含钆对比剂与肾源性系统性纤维化关联度变化趋势的Meta分析及因果解析

The change of association between nephrogenic systemic fibrosis and gadolinium-based contrast agents:an updated meta-analysis applying Hill's criteria

目的：探讨含钆对比剂（gadolinium-based contrast agents, GBCAs）与肾源性系统性纤维化（nephrogenic systemic fibrosis, NSF）二者之间是否为因果相关以及关联强度随时间变化的趋势。材料与方法检索PubMed、Wiley Online Library、Cochrane Library数据库。采用R软件进行统计学分析，计算OR值及95%CI，并进行累积Meta分析，采用希尔标准（Hill’s criteria）证明是否为因果相关。结果本研究共纳入14篇文献，6398例患者，其中3篇由于NSF发生例数为0而未能纳入最后的定量分析。Meta分析结果显示，钆对比剂暴露可能会增加肾源性系统性纤维化发生的风险（OR=16.50，95%CI：7.46～36.53，P＜0.01），其中包括钆双胺（OR=20.04，95%CI：3.72～107.78，P＜0.01）。希尔标准相关证据基本达到，表明二者之间为因果关系。累积Meta分析结果显示自2007年之后OR值呈减小趋势。结论钆对比剂暴露与肾源性系统性纤维化之间较强相关，且该相关性为因果关系，其关联强度在2007年之后较明显减弱。

Objective：To examine whether a causal link exists between gadolinium-based contrast agents （GBCAs） and nephrogenic systemic ifbrosis （NSF） and if the link changes over time. Materials and Methods：Studies for analysis were identiifed by searching the PubMed, the Wiley Online Library, and the Cochrane Central Register of Controlled Trials up to December 18, 2014. Pooled odds ratios （OR） with 95%conifdence intervals （CI） was calculated by using the ifxed-effects model. Statistical heterogeneity was assessed by Cochrane’s Q test and I2 statistics. Publication bias was evaluated using peters test, funnel plots and fail-safe N. Quality assessment of included studies using Newcastle-Ottawa Scale （NOS）. Inlfuence analysis and cumulative meta –analysis were also conducted in this study. All statistical analyses were performed by R software （R Core Team. R：A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL http：//www.R-project. org, 2014）. Hill’s criteria was used to evaluate evidence in support of a potential causal link between GBCAs and NSF. Results：A total of 14 studies including 6398 patients met the inclusion criteria, but 3 was excluded since they reported no NSF events. Meta-analysis of controlled trials indicated the GBCAs exposure may signiifcantly increase the risk of NSF （OR=16. 50, 95%CI：7.46-36.53, P〈0.01） and gadodiamide exposure may also increase the risk of NSF （OR=20.04, 95%CI： 3.72-107.78, P〈0.01）. No heterogeneity （P=0. 819, I2=0%;P=0. 873, I2=0%, respectively） was observed across studies. Hill’s criteria suggested a potential causal link between GBCAs and NSF. In addition, the cumulative analysis demonstrated that the pooled ORs for GBCAs and NSF decreased post-2007 compared to pre-2007 （OR=26.71;95%CI：10.27-69.44）. Conclusions：Although this meta-analysis suggests a strong association and potentially causal relation between GBCAs exposure and the incidence of NSF in patients with renal insufficiency, the relation decreased after 2007. More studies are warranted to examine the potential association between GBCAs other than gadodiamide and NSF.