As a global health problem, hepatocellular carcinoma (HCC) is the sixth most common cancer and the second leading cause of cancer-related death in men and the sixth in women (1). Although liver transplantation (LTx) is the most effective among all the therapeutic options, only about 5% of HCC patients are eligible for this therapy due to the strict indications (2). According to the National Comprehensive Cancer Network (NCCN) Guidelines, partial hepatic resection is the preferred option in patients without severe liver cirrhosis (excluding patients with Child–Pugh scores in classes B and C); meanwhile, locoregional therapy is the preferred option in patients unsuitable for surgery, which includes ablation, arterially directed therapies, and external beam radiation therapy (EBRT) (3).

Acute kidney injury (AKI) is one of the most common complications in cancer patients (4, 5). It refers to a rapid (hours to days) deterioration of renal function, which results in the failure to excrete waste and to maintain fluid balance, which can be severe as to require renal replacement therapy (RRT) (6). The management of these patients is a significant therapeutic challenge for physicians, and the chance of receiving optimal treatment might be less for those with poor kidney function since mortality from AKI remains high, particularly in critically ill patients (6). Efforts made to prevent AKI progression may contribute to survival and reduce the possibility of progressing to chronic kidney disease (CKD). As a clinical syndrome that results from severe or persistent events that may act as triggers, any diagnostic approach to investigating AKI should take into account the associated epidemiology (6). Although a large cohort study based on a Danish population reported that the risk of developing AKI in 1 year was about 33% in patients with liver cancer (7), there is still a lack of research focused on the association between AKI and HCC after treatment, especially regarding locoregional therapy or hepatectomy—the two major treatment options for HCC patients. The few previous studies that described AKI had limitations of a small study size, collection of data from a single medical center, or discussion of the incidence rates of AKI in newly diagnosed cancer, which present obvious restrictions regarding the generalizability of the findings. More comprehensive analyses are urgently needed to examine their authentic relationship in order to help provide proper management and to improve the clinical outcomes.

This meta-analysis was conducted based on HCC patients receiving locoregional therapy and hepatectomy, aiming to examine the risk factors and the impact on mortality of AKI in these HCC patients using available published data.

The major findings of these published data based on the meta-analyses were as follows: firstly, DM is a risk factor for AKI in patients with HCC either receiving TACE or hepatectomy, which means that close attention should be paid to HCC patients with DM for risk of AKI during these treatments. Secondly, the number of TACE sessions is another risk factor for AKI in patients with HCC receiving TACE treatment. Moreover, male gender, major resection of the liver, and transfusion due to hepatectomy are other risk factors for AKI in HCC patients after hepatectomy. Lastly, the incidence of AKI during TACE treatment is especially dangerous: the risk of mortality with AKI was up to 4.74 times higher than in those without AKI in the short-term period.

A lot of advanced HCC patients require locoregional treatment due to inadequate hepatic reserve, liver-confined disease, being inoperable by performance status, comorbidity, or having uncertain extrahepatic diseases (3). The efficiency and safety of the TACE procedure have been improved for several decades; it is also considered the main treatment option for patients who had four or more HCCs and with liver function assessed as Child–Pugh class A or B (28). Previously recognized as CIN, TACE treatment of patients with HCC is the third leading cause of hospital-acquired AKI, which contributes to prolonged hospital stay and readmission rates (11). The specific reasons, mechanisms, and the influence of AKI in these patients are still unclear. HCC often develops from chronic liver disease that has already progressed to advanced cirrhosis, which may contribute to the development process of AKI. Abnormal systemic hemodynamics, splanchnic arterial vasodilatation, and extrahepatic vasoconstriction are possibly involved in cirrhosis-related AKI (29). The application of iodinated radiocontrast agents potentially is an acute event further exaggerating the already disturbed hemodynamics and/or renal vasoconstriction in advanced cirrhosis, finally leading to renal dysfunction. In addition, nephrotoxic drugs such as iodinated radiocontrast agents, adriamycin, and lipiodol can lead to renal microcirculatory dysfunction, cell apoptosis, or endothelial injury independently (6). On the other hand, renal endothelial cells would be impaired even at quite early exposure to a hyperglycemic milieu, whereas prolonged hyperglycemia would promote the mesenchymal transition and fibrosis of endothelial cells (30), resulting not only in endothelial dysfunction and aggravating kidney fibrosis but also in being vulnerable to nephrotoxicity by radiocontrast agents. Once DM is a comorbidity, the nephrotoxicity of radiocontrast agents will obviously be strengthened due to either transient or persistent hyperglycemic conditions. These theories were further demonstrated in our research, where the incidence of AKI during TACE treatment is not radiocontrast agent dose-dependent, and a small dose is strong enough to cause AKI in HCC-DM patients. The age-related susceptibility of AKI in older individuals has been reported both in TACE and hepatectomy, and the reason may be that older age enhances renal vulnerability as well (9, 26).

The hemodynamic alterations following liver resection are similar to advanced cirrhosis (31). In addition, AKI in patients with HCC ensues from hepatectomy probably more related to transient/prolong renal hypoperfusion or ischemia, while major resection of the liver or preoperative/postoperative transfusion could significantly aggravate this course due to the persistence of extensive blood loss and reduction of oxygen delivery. Firstly, ischemia would induce a significant functional impairment or structural damage of small renal tubular and vascular malfunction (30), which serves as the initiation of systemic inflammatory response activation and leads to renal inflammation injury and microcirculation dysfunction (32). In addition, microvascular damage could obviously affect endothelial cell expansion, apoptosis, or necrosis, in turn leading to microvascular obstruction, further inhibiting post-ischemic reperfusion and delaying kidney regeneration. Furthermore, ischemia would diminish the total surface intrarenal vascular area, along with endothelial–mesenchymal transition, together leading to the loss of important intrinsic physiological defense mechanisms and finally increasing the vulnerability of nephrons to oxygen-free radicals (30, 32). Therefore, even a minor or a laparoscopic liver resection should not be considered a less harmless operation and the prevention of intraoperative hemorrhage should also be paid the same attention, and vice versa.

Different from the hypothesis of ischemia–reperfusion injury, investigation of the association between diabetes-induced endothelial dysfunction and ischemia leading to the vulnerability of the kidney is rare. However, this relationship has been found based on several animal research works: a diabetic mouse model showed a higher vulnerability to ischemia than did non-diabetic controls, and ischemia was even induced quite early (33). On the other hand, non-diabetic rats completely recovered from functional impairment and tissue damage caused by renal ischemia, while diabetic rats failed within about 2 months observation (34). Tumor protein 53 (TP53) is the most frequently mutated tumor-suppressor gene in HCC. Inactivating mutations of TP53 possibly present in 20% of HCCs in western countries, while they present in >50% of HCCs in aflatoxin B1 (AFB1)-exposed regions (35–38). Peng and colleagues demonstrated that P53 played a protective role against AKI in diabetic animal models, either in diabetic mice inducing P53-specific siRNAs or in proximal tubule-specific P53-knockout mice inducing diabetes (33). This may be one explanation for the different incidence rates of AKI consistently observed between the different ethnicities in this study.

Despite ischemia–reperfusion injury or the hemodynamic instability of renal perfusion, transfusion of red blood cells may be an independent risk factor for postoperative AKI: impaired oxygen unloading of hemoglobin due to 2,3­diphosphoglycerate deficiency, less deformability of stored red blood cells leading to the obstruction of smaller capillaries, increase in circulating free iron from stored red blood cell hemolysis, release of procoagulant phospholipids, and the accumulation of pro-inflammatory phospholipids together exaggerate the existing inflammatory response and lead to sepsis-associated AKI (39–41). Hepatorenal syndrome (HRS) describes a reversible AKI in patients with advanced hepatic failure, including advanced cirrhosis. Its varied performance depends on the volume and quality of the remnant liver after hepatectomy (steatosis/cirrhosis). Hepatic microcirculation is already impaired by steatosis or cirrhosis, and the liver presents more mitochondrial dysfunction and is less resistant to ischemia–reperfusion injury. TACE or hepatectomy intervention is a probable acute incident prompting the sudden decrease in the glomerular filtration rate (GFR) and renal perfusion. The potential pathophysiological mechanisms comprise significant splanchnic vasodilation and elevated abdominal pressure accompanied by ascites, causing overactivity of the renin–angiotensin–aldosterone system (RAAS) and sympathetic nervous system (SNS), followed by vasoconstriction/structural damage of the kidney and intravascular hypovolemia, accompanied by necrosis/apoptosis of tubular cells, which would drop off and obstruct the lumen, together causing complete deterioration of the GFR (31–41).

The study has several limitations. Firstly, analyses of the influence and the potential for publication bias could not be effectively performed due to the limited number of original studies (<10) for every meta-analysis. Secondly, statistical heterogeneity was always observed in the meta-analysis. One potential origin of the heterogeneity may be the ethnicity. When a subgroup analysis was performed according to the different ethnicities, the results showed no heterogeneity in the incidence rates of AKI in the non-Asian subgroup, but the statistical heterogeneity existing in the Asian group needs further exploration. As previously mentioned, P53 plays important roles both in HCC and AKI during DM; future studies could probably focus on HCC-AKI in diverse ethnicities. The accurate moment of earlier diagnosis of AKI by any definition is indeed difficult to establish in these patients due to the varied efficacy–efficiency balance of biomarker measurements, which is one of the reasons the International Club of Ascites (ICA) spent several years developing the new expert consensus on the diagnosis and treatment of AKI in patients with liver cirrhosis. This contention may be another source of the heterogeneity. Finally, since the clinical data are from publications and have limitations in terms of availability, not only could further sub-analyses not be performed (TNM stage, duration of hepatectomy, and tumor size, among others), but AKI in patients with HCC receiving other treatments (radiofrequency, microwave ablation, or systemic therapy) could also not be analyzed. Incidentally, further studies are still needed to support the conclusions and demonstrate more associations of AKI in HCC patients.

In conclusion, age, DM, and the number of TACE sessions are risk factors for AKI in patients with HCC receiving TACE, while age, male gender, DM, major resection of the liver, and operation-related transfusion are risk factors for AKI in patients with HCC after hepatectomy. Finally, the occurrence of AKI during TACE treatment is especially dangerous and should be considered a strong red flag, obviously with regard to the extremely high risk of death in a short period. Furthermore, studies are needed to detect more associations of AKI in patients with HCC (especially in patients receiving other treatments).

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

CL had the idea for the study and formulated its design, having had full access to all data in the study, and takes responsibility for the integrity of the data and the accuracy of the data analysis. ZM and TG contributed to data acquisition and the writing of the report. ZM contributed to critical revisions of the report and to the statistical analysis. All authors commented on previous versions of the manuscript. All authors contributed to the article and approved the submitted version.

This research was supported by the Xiamen Municipal Bureau of Science and Technology (grant no. 3502Z20199173).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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