[Acute renal failure of the donor in encephalic death: A real contraindication to kidney transplantation?] / L'insuffisance rénale aiguë du donneur en mort encéphalique : une réelle contre-indication à la transplantation rénale ?

INTRODUCTION: The shortage of kidney transplants encourages the expansion of the limits of eligibility criteria for donation. Many donors who are brain dead display acute renal failure at the time of death; is this a real contraindication to harvesting? The aim of this study was to assess kidney graft survival from donors after brain death with confirmed acute renal failure, with or without anuria previous donation. MATERIALS AND METHODS: All of the transplants performed in two university hospitals between 2010 and 2017 were analyzed retrospectively. All patients who underwent single kidney transplant from a brain-dead donor with acute renal failure (ARF) were included in this study. ARI was defined here by a decrease over 50 % of glomerular filtration rate (GFR) to a threshold below 45mL/min/1.73 m2 at the time of kidney procurement. Kidney graft survival, incidence of delayed graft function (DGF) and the GFR at 12 months were analyzed. Analysis of kidney transplant survival based on pre-implantation biopsies was additionally done. RESULTS: One hundred and sixty four patients were transplanted with a kidney from donor with ARF during the selected period. At the admission in ICU the average GFR was 67,7±19mL/min/1,73m2. At the time of donation, the average age of donors was 56.4±17.7 years, the GFR was 33.7±8.0mL/min/1.73 m2 16 % of donors were anuric. Cold ischemia time (CIT) was 16.8±5.0hours. The average age of recipients was 55.6±14.1 years. 81 % of the cases were primary transplants. Graft function took place within 7.8±9.4 days after transplantation. There were two non-primary functions (PNF). One hundred and fifty two patients (93 %) had a functional graft at 12 months. The mean GFR at 12 months was 46.8±20.1mL/min/1.73 m2 and 122 patients (73 %) had a GFR greater than 30mL/min/1.73 m2. Seventy-one percent of preimplantation biopsies revealed acute tubular necrosis (ATU); no cortical necrosis was observed. Survival of theses grafts was 85 %, comparable to the total population of study (P=0,21) CONCLUSION: The acute renal failure of the brain-dead donor should not alone be systematically a contraindication to harvesting and kidney transplantation.

Renal Operational Tolerance Is Associated With a Defect of Blood Tfh Cells That Exhibit Impaired B Cell Help.

Renal operationally tolerant patients (TOL) display a defect in B cell differentiation, with a deficiency in plasma cells. Recently described, T follicular helper (Tfh) cells play a critical role in B cell differentiation. We analyzed blood Tfh subsets in TOL and transplanted patients with stable graft function under immunosuppression (STA). We observed a reduced proportion of blood activated and highly functional Tfh subsets in TOL, without affecting Tfh absolute numbers. Functionally, Tfh cells from TOL displayed a modified gene expression profile, failed to produce interleukin-21, and were unable to induce IgG production by naive B cells. This Tfh defect is linked to a low incidence of postgraft de novo donor-specific antibody (dnDSA) immunization, suggesting that the lack of Tfh cells in TOL may induce a protolerogenic environment with reduced risk of developing dnDSA. Finally, we showed that elevated Tfh in STA precedes the occurrence of dnDSA during an alloresponse. These data provide new insights into the mechanisms of antibody response in operational tolerance. Disrupted homeostasis and impaired Tfh function in TOL could lead to a reduced risk of developing dnDSA and suggest a predictive role of blood Tfh cells on the occurrence of dnDSA in transplant recipients.

FR104, an antagonist anti-CD28 monovalent fab' antibody, prevents alloimmunization and allows calcineurin inhibitor minimization in nonhuman primate renal allograft.

Selective targeting of CD28 might represent an effective immunomodulation strategy by preventing T cell costimulation, while favoring coinhibition since inhibitory signals transmitted through CTLA-4; PD-L1 and B7 would not be affected. We previously showed in vitro and in vivo that anti-CD28 antagonists suppress effector T cells while enhancing regulatory T cell (Treg) suppression and immune tolerance. Here, we evaluate FR104, a novel antagonist pegylated anti-CD28 Fab' antibody fragment, in nonhuman primate renal allotransplantation. FR104, in association with low doses of tacrolimus or with rapamycin in a steroid-free therapy, prevents acute rejection and alloantibody development and prolongs allograft survival. However, when FR104 was associated with mycophenolate mofetil and steroids, half of the recipients rejected their grafts prematurely. Finally, we observed an accumulation of Helios-negative Tregs in the blood and within the graft after FR104 therapy, confirmed by Treg-specific demethylated region DNA analysis. In conclusion, FR104 reinforces immunosuppression in calcineurin inhibitor (CNI)-low or CNI-free protocols, without the need of steroids. Accumulation of intragraft Tregs suggested the promotion of immunoregulatory mechanisms. Selective CD28 antagonists might become an alternative CNI-sparing strategy to B7 antagonists for kidney transplant recipients.

The endoneurial response to microsurgically removed epi- and perineurium.

The purpose of the study was to examine the response of the endoneurium of the rat sciatic nerve after removal of the epi- and perineurium. For this purpose, segments (4-5 mm long) of the whole epi- and perineurium around the rat sciatic nerve were microsurgically removed (the peel-off area) and the endoneurium was left intact. The post-operative changes were followed up to 5 weeks post-operatively (PO) by histo- and immunohistochemical studies. Additionally, neuromorphometric analyses considering the number of Schwann cells, axons, macrophages and endothelial cells were examined in the peel-off area. The results showed that at the operative area the central part of the endoneurium (65% of the total area of the endoneurium) remained morphologically intact, but the outer part of the endoneurium (35% of the total area) reacted strongly and showed Wallerian type of degeneration. The number of axons and Schwann cells decreased 3 days PO. However, after 2 weeks the number of Schwann cells increased markedly and the highest number was noted 5 weeks PO. A great number of capillaries were observed in the outer part 1 week PO. A rapid invasion of macrophages was noted at the outer part of the endoneurium immediately after the operation. During the regeneration the endoneurial fibroblasts in the peripheral zone started to form minifascicle-like formations, which resulted in a distinct dense outer part of the endoneurium. This dense outer zone was preserved up to 5 weeks PO and participated in the formation of a new perineurium-like structure, but no distinct new perineurium was formed. At the border zone, areas beside the normal epi- and perineurium proliferation of preserved perineurial cells were noted, which fused to the outer part of the dense endoneurium. On focal areas, an attachment of the operated area to the adjoining muscle was observed. This study shows for the first time that despite the microsurgical removal of epi- and perineurium, the inner part of the endoneurium stays intact, but in the outer part of the endoneurium marked reactive changes ensue, probably to protect the injured peripheral nerve.