Perioperative approach to nephrotoxicity in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy

Abstract

BACKGROUND

Combining cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a promising treatment approach for peritoneal carcinomatosis (PC). However, intraperitoneal chemotherapeutic agents significantly increase the risk of acute kidney injury (AKI). Identifying perioperative risk factors plays a critical role in preserving renal function.

AIM

To evaluate postoperative renal outcomes in patients with PC who underwent CRS + HIPEC.

METHODS

Patients who underwent CRS + HIPEC for PC between 2017 and 2024 were included in this retrospective cohort study. Demographic data, preoperative estimated glomerular filtration rate, HIPEC agents used (cisplatin, mitomycin C, oxaliplatin), intraoperative fluid management, vasopressor use, and postoperative creatinine levels were recorded. AKI was defined according to the 2012 Kidney Disease: Improving Global Outcomes criteria. Independent predictors were identified through multivariate logistic regression analysis.

RESULTS

AKI developed in 61 of 445 patients (13.7%). Among them, 62.0% were stage I, 24.6% were stage II, and 13.1% were stage III. The highest AKI rate was observed in the cisplatin group (21.4%), with lower rates in the oxaliplatin group (9.6%) and the mitomycin C group (6.5%). Independent risk factors included cisplatin use [odds ratio (OR) = 2.8; 95% confidence interval: 1.6-4.9; P < 0.001), intraoperative fluid administration < 6000 mL (OR = 2.1; P = 0.02), vasopressor requirement (OR = 1.9; P = 0.03), and preoperative estimated glomerular filtration rate < 75 mL/minute/1.73 m² (OR = 2.3; P = 0.01). AKI was associated with a prolonged hospital stay. Three patients (0.7%) progressed to chronic kidney disease.

CONCLUSION

Independent risk factors such as cisplatin use, inadequate fluid replacement, vasopressor requirement, and preoperative renal function should be considered during perioperative planning to reduce AKI risk following CRS + HIPEC.

Key Words: Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy; Acute kidney injury; Cisplatin; Estimated glomerular filtration rate; Perioperative management

Core Tip: We report an acute kidney injury incidence of 13.7% following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy treatment in patients with peritoneal carcinomatosis. Independent risk factors include cisplatin use, inadequate fluid replacement, vasopressor requirement, and reduced preoperative estimated glomerular filtration rate. The collective findings emphasized the importance of thorough preoperative renal function assessment and personalized perioperative fluid management. Chemotherapy agent selection plays a key role in minimizing renal toxicity. Optimal perioperative care is essential in preventing long-term renal complications.

INTRODUCTION

Peritoneal carcinomatosis (PC) is a clinical condition frequently encountered in advanced stages of gastrointestinal and gynecological malignancies. It is associated with significant morbidity and mortality. The most effective treatment approach for improving survival in this patient population is the combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC)[1-3]. The combination of these treatments eliminates macroscopic tumor burden and eradicates microscopic residual disease through the local administration of high-concentration chemotherapy. There are significant systemic side effects of HIPEC, including nephrotoxicity, which is a major complication. Nephrotoxicity is reported in 10%-40% of patients treated with HIPEC and is associated with increased morbidity and healthcare costs[4,5]. The primary mechanism of this nephrotoxicity is the direct proximal tubular damage caused by chemotherapeutic agents (specifically cisplatin and mitomycin C)[2,6]. Factors such as hyperthermic fluid overload, intraoperative hypotension, fluid imbalances, and a systemic inflammatory response can also negatively affect renal function[7].

Recent studies have shown that the development of nephrotoxicity is influenced by the choice of chemotherapeutic agents as well as by various clinical variables, including preoperative performance score (e.g., Karnofsky score), intraoperative bleeding, inadequate urine output, high peritoneal cancer index (PCI), and prolonged intensive care unit stay[8-10]. Therefore, a multidisciplinary evaluation of patient selection, perioperative management, and renal function monitoring is crucial. In HIPEC protocols involving cisplatin, nephroprotective strategies such as sodium thiosulfate, cilastatin, and aggressive hydration effectively reduce nephrotoxicity[11-13]. Nevertheless, there is no standardization of these preventive measures in clinical practice, leading to significant variations in acute kidney injury (AKI) incidence. Moreover, a recent retrospective analysis revealed that overall survival significantly decreased in patients who developed AKI[14].

This study aimed to determine the incidence of AKI in patients with PC treated with CRS + HIPEC, to analyze perioperative risk factors associated with the development of nephrotoxicity, and to evaluate the effectiveness of potential preventive strategies. In recent years, publications on AKI associated with therapeutic agents used after CRS-HIPEC have been presented in the literature. The limited number of studies and the lack of data make it difficult to conduct prospective research. They are insufficient in terms of being conducted with a small number of patients and not being evaluated with multiple parameters. In our tertiary center with extensive CRS-HIPEC experience, we aim for our high-volume and multiple data study to contribute to filling this gap in the literature. The findings produced by this study contributed to the literature and provided guidance to clinicians in predicting and preventing renal complications.

MATERIALS AND METHODS

Study design and patient population

This retrospective cohort study was conducted at the Department of Surgical Oncology, University of Health Sciences, İstanbul Ümraniye Training and Research Hospital, which is a center specializing in peritoneal surface malignancies. A total of 445 patients with PC who were treated with CRS + HIPEC between January 2016 and December 2024 were included in the study. Inclusion criteria were as follows: (1) PC of colorectal, ovarian, gastric, appendiceal, or peritoneal mesothelioma origin confirmed by histopathology; (2) Age ≥ 18 years; and (3) Administration of standard HIPEC protocols following complete or near-complete CRS. Patients were excluded if they had: (1) Preoperative chronic kidney disease stage ≥ 3; (2) End-stage renal disease requiring dialysis; or (3) Incomplete perioperative records.

CRS + HIPEC procedure

During CRS, organ and tumor resections were performed to achieve macroscopic tumor-free status. Anastomoses were created before the HIPEC procedure. HIPEC catheters were placed in the abdominal cavity, and the abdomen was temporarily closed. For PC of gastric, ovarian, or mesothelioma origin, cisplatin [75 mg/m² body surface area (BSA)] dissolved in 0.9% sodium chloride solution was administered intraperitoneally at a temperature of 42-43 °C and a flow rate of 1200 mL/hour for 60 minutes. For PC of colorectal origin, intraperitoneal injections of mitomycin C (35 mg/m² BSA) or oxaliplatin (300 mg/m² BSA) in 0.9% sodium chloride solution were applied over a 60-minute period. We utilized the Belmont Hyperthermia Pump (Belmont Instrument Corporation, Billerica, MA, United States) for the HIPEC procedure.

Data collection

Demographic data (age, sex, BSA), comorbidities (hypertension, diabetes, baseline renal function), primary tumor origin, PCI, completeness of cytoreduction (CC) score, intraoperative variables (duration of surgery, estimated blood loss, intravenous fluid volume, vasopressor use, type and dose of HIPEC agent), and postoperative outcomes (with a focus on nephrotoxicity) were recorded. Patient data were obtained from the surgical oncology database through electronic medical records, anesthesia charts, and operative notes.

Perioperative management

All patients were managed using standardized perioperative protocols by the same multidisciplinary team consisting of surgical, anesthetic, and oncology specialists. Preoperative renal function was assessed by serum creatinine and estimated glomerular filtration rate (eGFR) levels. Perioperative fluid management was assessed by the cardiac index measured using FloTrac and by hemodynamic monitoring conducted with either the FloTrac/Vigileo system (Edwards Lifesciences, Irvine, CA, United States) or the pulse indicating continuous cardiac output catheter (PulsioCath PV2015 L20; Pulsion Medical Systems, Munich, Germany). Nephrotoxic agents such as aminoglycosides and nonsteroidal anti-inflammatory drugs were avoided during the perioperative period. For the cisplatin-based HIPEC regimens, hydration protocols were administered before and after HIPEC, and mannitol-induced diuresis was applied when necessary.

Definition of nephrotoxicity

AKI was defined according to the Kidney Disease: Improving Global Outcomes criteria. An increase in serum creatinine by ≥ 0.3 mg/dL within 48 hours or to ≥ 1.5 times the baseline within 7 days was categorized as AKI. Severity was classified into stages 1-3. In the absence of alternative causes (e.g., hypovolemia, sepsis, contrast nephropathy), renal injury occurring in the perioperative period was considered to be HIPEC-related nephrotoxicity.

Statistical analysis

Statistical analyses were performed using SPSS version 25.0 (IBM Corp., Armonk, NY, United States). Categorical variables were presented as counts and percentages, and continuous variables were expressed as mean ± SD or median (interquartile range). The associations between AKI incidence and perioperative variables were analyzed using the χ² test or Fisher’s exact test for categorical variables and the t-test or Mann–Whitney U test for continuous variables. Multivariate logistic regression analysis was performed to identify independent risk factors for nephrotoxicity. Model performance was assessed by calculating the area under the receiver operating characteristic curve, which demonstrated good discriminative ability. A P value < 0.05 was considered statistically significant.

Ethical approval

This study was approved by the Ethics Committee of Ümraniye Training and Research Hospital, No. 2025-11. Due to the retrospective design of the study, informed consent was not obtained. Patient confidentiality and data security were maintained by using anonymized records in accordance with the principles of the Declaration of Helsinki.

RESULTS

Demographic and clinical characteristics

Among the 445 patients included in the study, 255 (57.3%) were female and 190 (42.7%) were male. The median age was 58 years (range: 24-78 years). The mean body mass index was 26.8 ± 4.2. The most common primary tumor sites were colorectal (46.0%), ovarian (28.0%), gastric (12.0%), appendix (9.0%), and peritoneal mesothelioma (5.0%). The median PCI was 18 (interquartile range: 12-24). Complete (CC-0) or near-complete (CC-1) cytoreduction was achieved in 91.6% of patients (Table 1).

Table 1 Demographic data and association with acute kidney injury, n (%).

Variable	Total (N = 445)	AKI (n = 61)	No AKI (n = 384)	P value
Age (mean ± SD)	58.6 ± 11.4	62.1 ± 10.2	57.9 ± 11.6	0.021
Gender (female/male)	260/185	38/23	222/162	0.448
BMI (kg/m2)	26.1 ± 3.4	26.8 ± 3.2	26.0 ± 3.4	0.097
≥ 1 comorbidity	302 (67.8)	51 (83.6)	251 (65.3)	0.004
ASA score ≥ III	163 (36.6)	31 (50.8)	132 (34.3)	0.012
Preoperative eGFR < 75 mL/minute/1.73 m2	94 (21.1)	24 (39.3)	70 (18.2)	0.001

SD: Standard deviation, AKI: Acute kidney injury; BMI: Body mass index; ASA: American Society of Anesthesiologists; eGFR: Estimated glomerular filtration rate.

Perioperative findings

The mean duration of surgery was 8.4 ± 2.1 hours. The mean intraoperative fluid administration was 8200 ± 1700 mL. Vasopressor support ( > 1 dose) was required in 22.0% of patients. The mean estimated blood loss was 550 ± 210 mL, and 14.6% of patients required a blood transfusion. The mean urine output in the first 72 hours after CRS was 0.7 ± 0.2 mL/kg/hour. Within the first 5 days, 58 patients (13.0%) developed clinical hypervolemia due to fluid overload, of whom 41.0% had an increase in postoperative creatinine (> 0.3 mg/dL) (Table 2).

Table 2 Perioperative findings and association with acute kidney injury, n (%).

Variable	Total (N = 445)	AKI (n = 61)	No AKI (n = 384)	P value
Operation time (minutes, mean ± SD)	360 ± 75	376 ± 78	357 ± 74	0.114
Blood loss (mL, mean ± SD)	550 ± 180	590 ± 205	543 ± 176	0.198
Intraoperative fluid replacement < 6000 mL	173 (38.8)	36 (59.0)	137 (35.6)	0.001
Vasopressor use	128 (28.7)	29 (47.5)	99 (25.7)	0.002
Urine output < 0.5 mL/kg/hour	84 (18.8)	19 (31.1)	65 (16.9)	0.009

AKI: Acute kidney injury; SD: Standard deviation.

Renal function and nephrotoxicity

The preoperative mean serum creatinine was 0.87 ± 0.21 mg/dL, and the mean eGFR was 92 ± 14 mL/minute/1.73 m². No patients were preoperatively diagnosed with chronic kidney disease stage ≥ 3. Postoperative AKI developed in 61 patients (13.7%). According to the Kidney Disease: Improving Global Outcomes classification, 38 patients (62.3%) had stage 1 AKI, 15 patients (24.6%) had stage 2 AKI, and 8 patients (13.1%) had stage 3 AKI. Temporary hemodialysis was required for 3 patients (0.7%) with stage 3 AKI, all of whom recovered before discharge. The mean postoperative creatinine was 1.62 ± 0.48 mg/dL for patients with AKI compared with 0.94 ± 0.19 mg/dL in patients without AKI (P < 0.001). Similarly, mean eGFR was 58 ± 12 mL/minute/1.73 m² in the patients with AKI and 88 ± 15 mL/minute/1.73 m² in the patients without AKI (P < 0.001) (Table 3).

Table 3 Nephrotoxicity data and distribution by chemotherapy agent, n (%).

Variable	Total (N = 445)	Cisplatin (n = 126)	Other agents (n = 319)	P value
AKI incidence	61 (13.7)	27 (21.4)	34 (10.6)	0.005
AKI stage 1/2/3	38/15/8	18/6/3	20/9/5	0.839
Development of CKD	5 (1.1)	3 (2.4)	2 (0.6)	0.154

AKI: Acute kidney injury; CKD: Chronic kidney disease.

We determined the incidence of AKI after the administration of the different chemotherapeutic agents used for HIPEC. The incidence of AKI in patients who received cisplatin (n = 126) was 26.90% (34 patients). The incidence of AKI in patients who received oxaliplatin (n = 155) was 9.10% (14 patients). The incidence of AKI in patients who received mitomycin C (n = 164) was 7.80% (13 patients). The incidence of AKI was significantly higher in patients treated with cisplatin (P = 0.002). Compared with the mitomycin C group, the risk of nephrotoxicity in the cisplatin group was 3.2 times higher (OR = 3.2; 95% confidence interval: 1.6-6.4) (Figure 1). Among patients who received mannitol and high-volume hydration, the incidence of AKI was 9.2%. For patients who received standard hydration, it was 15.8% (P = 0.03) (Table 4).

Figure 1 Acute kidney injury incidence by chemotherapeutic agent (hyperthermic intraperitoneal chemotherapy). AKI: Acute kidney injury; HIPEC: Hyperthermic intraperitoneal chemotherapy.

Table 4 Acute kidney injury rates by hyperthermic intraperitoneal chemotherapy agents.

HIPEC agent	Total patients	AKI cases	AKI rate (%)	P value
Cisplatin	126	34	26.90
Oxaliplatin	155	14	9.10
Mitomycin C	164	13	7.80
Total	445	61		0.0008

HIPEC: Hyperthermic intraperitoneal chemotherapy; AKI: Acute kidney injury.

Clinical course and hospital outcomes

The mean length of hospital stay was 14.8 ± 5.3 days for patients with AKI and 10.2 ± 3.7 days for patients without AKI (P < 0.001). The postoperative morbidity rate was 42.0% for patients with AKI and 18.0% for patients without AKI (P = 0.004). However, there was no significant association between AKI and in-hospital mortality (P = 0.09). Before discharge, all patients had stable renal function.

DISCUSSION

The incidence of AKI was 13.7% in a cohort of 445 patients who received CRS + HIPEC for the treatment of PC. This rate is at the lower end of the 15%-23% range reported in studies by Carias et al[15] and Ramesh et al[16]. The incidence of AKI varies depending on the chemotherapeutic agents used in HIPEC and perioperative management protocols. AKI incidence in protocols using cisplatin ranges from 15% to 34%[2,13,17]. The AKI rate of 21.4% in the cisplatin group in our study is consistent with these studies. The incidence of AKI was significantly lower in the groups treated with oxaliplatin and mitomycin C. This finding aligns with previous studies showing a lower nephrotoxicity profile for oxaliplatin[18,19]. The distribution of AKI stages was similar to that reported in Asian cohorts[20]. In patients with stage 3 AKI, intensive care unit admission and morbidity rates increased significantly. Likewise, postoperative hospital stay was significantly prolonged in patients who developed AKI[21].

In the literature, the use of cisplatin, inadequate fluid replacement ( < 6000 mL), intraoperative vasopressor use, and preoperative eGFR < 75 mL/minute/m² have been shown to increase the risk of AKI development after CRS + HIPEC. Each of these factors has previously been identified as an independent predictor of AKI[22-24]. Reduced preoperative renal reserve increases the susceptibility to renal injury following HIPEC. The use of nephrotoxic medications such as angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers further increases this risk[2,4,15]. However, studies have shown that this risk can be mitigated by aggressive perioperative hydration and avoidance of nephrotoxic drugs[25-27].

The administration of hyperthermic fluid into the peritoneal cavity may lead to systemic vasodilation and hypovolemia. These conditions reduce renal perfusion and contribute to the development of AKI[2]. Therefore, the requirement of intraoperative vasopressor administration has been associated with the development of AKI, suggesting that hemodynamic instability further impairs renal perfusion[28,29]. Postoperative AKI progresses to acute kidney disease in 13.3% of cases[8]. Although this rate was lower in our study, patients who developed advanced-stage AKI were at an increased risk of developing chronic kidney disease. Because this condition affects long-term renal function, perioperative care and follow-up protocols after discharge are equally important. Selecting low-risk HIPEC agents (oxaliplatin, mitomycin C), ensuring adequate intraoperative fluid resuscitation, minimizing vasopressor use, and carefully assessing preoperative renal function may reduce the risk of developing AKI after CRS + HIPEC treatment. Moreover, close monitoring of urine output, fluid balance, and serum creatinine levels in the perioperative period plays a critical role in early AKI detection[30-33].

Limitations

Due to its retrospective design, recording bias and missing data are potential limitations of this study. Another limitation was that renal function was assessed only by serum creatinine and eGFR without the inclusion of sensitive biomarkers, such as neutrophil gelatinase-associated lipocalin, kidney injury molecule 1, or urine output, and this may affect early detection or subclinical AKI analysis. Although HIPEC protocols were standardized, variations in surgical technique and timing between surgeons should be considered as a limitation. Long-term renal outcomes (e.g., persistent damage, dialysis requirement) could not be evaluated in this study. The single-center design of this study may also limit the generalizability of the findings.

CONCLUSION

In this retrospective cohort study, the incidence of AKI was 13.7% in patients undergoing CRS + HIPEC for PC. Cisplatin-based regimens, preoperative eGFR < 75 mL/minute/1.73 m², intraoperative fluid replacement < 6000 mL, and the need for vasopressors were identified as independent risk factors. Careful preoperative evaluation of renal function and the use of less nephrotoxic agents may help reduce the risk of renal toxicity in patients undergoing CRS + HIPEC. Additionally, goal-directed fluid therapy and the maintenance of hemodynamic stability are of critical importance.