Acute Kidney Injury Following Hyperthermic Intraperitoneal Chemotherapy With Cisplatin

Discussion

Cisplatin nephrotoxicity is the result of multiple complex signalling pathways causing proximal renal tubular injury, oxidative stress, inflammation and ischaemic injury (10). Cisplatin can trigger various apoptotic pathways, including the direct activation of the extrinsic death receptor pathway, the intrinsic mitochondria, and the endoplasmic reticulum stress pathway (4, 11). These induce the production of proinflammatory cytokines such as TNF-alpha and IL-1b. Necrosis may also occur secondary to severe toxic injury or the post-apoptotic cellular milieu (10). Evidence suggests high doses of cisplatin results in a predominant necrosis response, whilst lower doses of cisplatin result in dominant apoptosis response (12). Finally, cisplatin may also cause renovascular injury, and contribute to nephrotoxicity through further ischaemic insult to the kidney (10).

The incidence of AKI following CRS and cisplatin-based HIPEC in our study population was 15.3% (17/111), as defined by the RIFLE criteria. Comparison with the literature reveals significant variation in the reported incidence rates of cisplatin-induced AKI. La Manna et al. reported the highest incidence of AKI with rates of 88.1% (37/42) (13). Sin et al. reported an AKI incidence of 40% (19/47) (14), and Angeles et al. found an AKI incidence of 48% (30/66) (15). Hakeam et al. reported the lowest AKI incidence in the literature, with rates of 3.7% (2/53) (6). The multiple different criteria used to define AKI in the literature likely contribute to the varying findings. Of note, Maeda et al. found urinary biomarkers such as NAG, Kim-1, and NGAL may be more sensitive than serum creatinine in detecting AKI in patients treated with cisplatin (16). Measurement of these urinary biomarkers should be considered in future studies to accurately identify all cases of AKI following cisplatin therapy. Other study factors contributing to heterogeneity in the literature includes differences in HIPEC protocols, cisplatin dosages, and inclusion of multiple primary tumours.

There are multiple well-known patient factors that can potentiate or synergise nephrotoxicity in patients receiving cisplatin-based HIPEC. Potentiating factors may include any cause of AKI, such as hypovolaemia, nephrotoxic medications including ACE inhibitors and IV contrast, or malignant post-renal obstruction (17).

In our study, we found patients with AKI were more likely to have reduced urine output intraoperatively and in the first 24 h post-operatively compared to patients without AKI.

These results are consistent with findings by Angeles et al. and Hakeam et al. who also demonstrated an association between low intraoperative urine output and AKI (6, 15). Low perioperative diuresis in patients undergoing cisplatin-based HIPEC suggests inadequate intravenous fluid hydration and resultant hypovolaemia. Hypovolaemia exacerbates the nephrotoxic effects of cisplatin by reducing its renal clearance, and further contributes to AKI by also causing reduced renal perfusion. Adequate perioperative hydration has therefore been shown to be an effective renoprotective strategy (18). Schmidt et al. found that adequate intraoperative fluid turnover during CRS and HIPEC exceeded the standard 6-8 ml/kg/h suggested for most major abdominal surgeries (19). This is supported by Owusu-Agyemang et al.’s findings, who found 6-15 ml/kg/h of fluid administration was required to maintain adequate urine output in paediatric patients undergoing CRS with cisplatin-based HIPEC (20).

Our study also found an association of AKI with higher PCI. Higher PCI is likely related to longer operative time, resulting in a longer duration of time the abdomen is open. An open abdomen with exteriorised bowel causes hypovolaemia, with up to 32 g/m² body surface area/hr or 1 ml/kg/h of fluid loss from evaporation and radiation (21). Additionally, a higher PCI is indicative of higher tumour burden. Higher burden of disease, particularly pelvic disease or tumour which encases the post-renal urinary system, is more likely to contribute to obstructive causes of AKI. Higher PCI therefore may be a surrogate marker of potential pre- and post-renal factors increasing the likelihood of AKI.

Cisplatin nephrotoxicity is characterised by increased blood urea nitrogen levels as well as electrolyte imbalance such as hypomagnesaemia (4). This was consistent with our findings, which demonstrated increased serum urea on days 3 and 7 post-operatively in patients with AKI. Hypomagnesaemia affects up to 90% of patients and may occur in the absence of AKI (17, 22). We did not find an association between hypomagnesaemia and AKI.

The authors recognise our study has several limitations. The retrospective nature of our study does not account for all confounding factors, and does not allow us to establish a causative relationship. Possible confounding factors that were not collected included methods used to reduce the incidence of AKI such as perioperative intravenous fluids, sodium thiosulfate and cessation of usual nephrotoxic medications (e.g. ACE inhibitors, metformin). Use of essential nephrotoxic medications in the first 7 days post-operatively, such as vasopressors, antibiotics, and intravenous contrast were also not collected. Future prospective studies should include data collection on such factors. Additionally, data was collected from a single centre, and hence selective bias may affect our findings. Finally, our data demonstrated a heterogeneous population with multiple primary tumours. This was due to the rarity of disseminated peritoneal disease, however in future studies, analysis should be stratified according to primary tumour.