Construction Of A Predicting Nomogram Model And Analysis Of Differentially Expressed Genes Of Acute Drug-induced Kidney And Liver Injury

Background: Acute drug-induced kidney injury and liver injury are the most common adverse drug reactions.Their incidence rates are increasing year by year.They are problems that can not be ignored in clinical diagnosis and treatment.Acute drug-induced kidney injury is closely related to liver injury.The study of the relationship between the two may provide some help for reducing adverse drug reactions and clinical diagnosis and treatment.Objective: This research from two aspects of clinical and genetic is aimed to structure a predicting nomogram model of patients with drug-induced kidney and liver injury,and to identify the differentially expressed genes(DEGs)from GEO database as potential diagnostic markers with using q PCR to validation.Methods: 1.A retrospective analysis was made of the acute drug-induced liver and/or kidney injury patients hospitalized in PLA General Hospital and Rocket Force Characteristic Medical Center from 2000 to 2019.We analyzed their drug use and the risk factors of drug-induced liver and/or kidney injury,and structured a nomogram prediction model by using the R language.2.GSE data sets related to drug-induced kidney and/or liver injury were downloaded from GEO database.The differentially expressed genes were identified by using the R language.We performed GO functional enrichment,KEGG pathway enrichment analyses,and constructed PPI network,to identify the hub genes.3.And we used q PCR method to verify the expression of genes in HK-2 and PHH cells.Results: 1.From 2000 to 2019,the number of cases of acute drug-induced kidney injury and liver injury increased significantly.In this study,the most common drugs caused kidney and/or liver injury were traditional Chinese medicine,antibiotics,anti-tumor drugs,non steroidal anti-inflammatory drugs,anti tuberculosis drugs and so on.In the past 20 years,the structures of common drugs caused acute drug-induced kidney and/or liver injury had changed.2.Univariate analysis:(1)Compared with patients with drug-induced kidney injury,patients with kidney combined with liver injury had more severe injuries to renal function and acute inflammatory reaction,which reflected in higher level of urea,urine bilirubin,NLR,lower red blood cells,and statistical differences in platelet and coagulation function.(2)Compared with patients with drug-induced liver injury,patients with kidney combined with liver injury had more severe injuries to liver function and acute inflammatory reaction,which reflected in higher level of bilirubin and neutrophils,lower level of red blood cells and total cholesterol,and statistical differences in platelet and coagulation function.3.In injury patterns of drug-induced kidney combined with liver injury patients,hepatocellular patterns were the most,and mixed patterns were the least.The injury patterns caused by traditional Chinese medicine were mainly hepatocellular patterns,and the antibiotics were mainly cholestatic patterns.4.The nomogram model was constructed with R language while its calibration was tested by Hosmer-Lemeshow,its discrimination was evaluated by AUC,and its clinical efficacy was evaluated by DCA.5.Three GSE data sets were obtained in GEO database.In kidney and liver cells,there are20 DEGs with the consistent expression.GO enrichment analysis showed that the main DEGs were involved in the negative regulation of transcription from RNA polymerase II promoter and the transcription corepressor activity,located in the nucleus and membrane.KEGG pathway analysis showed that the main DEGs were involved in the cysteine and methionine metabolism pathway.PPI network identified ten hub genes closely related to drug-induced liver and kidney injury.6.QPCR experiment confirmed that ATF3 gene expression increased in HK-2 cells and PHH cells after cyclosporine A or cisplatin intervention,while the expression of GINS1,DIAPH3 and MELK decreased.Conclusions: 1.In this study,antibiotics,non steroidal anti-inflammatory drugs and contrast agents were more likely to cause acute drug-induced kidney injury,while traditional Chinese medicine,anti-tumor drugs,anti tuberculosis drugs,antifungal drugs and lipid-lowering drugs were more likely to cause liver injury.2.Patients with kidney combined with liver injury had more severe renal injury than those with single kidney injury,and more severe liver injury than those with single liver injury.3.In injury patterns of drug-induced kidney combined with liver injury patients,hepatocellular patterns were the most.The injury patterns caused by traditional Chinese medicine were mainly hepatocellular patterns,and the antibiotics were mainly cholestatic patterns.4.The nomogram prediction model was good at discrimination,calibration,and clinical value.5.Ten hub genes such as BUB1B、MELK、ATF3、GINS1、DIAPH3、TRIB3、SLC3A2、AARS、LDLR、CTH,were identified by bioinformatics analysis.6.QPCR experiments confirmed that after drug intervention,the expression changes of genes ATF3,GINS1,DIAPH3 and MELK in HK-2 cells and PHH cells were consistent with the GEO analysis.In a word,drug-induced kidney injury and liver injury are inextricably linked.Further study on it is helpful for clinical rational drug use,reducing drug side effects and economic burden of patients.