KLF4 Affects Acute Renal Allograft Injury via Binding to MicroRNA-155-5p Promoter to Regulate ERRFI1.

Kruppel-like factor 4 (KLF4) owns the promising potential in treating kidney injury, which inevitably occurs during renal allograft. Given that, this research targets to unveil KLF4-oriented mechanism from microRNA-155-5p/ERBB receptor feedback inhibitor 1 (miR-155-5p/ERRFI1) axis in acute renal allograft injury. Mice were injected with miR-155-5p-related sequences before acute renal allograft modeling. Afterwards, serum inflammation, along with oxidative stress, renal tubular injury, and apoptosis in renal tissues were detected. HK-2 cells were processed by hypoxia/reoxygenation (H/R) and transfected with miR-155-5p- or ERRFI1-related sequences, after which cell proliferation and apoptosis were measured. KLF4, miR-155-5p, and ERRFI1 expressions and their interaction were tested. KLF4 and miR-155-5p levels were enhanced, and ERRFI1 level was repressed in mice after acute renal allograft and in H/R-treated HK-2 cells. KLF4 bound to the promoter of miR-155-5p. Depleting miR-155-5p reduced serum inflammation and attenuated oxidative stress, renal tubular injury, and apoptosis in mice with acute renal allograft injury. Downregulating miR-155-5p facilitated proliferation and repressed apoptosis of H/R-treated HK-2 cells. miR-155-5p targeted ERRFI1. Knocking down ERRFI1 antagonized the effects of downregulated miR-155-5p on acute renal allograft injury, as well as on H/R-treated HK-2 cell proliferation and apoptosis. A summary displays that silencing KLF4 suppresses miR-155-5p to attenuate acute renal allograft injury by upregulating ERRFI1, which provides a way to control acute renal allograft injury.

Delayed graft function is correlated with graft loss in recipients of expanded-criteria rather than standard-criteria donor kidneys: a retrospective, multicenter, observation cohort study.

BACKGROUND: Although the use of expanded-criteria donors (ECDs) alleviates the problem of organ shortage, it significantly increases the incidence of delayed graft function (DGF). DGF is a common complication after kidney transplantation; however, the effect of DGF on graft loss is uncertain based on the published literature. Hence, the aim of this study was to determine the relationship between DGF and allograft survival. METHODS: We conducted a retrospective, multicenter, observation cohort study. A total of 284 deceased donors and 541 recipients between February 2012 and March 2017 were included. We used logistic regression analysis to verify the association between clinical parameters and DGF, and Cox proportional hazards models were applied to quantify the hazard ratios of DGF for kidney graft loss. RESULTS: Among the 284 deceased donors, 65 (22.8%) donors were ECD. Of the 541 recipients, 107 (19.8%) recipients developed DGF, and this rate was higher with ECD kidneys than with standard-criteria donor (SCD) kidneys (29.2% vs. 17.1%; P = 0.003). The 5-year graft survival rate was not significantly different between SCD kidney recipients with and without DGF (95.8% vs. 95.4%; P = 0.580). However, there was a significant difference between ECD kidney recipients with and without DGF (71.4% vs. 97.6%; P = 0.001), and the adjusted hazard ratio (HR) for graft loss for recipients with DGF was 1.885 (95% confidence interval [CI] = 1.305-7.630; P = 0.024). Results showed that induction therapy with anti-thymocyte globulin was protective against DGF (odds ratio = 0.359; 95% CI = 0.197-0.652; P = 0.001) with all donor kidneys and a protective factor for graft survival (HR = 0.308; 95% CI = 0.130-0.728; P = 0.007) with ECD kidneys. CONCLUSION: DGF is an independent risk factor for graft survival in recipients with ECD kidneys, but not SCD kidneys.

Application of Contrast-Enhanced Sonography on the Diagnosis of Acute and Chronic Rejection After Renal Transplantation.

To test the reliability of CEUS on the diagnosis of acute (AR) or chronic rejection (CR) after renal transplantation, patients who received renal transplantation in our center from January 2011 and December 2015 were retrospectively included in the current study. All the included patients underwent contrast-enhanced ultrasonography tests. Two regions of interests were chosen to carry out time-intensity curves (TICs). The main indexes include time indexes, intensity indexes, and difference indexes. Separation of TIC1 and TIC2 was evaluated by the authors. Results revealed that time to peak 1 (TTP-1), TTP-2, absolute time to peak 1 (ATTP-1), and ATTP-2 in the CR group were significantly later than those in the graft function stable group. Peak intensity 2 is smaller in the AR group than that in the GFS group, velocity of intensity ascending 2 is slower in the CR group than that in the GFS group, terminal intensity 1 (TI-1) and TI-2 are lower in the CR group than those in the GFS group, and Vd-1 is faster in the CR group than that in the GFS group (P < 0.05). Those results indicated that contrast-enhanced ultrasonography test can satisfactorily reflect the microcirculation of transplanted kidney and can be used to assist in the early diagnosis of graft rejection.

Donation after brain death followed by circulatory death, a novel donation pattern, confers comparable renal allograft outcomes with donation after brain death.

BACKGROUND: Organ donation after brain death (DBD) is the standard strategy for organ transplantation; however, the concept of brain death is not universally accepted due to cultural beliefs and barriers amongst billions of people worldwide. Hence, a novel donation pattern has been established in China which outlines the concept of donation after brain death followed by circulatory death (DBCD). Differently from any current donation classification, this new concept is formulated based on combination of recognizing brain death and circulatory death. Should approval be gained for this definition and approach, DBCD will pave a novel donation option for billions of people who cannot accept DBD due to their cultural beliefs. METHODS: A multi-center, cohort study was conducted from February 2012 to December 2015. 523 kidney transplant recipients from four kidney transplant institutions were enrolled into the study, of which, 383 received kidneys from DBCD, and 140 from DBD. Graft and recipient survivals following transplantation were retrospectively analyzed. Postoperative complications including delayed graft function,, and acute rejection, were also analyzed for both groups. RESULTS: DBCD could achieve comparable graft and recipient survivals in comparison with DBD (Log-rank P = 0.32 and 0.86,respectively). One-year graft and recipient survivals were equal between DBCD and DBD groups (97.4% versus 97.9%, P = 0.10;98.4% versus 98.6%, P = 1.0, respectively). Furthermore, DBCD did not increase incidences of postoperative complications compared with DBD, including delayed graft function (19.3% versus 22.1%, P = 0.46) and acute rejection (9.1% versus 8.6%, P = 1.0). Additionally, antithymocyte globulin as induction therapy and shorter warm ischemia time decreased incidence of delayed graft function in DBCD group (16.8% on antithymocyte globulin versus 27.2% on basiliximab, P = 0.03; 16.7% on ≤18 min versus 26.7% on > 18 min group, P = 0.03). CONCLUSIONS: Kidney donation through DBCD achieves equally successful outcomes as DBD, and could provide a feasible path to graft availability for billions of people who face barriers to organ donation from DBD.

New Factors Predicting Delayed Graft Function: a Multi-Center Cohort Study of Kidney Donation After Brain Death Followed by Circulatory Death.

BACKGROUND/AIMS: Delayed graft function (DGF) is a common complication following kidney transplantation adversely affecting graft outcomes. Donation after brain death followed by circulatory death (DBCD), a novel donation pattern, is expected to correlate with high incidence of DGF. However, little information is available about factors associated with DGF in DBCD. METHODS: A total of 383 kidney transplants from DBCD donation in three institutions were enrolled. Associations of DGF with the clinical characteristics of recipients and donors were quantified. RESULTS: In this retrospective multi-center study, the incidence of DGF was 19.3%. Lower incidence of DGF was found in recipients for whom antithymocyte globulin was used for induction (p < 0.05), which was an independent protective factor against DGF (odds ratio [OR] = 0.48; 95% CI 0.27-0.86). Two novel explicative variables were recognized as independent risk factors, including use of vasoactive drugs (OR = 3.15; 95% CI 1.39-7.14) and cardiopulmonary resuscitation (OR = 2.51; 95% CI 1.05-6.00), which contributed significantly to increased risk of DGF (p < 0.05). Prolonged warm ischemia time (> 18 min; OR = 2.42; 95% CI 1.36-4.32), was also predictive of DGF in DBCD. A prediction model was developed and achieved an area under the curve of 0.89 in predicting DGF when combined with reported parameters. CONCLUSION: The novel factors, confirmed for the first time in our study, will help to improve risk prediction of DGF and to determine optimal interventions to prevent DGF in clinical practice.

Clinical significance of myeloid-derived suppressor cells in human renal transplantation with acute T cell-mediated rejection.

Myeloid-derived suppressor cells (MDSCs) are negative regulators of the immune response and are in part responsible for the inhibition of the T cell-mediated immune response. A recent paper indicated that MDSCs were involved in prolonged allograft survival in animal models of transplantation, but the significance of MDSCs in human renal transplantation is still unknown. In our study, 50 patients with biopsy-proven acute T cell-mediated rejection (ATCMR) were included. The ratio of MDSCs in peripheral blood mononuclear cell (PBMC) was evaluated with FACS, and the patients were divided into the MDSCs high group (MDSCs, >10 %) or the MDSCs low group (MDSCs, <10 %). We compared the allograft function, severity of tissue injury, and long-time survival between the two groups. In the MDSCs high group, allograft function was significantly increased compared with the MDSCs low group. Furthermore, we found that isolated MDSCs from transplant recipients are capable of expanding regulatory T cell (Treg), meanwhile, inhibiting production of IL-17 in vitro. We also found that the ratio between Foxp3(+) and IL-17-producing CD4(+) T cells positively correlated with MDSCs frequency in PBMC. In conclusion, we demonstrated a potential role for MDSCs in prolonging allograft survival after ATCMR, and this was associated with higher CD4(+)Foxp3(+)/CD4(+)IL-17(+) ratio in PBMC.

Two-dose basiliximab compared with two-dose daclizumab in renal transplantation: a clinical study.

BACKGROUND: Addition of the interleukin-2 receptor (IL-2R) antagonists basiliximab or daclizumab to a calcineurin inhibitor-based regimen significantly reduces risk of acute rejection with a tolerability profile similar to a placebo. Use of a truncated two-dose regimen of daclizumab has been reported, but till date, there has been no controlled study of two-dose daclizumab vs. two-dose basiliximab. METHODS: Deceased-donor renal transplant recipients were randomized to basiliximab (20 mg on days 0 and 4) or daclizumab (50 mg on days 1 and 14) with cyclosporine, mycophenolate mofetil and corticosteroids. Flow cytometry was used to calculate the proportion of CD25(+) T cells in peripheral blood. RESULTS: Thirty patients were randomized to basiliximab and 28 to daclizumab. There was one patient death in each group, with no other graft losses. By six months, the incidence of biopsy-proven acute rejection was 0% with basiliximab vs. 21.4% with daclizumab (p < 0.05). Three patients in the daclizumab group required OKT3 for steroid-resistant rejection. There were no between-group differences in the incidence of infection. The proportion of CD25(+) T cells declined markedly during the first two wk in both groups, but was significantly lower in the basiliximab group during weeks six to eight. CONCLUSION: Two doses of basiliximab are more effective than two 1 mg/kg doses of daclizumab in preventing acute rejection in de novo renal transplant patients receiving cyclosporine, mycophenolate mofetil and corticosteroid maintenance therapy. In patients receiving relatively low-level immunosuppression in order to minimize toxicity, basiliximab may be preferable to a truncated daclizumab regimen.