Protective Effects And Mechanism Of Dexmedetomidine On Renal Function In Patients With Gastrointestinal Tumor Received Neoadjuvant Chemotherapy

Part one Risk factors of acute kidney injury in patients with gastrointestinal tumor:a nested case-control studyObjective:To explore the epidemiology and risk factors of acute kidney injury in surgical patients with gastrointestinal tumor.Methods:A total of 78 946 surgical tumor patients from Fourth Hospital of Hebei Medical University,from January of 2013 to January of 2019,were retrospectively enrolled.The identification criteria included the 2012 KDIGO definition of AKI(KDIGO criteria),and the expanded criteria was an increase or decrease in serum creatinine by 50%during hospital stay for those who had no repeated serum creatinine assay within 7 days(using serum creatinine concentration at admission as a baseline).Combined with the exclusion criteria,patients with AKI were screened.Then the total incidence of AKI and the incidence of AKI with different tumor tupes were calculated.2.Gastrointestinal patients with AKI were screened.The ratio of AKI group and non-AKI group was 1:1 according to age and sex.The patients’data including height,weight,hypertension,diabetes,coronary heart disease,surgery,chemotherapy,white blood cell count,hemoglobin,red blood cell count,platelets,potassium,sodium,calcium,chlorine,albumin,creatinine,urea nitrogen,blood sugar,alanine transaminase(ALT)and aspartate aminotransferase(AST)were collected.Parameters with P<0.05 in the univariate analysis were included in the multivariate analysis,and the Forward:wald method was adopted,P<0.05 was included,and P>0.1 was excluded.Multivariate logistic regression analysis was performed to obtain the independent risk factors for AKI in patients with gastrointestinal tumor.Results:Among the 78 946 surgical tumor patients,1477 cases developed AKI(1.87%),including hepatobiliary and pancreatic tumor 3.79%(292/7 707 cases),gastrointestinal tumor 3.06%(433/14 169 cases),lung cancer 1.82%(508/27 969 cases).2.There were 501 cases in two groups respectively.Logistic multivariate regression analyses showed that surgery(OR 5.471,95%CI 3.934-7.608),chemotherapy(OR 1.940,95%CI 1.381-2.726),sodium<137 mmol/L(OR 2.315,95%CI 1.598-3.352),albumin<40 g/L(OR 2.204,95%CI 1.536-2.677),blood glucose>6.1 mmol/L(OR 2.198,95%CI 1.624-2.974)were independent risk factors for AKI in patients with gastrointestinal tumor.Conclusion:Surgery,chemotherapy,hyponatremia,hypoproteinemia,hyperglycemia are the risk factors for AKI in patients with gastrointestinal tumor.Part two Protective effects of dexmedetomidine on postoperative renal function in patients undergoing radical gastrectomy after neoadjuvant chemotherapy:a randomized controlled trialObjective:To investigate the effects of dexmedetomidine on postoperative renal function in patients with radical gastrectomy after neoadjuvant chemotherapy.Methods:A total of 29 patients underwent elective radical gastrectomy after neoadjuvant chemotherapy,aged≥18 years old,regardless of sex,ASA grade Ⅰ or Ⅱ.They were randomly divided into Con group(14 cases)and Dex group(15 cases),according to the random number table.In the Dex group,dexmetomidine was infused with 1 μg·kg-1·h-1 at 15 min before the surgery,and then at the rate of 0.2 μg·kg-1·h-1 until 30 min before the end of the surgery.Patients were received with saline at the same volume in the Con group.After entering the room,the patients were routinely monitored,the venous access of the upper limb was established,the arterial pressure of the radial artery was monitored,and the central vein puncture was performed.Anesthesia was induced by injection of sufentanil 0.4 μg/kg,propofol 0.2 mg/kg and cis-atracurium 0.2 mg/kg,followed by endotracheal intubation and mechanical ventilation.Anesthesia was maintained by intravenous combined with inhalation general anesthesia,2%-3%sevoflurane,remifentanil 0.05-0.10μg·kg-1·min-1,maintaining the depth of anesthesia(BIS 40-45),intermittent intravenous injection of cis-atracurium(0.05 mg/kg)to maintain muscle relaxation.Target-directed fluid therapy was performed,and if necessary,vasoactive drugs were infused intravenously to maintain the stability of hemodynamics.Blood samples were taken from internal jugular vein before anesthesia induction and at 2,12 and 24 hours after operation(T1-T4),and then centrifuged and stored at-80℃ for examination.Serum NGAL,Cys C were measured by ELISA.The general data of patients,preoperative laboratory examination indexes,surgery time,usage of vasoactive drugs,infusion volume,urine volume during surgery,the first off-bed time and the length of hospital stay were recorded.The quality of postoperative recovery was evaluated by QoR-15 scale at 1,2 and 3 days after surgery.Results:There was no significant difference in general data,complications and preoperative laboratory examination between groups(all P>0.05).The first off-bed time in Dex group was significantly shorter than that in Con group(P<0.05),but there were no significant differences in intraoperative usage of vasoactive drugs,infusion volume,urine volume during surgery,surgery time and length of hospital stay between groups(all P>0.05).Compared with Con group,the QoR score in Dex group was higher at 1 day after surgery(P<0.05),but there was no significant difference at 2 or 3 days after surgery between groups(all P>0.05).Compared with Con group,the concentrations of NGAL at T3 and T4 in Dex group were significantly lower(F=6.289,P=0.017;F=4.642,P=0.038),but they were higher than those in T1(all P<0.001).There were significant differences in the concentration of Cys C among all different time points(F=38.754,P<0.001),and between two groups(F=5.374,P<0.032).Compared with Con group,the concentration of IL-6 at T2,T3 and T4 in Dex group was significantly lower(F=7.713,P=0.008;F=6.745,P=0.013;F=4.217,P=0.047).Conclusions:Dexmedetomidine may improve the renal function and early recovery quality of patients undergoing radical gastrectomy after neoadjuvant chemotherapy.Part three Dexmedetomidine alleviates cisplatin-induced acute kidney injury by attenuating endoplasmic reticulum stress-induced apoptosis via the a2AR/PI3K/AKT pathwayObjective:Cisplatin(CP)is an effective antineoplastic agent;however,CP-induced acute kidney injury(AKI)seriously affects the prognosis of patients with cancer.Endoplasmic reticulum(ER)stress(ERS)-induced apoptosis serves a pivotal role in the pathogenesis of CP-induced AKI.Dexmedetomidine(Dex),a potent α2 adrenergic agonist,has been reported to exert protective effects against AKI.However,the protective effects of Dex against CP-induced AKI and the potential molecular mechanisms remain unknown.Methods:In the present study,male Sprague-Dawley rats were randomly divided into four groups(n=10/group),as follows:Con group;CP group,rats received an intraperitoneal(i.p.)injection of 5 mg/kg CP;Dex+CP group,rats received an i.p.injection of 25 μg/kg Dex immediately after CP treatment;and Dex+CP+atipamezole(Atip)group,rats received an i.p.injection of 250μg/kg Atip,an α2 adrenoreceptor(α2AR)antagonist,and then received the same treatment as the Dex+CP group.Rats were anesthetized and sacrificed 96 h after CP injection.Subsequently,serum blood urea nitrogen(BUN)and serum creatinine(Scr)were analyzed,and kidney tissue samples were collected for analyses.Pathological changes were examined using hematoxylin and eosin staining,and protein expression levels were assessed using western blotting and immunohistochemical staining.In addition,apoptosis was examined using a terminal deoxynucleotidyl transferase dUTP nick-end labeling assay.Results:Compared with Con group,CP group and Dex+CP+Atip group had lower body weight and higher RI,while CP group and Dex+CP+Atip group had lower body weight and higher RI than Dex+CP group(all P<0.05).Compared with Con group,the expression levels of BUN and Scr in CP group,Dex+CP group and Dex+CP+Atip group were higher,and the expression levels of BUN and Scr in CP group and Dex+CP+Atip group were higher than those in Dex+CP group(all P<0.05).The injury of renal tubules in CP group was more severe than that in Con group,and that in CP group and Dex+CP+Atip group was more severe than that in Dex+CP group(all P<0.05).Compared with Con group,the number of apoptosis in CP group,Dex+CP group and Dex+CP+Atip group was higher than that in Dex+CP group,and the number of apoptosis in CP group and Dex+CP+Atip group was higher than that in CP group and Dex+CP+Atip group(all P<0.05).Compared with Con group,the expression of GRP78,CHOP and Caspase-12 in CP group and Dex+CP+Atip group was higher,and the expression of GRP78,CHOP and Caspase-12 in CP group and Dex+CP+Atip group was higher than those in Dex+CP group(all P<0.05).Compared with Dex+CP group,the expression levels of p-PI3K and p-AKT in CP group and Dex+CP+Atip group were lower(all P<0.05).Conclusion:Dex may alleviate CP-induced AKI by attenuating ERS-induced apoptosis,partly through α2AR/PI3K/AKT signaling pathway.