Characterizing Foxp3+ and Foxp3- T cells in the homeostatic state and after allo-activation: resting CD4+Foxp3+ Tregs have molecular characteristics of activated T cells.

Due to the intracellular expression of Foxp3 it is impossible to purify viable Foxp3+ cells on the basis of Foxp3 staining. Consequently CD4+Foxp3+ regulatory T cells (Tregs) in mice have mostly been characterized using CD4+CD25+ T cells or GFP-Foxp3 reporter T cells. However, these two populations cannot faithfully represent Tregs as the expression of CD25 and Foxp3 does not completely overlap and GFP+Foxp3+ reporter T cells have been reported to be functionally altered. The aim of this study was to characterize normal Tregs without separating Foxp3+ and Foxp3- cells for the expression of the main functional molecules and proliferation behaviors by flow cytometry and to examine their gene expression characteristics through differential gene expression. Our data showed that the expressions of Foxp3, CD25, CTLA-4 (both intracellular and cell surface) and PD-1 was mostly confined to CD4+ T cells and the expression of Foxp3 did not completely overlap with the expression of CD25, CTLA-4 or PD-1. Despite higher levels of expression of the T cell inhibitory molecules CTLA-4 and PD-1, Tregs maintained higher levels of Ki-67 expression in the homeostatic state and had greater proliferation in vivo after allo-activation than Tconv. Differential gene expression analysis revealed that resting Tregs exhibited immune activation markers characteristic of activated Tconv. This is consistent with the flow data that the T cell activation markers CD25, CTLA-4, PD-1, and Ki-67 were much more strongly expressed by Tregs than Tconv in the homeostatic state.

Time to Move on: HLA Matching Should Be Reconsidered in Modern Deceased Donor Kidney Allocation.

HLA matching has been the cornerstone of deceased donor kidney allocation policies worldwide but can lead to racial inequity. Although HLA matching has been shown to improve clinical outcomes, the long-term impacts of nonallogenic factors are being increasingly recognized. This has led some transplant programs to include points for nonallogenic factors, for example, age. Our study looks at long-term graft and patient outcomes based on allocation cohorts rather than individual number of HLA mismatches. Methods: Using the Australia and New Zealand Dialysis and Transplant Registry, we analyzed 7440 adult deceased donor transplant events from 2000 to 2018. Transplants were classified as HLA matched or nonmatched according to the OrganMatch score and the local allocation algorithms. Graft function was studied with linear mixed modeling and graft rejection with logistic and binomial regression. Time to graft failure and recipient survival were examined with Kaplan-Meier curve and Cox regression models. Results: Forty percent of transplants were HLA matched. Mean glomerular filtration rate was 1.76 mL/min/1.73 m2 higher in the matched transplants (P < 0.001). Matched transplants had longer time to graft failure (15.9 versus 12.7 y; P < 0.001) and improved recipient survival (risk of death hazard ratio, 0.83; P = 0.003). Matched recipients spent less time on dialysis (28.1 versus 44.8 mo; P < 0.001), and this significantly contributed to the benefits seen in graft loss and recipient survival. Caucasian recipients were more likely to receive a matched transplant than non-Caucasians. Conclusions: Matched transplants showed benefits in graft and recipient outcomes; however, some of these results were of small magnitude, whereas others seemed to be due in part to a reduction in time on dialysis. The benefit for the matched cohort came at the expense of the nonmatched cohort, who spent longer on dialysis and were more likely to be of a minority racial background.

Renal transplant anastomotic time-Every minute counts!

The impact of anastomotic time in renal transplant is under recognized and not well studied. It is one of the few controllable factors that affect the incidence of delayed graft function (DGF). Our study aimed at quantifying the impact of anastomotic time. We performed a retrospective review of 424 renal transplants between the years 2006 and 2020. A total of 247 deceased donor renal transplants formed the study cohort. Patients were divided into two groups based on the presence or absence of DGF. Variables with p < 0.3 were analyzed using the binary logistic regression test. The final analysis showed anastomotic time to be significantly associated with DGF with odds ratio of 1.04 per minute corresponding to 4% increase in DGF incidence with every minute increment in anastomotic time. Other variables that had significant impact on DGF were DCD donor (odds ratio - 8.7) and donor terminal creatinine. We concluded that anastomotic time had significant impact on the development of DGF and hence should be minimized.

Assessment of Restored Kidney Transplantation Including the Use of Wider Criteria for Accepting Renal Donors After Cancer Excision.

The transplantation of kidneys after cancer excision (restored kidney transplantation, RKT) warrants further evaluation as a source of kidneys for transplantation. We determined whether larger cancers can be safely transplanted, the risks of adverse events from RKT, and whether RKT confers a survival advantage for patients waiting for transplantation. METHODS: In a retrospective cohort study, 23 dialysis patients awaiting transplant underwent RKT at John Hunter Hospital, Australia between 2008 and 2015. Patients were >60 years old and accepted onto the National Organ Matching Service. This RKT Group was divided into donor renal cancers ≤30 mm and >30-≤50 mm. Adverse event profiles for RKT recipients were compared with 22 standard live donor recipients using logistic regression analyses. Recipient and transplant survivals for RKT were compared with 2050 controls from Australian New Zealand Dialysis Transplant Registry using Cox regression models. To increase statistical power for survival analyses, data from 25 RKT recipients from Princess Alexandra Hospital, Brisbane were added, thus creating 48 RKT recipients. RESULTS: There were no significant differences in mortality, transplant failure nor AEs between the 2 cancer Groups. RKT increased the risks of Adverse event profiles (odds ratio: 6.48 [2.92-15.44]; P < 0.001). RKT reduced mortality risk by 30% (hazard ratio [HR]: 0.70 [0.36-1.07]; P = 0.299) compared with those continuing on the transplant list who may or may not be transplanted. RKT significantly reduced mortality risk for those remaining on dialysis (HR: 2.86 [1.43-5.72]; P = 0.003). Transplant survival for RKT was reduced compared with control deceased donor (HR: 0.42 [0.21-0.83]; P = 0.013) and live donor transplants (HR: 0.33 [0.02-0.86]; P =0.023). CONCLUSIONS: The use of larger carefully selected cancer-resected kidneys for transplantation appears safe and effective. RKT confers a possible survival advantage compared with waiting for transplantation, an increased survival compared with those remaining on dialysis but reduced transplant survival.

Functional significance and risk factors for lymphocele formation after renal transplantation.

BACKGROUND: Lymphocele development following renal transplantation is a significant adverse event. It may cause acute graft dysfunction or venous obstruction. There are no consistent risk factors reported in literature. Perioperative fluid balance may lead to increased lymphocele formation and has never been studied. We aimed to analyse incidence and risk factors for lymphocele formation. We hypothesized that overhydration in perioperative period is a risk factor. METHODS: We analysed 250 consecutive renal transplant recipients from 2006 to 2014. All recipients had undergone protocol screening by computerized tomography and ultrasound scan at 3 months post-transplant. We analysed risk factors for lymphocele formation. Comparisons between lymphocele and no-lymphocele groups were made with binary logistic regression analyses. Renal function was compared between treated, untreated and no-lymphocele groups with linear regression analyses. RESULTS: Thirty-one of 250 (12.4%) transplant recipients developed lymphocele. Fourteen of 31 (45.4%) recipients required intervention due to symptoms (venous obstruction being the most common). Surgical drainage was done in all symptomatic patients (11 laparoscopic and three open). Two of 11 (18%) recipients had recurrence after laparoscopic drainage. There were no significant differences in risk factors between the lymphocele and no-lymphocele groups. Renal function was comparable between no-lymphocele and treated lymphocele groups. Untreated lymphocele group trended towards better graft function at 1 year (P = 0.051). CONCLUSION: Post-transplant lymphocele developed one in eight transplant recipients and tended to occur in those with good renal function. Around half of the recipients with lymphocele required intervention with good recovery of long-term renal function. No risk factor for lymphocele development was established.

Effect of immunosuppression for primary renal disease on the risk of cancer in subsequent renal transplantation: a population-based retrospective cohort study.

BACKGROUND: To measure the risk of cancer in renal transplantation for recipients who had previously been treated with immunosuppressive agents for primary renal disease. METHODS: A retrospective population-based cohort study of 5970 renal transplant recipients in Australia registered on the Australia and New Zealand Dialysis and Transplant Registry between 1982 and 1997 and followed until 2007. Data about the incidence of a range of cancer types from this Registry were compared with cancer incidence data for the general population matched for cancer type, year of incidence, age, and gender derived from national cancer records. Outcome measures for each cancer group with or without pretransplantation immunosuppression were cancer-specific standardized incidence ratios and a multivariate hazard ratio (HR) standardized to 1. RESULTS: For those treated with pretransplantation immunosuppression, the risks for four cancer groups during renal transplantation were significantly increased: anogenital cancer (HR, 3.13; confidence interval [CI], 1.92-5.11; P<0.0001), non-Hodgkin's lymphoma (HR, 2.37; CI, 1.53-3.68; P=0.0001), breast cancer (HR, 2.52; CI, 1.13-5.61; P=0.024), and urinary tract cancer (excluding kidney) (HR, 1.84; CI, 1.13-3.01; P=0.015). However, the risks of cancer in the oral cavity and pharynx, kidney, thyroid, colon, leukemia, lung, melanoma, prostate, and stomach were not significantly increased. CONCLUSIONS: Pretransplantation immunosuppression for primary renal disease increases the risks of four cancer types in renal transplantation while sparing the others. Patients in whom this treatment is being considered should be informed of these risks.