Clinical Characteristics And Molecular Mechanisms Of Acute Kidney Injury Induced By Rhabdomyolysis After Heatstroke

BackgroundThe disability and mortality rates of exertion heat stroke(EHS)are increased significantly when rhabdomyolysis(RM)and acute kidney injury(AKI)occur.Thus,it is urgent to reveal the clinical characteristics and the underlying mechanisms that may provide clinical reference and potential therapeutic targets for patient treatment.Methods1.This retrospective study was performed in General Hospital of the Southern Theater Command from January 2008 to June 2019.Patients with EHS admitted to the department of intensive care unit(ICU)were recruited and the clinical data were collected.A case-control study was conducted with the patients’90-day outcomes,and cohort studies were performed on RM,AKI and RM&AKI,respectively.Multivariate logistics regression and Cox proportional risk regression model were used to determine the risk factors for AKI and 90-day mortality,and curve fitting and two-piecewise linear regression were used to determine the cut-off points of risk factors and their relationships between RM and vital organ functions,and further to investigate the relationships among myoglobin(MB)(≥1000ng/ml),vital organ function and prognosis of patients with severe heat stroke.2.In addition,a heat shock cell model of human MB and human tubular epithelial cells(HK-2)were constructed to simulate acute kidney injury induced by heat stroke related rhabdomyolysis.Firstly,cell survival rate,expression of ferropotosis related proteins(P53,SLC7A11,GPX4)and endoplasmic reticulum stress(ERS)related proteins,and levels of iron ion and ROS were detected.Secondly,4-PBA(ERS specific inhibitor)and baicalein intervention were used to detect the changes of the above parameters in models,respectively,and to clarify the mechanisms and related signal pathways of myoglobin on human kidney(HK-2)cell injury and the protective effect of baicalein.Results:1.The vital organ injury caused by severe heat stroke were acute liver injury(AHI,72.8%),RM(48.0%),AKI(43.9%),and disseminated intravascular coagulation(DIC,34.5%).The 90-day mortality of patients was 12.2%in all population,and the 90-day mortality of patients accompanied with RM,AKI and RM&AKI were 1.5%,26.8%,and 34.1%,respectively.Sequential Organ Failure Assessment(SOFA)score on admission was an independent risk factor for the 90-day mortality of patients with severe EHS,or accompanied RM and AKI,and its clinical cut-off points were all 7.5.2.The incidence of AKI was 48.8%in patients with RM.Compared with non-RM,PCT and CRP of RM group were increased,and there was a significant correlation between RM and DIC as well as AHI.The incidence of RM was 52.6%in patients with AKI.Compared with non-AKI,the PCT level and the incidence of DIC and AHI in AKI group were both increased.The incidence of DIC in patients with RM&AKI was increased comparing with non-RM&AKI patients.Mb≥1000ng/ml,inflammation and coagulation were independent risk factors for severe EHS complicated with AKI.D-D dimer is an independent risk factor for AKI caused by RM,and its clinical cutoff point is 0.4mg/L.Survival analysis showed that 90-day survival time was significantly shorter in both AKI and RM&AKI patients(P<0.001).3.The incidence of AHI,AKI and DIC in patients with MB>1000ng/ml were 94.0%,73.1%and 54.8%,respectively,and the 90-day mortality rate was 28.8%.MB>1000ng/ml,DIC and AKI were associated with increased 90-day mortality.Survival analysis showed that 90-day survival time was significantly shorter in patients with MB≥1000ng/ml(P<0.001).4.The survival rate of HK-2 cells decreased under heat shock cell model,P53 expression was increased,accompanied by decreased SLC7A11 and GPX4 expression and increased iron as well as ROS.After the knockdown of P53 by siRNA,the protein levels of SLC7A11 and GPX4 were reversed and ERS-related pathways were activated.Accordingly,the intervention of 4-PBA improved the survival rate of cells,with decreased protein level of P53,augment of SLC7A11 and GPX4,and dampened iron and ROS.5.Similar with the intervention of 4-PBA,the administration of baicalein significantly promotes the survival rate of cells in heat shock model.In baicalein-treated cells,the expression of ERS-related proteins,P53 protein,SLC7A11 and GPX4 and the levels of iron and ROS had similar trend in 4-PBA-treated group.Conclusion1.Severe heat stroke is prone to develop multiple organ dysfunctions,in particular in patients having rhabdomyolysis,AKI and DIC.Myoglobin is associated with the occurrence and development of AKI in severe heat stroke.Mb≥1000ng/ml would be a serological diagnostic criteria for rhabdomyolysis,which could accurately predict the occurrence of AKI and 90-day mortality in patients with severe heat stroke.Treatment strategy based on improving SOFA score on admission may be the second"key point" to improve the prognosis of severe heat stroke(including RM and AKI).2.Myoglobin involves ferropotosis of HK-2 cells under heat shock,and the mechanism may be related to ERS.Baicalin alleviates ferropotosis by inhibiting ERS.It is suggested that baicalein may be a potential targets drug for the treatment of RM related AKI in patients with severe heat stroke...