Shangxi Fu

Alemtuzumab induction in renal transplantation: A meta-analysis and systemic review

OBJECTIVE To compare the efficacy and safety of alemtuzumab versus traditional antibodies for induction therapy in renal transplantation. METHODS Literature searches for all randomized controlled trials comparing alemtuzumab with traditional antibodies for post renal transplant induction therapy were performed using MEDLINE, EMBASE and the Cochrane Library. Quality assessment was performed in each trial. Meta-analyses were performed to demonstrate the pooled effects of relative risk (RR) with 95% confidence intervals (CI). RESULTS A total of 808 participants from six randomized controlled trials (RCTs) were included. Alemtuzumab was associated with lower incidence of biopsy-proven acute rejection over traditional antibodies (RR 0.63, CI 0.45-0.87, p=0.005). This difference remained when only studies comparing alemtuzumab with rabbit antithymocyte globulin were included (RR 0.32, CI 0.11-0.91, p=0.03), but lost significance when only patients at high-risk were included (RR 0.86, CI 0.48-1.55, p=0.62). No significant differences were detected between alemtuzumab and traditional antibodies in terms of delayed graft function, patient death, graft loss, and safety profile. CONCLUSIONS Alemtuzumab induction is superior to traditional antibodies in preventing AR in renal transplantation, but this benefit may not extend to recipients at high immunologic risk. The lower rejection rates do not translate into a uniform increase in graft or patient survival.

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

Suberoylanilide hydroxamic acid (SAHA), as a histone deacetylase (HDAC) inhibitor (HDACi), was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors (CNIs) to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus (FK506) in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA- and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon (IFN)-γ but increased IL-10 expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4+ T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORγt in these cells. Moreover, SAHA enhances suppressive function of regulatory T (Treg) cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.

Is it safe to withdraw steroids within seven days of renal transplantation

The safety of very early steroid withdrawal (VESW) in renal transplant recipients remains unclear.

Saha, an Hdac Inhibitor, Attenuates Antibody-mediated Allograft Rejection

Background Antibody-mediated rejection (AMR) is gaining increasing recognition as a critical causative factor contributing to graft loss in organ transplantation. However, current therapeutic options for prevention and treatment of AMR are very limited and ineffective. The impact of epigenetic modification in B-cell function and its involvement in AMR is still yet to be explored. Methods The impacts of suberoylanilide hydroxamic acid (SAHA), a histone deacetylase inhibitor, on isolated murine B-cell viability, proliferation, apoptosis, expression of surface marker, and secretion of immunoglobulin and interleukin-10 were investigated. In vivo, a murine cardiac transplant model was used to evaluate the effect of SAHA on splenic B-cell subsets and on AMR in Rag1-/- recipient mice after reconstitution of allostimulated B cells. Results SAHA possesses capability to repress B-cell function. Specifically, SAHA is potent to decrease the viability of isolated B cells by inducing apoptosis. SAHA was also found capable of suppressing the expression of B-cell costimulatory molecules and, as a result, addition of SAHA into the cultures attenuated B-cell proliferation and immunoglobulin secretion. In line with these results, administration of SAHA significantly suppressed AMR in Rag1-/- recipient mice after reconstitution of allostimulated B cells along with enhanced cardiac allograft survival time. Mechanistic studies revealed that SAHA promotes B-cell secretion of interleukin-10. Conclusions Our data support that SAHA could be a promising immunosuppressive agent with potential beneficial effect on prevention and treatment of AMR.

The argument for the use of mizoribine in renal transplantation: A meta-analysis and systemic review

OBJECTIVE The aim of this study is to evaluate the efficacy and safety of mizoribine (MZR) for immunosuppressive therapy in renal transplantation. METHODS A systematic search of the eligible studies that compared MZR with azathioprine (AZA) for post renal transplant immunosuppressive therapy was performed by using MEDLINE, EMBASE, and the Cochrane Library. Meta-analyses were performed to study the pooled effects of relative risk (RR) and weighted mean difference with 95% confidence intervals (CI). RESULTS A total of 486 participants from seven clinical trials were included. MZR demonstrated comparable efficacy in terms of acute rejection, patient/graft survival, and serum creatinine. However, MZR was associated with a significantly lower incidence of adverse events as compared with AZA (RR 0.39, CI 0.21-0.73, p=0.003). Specifically, recipients receiving MZR suffered from significantly fewer episodes of myelosuppression (RR 0.12, CI 0.02-0.54, p=0.006) and leukopenia (RR 0.20, CI 0.06-0.70, p=0.01). Also, MZR seemed to offer more favorable outcomes in terms of hepatic dysfunction, infection and diabetes, although the differences were not statistically significant. CONCLUSIONS MZR is a safe, well-tolerated and effective immunosuppressive agent that can be recommended as an alternative to AZA in renal transplant recipients, although further studies are needed to balance its effect with mycophenolate mofetil.

Applied Research on Laparoscopic Simulator in the Resident Surgical Laparoscopic Operation Technical Training

The purpose of this study was to estimate the effects of surgical laparoscopic operation course on laparoscopic operation skills after the simulated training for medical students with relatively objective results via data gained before and after the practice course of laparoscopic simulator of the resident standardized trainees. Experiment 1: 20 resident standardized trainees with no experience in laparoscopic surgery were included in the inexperienced group and finished simulated cholecystectomy according to simulator videos. Simulator data was collected (total operation time, path length, average speed of instrument movement, movement efficiency, number of perforations, the time cautery is applied without appropriate contact with adhesions, number of serious complications). Ten attending doctors were included in the experienced group and conducted the operation of simulated cholecystectomy directly. Data was collected with simulator. Data of two groups was compared. Experiment 2: Participants in inexperienced group were assigned to basic group (receiving 8 items of basic operation training) and special group (receiving 8 items of basic operation training and 4 items of specialized training), and 10 persons for each group. They received training course designed by us respectively. After training level had reached the expected target, simulated cholecystectomy was performed, and data was collected. Experimental data between basic group and special group was compared and then data between special group and experienced group was compared. Results of experiment 1 showed that there is significant difference between data in inexperienced group in which participants operated simulated cholecystectomy only according to instructors’ teaching and operation video and data in experienced group. Result of experiment 2 suggested that, total operation time, number of perforations, number of serious complications, number of non-cauterized bleeding and the time cautery is applied without appropriate contact with adhesions in special group were all superior to those in basic group. There was no statistical difference on other data between special group and basic group. Comparing special group with experienced group, data of total operation time and the time cautery is applied without appropriate contact with adhesions in experienced group was superior to that in special group. There was no statistical difference on other data between special group and experienced group. Laparoscopic simulators are effective for surgical skills training. Basic courses could mainly improve operator’s hand-eye coordination and perception of sense of the insertion depth for instruments. Specialized training courses could not only improve operator’s familiarity with surgeries, but also reduce operation time and risk, and improve safety.

Sirtinol regulates the balance of Th17/Treg to prevent allograft rejection

BackgroundCurrent immunosuppressive medications used after transplantation induce significant toxicity , and a new medication regimen is needed. Based on recent research, Sirt1 exerts a proinflammatory effect on the immune response. Sirtinol is a Sirt1 inhibitor, but its impact on allograft rejection and its molecular mechanisms of action have not yet been reported.ReslutsIn this study, we examined the effect of sirtinol on prolonging allograft survival in a mouse cervical heterotopic heart transplantation model. Based on an examination of the allograft, allografts from sirtinol-treated recipients show significantly lower levels of IL-17A expression and higher levels of Foxp3 expression. In vivo, sirtinol reduces the proportion of Th17 cells and increases the proportion of Treg cells in splenocytes from recipients. In vitro, sirtinol reduces the proportion of Th17 cells and decreases the expression of IL-17A and RORγt in an isolated CD4+ T cell population. Moreover, we identified synergistic effects of sirtinol and FK506 on prolonging allograft survival, and sirtinol synergizes with FK506 to promote Foxp3 expression.ConclusionSirtinol, a Sirt1 inhibitor, may be a promising immunosuppressive drug to prevent the rejection reaction in combination with FK506.

Intravenous prograf in maintenance treatment of intestinal obstruction complicated with hepatic function injury after renal transplantation: a case report

Abstract For renal transplant recipients, intestinal obstruction caused by incisional hernia is a rarely encountered event. Until now, there is no specific literature concerning the adjustment of immunosuppressants under such clinical condition. We present such a case who received a successful long-term single intravenous prograf administration to transitionally maintain the immunosuppression.