Association of Preoperative Prognostic Nutritional Index and Postoperative Acute Kidney Injury in Patients with Colorectal Cancer Surgery

The prognostic nutritional index (PNI) has been reported to be associated with postoperative complications and prognosis in cancer surgery. However, few studies have evaluated the association between preoperative PNI and postoperative acute kidney injury (AKI) in colorectal cancer patients. This study evaluated association of preoperative PNI and postoperative AKI in patients who underwent colorectal cancer surgery. This study retrospectively analyzed 3543 patients who underwent colorectal cancer surgery between June 2008 and February 2012. The patients were classified into four groups by the quartile of PNI: Q1 (≤43.79), Q2 (43.79–47.79), Q3 (47.79–51.62), and Q4 (≥51.62). Multivariate regression analysis was performed to assess the risk factors for AKI and 1-year mortality. AKI was defined according to Kidney Disease Improving Global Outcomes classification (KDIGO) criteria. Additionally, we assessed surgical outcomes such as hospital stay, ICU admission, and postoperative complications. The incidence of postoperative AKI tended to increase in the Q1 group (13.4%, 9.2%, 9.4%, 8.8%). In the multivariate analysis, high preoperative PNI was significantly associated with low risk of postoperative AKI (adjusted odds ratio [OR]: 0.96, 95% confidence interval [CI]: 0.93–0.99, p = 0.003) and low 1-year mortality (OR: 0.92, 95% CI: 0.86–0.98, p = 0.011). Male sex, body mass index, diabetes mellitus, and hypertension were risk factors for AKI. The Q1 (≤43.79) group had poor surgical outcomes, such as postoperative AKI (OR: 1.52, 95% CI: 1.18–1.95, p = 0.001), higher rates of ICU admission (OR: 3.13, 95% CI: 1.82–5.39, p < 0.001) and higher overall mortality (OR: 3.81, 95% CI: 1.86–7.79, p < 0.001). In conclusion, low preoperative PNI levels, especially in the Q1 (≤43.79), were significantly associated with postoperative AKI and surgical outcomes, such as hospital stay, postoperative ICU admission, and mortality.


Introduction
Acute kidney injury (AKI) is one of common postoperative complications in colorectal cancer patients. The incidence of AKI in patients with colorectal cancer surgery has been reported to be 3.8-20.8% [1,2]. AKI increases the risk of developing chronic kidney disease (CKD) and end stage renal disease (ESRD) [3] and increases morbidity, mortality, and hospital cost [4,5]. Therefore, there have been many studies to determine the risk factors of postoperative AKI in colorectal cancer patients [1,6,7].
The prognostic nutritional index (PNI), which is calculated from the serum albumin concentration and the total lymphocyte count in the peripheral blood [8], reflects nutritional and inflammatory status [9]. Malnutrition has a significant impact on patient prognosis by reducing immune function, and lymphocyte count is an indicator of cell-mediated immunity and plays an important role in cancer prevention [8,9]. Therefore, more attention has been paid to the impact of nutritional and immune status on the prognosis of various cancers. PNI has been reported as a simple and objective indicator of patient survival and complications in acute and chronic diseases, such as AKI, heart failure, and various cancers [10][11][12][13][14]. Moreover, PNI was reported to be associated with postoperative complications and surgical prognosis in patients with colorectal cancer surgery [15][16][17][18].
However, to our knowledge, no studies have evaluated the association between preoperative PNI and postoperative AKI development in colorectal cancer patients. Therefore, this study was performed to evaluate the association preoperative PNI and postoperative AKI in patients who underwent colorectal cancer surgery. We also assessed hospital days, postoperative intensive care unit (ICU) admission and complications, and 1-year and overall mortality.

Study Design and Patient Population
The institutional review board (IRB) of the Asan Medical Center (protocol number: 2020-1806) approved this retrospective study, and the requirement for written informed consent was waived by the IRB. Based on the 10th revision of the International Classification of Diseases (ICD-10), we reviewed all patients diagnosed with colorectal cancer and undergoing surgery between June 2008 and February 2012. Adult patients over 18 years of age were included in the study.
The exclusion criteria were as follows: Patients with severe cardiopulmonary diseases; patients diagnosed with chronic kidney disease; patients who had already undergone kidney replacement therapy; patients requiring interventions pertaining to urethra, ureter, or kidneys during operation; patients who underwent emergency surgery; and patients with incomplete data or laboratory values.

General Anesthesia and Surgical Technique
Regardless of the surgical approach, all patients underwent general anesthesia (open vs. laparoscopy). All surgeries were performed by a qualified and experienced surgical team. Conventional and laparoscopic surgeries were performed using standard protocols [19]. For laparoscopic surgery, pneumoperitoneum with carbon dioxide at 10-15 mmHg was established. Crystalloid and colloid solutions were administered during surgery. The total volume of infused synthetic colloids did not exceed 20 mL kg −1 . During surgery, packed red blood cells (RBC) were transfused if plasma hemoglobin level was less than 8 g dL −1 , and inotropes or vasopressors were administered if the mean blood pressure was less than 65 mmHg.

Clinical Data Collection and Outcome Assessments
All clinical data were obtained from computerized medical record system. Demographic data, intraoperative data, and pre-and postoperative laboratory data were collected. Demographic data included age, sex, weight, height, body mass index (BMI), diabetes mellitus (DM), hypertension (HTN), cerebrovascular accident (CVA), smoking history, and the American Society of Anesthesiologists (ASA) physical status classification. Intraoperative data included tumor location, tumor invasion, lymph node invasion, distant metastasis, operation time, lowest mean blood pressure (MBP), laparoscopic surgery, and administered fluid volumes, such as crystalloid, colloid, transfused packed RBC, urine output, and diuretics. The laboratory data included preoperative white blood cell (WBC), hemoglobin, albumin, creatinine, estimated glomerular filter ratio (eGFR), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), red cell distribution width (RDW), and PNI. NLR was defined as the ratio between absolute neutrophil count to absolute lymphocyte count. PLR was determined as the ratio between absolute platelet counts to absolute lymphocyte count. PNI was calculated using the following equation: [10 × serum albumin (g dL −1 )] + [0.005 × total lymphocyte count]. Serum creatinine (sCr) levels were checked daily from postoperative day 1 to postoperative day 7 to identify postoperative AKI by Kidney Disease Improving Global Outcomes classification (KDIGO): Increase in sCr by >1.5-fold from preoperative baseline within 7 days or increase in sCr ≥ 0.3 mg dL −1 within 48 h. The KDIGO classification is a newly introduced and rapidly adopted AKI definition for high sensitivity and early diagnosis [20]. Data on the length of hospital stay, postoperative ICU admission, prolonged ICU stay (more than 2 days), postoperative complications (cardiac and pulmonary problems, and bleeding,), 1-year mortality (calculated from the date of surgery to 1-year follow-up), and overall mortality (determined from the date of surgery to the last follow-up) were also collected.

Primary and Secondary Outcomes
The primary outcome was the incidence of postoperative AKI as defined by KDIGO criteria. The secondary outcomes were the length of hospital stay, postoperative ICU admission, prolonged ICU stay (>2 days), postoperative complications (cardiac and pulmonary problems, and bleeding), 1-year mortality, and overall mortality.

Statistical Analysis
Categorical data were analyzed using the chi-square test, and continuous data were evaluated by analysis of variance (ANOVA). Data are presented as mean and standard deviation (SD), median with interquartile range, or numbers with proportions, as appropriate. We used multivariate logistic regression analysis to determine independent predictors of AKI. We included all variables that showed statistical difference over increasing quartiles of PNI (standardized mean difference [SMD] >0.1), variables with p < 0.1 in univariate, and prior knowledge of important variables for AKI and mortality to the multivariable adjusted analysis. To assess the adjusted odd ratios (OR) of the risk factors of 1-year mortality, multivariable logistic regression analysis was also used. The cumulative survival rate among quartile groups was analyzed using the Kaplan-Meier method, and variations between curves were assessed using the log-rank test. We used two-tailed p values in tests of significance. All p values < 0.05 were considered statistically significant. Data manipulation and statistical analysis were performed using IBM SPSS Statistics for Windows, version 22.0 (IBM Corp., Armonk, NY, USA).

Results
Of the 3843 enrolled patients, 300 met the exclusion criteria. Finally, a total of 3543 patients were enrolled in this study. The included 3543 patients were classified into four groups by PNI quartile; Quartile I (PNI ≤ 43.79, n = 885), Quartile II (43.79 < PNI ≤ 47.79, n = 885), Quartile III (47.79 < PNI ≤ 51.62, n = 887), Quartile IV (PNI > 51.62, n = 886) ( Figure 1). Table 1 shows demographic and perioperative variables of study population and SMD of each variable. The lower preoperative PNI groups tended to be older, more likely to be female, lower BMI, poor ASA class, and an increased chance of history of CVA and smoking than higher preoperative PNI groups ( Table 1). The groups with lower preoperative PNI tended to have lower levels of hemoglobin, albumin, and creatinine, and higher levels of NLR, PLR, and RDW (Table 1). Operation time tended to be more in the lower preoperative PNI groups, and total fluid, crystalloid, and RBC transfusion rates tended to be higher in the lower preoperative PNI groups (Table 1). In the lower preoperative PNI groups, lowest MBP tended to be lower, and laparoscopic surgery was performed more in the higher preoperative PNI group (Table 1).

Discussion
Our study demonstrated that low preoperative PNI was significantly associated with postoperative AKI in patients who underwent colorectal cancer surgery. In addition, low preoperative PNI was significantly associated with surgical outcomes, such as increased hospital days, prolonged (more than 2 days) ICU stay, and reduced 1-year and overall mortality. This suggests that the preoperative PNI might be a prognostic factor for postoperative AKI incidence and surgical outcome in colorectal cancer patients.
PNI comprises of assessment of albumin, a major component of plasma protein, and lymphocytes, which are important cells in immunity, indicating patient's nutritional and immune status [21]. There have been many studies reporting that low PNI is significantly associated with postoperative complications, including surgical site infection, anastomotic leakage, bleeding, cardiopulmonary failure, and pulmonary embolism [22][23][24][25]. However, only few studies have reported the association between PNI and AKI in surgical patients. Min and colleagues suggested that the modified PNI predicted postoperative AKI within 1-week better than the conventional model of end-stage liver disease score (MELD) in patients receiving living donor liver transplantation and recommended a cutoff-value of 8.7 (area under curve 0.823, sensitivity 72.2%, specificity 83.2%) [26].

Discussion
Our study demonstrated that low preoperative PNI was significantly associated with postoperative AKI in patients who underwent colorectal cancer surgery. In addition, low preoperative PNI was significantly associated with surgical outcomes, such as increased hospital days, prolonged (more than 2 days) ICU stay, and reduced 1-year and overall mortality. This suggests that the preoperative PNI might be a prognostic factor for postoperative AKI incidence and surgical outcome in colorectal cancer patients.
PNI comprises of assessment of albumin, a major component of plasma protein, and lymphocytes, which are important cells in immunity, indicating patient's nutritional and immune status [21]. There have been many studies reporting that low PNI is significantly associated with postoperative complications, including surgical site infection, anastomotic leakage, bleeding, cardiopulmonary failure, and pulmonary embolism [22][23][24][25]. However, only few studies have reported the association between PNI and AKI in surgical patients. Min and colleagues suggested that the modified PNI predicted postoperative AKI within 1-week better than the conventional model of end-stage liver disease score (MELD) in patients receiving living donor liver transplantation and recommended a cutoff-value of 8.7 (area under curve 0.823, sensitivity 72.2%, specificity 83.2%) [26]. Dolapoglu and colleagues demonstrated that an association between PNI and AKI in patients with normal serum creatinine levels who underwent coronary artery bypass grafting [27].
Our study has clinical significance as it is the first study to investigate the association between preoperative PNI and postoperative AKI in patients undergoing colorectal cancer surgery. The results of the current study are consistent with those of the other two studies mentioned above, which reported the association between PNI and AKI. In our study, after dividing the PNI level into quartiles, the incidence of postoperative AKI decreased significantly as the PNI quartile increased sequentially, which was statistically significant. In particular, the incidence of AKI increased significantly in patients with PNI level of quartile 1. This finding suggests that low preoperative PNI is significantly associated with postoperative AKI.
Following multivariate logistic regression analysis, male gender, DM, HTN, BMI, and preoperative PNI were found to be significantly associated with postoperative AKI. Male gender has been reported to be associated with an increased risk of hospital-associated AKI [28]. One recent animal study found that female sex prevents the development of AKI, and sex hormones might be involved in this protection against AKI [29].
DM and HTN have been reported as risk factors of AKI in surgical patients [30,31]. DM is related to post-ischemic micro-vasculopathy and interstitial inflammation [31]. Furthermore, DM and HTN were known to be associated with conditions that can cause AKI even in the absence of chronic kidney disease [30]. Previous studies on the marginal association between BMI and AKI have reported potential confounding factors, including DM and HTN [32].
Recent studies have reported that biological markers, neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), are significantly associated with AKI and renal replacement therapy in surgical patients [33,34]. However, in our study, NLR and PLR were not significantly associated with postoperative AKI in colorectal cancer patients. In the studies by Bi et al. and Kim et al.,8.38 and 11.7 were proposed as cutoff values of NLR predicting AKI [33,34]. However, in our study, patients with NLR ≥ 8.38 were 1.0% (37/3543), and with NLR ≥ 11.7 were 0.5% (18/3543), and few patients had high preoperative NLR levels, so, there might be no association between NLR and AKI.
In the present study, preoperative PNI was the only biological marker associated with postoperative AKI, and this association between AKI and PNI seems to be due to the characteristics of PNI that reflect the function of albumin and lymphocytes. Albumin is responsible for maintaining oncotic pressure, microvascular permeability, and acid-base balance, and preventing platelet aggregation [35]. These functions of albumin might be associated with the reno-protective properties. Potent renal vasodilation caused by serum albumin and nitric oxide due to the formation of S-nitroso-albumin has been reported to increase renal perfusion in animal models [36]. Serum albumin plays an important role in proximal tubular homeostasis, and hypoalbuminemia has been reported as a strong risk factor for postoperative AKI in both cardiac and non-cardiac surgery [37,38]. Additionally, it has also been reported that albumin may mitigate the effects of nephrotoxic drugs [39] and stimulate renal cell proliferation through a pathway mediated by phosphatidyl inositide 3-kinase [40]. Lymphocytes are also known to play an important role in the process of AKI initiation, proliferation, and recovery [41], and one study showed a significant association between preoperative lymphocytopenia and postoperative AKI in cardiac surgery [42]. Additionally, recently newly identified renal T lymphocytes have been reported to have complex functions, such as potentially playing an anti-inflammatory role in AKI [43].
Our study demonstrated that PNI level of quartile 1 (PNI ≤ 43.79) was significantly associated with postoperative AKI and surgical outcomes, such as hospital day, prolonged (more than 2 days) ICU stay, and 1-year and overall mortality. In Korea, all citizens are required to sign up for a national health insurance system, and when a patient dies, the death report is included in the database. In addition, patient survival data are automatically updated in the patient medical records in our center, accompanied by loss of health insurance eligibility. In recent studies, PNI < 45 was proposed as a cut off value that was significantly associated with postoperative complications or survival rate [21][22][23][24]44,45], which is consistent with our results. Therefore, it seems that a preoperative PNI level of less than 45 may be associated with a surgical prognosis.
There are several limitations in our study. First, our study is retrospective, and it is possible that confounding factors that have not been considered might have caused potential errors. A total of 193 patients (5.2%) with missing data such as hemoglobin (77 patients), eGFR (48 patients), RDW (32 patients) were excluded from the study, which may have affected surgical outcome. However, their characteristics were not significantly different from the patients who included in the study (Supplementary Table S1) and because of their small number, we do not think it would have had a significant impact on our findings. In our study, stoma creation rates and surgical site leakage were not analyzed. Therefore, careful interpretation of some surgical results is required. Second, since our data were collected from a single medical center, the results might have been biased due to homogeneous groups; thus, further study of heterogeneous groups is needed. Third, to date, there is no exact agreement on the cutoff value of PNI, and there are slight differences depending on the study. More well-designed studies are needed for accurate validation of preoperative PNI cutoff value that predict complications and survival rates.

Conclusions
In conclusion, preoperative PNI was associated with postoperative AKI and surgical outcomes in patients who underwent colorectal cancer surgery. These results suggest that preoperative PNI can provide useful information about postoperative AKI and surgical prognosis in colorectal cancer.