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.

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.

Policies and practice of solid organ donation amongst people living with HIV in Canada: time for education and re-evaluation.

The numbers of organ donors in Canada and the USA fall short of increasing demand, resulting in increased morbidity, poor health outcomes, higher medical costs and death of many individuals waitlisted for transplantation. In the US, since 2013 when the US HIV Organ Policy Equity (HOPE) Act lifted the ban on organ donation between people living with HIV, the option of using organs from People with HIV became a reality. In Canada, HIV diagnosis was an exclusion criterion to organ donation until 2017, when permission was granted if requirements for 'exceptional distribution' could be met. Still, donation of organs from people with HIV poses challenges. Herein, we overview policies involving donors with HIV in Canada in order to inform healthcare providers, researchers and the community. We also advocate for the need to reassess these policies, highlight educational needs and engage interest in advancing research to inform policy reforms.

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.

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.

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.

Relative decrease in hemoglobin and outcomes in patients undergoing kidney transplantation surgery: A retrospective cohort study.

BACKGROUND: Recent surgical literature suggests that a relative decrease in hemoglobin (ΔHb) is predictive of adverse outcomes regardless of the absolute level. We aimed to examine the association between perioperative ΔHb and kidney transplantation (KT) outcomes. METHODS: This was a retrospective cohort study of transplant recipients, where ΔHb = [Hb0- Hb1Hb0]x 100 (Hb0 = hemoglobin pre-KT and Hb1 = lowest hemoglobin 24-h post-KT). The main outcome of interest was immediate graft function (IGF). RESULTS: Of the 899 eligible patients, 38% experienced IGF, and ΔHb was associated with 36% lower odds of IGF. Also, ΔHb was associated with higher all-cause graft failure and longer length of stay but not death-censored graft failure or mortality. ΔHb ≥30% was the threshold beyond which the odds of IGF were significantly lower even if Hb1 was ≥7 g/dL. CONCLUSION: ΔHb is associated with inferior outcomes independent of Hb1; whether it can be used to guide transfusion practices should be explored.

Successful surgical weight loss with laparoscopic sleeve gastrectomy for morbid obesity prior to kidney transplantation.

Morbid obesity in kidney transplant (KT) candidates is associated with increased complications and graft failure. Multiple series have demonstrated rapid and significant weight loss after laparoscopic sleeve gastrectomy (LSG) in this population. Long-term and post-transplant weight evolutions are still largely unknown. A retrospective review was performed in eighty patients with end-stage kidney disease (ESKD) who underwent LSG in preparation for KT. From a median initial BMI of 43.7 kg/m2 , the median change at 1-year was -10.0 kg/m2 . Successful surgical weight loss (achieving a BMI < 35 kg/m2 or an excess body weight loss >50%) was attained in 76.3% and was associated with male gender, predialysis status, lower obesity class and lack of coronary artery disease. Thirty-one patients subsequently received a KT with a median delay of 16.7 months. Weight regain (increase in BMI of 5 kg/m2 postnadir) and recurrent obesity (weight regain + BMI > 35) remain a concern, occurring post-KT in 35.7% and 17.9%, respectively. Early LSG should be considered for morbidly obese patients with ESKD for improved weight loss outcomes. Early KT after LSG does not appear to affect short-term surgical weight loss. Candidates with a BMI of up to 45 kg/m2 can have a reasonable expectation to achieve the limit within 1 year.

Predicting Clinical Outcome in Expanded Criteria Donor Kidney Transplantation: A Retrospective Cohort Study.

BACKGROUND: The gaps in organ supply and demand necessitate the use of expanded criteria donor (ECD) kidneys. OBJECTIVE: To identify which pre-transplant and post-transplant predictors are most informative regarding short- and long-term ECD transplant outcomes. DESIGN: Retrospective cohort study. SETTING: Single center, Quebec, Canada. PATIENTS: The patients were 163 consecutive first-time ECD kidney only transplant recipients who underwent transplantation at McGill University Health Centre (MUHC) between January 1, 2008 and December 31, 2014 and had frozen section wedge procurement biopsies. MEASUREMENTS: Short-term graft outcomes, including delayed graft function and 1-year estimated glomerular filtration rate (eGFR), as well as long-term outcomes including all-cause graft loss (defined as return to dialysis, retransplantation, and death with function). METHODS: Pre-transplant donor, recipient, and transplant characteristics were assessed as predictors of transplant outcomes. The added value of post-transplant predictors, including longitudinal eGFR, was also assessed using time-varying Cox proportional hazards models. RESULTS: In univariate analyses, among the pre-transplant donor characteristics, histopathologic variables did not show evidence of association with delayed graft function, 1-year post-transplant eGFR or all cause graft loss. Recipient age was associated with all-cause graft loss (hazard ratio: 1.038 [95% confidence interval: 1.002-1.075] and the model produced only modest discrimination (C-index: 0.590; standard error [SE]: 0.045). Inclusion of time-dependent post-transplant eGFR improved the model's prediction accuracy (C-index: 0.711; SE = 0.047). Pre-transplant ECD characteristics were not associated with long-term survival, whereas post-transplant characteristics allowed better model discrimination. LIMITATIONS: Single-center study, small sample size, and potential incomplete capture of all covariate data. CONCLUSIONS: Incorporation of dynamic prediction models into electronic health records may enable timely mitigation of ECD graft failure risk and/or facilitate planning for renal replacement therapies. Histopathologic findings on preimplantation biopsies have a limited role in predicting long-term ECD outcomes. TRIAL REGISTRATION: Not applicable.

CONTEXTE: Les écarts entre l'offre et la demande d'organes nécessitent le recours à des donneurs répondant à des critères élargis (DCÉ). OBJECTIF: Déterminer les prédicteurs pré- et post-transplantation qui s'avèrent les plus instructifs quant aux résultats à court et à long terme des greffes d'organes provenant de DCÉ. TYPE D'ÉTUDE: Étude de cohorte rétrospective. CADRE: Étude monocentrique tenue au Québec (Canada). SUJETS: L'étude porte sur 163 patients consécutifs greffés d'un rein seulement au center universitaire de santé McGill (CUSM) entre le 1er janvier 2008 et le 31 décembre 2014. L'organe reçu provenait d'un DCÉ et la biopsie avait été effectuée sur des sections congelées de l'organe. MESURES: Les résultats à court terme, notamment la reprise retardée de la fonction du greffon et le débit de filtration glomérulaire estimé (DFGe) après un an. Les résultats à long terme dont la perte du greffon toute cause (retour en dialyse, retransplantation ou décès avec greffon fonctionnel). MÉTHODOLOGIE: Les caractéristiques du donneur, du receveur et de la transplantation ont été examinées avant l'intervention comme prédicteurs de l'issue de la greffe. Des modèles des risques proportionnels de Cox variant dans le temps ont servi à évaluer la valeur ajoutée des prédicteurs post-greffe, notamment du DFGe longitudinal. RÉSULTATS: Dans l'analyse univariée des caractéristiques pré-transplantation, les variables histopathologiques n'ont montré aucune association avec la fonction retardée du greffon, le DFGe un an après la greffe ou la perte du greffon. L'âge du receveur a été associé à la perte du greffon toute cause (RR : 1,038 [IC 95 % : 1,002-1,075]) et le pouvoir discriminant du modèle s'est avéré modeste (indice C : 0,590; ÉT = 0,045). L'inclusion du DFGe post-greffe en fonction du temps a amélioré la précision prédictive du modèle (indice C : 0,711; ÉT = 0,047). Les caractéristiques pré-greffe du DCÉ n'ont pas été associées à la survie à long terme, alors que les caractéristiques post-greffe ont permis d'améliorer le pouvoir discriminant du modèle. LIMITES: Étude monocentrique sur un faible échantillon et dont la saisie des données sur les covariables est potentiellement incomplète. CONCLUSION: L'incorporation de modèles prédictifs dynamiques aux dossiers médicaux électroniques pourrait permettre, en temps opportun, d'atténuer les risques de défaillance du greffon provenant d'un DCÉ et faciliter la planification d'une thérapie de remplacement rénal. Les résultats histopathologiques des biopsies pré-transplantation jouent un rôle mineur pour prédire les résultats à long terme des DCÉ. ENREGISTREMENT DE L'ESSAI: Sans objet.

Safety and efficacy of the sleeve gastrectomy as a strategy towards kidney transplantation.

BACKGROUND: Obese individuals suffering from advanced chronic kidney disease (CKD) may be precluded from accessing kidney transplantation. Bariatric surgery is an effective treatment for obesity and related conditions but its use in those with severe CKD remains limited due to morbidity concerns. We aimed to evaluate the safety and efficacy of sleeve gastrectomy (SG) in patients with severe CKD as a bridging strategy towards kidney transplant candidacy. METHODS: This is a single-center retrospective study of a prospectively collected database of obese patients referred by the multi-organ transplant team for surgical weight loss, who underwent SG during 2013-2018. The primary outcome was 90-day major morbidity. Secondary outcomes included weight loss, and successful kidney transplantation. Descriptive statistics are expressed as count (percent) or median (interquartile range). RESULTS: 32 patients met inclusion criteria. 18 (56%) were male with a median age and BMI of 51 (11) years and 42.3 (5.2) kg/m2, respectively. 29 (91%) patients were on dialysis for a median duration of 28 months before SG. Diabetes, hypertension, and dyslipidemia were present in 15 (47%), 25 (78%), and 21 (66%) patients, respectively. At 90 days after SG, there were no leaks, reoperations, or mortality. The median length of stay was 2 (1.3) days. At 1 year, change in BMI and percent excess weight loss (EWL) were -9.8 (3.7) kg/m2 and 56% (27), respectively. In the year after SG, 20 (63%) patients were listed for transplant. 14 (44%) underwent successful kidney transplantation. One patient died while waiting for transplant. At time of transplant, median change in BMI and EWL were -9.0 (5.5) kg/m2 and 59% (30), respectively. After transplant, no patient required dialysis at a median follow-up of 17 (32) months. CONCLUSION: SG is safe and effective for weight loss and bridging to candidacy for kidney transplantation in patients with severe CKD. The acceptable safety and efficiency of SG in this high-risk population makes it an optimal choice as a bridging procedure.

Renal actinomycosis presenting as uro-cutaneous fistula.

Renal actinomycosis is a rare clinical entity. Diagnosis is usually made after resection. A 36-year-old male presented with uro-cutaneous fistula and left xanthogranulomatous pyelonephritis. He was offered left open radical nephrectomy. Intra-operatively, there was "woody" inflammation of the left kidney fistulizing to the splenic flexure of the colon. We successfully resected it and a segment of the colon that had fistulized. His tissue cultures grew Actinomyces odontolyticus. Post-operatively, he received 6 weeks of intravenous beta-lactam antibiotic. He recovered well without any complications. In conclusion, renal actinomycosis can be challenging to diagnose, operate and eradicate. Perioperative considerations are presented for successful management.

Immune Response to Extracellular Vesicles From Human Islets of Langerhans in Patients With Type 1 Diabetes.

The autoimmune response that characterizes type 1 diabetes (T1D) has no clear cause. Extracellular vesicles (EVs) play an important role in triggering the immune response in other contexts. Here, we propose a model by which EVs isolated from human islets stimulate proinflammatory immune responses and lead to peripheral blood mononuclear cell (PBMC) activation. We show that human islet EVs are internalized by monocytes and B cells and lead to an increase in T-helper 1, 2, and 17 cytokine expression, as well as T and B cell proliferation. Importantly, we demonstrate memory T and B cell activation by EVs selectively in PBMCs of patients with T1D. Additionally, human islet EVs induce an increase in antibodies against glutamic acid decarboxylase 65 (GAD65) in T1D PBMCs. Furthermore, pretreatment of T1D PBMCs with ibrutinib, an inhibitor of Bruton tyrosine kinase, dampens EV-induced memory B cell activation and GAD65 antibody production. Collectively, our findings indicate a role for human islet EVs in mediating activation of B and T cells and GAD65 autoantibody production.

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.

Impact of acute kidney injury following liver transplantation on long-term outcomes.

BACKGROUND: The incidence of acute kidney injury (AKI) after liver transplantation (LTx) ranges from 17% to 94%. AKI is associated with prolonged hospitalization and increased early mortality. In our cohort study, we examined the impact of AKI on long-term patient survival and on the incidence of stage 4-5 chronic kidney disease (CKD). METHODS: We studied 491 LTx recipients at a single center between 1990 and 2012. We identified 278 pts (56.6%) with AKI defined as either an increase in serum creatinine (SCr) ≥26.5 µmol/L within 48 hour or elevation in SCr 1.5× baseline within 7 days (KDIGO criteria). RESULTS: In a multivariable Cox proportional hazards model, survival was worse in patients with AKI (HR: 1.41, 95% CI 1.03-1.92). Severe (stage 3) AKI was associated with worse patient survival (HR: 2.29, 95% CI 1.46-3.58). The risk of developing stage 4-5 CKD was also higher in patients with AKI (17.5% vs 9.1%) with a HR of 2.39 (95% CI 1.27-4.47). Delaying initiation of calcineurin inhibitors >48H was not associated with a decreased risk of CKD. CONCLUSIONS: Our findings suggest that AKI after LTx is associated with poor long-term outcomes, including worse survival and higher incidence of CKD stage 4-5. Strategies to prevent and manage LTx patients with AKI need to be developed.

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.

Pretransplant Recipient Circulating CD4+CD127lo/- Tumor Necrosis Factor Receptor 2+ Regulatory T Cells: A Surrogate of Regulatory T Cell-Suppressive Function and Predictor of Delayed and Slow Graft Function After Kidney Transplantation.

BACKGROUND: Delayed graft function (DGF) and slow graft function (SGF) are ischemia-reperfusion-associated acute kidney injuries (AKI) that decrease long-term graft survival after kidney transplantation. Regulatory T (Treg) cells are protective in murine AKI, and their suppressive function predictive of AKI in kidney transplantation. The conventional Treg cell function coculture assay is however time-consuming and labor intensive. We sought a simpler alternative to measure Treg cell function and predict AKI. METHODS: In this prospective observational cohort study, pretransplant recipient circulating CD4+CD25+CD127lo/- and CD4+CD127lo/- tumor necrosis factor receptor 2 (TNFR2)+ Treg cells were measured by flow cytometry in 76 deceased donor kidney transplant recipients (DGF, n = 18; SGF, n = 34; immediate graft function [IGF], n = 24). In a subset of 37 recipients, pretransplant circulating Treg cell-suppressive function was also quantified by measuring the suppression of autologous effector T-cell proliferation by Treg cell in coculture. RESULTS: The TNFR2+ expression on CD4+CD127lo/- T cells correlated with Treg cell-suppressive function (r = 0.63, P < 0.01). In receiver operating characteristic curves, percentage and absolute number of CD4+CD127lo/-TNFR2+ Treg cell predicted DGF from non-DGF (IGF + SGF) with area under the curves of 0.75 and 0.77, respectively, and also AKI (DGF + SGF) from IGF with area under the curves of 0.76 and 0.72, respectively (P < 0.01). Prediction of AKI (DGF + SGF) from IGF remained significant in multivariate logistic regression accounting for cold ischemic time, donor age, previous transplant, and pretransplant dialysis modality. CONCLUSIONS: Pretransplant recipient circulating CD4+CD127lo/-TNFR2+ Treg cell is potentially a simpler alternative to Treg cell function as a pretransplant recipient immune marker for AKI (DGF + SGF), independent from donor and organ procurement characteristics.