| ObjectivesThis study is aimed to conduct a systematic evaluation on the safety(nephrotoxicity)of Tripterygium Wilfordii Hook.f(TWP)preparations through a method combined bibliometrics research with evidence-based evaluation research,to provide evidence-based safety information of the TWP preparationss(nephrotoxicity)for the government decision-making and clinical application,and to provides methods and suggestions for evaluating nephrotoxicity of Chinese Herbal medicine(CHM)in the future.Methods1.Nephrotoxicity of Chinese Herbal medicine:a bibliometrical studyIn our study,we defined nephrotoxicity as all adverse reactions related to kidney caused by all CHM such as kidney failure,renal insufficiency,hematuresis,oliguria,creatinine elevation,urea nitrogen elevation etc.Overseas study:Two English databases including Pubmed and Cochrane library were systematically searched form their inception to January 1st,2017.The study type is not limited.All potential CHM with nephrotoxicity in overseas research were included.Domestic study:We searched China Food and Drug Administration(CFDA)adverse drug reaction monitoring center database form the first-phase published "adverse drug reaction information notifications(June 26th,2008)" to January 1st,2017,and screened all the reports about nephrotoxicity of CHM.We concluded results of the bibliometrical study,and found out the CHM with potential risk of nephrotoxicity currently reported much in foreign and domestic studies,and take them as the objects of the evaluation study on nephrotoxicity system.2.Systematic evaluation research on nephrotoxicity of TWP preparationsBased on the bibliometrical studies,we selected TWP preparations and made a systematic review on the nephrotoxicity of TWP preparations.Six Chinese and English databases including CNKI,SinoMed,VIP,Wanfang,Pubmed,and Cochrane library were systematically and comprehensively searched.We collected all types of research documents about the nephrotoxicity of TWP preparations.We screened the literature and extracted data based on inclusion and exclusion criteria.The methodology quality of all included studies were assessed by internationally recognized evaluation tools or standards.R software was adopted to make a Meta-analysis of the incidence of nephrotoxicity of TWP preparations.Subgroup analysis will be conducted according to the type of disease treated,drug deliverly way,and medication time.3.Report quality evaluation on nephrotoxicity of TWP preparations in RCTsAccording to CONSORT HARMS(Better RePorting of Harms in Randomized Trials:An ExtGnsion Of the CONSORT Statement),we evaluated the report quality of included RCTS on nephrotoxicity of the TWP preparations,and calculated each item conforming to CONSORT statement extended,evaluated the report quality of related adverse reactions of TWP preparations' nephrotoxicity in RCT,to conclude the related adverse reaction problem of nephrotoxicity in domestic researches.4.The application of rapid review method in the study of nephrotoxicity of TWP preparationsWe used four methods to search the relevant studies on nephrotoxicity of TWP.The first method was not to limit any search terms,which was,adopted the classic searching method of systematic review.The second way,the relevant search terms of TWP were limited to "CFDA approved the listing of all CHMs containing TWP.The third one was to limit related retrieval terms of nephrotoxicity as the most frequently reported terms related to nephrotoxicity found in the second part of screening process.The fourth method was to limit the TWP and nephrotoxicity-related search terms.Finally,the results of the last three search methods were compared with the first search method,and the feasibility of the rapid review method in the study of nephrotoxicity of CHM was discussed.Results1.Nephrotoxicity of traditional Chinese medicine:a bibliometrical studyEnglish literature:We initially retrieved 243 documents and excluded 215 documents about related adverse reactions of non-CHM and non-nephrotoxicity after screening.Totally 28 articles were included,including 1 cohort study,1 case series,15 case reports,9 animal experiment and 2 vitro studies.The publishing time was from 1989 to 2015,2 articles were about kidney disease,8 articles about other diseases,4 articles about healthy people,and 3 articles did not report which kind of disease was studied.There were 97 kinds of single Chinese herb and Chinese medicinal formulae with nephrotoxicity in the report,of which the top 6 kinds of CHMs with nephrotoxicity risk were as follews:acid-containing herbs(5 articles),TWP(4 articles),Atractylodes Lancea(Thunb.)DC.(2 articles),Ephedra sinica Stapf(2 articles),and Rheum palmatum L(2 articles).The remaining 91 kinds of CHMs with nephrotoxicity risk was report once.Chinese literature:CFDA adverse drug reaction monitoring center database began to report since June 26th,2008,the reported earliest adverse reaction of TWP preparations can be traced back to 2004.Till January 1st,2017,CFDA adverse drug reaction monitoring center database has reported 73 times about adverse reactions in total(the patients involved with adverse reactions of TWP preparations were 839 cases in total),among which there were 32 reports related to nephrotoxicity mvolving 16 kinds of CHMs with nephrotoxicity risk.The release time was from 2008 to 2015.Therein,the instruction of TWP preparations indicates it was applicable to kidney disease,the instruction of 12 kinds of CHMs indicate it was applicable to other diseases,and 3 kinds of CHMs' instruction can not be found,so their adaptation diseases are indeterminacy.In conclusion,nephrotoxicity on acid-containing herbs and TWP preparations were studied most in Chinese and English literature.2.Systematic evaluation research on nephrotoxicity of TWP preparationsAfter the retrieval of CFDA domestic drug database,there were 58908 kinds of Chinese patent medicines approved to market by the CFDA currently,among which 26 Chinese patent medicines contain TWP ingredients.We searched the 6 databases and retrieved 4775 articles about these 26 Chinese patent medicines.After excluding non-CHM articles and papers without reporting adverse reactions through screening,totally 36 studies were included.The included studies involved 2017 participants,among which 1573 used TWP preparations.The study types included RCT,CCT,case series and case reports.A meta analysis of 28 studies involving 1999 participants were conducted,of which the research types were RCT,CCT and case series,and 93 used TWP preparations.The result showed that the nephrotoxicity prevalence of TWP preparations was 5.81%(95%CI:[4.43%;7.57%]).The pooled result of 13 studies with control group showed that there was no significant difference in renal toxic risk between TWP preparations group and control group(OR=2.16,95%CI:0.89-5.27,random effect model).Subgroup analysis showed that there was no significant difference in prevalence rate according to diseases(kidney diseases versus other diseases when treated by TWP preparations),medicine type(single medicine versus compound medicine),and duration(within 3 months versus 3-12 months versus more than 12 months).According to the 26 kinds of Chinese patent medicines for retrieval,initially retrieved 4775 articles,after screening,exclude the research on non-TCM and unreported adverse reaction,36 studies are included in total,whose research type includes RCT,CCT,case series,and case reports,involving 2017 research subjects,among which there were 1573 case using TWP preparations.There were 28 studies in total,we took 1999 subjects into meta-analysis,whose research type includes RCT,CCT and case series,of which 93 patients are treated with TWP preparations.The results showed that the incidence rate of nephrotoxicity in TWP preparations was5.81%(95%CI:[4.43%;7.57%]).The results of subgroup analysis showed that there was no statistical significance of renal toxic incidence rate between the treatment of kidney disease and the treatment of other diseases by TWP preparations,between single pharmacy and combined pharmacy,medication time within three months,3-12 months and over 12 months.3.Report quality evaluation on RCT nephrotoxicity of TWP preparationsThe overall report quality of related RCTs on nephrotoxicity of TWP preparations was poor,and each research only conformed to seven items of CONSORT HARMs.The most inadequate reporting items were:which method was used to judge nephrotoxicity attributed to TWP preparations,the impossibility to judge nephrotoxicity was attributed to TWP,as well as manufacturers without reported drug(mainly due to different drugs components of different manufacturers),the name of drug combination,and syndrome differentiation of the research object.We Suggest that the future relevant studies on adverse reactions of TCM should strictly follow the suggested items of CONSORT extended statement to make a detailed report.In terms of TCM decoction,-composition herbs,dosage,medication method,and medication time should be reported;For Chinese patent medicine,the detailed report includes drug production manufacturers,batch number,dosage,usage,and medication time;The syndrome differentiation type and the standards for syndrome differentiation should be detailed.4.The application of rapid review method in the study of nephrotoxicity of TWP preparationsThe total number of literature searched:The result of unrestricted the searching terms:A total of 10024 articles were retrieved.The result of limiting the related search terms of TWP:A total of 4775 articles were were retrieved.The result of limiting the related search terms of nephrotoxicity;A total of 4790 articles were retrieved.The result of limiting both the related search terms of TWP and nephrotoxicity:A total of 1594 articles were retrieved.The number of articles that meets the inclusion criteria:The included literatures of the four kinds of search methods were 32 articles,36 articles,32 articles,and 34 articles.There was no significant difference between them.The type of studies included:The result of unrestricted the searching terms:including 15 RCTs,1 CCT,4 case series and 12 case reports.The result of limiting the related search terms of TWP:Compared with the first searching strategy,additional one RCT,two case series and one case report were detected,and the search results were more comprehensive than the unqualified search terms.The result of limiting the related search terms of nephrotoxicity:Compared with the first searching strategy,one case report was missed,and the coincidence degree was high.The result of limiting both the related search terms of TWP and nephrotoxicity:Compared with the search results of the unrestricted search method,additional one RCT,two case series and one case report were detected;one case report was missed,and the coincidence degree was high.Because the case report can not do meta-analysis,we think that the latter three methods of limiting the search terms are adopted the classic searching method of systematic review.While the mothed of limiting both the related search terms of TWP and nephrotoxicity is best because it is not only consistent with the results,but it can minimize the workload.ConclusionsNephrotoxicity of CHM is a problem that cannot be ignored.At present,in addition to the aristolochic acid containing herbs,the most reported herbs with nephrotoxicity risk was TWP preparations.The incidence of nephrotoxicity of TWP preparations was 5.81%._However,we did not include studies that reported no adverse reactions_and the inclusion of a small number of literatures,the sample size was small,so even if there was a positive conclusion,it may be due to the chance.In this case,the incidence of renal toxicity of Tripterygiumwilfordii preparations may be overestimated.Subgroup analysis showed that there was no significant correlation among the therapeutic disease type,different medication way,medication time and incidence rate of nephrotoxicity.However,due to the small number of the included studies,the research type most on case series,poor quality of methodology,and other reasons,the affirmative conclusion cannot be acquired.We suggest that the future relevant study on adverse reactions of CHM,should strictly follow the suggested items of CONSORT HARMS to make a detailed report.Rapid review method in the study of CHM nephrotoxicity is feasible.For the study of nephrotoxicity in CHM,the recommended search strategy is as follows:#1 Search terms related to Chinese medicine[tiab]/[mh]#2 Nephrotoxicity OR renal injury OR renal function injury OR abnormal renal function OR renal insufficiency OR kidney failure OR urea nitrogen elevation OR creatinine elevation OR hematuria OR oliguria#3 poisoning[ti]#4 animals[mh]NOT humans[mh]#5#2 OR#3#6#1 AND#5#7#6 NOT#4... |
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