Screening And Validation Of Risk Markers For Drug-induced Kidney Injury

Objective:Drug induced kidney injury(DIKI)is a common disease with a complex etiology but lack of specificity in diagnosis,so early identification and prevention are of great importance to delay its development.In this study,based on the perspective of "drug-risk marker-nephropathy",we screened and validated potential drug and disease-related targets to identify risk markers closely associated with DIKI.The aim was to provide a theoretical basis for early identification and monitoring of people at high risk of DIKI and to guide the clinical use of medications.Methods:The SIDER and CTD databases were used to search for drug and target information,followed by the application of protein interaction networks and enrichment analysis to screen for core targets that were closely linked to drugs,with high enrichment counts of core targets used as potential risk markers.Meta analysis was applicated to screen disease-related targets,the Chinese and English literature on case-control studies related to markers and kidney disease published in domestic and international databases before May 2022 was retrieved.All the studies enrolled patients with kidney disease as case group and healthy volunteers as control group,and the level of markers in serum or urine were detected.The quality evaluation and data extraction were according to the inclusion and exclusion criteria.The quantitative effect values were exhibited by forest plot and parallel subgroup analysis was performed.Finally,validation with a clinical observational study,clinical specimens and data were retrospectively collected from patients with renal biopsy specimens left from January 2018 to April 2022 in a 3a grade hospital.Patients with pathology suggestive of renal insufficiency were the case control,while patients who underwent paracentesis of the kidney for cancer were the control group.Immunohistochemical was used to detect the expression of risk markers in the specimens of both groups,and then the relationship between clinical indicators such as gender,age,hypertension,serum albumin and glomerular filtration rate and the expression of markers were analyzed.Results:22 targets with the highest connectivity were obtained through protein-protein interactions network,and enrichment analysis suggested that the targets were mainly involved in inflammatory responses,chemokine activities,complement and coagulation cascade systems,etc.Finally,five potential risk markers with the strongest drug relevance were filtered after sorting by the number of enrichments,including VEGFA,TGF β 1,EGF,CXCL12 and IGF1 in meta analysis,a total of 34,28,24 and 24 literature were included of serum VEGFA,urinary TGF β1,urinary EGF and serum IGF1,respectively.The quantitative results showed statistically significant differences in levels of all four compared to the control group.In the clinical study,50 cases and 16 controls were included.Immunohistochemical results showed that the expression of VEGFA,TGF β 1,EGF and IGF1 in the kidney tissue of patients with nephropathy was significantly higher than in the control group(P all<0.05);no significant correlation was shown between the expression of all four and the patients’ age,hypertension,serum albumin and glomerular filtration rate(P all>0.05).Conclusions:After multiple screening by bioinformatics and meta analysis,the results suggested that the targets more closely associated with drugs and nephropathy were VEGFA,TGF β 1,EGF and IGF 1.The four were highly expressed in renal tissues in nephropathy and independently associated with the disease and could be monitored through serum or urine,suggesting that they might participate in the development and regression of different renal diseases.Combined with the results of screening and validation,we suggested that VEGFA,TGF β 1,EGF and IGF1 were closely associated with DIKI,and the risk of causing drug-related nephropathy will increase exponentially when clinically treated with target-associated drugs,so attention should be paid to monitoring patients with high risk.However,the lack of quality of the literature and clinical information included,the results we have obtained so far may only provide a reference at a theoretical level.