Risk factors and outcomes associated with acute kidney injury following extracardiac total cavopulmonary connection: a retrospective observational study

Introduction

With increasing refinements of surgical techniques and perioperative management, total cavopulmonary connection (TCPC) has become an important operation for the treatment of complex congenital heart disease. Systemic venous blood enters the pulmonary circulation by bypassing the right ventricle through an artificial conduit in order to correct hypoxia caused by the mixing of oxygenated and deoxygenated blood in the single ventricle (1). Patients undergoing TCPC operations are vulnerable to postoperative acute kidney injury (AKI). Alterations in physiology due to the incorporation of the vena cava into pulmonary arteries result in systemic venous hypertension and low cardiac output, and is related to a decrease in glomerular filtration rate (2,3).

However, studies evaluating the incidence and clinical outcomes of AKI in children following extracardiac TCPC are limited. Esch et al. (4) reported that preoperative atrioventricular valve regurgitation, pulmonary vascular resistance, cardiopulmonary bypass (CPB) time, postoperative renal perfusion, and peak inotrope score on the day of surgery were independent risk factors for postoperative AKI in children undergoing Fontan procedures (mainly lateral tunnel-type). In addition, Algaze et al. explored AKI associations in a cohort of purely extracardiac Fontan patients with or without the support of CPB (5). In our center, most patients received extracardiac TCPC under CPB, either with or without an aortic x-clamp. The extracardiac conduit TCPC better prevents late occurrence of postoperative arrhythmia and simplifies the operation, compared to the lateral tunnel procedure (6).

This study investigates the incidence and risk factors for the development of AKI in patients undergoing on-pump extracardiac TCPC, and the influence of AKI on postoperative clinical outcomes. We present the following article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-21-474/rc).

Methods

Study design and patient selection

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics board of Fuwai Hospital (No. 2014-600) and individual consent for this retrospective analysis was waived. The medical records of consecutive patients (age at surgery <18 years) who had extracardiac TCPC surgery in the Pediatric Cardiac Surgical Center of Fuwai Hospital between January 2008 and January 2020 were reviewed. Exclusion criteria were: (I) preoperative serum creatinine ≥69.7 µmol/L, which is usually considered as the maximum normal range of serum creatinine in children (7), or received preoperative renal replacement therapy; (II) incomplete data of perioperative serum creatinine; (III) off-pump surgery; (IV) TCPC failure (patients who underwent TCPC surgery but failed to tolerance the anatomic change and ended with reoperation to other palliative connection) within 3 days after surgery; (V) patients with preoperative infection; (VI) primary hematological or immunological disease; (VII) patients with preoperative antibiotic administration after hospital admission.

Data collection and variable definition

Perioperative variables including demographic characteristics, cardiac morphology, echocardiographic parameters, cardiac catheterization hemodynamics, intraoperative records, and postoperative data were reviewed for all patients. Baseline blood laboratory parameters 48 h before, or the latest preoperative time were collected. All patients were routinely performed postoperative blood biochemical examination on the first day morning after ICU admission. Postoperative peak serum creatinine levels between postoperative day (POD) 1 and 3 were documented to determine postoperative estimated creatinine clearance (eCCL). The approach of creatinine measurement is standard. Postoperative clinical data included central venous pressure, mean arterial pressure, vasoactive drug dosage, and routine blood examination data on POD0. The hemodynamic data were recorded every hour through bedside monitoring in ICU. We collected the first measurements of hemodynamic data as the POD0 values.

AKI was defined using the pediatric-modified risk, injury, failure, loss of function, and end-stage renal disease (pRIFLE) criteria, and patients with AKI were divided into three stages: acute kidney injury-risk (AKI-R, eCCL decreased by 25%), acute kidney injury-injury (AKI-I, eCCL decreased by 50%), and acute kidney injury-failure (AKI-F, eCCL decreased by 75% or <35 mL/min/1.73 m²). Postoperative urine output was not used to estimate AKI since diuretics were routinely used after cardiac surgery. As in previous studies, AKI-I and AKI-F stages were considered severe AKI. The patients were divided into three groups: non-AKI, AKI-R, and AKI/F. eCCL was calculated using the modified Schwartz formula (8): eCCL = k × body length (cm)/serum creatinine value (mg/dL), with a k coefficient of 0.55 for children 2–12 years old, and 0.7 for children 12–18. Renal perfusion pressure was calculated by the following equation: mean arterial pressure (mmHg) – central venous pressure (mmHg) (2). Vasoactive-inotropic score was calculated as: dopamine (µg/kg/min) + dobutamine (µg/kg/min) + 10 × milrinone (µg/kg/min) + 100 × epinephrine (µg/kg/min) + 100 × norepinephrine (µg/kg/min) + 10,000 × vasopressin (U/kg/min). Inotrope score was calculated as: dopamine (µg/kg/min) + dobutamine (µg/kg/min) + 100 × epinephrine (µg/kg/min) (9). The neutrophil-to-lymphocyte ratio (NLR) was calculated from the whole blood count: NLR = absolute count of neutrophil (×10⁹/L)/absolute count of lymphocyte (×10⁹/L).

Clinical outcomes

The primary clinical outcome in our cohort was the incidence of AKI after extra-cardiac TCPC operation. Early outcomes included prolonged mechanical ventilation (>81 h, 90^th percentile), prolonged intensive care unit (ICU) stay (>10 days, 90^th percentile), in-hospital mortality, infection, pleural effusion, ascites, re-intubation, extracorporeal membrane oxygenation, and arrhythmia. Major adverse outcomes were defined as a composite of events including death, extracorporeal membrane oxygenation, re-intubation, and re-admission to ICU.

Statistical analysis

Continuous variables are presented as means and standard deviation if the distribution was approximately symmetrical, and compared using the one-way ANOVA test; otherwise, median and interquartile range are presented along with the Kruskal-Wallis H test. Categorical variables are presented as frequencies and percentages. The χ² test and Fisher’s exact test were used for categorical variables. Pairwise comparisons were performed among the three groups. The significance level (α level) was adjusted according to the Bonferroni method to reduce the risk of type I errors (P<0.017). Univariable and multivariable logistic regression models were performed to investigate the association between AKI, different risk factors and complications. Variables with P≤0.15, and those factors of clinical significance in the univariable analysis were incorporated in the multivariable logistic regression model. In addition, multiple ordinal logistic regression was performed to determine those factors associated with severity of AKI. Spearman correlation coefficients were used to assess the relationships between NLR and parameters of renal function. The time-related survival was estimated using the Kaplan-Meier method and compared by the log-rank test. All statistical analyses were performed by SPSS 26.0 software (SPSS Inc., Chicago, IL, USA) and MedCalc 18.2. All tests were two-sided, and P values <0.05 were considered significant.

Results

Characteristics of patients and AKI incidence

A total of 377 patients were included in this study; 59.4% (n=224) of the cohort was male. Median age at TCPC surgery was 4.9 (3.9, 6.4) years. Palliative surgery before TCPC was performed in 259 (68.7%) patients, the majority of whom underwent bidirectional Glenn operations (96.5%; n=250). Seven patients had pulmonary artery banding (4 of 7 had bidirectional Glenn at the same time) while 9 patients had BT shunt (3 of 9 had bidirectional Glenn at the same time) before TCPC operation. Based on the pRIFLE criteria, 123 patients (32.6%) developed AKI: 82.1% (101/123) AKI-R, 13.0% (16/123) AKI-I, and 4.9% (6/123) AKI-F. Severe AKI was diagnosed in 22 of the 123 patients with AKI.

Perioperative data of patients among different AKI severity groups

As shown in Table 1, patients were comparable in terms of sex, age, weight, height, and cardiac morphology (P>0.05). The AKI/F group had a significantly lower incidence of bidirectional Glenn when compared with the AKI-R group (45.5% vs. 73.3%, P=0.037). There were no significant differences in preoperative cardiac catheterization and echocardiographic parameters among the groups.

Patients with AKI-R or AKI/F had lower preoperative serum creatinine (P<0.001) and higher preoperative eCCL (P<0.001) than those without AKI. There were no significant differences in CPB time, aortic x-clamp time, lowest rectal temperature during CPB, and incidence of fenestration among the three groups (P>0.05). NLR levels were higher in the AKI/F and AKI-R groups than the non-AKI group on the day of ICU admission (7.9 vs. 8.9 vs. 5.4, P<0.001). In addition, the AKI/F group had significantly higher central venous pressure (15.0 vs. 13.0 vs. 12.0 mmHg, P<0.001) and lower renal perfusion pressure (39.7 vs. 42.8 vs. 46.7 mmHg, P=0.001) on POD0 than the AKI-R and non-AKI groups. Mean arterial pressure differed only between the AKI-R and non-AKI groups (55.6 vs. 59.0 mmHg, P=0.024) (Table 2).

Risk factors associated with AKI

Those variables associated with the development of AKI with P≤0.15 in univariable logistic regression analysis (preoperative eCCL, CPB time, POD0 NLR, POD0 renal perfusion pressure, and POD0 inotrope score) and with clinical significance (bidirectional Glenn before TCPC) were used to create a multiple regression model of AKI. Preoperative eCCL (OR: 1.039, 95% CI: 1.024–1.055, P<0.001), POD0 NLR (OR: 1.208, 95% CI: 1.128–1.294, P<0.001), and POD0 renal perfusion pressure (OR: 0.962, 95% CI: 0.938–0.986, P=0.002) were significantly associated with the occurrence of AKI after TCPC surgery. The multivariable model for AKI showed a good fit (Hosmer-Lemeshow test P=0.229), and the discriminating ability was good (area under the curve was 0.809). Spearman correlation analysis found that the POD0 NLR had a negative relation with postoperative eCCL (correlation coefficient =−0.237, P<0.001), and a positive relation with postoperative serum creatinine (correlation coefficient =0.368, P<0.001) (Figure 1). From the ordinal logistic multivariable model, previous bidirectional Glenn was significantly associated with severity of postoperative AKI (OR: 0.253, 95% CI: 0.088–0.731, P=0.011) (Table 3).

Figure 1 The relationship between POD0 NLR and postoperative renal function. POD, postoperative day; NLR, neutrophil to lymphocyte ratio.

Early- and long-term outcomes

Table 4 shows the early- and long-term clinical outcomes after surgery. In terms of early postoperative complications, patients with AKI/F were more likely to experience prolonged mechanical ventilation duration (P<0.001), prolonged ICU stay (P=0.030), infection (P<0.001), ascites (P=0.007), extracorporeal membrane oxygenation support (P=0.001), and ventricular fibrillation (P=0.003) than those without AKI. Of the six patients who died in ICU, all had AKI (one with AKI-R, five with AKI/F). The available data for 363 patients showed a median long-term follow-up time of 4 [2, 7] years. Compared with the non-AKI group, patients with AKI-R or AKI/F had a comparable survival rate at 1-year after TCPC surgery (98.7 vs. 97.9% vs. 94.1%, P=0.392). However, the overall 10-year survival rate of patients with AKI/F was significantly lower than those without AKI (65.9% vs. 95.5%, P=0.009) (Figure 2).

Figure 2 Comparing the 1- and 10-year survival rates among patients with different stages of AKI after TCPC operation. AKI-R, acute kidney injury-risk; AKI/F, acute kidney injury/failure; TCPC, total cavopulmonary connect.

Association of outcomes with AKI or severe AKI in multivariable analysis

As shown in Table 5, multivariable regression analysis confirmed that AKI was an independent risk factor for prolonged mechanical ventilation (OR: 4.364, 95% CI: 1.796–10.601, P=0.001) and prolonged ICU duration (OR: 2.890, 95% CI: 1.142–7.317, P=0.025). Furthermore, severe AKI was independently associated with the composite adverse outcome (OR: 5.013, 95% CI: 1.797–13.985, P=0.002).

Discussion

Limited evidence exists regarding the postoperative AKI epidemiology in pediatric extra-cardiac TCPC surgery. Our study demonstrates that AKI occurred in 32.6% of this population according to the pRIFLE criteria, lower than what has been described in previous studies (4,5). After adjusting for possible confounding variables by multivariable logistic regression analysis, preoperative eCCL, POD0 NLR, and POD0 renal perfusion pressure were independent risk factors of AKI. It is worth noting that higher NLR on POD0 could increase the risk of AKI, and has never been identified in patients who underwent TCPC operations. We also noticed that AKI was an independent risk factor for prolonged mechanical ventilation, prolonged ICU stay, and composite adverse outcome. The most important finding of this study is the significantly lower 10-year survival of patients with severe AKI.

In our cohort, children with higher preoperative eCCL had a higher chance of developing AKI. Increased glomerular filtration could increase intraoperative exposure of renal tubules to harmful substances such as cell-free hemoglobin in the plasma, or toxic-free iron generated by blood damage (10). Additionally, children with higher preoperative eCCL may have lower muscle mass, a poor nutritional state, or fluid overload, factors also increase the risk of AKI (11). Further studies are needed to explore why higher preoperative eCCL increases the risk of AKI after pediatric cardiac surgery. In our study, we found renal perfusion pressure was also an important predictor for the occurrence of AKI, consistent with the previous reports from Esch et al. and Algaze et al. (4,5). Compared with non-AKI patients, the postoperative renal perfusion pressure of patients with severe AKI was significantly lower. In terms of inotropic support, we found that the inotropic score on POD 0 were comparable in different stages of AKI. However, compared to patients without AKI, the inotrope requirement on POD 1 to POD 3 were significantly higher in those with AKI, indicating that AKI patients may require more support with inotropes to support a higher MAP and increase renal perfusion pressure. The management of renal perfusion pressure is a complex problem, especially after cardiac surgery and the ability to improve renal perfusion pressure by enhancing rhe inotrope requirement was limited (12).

In our study, 111 patients (29.4%) underwent fenestration during TCPC. Some studies considered that fenestration could reduce drainage from chest tubes and duration of hospitalization because of the lower extra-cardiac conduit pressure and larger cardiac output in the early postoperative period, where some others studies found no significant difference of perioperative data between patients with and without fenestration in TCPC operation. These different opinions also influenced the surgeons’ operation procedures in our center. Our results showed no significant differences in postoperative mean arterial pressure, central venous pressure, and renal perfusion pressure between patients with and without fenestration, but this kind of right-to-left shunting could alleviate the sudden changes in hemodynamics induced by crying, asphyxia, or airway obstruction after operation. Although we did not find any association between fenestration and AKI, Fan et al. (13) reported that for patients undergoing high-risk TCPC, intraoperative fenestration was beneficial for reducing postoperative chest tube drainage volume and duration, consistent with our results.

For the AKI patients in our cohort, the proportion of receiving bidirectional Glenn before TCPC was lower in severe AKI patients, and indicates that a bidirectional Glenn before TCPC decreases AKI severity, something which has not been reported. Staged palliation with a bidirectional Glenn and subsequent TCPC is a common treatment strategy in patients with functional single ventricle, and has the advantages of improving oxygen saturations and further reducing the volume load. While these favorable effects of the bidirectional Glenn can improve pulmonary hemodynamics, the influence on kidney function and association with AKI remain unclear. Hypoxemia may induce hyperviscosity due to secondary erythrocytosis, leading to glomerular blood flow and pathological glomerular changes (2). The mechanism by which a bidirectional Glenn decreased the risk of severe AKI may be due to palliation improving oxygen saturation and decreasing blood viscosity, thereby attenuating pathological glomerular changes (14).

Another major finding of our study was that POD0 NLR was associated with AKI. The relationship between postoperative NLR and AKI has been evaluated in cardiac surgery and septic shock (15,16). As an indicator of inflammatory response, NLR is a common clinical index, and is easily obtained from a routine blood test. Furthermore, it has been shown to predict mortality and major adverse events after cardiac surgery (17-19). Recently, Manuel et al. (20) found an association between a high preoperative NLR and severe AKI after tetralogy of Fallot repair. We did not find any differences in preoperative NLR among different stages of AKI after TCPC operation. The inflammatory levels were comparable in patients before surgery. In our study, the negative correlation of POD0 NLR with postoperative eCCL, and the positive correlation with postoperative serum creatinine also indirectly indicate that the NLR plays an important role in the prediction of AKI. Unlike other inflammatory markers such as TNF-a and IL-6, NLR is a convenient and low-cost biomarker that could be used for AKI prediction.

Consistent with other studies of AKI after pediatric cardiac surgery, AKI was an independent risk factor of prolonged ICU stay and mechanical ventilation in our cohort (11,21,22). AKI was also shown to be independently associated with increased mortality in children (23-25). In this study, early-term mortality after TCPC was 1.6% (6/377), and patients with severe AKI had higher in-hospital mortality and other complications than those without AKI. The follow-up results of our study showed that the 10-year survival was significantly lower in severe AKI patients. Although most AKI cases after TCPC were mild and had a favorable prognosis, the early and long-term clinical outcomes of patients with severe AKI are poor. Early postoperative identification and intervention are important steps to improve the outcomes of patients with severe AKI.

This study had several limitations. Since this was a single-center retrospective study, the patient selection criteria are not completely random, and the inherent bias associated with a retrospective study exists. A multicenter study or random controlled trial needs to be carried out to further evaluate the results of our study. Secondly, only a biochemical test was used to assess kidney function. Since serum creatinine levels were not measured in most patients after discharge from ICU, the recovery time from AKI could not be exactly determined. Furthermore, our limited examination data were not enough to evaluate long-term kidney function after discharge from the hospital. Finally, although we found several risk factors for AKI after TCPC, we could not conclude that modifying any factor would improve patient outcome.

In conclusion, the incidence of AKI was high in patients undergoing TCPC surgery, but most cases were AKI-R. Preoperative eCCL, NLR and renal perfusion pressure on POD0 were independently associated with AKI. Bidirectional Glenn procedures were found to be associated with AKI severity. Although there were no significant differences in 1-year survival rates between patients with and without AKI, severe AKI was significantly associated with early adverse outcomes and poor long-term survival.

Acknowledgments

The authors thank Mr. Ricardo Annon for his great contribution in language editing assistance.

Funding: This work was supported by National Natural Science Fund (grant number: 81670375) and Innovation Fund for Medical Science (grant number: 2020-I2M-C&T-B-063).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-21-474/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-21-474/dss

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-21-474/coif). All authors report that this work was supported by National Natural Science Fund (grant number: 81670375) and Innovation Fund for Medical Science (grant number: 2020-I2M-C&T-B-063). The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by institutional ethics board of Fuwai Hospital (No. 2014-600) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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