Does chronic kidney disease affect the short-term outcomes and prognosis of colorectal cancer surgery? A propensity score matching analysis

Purpose The aim of this study was to analyze the effect of chronic kidney disease (CKD) on the short-term outcomes and prognosis of colorectal cancer (CRC) patients who underwent primary surgery. Methods CRC patients who underwent radical surgery were included from Jan 2011 to Jan 2020 in a single hospital. The short-term outcomes and prognosis were compared between the CKD group and the Non-CKD group using propensity score matching (PSM) analysis. Results A total of 4056 patients undergoing CRC surgery were included, including 723 patients in the CKD group and 3333 patients in the Non-CKD group. After 1:1 PSM, there were 666 patients in each group, respectively. No significant difference was found in baseline characteristics between the two groups. (p>0.05). After PSM, the CKD group had a longer postoperative hospital stay (P=0.009) and a higher incidence of overall complications (p=0.050). Cox analysis was performed on matched patients to find predictors of overall survival (OS) and disease-free survival (DFS). We found that age (p<0.01, HR=1.045, 95% CI=1.028–1.062), tumor stage (p<0.01, HR=1.931, 95% CI=1.564–2.385) and overall complications (p<0.01, HR=1.858, 95% CI=1.423–2.425) were independent predictors of OS. Age (p<0.01, HR=1.034, 95% CI=1.020–1.049), tumor stage (p<0.01, HR=1.852, 95% CI=1.537–2.231), and overall complications (p<0.01, HR=1.651, 95% CI=1.295–2.10) were independent predictors of DFS. However, CKD was not an independent predictor of OS or DFS (OS: p=0.619, HR=1.070, 95% CI=0.820–1.396; DFS: p=0.472, HR=1.092, 95% CI=0.859–1.389). Conclusion CKD prolonged postoperative hospital stay; however, CKD might not affect major postoperative complications, OS or DFS of CRC.


Introduction
According to the global statistics released by the International Agency for Research on Cancer in 2022, the new cases of colorectal cancer (CRC) accounted for 9.6% of the new cases of malignant tumors in the world annually, ranking second only to breast and lung cancer in women.Moreover, CRC-related deaths accounted for 9.3% of cancer-related deaths, making it the second leading cause of cancer mortality after lung cancer (1)(2)(3)(4).
Nowadays, chronic kidney disease (CKD) has become a global public health problem, and Asia has one of the highest prevalence of CKD (5)(6)(7).According to statistics, in 2019, there were 9.8 million new CKD cases and 763,024 CKD-related deaths in Asia (8,9).
Several studies have shown that CKD was significantly associated with an increased incidence of CRC (10)(11)(12).However, the precise effect of CKD on postoperative complications and prognosis in CRC remains a subject of debate.While Currie A et al. suggested that CKD patients might be more likely to develop cardiovascular complications after CRC resection and had an increased risk of disease-free survival (DFS) (13); Huang CS et al. found that the CKD group had a significantly lower 3-year DFS rate compared to the Non-CKD group (14); Moreover, Nozawa H et al. concluded that CKD had little effect on overall survival (OS) in TNM stage III CRC patients (15).
As previous studies reported, it was unclear the effect of CKD on postoperative complications and prognosis in CRC, Therefore, the purpose of the current study was to analyze the effect of CKD on the short-term outcomes and prognosis of CRC patients undergoing primary surgery for CRC.

Methods
Patients CRC patients who underwent radical surgery were included from Jan 2011 to Jan 2020 in a single clinical teaching hospital.This study was performed following the World Medical Association Declaration of Helsinki.And this study obtained Ethical approval from the institutional review board (The First Affiliated Hospital of Chongqing Medical University, 2024-010-01).All patients participating in the study obtained written informed consent.

Inclusion and exclusion criteria
Patients who underwent primary CRC surgery were included in this study (n=5473).The exclusion criteria were as follows: 1, patients with incomplete clinical information (n=323); 2, non-R0 surgery (n=25); 3, stage IV CRC (n=875); and 4, incomplete renal function examination (n=194).Finally, a total of 4056 patients were included in this study.The flowchart and inclusion and exclusion criteria were shown in Figure 1.

Surgery management and follow-up
All included patients underwent total mesorectal resection or total mesocolic resection based on the oncological principles, with postoperative pathology confirming R0 resection.Routine followup was performed after surgery: every three months for three years, and every six months thereafter.

Definitions
We used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine equation to calculate eGFR to assess renal function in all the included patients.The CKD-EPI equation was gender-specific, and the specific formula was as follows: eGFR = 141 × min (Scr/k, 1)a × max (Scr/k, 1)-1.209×0.993 Age× 1.018 [if female], where Scr was serum creatinine, k was 0.7 for females and 0.9 for males, a was −0.329 for females and −0.411 for males, min indicated the minimum of Scr/k or 1, and max indicated the maximum of Scr/k or 1 (16, 17).CKD was defined as persistent proteinuria or eGFR<60ml/min/1.73m 2 (18), therefore, we defined patients with eGFR< 60ml/min/1.73m 2 as the CKD group and those with eGFR≥ 60ml/min/1.73m 2 as the Non-CKD group.The pathological staging of tumors was basically based on the AJCC 8th edition diagnosis (19).Complications were defined according to the Clavien-Dindo classification (20) and major complications were defined as Clavien-Dindo classification ≥ III complications.III Complications Includes complications requiring surgical, endoscopic, or radiologic intervention; OS was defined as the time from the date of surgery to the individual patients' death of any cause or the last follow-up time; DFS was defined as the time from the date of surgery to the date of radiographic or pathological confirmation of recurrence, death or the last follow-up.

Data collection
We retrospectively collected baseline information and postoperative short-term outcomes through the inpatient system.Baseline information included age, gender, body mass index (BMI), smoking and drinking history, hypertension, type 2 diabetes mellitus (T2DM), tumor location, tumor size and tumor stage (Table 1).Postoperative short-term outcomes included operative time, blood loss, hospital stay, overall complications and major complications (Table 2).Survival data were mainly obtained through the outpatient follow-up system and telephone interviews.

Propensity score matching (PSM)
Since the grouping of the CKD group and the Non-CKD group was non-random, and variables were unbalanced.Therefore, we used PSM in this study.Propensity scores are most commonly estimated by logistic regression, where treatment group is considered the outcome and regressed against observed baseline characteristics (21).We initiated a 1:1 (CKD group vs Non-CKD group) matching analysis by PSM and nearest neighbor matching algorithms and specified a caliper width with 0.01 standard deviation to adjust for differences in baseline characteristics between the two groups.Baseline information for PSM included age, gender, BMI, smoking and drinking history, hypertension, T2DM, tumor location, tumor size and tumor stage.

Statistical analysis
In this article, continuous variables were expressed as mean ± SD, and Frequency variables were expressed as n (%).We use independent samples t-test to analyze differences in eGFR, age, BMI, operation time, blood loss and hospital stay between the CKD group and the Non-CKD group.The chi-square test or Fisher's exact test was used to analyze differences in sex, smoking, drinking, hypertension, T2DM, tumor location, tumor size, tumor stage, overall complications and major complication between the CKD group and the Non-CKD group.Furthermore, to identify

Patients
According to the relevant inclusion and exclusion criteria, a total of 4056 patients undergoing CRC surgery were finally included in this analysis, including 723 patients in the CKD group and 3333 patients in the Non-CKD group.After 1:1 PSM, there were 666 patients in each group (Figure 1).

Baseline characteristics
Before PSM, there were significant differences in the baseline information between the CKD group and the Non-CKD group.The CKD group had older age (P<0.01), a higher proportion of male (P<0.01),higher BMI (P=0.013),higher proportions of smoking and drinking (P<0.01), and more patients with hypertension and T2DM (P<0.01).After 1:1 PSM, there was no significant difference in baseline information between the two groups (p>0.05)(Table 1).

Short-term outcomes
Compared the short-term postoperative outcomes between the CKD group and the Non-CKD group, we found that the CKD group had more blood loss (P=0.025),longer postoperative hospital stay (P<0.01),more overall complications (P<0.01) and more major complications (P=0.003).After PSM, the CKD group still had a longer postoperative hospital stay (P=0.009) and a higher incidence of overall complications (p=0.050).CKD might not affect major complications (P=0.358)(Table 2).

Univariate and multivariate analysis of OS and DFS before and after PSM
The median follow-up time was 33

Discussion
A total of 4056 patients with CRC surgery were included in this analysis finally.After PSM, there were 666 in the CKD group and the Non-CKD group, respectively.After PSM, the CKD group had a longer postoperative hospital stay.However, CKD was not an independent predictor of OS or DFS.
The effect of CKD on the surgical outcomes has been a hot topic.Aune D et al. believed that after cardiac surgery, patients with end-stage renal disease had a significantly higher mortality rate than patients with normal renal function (6) Ciriaco P et al. concluded that hemodialysis (HD) patients who underwent pneumonectomy had a higher incidence of postoperative complications (22); Han IH et al. concluded that patients with end-stage renal disease who underwent spinal surgery had higher morbidity and mortality (23).We concluded that CKD was associated with an increased risk of most surgical outcomes, but the effect of CKD on patients after CRC surgery was controversial.Some studies suggested that CKD increased postoperative morbidity and mortality in CRC patients (12,13,(24)(25)(26)(27).Therefore, the purpose of this study was to analyze the effect of CKD on short-term outcomes and prognosis of CRC undergoing primary surgery.
Our study showed that CKD patients who underwent CRC surgery had longer hospital stays after harmonizing the differences in baseline data, which was consistent with previous studies (12,13).Many clinicians believed that the kidneys and the heart were two organs that interacted with each other (28)(29)(30)(31).Studies had shown that CKD was associated with a significantly increased risk of myocardial infarction, coronary artery disease, left ventricular hypertrophy and death from cardiac causes (28)(29)(30)(31)(32).In addition, CKD led to elevated levels of inflammatory factors, arterial hypercalcification and endothelial dysfunction (32).All of these mechanisms might contribute to delayed postoperative recovery after surgery, thereby increasing the length of hospital stay.Additionally, this endothelial injury could explain the proinflammatory environment in CKD due to uremia, malnutrition, volume overload, or altered calcium and phosphorus metabolism (32).Since inflammatory mediators might lead to malignancy through induction of precancerous mutations, adaptive responses, and environmental changes (33), this also confirmed the association of CKD with the incidence of CRC (7)(8)(9).
In this present study, age, tumor stage, and overall complications were independent predictors of OS and DFS, consistent with previous studies (34,35).Therefore, we should pay attention to the control of operative complications.However, it was worth noting that in the PSM analysis of major postoperative complications, OS and DFS in CRC patients, no significant difference was found between the CKD group and the Non-CKD group.Even though the CKD group showed a higher overall postoperative complication rate before and after PSM, the incidence of major complications was similar between groups.Despite this higher incidence of overall complications, the OS and DFS remained similar between CKD and Non-CKD groups after PSM.Therefore, further research is warranted to elucidate the precise impact of CKD on prognosis.
After reviewing the relevant studies, we learned that although there were few previous studies on the effect of CKD on CRC surgery, this study was the first to use PSM to analyze the impact of CKD on the short-term outcomes and prognosis of CRC patients.The use of PSM greatly reduced differences in the baseline characteristics and made conclusions more reliable.And compared to conventional PSM articles, this study also analyzed pre-matching data, which better illustrated the effect size of potential confounding factors.However, this study also had some limitations.First, this was a retrospective single-center study; second, the follow-up time was relatively short; third, this study only compared the CKD group and the Non-CKD group, and lacked specific staging studies of CKD; fourth, our results might still be biased due to selection bias stemming from unbalanced data.Therefore, we are looking forward to more comprehensive multicenter prospective randomized controlled studies to further confirm our findings in the future.In future research, we also would like to use advanced methodologies, such as Cox regression with shared frailty, to enhance the methodological robustness and better align with the standards of academic excellence.
In conclusion, CKD prolonged postoperative hospital stay; however, CKD might not affect major postoperative complications, OS or DFS of CRC.

FIGURE 1 Flow
FIGURE 1Flow chart of patient selection.

TABLE 1
Baseline characteristics of CKD before and after PSM.

TABLE 2
Short-term outcomes before and after PSM.

TABLE 3
Univariate and multivariate analysis of overall survival of the whole cohort and disease free survival of the whole cohort before PSM.

TABLE 4
Univariate and multivariate analysis of overall survival of matching cohort and disease free survival of matching cohort after PSM.