Clinical Effect And Mechanism Of Glucocorticoid On Kidney Injury Associated With Severe Acute Pancreatitis

The First Part Clinical effect of glucocorticoid on kidney injury associated with severe acute pancreatitisBackgroundSevere acute pancreatitis(SAP)is a critical illness with high mortality and morbidity,in which the multiple organ failure is the leading cause of death in the early stage.Acute kidney injury(AKI)is one of the most common complications caused by systemic inflammatory response syndrome(SIRS)during SAP and significantly increases mortality.Although organ function support in intensive care is becoming more and more powerful,there is still no effective treatment for AKI.AKI induced by SAP is considered to be caused by severe inflammatory reaction.Glucocorticoids have certain anti-inflammatory effects.Although some clinical and basic studies suggest that glucocorticoids can prevent and improve AKI caused by sepsis,trauma and major surgery,there is still no relevant research on whether glucocorticoids can improve AKI caused by SAP.ObjectiveTo investigate the clinical effect of methylprednisolone(MP)on SAP-induced AKI,and evaluate its effects on mortality,incidence of renal replacement therapy,incidence of surgery,ICU and total hospital stay,and its side effects on the new onset of infection,gastrointestinal bleeding and hyperglycemia.MethodA retrospective cohort analysis of the SAP patients complicated with AKI who were admitted into our center from January 2006 to December 2016.According to the principle of voluntary use of MP,the patients were divided into two groups:MP treatment group and non-MP treatment group.The 90-day and 28-day overall mortality rate,incidence of renal replacement therapy,surgical treatment rate,the length of ICU and total hospital stay and the incidence of long-term hemodialysis were analyzed.In addition,the side effects include new onset of infection,gastrointestinal bleeding and hyperglycemia also were compared between the two groups.ResultsA total of 302 patients were enrolled in this study,including 147 in the MP treatment group and 155 in the non-MP treatment group.The overall incidence of SAP complicated with AKI was 66.85%.The incidence of renal replacement therapy in MP group was significantly lower than that in non-MP group(31.29%VS 57.41%;OR,2.96;95%CI,1.85-4.75;p<0.01),especially among the patients with KIDGO grade 2.Furthermore,the application of MP can significantly shorten the length of ICU stay(30.49%VS 89.02%;OR,18.47;95%Cl,8.23-41,43;p<0.01).There was no significant difference in 90-day and 28-day overall mortality,incidence of surgical treatment rate,total hospital stays and long-term hemodialysis dependence rate between the two groups.In addition,there was also no significant difference in the new onset of infection and gastrointestinal bleeding between the two groups.However,the incidence of hyperglycemia in the MP group was significantly higher than that of patients in the non-MP group(14.01±2.1 VS 11.95±1.25 mmol/L;p=0.04).Although there was no difference in the overall new onset of infection between the two groups,the fungal infection rate in the MP treatment group was significantly higher than that in the non-MP treatment group.ConclusionsThe use of MP in the early stage of SAP can reduce the new usage rate of renal replacement therapy and the lengths of ICU stay.In contrast,MP was associated with higher blood glucose levels and new fungal infection rate.Since this study was a retrospective cohort study and the homogeneity of patients was not strong enough,the clinical effects of glucocorticoids on SAP-induced AKI still need a prospective,multicenter,randomized controlled study to validate the results of this study.The second part The protective effect and mechanism of dexamethasone on glycocalyx on the kidney microvascular endothelium during severe acute pancreatitisBackgroundAcute kidney injury is a common complication in the early stage of SAP which significantly increases the mortality of the patients.There are many reasons for leading to AKI during SAP,among which the renal microcirculation dysfunction caused by inflammation may play a key role in AKI.Glycocalyx is a villous structure which lays on the surface of vascular endothelium.As a microvascular barrier,it has powerful functions,which include maintaining vascular permeability and resisting adhesion of leukocyte and platelet to the endothelium.Degradation of glycocalyx leads to outbreak of inflammation by adhesion of leukocyte and microvascular thrombosis by adhesion of platelets,and it also increases permeability of the vascular,which resulting in tissue edema,microcirculation malfunction and kidney injury.Infection,trauma and major surgery are considered as important factors in activiting inflammatory cells,such as monocytes,macrophages and endothelial cells,which inducing severe inflammatory reaction and release a large number of cytokines.TNF-alpha as one of the cytokines may lead to hydrolysis of glycosaminoglycan and destroy the integrity and continuity of the glycocalyx.Furthermore,it also can induce the entry of macrophages into glycocalyx,which resulting in aggravation of vascular endothelial injury and microcirculation dysfunction.Glucocorticoids,as an anti-inflammatory agent,can alleviate the early inflammatory reaction of SAP.Some studies suggest that glucocorticoids can alleviate oxidative stress after ischemia and hypoxia,and reduce the release of active oxidative products caused by TNF-alpha,which might protect endothelial glycocalyx from degradation,and improve the function of microvascular barrier.In addition,dexamethasone may inhibit the activation and phosphorylation of nuclear factor-kappa B(NF-kB),and reduce the release of TNF-alpha,which may protect endothelial glycocalyx,improve capillary permeability and correct microcirculatory dysfunction.SAP is a process of systemic inflammation and whether glucocorticoids can attenuate the inflammatory reaction caused by SAP and protect endothelial glycocalyx from inflammation,thereby improving renal microcirculation dysfunction and its related molecular biological mechanisms still deserve further study.ObjectiveTo study the mechanism of kidney microcirculation dysfunction and the effect of dexamethasone on glycocalyx on the kidney microvascular endothelium during severe acute pancreatitis.MethodsWild-type mice(C57/B6)were randomly divided into sham-operated group(SHAM,sham-operated+dexamethasone treatment group(SHAM+DEX),severe acute pancreatitis group(SAP)or severe acute pancreatitis+dexamethasone treatment group(SAP+DEX group).The model of SAP was established by the method of"pancreatic duct ligation and intraperitoneal injection of cerulein",while the sham operation was performed only by laparotomy without pancreatic duct ligation and injection of cerulein.The mean arterial pressure(MAP)and renal perfusion in mice of each group were analyzed by tail-cuff and laser Doppler technique,respectively.The serum creatinine and urea nitrogen were measured by biochemical analyzer to evaluate renal function,while the histopathology changes of kidney were evaluated by paraffin section and HE staining.Furthermore,the renal vascular permeability in mice were observed by dual fluorescence localization technique,and the injury of endothelial glycocalyx were detected by transmission electron microscopy.In addition,western-blot and ELISA technique were used to analyze the expression of biomolecules which might explain the possible mechanism of kidney vascular glycocalyx injury and microcirculation dysfunction.Combined with the treatment of dexamethasone,that can be explained whether dexamethasone can inhibit related pathways and protect glycocalyx on kidney vascular,which may improve kidney microcirculation and function.ResultsIn this study,we found that SAP induced kidney injury,which resulting in a significant increase of creatime and urea nitrogen in serum,and the H&E staining of the kidney demonstrated necrosis of tubular and inflammatory cell infiltration.The transmission electron microscopy showed that the endothelial glycocalyx was damaged obviously and distributed discontinuously,some endothelial cells were exposed to vascular lumen,and the concentration of sydecan-1 and heparin sulfate in blood also increased significantly.Furthermore,the renal vascular permeability of the SAP mice was also significantly increased,most of the dextran injected via caudal vein was observed in the kidney tissue under fluorescence microscope.Interestingly,the expression of phosphorylated NF-?B and P38-MAPK in kidney tissue of SAP mice was significantly up-regulated,and the concentration of pro-inflammatory factor TNF-? in blood was significantly increased.After application of dexamethasone,the expression of phosphorylated NF-?B and P38-MAPK was significantly down-regulated and the concentration of TNF-? was also markedly decreased.Furthermore,the damage of glycocalyx was decreased and the permeability of renal vascular was also improved,while the concentration of serum creatinine and urea nitrogen in the SAP+DEX mice were significantly lower than those in SAP mice.ConclusionsSevere acute pancreatitis may activate and phosphorylate the molecules of NF-?B and p38-MAPK.The proinflammatory factor of TNF-a was then synthesized and released,which might lead to damage of glycocalyx on kidney vascular and increase permeability of capillaries.Finally,the kidney microcirculation is disturbed and kidney injury occurred.The dexamethasone could possibly inhibit the NF-?B and p38-MAPK signal pathway,decrease the release of TNF-a and protect the glycocalyx from degradation,which may improve kidney perfusion and reduce kidney injury.