HIPEC-Induced Acute Kidney Injury: A Retrospective Clinical Study and Preclinical Model

Abstract

Background: Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery (CRS) is the treatment of choice for selected patients with peritoneal malignancies. HIPEC is accompanied by moderate-to-high patient morbidity, including acute kidney injury. The significance of nephrotoxic agents such as cisplatin versus hyperthermia in HIPEC-induced nephrotoxicity has not been defined yet.

Patients and methods: A total of 153 patients treated with HIPEC were divided into groups with (AKI+) and without (AKI-) kidney injury. Laboratory parameters and data concerning patient demographics, underlying disease, surgery, complications, and HIPEC were gathered to evaluate risk factors for HIPEC-induced AKI. A preclinical mouse model was applied to assess the significance of cisplatin and hyperthermia in HIPEC-induced AKI, as well as protective effects of the cytoprotective agent amifostine.

Results: AKI occurred in 31.8% of patients undergoing HIPEC. Treatment with cisplatin-containing HIPEC regimens represented a major risk factor for HIPEC-related AKI (p < 0.001). Besides, angiotensin receptor blockers and increased preoperative creatinine and urea levels were independent risk factors for AKI after HIPEC. In a preclinical mouse model, intraperitoneal perfusion with cisplatin induced AKI, whereas hyperthermia alone, or in combination with cisplatin, did not induce or enhance renal injury. Amifostine failed to confer nephroprotective effects in a miniaturized HIPEC model.

Conclusions: AKI is a frequent complication after HIPEC. The risk of renal injury is particularly high in patients treated with cisplatin-containing HIPEC regimens. Hyperthermic perfusion of the abdomen by itself does not seem to induce or aggravate HIPEC-induced renal injury.

© 2021. The Author(s).

Figures

Fig. 1

HIPEC-induced acute kidney injury in patients. a Occurrence of AKI after HIPEC regimens containing (CPL+) and not containing (CPL−) cisplatin. CPL cisplatin, DOX doxorubicin, LV leucovorin, MMC mitomycin C, OXA oxaliplatin, TAX taxol, 5-FU 5-fluorouracil. b Staging of patients (n = 45) with HIPEC-induced kidney injuries according to KDIGO classification. c Comparison of urine output and d fluid balance between patients with (AKI+) and without (AKI−) kidney injury after HIPEC on day of operation (0th), 1st, and 2nd POD. Data are expressed as mean ± range. e Quantity of patients diagnosed with HIPEC-induced AKI per postoperative day. *p < 0.05; nsp ≥ 0.05

Fig. 2

Influence of cisplatin, hyperthermia, and amifostine on HIPEC-induced AKI in a preclinical mouse model. a Plasma levels of creatinine, urea, and cystatin C, 48 h and 72 h after single i.p. injection of cisplatin (20 mg/kg). Data are expressed as mean ± SD; n = 6, *p < 0.05. b–d Percentage changes in creatinine (b), urea (c) and cystatin C levels (d), 72 h after i.p. perfusion (90 min) with saline (0.9%; circles) or cisplatin (75 mg/m2 in 2 L/m2 perfusate; triangles), or after single i.p. injection with cisplatin as a positive control (20 mg/kg; black circles, POSctrl). Perfusion was performed under either normothermia (38 °C, open circles, 38C; and open triangles, CPL38C) or under hyperthermic conditions (41–42 °C; gray circles, 42C; and gray triangles, CPL42C). Amifostine (200 mg/kg; diamonds, AF) was injected s.c. 15 min prior to perfusion with cisplatin at 38 °C. Individual animals are expressed as one datapoint each. n = 6 (38C, 42C, CPL42), n = 10 (CPL38, AF); *p < 0.05; nsp ≥ 0.05. e Representative PAS staining revealing histopathological changes in murine kidneys, 72 h after i.p. perfusion with saline at 38 °C (left panels, 38C), saline at 42 °C (middle left panels, 42C), cisplatin (75 mg/m2) at 38 °C (center panels, CPL38C), cisplatin at 42 °C (middle right panels, CPL42C), or cisplatin at 38 °C after amifostine treatment (200 mg/kg s.c.; right panels, AF). Note hyaline casts (#), apoptosis (*), and necrosis (x) of tubular epithelial cells in kidneys of animals perfused with cisplatin (in center and right panels), and regular proximal (>) and distal (<) tubules in kidneys of those treated with saline (left panels). Images in upper panels are taken at 100× magnification and in lower panels at 400× magnification. f, g Histomorphometric scoring of tubular injury quantity (f) and severity (g), 72 h after i.p. perfusion with saline at 38 °C (38C), saline at 42 °C (42C), cisplatin at 38 °C (CPL38C), cisplatin at 42 °C (CPL42C), or cisplatin at 38 °C after amifostine treatment (AF). Data are expressed as mean ± SD, *p < 0.05