Systematic Review Of Tacrolimus Versus CsA-ME In The Efficacy, Safety And Cost-Effective Analysis Of SPK Recipients, And Study Of Their Effect On The PSCs In Fibrosis

Objective simultaneous pancreas and kidney transplantation has been widely used in the treatment of typeⅠdiabetes and end-stage renal disease. With the lower episodes of acute rejection, chronic graft dysfunction (CGD) has been regarded as the obstacles disturbing graft long-term function, and the feature of CGD is the progressing fibrosis of parenchyma cell and dysfunction, but the mechanism is unclear. The immunosuppressant greatly improved the graft survival but its side effect becomes the stress and risk factor for CGD.With the wide acceptance of Tac and CsA-ME in SPK transplant recipients, the efficacy, safety and cost-effective of the two agents are unclear, the study was initiated based on the problem and our previous background.The side effect of immunosuppressant including Tac and CsA—ME can trigger CGD, and its relationship need to explore further, PSCs play a vital role in pancreas fibrosis only reported in pancreatitis and pancreatic cancer, we intiated our study on the PSCs influenced by the two agents.Methods 1) Relevant trials were obtained from the following sources: Cochrane Renal Group Specialised Register of RCTs, Cochrane Central Register of Controlled Trials (CENTRAL), and Medline (1994-2007.3), EMBASE (1994-2007.3), Conference proceedings and nephrology scientific meetings (from 1990 to present) etc. The search strategy described above was developed and performed to identify eligible studies. The search results were combined and all titles, abstracts, or where necessary the full text, were independently screened by two authors. In cases of disagreement between the two authors, the full article was obtained and inspected independently by a third author. We used the RevMan 4.2.10 to do the assessment. Heterogeneity was firstly analysed and subgroup analysis was initiated. Heterogeneity between trials results were tested using a standard Chi squared test and the 12 statistic (Higgins 2003).If clinical heterogeneity between trials, studies were only described. If homogeneity were bwteen trials, data were combined in fixed-effect meta-analyses. Sensitivity analyses (Random-effects meta-analyses) were used due to the heterogeneity from low quality study. For dichotomous outcomes (e.g. patients survival rates) results were expressed as relative risk (RR) with 95% confidence intervals (CI). Data were pooled using the random effects model but the fixed effects model was analyzed to ensure robustness of the model chosen and susceptibility to outliers. Where continuous scales of measurement were used to assess the effects of treatment, the weighted mean difference (WMD) was used.2) Established primary culture of Wistar rat pancreatic stellate cells, used perfusion method to obtain the pancreas, and enzyme digestion and gradient centrifugation.3) PSCs were incubated with tacrolimus and CsA-ME in different concentration and different period4) Used IHC to detect the protein expression of collagenⅠ, laminin, fibronectin.5) Administration of YS was to relieve the toxicity to PSCs.Results1) patients survival rates (1 year: RR=1.02, 95%CI 0.97-1.06, P=0.43; 3 years: RR=0.98, 95%CI 0.94-1.04, P=0.55) pancreas graft loss rates (1 year: RR=0.34, 95%CI 0.17-0.68, P=0.002; 3 years: RR=0.44, 95%CI 0.24-0.80, P=0.008) kidney graft loss rates (1 year: RR=0.57, 95%CI 0.21-1.58, P=0.28; 3 years: RR=0.76, 95%CI 0.29-1.97, P=0.57) rejection rates(l year: RR=1.65, 95%CI 0.24-11.28, P=0.61;3 years: RR=1.75, 95%CI 0.23-13.21, P=0.59) hospital stay (WMD=0.62, 95%CI 14.76-16.00, P=0.94)the cost of tacrolimus versus CsA-ME (WMD=387.47, 95%CI 290.01 to 484.93; WMD=315.45, 95%CI 226.31 to 404.59; WMD=315.45, 95%CI 226.31 to 404.59). Urinary tract infection at 1 and 3 years (WMD=0.97, 95%CI 0.68 to 1.36; WMD=0.95, 95%CI 0.69 to 1.30) Cytomegalovirus (infection and disease) at 1 and 3 years (WMD=0.96, 95%CI 0.65 to 1.41; WMD=0.99, 95%Cl 0.68 to 1.45)Peritonitis at 1 and 3 years (WMD=0.61, 95%CI 0.30 to 1.22; WMD=0.61, 95%CI 0.30 to 1.22)Number of patients receiving lipid-Iowering drugs at 3 years (WMD=0.87, 95%CI 0.46 to 1.65) Peripheral vascular event at 3 years (WMD=1.06, 95%CI 0.55 to 2.02) Cardiovascular event at 3 years (WMD=1.16, 95%CI 0.40 to 3.32) Cancer at 3 years (WMD=0.33, 95%CI 0.03 to 3.12)2) In the control group, low level of collagenⅠ, laminin, fibronectin was expressed in PSCs.3) In the concentration 70ng/ml,140ng/ml of Tac, 1.5ug/rnk 3ug/ml of CsA-ME: the expression of collagenⅠI, laminin, and fibronectin were significantly higher than control group, and there was no different in 4h, 8h, and 12h.4) The expression of collagenⅠ, laminin, fibronectin in CsA-ME were significantly higher than tacrolimus group in 4h, 8h, and 12h at the two concentrations.5) Administration of YS (1ug/ml) significantly reduced the expression of collagenⅠ, laminin, fibronectin to control level.Conclusion1) Tac is superior in pancreas graft loss, and trends to reduce the rejection rates, but has more than 43% cost compared to CsA-ME, There is no difference in patients survival rates, renal graft loss, adverse reaction rates, and hospital stay. It implys that Tac would be more favorable in the long-term survivl rates and quality of pancreas, but more expensive. 2) The excessive dosage of the two drugs both triggered the high expression of colleganⅠ, laminin, and fibronectin compared to control group, it iraplys that the two drugs both have the effect on fibrogenesis.3) The higher expression of collagenⅠ, laminin, fibronectin were higher in CsA-ME group in different time and concentration, it implys CsA-ME easily trigger fibrosis and cause CGD4) Administration of YS was effective to reduce the expression of collagenⅠ, laminin, fibronectin to control level, in terms of the effective outcome from our lab, YS maybe be regarded as a natural drug for transplantation.