Cilastatin versus sodium thiosulfate for prevention of cisplatin-induced acute kidney injury during cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC): a randomized non-inferiority trial protocol

Abstract

Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS–HIPEC) using cisplatin is an established treatment for selected patients with peritoneal malignancies, but acute kidney injury (AKI) remains a common and clinically significant complication. Perioperative nephroprotection is therefore an integral component of cisplatin-based HIPEC protocols. Sodium thiosulfate is widely used in this setting and has demonstrated effectiveness in reducing postoperative renal toxicity. Cilastatin, a drug with a long-standing clinical safety record, has shown consistent nephroprotective effects in experimental models and emerging clinical studies, and may offer an alternative strategy for renal protection during HIPEC. However, comparative randomized evidence between these two approaches is currently lacking. This study is a prospective, randomized, double-blind, non-inferiority clinical trial conducted at a high-volume tertiary referral center. Adult patients undergoing CRS followed by cisplatin-based HIPEC are randomized in a 1:1 ratio to receive either intravenous cilastatin or sodium thiosulfate administered according to standardized nephroprotection regimens. Randomization and drug preparation are managed by the hospital pharmacy to ensure allocation concealment and blinding of participants, clinicians, and outcome assessors. The primary outcome is the incidence of AKI within the first 7 postoperative days, defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Secondary outcomes include cisplatin pharmacokinetics and its concentration in tumor nodules after HIPEC, perioperative adverse events, the evolution of renal dysfunction up to postoperative day 14 in patients who develop AKI, and exploratory analyses of urinary biomarkers of renal injury. A total sample size of 90 patients provides 80% power to demonstrate non-inferiority with a one-sided significance level of 0.025 and a predefined non-inferiority margin of 20%. This randomized, double-blind, non-inferiority trial is designed to provide comparative evidence on renal protection strategies during cisplatin-based CRS–HIPEC. By evaluating cilastatin against sodium thiosulfate within routine clinical practice, the study aims to clarify whether cilastatin offers a level of nephroprotection comparable to current standard approaches. In addition, exploratory pharmacokinetic and biomarker analyses may contribute to a better understanding of renal injury and protection mechanisms in this high-risk surgical oncology population. The trial is registered in the EU Clinical Trials Information System (CTIS) under EU Clinical Trial number 2024–518854-18–00 and was previously registered in the EudraCT database (2022–001417-39). In addition, it is also registered on the National Library of Medicine Clinicaltrials.gov under the code NCT07229040.