Incidence, Risk Factors, and Outcomes of Transition of HIPEC- Induced Acute Kidney Injury to Acute Kidney Disease: A Retrospective Study

doi:10.21203/rs.3.rs-1820140/v1

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Incidence, Risk Factors, and Outcomes of Transition of HIPEC- Induced Acute Kidney Injury to Acute Kidney Disease: A Retrospective Study

https://doi.org/10.21203/rs.3.rs-1820140/v1

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Background: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has benefited selected patients with peritoneal malignancies. Acute kidney injury (AKI) is recognized as a common complication following the CRS-HIPEC procedure. Characterized with prolonged renal function impairment, acute kidney disease (AKD) is associated with a higher risk of chronic kidney disease (CKD) and mortality. Unlike AKI, accurate estimates of the prevalence, risk factors, and prognosis of AKD have not been thoroughly studied.

Methods: From January 2018 to December 2021, a total of 158 patients undergoing CRS-HIPEC were retrospectively reviewed. Patients were separated into non-AKI, AKI, and AKD cohorts. Laboratory parameters and perioperative features were gathered to evaluate risk factors for both HIPEC-induced AKI and AKD, with the 90-day prognosis of AKD patients.

Results: AKI developed in 21.5% of patients undergoing CRS-HIPEC, while 13.3% of patients progress to AKD. The multivariate analysis identified that ascites, GRAN%, eGFR, and intraoperative hypotension duration were associated with the development of HIPEC-induced AKI. Higher uric acid, elevated eGFR, and prolonged intraoperative hypotension duration were more predominant in patients proceeding with AKD. The AKD cohort presented a higher risk of 30 days of in-hospital mortality (14.3%) and CKD progression (42.8%).

Conclusions: Our study reveals that the incidence of AKI and AKI-to-AKD transition are high. Early identification of risk factors for HIPEC-induced AKD would assist clinicians in taking measures to mitigate the incidence.

HIPEC

AKI

AKD

Acute kidney injury (AKI) has been increasingly identified as an intractably postoperative complication [1]. It has been reported that postoperative AKI accounted for one-third of all hospital-acquired cases of AKI [2], associated with potentially serious consequences, including proceeding to chronic kidney disease (CKD) [3], end-stage renal disease (ESRD) [4], and increased mortality [5]. Persistent AKI stage 1 status or greater beyond 7 days but for less than 90 days is considered an occurrence of acute kidney disease (AKD) [6]. Indeed, AKD showed lower chances of renal function recovery at 90 days and accelerated progression of further renal function deterioration, reflecting the association with short-term and long-term mortality outcomes [7]. Therefore, this group of patients may require more exhaustive monitoring and follow-up care.

Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have transformed from palliative therapy into a curative one [8]. Through this operation, the macroscopic lesions are treated by carefully total resection, and the residual microscopic tumors are treated with HIPEC [9]. Nevertheless, the incidence of postoperative complications remains high, significantly influencing the survival of patients [10, 11]. To date, only a handful of studies revealed the morbidity of perioperative complications such as AKI, ranging from 1% to 48% [12, 13]. Independent risk factors for HIPEC-associated AKI have been revealed, consisting of age, body mass index (BMI), baseline serum creatinine (SCr), estimated glomerular filtration rate (eGFR), preoperative albumin (ALB), intraoperative bleeding loss, and nephrotoxicity of intraperitoneal cisplatin therapy [14-18]. Along with the highlighted concepts of the AKI-to-AKD-to-CKD transition, a sizable of researchers have paid attention to AKD prevention and management. However, there is a paucity of the prevalence of HIPEC-associated AKD, and it is not clear what risk parameters are associated with AKD.

The first aim of this study was to reveal the incidence and risk factors for AKI in patients undergoing CRS-HIPEC. The second purpose was to investigate the prevalence of AKI-to-AKD transition, identify possible factors contributing to its development, and evaluate its impact on short-term and long-term outcomes. Given that early recognition of patients at high risk of progression AKD may assist clinicians in providing timely implementation of interventions to facilitate recovery to mitigate poorer outcomes.

Study population

Between January 2018 to December 2021, we retrospectively studied a series of patients who underwent CRS-HIPEC for various primary malignancies with peritoneal dissemination at our institution. Patients were excluded from this study if they were with incomplete perioperative data, identified to have chronic kidney disease (CKD), or only underwent diagnostic laparoscopy. Patients were firstly distinguished into two cohorts according to the occurrence (AKI) or nonoccurrence of postoperative AKI (non-AKI). We further identified those belonging to the AKD group according to the AKI duration. The study was approved by the Institutional Review Board of our institution (7222199).

Variables

Clinicopathologic variables, laboratory parameters, and perioperative and HIPEC details were collected from the electronic clinical records. Preoperative characteristics collected including age, gender, body mass index (BMI), comorbidities (hypertension, diabetes mellitus, heart disease, and hepatitis), use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blockers (ARB), ascites, neoadjuvant therapy, American Society of Anesthesiologists (ASA) score, primary tumor, hemoglobin (Hb), red blood cell (RBC), hematocrit (HCT%), white blood cell (WBC), platelet (PLT), neutrophil ratio (GRAN%), lymphocyte ratio (LYM%), SCr, urea, uric acid, eGFR, ALB, C-reactive protein (CRP), procalcitonin (PCT), and urine microalbumin.

Included in the intraoperative (IO) variables were ureteral catheter implementation, operative duration, blood loss, fluid volume, urine output volume, hypotension duration (defined as episodes of systolic blood pressure [SBP] < 100 mmHg), RBC transfusion, plasma transfusion, use of vasopressors, and use of furosemide. HIPEC-related features included regimens (5-fluorouracil [5-FU], cisplatin, paclitaxel [TAX], and raltitrexed) and cycles.

Primary postoperative outcomes were assessed as the development of AKI, AKD, in-hospital mortality (at 30 days), length of intensive care unit (ICU) stay, and length of hospital stay. We follow up with all patients in the AKD group 90 days after the diagnosis of AKD to identify whether they develop CKD.

Definition of AKI and AKD

Baseline SCr was defined as the first record after patient admission. The AKI diagnosis was based on the Kidney Disease Improving Global Outcomes (KDIGO) criteria. Accordingly, AKI stage I was defined as an increase in serum creatinine > 0.3 mg/dl within 48 h; stage II was defined as increasing in creatinine 2–2.9 times baseline; stage III was defined as increasing in serum creatinine > 4 mg/dl or 3 times baseline, or needing renal replacement therapy [19]. According to the ADQI 16 Workgroup, diagnosis of AKD was determined by the persistence of AKI stage I or greater (KDIGO criteria) beyond 7 to 90 days after the initial recognized AKI [6].

Cytoreductive surgery and HIPEC

All patients underwent CRS, which included primary tumor resection, involved regional viscera dissection, lymphadenectomy, and peritoneal resection [20]. Intraoperative or postoperative HIPEC followed the completion of CRS. Closed-abdomen HIPEC was performed, delivered chemotherapy agent by two inflow catheters, and drained via two outflow probes. For perfusion, the temperature was administered at 44℃ for 60 minutes. Perfusate volume and chemotherapy dose varied according to abdominal cavity volume and body surface area (BSA) (mg/m²) area-based dosing protocol [21], respectively.

Statistical Analyses

Continuous variables were expressed as mean ± standard deviation (SD), and categorical variables were reported as frequency and percentage (n, %). Differences in categorical variables were compared using Pearson’s chi-squared test or Fisher’s exact test, while the nonparametric Mann–Whitney test was used to assess continuous variables. Associations between risk factors and the occurrence of AKI and AKD were tested using univariate logistic regression, respectively. Variables with P < 0.05 on univariate analysis were included in multivariate logistic regression analysis. Adjusted odd ratios (OR) with 95% confidence intervals (CI) were calculated. We considered a P value < 0.05 (two-tailed) statistically significant. Statistical analyses were performed using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp. Released 2019, Armonk, NY).

A total of 158 patients who underwent CRS-HIPEC between January 2018 to December 2021 were identified. The characteristics of all patients were presented in Table 1. The mean age was 60 years, and the majority were female (60.1%). Hypertension (21.5%) and diabetes mellitus (12.0%) were the most common comorbidities. Half of the patients presented ascites, and over 60% of patients had an ASA score of 2. A minor percentage of patients (19.6%) underwent neoadjuvant therapy.

A third of patients were treated with CRS-HIPEC for colorectal cancer (32.3%). Other primary tumors included: gastric (26.6%), appendiceal (20.9%), ovarian (12.7%), and other cancers (7.6%). The duration of CRS was 242.8±111.0 minutes, and the majority of patients underwent three cycles (43.0%) of HIPEC. The mean ICU length of stay was 1.1±2.7 days, and the hospital length of stay was 19.4±11.1 days.

Comparisons of clinical features between AKI and non-AKI cohorts

Patients with AKI were more likely to develop ascites before surgery compared to patients without AKI (27 [79.4%] vs. 52 [41.9%], P < 0.001). Before CRS-HIPEC therapy, functions of vital organs such as blood, liver, and kidney were evaluated. As compared with the non-AKI cohort, the counts of WBC (5.7±2.4 vs. 6.9±3.3, P < 0.05), GRAN% (60.2±13.3 vs. 70.2±11.8, P < 0.001), CRP (18.6±40.2 vs. 41.4±44.6, P < 0.05), PCT (0.1±0.2 vs. 0.5±1.1, P < 0.01), urea (4.8±1.7 vs. 6.1±3.6, P < 0.05) were significantly higher in AKI cohort, while the LYM% was lower (26.4±9.5 vs. 19.8±10.0, P < 0.001). On the contrary, the serum levels of eGFR in the non-AKI group were notably higher than in the AKI group (96.4±14.0 vs. 84.2±25.9, P < 0.05). The percentage of patients who encountered the duration of intraoperative hypotension was significantly longer in the AKI cohort than in the non-AKI cohort (31.7±28.0 vs. 18.7±16.5 minutes, P < 0.05). In addition, AKI patients (32.4%) received more intraoperative plasma transfusion than non-AKI patients (16.9%) (P < 0.05). The mean ICU length of stay was significantly prolonged in AKI patients than in non-AKI patients (2.4±4.3 vs. 0.6±1.7, P < 0.01) (Table 1).

Features of patients in the AKD cohort

Patients with AKD had the highest incidence of ascites manifestation (76.2%). The higher GRAN% (69.4±11.6 vs. 60.2±13.3, P < 0.01), urea (6.0±2.8 vs. 4.8±1.7, P < 0.05), and uric acid (381.9±181.0 vs. 295.1±79.2, P < 0.05), but lower LYM% (20.3±9.9 vs. 26.4±9.5, P < 0.05) and eGFR (80.3±27.8 vs. 96.4±14.0, P < 0.05) were presented in patients diagnosed with postoperative AKD than those in non-AKI group. The duration of intraoperative hypotension was notably longer in the AKD cohort compared with the non-AKI cohort (32.2±27.3 vs. 18.7±16.5 minutes, P < 0.05) (Table 1).

Postoperative outcomes and follow-up results

Overall, 34 (21.5%) patients developed postoperative AKI. According to the KDIGO classification, 21 (13.3%) suffered from stage I, 6 (3.8%) developed stage II, and 7 (4.4%) occurred from stage III (Figure 1). Additionally, 21 (61.8%) of these AKI patients coincided with the AKD diagnosis. During the 90-day follow-up for the AKD group, 42.8% of patients were diagnosed with CKD (Table 2).

The recorded thirty-day mortality was in 3.2% (n = 5) of total patients, while all these adverse events occurred in the AKI group (14.7%) (Table 2). In-hospital mortality was owing to suffering acute kidney failure, infectious shock, and multiple organ dysfunction syndromes (MODS) in all three patients, who were belonging to the AKD cohort. In addition, one patient developed cerebral infarction and MODS, while hemorrhagic shock was due to lower gastrointestinal hemorrhage in another (Table 3).

Factors associated with AKI

We performed univariate and multivariate logistic regression to identify the risk factors of AKI development in this patient population. By the former, the univariate model identified Hct, WBC, GRAN%, LYM%, baseline SCr, urea, uric acid, eGFR, ASA status, intraoperative blood loss, duration of intraoperative hypotension, and use of 5-FU as associated factors of the occurrence of postoperative AKI. After multivariable analysis, patients with AKI were more likely to have ascites (adjusted OR, 3.501; 95% CI, 1.149-10.663; p < 0.05), present with higher GRAN% (adjusted OR, 1.195; 95% CI, 1.022-1.399; p < 0.05), show lower eGFR (adjusted OR, 0.949; 95% CI, 0.905-0.995; p < 0.05), and experience prolonged duration of intraoperative hypotension (adjusted OR, 1.030; 95% CI, 1.005-1.054; p < 0.05) (Table 4).

Risk Factors for AKD

Univariate analysis for predictors associated with AKD were shown in Table 5. After multivariate regression analysis, uric acid (adjusted OR, 1.012; 95% CI, 1.001-1.023; p < 0.05), eGFR (adjusted OR, 0.942; 95% CI, 0.889-0.998; p < 0.05), and duration of intraoperative hypotension (adjusted OR, 1.036; 95% CI, 1.003-1.070; p < 0.05) remained independent predictors of AKD.

CRS-HIPEC has become a standard treatment for peritoneal metastasis in selected patients, delivering more prolonged survival [20, 22]. Nevertheless, several relevant morbidities were identified after this procedure [23, 24]. Among these complications, AKI has been recognized as the most common complication following CRS-HIPEC [25]. Therefore, this study set out to analyze the prevalence and risk factors of AKI in patients treated with CRS-HIPEC. Furthermore, with the popular concepts of the AKI-to-AKD-to-CKD interplay and the association between AKD and incremental future risk of mortality, many researchers have drawn attention to AKD prevention and management. However, little is known about the incidence of HIPEC-associated AKD, and it is not clear what parameters are associated with AKD. Thereby, the present research explores, for the first time, the risk factors for HIPEC-associated AKD.

The incidences of HIPEC-induced AKI varied between 1% and 48% [12, 13] widely. In this paper, we detected that 21.5% of patients experienced AKI after the CRS-HIPEC procedure. Hakeam et al. found that 3.7% of patients in their study developed AKI after CRS-HIPEC [14]. In another study, Sin and colleagues reported that AKI occurred in 40.4% of ovarian cancer patients undergoing the CRS-HIPEC procedure [15]. Additionally, with the larger sample size (n = 475) and the AKIN criteria, Cata et al. presented an AKI rate similar to ours. They found that 21.3% of patients had HIPEC-induced AKI [17].

Prior studies have noted several risk factors for HIPEC-associated AKI. In our study, we demonstrated that ascites were significantly associated with the development of AKI. This may be explained by the fact that ascites can increase intra-abdominal pressure, which negatively affects renal function [26]. For those patients who suffered from advanced carcinoma, peritoneal carcinomatosis increased the incidence of ascites, leading to higher intra-abdominal pressure. In addition, patients with higher preoperative GRAN% were confirmed at an incremental risk for HIPEC-induced AKI. Indeed, inflammatory processes mediated by the immune system are pivotal in mediating renal injury [27]. Therefore, we included several inflammatory parameters in our research, while only GRAN% presented the predisposing risk factor status.

Our results proved that those with lower preoperative eGFR were more likely to occur HIPEC-induced renal impairment, and this finding was similar to what has been described in previous studies [15]. Identifying patients at risk preoperatively, especially those with lower eGFR, would assist us in adopting suitable preventive measures. Furthermore, our study found that intraoperative blood loss and duration of hypotension were significantly higher in patients suffering from HIPEC-induced AKI, suggesting that hypotension substantially contributes to causing an ischemia-reperfusion injury, which may manifest as postoperative AKI [28, 29].

Among those who developed HIPEC-associated AKI, 61.8% of patients occurred AKI-to-AKD transition. Nonetheless, a previous study by Kellum et al. found that 36% of patients diagnosed with AKI have proceeded to AKD [30]. Although this figure is lower than in our study, the authors only included critically ill patients with stage 2 or 3 AKI. Based on a retrospective study including 1341 patients, Peerapornratana et al. reported the association of AKD with deficient kidney recovery at hospital discharge among critically ill septic patients [31]. Indeed, a recent meta-analysis demonstrated that prolonged AKI duration was independently associated with cardiovascular adverse events, development of incident CKD, and long-term mortality [32]. Take together, punctuating the clinical influence of persistently reduced kidney function from AKI-to-AKD. Therefore, we draw attention to examining the prevalence and independently associated factors of AKD in patients with CRS-HIPEC procedure. In our population, 42.8% of patients with AKD propagated the transition to CKD, while 14.3% of in-hospital mortality occurred in the AKD cohort.

Our study also demonstrated that the development of AKD was significantly associated with preoperative eGFR, uric acid level, and intraoperative hypotension duration. Patients who had lower preoperative eGFR were more prone to beget AKI and proceed with AKD than those with normal parameters. Consistent with our present findings, previous studies have shown that lower eGFR was a risk factor for hospitalization, which was itself a risk factor for renal function impairment [33-35]. The uric acid level was affirmed as a possible determinant of transient and persistent kidney dysfunction [36]. Furthermore, baseline uric acid was presented to increase the incidence rate of both CKD and ESRD, with accelerated CKD progression. In our patient collective, preoperative uric acid was recognized as the leading risk factor for AKD after HIPEC. Prolonged episodes of hypotension during the intraoperative period may decrease renal perfusion, resulting in renal function injury in patients with impaired autoregulation [37]. It thus appears rational to recommend that the duration of the intraoperative hypotensive episode should be kept as short as possible [38].

The shortcomings of the current study include our data from a single medical center, which limits generalizability. Additionally, this is a retrospective analysis of prospectively collected data, and as a result, there is an inherent selection bias. We attempted to select patients by two investigators using narrow inclusion criteria to mitigate this, and all records were reviewed. Finally, we only used SCr concentration to define AKI, while urine output was not included to diagnose postoperative AKI due to incomplete data on urine output. To our knowledge, however, this is the first study explicitly examining the epidemiology and risk factors of HIPEC-associated both AKI and AKD. There is abundant room for further progress in designing prospective randomized trials regarding the sample size necessary to detect the long-term renal function difference in AKI and AKD cohorts.

Our present study implies that the incidence of AKI in patients undergoing CRS-HIPEC is high, and the transition to AKD is a common outcome following AKI, which confirms the association with more risk for both in-hospital mortality consulting from renal function failure and CKD progression. Patients at higher risk of AKI after the CRS-HIPEC procedure include those who have ascites, incremental GRAN%, lower eGFR, and prolonged intraoperative hypotension duration. Further independent risk factors for developing AKD are higher preoperative uric acid levels, lower eGFR, and longer intraoperative hypotension duration. The indispensability of early recognition of HIPEC-induced AKD is beyond diagnostic purposes because it provides the opportunity for timely interventions to mitigate detrimental post-AKI complications.

Ethical Approval

This was a retrospective study, which included patient information. This study was not included genetics information. The study was approved by the Institutional Review Board of our institution (7222199).

Competing Interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Authors' contributions

Yunwei Lu drafted the initial manuscript with oversight by Fengxue Zhu and all other authors critically reviewed and revised the manuscript. Xiujuan Zhao and Fuzheng Guo collected all data and completed figure making. Yingjiang Ye and Shu Li assisted with interpretation of the results. All authors reviewed and approved the final manuscript.

Funding

This was not applicable.

Availability of data and materials

The raw data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.

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Table 1 Patient demographics and clinical characteristics

Characteristics	Total	non-AKI	AKI	AKD	P value¹	P value²
	158 (100)	124 (78.5)	34 (21.5)	21 (13.3)
Gender					0.538	0.500
Male	63 (39.9)	51 (41.1)	12 (35.3)	7 (33.3)
Female	95 (60.1)	73 (58.9)	22 (64.7)	14 (66.7)
Age (years)	59.5 ± 11.9	59.3 ± 11.7	60.2 ± 12.9	62.0 ± 13.8	0.864	0.468
BMI (kg/m²)	22.7 ± 3.2	22.8 ± 3.1	22.2 ± 3.2	22.5 ± 3.7	0.278	0.759
Comorbidities
Hypertension	34 (21.5)	24 (19.4)	10 (29.4)	5 (23.8)	0.206	0.637
Diabetes mellitus	19 (12.0)	14 (11.3)	5 (14.7)	3 (14.3)	0.588	0.693
Heart disease	7 (4.4)	5 (4.0)	2 (5.9)	2 (9.5)	0.642	0.278
Hepatitis	10 (6.3)	8 (6.5)	2 (5.9)	0 (0.0)	0.904	0.231
ACEI/ARB	11 (7.0)	8 (6.5)	3 (8.8)	3 (14.3)	0.630	0.210
Neoadjuvant therapy	31 (19.6)	25 (20.2)	6 (17.6)	5 (23.8)	0.744	0.703
Ascites	79 (50.0)	52 (41.9)	27 (79.4)	16 (76.2)	0.000	0.004
Preoperative laboratory parameters
Hb (g/L)	117.6 ± 20.8	119.0 ± 21.0	112.9 ± 19.7	113.0 ± 14.8	0.107	0.071
RBC (10^12/ L)	4.0 ± 0.5	4.0 ± 0.5	3.9 ± 0.6	3.9 ± 0.5	0.272	0.212
HCT (%)	35.5 ± 5.3	35.9 ± 5.2	33.9 ± 5.6	34.0 ± 4.5	0.080	0.078
WBC (10^9/ L)	6.0 ± 2.6	5.7 ± 2.4	6.9 ± 3.3	6.6 ± 3.0	0.037	0.205
PLT (10^9/ L)	246.0 ± 110.1	238.2 ± 107.1	274.2 ± 117.9	271.6 ± 101.0	0.081	0.095
GRAN (%)	62.4 ± 13.6	60.2 ± 13.3	70.2 ± 11.8	69.4 ± 11.6	0.000	0.005
LYM (%)	25.0 ± 9.9	26.4 ± 9.5	19.8 ± 10.0	20.3 ± 9.9	0.001	0.016
Baseline SCr (μmol/L)	65.0 ± 20.2	62.9 ± 15.0	72.6 ± 32.0	76.7 ± 35.7	0.307	0.281
Urea (mmol/L)	5.1 ± 2.3	4.8 ± 1.7	6.1 ± 3.6	6.0 ± 2.8	0.041	0.041
Uric acid (μmol/L)	305.1 ± 103.7	295.1 ± 79.2	341.6 ± 161.3	381.9 ± 181.0	0.112	0.018
eGFR (mL/min/1.73m²)	93.7 ± 17.9	96.4 ± 14.0	84.2 ± 25.9	80.3 ± 27.8	0.020	0.010
ALB (g/L)	37.8 ± 4.5	38.1 ± 4.3	36.8 ± 5.2	36.0 ± 5.3	0.216	0.076
CRP (mg/L)	22.0 ± 41.4	18.6 ± 40.2	41.4 ± 44.6	48.8 ± 48.5	0.015	0.021
PCT (pg/mL)	0.2 ± 0.5	0.1 ± 0.2	0.5 ± 1.1	0.2 ± 0.3	0.009	0.035
Urine Microalbumin	29 (18.4)	21 (17.4)	8 (25.8)	5 (23.8)	0.285	0.350
Primary tumor					0.000	0.006
Colorectal	51 (32.3)	44 (35.5)	7 (20.6)	3 (14.3)
Appendiceal	33 (20.9)	27 (21.8)	6 (17.6)	5 (23.8)
Gastric	42 (26.6)	37 (29.8)	5 (14.7)	4 (19.0)
Ovarian	20 (12.7)	12 (9.7)	8 (23.5)	5 (23.8)
Others	12 (7.6)	4 (3.2)	8 (23.5)	4 (19.0)
ASA					0.042	0.144
Ⅰ	16 (10.1)	14 (11.3)	2 (5.9)	1 (4.8)
Ⅱ	110 (69.6)	90 (72.6)	20 (58.8)	13 (61.9)
Ⅲ	32 (20.3)	20 (16.1)	12 (35.3)	7 (33.3)
Intraoperative parameters
Operative duration (min)	242.8 ± 111.0	244.1 ± 93.7	238.1 ± 160.9	224.8 ± 131.8	0.068	0.127
Blood loss (ml)	278.9 ± 377.8	236.6 ± 298.3	432.9 ± 562.3	401.9 ± 541.0	0.513	0.756
Fluid (ml)	3203.2 ± 1290.1	3121.8 ± 1134.7	3500.0 ± 1733.1	3369.1 ± 1527.3	0.505	0.690
Urine output (ml)	746.3 ± 499.9	744.8 ± 493.2	751.8 ± 531.7	727.6 ± 492.5	0.980	0.964
SBP<100 mmHg duration (min)	21.5±20.2	18.7 ± 16.5	31.7 ± 28.0	32.2 ± 27.3	0.029	0.044
RBC transfusion	27 (17.1)	20 (16.1)	7 (20.6)	4 (19.0)	0.541	0.739
Plasma transfusion	32 (20.3)	21 (16.9)	11 (32.4)	7 (33.3)	0.048	0.078
Vasopressors	97 (61.4)	75 (60.5)	22 (64.7)	16 (76.2)	0.654	0.169
Furosemide	18 (11.4)	15 (12.1)	3 (8.8)	3 (14.3)	0.595	0.778
Ureteral catheters	18 (11.4)	13 (10.5)	5 (14.7)	2 (9.5)	0.492	0.894
HIPEC regimens
5-FU	75 (47.5)	64 (51.6)	11 (32.4)	5 (23.8)	0.046	0.018
Cisplatin	114 (72.2)	90 (72.6)	24 (70.6)	16 (76.2)	0.818	0.730
TAX	36 (22.8)	29 (23.4)	7 (20.6)	5 (23.8)	0.730	0.966
Raltitrexed	15 (9.5)	14 (11.3)	1 (2.9)	1 (4.8）	0.141	0.364
Cycles of HIPEC					0.204	0.224
1	24 (15.2)	15 (12.1)	9 (26.5)	6 (28.6)
2	35 (22.2)	29 (23.4)	6 (17.6)	5 (23.8)
3	68 (43.0)	54 (43.5)	14 (41.2)	6 (28.6)
4	31 (19.6)	26 (21.0)	5 (14.7)	4 (19.0)
AKI stage
1	21 (13.3)		21 (61.8)	10 (47.6)
2	6 (3.8)		6 (17.6)	4 (19.0)
3	7.0 (4.4)		7 (20.6)	7 (33.3)

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; AKD, acute kidney disease; AKI, acute kidney injury; ALB, albumin; ASA, American Society of Anesthesiologists score; BMI, body mass index; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; GRAN, neutrophil ratio; Hb, hemoglobin; HCT, hematocrit; LYM, lymphocyte ratio; PLT, platelet; PCT, procalcitonin; RBC, red blood cell; SBP, systolic blood pressure; SCr, serum creatinine; TAX, paclitaxel; WBC, white blood cell, 5-FU, 5-fluorouracil.

P value¹ for AKI compared with non-AKI groups. P value² for AKD compared with non-AKI cohorts.

Data are shown as n (%) or mean ± standard deviation (SD).

Table 2 Postoperative outcomes of patients undergoing CRS-HIPEC

Outcomes	Total (n=158)	non-AKI (n=124)	AKI (n=34)	AKD (n=21)	P value¹	P value²
AKD	21 (13.3)		21 (61.8)
CKD	9 (5.7)		9 (26.5)	9 (42.8)
30-Day mortality	5 (3.2)	0 (0)	5 (14.7)	3 (14.3)	0.000	0.000
ICU length of stay (days)	1.1 ± 2.7	0.6 ± 1.7	2.4 ± 4.3	2.0 ± 3.5	0.004	0.117
Length of stay (days)	19.4 ± 11.1	18.6 ± 7.6	22.0 ± 19.1	22.0 ± 22.0	0.963	0.481

Abbreviations: AKD, acute kidney disease; AKI, acute kidney injury; CKD, chronic kidney disease; ICU, intensive care unit.

P value¹ for AKI compared with non-AKI groups. P value² for AKD compared with non-AKI cohorts.

Data are shown as n (%) or mean ± standard deviation (SD).

Table 3 Characteristics and causes for patients occurred in-hospital death

	Age	Gender	Ascites	Primary tumor	AKI stage	GRAN%	eGFR	Uric acid	Intraoperative hypotension duration (min)	Death causes
Case 1	71	F	Y	Colorectal	Ⅱ	87.4	119.42	43	100	Acute renal failure, Infectious shock, MODS
Case 2	64	M	Y	Gastric	Ⅰ	88.2	56.02	378	50	MODS, Cerebral infarction
Case 3	63	M	Y	Liver	Ⅰ	75.7	61.63	608	50	Lower gastrointestinal hemorrhage
Case 4	83	F	Y	Colorectal	Ⅲ	78.1	20.97	986	60	Acute renal failure, Infectious shock, MODS
Case 5	56	M	N	Gastric	Ⅲ	60.4	96.95	337	20	Acute renal failure, Infectious shock, MODS

Abbreviations: F, female; eGFR, estimated glomerular filtration rate; GRAN, neutrophil ratio; M, male; MODS, multiple organ dysfunction syndromes.

Table 4 Univariate and multivariate analysis of risk factors for AKI after CRS-HIPEC procedure

Characteristics	Unadjusted OR (95% CI)	P value	Adjusted OR (95% CI)	P value
Gender
Male	Reference
Female	1.281 (0.582-2.820)	0.539
Age	1.006 (0.974-1.039)	0.706
BMI	0.938 (0.829-1.061)	0.308
Comorbidities
Hypertension	1.736 (0.733-4.110)	0.210
Diabetes mellitus	1.355 (0.451-4.070)	0.589
Heart disease	1.487 (0.276-8.026)	0.644
Hepatitis	0.906 (0.183-4.480)	0.904
ACEI/ARB	1.403 (0.351-5.605)	0.632
Neoadjuvant therapy	0.849 (0.317-2.272)	0.744
Ascites	5.341 (2.161-13.196)	0.000	3.501 (1.149-10.663)	0.027
Preoperative laboratory parameters
Hb	0.987 (0.970-1.004)	0.138
RBC	0.594 (0.296-1.192)	0.143
HCT	0.932 (0.869-1.000)	0.050	0.956 (0.870-1.051)	0.354
WBC	1.165 (1.019-1.333)	0.026	0.861 (0.672-1.104)	0.239
PLT	1.003 (1.000-1.006)	0.096
GRAN	1.069 (1.032-1.108)	0.000	1.195 (1.022-1.399)	0.026
LYM	0.931 (0.892-0.971)	0.001	1.104 (0.924-1.318)	0.276
Baseline SCr	1.022 (1.003-1.041)	0.023	0.974 (0.925-1.025)	0.305
Urea	1.278 (1.069-1.528)	0.007	1.009 (0.773-1.317)	0.948
Uric acid	1.004 (1.000-1.008)	0.035	1.007 (0.999-1.016)	0.084
eGFR	0.964 (0.943-0.985)	0.001	0.949 (0.905-0.995)	0.030
ALB	0.939 (0.865-1.021)	0.140
CRP	1.010 (0.999-1.021)	0.073
PCT	5.861 (0.959-35.819)	0.056
Urine Microalbumin	1.656 (0.652-4.206)	0.289
ASA		0.050
Ⅰ	Reference
Ⅱ	1.556 (0.327-7.394)	0.579
Ⅲ	4.200 (0.810-21.769)	0.087
Intraoperative parameters
Operative duration	0.999 (0.996-1.003)	0.779
Blood loss	1.001 (1.000-1.002)	0.012	1.001 (1.000-1.003)	0.075
Fluid	1.000 (1.000-1.000)	0.134
Urine output	1.000 (0.999-1.001)	0.942
SBP < 100 mmHg duration	1.030 (1.011-1.049)	0.002	1.030 (1.005-1.054)	0.016
RBC transfusion	1.348 (0.517-3.518)	0.542
Plasma transfusion	2.346 (0.994-5.533)	0.052
Vasopressors	1.198 (0.544-2.640)	0.654
Furosemide	0.703 (0.191-2.586)	0.596
Ureteral catheters	1.472 (0.485-4.465)	0.494
HIPEC regimens
5-FU	0.448 (0.201-0.998)	0.049	0.659 (0.223-1.950)	0.452
Cisplatin	0.907 (0.393-2.093)	0.818
TAX	0.849 (0.335-2.151)	0.731
Raltitrexed	0.238 (0.030-1.879)	0.173
Cycles of HIPEC		0.224
1	Reference
2	3.120 (0.881-11.049)	0.078
3	1.076 (0.293-3.946)	0.912
4	1.348 (0.438-4.145)	0.602

Abbreviations: ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blockers; ALB, albumin; ASA, American Society of Anesthesiologists score; BMI, body mass index; CI: confidence interval; CRP, C-reactive protein; eGFR, estimated glomerular filtration rate; GRAN, neutrophil ratio; Hb, hemoglobin; HCT, hematocrit; LYM, lymphocyte ratio; PLT, platelet; PCT, procalcitonin; RBC, red blood cell; SBP, systolic blood pressure; SCr, serum creatinine; TAX, paclitaxel; WBC, white blood cell, 5-FU, 5-fluorouracil.

Table 5 Univariate and multivariate analysis for predictors of HIPEC-induced AKD

Characteristics	Unadjusted OR (95% CI)	P value	Adjusted OR (95% CI)	P value
Gender
Male	Reference
Female	1.397 (0.527-3.705)	0.501
Age	1.020 (0.979-1.061)	0.346
BMI	0.972 (0.841-1.125)	0.705
Comorbidities
Hypertension	1.302 (0.434-3.906)	0.638
Diabetes mellitus	1.310 (0.342-5.015)	0.694
Heart disease	2.505 (0.453-13.849)	0.292
ACEI/ARB	2.417 (0.586-9.966)	0.222
Neoadjuvant therapy	1.237 (0.414-3.702)	0.703
Ascites	4.431 (1.526-12.861)	0.006	3.441 (0.911-12.991)	0.068
Preoperative laboratory parameters
Hb	0.987 (0.966-1.008)	0.215
RBC	0.567 (0.238-1.350)	0.200
HCT	0.933 (0.855-1.018)	0.119
WBC	1.135 (0.960-1.342)	0.137
PLT	1.003 (0.999-1.007)	0.189
GRAN	1.064 (1.020-1.111)	0.004	1.180 (0.980-1.421)	0.081
LYM	0.935 (0.888-0.984)	0.010	1.141 (0.912-1.427)	0.250
Baseline SCr	1.029 (1.006-1.052)	0.012	0.976 (0.916-1.039)	0.444
Urea	1.351 (1.084-1.683)	0.007	0.910 (0.626-1.321)	0.619
Uric acid	1.007 (1.002-1.012)	0.005	1.012 (1.001-1.023)	0.030
eGFR	0.954 (0.929-0.980)	0.001	0.942 (0.889-0.998)	0.043
ALB	0.903 (0.818-0.998)	0.045	0.973 (0.837-1.130)	0.716
CRP	1.011 (0.999-1.023)	0.067
PCT	5.598 (0.488-64.283)	0.167
Urine Microalbumin	1.701 (0.553-5.235)	0.355
ASA		0.162
Ⅰ	Reference
Ⅱ	2.022 (0.245-16.687)	0.513
Ⅲ	4.900 (0.541-44.391)	0.158
Intraoperative parameters
Operative duration	0.998 (0.993-1.003)	0.411
Blood loss	1.001 (1.000-1.002)	0.054
Fluid	1.000 (1.000-1.001)	0.382
Urine output	1.000 (0.999-1.001)	0.882
SBP < 100 mmHg duration	1.033 (1.010-1.057)	0.005	1.036 (1.003-1.070)	0.032
RBC transfusion	1.224 (0.372-4.021)	0.740
Plasma transfusion	2.452 (0.883-6.811)	0.085
Vasopressors	2.091 (0.719-6.075)	0.175
Furosemide	1.211 (0.318-4.607)	0.779
Ureteral catheters	0.899 (0.188-4.304)	0.894
HIPEC regimens
5-FU	0.293 (0.101-0.849)	0.024	0.265 (0.070-1.003)	0.051
Cisplatin	1.209 (0.411-3.556)	0.730
TAX	1.024 (0.345-3.035)	0.966
Raltitrexed	0.393 (0.049-3.157)	0.380
Cycles of HIPEC		0.253
1	Reference
2	0.431 (0.113-1.647)	0.219
3	0.278 (0.078-0.987)	0.048
4	0.385 (0.093-1.585)	0.186

No competing interests reported.

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published 11 Apr, 2024

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Incidence, Risk Factors, and Outcomes of Transition of HIPEC- Induced Acute Kidney Injury to Acute Kidney Disease: A Retrospective Study

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Introduction

Patients and methods

Results

Comparisons of clinical features between AKI and non-AKI cohorts

Features of patients in the AKD cohort

Postoperative outcomes and follow-up results

Factors associated with AKI

Risk Factors for AKD

Discussion

Conclusion

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References

Tables

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