Effect of hemodialysis on short-term outcomes after colon cancer surgery.

BACKGROUND: Hemodialysis patients who undergo surgery have a high risk of postoperative complications. The aim of this study was to determine whether colon cancer surgery can be safely performed in hemodialysis patients.
METHODS: This multicenter retrospective study included 1372 patients who underwent elective curative resection surgery for colon cancer between April 2016 and March 2020.
RESULTS: Of the total patients, 19 (1.4%) underwent hemodialysis, of whom 19 (100%) had poor performance status and 18 had comorbidities (94.7%). Minimally invasive surgery was performed in 78.9% of hemodialysis patients. The postoperative complication rate was significantly higher in hemodialysis than non-hemodialysis patients (36.8% vs. 15.5%, p = 0.009). All postoperative complications in the hemodialysis patients were infectious type. Multivariate analysis revealed a significant association of hemodialysis with complications (odds ratio, 2.9362; 95%CI, 1.1384-7.5730; p = 0.026).
CONCLUSION: Despite recent advances in perioperative management and minimally invasive surgery, it is necessary to be aware that short-term complications can still occur, especially infectious complications in hemodialysis patients.

Introduction

Colorectal cancer is the third most commonly diagnosed cancer worldwide and the number of patients continues to increase; there were an estimated 1.8 million new cases in 2018 [1]. The increased use of minimally invasive surgery and advances in perioperative management have improved perioperative performance following surgery for colorectal cancer [2-5].

The prevalence of chronic kidney disease has been estimated as 9.1%, and the number of patients receiving renal replacement therapy exceeded 2.5 million worldwide in 2017 [6]. Although long-term survival has improved following advances in oral medications and medical devices, including hemodialysis (HD), HD patients encounter additional obstacles because they often have numerous other systemic comorbidities and are more likely to suffer postoperative complications [7].

In recent years, the number of patients requiring long-term HD has increased; accordingly, the number of HD patients who develop colon cancer that requires surgery has also increased [8]. However, few studies have reported surgery for colon cancer in HD patients [8-11]. The aim of this multicenter retrospective study is to determine whether colon cancer surgery can be safely performed in HD patients.

Materials and methods

This study design was approved by the Nagasaki University Hospital Clinical Research Ethics Committee (Permission number: 16062715–2). We gave the patients written and oral explanation using the consent statement and obtained consent signature document. This multicenter, retrospective study was designed by the Nagasaki Colorectal Oncology Group (NCOG). We retrospectively reviewed the medical records of 1387 patients, including incomplete clinicopathological data, of consecutive colon cancer patients who underwent curative resection between April 2016 and March 2020 at a participating hospital (Nagasaki University Hospital, Sasebo City General Hospital, Nagasaki Medical Center, Isahaya General Hospital, Ureshino Medical Center, and Saiseikai Nagasaki Hospital). After excluding patients with synchronous colon cancer (n = 15), 1372 patients were eligible for analysis. The study protocol was reviewed and approved by the Clinical Research Review Boards of all participating hospitals.

The patients were divided into three groups according to renal function, as follows: HD group (n = 19), renal dysfunction group (n = 59), and normal group (n = 1294). The renal dysfunction and normal patients together were classified as the non-HD group. In Japan, chronic kidney disease is generally defined as persistence for ≥3 months of one or more of the following: obvious kidney disease in pathological examination, estimated glomerular filtration rate <60 ml/min/1.73m2 in blood test, or proteinuria in urinalysis. In this study, renal dysfunction was defined as chronic kidney disease without HD.

We compared the clinical features among the groups and collected the following data: sex, age at surgery, body mass index (BMI), American Society of Anesthesiologists (ASA)-performance status (PS), comorbidities, tumor location, tumor size, preoperative chemotherapy, preoperative stent placement, clinical T status, clinical N status, and distant metastasis. Comorbidities included such as hypertension, diabetes, heart disease, and cerebrovascular disease. Regarding tumor location, we defined right-side colon as from the cecum to the transverse colon, and left-side colon as from the descending to the sigmoid colon. The following surgical and pathological data were collected: approach, combined resection of adjacent organs, number of retrieved lymph nodes, tumor size, operation time, estimated blood loss, postoperative complications, and postoperative hospital stay. Table 1 lists all comorbidities that were assessed, including hypertension, diabetes, dyslipidemia, heart disease, and cerebrovascular disease. Table 2 shows the presence or absence of the same comorbidities as in Table 1, except for HD and renal dysfunction. Postoperative complications were defined as those occurring within 30 days of the primary surgery.

Table 1

Patient characteristics.

	All patients (n = 1372) (%)
Sex
Male	714 (52.0)
Female	658 (48.0)
Age, y (range)	72 (24–96)
Body mass index, kg/m2 (range)	22.1 (12.9–42.0)
ASA performance status
1	429 (31.3)
2	815 (59.4)
3–	118 (8.6)
Comorbidity, present	874 (63.7)
Renal function
HD	19 (1.4)
Renal dysfunction	59 (4.3)
Normal	1294 (94.3)
Tumor location
Right-side colon	715 (52.1)
Left-side colon	656 (47.8)
Tumor size, mm (range)	40 (0.6–190)
Preoperative chemotherapy	43 (3.1)
Preoperative stent placement	119 (8.7)
Clinical T status
1	312 (22.7)
2	187 (13.6)
3	577 (42.1)
4	278 (20.3)
Clinical N status
0	771 (56.2)
1	352 (25.7)
2	190 (13.8)
3	40 (2.9)
Distant metastasis, present	173 (12.6)
Approach
Open	197 (14.4)
Laparo	1173 (85.5)
Combined resection
None	1267 (92.3)
Yes	99 (7.2)
Retrieved lymph nodes, n (range)	16 (0–115)
Operation time, min (range)	211 (55–725)
Blood loss, mL (range)	25 (0–3935)
Postoperative complications, CD ≥ 2	217 (15.8)
Hospital stay, days (range)	13 (3–155)

Data are presented as the number of patients or the median (range).

ASA, American Society of Anesthesiologists; HD, hemodialysis; CD, Clavien–Dindo.

Table 2

Comparison of clinicopathological characteristics by renal function group.

	HD (n = 19) (1.4%)	Renal dysfunction (n = 59) (4.3%)	Normal (n = 1294) (94.3%)	p-value	HD vs Non-HD p-value
Sex				0.518	0.959
Male	10 (52.6)	35 (59.3)	669 (51.7)
Female	9 (47.4)	24 (40.7)	625 (48.3)
Age, y (range)	77 (60–86)	81 (58–96)	71 (24–96)	<0.001	0.282
Body mass index, kg/m2 (range)	21.7 (16.2–31.8)	22.5 (16.0–37.6)	22.0 (12.9–42.0)	0.584	0.482
ASA performance status				<0.001	<0.001
1	0 (0)	11 (18.6)	418 (32.3)
2	0 (0)	33 (55.9)	782 (60.4)
3–	19 (100)	15 (25.5)	84 (6.5)
Comorbidity				<0.001	0.012
None	1 (5.3)	7 (11.9)	400 (30.9)
Yes	18 (94.7)	52 (88.1)	804 (62.1)
Tumor location				0.894	0.966
Right-side colon	10 (52.6)	29 (49.2)	676 (52.2)
Left-side colon	9 (47.4)	30 (50.8)	617 (47.7)
Preoperative chemotherapy				0.508	0.429
None	19 (100)	56 (94.9)	1250 (96.6)
Yes	0 (0)	3 (5.1)	40 (3.1)
Preoperative stent placement				0.399	0.176
None	19 (100)	54 (91.5)	1180 (91.2)
Yes	0 (0)	5 (8.5)	114 (8.8)
Clinical T status				0.164	0.368
1	4 (21.1)	16 (27.1)	292 (22.6)
2	5 (26.3)	3 (5.1)	179 (13.8)
3	8 (42.1)	31 (52.5)	538 (41.6)
4	2 (10.5)	9 (15.3)	267 (20.6)
Clinical N status				0.300	0.267
0	13 (68.4)	38 (64.4)	720 (55.6)
1	6 (31.6)	12 (20.3)	334 (25.8)
2	0 (0)	9 (15.3)	181 (14.0)
3	0 (0)	0 (0)	40 (3.1)
Distant metastasis				0.085	0.093
Absence	19 (100)	55 (93.2)	1108 (85.6)
Presence	0 (0)	4 (6.8)	169 (13.1)
Approach				0.591	0.404
Open	4(21.1)	10 (16.9)	183 (14.1)
Laparo	15(78.9)	49 (83.1)	1109(85.7)
Combined resection				0.372	0.220
None	19 (100)	56 (94.9)	1192 (92.1)
Yes	0 (0)	3 (5.1)	96 (7.4)
Retrieved lymph nodes, n (range)	18 (3–76)	14 (0–45)	16 (0–115)	0.015	0.933
Tumor size, mm (range)	30 (8–80)	42 (4.5–90)	40 (0.6–190)	0.920	0.482
Operation time, min (range)	237 (137–366)	198 (84–461)	211 (55–725)	0.047	0.039
Open	176 (137–366)	138 (84–221)	207 (55–719)	0.014	0.303
Laparo	250 (160–327)	197 (84–461)	211 (82–725)	0.009	0.005
Blood loss, mL (range)	30 (0–243)	30 (0–566)	25 (0–3935)	0.579	0.528
Postoperative complications,				0.070	0.009
CD <2	12 (63.2)	48 (81.4)	1078 (83.3)
CD ≥2	7 (36.8)	11 (18.6)	199 (15.4)
Hospital stay, days (range)	17 (9–155)	15 (8–89)	13 (3–125)	<0.001	0.005

Data are presented as the number of patients or the median (range).

HD, hemodialysis; ASA, American Society of Anesthesiologists; CD, Clavien–Dindo.

Differences in categorical variables were compared using Fisher’s exact test or the chi-squared test, as appropriate. Differences in continuous variables were analyzed with One-way ANOVA (analysis of variance).

Anastomotic leak was defined as stool-like changes in abdominal drainage or abscess formation around the anastomotic site, confirmed by imaging examination. Pneumonia was defined as the presence of respiratory symptoms and imaging findings of pneumonia. Surgical site infection (SSI) was defined as that in an incision, organ, or abdominal cavity affected by surgery. Urinary tract infection was defined as pyuria according to urinalysis. Among the postoperative complications in the HD group, urinary tract infection was defined as patients with urine output who had findings of urinary tract infection. Pseudomembranous colitis and MRSA colitis in which the cause could be identified was termed colitis. Paralytic ileus was defined as the presence of abdominal distension or vomiting, with imaging findings of a dilated intestinal tract suggestive of ileus. Anastomotic bleeding was defined as the presence of melena after surgery and that was confirmed by colonoscopy. Delirium was defined as a transient psychiatric symptom that developed postoperatively. Thrombosis was defined as symptoms of lower limb pain and dyspnea, elevated D-dimer in blood tests, with thrombus identified by ultrasonography or contrast CT, including deep vein thrombosis and pulmonary embolism. Lymphorrhea was defined as milky white ascites with high triglyceride levels and without infectious from abdominal drainage. “Other” included postoperative cholecystitis, neuroleptic malignant syndrome, or stomach volvulus. CD > 2 complications were defined as those requiring antibiotic treatment, surgery or advanced medical care; and death. This time, we focused on CD grades 2 and higher because these are clinically problematic.

Statistical analysis was performed using Bell Curve for Excel software, version 3.00. The data are presented as median values with ranges. Differences in categorical variables were compared using Fisher’s exact test or the chi-squared test. Differences in continuous variables were analyzed with One-way ANOVA (analysis of variance).

Multivariate analysis using binary logistic regression analysis was used to identify the independent risk factors for postoperative complications. Clinical variables with a p value <0.2 in the univariate analysis were included in the multivariate analysis. All p values <0.05 were considered significant.

Results

Table 1 lists the clinicopathological characteristics of the 1372 patients. The study population included 714 male and 658 female patients, with median age of 72 (range, 24–96) years. The median BMI was 22.1 (range, 12.9–42.0) kg/m2, 933 patients (68.0%) had poor PS (PS≥2), 874 patients (63.7%) had preoperative comorbidities, and 1173 patients (85.5%) received laparoscopic surgery. The median operation time and blood loss were 211 (range, 55–725) min and 25 (range, 0–3935) mL, respectively. Postoperative complications (CD ≥2) occurred in 217 patients (15.8%). The median postoperative hospital stay was 13 (range 3–155) days.

Table 2 shows the comparison of clinicopathological differences among the three renal function groups. Age, ASA-PS, preoperative comorbidities excluding renal dysfunction, number of retrieved lymph nodes, operation time, postoperative complications, and postoperative hospital stay showed significant difference among the groups. There were also significant differences in postoperative complications (CD ≥2) between the HD and non-HD groups (p = 0.009). The rate of patients with postoperative complications (CD >2) was 36.8% (n = 7) in the HD group, 18.6% (n = 11) in the renal dysfunction group, and 15.4% (n = 199) in the normal group. There were no significant differences in any other factors among the three groups. There were significant differences between the HD and non-HD groups in terms of ASA-PS, preoperative comorbidities excluding renal dysfunction, operation time, postoperative complications, and postoperative hospital stay.

Table 3 lists the postoperative complications (CD ≥2) in the three groups. The overall postoperative complication (CD ≥2) rate was 17.2% (n = 236): 7 (36.8%) in the HD group (n = 19), 11 (18.6%) in the renal dysfunction group (n = 59) and 218 (16.8%) in the normal group (n = 1294). All postoperative complications in the HD group (n = 7) were infectious complications: anastomotic leak (n = 3), pneumonia (n = 2), surgical site infection (SSI) (n = 1), and urinary tract infection (n = 1). All those in the renal dysfunction group (n = 11) were infectious complications, including anastomotic leak (n = 5), SSI (n = 4), urinary tract infection (n = 1), and intraperitoneal abscess (n = 1). Those in the normal group were SSI (n = 50), anastomotic leak (n = 48), and paralytic ileus (n = 45).

Table 3

Postoperative complications (CD ≥2).

	HD (n = 19) (%)	Renal dysfunction (n = 59) (%)	Normal (n = 1294) (%)
Postoperative complication, CD ≥ 2	7 (36.8)	11 (18.6)	218 (16.8)
Infectious complications	7 (36.8)	11 (18.6)	131 (10.1)
Anastomotic leak	3 (15.8)	5 (8.5)	48 (3.7)
Pneumonia	2 (10.5)	-	13 (1.0)
SSI	1 (5.3)	4 (6.8)	50 (3.9)
Urinary tract infection	1 (5.3)	1 (1.7)	8 (0.6)
Intraperitoneal abscess	-	1 (1.7)	4 (0.3)
Pseudomembranous colitis	-	-	7 (0.5)
MRSA colitis	-	-	1 (0.1)
Non-infectious complications	-	-	87 (6.7)
Paralytic ileus	-	-	45 (3.5)
Anastomotic bleeding	-	-	9 (0.7)
Delirium	-	-	4 (0.3)
Lymphorrhea	-	-	4 (0.3)
Thrombosis	-	-	3 (0.2)
Other	-	-	22 (1.7)

Differences in categorical variables were compared using Fisher’s exact test or the chi-squared test, as appropriate.

HD, hemodialysis; CD, Clavien–Dindo; SSI, surgical site infection.

Table 4 lists the results of univariate and multivariate analyses. Multivariate analysis revealed HD (odds ratio, 2.9362; 95%CI, 1.1384–7.5730; p = 0.026) as a risk factor significantly associated with complications.

Table 4

Clinicopathological factors predicting postoperative complications in colon cancer patients.

	Univariate analysis			Multivariate analysis
	Odds ratio	95%CI	p value	Odds ratio	95%CI	p value
Sex			0.908
Female	1
Male	1.0172	0.7606–1.3604
Age, y			0.426
<70	1
≥70	1.1278	0.8385–1.5169
Body mass index, kg/m2			0.242
<25	1
≥25	0.8030	0.5561–1.1595
ASA performance status			0.610
1	1
2–	1.0858	0.7913–1.4899
HD			0.018			0.026
None	1			1
Yes	3.1278	1.2173–8.0369		2.9362	1.1384–7.5730
Tumor location			0.893
Right-side colon	1
Left-side colon	1.0201	0.7629–1.3640
Preoperative chemotherapy			0.945
None	1
Yes	1.0292	0.4519–2.3441
Clinical T status			0.500
–3	1
4	1.1300	0.7923–1.6117
Clinical N status			0.966
Absence	1
Presence	1.0064	0.7480–1.3542
Distant metastasis			0.247
Absence	1
Presence	1.2784	0.8434–1.9378
Approach			0.427
Laparo	1
Open	1.1755	0.7891–1.7510
Combined resection			0.938
None	1
Yes	1.0222	0.5859–1.7833
Operation time, min			0.070			0.0935
<222	1			1
≥222	1.3107	0.9785–1.7557		1.2856	0.9585–1.7244

HD, hemodialysis; ASA, American Society of Anesthesiologists; CD, Clavien–Dindo.

Discussion

This multicenter, retrospective study investigated the short-term outcomes of consecutive colon cancer patients who underwent curative resection. The postoperative complication rate was significantly higher in HD than non-HD patients (36.8% vs. 15.5%, p = 0.009). All postoperative complications in the HD patients were infectious type. Univariate and multivariate analyses revealed HD as a risk factor for postoperative complications.

In a retrospective and multi-institutional study regarding the relationship between dialysis and postoperative outcomes in colorectal cancer, Hu et al. reported that 0.6% of patients were undergoing dialysis [12]. Gajdos et al. performed a retrospective cohort study of the complications and short-term outcomes of elective general surgery in dialysis patients, and found that 0.9% of all patients were dialysis patients and 97.7% of dialysis patients were ASA-PS>3 [13]. In the present study, the proportion of HD patients in the overall cohort was 1.4%, and these patients had poorer PS (ASA-PS>3, n = 19 [100%]) and a higher rate of comorbidities (94.7%).

Dialysis patients undergoing surgery are known to have a high risk of postoperative complications, including infectious complications, acute coronary syndrome (ACS), ischemic bowel disease, and bleeding [10,14]. A previous study reported a complication rate of 41.4% in HD patients after elective abdominal surgery [8], whereas in the present study, postoperative complications occurred in 36.8% of HD patients. Surprisingly, all of the present complications were infectious. Several other studies have also reported a tendency for dialysis patients to develop postoperative infections, especially pneumonia and SSI [12,13]. A possible reason for this tendency is that patients with uremia are more susceptible to infectious agents; in addition, renal anemia and hypoproteinemia suppress the healing process and cause proliferation of fibroblasts and delayed wound healing, resulting in SSI or anastomotic leakage [9,15-17]. Another possible explanation is that dialysis treatment induces diffusion of carbon dioxide in the dialysate, resulting in hypoxemia and reflex hypoventilation, which increases the risk of postoperative atelectasis and pneumonia [18]. The low head position that is often used in colorectal cancer surgery can also cause respiratory complications, including atelectasis; accordingly, anesthesiologists set high positive end-expiratory pressure or allow high airway pressure.

A previous study reported that 33% of dialysis patients and 42% of non-dialysis patients underwent laparoscopic surgery for colorectal cancer surgery, and concluded that in dialysis patients, the laparoscopic approach was associated with fewer postoperative complications, lower mortality, and shorter total length of hospital stay [12]. In the present study, a high proportion of HD patients (78.9%) underwent laparoscopic surgery; compared with open surgery, the laparoscopic approach has a lower risk of infectious complications because it is less invasive and the length of the wound is shorter. However, the rate of infectious complications in the present study was still high, which may be due in part to the long operation time. Accordingly, we consider that surgery for HD patients should be performed in the shortest possible time by an experienced surgical team. In addition to consideration of the best surgical approach, it is also important to pay attention to the perioperative care of HD patients who undergo surgery for colon cancer.

It is noteworthy that the complications of ACS or ischemic bowel disease were not observed in our study. Dialysis patients are likely to develop conditions that promote arteriosclerosis, such as storage of uremic toxins, abnormal metabolism of minerals such as phosphorus and calcium, and increased fluid volume. Accordingly, they often develop vascular complications such as ACS and ischemic bowel disease. In fact, a dialysis regimen has been reported that employs strict fluid management for patients undergoing elective colorectal surgery, with the aim of reducing the rates of postoperative cardiopulmonary and tissue-healing complications [19,20]. Currently, dialysis treatment is often performed the day before and after elective surgery, and advances in intraoperative and postoperative management include such as fluid restriction and the use of vasodilators. In the present study, surgeries for HD patients were performed at high-volume centers that have nephrology and cardiology facilities. It is desirable that surgeries for HD patients should be performed at such well-managed facilities.

This study has several limitations. First, it was a retrospective study and the sample size of HD patients was small. The proportion of HD patients was reported to be ~0.3% in the general population and 0.6% in a colorectal cancer cohort [12]. In the present study, 1.4% of all participants were HD patients, which is similar to previous reports [12,13]. To further examine the number of HD patients, a larger scale study is needed. Second, we analyzed only patients who underwent colon cancer surgery, and excluded those who were unable to undergo surgery due to poor general condition or underwent emergency surgery. Anastomotic leakage is a serious complication and the rate was high in our study. Although recent studies have proposed that blood flow evaluation by indocyanine green is useful for detecting anastomotic leakage, we did not perform this evaluation due to a lack of specific equipment and because performing the test would require the consensus of all attending physicians [21,22]. Further prospective evaluation is needed to resolve this issue. Third, although Hb and albumin are also very important factors, it is difficult to collect additional blood test data because the present data were collected from multiple facilities. However, we calculated variance inflation factors (VIFs) to detect multi-collinearity among the predictors in our regression model. The VIFs were 1.902 (sex), 2.355 (age), 1.279 (BMI), 3.214 (ASA-PS), 1.039 (HD), 1.678 (tumor location), 1.168 (preoperative chemotherapy), 1.832 (clinical T), 2.131 (clinical N), 1.375 (clinical M), 1.345 (combined resection), 1.272 (surgical approach), and 2.132 (operation time). Therefore, we consider that multi-collinearity is not a significant problem in our model.

Conclusion

It is expected that the number of colon cancer surgeries performed in HD patients will continue to increase. As advances in perioperative management and minimally invasive surgery have become mainstream, it is necessary to remain aware that short-term complications can occur, especially infectious complications in HD patients.

(XLSX)

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28 Apr 2021

PONE-D-21-10207

Effect of hemodialysis on short-term outcomes after colon cancer surgery

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Reviewer #1: Since “Hemodialysis patients who undergo surgery have a high risk of postoperative complications” has well documented in many studies, conclusions of this study did not provide new information for readers. I teject this study due to lack of novelty.

Reviewer #2: In this manuscript, Shiraishi and colleagues used a multicenter and retrospective analysis to examine the association between hemodialysis patients and elective curative resection surgery for colon cancer based on the multicenter and retrospective study. This research involved 1165 patients who had colon cancer surgery and included 19 patients on hemodialysis, 59 patients with renal disfunction, and 1087 patients who had normal renal function. Male sex and hemodialysis had a significant correlation in postoperative complications in patients following colon cancer surgery, according to the univariate and multivariate analysis. The following are my questions and recommendations for the authors to consider improving the manuscript:

1. The aim of this study is to explore whether colon cancer surgery can be done safely in hemodialysis patients. The hemodialysis patients are the main topic, but the samples size of hemodialysis analyzed is slightly smaller. While I am aware that the authors include a summary in the discussion section, may key question remains.

Please provide a more detailed explanation about the blind spots caused by this point.

2. In Table 4, the univariate and multivariate analysis revealed sex had a significantly association with complications. Please clarify this in the discussion. In addition, Table 4 is difficult to understand. For example, authors mentioned that univariate analysis revealed male sex (Odds ratios, 1.8537; 95%CI, 1.3445-2.5556; p<0.001) and HD (Odds ratio, 2.9593; 95%CI, 1.1163-7.8451; P=0.029) are risk factors significantly associated with complications in the result section. Please confirm in Table 4.

3. In the result section, authors mentioned that the rate of patients with postoperative complications (CD>2) was 36.5% (n=7) in the hemodialysis group, 18.6% (n=11) in the renal disfunction group, and 16.2% (n=176) in the normal group. This result is from Table 3, not in Table 2. Please confirm if the rate of patients with postoperative complications in the hemodialysis group is 36.5% or 36.8%.

5. Please revise the abstract to explain the research’s findings and conclusions more clearly. The abstract need to be remodeled.

6. The manuscript is not well written and requires an English language editing

Reviewer #3: # The major concern is the definition of the outcome. How were the outcomes measured? In the Methods session, the authors defined the postoperative complications as patients with Clavien–Dindo (CD) grade 2 or higher that occurred within 30 days of the primary surgery. However, the author did not indicate the definitions of the complications clearly and what is Clavien–Dindo (CD) grade 2 or higher. In the Results session (Table 3), the authors listed the complications they included, but they still not defined them clearly. In addition, is anastomotic leak usually defined as infectious complication as shown in the Table 3, or is it related to technique problem and leading to secondary infection? Furthermore, one of the post-op complications among HD patients is UTI. The concern is that is this patient truly has UTI or just asymptomatic pyuria?

# In the Methods session, the authors excluded patients with incomplete laboratory data or synchronous colon cancer; 1165 patients were included in the final analysis. However, the authors did not show that how many patients were evaluated initially and how many were excluded due to incomplete laboratory data and synchronous colon cancer, respectively? Are there any differences in characteristics between those who were excluded and those who included in the analysis? In addition, in the results session, the authors did not present any lab data. Why did they need to exclude patients with incomplete laboratory data? I think it is more reasonable that the authors included those patients in the analysis and treated incomplete laboratory data as missing data.

# In the Methods session, the authors should define renal disfunction more clearly. What are the definitions of proteinuria and low glomerular filtration rate according to blood and urinary tests? In addition, the authors did not indicate clearly what comorbidities did they include?

# In the statistical analysis of Methods session, there is a sentence: “Differences in continuous variables were analyzed with the chi-squared test.” This is a wrong statement.

# In the Table 4, the author did not show the odds ratio and 95% C.I. of the univariable analysis. It is kind of weird. In addition, the authors did not indicate what variables were adjusted in the multivariable logistic regression. Particularly, comorbidity such as diabetes mellitus may be confounders.

# The authors concluded that to reduce the risk of postoperative complications, it is important that surgery for HD patients is performed in facilities with experienced surgical teams and excellent perioperative management. The authors did not evaluate whether experienced surgical teams and perioperative management were associated with less complications among HD patients, so they should not draw this conclusion.

**********

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Reviewer #2: No

Reviewer #3: Yes; Dr. Ming-Yan Jiang

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28 Sep 2021

Response to Reviewer #1:

Since “Hemodialysis patients who undergo surgery have a high risk of postoperative complications” has well documented in many studies, conclusions of this study did not provide new information for readers. I teject this study due to lack of novelty.

Response: As you pointed out, previous studies have reported the problem of increased risk of short-term complications in HD patients. However, in recent years the spread of minimally invasive surgery and improvements in perioperative management have contributed to a reduction in the complication rate. In the present manuscript, we report the current status of surgery for HD patients, with relatively recent data.

Response to Reviewer #2:

1. The aim of this study is to explore whether colon cancer surgery can be done safely in hemodialysis patients. The hemodialysis patients are the main topic, but the samples size of hemodialysis analyzed is slightly smaller. While I am aware that the authors include a summary in the discussion section, may key question remains.

Please provide a more detailed explanation about the blind spots caused by this point.

Response: The proportion of HD patients was reported as ~0.3% in the general population, and 0.6% in a colorectal cancer cohort (Hu WH et al., Int J Colorectal Dis 2015;30:1557-1562). In the present study, 1.4% of all participants were HD patients, which is similar to previous reports (Hu WH et al., Int J Colorectal Dis 2015;30:1557-1562) (Gajdos C et al., JAMA Surg. 2013; 148(2): 137-143). To further examine the number of HD patients, a larger scale study is needed. We have added these sentences to the Limitations section, and rewrote the sentence “Postoperative complications were most frequent in HD patients, and were infectious in all cases.” to “The postoperative complication rate was significantly higher in HD than non-HD patients (36.8% vs. 15.5%, p = 0.009). All postoperative complications in the HD patients were infectious type.” in the Discussion section.

2. In Table 4, the univariate and multivariate analysis revealed sex had a significantly association with complications. Please clarify this in the discussion. In addition, Table 4 is difficult to understand. For example, authors mentioned that univariate analysis revealed male sex (Odds ratios, 1.8537; 95%CI, 1.3445-2.5556; p<0.001) and HD (Odds ratio, 2.9593; 95%CI, 1.1163-7.8451; P=0.029) are risk factors significantly associated with complications in the result section. Please confirm in Table 4.

Response： I apologize for this error. We have corrected “univariate” to “multivariate” in this sentence. As pointed out by reviewer #3, we did not show how many patients were evaluated initially and how many were excluded due to incomplete laboratory data and synchronous colon cancer, respectively. Accordingly, we performed the statistical analysis again in the total of 1372 cases, including those with missing data. Although there was almost no change in the content, “male sex” was not used in multivariate analysis because there was no significant difference in the univariate analysis (p > 0.20). Therefore, we deleted the reference to “male sex” in Table 4 from the Results and Discussion sections.

3. In the result section, authors mentioned that the rate of patients with postoperative complications (CD>2) was 36.5% (n=7) in the hemodialysis group, 18.6% (n=11) in the renal disfunction group, and 16.2% (n=176) in the normal group. This result is from Table 3, not in Table 2. Please confirm if the rate of patients with postoperative complications in the hemodialysis group is 36.5% or 36.8%.

Response： We apologize for this error. The complication rate in Table 2 was incorrect, and that in Table 3 was correct. We have corrected “36.5%” to “36.8%” in this sentence.

5. Please revise the abstract to explain the research’s findings and conclusions more clearly. The abstract need to be remodeled.

Response： Thank you this suggestion. We have modified the abstract and clarified the conclusion accordingly.

6. The manuscript is not well written and requires an English language editing

Response: The manuscript has been edited by a professional native-English-speaking editor (FORTE Science Communications, https://www.fortescience.com/) and a certificate of editing is provided.

Response to Reviewer #3:

# The major concern is the definition of the outcome. How were the outcomes measured? In the Methods session, the authors defined the postoperative complications as patients with Clavien–Dindo (CD) grade 2 or higher that occurred within 30 days of the primary surgery. However, the author did not indicate the definitions of the complications clearly and what is Clavien–Dindo (CD) grade 2 or higher. In the Results session (Table 3), the authors listed the complications they included, but they still not defined them clearly. In addition, is anastomotic leak usually defined as infectious complication as shown in the Table 3, or is it related to technique problem and leading to secondary infection? Furthermore, one of the post-op complications among HD patients is UTI. The concern is that is this patient truly has UTI or just asymptomatic pyuria?

Response: Thank you for this important comment. As suggested, we have added definitions for each complication and condition of CD>2 in the Materials and Methods section. We classified anastomotic leak as an infectious complication because it occurs despite measures against suture failure such as leak test, reinforcement, and blood flow confirmation with ICG at the anastomotic site. We included one case of urinary tract infection in the postoperative complications of the HD group, that was diagnosed based on the laboratory findings in a patient with residual urine.

# In the Methods session, the authors excluded patients with incomplete laboratory data or synchronous colon cancer; 1165 patients were included in the final analysis. However, the authors did not show that how many patients were evaluated initially and how many were excluded due to incomplete laboratory data and synchronous colon cancer, respectively? Are there any differences in characteristics between those who were excluded and those who included in the analysis? In addition, in the results session, the authors did not present any lab data. Why did they need to exclude patients with incomplete laboratory data? I think it is more reasonable that the authors included those patients in the analysis and treated incomplete laboratory data as missing data.

Response: I apologize for the incorrect sentence “incomplete laboratory data” in the Materials and Methods, which should have been “incomplete clinicopathological data”. In response to the reviewer’s suggestion, we performed the statistical analysis again, in a total of 1372 cases, including those with missing data. We excluded 15 patients with synchronous colon cancer from the total 1387 patients whose data were collected. We have checked all Tables accordingly, but made almost no change to the content. Although multivariate analysis revealed “male sex” as a risk factor significantly associated with complications at the time of the first submission, “male sex” was not used in the multivariate analysis this time because there was no significant difference in the univariate analysis and p >0.20, unlike last time. Multivariate analysis revealed HD (Odds ratio, 2.9362; 95%CI, 1.1384–7.5730; p=0.026) as a risk factor significantly associated with complications, as in the manuscript submitted initially.

# In the Methods session, the authors should define renal disfunction more clearly. What are the definitions of proteinuria and low glomerular filtration rate according to blood and urinary tests? In addition, the authors did not indicate clearly what comorbidities did they include?

Response: We have added definitions for renal dysfunction, urinary infection, and condition of CD>2 in the Materials and Methods section, as follows:

“In Japan, chronic kidney disease is generally defined as persistence for �3 months of one or more of the following: obvious renal dysfunction in pathological examination, estimated glomerular filtration rate <60 ml/min/1.73m2 in blood test, or proteinuria in urinalysis. In this study, renal dysfunction was defined as chronic kidney disease without HD.”

“Comorbidities included such as hypertension, diabetes, heart disease, and cerebrovascular disease.”

“Urinary tract infection was defined as pyuria according to urinalysis. Among the postoperative complications in the HD group, urinary tract infection was defined as patients with urine output who had findings of urinary tract infection.”

# In the statistical analysis of Methods session, there is a sentence: “Differences in continuous variables were analyzed with the chi-squared test.” This is a wrong statement.

Response: I apologize for this incorrect sentence, which has been deleted.

# In the Table 4, the author did not show the odds ratio and 95% C.I. of the univariable analysis. It is kind of weird. In addition, the authors did not indicate what variables were adjusted in the multivariable logistic regression. Particularly, comorbidity such as diabetes mellitus may be confounders.

Response: In response to the reviewer’s suggestion, we have added the odds ratio and 95% C.I. of the univariable analysis to Table 4, and added the sentence “Clinical variables with a p value <0.2 in the univariate analysis were included in the multivariate analysis.” to the Materials and Methods section. We appreciate the reviewer’s important comment about confounders. As pointed out, HD was significantly associated with diabetes mellitus (p = 0.011; Fisher’s exact test).

We calculated variance inflation factors (VIFs) to detect multi-collinearity among the predictors in our regression models. The VIFs were 1.902 (sex), 2.355 (age), 1.279 (BMI), 3.214 (ASA-PS), 1.039 (HD), 1.678 (tumor location), 1.168 (preoperative chemotherapy), 1.832 (clinical T), 2.131 (clinical N), 1.375 (clinical M), 1.345 (combined resection), 1.272 (surgical approach), and 2.132 (operation time). Therefore, we consider that multi-collinearity is not a significant problem in our model.

# The authors concluded that to reduce the risk of postoperative complications, it is important that surgery for HD patients is performed in facilities with experienced surgical teams and excellent perioperative management. The authors did not evaluate whether experienced surgical teams and perioperative management were associated with less complications among HD patients, so they should not draw this conclusion.

Response: Thank you for this important comment. We have modified the Abstract and clarified the Conclusion accordingly. We have added the following sentence to the Abstract: “Despite recent advances in perioperative management and minimally invasive surgery, it is necessary to be aware that short-term complications can still occur, especially infectious complications in hemodialysis patients.”

Submitted filename: renamed_75aef.docx

Click here for additional data file.

1 Nov 2021

PONE-D-21-10207R1Effect of hemodialysis on short-term outcomes after colon cancer surgeryPLOS ONE

Dear Dr. Tominaga,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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PLOS ONE

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #3: No

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #3: No

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #3: No

**********

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Reviewer #2: Yes

Reviewer #3: No

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

Reviewer #3: Major

#1. Why did the authors include those complications? What are they based on?

#2. The authors mentions that the variables with a p value < 0.2 in the univariate analysis were included in the multivariate analysis. That is, in the regression analysis in table 4, they only included HD and operation time in the multivariate model. As shown in their table 2, HD group is associated with comorbidities, which could be confounders and should be adjusted in the regression model. In addition, anemia and malnutrition were also risk factors of post-operational complications. I suggest the authors also to collect lab data such as Hb and albumin and adjust these potential confounders.

Minor

#1. The authors should mention what comorbidity they included in the method session or table 1 and table 2.

#2. In table 4, the authors divided continuous variables such as age, BMI, and operation time into binary variables. They also divided the ordinal variable ASA performance status into binary variable. What do they based on to decide the cut points?

#3. In the methods session, the author indicated the definitions of CKD. What did they mean by “obvious renal dysfunction in pathological examination”? How are the estimated glomerular filtration rates calculated?

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Reviewer #3: Yes: Ming-Yan Jiang

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

30 Nov 2021

Response to reviewers’ comments

November 30, 2021

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Dear Dr. Chen,

Thank you for considering our paper entitled “Effect of hemodialysis on short-term outcomes after colon cancer surgery” (PONE-D-21-10207) for publication in PLOS ONE, subject to revision. We have revised our manuscript according to the helpful comments provided by the reviewers, addressed the concerns raised, and accepted their valuable advice.

Changes in the revised manuscript are shown in bold red font. Our point-by-point responses to the reviewers’ comments are provided below.

Response to Reviewer 3

Major

#1. Why did the authors include those complications? What are they based on?

Response:

We chose the postoperative complications listed in the Clavien Dindo (CD) classification. This time, we focused on CD grades 2 and higher because these are clinically problematic. We have added the following sentence to the Materials and methods section: “This time, we focused on CD grades 2 and higher because these are clinically problematic.”

#2. The authors mentions that the variables with a p value < 0.2 in the univariate analysis were included in the multivariate analysis. That is, in the regression analysis in table 4, they only included HD and operation time in the multivariate model. As shown in their table 2, HD group is associated with comorbidities, which could be confounders and should be adjusted in the regression model. In addition, anemia and malnutrition were also risk factors of post-operational complications. I suggest the authors also to collect lab data such as Hb and albumin and adjust these potential confounders.

Response:

Thank you for this important comment. We calculated variance inflation factors (VIFs) to detect multi-collinearity among the predictors in our regression models. The VIFs were 1.902 (sex), 2.355 (age), 1.279 (BMI), 3.214 (ASA-PS), 1.039 (HD), 1.678 (tumor location), 1.168 (preoperative chemotherapy), 1.832 (clinical T), 2.131 (clinical N), 1.375 (clinical M), 1.345 (combined resection), 1.272 (surgical approach), and 2.132 (operation time). Therefore, we consider that multi-collinearity is not a significant problem in our model. We agree with the reviewer that Hb and albumin are very important factors. However, it is difficult to collect additional blood test data because we have dealt with data from multiple facilities this time. Therefore, we will mention this point as a limitation.

In response, we have added the following to the limitation section: “Although Hb and albumin are also very important factors, it is difficult to collect additional blood test data because the present data were collected from multiple facilities. However, we calculated variance inflation factors (VIFs) to detect multi-collinearity among the predictors in our regression model. The VIFs were 1.902 (sex), 2.355 (age), 1.279 (BMI), 3.214 (ASA-PS), 1.039 (HD), 1.678 (tumor location), 1.168 (preoperative chemotherapy), 1.832 (clinical T), 2.131 (clinical N), 1.375 (clinical M), 1.345 (combined resection), 1.272 (surgical approach), and 2.132 (operation time). Therefore, we consider that multi-collinearity is not a significant problem in our model.”

Minor

#1. The authors should mention what comorbidity they included in the method session or table 1 and table 2.

Response:

Table 1 lists all comorbidities that were assessed, including hypertension, diabetes, dyslipidemia, heart disease, and cerebrovascular disease. Table 2 shows the presence or absence of the same comorbidities as in Table 1, except for HD and renal dysfunction. We have clarified this point in the Materials and methods section.

#2. In table 4, the authors divided continuous variables such as age, BMI, and operation time into binary variables. They also divided the ordinal variable ASA performance status into binary variable. What do they based on to decide the cut points?

Response:

In Japan, ‘elderly’ is defined as age 65 and over, but many people have good PS even if they are aging and have comorbidities. Therefore, it is common in Japan that those aged 70 and over are considered ‘elderly’ when comparing the results statistically.

The BMI considered to indicate obesity differs among countries. In Japan, BMI �25 is generally used as the standard, and for this reason we set the BMI cutoff point to 25.

Regarding operation time, we decided the cutoff point using the ROC curve tool of Bell Curve for Excel software.

We divided ASA-PS into 1 and 2 or more to enable comparison of patients who had good general condition without comorbidities with those who had some comorbidities.

#3. In the methods session, the author indicated the definitions of CKD. What did they mean by “obvious renal dysfunction in pathological examination”? How are the estimated glomerular filtration rates calculated?

Response:

Thank you for this important comment. Many kidney diseases are confirmed by histopathology, and the histopathological findings lead to estimation of renal function prognosis and treatment policy decisions. I apologize that this sentence was incorrect. We have replaced “obvious renal dysfunction” with “obvious kidney disease”. In Japan, the following formula is generally used to calculate eGFR:

eGFR = 194 × serum Cr-1.094 × age-0.287 (× 0.739 for females).

Please also note that we have identified an error in Table 1. Although not directly related to the main focus of this article, the number has been corrected. We apologize for this oversight.

I confirm that all authors have approved the revised manuscript. We hope that we have satisfied the concerns of the reviewers, and that the manuscript will now be considered suitable for publication in PLOS ONE. Please feel free to contact me if any questions arise.

Sincerely,

Tetsuro Tominaga, MD, PhD

Department of Surgical Oncology

Nagasaki University Graduate School of Biological Sciences

1-7-1 Sakamoto, Nagasaki 852-8501, Japan

Phone: +81-95-819-7304 Fax: +81-95-819-7306

E-mail: tetsuro.tominaga@nagasaki-u.ac.jp

Submitted filename: renamed_b4696.docx

Click here for additional data file.

28 Dec 2021

Effect of hemodialysis on short-term outcomes after colon cancer surgery

PONE-D-21-10207R2

Dear Dr. Tominaga,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

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Comments to the Author

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Reviewer #2: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #2: Yes

Reviewer #4: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #2: Yes

Reviewer #4: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

Reviewer #4: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #2: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #2: (No Response)

Reviewer #4: (No Response)

**********

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Reviewer #2: No

Reviewer #4: No

3 Jan 2022

PONE-D-21-10207R2

Effect of hemodialysis on short-term outcomes after colon cancer surgery

Dear Dr. Tominaga:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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