Efficacy and safety of induction therapy with alemtuzumab in kidney transplantation： a meta-analysis

Background Alemtuzumab, a humanized CD52 monoclonal antibody, with its profound lymphocyte depletion property, was expected to be a promising induction therapy agent for kidney transplantation （KTx）. However, currently no consensus is available about its efficacy and safety. The aim of this meta-analysis was to make a profound review and an objective appraisal of this issue. Methods Relevant papers were searched, essentially in the PubMed database and the Cochrane library. After a thorough review, randomized controlled trials （RCTs） comparing the outcome of KTx using alemtuzumab induction therapy （test group） with a control group were collected according to the inclusion criteria. Data of general characteristic of studies and major outcomes of Ktx were extracted and meta-analyses were performed with RevMan 4.2 software. The odds ratio （OR） with a 95% confidence intervals （Co was the principle measurement of effect. Results Five RCTs were included. The chi square test showed no significant between-study heterogeneity, thus fixed effect model was employed. Sub-group analysis with studies including alemtuzumab induction followed by a tacrolimus-based immunosuppressive regimen showed that the acute rejection rate （ARR） was lower relative to the control （OR=0.59, 95% CI 0.34-1.01, P=0.05）. However, meta-analysis with all included studies revealed that neither ARR nor patient/graff survival rates differ significantly between the test and the control group, but the cytomegalovirus （CMV） infection rate was higher in the test group （OR 2.50, 95% CI 1.22-5.12, P=0.01）. A great number of the test group recipients safely remained on a regimen that was steroid-free and with a reduced dose of conventional immunosuppressive drugs. Conclusions Alemtuzumab induction therapy for KTx was an effective and safe protocol in the tested follow-up period. Steroid avoidance and a dose reduction of conventional immunosuppressive drugs after alemtuzumab induction therapy may have clinical importance. However, high quality RCTs with larger population and longer follow-up are needed for a more accurate and objective appraisal of this novel protocol.

PI-3 kinase pathway can mediate the effect of TGF-β1 in inducing the expression of SHARP-2 in LLC-PK1 cells

We aim to investigate the effect of transforming growth factor （TGF）-β1 on the expression of enhancer of split- and hairy-related protein-2 （SHARP-2） messenger RNA （mRNA） and its signaling pathway. In this study, several cell lines including LLC-PK1 （a porcine kidney tubular epithelial cell line）, MDCK （Madin-Darby canine kidney） and CTLL-2 （cytotoxic T-lymphocyte line） were treated with recombinant human TGF-131, and a series of experiments were carried out, involving Northern blot analysis of total RNA from these cells. Further, several specific chemical inhibitors were applied before TGF-β1 treatment to probe the signaling pathway. The results showed that TGF-β1 can significadtly up-regulate SHARP-2 mRNA expression in the LLC-PK1 cell line. The peak level of induction was found 2 h after TGF-β1 stimulation. While one phospho- inositide 3-kinases （PI-3） kinase inhibitor, LY294002, completely blocked the effect of TGF-131 on SHARP-2 mRNA expression in LLC-PK1 cells at a low concentration, other inhibitors, including PD98059, staurosporine, AG490, wortmannin, okadaic acid and rapamycin, had no effect. The effect of LY294002 was dose-dependent. We conclude that, in LLC-PK1 cells at least, TGF-β1 can effectively induce the SHARP-2 mRNA expression and that the PI-3 kinase pathway can mediate this effect.