Risk Factors for Acute Kidney Injury in Acute Pancreatitis

Objective The aim of our study was to investigate the risk factors for acute kidney injury (AKI) in patients with acute pancreatitis (AP). Methods Acute pancreatitis patients were retrospectively divided into 2 groups: AKI and non-AKI. We used logistic regression analysis to investigate the risk factors for AP patients with AKI. We also compared the incidence of complications and mortality between the non-AKI and AKI groups. Results A total of 1255 AP patients without AKI and 430 AP patients with AKI were included. The risk factors for AKI in AP were hypertriglyceridemia (P = 0.001), severity (P = 0.001), etiology (P = 0.001), and Acute Physiology and Chronic Health Evaluation II scores (P = 0.001). The incidences of organ failure (P = 0.001), pancreatic necrosis (P = 0.001), and mortality (P = 0.001) were greater in the AKI group than in the non-AKI group. Conclusions Hypertriglyceridemia, severity, etiology, and Acute Physiology and Chronic Health Evaluation II scores are independent risk factors for AKI in AP patients. Those patients have serious outcomes such as high rate of organ failure, pancreatic necrosis, and debridement of necrosis.

A cute pancreatitis (AP) is characterized by edema, hemorrhage, and necrosis caused by various mechanisms and is a potentially life-threatening disease due to the risk of organ failure. 1,2 A previous study proposed that 20% to 25% of AP patients develop acute kidney injury (AKI) and that the total mortality among AP patients with AKI is nearly 25%. 3,4 Thus, managing AP patients with AKI remains challenging. The pathogenesis and the exact mechanism of AP with AKI may involve the following processes. First, cytokine cascades caused by systemic inflammatory response syndrome (SIRS) in the early phase of AP lead to the development of AKI. [5][6][7] Second, endotoxins and reactive oxygen species also play key roles in the pathophysiology of AKI in AP patients. Third, serum phospholipase A2 activity is related to renal tubular cell injury in AP patients. [8][9][10] All the previously mentioned pathological processes of AKI may aggravate AP progression. Therefore, we hypothesized that identifying possible risk factors for AKI in AP patients could substantially reduce the complication and mortality rates associated with this disease.
To date, many studies 10 have proposed that hypoxemia, a history of renal disease, abdominal compartment syndrome, and other conditions are associated with AKI in AP patients. However, the risk factors for the development of AKI in the early phase of AP have not been well defined. Thus, the relationships between such risk factors and AKI in AP patients must be investigated.
In general, AKI may emerge within a few hours after AP onset and cytokines act as triggers in the course of AKI in AP. 11 The seriousness of AKI in AP patients cannot be overlooked. Obesity, diabetes, body mass index (BMI), and hypertriglyceridemia (HTG) are often complicated by AP and are closely related to renal diseases. [12][13][14] Hence, the relationship between these factors and AKI in AP patients is a reasonable consideration.
The aims of our study were to verify risk factors in the early phase of AP related AKI and to clarify the relationship between prognostic factors and AKI based on retrospectively collected AP patient data.

MATERIALS AND METHODS
A total of 1655 patients who presented with AP at the Department of Digestion, the First Affiliated Hospital of Nanchang University between January 2012 and December 2018 were eventually identified in this study. Two of the following 3 features are needed for a diagnosis of AP: (1) abdominal pain consistent with AP, (2) serum amylase and/or lipase of 3 times or more the upper limit of normal, and (3) characteristic findings of AP on a computed tomography (CT) scan, magnetic resonance imaging, or transabdominal ultrasonography. 11 We enrolled patients admitted to the hospital within 72 hours of AP onset. This was a large retrospective study with patient data from the AP database of the First Affiliated Hospital of Nanchang University, which collected AP hospitalization data. This study was approved by the ethics committee (database approval number: 2011001). We recorded detailed basic information such as age, sex, history of smoking and drinking, etiologies, severity, comorbidities, and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores. Body mass index was measured as the weight (in kilogram) divided by height (in square meter, kilogram per square meter). Biliary pancreatitis was defined as the presence of at least one of the following criteria: (1) gallstones and/or sludge on ultrasonography or CT; (2) dilated common bile duct on ultrasonography or CT (diameter >8 mm for patients 75 years or younger and diameter >10 mm for patients older 75 years); and (3) 2 of the following 3 laboratory abnormalities: (1) serum bilirubin level concentration higher than 2.3 mg/dL, (2) alanine amino transferase activity above 100 U/L higher than aspartate aminotransferase activity, and (3) alkaline phosphatase activity of greater than 195 U/L with γ-glutamyl-transferase activity of greater than 45 U/L. 15 We defined alcohol abuse as a history of drinking more than 80 g of alcohol a day for at least 5 years. 16,17 The diagnostic criteria of HTG-induced AP were defined as an increase in serum triglycerides (TGs) greater than 1000 mg/dL in the absence of gallstones and/or a significant history of alcohol use or another known cause of AP. 17,18 Patients who had pancreatitis with an unclear etiology were considered as other types of pancreatitis.
The early phase of AKI in AP was defined as within 72 hours of AP onset. The time interval was regarded as the duration between the onset of AP diagnosis and organ failure. Organ failure was defined as AKI (creatinine ≥2.0 mg/dL), acute respiratory distress syndrome (PaO 2 /FiO 2 <300 mm Hg), and shock (a vasoactive agent was needed). In this study, infected necrosis was the principal local complication; it was diagnosed by CT and/or a positive culture of necrosis through image-guided fine-needle aspiration or drainage/necrosectomy. 19,20 We performed univariate and multivariate logistic regression analyses to investigate risk factors for AKI in the early phase of AP. All kinds of possible risk factors were assessed for each patient, including sex, age, BMI, history of smoking and drinking, APACHE II scores, HTG, etiology, and severity. Moreover, factors with a P value of less than 0.05 in the univariate analysis were entered into the multivariate logistic regression analysis. We also analyzed the incidence of pancreatic complications after AP by logistic regression.

Statistical Analyses
SPSS Version 21 (IBM Corp, Armonk, NY) was used for all analyses. Data were expressed as mean (standard deviation [SD]). χ 2 test and 2-tailed Fisher exact test were used for categorical variables. Student t test or Mann-Whitney U test was used for continuous variable. A P value of less than 0.05 was considered statistically significant. Risk factors were examined using univariate logistic regression analysis. Subsequently, variables with a P value of less than 0.05 on the univariate analysis were entered into the multivariable logistic regression to identify independent risk factors.

Baseline Patient Characteristics
A total of 1655 patients were admitted in our hospital within 72 hours of AP onset between January 2012 and December 2018 in this study. A total of 1225 patients were included in the non-AKI group and 430 patients were included in the AKI group. There were 1036 male patients (62.6%) and 619 female patients (37.4%) among the enrolled patients (P = 0.96). The mean patient age was 45.90 (SD, 11.73) years (P = 0.908). The mean BMI and APAPCHE II score were 24.67 (SD, 12.60; P = 0.079) and 7.37 (SD, 4.73; P = 0.001), respectively. Among the 1655 patients, 259 (15.6%) had severe AP (SAP), 578 (34.9%) had mild AP, and the remaining 818 (49.4%) had moderately SAP. There were 634 patients (38.3%) patients with HTG among all AP patients (P = 0.001). Acute pancreatitis in 829 patients (50.1%) was caused by biliary pancreatitis, whereas AP in 152 (9.2%) and 524 (31.7%) patients was caused by alcoholic pancreatitis and HTG-induced pancreatitis, respectively. For all patients, the incidence of organ failure was 25.0% (n = 413), the incidence of pancreatic necrosis was 32.2% (n = 533), the incidence of percutaneous catheter drainage (PCD) and operative necrosectomy (ON) was 10.9% (n = 181) and the mortality rate was 6.3% (n = 104). The detailed data are listed in Figure 1 and Tables 1 and 2.

Risk Factors for AP Patients With AKI
In the univariate analysis, there were 4 factors with a P value of less than 0.05: APACHE II score (odds ratio [OR], 1.107; 95% confidence interval [CI], 1.082-1.132; P = 0.001), HTG (OR, 3.509; 95% CI, 2.791-4.411; P = 0.001), severity (P = 0.001), and etiology (P < 0.05). Then, multivariate logistic regression analysis was used with the 4 risk factors. The P values showed that the APACHE II score (P = 0.001), etiology (P < 0.05), and severity (P = 0.001) were significant risk factors for AP patients with AKI. The detailed data are listed in Table 3.

Incidence of Mortality in AP Patients
We analyzed mortality of AP with AKI patients and performed logistic regression analysis. The results showed no significant difference in mortality between the AKI and non-AKI groups (OR, 1.150; 95% CI, 0.651-2.029; P = 0.631). The detailed data are listed in Table 4.

Hospital and Intensive Care Unit Lengths of Stay of AP Patients
Univariate logistic regression analysis was used and the hospital length of stay in days (OR, 1.005; 95% CI, 1.002-1.007; P = 0.001) and the intensive care unit (ICU) length of stay in days (OR, 1.206; 95% CI, 1.168-1.244; P = 0.001) were enrolled in the multivariate logistic regression analysis in AP patients with AKI. Next, we used multivariate logistic regression analysis to assess the above 2 factors, and there were no significant difference between the AKI and non-AKI groups of the hospital length of stay in days (OR, 0.999; 95% CI, 0.996-1.001; P = 0.309) and the ICU length of stay in days (OR, 0.010; 95% CI, 0.987-1.035; P = 0.391). The detailed data are listed in Table 4.

DISCUSSION
Acute pancreatitis has a wide range of mortality depending on its severity. Acute kidney injury is one of the most common complications in AP patients and has a dramatic impact on clinical outcomes in the course of AP. Acute kidney injury often occurs in the early phase of AP, especially within the first week of AP onset, and is closely related to an increased mortality rate, costs, and days of hospitalization. In this study, the results showed that most AKI patients are diagnosed within the first 48 hours after AP onset and that renal function injury occurs even earlier. As most AP patients have already experienced AKI on admission, it is necessary for us to investigate the risk factors for AKI in the early phase of AP.
In a previous study several years ago, HTG was proposed to be an etiological factor of AP 21-23 and HTG-associated AP is a potentially fatal disease with high mortality and complication rates. 24 Although the exact pathogenesis of HTG-associated AP is not clearly defined, it may be associated with toxic damage to acinar cells. 25,26 The proportion of the etiology of HTG in AP etiologies varies according to different studies. Twenty years ago, Fortson et al 27 reported that HTG accounted for 1.3% to 3.8% of the etiologies of AP. A multicenter study performed in Taiwan a decade ago showed that HTG-associated pancreatitis accounted for 12.3% of AP episodes. 28 In addition, another study performed by Wu et al 29 also reported that HTG is a risk factor for AP patients 29 and the varied level of HTG may be related to the outcomes in the early phase of AP patients with AKI. 30 An experimental animal model of AP also showed that high levels of HTG, especially severe levels of HTG, could accelerate kidney damage during the course of AP in mice. 30 The previously mentioned studies indicate that HTG is an important risk factor when predicting the occurrence of AKI in AP patients and plays a critical role in influencing the progression of AP. These results are similar to this study that HTG is an independent risk factor for AKI in the early phase of AP, with an HTG prevalence of 38.3% among the entire population and a prevalence as high as 49.2% in the AKI group.
Hypertriglyceridemia is a well-recognized cause of AP 31 and Havel et al 23 reported that a high level of free fatty acids (FFAs), which is caused by the hydrolysis of TG by pancreatic lipase, is a potential cause of AP. We hypothesize that the mechanism of AKI development in the early phase of AP involves the following processes: pancreatic lipase hydrolyzes excess TG in the serum, leading to the accumulation of FFAs, which are damaging to organ function. Triglyceride depositing around kidney tubules will react with pancreatic lipase, and this may directly impair renal parenchyma and produce a high level of FFAs around renal cells.  The levels of pancreatic enzymes are much higher in glomerulus because of concentration and aggravate the damage of renal function. This mechanism can explain why HTG is an independent risk factor for AP patients with AKI and why AKI occurs very early in most cases. We believe that patients presenting with AKI in the early phase of AP have a special physiology that can be described as a "time bomb," leading to the progression of AP. Preexisting disorders such as diabetes mellitus, chronic kidney disease, and hypertension are responsible for the severity of AP. Hence, the identification of those high risks in AP patients with AKI is important. Physicians should pay close attention to SAP patients complicating those disorders.
The revised Atlanta classification mentioned that organ failure in the early phase is set by the stimulation of cytokine cascades resulting in SIRS. 11 Severe AP often begins with SIRS in the early phase, especially in patients with organ failure, and cytokines are clearly and directly responsible for organ failure in SIRS and sepsis. It is rational to bring inflammation and organ failure together in SAP patients. 5,[31][32][33][34][35][36][37] In this study, we found that severity was one of the independent risk factors for AKI in AP patients. The results in our study may be a potential supplementary to this widely accepted hypothesis that the occurrence of AKI often occur in the early phase of more SAP patients.
Previous research has proven that HTG-related AP is more likely to cause organ failure. 30 This finding is consistent with the proposed mechanism of TG hydrolysis and the formation of FFAs, which is toxic to organ function. In our study, we also found that HTG is an independent risk factor for AP patients with AKI and is associated with organ failure. It provides us a guide that we should attach more importance to HTG-induced AP patients.  The APACHE II score is an assessment tool for AP that contains a variety of indicators, including creatinine and HTG. In clinical practice, APACHE II scores are often used as a general measure to evaluate AP. Studies have shown that APACHE II scores can predict the severity of AP with 100% accuracy. 38 In this study, the APACHE II score in the AKI group was significantly higher than that in the non-AKI group. Hence, the APACHE II score may also reflect the severity of AP in AKI. However, we should also analyze SIRS scores and Ranson scores for comparison with APACHE II scores in future studies.
A previous study reported that severe HTG is usually associated with high mortality in AP patients with AKI and reflects a poor prognosis. 39,40 In our study, the mortality rate in the AKI group was higher than that in the non-AKI group. However, no significant difference was found between the 2 groups in this study. We speculate that the reasons for this finding are the small number of cases of mortality among the AP patients, which makes it difficult to perform statistical analysis. In addition, the AP patients with AKI in this study usually had longer hospital stays and ICU stays than AP patients without AKI. More importantly, these patients also had higher rates of pancreatic necrosis and debridement of necrosis (PCD and/or ON). According to the above results, we know that AP patients with AKI can easily progress to a serious condition. Therefore, it is important to identify those risk factors for AKI in the early phase of AP patients and physicians should pay close attention to patients with SAP.

Strengths and Limitations
This study has several strengths. This is the first large-sample study to explore risk factors for the development of AKI in the early phase of AP. Our data show that HTG is an independent risk factor for AKI in AP patients. The data also show that severity, etiology and APACHE II scores are independent risk factors. Finally, the results in this study provide good guidance for further clinical work.
There are several limitations to this study. First, this is a retrospective observational study. A prospective study is needed to further address the role of HTG in AP patients with AKI. Second, there is slight bias in the results of this study because we excluded 281 patients with a history of diabetes, kidney disease, or hypertension, which would substantially impact serum creatinine levels.

CONCLUSIONS
Acute kidney injury is a complication in the early phase of AP. Hypertriglyceridemia, severity, etiology, and APACHE II scores are independent risk factors for AKI in the early phase of AP. We speculate that the accumulation of FFAs and cytokines in renal tissue may be an underlying mechanism. Acute pancreatitis patients with AKI have serious outcomes, such as high rate of organ failure, pancreatic necrosis, and debridement of necrosis (PCD and/or ON).