The Impact of Serum Parameters Associated with Kidney Function on the Short-Term Outcomes and Prognosis of Colorectal Cancer Patients Undergoing Radical Surgery

Purpose The current study was designed to investigate the impact of blood urea nitrogen (BUN), serum uric acid (UA), and cystatin (CysC) on the short-term outcomes and prognosis of colorectal cancer (CRC) patients undergoing radical surgery. Methods CRC patients who underwent radical resection were included from Jan 2011 to Jan 2020 in a single clinical centre. The short-term outcomes, overall survival (OS), and disease-free survival (DFS) were compared in different groups. A Cox regression analysis was conducted to identify independent risk factors for OS and DFS. Results A total of 2047 CRC patients who underwent radical resection were included in the current study. Patients in the abnormal BUN group had a longer hospital stay (p=0.002) and more overall complications (p=0.001) than that of the normal BUN group. The abnormal CysC group had longer hospital stay (p < 0.01), more overall complications (p=p < 0.01), and more major complications (p=0.001) than the normal CysC group. Abnormal CysC was associated with worse OS and DFS for CRC patients in tumor stage I (p < 0.01). In Cox regression analysis, age (p < 0.01, HR = 1.041, 95% CI = 1.029–1.053), tumor stage (p < 0.01, HR = 2.134, 95% CI = 1.828–2.491), and overall complications (p=0.002, HR = 1.499, 95% CI = 1.166–1.928) were independent risk factors for OS. Similarly, age (p < 0.01, HR = 1.026, 95% CI = 1.016–1.037), tumor stage (p < 0.01, HR = 2.053, 95% CI = 1.788–2.357), and overall complications (p=0.002, HR = 1.440, 95% CI = 1.144–1.814) were independent risk factors for DFS. Conclusion In conclusion, abnormal CysC was significantly associated with worse OS and DFS at TNM stage I, and abnormal CysC and BUN were related to more postoperative complications. However, preoperative BUN and UA in the serum might not affect OS and DFS for CRC patients who underwent radical resection.


Introduction
Colorectal cancer (CRC) is the second most fatal tumor worldwide, and it was estimated that nearly 9.4% of cancerrelated deaths would be caused by CRC in 2020 [1][2][3]. Te most efective method for the therapy of CRC is still radical surgery [4][5][6]. Although great progress was made in the surgical techniques, the prognosis of these patients varied for diferent reasons, such as tumor stage [7,8], comorbidities [9][10][11], and complications [12,13]. For better clinical decisions and to improve the survival of CRC patients, many biochemical indicators, such as albumin [14,15] and bilirubin [16,17], were identifed to fnd patients with high risks of postoperative complications and a poor prognosis.
It was reported that chronic kidney disease (CKD) could increase postoperative complications and worsen the OS for patients who accepted radical surgery [18][19][20]. CKD is usually identifed and classifed by the glomerular fltration rate (GFR) [21]. Besides GFR, when the glomerular fltration function began to deteriorate, blood urea nitrogen (BUN) [22], cystatin C (CysC) [23], and serum uric acid (UA) [24] were also elevated. What's more, the changes in CysC and serum UA were more sensitive and prominent than serum creatinine in the early period when glomerular fltration function was impaired [25]. As a result, we deduced that BUN, UA, and CysC might be related to the short-term outcomes and prognosis for CRC patients undergoing radical resection as well.
Both CysC and UA were proved to be interacted with tumor development and invasion. Previous studies reported the CySc was a marker for the prognosis of urinary system carcinoma [26,27], esophageal cancer [28], and lung cancer patients [29]. Only Kos J et al. reported that CRC patients, after surgery with high cystatin C, had lower survival [30]. Similarly, the level of UA in the serum was correlated with the survival of patients with pancreatic cancer [31], laryngeal cancer [32], and so on, but its specifc role in the prognosis for CRC patients remained controversial. Meanwhile, little was known about the predictive value of these factors for short-term outcomes.
As a result, the current study was designed to investigate the impact of BUN, CysC, and UA in serum on the shortterm outcomes and prognosis of CRC patients undergoing radical surgery.

Patients.
Patients who underwent radical CRC surgery were included from Jan 2011 to Jan 2020 in a single clinical center. Te study was approved by the ethics committee of our institution (the First Afliated Hospital of Chongqing Medical University, 2022-135-2), and all patients signed informed consent forms. Tis study was conducted in accordance with the World Medical Association Declaration of Helsinki as well.

Data Collection.
Te values of BUN, UA, and CysC were determined by the blood tests conducted a week before surgery. Te baseline characteristics collected were as follows: age, sex, body mass index (BMI), smoking, drinking, hypertension, type 2 diabetes mellitus (T2DM), coronary heart disease (CHD), surgical method, tumor location, tumor node metastasis (TNM) stage, and tumor size. Te short-term outcomes included operation time, intraoperative blood loss, postoperative hospital stay, overall complications, and major complications. Te long-term prognosis was estimated by the OS and DFS. All the data were collected from the electronic medical record system, outpatient visits, and telephone interviews.

Defnitions.
Te TNM stage was identifed according to the AJCC 8th Edition [33]. Te postoperative complications were classifed on the basis of the Clavien-Dindo classifcation [34], and major complications were regarded as ≥ grade III. OS was defned as the time from surgery to death or loss of follow-up. DFS was calculated from the date of surgery to the date of recurrence or death.
2.5. Treatment and Follow-Up. All patients underwent radical surgery according to standard principles, and R0 resection was confrmed by pathology. Patients were regularly followed up every six months in the frst three years and every year in the next years.

Optimal Cut-Of and Groups.
According to the upper limits of the reference ranges of BUN, UA, and CysC, patients were divided into the abnormal BUN group (BUN>8.2 mmol/ L) and the normal BUN group (BUN≤8.2 mmol/L); the abnormal UA group (UA>357 μmol/L) and the normal UA group (UA≤357 μmol/L); as well as the abnormal CysC group (CysC>1.09 mg/L) and the normal CysC group (CysC≤1.09 mg/L).

Statistical Analysis.
A normality test was performed on the measurement data. Te measurement data conforming to the normal distribution were expressed as mean ± standard deviation (SD), and an independent-samplet-test was used to compare the indicators between groups; the measurement data not conforming to the normal distribution were expressed as the median (minimum value and maximum value), and a Mann−Whitney U test was adopted for comparison between groups. Categorical variables are expressed as absolute values and percentages, and Chi-square test or Fisher's exact test was performed. Te Kaplan−Meier method was used to estimate the OS and DFS, and a log-rank test was conducted to compare the OS and DFS between the CysC groups in diferent tumor stages. Moreover, Cox regression analysis was performed to identify independent risk factors for OS and DFS. Data were analyzed using SPSS (version 22.0) statistical software. A bilateral p value of <0.05 was considered statistically signifcant.

Patients and Characteristics.
A total of 2047 CRC patients who underwent radical resection were included in the current study, and these patients were divided into diferent groups according to the values of BUN, UA, and CysC.
As a result, there were 1937 patients in the normal BUN group and 110 patients in the abnormal BUN group. Te abnormal BUN group had an older age (p < 0.01), more males (p < 0.01), higher portion of smoking (p � 0.001), drinking (p � 0.004), hypertension (p < 0.01), and T2DM (p � 0.001) than the normal BUN group (Table 1).
Similarly, 1756 patients were in the normal UA group, and 291 patients were in the abnormal UA group. Te abnormal UA group had an older age (p � 0.009), a higher BMI (p < 0.01), higher incidence of hypertension (p < 0.01) and CHD (p � 0.038), and more tumor size< 5 cm (p � 0.016). (Table 2).

Short-Term
Outcomes. Te short-term outcomes were compared in diferent groups. Accordingly, no diference was found between the normal UA group and the abnormal UA group (p > 0.05). Patients in the abnormal BUN group had a longer hospital stay (p � 0.002) and more overall complications (p � 0.001) than the normal BUN group. Te abnormal CysC group had a longer hospital stay (p < 0.01), more overall   A total of 5473 CRC patients performed with radical resection at a single clinical medical center Te exclusion criteria: (n=3426) 1, non-R0 CRC surgery (n=25); 2, incomplete clinical data (n=849); 3, incomplete records of blood urea nitrogen (BUN), serum uric acid (UA) and cystatin C (CysC) before surgery (n=2552).

Cox Analyses for OS and DFS.
Cox regression analyses were conducted to identify the independent risk factors for OS and DFS.  (Table 5).
However, none of BUN, CysC, or UA were independent risk factors for OS or DFS (p > 0.05).

Kaplan−Meier Curves in Diferent TNM Stages.
Te median follow-up time was 35 (1-114) months. Since CysC was found to be a potential risk factor for OS and DFS, we adopted the Kaplan−Meier method and log-rank test to compare the OS ( Figure 2) and DFS (Figure 3) between the abnormal CysC group and the normal CysC group in TNM stages I-IV. Consequently, abnormal CysC were associated with worse OS (p < 0.01) and DFS (p < 0.01) for CRC patients in TNM stage I. However, no signifcant diference was found between the two groups for OS and DFS in stages II-IV (p > 0.05).

Discussion
A total of 2047 CRC patients were enrolled in the current study. We investigated the impact of biochemical indicators, including BUN, UA, and CysC, which were associated with kidney function, on the short-term outcomes and prognosis of CRC patients who underwent radical surgery.
It was reported that nearly 15% of CRC patients had CKD [35]. Previous studies found that CRC patients with CKD had more postoperative complications, especially cardiovascular diseases [18][19][20]. Te abnormal renal function also led to an increase in BUN, UA, and CysC in serum.  In this study, patients in the abnormal BUN group had longer hospital stay and more overall complications than the normal BUN group, and patients in the abnormal CysC group had a longer hospital stay and more overall complications and major complications than the normal CysC group. However, we found the abnormal level of UA did not afect the short-term outcomes. Te CysC was a sensitive indicator which could early identify the injury of kidney fltration function [23]. Tus, the monitoring of preoperative CysC might help to early identify patients with postoperative complication risks. BUN was one of the main products in protein metabolism, and it was usually used to estimate glomerular fltration function [22]. Te BUN in the serum began to   increase only if the GFR decreased to less than 50%, which refected the severity of CKD. Sohal DP et al. found elevated BUN before surgery indicated worse OS in pancreatic adenocarcinoma, which was simply explained as that higher BUN might imply subclinical organ dysfunction. However, whether preoperative BUN afected the prognosis of CRC  patients was rarely reported, and our study found that BUN was not associated with the OS or DFS. Te underlying mechanism needs to be further studied.
UA was an antioxidant as well as a pro-oxidant, which was produced from purine nucleotides, and the process was mediated by xanthine oxidase [36,37]. It was widely reported that oxidative stress could facilitate the development of tumors; therefore, the prognostic value of UA might be controversial. Dziaman et al. frst reported that CRC patients with high levels of UA in their serum had longer survival in a cohort study conducted in Poland [38]. However, in China, Mao et al. obtained the opposite conclusion that lower UAlevel patients lived longer than those with higher serum UA [39]. Te author attributed the incongruity to racial differences. Moreover, in a retrospective study including 332 patients, it was found that a higher preoperative UA was a risk factor for OS [40]. Nevertheless, diferent from the conclusions above, we found that preoperative UA had no obvious impact on OS or DFS for CRC patients.
In this study, although higher CysC was found to be associated with worse OS and DFS in CRC patients in tumor stage I, CysC was not an independent risk factor for DFS and OS. Kos demonstrated that patients with higher CysC had worse OS but it was not an independent indicator as well [30]. Besides the capacity to indicate the injury of kidney function, CysC was an inhibitor of cysteine proteinases, and the imbalance between cysteine proteinases and its inhibitors was proved to promote tumor invasion and metastasis [41]. As a result, the level of CysC in the serum might refect the activity of tumor cells and the intensity of antitumor reactions in the body of cancer patients, which partly helped to explain the correlation between CysC and prognosis. However, it remained unclear why only patients in TNM stage I had worse OS and DFS.
To our knowledge, this was the frst study to fnd that abnormal CysC was associated with more postoperative complications and worse OS and DFS in CRC patients with a relatively large sample size. Meanwhile, we also pointed out that preoperative UA had no obvious impact on OS and DFS for CRC patients, which was inconsistent with previous studies. Nevertheless, there were some limitations in our study as well. For this was a retrospective study conducted in a single clinical center, confounding bias was inevitable. Second, chemotherapeutic information was lacking in TNM III-IV patients, which might impair the reliability of the survival analysis. Terefore, multicenter prospective studies with a large sample size are needed to identify the predictive roles of these indicators.  In conclusion, abnormal CysC was signifcantly associated with worse OS and DFS at TNM stage I, and abnormal CysC and BUN were related to more postoperative complications. However, preoperative BUN and UA in the serum might not afect OS and DFS for CRC patients who underwent radical resection.

Data Availability
Te data used to support the fndings of this study are available from the corresponding author upon request.

Ethical Approval
Te study was approved by the Ethics Committee of our institution (the First Afliated Hospital of Chongqing Medical University, 2022-135-2). Tis study was conducted in accordance with the World Medical Association Declaration of Helsinki as well.

Consent
All patients signed informed consent.

Conflicts of Interest
Te authors declare that they have no conficts of interest.