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Synergistic impact of pre-sensitization and delayed graft function on allograft rejection in deceased donor kidney transplantation.

ABSTRACT: The aim of this study is to investigate whether or not delayed graft function (DGF) and pre-transplant sensitization have synergistic adverse effects on allograft outcome after deceased donor kidney transplantation (DDKT) using the Korean Organ Transplantation Registry (KOTRY) database, the nationwide prospective cohort. The study included 1359 cases between May 2014 and June 2019. The cases were divided into 4 subgroups according to pre-sensitization and the development of DGF post-transplant [non-pre-sensitized-DGF(-) (n = 1097), non-pre-sensitized-DGF(+) (n = 127), pre-sensitized-DGF(-) (n = 116), and pre-sensitized-DGF(+) (n = 19)]. We compared the incidence of biopsy-proven allograft rejection (BPAR), time-related change in allograft function, allograft or patient survival, and post-transplant complications across 4 subgroups. The incidence of acute antibody-mediated rejection (ABMR) was significantly higher in the pre-sensitized-DGF(+) subgroup than in other 3 subgroups. In addition, multivariable cox regression analysis demonstrated that pre-sensitization combined with DGF is an independent risk factor for the development of acute ABMR (hazard ratio 4.855, 95% confidence interval 1.499-15.727). Moreover, DGF and pre-sensitization showed significant interaction (p-value for interaction = 0.008). Pre-sensitization combined with DGF did not show significant impact on allograft function, and allograft or patient survival. In conclusion, the combination of pre-sensitization and DGF showed significant synergistic interaction on the development of allograft rejection after DDKT.

SUBMITTER: Lee H

PROVIDER: S-EPMC8352860 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Several recipient biomarkers are reported to predict graft dysfunction, but these are not useful in decision making for the acceptance or allocation of deceased donor kidneys; thus, it is necessary to develop donor biomarkers predictive of graft dysfunction. To address this issue, we prospectively enrolled 94 deceased donors and their 109 recipients who underwent transplantation between 2010 and 2013 at 4 Korean transplantation centers. We investigated the predictive values of donor urinary neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), and L-type fatty acid binding protein (L-FABP) for reduced graft function (RGF). We also developed a prediction model of RGF using these donor biomarkers. RGF was defined as delayed or slow graft function. Multiple logistic regression analysis was used to generate a prediction model, which was internally validated using a bootstrapping method. Multiple linear regression analysis was used to assess the association of biomarkers with 1-year graft function. Notably, donor urinary NGAL levels were associated with donor AKI (P = 0.014), and donor urinary NGAL and L-FABP were predictive for RGF, with area under the receiver-operating characteristic curves (AUROC) of 0.758 and 0.704 for NGAL and L-FABP, respectively. The best-fit model including donor urinary NGAL, L-FABP, and serum creatinine conveyed a better predictive value for RGF than donor serum creatinine alone (P = 0.02). In addition, we generated a scoring method to predict RGF based on donor urinary NGAL, L-FABP, and serum creatinine levels. Diagnostic performance of the RGF prediction score (AUROC 0.808) was significantly better than that of the DGF calculator (AUROC 0.627) and the kidney donor profile index (AUROC 0.606). Donor urinary L-FABP levels were also predictive of 1-year graft function (P = 0.005). Collectively, these findings suggest donor urinary NGAL and L-FABP to be useful biomarkers for RGF, and support the use of a new scoring system based on donor biomarkers to facilitate decision-making in acceptance and allocation of deceased donor kidneys and contribute to maximal organ utilization.

Project description:BackgroundUsing kidneys from deceased donors is an available strategy to meet the growing need of grafts. However, higher incidences of delayed graft function (DGF) and acute rejection exert adverse effects on graft outcomes. Since ischemia-reperfusion injury (IRI) and ongoing process of immune response to grafts are the major causes of DGF and acute rejection, the optimal induction intervention should possess capacities of both repairing renal structure injury and suppressing immune response simultaneously. Mesenchymal stem cells (MSCs) with potent anti-inflammatory, regenerative and immune-modulatory properties are considered as a candidate to prevent both DGF and acute rejection in renal transplantation. Previous studies just focused on the safety of autologous MSCs on living-related donor renal transplants, and lack of concomitant controls and the sufficient sample size and source of MSCs. Here, we propose a prospective multicenter controlled study to assess the clinical value of allogeneic MSCs in preventing both DGF and acute rejection simultaneously as induction therapy in deceased-donor renal transplantation.Methods/designRenal allograft recipients (n = 100) will be recruited and divided into trial and control groups, and 50 patients in the trial group will be administered with a dose of 2 × 106 per kilogram human umbilical-cord-derived MSCs (UC-MSCs) via peripheral vein injection preoperatively, and a dose of 5 × 106 cells via renal arterial injection during surgery, with standard induction therapy. Incidences of postoperative DGF and biopsy-proved acute rejection (BPAR) will be recorded and analyzed. Additionally, other clinical parameters such as baseline demographics, graft and recipient survival and other severe postoperative complications, including complicated urinary tract infection, severe pneumonia, and severe bleeding, will be also assessed.DiscussionThis study will clarify the clinical value of UC-MSCs in preventing DGF and acute rejection simultaneously in deceased-donor renal transplantation, and provide evidence as to whether allogeneic MSCs can be used as clinically feasible and safe induction therapy.Trial registrationClinicalTrials.gov, NCT02490020 . Registered on 29 June 2015.

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Synergistic impact of pre-sensitization and delayed graft function on allograft rejection in deceased donor kidney transplantation.

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