The Role Of Hypertriglyceridemia In Acute Kidney Injury In The Course Of Severe Acute Pancreatitis—Clinical And Experimental Study

In clinical work, we observe hypertriglyceridemia (HTG) plays an important role in patient with acute kidney injury (AKI) in the course of severe acute pancreatitis (SAP). This is a neglected but important field. AKI is a crucial factor determining the prognosis of SAP with high mortality. HTG attracts more attention as a common comorbidity and a pathogenic factor. However, only a few of authors pay their attentions to the relationship of HTG and the severity of SAP. We will discuss the specific role of HTG in AKI complicating with SAP, and investigate the potential pathophysiological mechanisms.Part 1 hypertriglyceridemia is an independent risk factor of acute kidney injury in the course of acute pancreatitisObjective:this study aimed to clarify the clinical characteristics of acute kidney injury (AKI) in severe acute pancreatitis (SAP), and to investigate the independent risk factors for AKI. Methods:A total of 245 patients admitted within 48 hours of acute pancreatitis (AP) onset were retrospectively included. Patients were divided into two groups of non-AKI group and AKI group. The basic characteristics, complications, interventions, lengths of hospital stay and mortality were compared between the two groups. The time interval between AP onset and AKI diagnosis was calculated. Basic characteristics and pre-existing diseases were brought into logistic regression analysis as independent risk factors for AKI in the early stage of AP. Results:There were 43 AKI patients and 202 non-AKI patients. There was statistical difference of body mass index between AKI group and non-AKI group (26.8+3.6 vs. 25.0±3.1 kg/m2,P=0.001). The incidences of acute respiratory distress disease, hemorrhage, fungal infections, septic shock, intestinal fistula and infected (peri)pancreatic necrosis were significantly higher in AKI group than that in non-AKI group. AKI group needed longer length of ICU stay and hospital stay with a mortality rate of 25.6%. There were 27 patients diagnosed AKI within the first 24 hours of AP onset,15 patients within the next 24 hours, only 1 patients emerged AKI on the 10 th day due to sepsis. Logistic regression analysis presented hypertriglycridemia was an independent risk factor for AKI (odd risk=2.964,95% confidence interval 1.485-5.915, P=0.007). Conclusions:The disease severity of AKI groups was more serious than non-AKI group. Most AKI emerges within the first 48 hours of AP onset. Hypertriglycridemia was an independent risk factor for AKI during the early stage of AP.Part Ⅱ Severe hypertriglyceridemia is associated with disease severity of acute pancreatitisObjective:This study aimed to further investigate the role of hypertriglyceridemia (HTG) on the disease course of acute pancreatitis (AP). Methods:A total of 262 patients admitted within 48 hours of acute pancreatitis (AP) onset were retrospectively included. Patients were divided into four categories: normal group (TG<150mg/dL), mild HTG group (150-500mg/dL), moderate HTG group (500～1000mg/dL), and severe HTG group (TG>1000mg/dL). The basic characteristics, complications, interventions, lengths of hospital stay and mortality were compared among these groups. Disease severities of subgroups between patients with TG<500mg/dL and patients with TG≥500mg/dL were compared, in patients with and without organ failure, separately. Results:There were 104 normal patients, 72 mild HTG patients,47 moderate HTG patients, and 39 severe HTG patients. Acute respiratory distress disease and shock had no statistical differences between these groups. The incidence of AKI in severe HTG group was 38.5%, significantly higher than that of normal and mild HTG group. Severe HTG group needed longer length of ICU stay and hospital stay, but mortalities had no statistical differences among the four groups. For patients without organ failure, whether TG above of 500mg/dL did not influence disease severity of AP. For patients with organ failure, subgroup with TG above of 500mg/dL had higher admission SOFA score than that of the other group. Results:HTG was an independent risk factor for organ failure of AP. For patients with organ failure, HTG influences organ function.Part III Establish mouse model of hypertriglyceridemic severe acute pancreatitisObjective:this study aimed to establish mouse model of hypertriglyceridemic severe acute pancreatitis. Methods:For wild type ICR mouse, retrograde pancreatic injection of sodium taurocholate bypass duodenum was used to establish the model of acute necrotizing pancreatitis. The concentrations of sodium taurocholate were 0.5%, 1.0% and 2.0%, respectively. Time points to collect samples were 0,3, and 6 hours, respectively. The levels of serum triglyceride, amylase, IL-6, and TNF-αwere detected. A proper concentration of sodium taurocholate was investigated as ApoC3 transgenic mice were used. Results:The levels of serum amylase, IL-6, and TNF-α increased after acute necrotic pancreatitis was established. The higher concentrations of sodium taurocholate, the higher levels of serum amylase, IL-6, and TNF-α at a same time point. When the concentration of sodium taurocholate was 0.5%, the survival time of ApoC3 transgenic mice was much shorter than wild type mice (17.3 ±3.0天vs.29.1±7.3 days, P<0.05). Conclusions:The mouse model of hypertriglyceridemic severe acute pancreatitis was established by etrograde pancreatic injection of 0.5% sodium taurocholate bypass duodenum with ApoC3 transgenic mice.Part Ⅳ Mechanisms of hypertriglyceridemia on renal function in severe acute pancreatitisObjective:This study aimed to investigate the mechanisms of hypertriglyceridemia on renal function in severe acute pancreatitis. Methods:Animal models were established by retrograde pancreatic injection of 0.5% sodium taurocholate bypass duodenum with ApoC3 transgenic mice and wild type mice. At time points of 0,3,6, and 9 hours, blood and tissue samples were collected. Mechanisms were investigated from four aspects:(1) the functions of pancreas and renal; (2) the levels of serum triglyceride and free fatty acids; (3) inflammatory response and immunologic function, including IL-1、IL-6, TNF-α, CD4+, and CD4+/CD8+;(4) mechanisms of renal itself, including oil red for triglyceride and fat, sterol regulatory element binding protein-1c, liver-fatty acid binding protein, peroxisome proliferation activated receptor-a, malonaldehyde, and cyclooxygenase 2 (Cox2). Results:(1)ApoC3 transgenic mice had higher level of serum neutrophil gelatinase-associated lipocalin than wild type mice, with more necrosis of pancreas; (2)the level of serum free fatty acids was higher in ApoC3 transgenic mice than wild type mice; ApoC3 transgenic mice had decreased level of serum triglyceride decreased and increased level of free fatty acids after SAP onset; (3) the levels of serum IL-1、IL-6, TNF-α increased in both ApoC3 transgenic mice and wild type mice, while ApoC3 transgenic mice were more obvious; the percentage of CD4+, and CD4+/CD8+ decreased in both ApoC3 transgenic mice and wild type mice, while ApoC3 transgenic mice were more obvious; (4) there were a large number of red dye in glomerular and renal tubular epithelial cells in ApoC3 transgenic mice using oil red staining, so was sterol regulatory element binding protein-1c in ApoC3 transgenic mice using immunohistochemistry; ApoC3 transgenic mice had higher express of liver-fatty acid binding protein at time points of 6 hours and 9 hours than that of wild type mice; peroxisome proliferation activated receptor-a significantly decreased in ApoC3 transgenic mice at time point of 3 hours, while in wild type mice at time point of 6 hours; ApoC3 transgenic mice had higher levels of malonaldehyde than wild type mice; the express of Cox2 was higher in ApoC3 transgenic mice than wild type mice at time point of 9 hours. Conclusions:Hypertriglyceridemia increases renal injury in severe acute pancreatitis, the mechanisms involves dysfunction of other organs, systemic inflammatory response and immune disturbance. Lipid metabolis disorder, lipotoxicity, oxidative stress and disturbance of microcirculation induce and increase renal dysfunction in hypertriglyceridemic severe acute pancreatitis.