Systematic Evaluation And Real World Study Of Adverse Reactions Of Tacrolimus In The Treatment Of Patients With Henoeh-sehonlein Purpura Nephritis

Objective:To analyze the adverse reactions of Tacrolimus(TAC)in the treatment of Henoch-Schonlein purpura nephritis(HSPN),and to provide reference for clinical rational drug use.Methods:First,a comprehensive search was conducted in CNKI,Wanfang Database,CBM,VIP,Pub Med,Cochrane Library and Embase databases.Literature was screened according to inclusion and exclusion criteria,and the software Rev Man5.3 and Stata14.0 were used for statistical analysis.Then the clinical data of 111 children with Henoch-Schonlein purpura nephritis admitted to Hebei Children’s Hospital from January 2014 to July2019 who were treated with Tacrolimus combined with glucocorticoid and followed up for at least 12 months was analyzed retrospectively.We calculated the incidence of total and various adverse drug reaction(ADR)and explored the relevant influencing factors.Results: 9 articles were finally included in this systematic evaluation.The outcome indicators of the study show:The total incidence of ADR in Henoch-Schonlein purpura nephritis treated with Tacrolimus was10.2%(95%CI:6.0%～15.3%),and the highest incidence of ADR was tremor or headache(3.7%,95%CI:0.5% ～ 8.8%),followed by gastrointestinal reactions(3.1%,95%CI:0.8%～6.4%).Subgroup analysis showed that,among the different types of research,the highest incidence of ADR was non-randomized current controlled trials,which was 15.6%(95%CI:9.8%～22.4%).The lowest incidence of ADR was randomized controlled trials,which was 5.4%(95%CI:2.2%～9.7%).The incidence of ADR of total adverse reactions in children was 9.5%(95%CI:5.2%～15.0%),which was lower than that of all ages(12.9%,95%CI:5.5% ～ 22.6%).The incidence of adverse reactions of the high dose group was 11.6%(95%CI:2.8%～24.3%),which was higher than that of the low dose group(8.7%,95%CI:5.0%～13.3%).The incidence of adverse reactions was no significantly lower in domestic TAC(5.4%,95%CI:2.2%～9.7%)than in imported TAC(19.5%,95%CI:12.2%～27.8%).According to different dose of glucocorticoid combined with Tacrolimus,the highest incidence of ADR was oral prednisone1-2mg/kg/d after intravenous methylprednisolone,which was 8.7%(95%CI:5.0% ～13.3%).The lowest incidence of ADR was oral prednisone0.5mg/kg/d,which was3.9%(95%CI:0.5%～13.5%).Analysis by pathological grade of HSPN,the lowest incidence of ADR was grades Ⅰ～Ⅲ(3.9%,95%CI:0.5%～13.5%),and the highest incidence of ADR was grades Ⅲ～Ⅴ(9.8%,95%CI:3.6%～18.2%).As a whole,with the aggravation of HSPN pathological grade,the incidence of adverse reactions increased.The difference of incidence of ADR among different study types,different population,different TAC dose,different dose of glucocorticoid combined with Tacrolimus and different pathological grade subgroups was statistically significant.In the real-world study,13 of 111 children with Henoch-Schonlein purpura nephritis had 17 adverse drug reactions.The total incidence of ADR was 11.71%.Among 17 adverse reactions,8 cases(7.21%)with hand tremor,4cases(3.60%)with decreased renal function,2 cases(1.80%)with elevated fasting blood glucose,2 cases(1.80%)with hypokalemia,and 1case(0.90%)with hypertension.The incidence of ADR in HSPN Ⅲ～IV was higher than that of grade I～II,but there was no significant difference in ADR incidence between different pathological grades.Adverse reactions occurred within 3 months after treatment.Conclusions: In systematic review,the total incidence of ADR in the clinical use of Tacrolimus to treat Henoch-Schonlein purpura nephritis was10.2%.The incidence of ADR was higher in adults,higher doses of TAC,high dose of glucocorticoid combined with Tacrolimus,patients with severe pathological grade.Based on real world study,the incidence of ADR was basically cansistent with the result of systematic review.In both studies,the most common adverse reaction was tremor.ADR tended to increase with the aggravation of pathological grade,and mainly occurred in the first 3months.In conclusion,the pathological grade of HSPN is the influencing factor of adverse reactions,and other influencing factors need to be confirmed by more researches.