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Article(id=1200147841042706791, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147837586604797, articleNumber=1001-2494(2024)10-0945-06, orderNo=null, doi=10.11669/cpj.2024.10.012, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1690905600000, receivedDateStr=2023-08-02, revisedDate=null, revisedDateStr=null, acceptedDate=null, acceptedDateStr=null, onlineDate=1764067142973, onlineDateStr=2025-11-25, pubDate=1716307200000, pubDateStr=2024-05-22, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1764067142973, onlineIssueDateStr=2025-11-25, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1764067142973, creator=13701087609, updateTime=1764067142973, updator=13701087609, issue=Issue{id=1200147837586604797, tenantId=1146029695717560320, journalId=1190317699101192196, year='2024', volume='59', issue='10', pageStart='857', pageEnd='950', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1764067142149, creator=13701087609, updateTime=1764067345188, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1200148689244225889, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147837586604797, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1200148689244225890, tenantId=1146029695717560320, journalId=1190317699101192196, issueId=1200147837586604797, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=945, endPage=950, ext={EN=ArticleExt(id=1200147841420194152, articleId=1200147841042706791, tenantId=1146029695717560320, journalId=1190317699101192196, language=EN, title=Development and Validation of a Risk Prediction Model for Tacrolimus Blood Concentration Failure, columnId=null, journalTitle=Chinese Pharmaceutical Journal, columnName=null, runingTitle=null, highlight=null, articleAbstract=

OBJECTIVE To analyze the influencing factors of tacrolimus (FK506) blood concentration non-attainment in renal transplant patients and construct a risk prediction column-line diagram model. METHODS Two hundred patients admitted to the hospital from June 2020 to June 2023 who were treated with FK506 after renal transplantation and whose blood concentration was monitored for 30 d were selected for the study, and according to the monitoring results, they were categorized into 126 cases in the group of meeting the standard (5-15 μg·L-1) and 74 cases in the group of failing to meet the standard (<5 μg·L-1 or>15 μg·L-1), and the clinical data were collected, and independent risk factors for failing to meet the standard of FK506 were screened and fit into a predictive model by single-factor and multifactorial logistic regression analysis. Clinical data of the two groups were collected, and the independent risk factors for FK506 blood concentration non-compliance were screened by single-factor and multifactor logistic regression analyses, according to which, a prediction model for the risk of FK506 blood concentration non-compliance was constructed with a line graph and tested for goodness-of-fit. RESULTS Of the 1 200 FK506 concentration monitoring sessions in 200 patients within 30 d after surgery, the number of sessions in which the target concentration of 5-15 μg·L-1 was reached was 756, with an attainment rate of 63.0%. A total of 126 patients reached the target concentration (target group), and 74 patients did not reach the target concentration (non-target group). The proportion of patients with age >60 years, male, intravenous, fasting blood glucose (FPG) >7 mmol·L-1, total bilirubin (TB) >20 μmol·L-1, white blood cell count (WBC)≤4×109·L-1, and blood creatinine (Cr) >133 μmol·L-1 was higher in the non-attainment group than in the attainment group, and the difference was statistically significant (P<0.05). Multifactorial logistic regression analysis was performed, and the results showed that age >60 years, male, FPG>7 mmol·L-1, TB>20 μmol·L-1, and Cr>133 μmol·L-1 were independent risk factors for substandard FK506 blood concentration in renal transplant patients (all P<0.05). The AUC of the constructed column-line graph model reached 0.859 (0.795-0.924), the model calibration curve validation C-index was 0.836, and the H-L deviation test χ2=4.203, P=0.516, the calibration curve was basically the same as the ideal curve trend, with a good degree of precision and differentiation. DCA analysis showed that the column-line graph prediction model displayed a large range of threshold probabilities (0.05 to 0.95), which corresponded to the largest area of the red curve to the gray curve and the horizontal axis, indicating a better clinical utility value of the model. CONCLUSION Age >60 years, male, FPG >7 mmol·L-1, TB >20 μmol·L-1, and Cr >133 μmol·L-1 are the risk factors for substandard FK506 blood concentration in renal transplantation patients, and the column-line graph model constructed accordingly can effectively predict the degree of risk for substandard FK506 blood concentration in renal transplantation patients.

, correspAuthors=Shuzhang DU, authorNote=null, correspAuthorsNote=null, copyrightStatement=null, copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, authorCompany=null, fund=null, authors=null, authorsList=Zeng LI, Zhao YIN, Shuzhang DU), CN=ArticleExt(id=1200147843081138570, articleId=1200147841042706791, tenantId=1146029695717560320, journalId=1190317699101192196, language=CN, title=他克莫司血药浓度不达标风险预测模型的建立及验证, columnId=1190352405612040510, journalTitle=中国药学杂志, columnName=论著, runingTitle=null, highlight=null, articleAbstract=

目的 分析肾移植患者他克莫司(FK506)血药浓度不达标的影响因素,并构建风险预测列线图模型。方法 选取2020年6月至2023年6月医院收治的肾移植术后服用FK506治疗并监测30 d内血药浓度的200例患者为研究对象,根据监测结果将其分为达标组(5~15 μg·L-1)126例和未达标组(<5 μg·L-1或>15 μg·L-1)74例,收集两组患者的临床资料,采用单因素和多因素Logistic回归分析筛选FK506血药浓度不达标的独立危险因素,据此构建FK506血药浓度不达标的风险列线图预测模型并进行拟合优度检验。结果 术后30 d内200例患者的1 200次FK506浓度监测中,达到目标浓度5~15 μg·L-1的次数为756次,达标率为63.0%。其中达到目标浓度的患者共126例(达标组),未达到目标浓度的患者共74例(未达标组)。未达标组年龄>60岁、男性、静脉注射、空腹血糖>7 mmol·L-1、总胆红素>20 μmol·L-1、白细胞计数≤4×109·L-1、血肌酐>133 μmol·L-1的患者比例均高于达标组,差异有统计学意义(P<0.05)。多因素Logistic回归分析,结果显示,年龄>60岁、男性、空腹血糖>7 mmol·L-1、总胆红素>20 μmol·L-1、血肌酐>133 μmol·L-1为肾移植患者FK506血药浓度不达标的独立危险因素(均P<0.05)。构建的列线图模型AUC达到0.859(0.795~0.924),模型校准曲线验证C-index为0.836,H-L偏差度检验χ2=4.203,P=0.516,校正曲线与理想曲线走势基本一致,精准度和区分度良好,决策曲线(DCA)分析显示,列线图预测模型显示的阈值概率(0.05~0.95)范围较大,其对应红色曲线到灰色曲线和横坐标轴的面积最大,表明模型临床效用价值较好。结论 年龄>60岁、男性、空腹血糖>7 mmol·L-1、总胆红素>20 μmol·L-1、血肌酐>133 μmol·L-1是肾移植患者FK506血药浓度不达标的危险因素,据此构建的列线图模型能有效预测肾移植患者FK506血药浓度不达标风险程度。

, correspAuthors=杜书章, authorNote=null, correspAuthorsNote=
*杜书章,男,主任药师 研究方向:药物经济学、医院药学 Tel:(0371)66913047
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李增,男,本科,主管药师 研究方向:医院药学

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Gastroenterology, 2021, 160(4):1151-1163., articleTitle=Protective role of tacrolimus, deleterious role of age and comorbidities in liver transplant recipients with Covid-19: Results from the ELITA/ELTR multi-center european study, refAbstract=null), Reference(id=1200147849905271419, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, doi=null, pmid=null, pmcid=null, year=2022, volume=42, issue=2, pageStart=94, pageEnd=105, url=null, language=null, rfNumber=[16], rfOrder=15, authorNames=TORNATORE K M, MEANEY C J, ATTWOOD K, journalName=Pharmacotherapy, refType=null, unstructuredReference=TORNATORE K M, MEANEY C J, ATTWOOD K, et al. Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients[J]. Pharmacotherapy, 2022, 42(2):94-105., articleTitle=Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients, refAbstract=null), Reference(id=1200147850064654977, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, doi=null, pmid=null, pmcid=null, year=2022, volume=19, issue=6, pageStart=371, pageEnd=375, url=null, language=null, rfNumber=[17], rfOrder=16, authorNames=JI J J, WANG C J, ZHA L, journalName=Chin J Drug Appl Mon(中国药物应用与监测), refType=null, unstructuredReference=JI J J, WANG C J, ZHA L, et al. Analysis of innuence factors of tacrolimus concentration in patients with nephrotic syndrome[J]. 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Organ Transplant(器官移植), 2019, 10(1):1-9., articleTitle=Technical Specification for Diagnosis and Treatment of Post-transplant Diabetes in China (2019), refAbstract=null), Reference(id=1200147850307924614, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, doi=null, pmid=null, pmcid=null, year=2022, volume=13, issue=6, pageStart=776, pageEnd=782, url=null, language=null, rfNumber=[19], rfOrder=18, authorNames=WANG Z Y, DONG C, WANG H Y, journalName=Organ Transplant(器官移植), refType=null, unstructuredReference=WANG Z Y, DONG C, WANG H Y, et al. Correlation between tacrolimus and diabetes mellitus after kidney transplantation: a single center study[J]. Organ Transplant(器官移植), 2022, 13(6):776-782., articleTitle=Correlation between tacrolimus and diabetes mellitus after kidney transplantation: a single center study, refAbstract=null), Reference(id=1200147850408587913, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, doi=null, pmid=null, pmcid=null, year=2022, volume=29, issue=4, pageStart=440, pageEnd=443, url=null, language=null, rfNumber=[20], rfOrder=19, authorNames=LU Y X, CHEN L, ZOU D Y, journalName=Chin J Integr Tradit West Med Intensive Crit Care(中国中西医结合急救杂志), refType=null, unstructuredReference=LU Y X, CHEN L, ZOU D Y, et al. Influence of Hugan tablets, a traditional Chinese medicine preparation, on metabolism of tacrolimus in liver transplantation recipients and its drug safety and economic evaluation[J]. Chin J Integr Tradit West Med Intensive Crit Care(中国中西医结合急救杂志), 2022, 29(4):440-443., articleTitle=Influence of Hugan tablets, a traditional Chinese medicine preparation, on metabolism of tacrolimus in liver transplantation recipients and its drug safety and economic evaluation, refAbstract=null), Reference(id=1200147850496668301, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, doi=null, pmid=null, pmcid=null, year=2023, volume=8, issue=23, pageStart=S1569, pageEnd=7, url=null, language=null, rfNumber=[21], rfOrder=20, authorNames=TACHTATZIS P, SPOLETINI G, CLIFTON I, journalName=J Cyst Fibros, refType=null, unstructuredReference=TACHTATZIS P, SPOLETINI G, CLIFTON I, et al. Changes in liver biochemistry and tacrolimus levels following the introduction of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and liver transplant[J]. J Cyst Fibros, 2023, 8:S1569- 1993(23)00129-7., articleTitle=Changes in liver biochemistry and tacrolimus levels following the introduction of elexacaftor/tezacaftor/ivacaftor in patients with cystic fibrosis and liver transplant, refAbstract=null), Reference(id=1200147850597331600, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, doi=null, pmid=null, pmcid=null, year=2022, volume=535, issue=null, pageStart=131, pageEnd=139, url=null, language=null, rfNumber=[22], rfOrder=21, authorNames=FRANCKE M I, VAN DOMBURG B, BOUARFA S, journalName=Clin Chim Acta, refType=null, unstructuredReference=FRANCKE M I, VAN DOMBURG B, BOUARFA S, et al. The clinical validation of a dried blood spot method for simultaneous measurement of cyclosporine A, tacrolimus, creatinine, and hematocrit[J]. Clin Chim Acta, 2022, 535:131-139., articleTitle=The clinical validation of a dried blood spot method for simultaneous measurement of cyclosporine A, tacrolimus, creatinine, and hematocrit, refAbstract=null), Reference(id=1200147850685411987, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, doi=null, pmid=null, pmcid=null, year=2022, volume=105-106, issue=null, pageStart=25, pageEnd=34, url=null, language=null, rfNumber=[23], rfOrder=22, authorNames=MATHEW B S, MATHEW S K, ARULDHAS B W, journalName=Clin Biochem, refType=null, unstructuredReference=MATHEW B S, MATHEW S K, ARULDHAS B W, et al. Analytical and clinical validation of dried blood spot and volumetric absorptive microsampling for measurement of tacrolimus and creatinine after renal transplantation[J]. Clin Biochem, 2022, 105-106:25-34., articleTitle=Analytical and clinical validation of dried blood spot and volumetric absorptive microsampling for measurement of tacrolimus and creatinine after renal transplantation, refAbstract=null)], funds=null, companyList=[AuthorCompany(id=1200147843324408216, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, xref=null, ext=[AuthorCompanyExt(id=1200147843332796825, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, companyId=1200147843324408216, language=EN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China), AuthorCompanyExt(id=1200147843341185434, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, companyId=1200147843324408216, language=CN, country=null, province=null, city=null, postcode=null, companyName=null, departmentName=null, remark=郑州大学第一附属医院药学部, 郑州 450052)])], figs=[ArticleFig(id=1200147845471891970, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=EN, label=null, caption=null, figureFileSmall=Jjj75YCF8A1PjyJNtoeXPQ==, figureFileBig=E/LFCt6Mrqo2jbgMtxUv4A==, tableContent=null), ArticleFig(id=1200147845698384391, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=CN, label=图1, caption=预测肾移植患者FK506血药浓度不达标的列线图模型, figureFileSmall=Jjj75YCF8A1PjyJNtoeXPQ==, figureFileBig=E/LFCt6Mrqo2jbgMtxUv4A==, tableContent=null), ArticleFig(id=1200147846105231891, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=EN, label=null, caption=null, figureFileSmall=3o1TIty7k1Hou47KICQxCg==, figureFileBig=64dnjw1uN91bAk+TXUeP8A==, tableContent=null), ArticleFig(id=1200147846247838228, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=CN, label=图2, caption=预测肾移植患者FK506血药浓度不达标列线图的受试者工作特征(ROC)曲线验证图, figureFileSmall=3o1TIty7k1Hou47KICQxCg==, figureFileBig=64dnjw1uN91bAk+TXUeP8A==, tableContent=null), ArticleFig(id=1200147846369473051, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=EN, label=null, caption=null, figureFileSmall=gZM/Cy495Adw3TEcVej4vw==, figureFileBig=aKqfGcmU6sPQnevJ4sy2yg==, tableContent=null), ArticleFig(id=1200147846549828129, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=CN, label=图3, caption=预测肾移植患者FK506血药浓度不达标列线图的校正曲线验证图, figureFileSmall=gZM/Cy495Adw3TEcVej4vw==, figureFileBig=aKqfGcmU6sPQnevJ4sy2yg==, tableContent=null), ArticleFig(id=1200147846734377508, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=EN, label=null, caption=null, figureFileSmall=hXWCh9bKWkkwSA7C71ad2g==, figureFileBig=P8mD1MjowHzMM9CeCI4/9Q==, tableContent=null), ArticleFig(id=1200147846914732587, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=CN, label=图4, caption=预测肾移植患者FK506血药浓度不达标列线图的临床决策曲线, figureFileSmall=hXWCh9bKWkkwSA7C71ad2g==, figureFileBig=P8mD1MjowHzMM9CeCI4/9Q==, tableContent=null), ArticleFig(id=1200147847053144625, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
临床资料 达标组/例(%)
(n=126)		 未达标组/例(%)
(n=74)		 χ2值 P值
年龄/岁
>60 33(26.19) 41(55.41) 17.070 <0.001
≤60 93(73.81) 33(44.59)
性别
男 62(49.21) 51(68.92) 7.371 0.007
女 64(50.79) 23(31.08)
BMI/kg·m-2
>18.5 71(56.35) 49(66.22) 1.891 0.169
≤18.5 55(43.65) 25(33.78)
吸烟史
有 82(65.08) 56(75.68) 2.447 0.118
无 44(34.92) 18(24.32)
给药途径
口服 47(37.30) 42(56.76) 7.145 0.008
静脉注射 79(62.70) 32(43.24)
FPG/mmol·L-1
>7 43(34.13) 41(55.41) 8.665 0.003
≤7 83(65.87) 33(44.59)
SBP/mmHg
>140 38(30.16) 29(39.19) 1.707 0.191
≤140 88(69.84) 45(60.81)
DBP/mmHg
>90 45(35.71) 33(44.59) 1.545 0.214
≤90 81(64.29) 41(55.41)
TG/mmol·L-1
>1.7 40(31.75) 31(41.89) 2.096 0.148
≤1.7 86(68.25) 43(58.11)
TB/μmol·L-1
>20 44(34.92) 39(52.70) 6.072 0.014
≤20 82(65.08) 35(47.30)
WBC/×109L-1
>4 66(52.38) 26(35.14) 5.582 0.018
≤4 60(47.62) 48(64.86)
RBC/×109·L-1
>5.5 71(56.35) 36(48.65) 1.111 0.292
≤5.5 55(43.65) 38(51.35)
ALB/g·L-1
>35 39(30.95) 29(39.19)
≤35 87(69.04) 45(60.81)
HB/g·L-1
>90 70(55.56) 33(44.59) 2.242 0.134
≤90 56(44.44) 41(55.41)
PLT/×109·L-1
>100 63(50.00) 36(48.65) 0.034 0.854
≤100 63(50.00) 38(51.35)
AST/U·L-1
>40 60(47.62) 39(52.70) 0.482 0.488
≤40 66(52.38) 35(47.30)
ALT/U·L-1
>50 59(46.83) 40(54.05) 0.975 0.324
≤50 67(53.17) 34(45.95)
Cr/μmol·L-1
>133 33(26.19) 31(41.89) 5.282 0.022
≤133 93(73.81) 43(58.11)
BUN/mmol·L-1
>7.1 35(27.78) 30(40.54) 3.462 0.063
≤7.1 91(72.22) 44(59.46)
), ArticleFig(id=1200147847246082610, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=CN, label=表1, caption=

FK506血药浓度达标组与未达标组肾移植患者临床资料比较

, figureFileSmall=null, figureFileBig=null, tableContent=
临床资料 达标组/例(%)
(n=126)		 未达标组/例(%)
(n=74)		 χ2值 P值
年龄/岁
>60 33(26.19) 41(55.41) 17.070 <0.001
≤60 93(73.81) 33(44.59)
性别
男 62(49.21) 51(68.92) 7.371 0.007
女 64(50.79) 23(31.08)
BMI/kg·m-2
>18.5 71(56.35) 49(66.22) 1.891 0.169
≤18.5 55(43.65) 25(33.78)
吸烟史
有 82(65.08) 56(75.68) 2.447 0.118
无 44(34.92) 18(24.32)
给药途径
口服 47(37.30) 42(56.76) 7.145 0.008
静脉注射 79(62.70) 32(43.24)
FPG/mmol·L-1
>7 43(34.13) 41(55.41) 8.665 0.003
≤7 83(65.87) 33(44.59)
SBP/mmHg
>140 38(30.16) 29(39.19) 1.707 0.191
≤140 88(69.84) 45(60.81)
DBP/mmHg
>90 45(35.71) 33(44.59) 1.545 0.214
≤90 81(64.29) 41(55.41)
TG/mmol·L-1
>1.7 40(31.75) 31(41.89) 2.096 0.148
≤1.7 86(68.25) 43(58.11)
TB/μmol·L-1
>20 44(34.92) 39(52.70) 6.072 0.014
≤20 82(65.08) 35(47.30)
WBC/×109L-1
>4 66(52.38) 26(35.14) 5.582 0.018
≤4 60(47.62) 48(64.86)
RBC/×109·L-1
>5.5 71(56.35) 36(48.65) 1.111 0.292
≤5.5 55(43.65) 38(51.35)
ALB/g·L-1
>35 39(30.95) 29(39.19)
≤35 87(69.04) 45(60.81)
HB/g·L-1
>90 70(55.56) 33(44.59) 2.242 0.134
≤90 56(44.44) 41(55.41)
PLT/×109·L-1
>100 63(50.00) 36(48.65) 0.034 0.854
≤100 63(50.00) 38(51.35)
AST/U·L-1
>40 60(47.62) 39(52.70) 0.482 0.488
≤40 66(52.38) 35(47.30)
ALT/U·L-1
>50 59(46.83) 40(54.05) 0.975 0.324
≤50 67(53.17) 34(45.95)
Cr/μmol·L-1
>133 33(26.19) 31(41.89) 5.282 0.022
≤133 93(73.81) 43(58.11)
BUN/mmol·L-1
>7.1 35(27.78) 30(40.54) 3.462 0.063
≤7.1 91(72.22) 44(59.46)
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变量 回归系数 标准误差 Wald χ2值 OR值(95%CI) P值
年龄>60岁 0.704 0.252 8.952 2.125(1.225~3.026) 0.012
男性 0.722 0.198 10.188 1.881(1.354~2.409) 0.005
静脉注射 0.690 0.463 2.221 1.994(0.586~3.401) 0.093
FPG>7 mmol·L-1 0.703 0.120 36.031 2.061(1.086~3.035) <0.001
TB>20 μmol·L-1 0.788 0.105 42.934 1.990(1.114~2.865) <0.001
WBC≤4×109·L-1 0.109 0.267 0.167 1.115(1.008~1.222) 0.224
Cr>133 μmol·L-1 0.739 0.166 31.997 2.557(1.019~4.096) <0.001
常量 -5.362 0.825 18.526 - <0.001
), ArticleFig(id=1200147847564849726, tenantId=1146029695717560320, journalId=1190317699101192196, articleId=1200147841042706791, language=CN, label=表2, caption=

FK506血药浓度不达标的影响因素Logistic回归分析

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变量 回归系数 标准误差 Wald χ2值 OR值(95%CI) P值
年龄>60岁 0.704 0.252 8.952 2.125(1.225~3.026) 0.012
男性 0.722 0.198 10.188 1.881(1.354~2.409) 0.005
静脉注射 0.690 0.463 2.221 1.994(0.586~3.401) 0.093
FPG>7 mmol·L-1 0.703 0.120 36.031 2.061(1.086~3.035) <0.001
TB>20 μmol·L-1 0.788 0.105 42.934 1.990(1.114~2.865) <0.001
WBC≤4×109·L-1 0.109 0.267 0.167 1.115(1.008~1.222) 0.224
Cr>133 μmol·L-1 0.739 0.166 31.997 2.557(1.019~4.096) <0.001
常量 -5.362 0.825 18.526 - <0.001
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他克莫司血药浓度不达标风险预测模型的建立及验证
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李增 , 尹钊 , 杜书章 *
中国药学杂志 | 论著 2024,59(10): 945-950
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中国药学杂志 | 论著 2024, 59(10): 945-950
他克莫司血药浓度不达标风险预测模型的建立及验证
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李增, 尹钊, 杜书章*
作者信息
  • 郑州大学第一附属医院药学部, 郑州 450052

    • 李增,男,本科,主管药师 研究方向:医院药学

通讯作者:

*杜书章,男,主任药师 研究方向:药物经济学、医院药学 Tel:(0371)66913047
Development and Validation of a Risk Prediction Model for Tacrolimus Blood Concentration Failure
Zeng LI, Zhao YIN, Shuzhang DU*
Affiliations
  • Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
出版时间: 2024-05-22 doi: 10.11669/cpj.2024.10.012
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目的 分析肾移植患者他克莫司(FK506)血药浓度不达标的影响因素,并构建风险预测列线图模型。方法 选取2020年6月至2023年6月医院收治的肾移植术后服用FK506治疗并监测30 d内血药浓度的200例患者为研究对象,根据监测结果将其分为达标组(5~15 μg·L-1)126例和未达标组(<5 μg·L-1或>15 μg·L-1)74例,收集两组患者的临床资料,采用单因素和多因素Logistic回归分析筛选FK506血药浓度不达标的独立危险因素,据此构建FK506血药浓度不达标的风险列线图预测模型并进行拟合优度检验。结果 术后30 d内200例患者的1 200次FK506浓度监测中,达到目标浓度5~15 μg·L-1的次数为756次,达标率为63.0%。其中达到目标浓度的患者共126例(达标组),未达到目标浓度的患者共74例(未达标组)。未达标组年龄>60岁、男性、静脉注射、空腹血糖>7 mmol·L-1、总胆红素>20 μmol·L-1、白细胞计数≤4×109·L-1、血肌酐>133 μmol·L-1的患者比例均高于达标组,差异有统计学意义(P<0.05)。多因素Logistic回归分析,结果显示,年龄>60岁、男性、空腹血糖>7 mmol·L-1、总胆红素>20 μmol·L-1、血肌酐>133 μmol·L-1为肾移植患者FK506血药浓度不达标的独立危险因素(均P<0.05)。构建的列线图模型AUC达到0.859(0.795~0.924),模型校准曲线验证C-index为0.836,H-L偏差度检验χ2=4.203,P=0.516,校正曲线与理想曲线走势基本一致,精准度和区分度良好,决策曲线(DCA)分析显示,列线图预测模型显示的阈值概率(0.05~0.95)范围较大,其对应红色曲线到灰色曲线和横坐标轴的面积最大,表明模型临床效用价值较好。结论 年龄>60岁、男性、空腹血糖>7 mmol·L-1、总胆红素>20 μmol·L-1、血肌酐>133 μmol·L-1是肾移植患者FK506血药浓度不达标的危险因素,据此构建的列线图模型能有效预测肾移植患者FK506血药浓度不达标风险程度。

他克莫司  /  血药浓度  /  危险因素  /  风险预测模型

OBJECTIVE To analyze the influencing factors of tacrolimus (FK506) blood concentration non-attainment in renal transplant patients and construct a risk prediction column-line diagram model. METHODS Two hundred patients admitted to the hospital from June 2020 to June 2023 who were treated with FK506 after renal transplantation and whose blood concentration was monitored for 30 d were selected for the study, and according to the monitoring results, they were categorized into 126 cases in the group of meeting the standard (5-15 μg·L-1) and 74 cases in the group of failing to meet the standard (<5 μg·L-1 or>15 μg·L-1), and the clinical data were collected, and independent risk factors for failing to meet the standard of FK506 were screened and fit into a predictive model by single-factor and multifactorial logistic regression analysis. Clinical data of the two groups were collected, and the independent risk factors for FK506 blood concentration non-compliance were screened by single-factor and multifactor logistic regression analyses, according to which, a prediction model for the risk of FK506 blood concentration non-compliance was constructed with a line graph and tested for goodness-of-fit. RESULTS Of the 1 200 FK506 concentration monitoring sessions in 200 patients within 30 d after surgery, the number of sessions in which the target concentration of 5-15 μg·L-1 was reached was 756, with an attainment rate of 63.0%. A total of 126 patients reached the target concentration (target group), and 74 patients did not reach the target concentration (non-target group). The proportion of patients with age >60 years, male, intravenous, fasting blood glucose (FPG) >7 mmol·L-1, total bilirubin (TB) >20 μmol·L-1, white blood cell count (WBC)≤4×109·L-1, and blood creatinine (Cr) >133 μmol·L-1 was higher in the non-attainment group than in the attainment group, and the difference was statistically significant (P<0.05). Multifactorial logistic regression analysis was performed, and the results showed that age >60 years, male, FPG>7 mmol·L-1, TB>20 μmol·L-1, and Cr>133 μmol·L-1 were independent risk factors for substandard FK506 blood concentration in renal transplant patients (all P<0.05). The AUC of the constructed column-line graph model reached 0.859 (0.795-0.924), the model calibration curve validation C-index was 0.836, and the H-L deviation test χ2=4.203, P=0.516, the calibration curve was basically the same as the ideal curve trend, with a good degree of precision and differentiation. DCA analysis showed that the column-line graph prediction model displayed a large range of threshold probabilities (0.05 to 0.95), which corresponded to the largest area of the red curve to the gray curve and the horizontal axis, indicating a better clinical utility value of the model. CONCLUSION Age >60 years, male, FPG >7 mmol·L-1, TB >20 μmol·L-1, and Cr >133 μmol·L-1 are the risk factors for substandard FK506 blood concentration in renal transplantation patients, and the column-line graph model constructed accordingly can effectively predict the degree of risk for substandard FK506 blood concentration in renal transplantation patients.

tacrolimus  /  blood concentration  /  risk factor  /  risk prediction modeling
李增, 尹钊, 杜书章. 他克莫司血药浓度不达标风险预测模型的建立及验证. 中国药学杂志, 2024 , 59 (10) : 945 -950 . DOI: 10.11669/cpj.2024.10.012
Zeng LI, Zhao YIN, Shuzhang DU. Development and Validation of a Risk Prediction Model for Tacrolimus Blood Concentration Failure[J]. Chinese Pharmaceutical Journal, 2024 , 59 (10) : 945 -950 . DOI: 10.11669/cpj.2024.10.012
正文
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他克莫司(FK506)具有强大的免疫抑制作用,通过与T淋巴细胞内的FK506受体结合蛋白-12结合形成复合体,抑制钙调磷酸酶活化,干扰相关细胞因子的合成及表达,减轻细胞毒性,降低急性排斥反应发生风险,提高移植器官的存活率[1-2]。但FK506治疗指数窄,受药动学和药效学影响,生物代谢个体差异较大,其血药浓度过低可能导致治疗失败或耐药风险增加,血药浓度过高则会增加肾毒性和神经毒性,减少器官移植患者的生存时间[3]。既往研究显示,FK506血药浓度主要与人口生物学因素、服药剂量以及基因多态性等因素有关,但不同报道之间研究结论存在较大差异[4-5],且缺少早期预测肾移植患者术后FK506血药浓度不达标的研究。列线图是一种建立在多因素回归分析基础上的风险预测工具,它将复杂的回归方程转变为可视化平面模型,具有直观且便于理解的特点,在临床事件预测中广泛应用[6-7]。基于此,本研究通过分析肾移植患者术后FK506血药浓度不达标的影响因素,构建相关列线图风险预测模型,初步筛选出高危患者,进一步进行基因检测,减轻患者经济负担,降低术后排异反应发生率,提高移植器官存活率。
1 资料与方法
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1.1 研究对象
选取2020年6月至2023年6月医院收治的肾移植术后服用FK506治疗并监测血药浓度的200例患者为研究对象。纳入标准:肾移植患者,术后服用FK506;年龄>18岁;术后30 d内监测FK506血药浓度;临床资料及相关检查结果完整。排除标准:术后发生明显药源性腹泻;移植后30 d内更换免疫抑制剂;服用过其他可能影响FK506血药浓度的药物;合并其他脏器功能不全或其他恶性肿瘤疾病;移植后30 d内死亡;临床资料不完整。
1.2 免疫抑制用药方案
术后以FK506作为基础免疫抑制剂,与吗替麦考酚酯、泼尼松组成三联免疫抑制方案。FK506初始剂量:口服,每天0.05~0.25 mg·kg-1,给药时间间隔12 h;静脉注射,每天0.05~0.10 mg·kg-1,24 h持续静脉滴注;替麦考酚酯的剂量为1~2 g·d-1;围术期甲泼尼龙500 mg,静脉注射(qd,1~3 d),移植后第3天起转为每天口服泼尼松20~30 mg,此后每2周减少5 mg,最终为泼尼松5~10 mg·d-1长期维持[8-9]。
1.3 FK506血药浓度监测
于清晨服药前半小时,抽取患者空腹静脉血1 mL,经EDTA-2K抗凝处理后,使用Architect i1000SR血药浓度分析仪(美国雅培公司),采用均相酶扩大免疫分析法测定FK506全血血药浓度。移植后的前1~2周,每周监测1~2次,以后逐渐减少,第3、4周每周监测1次。根据相关指南[10]、文献[11]及我院器官移植中心的用药经验,当FK506与吗替麦考酚酯和激素联用时,其目标浓度范围在术后30 d内为5~15 μg·L-1,在此范围内的患者纳入达标组,反之纳入未达标组。
1.4 临床资料收集
收集患者的临床资料,包括年龄、性别、体质量指数(body mass index,BMI)、吸烟史、给药途径、空腹血糖(fasting plasma glucose,FPG)、收缩压(systolic blood pressure,SBP)、舒张压(diastolic blood pressure,DBP)、甘油三酯(triglyceride,TG)、总胆红素(total bilirubin,TB)、白细胞计数(white blood cell,WBC)、红细胞计数(red blood cell,RBC)、白蛋白(albumin,ALB)、血红蛋白(haemoglobin,HB)、血小板计数(blood platelet,PLT)、天冬氨酸转氨酶(aminotransferase,AST)、丙氨酸转氨酶(alanine aminotransferase,ALT)、血肌酐(creatinine,Cr)、血尿素氮(blood urea nitrogen,BUN)。
1.5 统计学方法
数据采用SPSS 26.0统计学软件进行统计分析。定性资料用例(%)表示,组间比较采用χ2分析。危险因素筛选用二元Logistic回归分析。选用R3.5.1软件包和R3.5.1软件RMS程序包建立列线图模型,采用Bootstrap法作内部验证(将原始数据重复抽样1 000次后完成),采用一致性指数(C-index)、H-L拟合优度检验、受试者工作特征(receiver operating characteristic,ROC)曲线评估模型的预测效能。
2 结果
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2.1 达标组与未达标组临床资料比较
术后30 d内200例患者的1 200次FK506浓度监测中,达到目标浓度5~15 μg·L-1的次数为756次,达标率为63.0%。其中达到目标浓度的患者共126例(达标组),未达到目标浓度的患者共74例(未达标组)。未达标组年龄>60岁、男性、静脉注射、FPG>7 mmol·L-1、TB>20 μmol·L-1、WBC≤4×109·L-1、Cr>133 μmol·L-1的患者比例均高于达标组(P<0.05)。两组BMI、吸烟史、SBP、DBP、TG、RBC、ALB、HB、PLT、AST、ALT、BUN的患者比例比较无差异(P>0.05)。见表1。
2.2 FK506血药浓度不达标的影响因素Logistic回归分析
以肾移植患者FK506血药浓度不达标为因变量(否=0,是=1),以临床资料分析中差异有统计学意义的因素:年龄>60岁(否=0,是=1)、男性(否=0,是=1)、静脉注射(否=0,是=1)、FPG>7 mmol·L-1(否=0,是=1)、TB>20 μmol·L-1(否=0,是=1)、WBC≤4×109·L-1(否=0,是=1)、Cr>133 μmol·L-1(否=0,是=1)作为自变量,进行多因素Logistic回归分析,结果显示,年龄>60岁、男性、FPG>7 mmol·L-1、TB>20 μmol·L-1、Cr>133 μmol·L-1为肾移植患者FK506血药浓度不达标的独立危险因素(P<0.05)。见表2。
2.3 肾移植患者FK506血药浓度不达标列线图风险预测模型的建立
基于筛选出的危险因素构建预测肾移植患者FK506血药浓度不达标风险列线图模型,年龄>60岁、男性、FPG>7 mmol·L-1、TB>20 μmol·L-1、Cr>133 μmol·L-1评分线评分依次为60、70、50、90、80分,总分350分,见图1。
2.4 肾移植患者FK506血药浓度不达标列线图风险预测模型的效能评价
2.4.1 区分度评价
该模型的区分度即C-index为0.836[95%CI(0.775,0.893)]。绘制的ROC曲线发现,列线图预测模型预测肾移植患者FK506血药浓度不达标的曲线下面积(area under the curve,AUC)为0.859(0.795~0.924),均较其他危险因素预测的AUC值高,提示该列线图预测模型具有良好的精准度和区分度,见图2。
2.4.2 一致性评价
模型校准曲线验证结果显示,H-L偏差度检验χ2=4.203,P=0.516,表明该模型具有较好的校准度,预测值与实际值一致性较好,能够准确预测肾移植患者FK506血药浓度不达标的发生,见图3。
2.4.3 临床实用性评价
纳入影响肾移植患者FK506血药浓度不达标的各危险因素及列线图预测模型行决策曲线分析,结果显示,与各危险因素相比,列线图预测模型显示了更大范围的阈值概率(0.05~0.95),且列线图预测模型对应红色曲线到灰色曲线和横坐标轴的面积最大,表明模型临床效用价值较好,见图4。
3 讨论
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本研究结果显示,术后30 d内200例患者的1 200次FK506浓度监测中,达到目标浓度5~15 μg·L-1的次数为756次,达标率为63.0%,高于Chen等[12]报道的48.26%,可能与本研究受试者均为成人肾移植患者,也可能与样本量、研究对象、研究方法等不同有关。临床上一般将FK506血药浓度控制在5~15 μg·L-1,低于5 μg·L-1可能导致移植肾排异反应风险增加,超过15 μg·L-1则可能增加肾毒性等不良反应风险[13]。此外,影响FK506血药浓度的相关因素较多,故在加强FK506血药浓度监测的基础上,还需综合考量其影响因素,从而进行必要的剂量调整,将血药浓度控制在目标范围内,实现移植器官的高存活率。
研究结果显示,年龄>60岁、男性、FPG>7 mmol·L-1、TB>20 μmol·L-1、Cr>133 μmol·L-1为肾移植患者FK506血药浓度不达标的独立危险因素。有研究发现,相较于中青年,年龄≥60岁的肾移植受者达到同样的药物暴露需要的FK506剂量更高,而FK506清除率更低,说明老年移植受者使用FK506的剂量应适度降低[14]。FK506在体内主要通过肝脏药物代谢酶细胞色素P450代谢排出体外,而随着年龄的增加,肝体积和肝血流量减少,肝脏代谢能力减弱,细胞色素P450酶的Ⅰ相代谢和活性降低,从而影响FK506清除率[15]。Tornatore等[16]研究发现,相较于女性患者,男性患者术后FK506血药浓度更高,意味着女性患者需要更高的给药剂量才能达到有效血药浓度,说明性别是影响FK506血药浓度的因素之一,与本研究结果相一致。而Ji等[17]的研究结果则显示,服用相同剂量时,男性与女性患者平均血药浓度并无统计学差异。可能与研究样本量不同以及研究对象的个体差异有关。
肾移植后新发糖尿病发病率为2%~50%,增加全身及局部感染风险,影响移植肾的存活[18]。此外,高浓度的FK506会引起机体糖代谢异常,抑制胰岛素的合成与分泌,影响血糖水平,且呈剂量依赖性[19]。故对于发生新发糖尿病的高危受者,应尽量不使用糖皮质激素,同时给予FK506血药浓度进行监测,以及时调整其用量。TB是衰老红细胞中血红蛋白通过血红素降解而产生的物质,是肝胆疾病的重要诊断及疗效评估指标,当肝功能异常时,TB代谢受到影响,进而影响FK506在体内的消除[20]。研究指出,FK506稳态谷浓度与TB水平呈正相关性,即随着TB水平的升高,FK506稳态谷浓度随之升高[21],提示在临床实践中可依据TB水平对器官移植患者FK506给药剂量进行相应调整。一般情况下,Cr由肾小球滤过,随尿液排出,若肾脏功能受损,其水平会上升[22]。值得关注的是,在器官移植早期,患者肝功能尚未恢复,FK506无法经肝药酶P450代谢,导致体内蓄积药物剂量过高,造成血药浓度升高,进一步损伤肾功能[23]。
总之,FK506血药浓度个体差异大,影响因素复杂,及时对肾移植患者FK506血药浓度未达标风险程度进行评估则具有重要意义,而列线图模型的构建可以更为直观地反映肾移植患者FK506血药浓度未达标的风险程度。本研究基于上述多因素Logistic回归分析构建列线图模型,年龄>60岁、男性、FPG>7 mmol·L-1、TB>20 μmol·L-1、Cr>133 μmol·L-1评分线评分依次为60、70、50、90、80分,总分350分,AUC为0.859(0.795~0.924),表明该模型对肾移植患者FK506血药浓度未达标风险有良好预测效能,模型校准曲线验证表明列线图预测概率与实际概率之间具有最佳一致性,具备良好的精准度和区分度,决策曲线分析(DCA)显示,模型临床效用价值较好。
综上所述,肾移植患者FK506血药浓度未达标主要与年龄、性别、FPG、TB、Cr等有关,据此构建的列线图风险预测模型有助于直观地对患者的FK506血药浓度进行定量评分,评估血药浓度未达标风险程度。本研究建立FK506血药浓度不达标风险预测模型,既往文献未见类似研究报道。但本研究仍存在一定局限性:①无法对未知混杂因素进行分析,结果可能存在一定偏倚;②本研究为回顾性研究,纳入的样本量有限,纳入因素可能不够全面。课题组下一步会进行更全面深入的研究。
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2024年第59卷第10期
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doi: 10.11669/cpj.2024.10.012
  • 接收时间：2023-08-02
  • 首发时间：2025-11-25
  • 出版时间：2024-05-22
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  • 收稿日期：2023-08-02
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    郑州大学第一附属医院药学部, 郑州 450052

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*杜书章,男,主任药师 研究方向:药物经济学、医院药学 Tel:(0371)66913047
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
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