Risk of Acute Kidney Injury in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intra-peritoneal Chemotherapy

Introduction Peritoneal carcinomatosis (PC) is a serious oncological condition in patients with metastatic malignancy, for which cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) has become the treatment of choice. In this procedure, chemotherapeutic drugs are introduced intraoperatively into the peritoneal cavity at temperature 41-43 °C. The abdominal cavity is perfused for about 60-90 minutes, thereby exposing potential microscopic residual cancer cells directly to the synergistic effects of hyperthermia (Sugarbaker 2016). In highly selected patients with colorectal cancer, CRS/HIPEC has shown benefits in disease-free and overall survival compared to systemic chemotherapy alone, with a 5-year survival rate of up to 45% for patients with no residual tumor after completing CRS. Furthermore, in patients with PMP receiving CRS/HIPEC, the survival rate beyond 10 years has been reported to reach 63% (Yan, Stuart et al. 2006, Verwaal, Bruin et al. 2008).

CRS/HIPEC is an aggressive treatment modality, often associated with high-grade complications. Recent publications have reported morbidity and mortality rates of 2.5-25% and 1.5-11%, respectively, with renal toxicity and bone marrow failure accounting for most causes of systemic toxicity (Ihemelandu, McQuellon et al. 2013, Wang, Chen et al. 2017). Acute kidney injury (AKI) is a serious morbidity that is associated with a greater duration of hospitalization, higher risk of mortality and increased risk of progressive chronic kidney disease. It has been described after the administration of HIPEC with cisplatin, with the quoted incidence of major renal toxicity ranging from 1.3-5.9% (Sin, Chia et al. 2017).

Renal toxicity of HIPEC Chemotherapy effect Cisplatin, a platinum-based anticancer agent, exerts its cytotoxic effect by binding and cross-linking DNA. It has been utilized as a cornerstone in many HIPEC protocols at variable doses for the treatment of tumors with PC, including primary peritoneal neoplasms, sarcomas, and gynecological tumors. Cisplatin-induced nephrotoxicity is a complex process involving acute cytotoxicity to tubular epithelium, followed by inflammatory cell infiltration and fibroproliferative changes. A recent pharmacokinetic study of this regimen yielded a cisplatin perfusate-to-blood area under the curve ratio of 6.28. These data indicate the absorption of cisplatin into the circulation during HIPEC, hence systemic complications cannot be excluded. Western literatures reported that 4-6% incidence of renal toxicity among patients who underwent HIPEC using cisplatin at variable doses and combinations (Hakeam, Breakiet et al. 2014). However, higher incidence of renal toxicity was reported by Singapore. Tan et al reported that among the 47 patients, 19 (40.4%) experienced post-operative AKI, of which 5 (8.5%) developed grade 3 and 4 impairment. Two (4.3%) required long-term dialysis.

In addition, mitomycin and doxorubicin which are also often used as HIPEC regimens, are also known nephrotoxins (Hakeam, Breakiet et al. 2014).

Comorbidity effect Preexisting kidney damage, hypomagnesemia and concomitant use of other nephrotoxic agents may potentiate the development of renal impairment. Other factors associated with nephrotoxicity were possible lower intraoperative urine output, and diabetes mellius (Yan, Stuart et al. 2006, Hakeam, Breakiet et al. 2014).