed a basal modulatory activity of the tested 2,3 derivatives of 4,5,6,7-tetrahydro-benzothiophene toward RORγt due to the interactions with the Cys320-Glu326 and Arg364-Phe377 hydrophilic regions. The drug discovery approach reported in the current study can be employed to discover modulators of nuclear receptors and other globular protein targets.

Renal function in recipients of pancreas transplant alone.

PURPOSE OF REVIEW: Pancreas transplant alone (PTA) has become an accepted therapy for selected nonuremic patients with type 1 diabetes mellitus. We report a literature review, as well as data from the McGill University pancreas transplant program. RECENT FINDINGS: The published literature suggests that there is reversibility of diabetic nephropathy when normoglycemia is maintained for 5-10 years after successful PTA. There is also evidence of development and progression of histological lesions compatible with calcineurin inhibitor nephrotoxicity, as well as a decline in renal function overtime, with an increased risk of end-stage renal disease (ESRD). We studied 43 patients with PTA. Nine patients had a pretransplant estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73 m, and 34 patients had an eGFR greater than 60 ml/min/1.73 m. The actuarial incidence of ESRD at 1, 3 and 5 years was 0, 28.57 and 61.9% in patients with pretransplant eGFR less than 60 ml/min/1.73 m, and 0, 8.2 and 12.5% in patients with pretransplant eGFR greater than 60 ml/min/1.73 m, respectively (P=0.006). Multivariate analysis confirmed that age, sex, duration of diabetes prior to PTA and eGFR pretransplant were significant predictors of ESRD. SUMMARY: The ideal management of candidates for PTA with eGFR less than 60 ml/min/1.73 m remains to be determined. Future studies should focus on determining potentially reversible predictive factors of progression to ESRD after PTA, as well as the outcomes of these patients on chronic dialysis.

TFNR2 in Ischemia-Reperfusion Injury, Rejection, and Tolerance in Transplantation.

Tumor necrosis factor receptor 2 (TNFR2) has been shown to play a crucial role in CD4+ T regulatory cells (CD4+Tregs) expansion and suppressive function. Increasing evidence has also demonstrated its role in a variety of immune regulatory cell subtypes such as CD8+ T regulatory cells (CD8+ Tregs), B regulatory cells (Bregs), and myeloid-derived suppressor cells (MDSCs). In solid organ transplantation, regulatory immune cells have been associated with decreased ischemia-reperfusion injury (IRI), improved graft survival, and improved overall outcomes. However, despite TNFR2 being studied in the context of autoimmune diseases, cancer, and hematopoietic stem cell transplantation, there remains paucity of data in the context of solid organ transplantation and islet cell transplantation. Interestingly, TNFR2 signaling has found a clinical application in islet transplantation which could guide its wider use. This article reviews the current literature on TNFR2 expression in immune modulatory cells as well as IRI, cell, and solid organ transplantation. Our results highlighted the positive impact of TNFR2 signaling especially in kidney and islet transplantation. However, further investigation of TNFR2 in all types of solid organ transplantation are required as well as dedicated studies on its therapeutic use during induction therapy or treatment of rejection.

Extracellular Vesicles From Kidney Allografts Express miR-218-5p and Alter Th17/Treg Ratios.

Delayed graft function (DGF) in kidney transplantation is associated with ischemic injury and carries long term functional and immunological risks. Extracellular vesicles (EV) released from allografts may signal a degree of ischemic stress, and are thought to play an important role in the development of anti-donor immunity. Here, we show that kidney perfusate-derived extracellular vesicles (KP-EV) express donor-specific human leukocyte antigen. KP-EV from kidneys that experience DGF increase the T-helper 17 (Th17) to T-regulatory (Treg) ratio in third party peripheral blood mononuclear cells to a greater degree than those from kidneys with immediate function. We report miR-218-5p upregulation in KP-EV of kidney transplant recipients with DGF. Levels of miR-218-5p in KP-EV inversely correlated with recipient eGFR at multiple time points following transplantation. Additionally, the degree of increase in Th17/Treg ratio by KP-EV positively correlated with miR-218-5p expression in KP-EV samples. Taken together, these data provide evidence that KP-EV may contribute to modulating immune responses in transplant recipients. This could lead to novel intervention strategies to inhibit DGF in order to improve graft function and survival.

Association of preoperative parameters with postoperative mortality and long-term survival after liver transplantation.

BACKGROUND: The ability of Child-Turcotte-Pugh (CTP) or Model for End-Stage Liver Disease (MELD) scores to predict recipient survival after liver transplantation is controversial. This analysis aims to identify preoperative parameters that might be associated with early postoperative mortality and long-term survival after liver transplantation. METHODS: We studied a total of 15 parameters, using both univariate and multivariate models, among adults who underwent primary liver transplantation. RESULTS: A total of 458 primary adult liver transplants were performed. Fifty-seven (12.44%) patients died during the first 3 postoperative months and composed the early mortality group. The remaining 401 patients composed the long-term patient survival group. The parameters that were identified through univariate analysis to be associated with early postoperative mortality were CTP score, MELD score, bilirubin, creatinine, international normalized ratio and warm ischemia time (WIT). In all multivariate models, WIT retained its statistical significance. The 10-year long-term survival was 65%. The parameters that were identified to be independent predictors of long-term survival were the recipient's sex (improved survival in women, p = 0.005), diagnosis of hepatocellular cancer (p=0.015) and recipient's age (p=0.024). CONCLUSION: Either CTP or MELD score, in conjunction with WIT, might have a role in predicting early postoperative mortality after liver transplantation, whereas the recipient's sex and the absence of hepatocellular cancer are associated with improved long-term survival.

Kidney Transplantation in Times of Covid-19: Decision Analysis in the Canadian Context.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic impacted transplant programs across Canada. OBJECTIVE: We evaluated the implications of delays in transplantation among Canadian end-stage kidney disease (ESKD) patients to allow pretransplant vaccination. DESIGN: We used a Markov microsimulation model and ESKD patient perspective to study the effectiveness (quality-adjusted life years [QALY]) of living (LD) or deceased donor (DD) kidney transplantation followed by 2-dose SARS-CoV-2 vaccine versus delay in LD ("Delay LD") or refusal of DD offer ("Delay DD") to receive 2-dose SARS-CoV-2 vaccine pretransplant. SETTING: Canadian dialysis and transplant centers. PATIENTS: We simulated a 10 000-waitlisted ESKD patient cohort, which was predictively modeled for a lifetime horizon in monthly cycles. MEASUREMENTS: Inputs on patient and graft survival estimates by patient, LD or DD characteristics, were extracted from the Treatment of End-Stage Organ Failure in Canada, Canadian Organ Replacement Register, 2009 to 2018. In addition, a literature review provided inputs on quality of life, SARS-CoV-2 transmissibility, new variants of concern, mortality risk, and antibody responses to 2-dose SARS-CoV-2 mRNA vaccines. METHODS: We conducted base case, scenario, and sensitivity analyses to illustrate the impact of patient, donor, vaccine, and pandemic characteristics on the preferred strategy. RESULTS: In the average waitlisted Canadian patient, receiving 2-dose SARS-CoV-2 vaccine post-transplant provided an effectiveness of 22.32 (95% confidence interval: 22.00-22.7) for LD and 19.34 (19.02-19.67) QALYs for DD. Delaying transplants for 6 months to allow 2-dose SARS-CoV-2 vaccine before LD and DD transplant yielded effectiveness of 22.83 (21.51-23.14) and 20.65 (20.33-20.96) QALYs, respectively. Scenario analysis suggested a benefit to short delays in DD transplants to receive 2-dose SARS-CoV-2 vaccine in waitlisted patients ≥55 years. Two-way sensitivity analysis suggested decreased effectiveness of the strategy prioritizing 2-dose SARS-CoV-2 vaccine prior to DD transplant the longer the delay and the higher the Kidney Donor Risk Index of the eventual DD transplant. When assessing the impact of SARS-CoV-2 variants of concern (infection rates ≥10-fold and associated mortality ≥3-fold vs base case), we found short delays to allow 2-dose SARS-CoV-2 vaccine administration pretransplant to be preferable. LIMITATIONS: Risks associated with nosocomial exposure of LDs were not considered. There was uncertainty regarding input parameters related to SARS-CoV-2 infection, new variants, and COVID-19 severity in ESKD patients. Given rollout of population-level SARS-CoV-2 vaccination, we assumed a linear decrease in infection rates over 1 year. Proportions of patients mounting an antibody response to 2-dose SARS-CoV-2 mRNA vaccines were considered in lieu of data on vaccine efficacy in dialysis and following transplantation. Non-age-stratified annual mortality rates were used for waitlisted candidates. CONCLUSIONS: Our analyses suggest that short delays allowing pretransplant vaccination offered comparable to greater effectiveness than pursuing transplantation without delay, proposing transplant candidates should be prioritized to receive at least 2 doses of SARS-CoV-2 vaccine. Our scenario and sensitivity analyses suggest that caution must be exercised when declining DD offers in patients offered low risk DD and who are likely to incur significant delays in access to transplantation. While population-level herd immunity may decrease infection risk in transplant patients, more data are required on vaccine efficacy against SARS-CoV-2 and variants of concern in ESKD, and how efficacy may be modified by a third vaccine dose, maintenance immunosuppression and timing of induction and rejection therapies.