Epidemiology of acute kidney injury among paediatric patients after repair of anomalous origin of the left coronary artery from the pulmonary artery

Abstract

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OBJECTIVES

Acute kidney injury (AKI) is a prevalent complication after the surgical repair of paediatric cardiac defects and is associated with poor outcomes. Insufficient renal perfusion secondary to severe myocardial dysfunction in neonates is most likely an independent risk factor in patients undergoing repair for anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). We retrospectively investigated the epidemiology and outcomes of children with ALCAPA who developed AKI after repair.

METHODS

Eighty-nine children underwent left coronary reimplantation. The paediatric-modified risk, injury, failure, loss and end-stage (p-RIFLE) criteria were used to diagnose AKI.

RESULTS

The incidence of AKI was 67.4% (60/89) in our study. Among the patient cohort with AKI, 23 (38.3%) were diagnosed with acute kidney injury/failure (I/F) (20 with acute kidney injury and 3 with acute kidney failure). Poor cardiac function (left ventricular ejection fraction < 35%) prior to surgery was a significant contributing factor associated with the onset of AKI [odds ratio (OR) 5.55, 95% confidential interval (CI) 1.39–22.13; P = 0.015], while a longer duration from diagnosis to surgical repair (OR 0.97, 95% CI 0.95–1.00; P = 0.049) and a higher preoperative albumin level (OR 0.83, 95% CI 0.70–0.99; P = 0.041) were found to lower the risk of AKI. Neither the severity of preoperative mitral regurgitation nor mitral annuloplasty was associated with the onset of AKI. After reimplantation, there was 1 death in the no-AKI group and 2 deaths in the AKI/F group (P = 0.356); the remaining patients survived until hospital discharge. The median follow-up time was 46.5 months (34.0–63.25). During follow-up, patients in the AKI cohort were seen more often by specialists and reassessed more often by echocardiography.

CONCLUSIONS

Paediatric AKI after ALCAPA repair occurs at a relatively higher incidence than that suggested by previous reports and is linked to poor clinical outcomes. Preoperative cardiac dysfunction (left ventricular ejection fraction < 35%) is strongly associated with AKI. The beneficial effect of delaying surgery seen in some of our cases warrants further investigation, as it is not concordant with standard teaching regarding the timing of surgery for ALCAPA.

INTRODUCTION

Acute kidney injury (AKI) has been recognized as a typical postoperative complication among the children undergoing surgical repair of a congenital cardiac defect. It is associated with increased morbidity and mortality in the intensive care unit (ICU) and a higher utilization of hospital resources [1]. To date, reports on the epidemiology of AKI have focused on the whole spectrum of congenital cardiac surgery with the exception of aortic arch repair [2], extracardiac Fontan operation [3, 4], cardiac transplant [5] or the Norwood procedure for single-ventricle disease [6, 7]. However, none have studied the relationship between AKI and the repair of complex congenital cardiac diseases such as anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). It is well known that ALCAPA is deadly for patients who suffer from long-term cardiac dysfunction since birth. In addition, studies have mainly focused on the mortality and other poor outcomes associated with ALCAPA at follow-up without taking AKI into consideration. Hence, we hypothesized that AKI after ALCAPA repair would not be worse than that investigated previously among all other forms of paediatric cardiac surgery because of the generally acceptable surgical outcomes.

METHODS

Patient population

The study was approved by the Board of Ethic Institution of Fuwai Hospital, and no informed consent was obtained because of its retrospective nature. It was conducted using a paediatric cardiac surgery database by reviewing historical records and collecting information pertaining to patient characteristics, surgery data and various postoperative events in Fuwai Hospital, Beijing. Eighty-nine consecutive paediatric patients underwent ALCAPA repair with cardiopulmonary bypass (CPB) between June 2010 and September 2017. In our institution, the surgical technique used was left coronary reimplantation.

Acute kidney injury

Patients were classified as having AKI if they met the following p-RIFLE criteria: risk (eCCl decreased by 25%), injury (eCCl decrease by 50%) and failure (eCCl decrease by 75% or <35 ml/min/1.73 m²). Similar to previous studies, severe AKI was defined according to criteria including injury (I) or failure (F).

Baseline serum creatinine (SCr) levels were obtained 24 h prior to surgery for all patients. Daily consecutive SCr after repair was not measured for all patients, thus we could not determine the exact time of renal recovery. Peak SCr levels on 7 postoperative days were documented to determine eCCl. Of note, baseline SCr is dependent on muscle mass, fluid balance prior to surgery, nutritional status such as low preoperative caloric intake and the process of nephrogenesis. In addition, glomerular filtration is lower in paediatric patients. Thus, in our study, baseline SCr was not considered in the analysis model of AKI.

Inotrope score and vasoactive–inotropic score

The dosage of the following inotropic and vasoactive agents were recorded for the first 24 h and 48 h, respectively, after the patients were transferred to the ICU: dopamine, dobutamine, milrinone, epinephrine, norepinephrine and a vasopressor. Inotropic score (IS) and vasoactive–inotropic score (VIS) were obtained, respectively [11]. VIS within the first 24 h was divided into 3 categories to indirectly assess postoperative cardiac function: <10, 10–20 and ≥20.

Fluid balance

The cut-off value of early FO in our study was 5%, identified as a positive fluid balance of 50 ml/kg, consistent with the published research and providing evidence that FO could precede the development of AKI among the paediatric population after cardiac surgery [12].

Short-term and long-term clinical outcomes

The short-term outcomes in our study cohort were defined as: mortality, prolonged ICU stay, prolonged mechanical ventilation, requirement for peritoneal dialysis (PD), extracorporeal membrane oxygenation, reintubation and tracheotomy. An ICU stay longer than 9 days and mechanical ventilation of more than 100 h were defined as prolonged, as these cut-offs were the upper 75% limit of interquartile range of events. The long-term outcomes after hospital discharge included the number of specialists visits, the number of echocardiographic re-examinations after hospital discharge and indicators of cardiac recovery such as left ventricular ejection function and severity of mitral regurgitation. Children were visited and followed up with echocardiography without exception within 3–6 months after reimplantation; additional check-ups and revisits were scheduled based on the patients’ recovery.

Statistical analysis

The Shapiro–Wilk test was used to assess the normality of the continuous variables. Categorical and continuous variables were presented as frequencies and percentages, and as means ± standard deviation or medians (25th–75th percentiles), respectively. The t-test was used for normal variables and the Mann–Whitney U-test was used when the assumption of normality was not satisfied. To compare categorical variables, the Yates’s continuity correction was used in conjunction with the χ² test and an alternative was to use the Fisher’s exact test. Risk factors associated with events such as AKI were analysed after collecting demographic variables, preoperative biomarker levels, surgical data and other perioperative-related information by logistic regression models. Logistic regression models were also used to examine associations between AKI/severe AKI and several postoperative outcomes. All variables with a P-value <0.2 on univariable analysis were entered into multivariable logistic models. All statistical procedures were performed by SPSS 24.0 software. P-value <0.05 was regarded as statistically significant.

RESULTS

Characteristics of the paediatric population with anomalous origin of the left coronary artery from the pulmonary artery

Almost half of the patients (49.4%; 44/89) underwent concomitant mitral annuloplasty during the study procedure. Fifty-three males and 36 females were included in study. The median age of the study was 13.0 months (6.5–43.0), and the median weight was 9.0 kg (6.5–14.0).

Predictors of acute kidney injury

Sixty of 89 patients (67.4%) in the ALCAPA repair population were found to have AKI, of whom 33.3% (20/60) and 5% (3/60) had AKI and AKF, respectively. Severe AKI was diagnosed in 23 of the 60 patients with AKI. Demographic, preoperative information and surgical data between groups are shown in Table 1. When compared with the no-AKI group, patients with AKI were more likely to be premature and underweight. In addition, in the AKI group, left ventricular systolic function was significantly worse, and left ventricular ejection fraction (LVEF) values were nearly one-half of the no-AKI group before surgical intervention. After multivariable regression, LVEF ≤35% [odds ratio (OR) 5.55, 95% confidential interval (CI) 1.39–22.13; P = 0.015] was found to contribute to the development of AKI, while a longer duration between diagnosis of ALCAPA and the repair operation (OR 0.97, 95% CI 0.95–1.00; P = 0.049) and higher albumin level (OR 0.83, 95% CI 0.70–0.99; P = 0.041) could prevent it from occurring.

The duration from diagnosis to operation was 2.0 months (1.0–3.25) in patients with LVEF >35% and 6.0 months (1.0–27.0) in the LVEF ≤35% group, which was revealed to be significantly different (P = 0.003). The proportion diagnosed with AKI or severe AKI was greater in the LVEF ≤35% group compared with patients in the LVEF >35% group [91.43% (32/35) vs 51.86 (28/54), P < 0.001; 37.14% (13/35) vs 18.52% (10/54), P = 0.05].

Inotropic score and vasoactive–inotropic score

Figure 1 showed that patients in the AKI-R or -I/F group had higher composite scores than those without AKI at all assessment time points: 24-h IS, 24-h VIS, 48-h IS and 48-h VIS (P = 0.058, P = 0.022, P = 0.007 and P = 0.002, respectively). The number of patients who did not develop AKI recorded as 24-h VIS $<$<10 was higher than that in the AKI-R or AKI/F group (53.6% vs 24.3% vs 19.0%, P = 0.022). The distribution of 24-h postoperative VIS is shown in Fig. 2. In addition, when using a multivariable model, there was no evidence to suggest that the administration of inotropes such as milrinone or levosimendan had any impact on the development of AKI (Table 2).

Peritoneal dialysis requirement

The AKI group had a significantly higher need for intermittent PD when compared with the no-AKI group [18.3% (11/60) vs 3.4% (1/29), P = 0.033]. Among the AKI cohort, 3 patients in the AKI-R group required PD, compared to 7 patients in the AKI group, and 1 patient in the AKI-F group. In the no-AKI group, the 1 patient was treated with PD intermittently for 2 days, which was initiated 24 days postoperatively. In contrast, patients diagnosed with AKI were managed with PD for 2 days on average (min–max, 1–6 days), and the treatment was initiated 1 day (min–max, 0.5–9 days) after transfer to the ICU. There were 2 patients in the AKI-R group who had a catheter prophylactically inserted during the ICU period, and another patient diagnosed with criteria I also had a catheter placed because of oliguria when the repair was finished. None of the 3 patients mentioned above received dialysis.

After adjusting for weight, age, sex, any criteria of AKI, preoperative haemoglobin concentration, surgical process including CPB and aortic cross-clamp time, FO and priming volume in CPB, LVEF ≤35% was found to predict a higher risk of PD (OR 22.61, 95% CI 2.73–187.12; P = 0.004). However, univariable logistic regression demonstrated that it was AKI/F, not the occurrence of AKI, that was associated with postoperative PD (OR 5.34, 95% CI 1.50–19.06; P = 0.01; Table 3).

Fluid overload

A FO >5% was not found to be associated with AKI (31.0% vs 42.4%, P = 0.305). Furthermore, there was no association of FO with the development of AKI or even AKI/F.

Clinical outcomes related to acute kidney injury

Table 4 describes the short- and long-term outcomes after the development of AKI.

Short-term clinical outcomes

There were 3 patient deaths in the cohort: 1 (3.4%) in the no-AKI group and 2 (8.7%) in the AKI/F group, P-value = 0.037. Patients with AKI-R or AKI/F were more likely to experience prolonged mechanical ventilation duration and prolonged ICU stay (P = 0.025 and P = 0.004, respectively). Another 3 patients required extracorporeal membrane oxygenation to treat low cardiac output syndrome after repair and were in the AKI/F cohort. No significant association between AKI or even AKI/F and mechanical ventilation, ICU stay or postoperative hospital length of stay were found. However, univariable regression analysis confirmed that the onset of AKI or AKI/F was a risk predictor for either prolonged ICU stay or prolonged duration of mechanical ventilation (Table 3).

Long-term clinical outcomes

The median follow-up time in the cohort was 46.5 months (34.0–63.25). During the follow-up period, patients in the AKI/F group were visited more often by specialists compared to those in the no-AKI or AKI-R groups (P = 0.193). Patients with AKI/F were more frequently followed up with echocardiography to assess myocardial recovery (P = 0.078). However, patients in the AKI/F cohort had a relatively lower LVEF at the 1-year follow-up compared to the groups, although this difference was not statistically significant (P = 0.179).

DISCCUSION

This retrospective study primarily focused on investigating the development of AKI among paediatric patients following ALCAPA repair, and at present, little research has been done in this field.

In our study, the prevalence of postoperative AKI after repair of ALCAPA was as high as 67.4% according to p-RIFLE criteria, which is second only to that after heart transplantation. The AKI occurred in 73% of children following transplant [5]. After adjusting for all possible confounding variables in our analysis, preoperative moderate to severe left ventricular dysfunction was found to be an independent risk factor associated with the progression of AKI. Interestingly, longer waiting times for elective surgery after the diagnosis of ALCAPA as well as higher albumin levels could lower the risk of AKI. None of these variables has ever been previously documented or identified in the setting of paediatric cardiac surgery. We also noticed that AKI could lead to a higher incidence of negative short- and long-term outcomes.

To the best of our knowledge, when compared with other studies on paediatric AKI using any of 3 available assessment systems, the AKI prevalence in our cohort was the highest. One potential explanation for this was that the diagnostic time window of AKI was prolonged to 7 days after the operation by p-RIFLE, thus more cases could be confirmed. Previous reports on the prevalence of AKI after the repair of paediatric cardiac defects were mostly retrospective in nature, as is the case in our study. A few studies also illustrated the specific pathology associated with AKI among some specific types of repair. Algaze et al. [3] demonstrated in their cohort of patients undergoing Fontan operation with or without CPB that the lower the renal perfusion pressure was on the day of surgery, defined as mean artery pressure minus mean Fontan pressure, the greater the likelihood was that stage 2 or 3 postoperative AKI would occur. Jang et al. [2] demonstrated that among paediatric aortic arch repairs, circulatory arrest below the descending thoracic artery itself would cause the development of postoperative AKI. Surprisingly, they found that prerenal impairment had a higher association with the development of AKI. They suspected that preconditioning effect followed by circulatory arrest or insufficient renal perfusion may reduce the occurrence of AKI to some extent.

Our findings have shed light on the concept of typical cardio-renal syndrome. In the paediatric ALCAPA population, cardiac dysfunction is considered to be extremely severe, renal perfusion impaired since birth and renal venous pressure likely to be increased prior to surgery. Historically, the idea that early diagnosis and intervention can lead to better outcomes is prevalent. On the contrary, our findings show a different and novel perspective that early surgery is not a good strategy and should even be avoided. In our study, children without severe left cardiac dysfunction, that is, LVEF >35%, had a lower chance of developing AKI and even severe AKI, if the time from their diagnosis to surgery was significantly delayed (6 months vs 2 months). Thus, for some patients with LVEF ≤35%, it may be beneficial to spend a longer period of time on medications that improve cardiac dysfunction and allow coronary collateral arteries to fully develop [13]. This strategy can help patients to better tolerate a surgical repair and protect the kidneys. However, this may not be feasible for all paediatric patients with ALCAPA. Urgent surgery is indicated if inotropes and furosemide given continuously for several days still have no effect on cardiac dysfunction or symptoms of heart failure, or at the discretion of the individual cardiac surgeon. Lower preoperative albumin as a marker of malnourishment is associated with poor cardiac function and a longer postoperative duration of inotropic infusion [14]. In our study, lower preoperative albumin levels as a marker of poor nutritional status was analysed among patients with AKI and higher levels were confirmed to be protective against AKI. Thus, a longer waiting time to surgery may be helpful in improving a patient’s nutritional status. Whether to perform early surgical repair is still debatable and needs further research.

It was validated by several studies that the higher the risk adjustment for congenital heart surgery (RACHS-1) was, the more likely the progression of postoperative AKI would occur. Alabbas et al. [15] found that a RACHS-1 score >3 could only predict severe AKI (stage 3) among the neonate cardiac surgery population. A retrospective study enrolling 451 children with a mean age of 5 months confirmed that only RACHS-1 ≥4 was associated with postoperative AKI [16]. To be even more precise, a single-ventricle status carried greater odds of developing postoperative renal problems because of its greater surgical complexity according to Fraser et al.’s finding [17]. ALCAPA itself is recognized as a complex heart defect, and the surgical reimplantation procedure is classified by RACHS-1 as category 3 [18]. Hence, prolonging surgery for ALCAPA may be beneficial and it is crucial for our heart teams to develop strategies to optimize a patient’s cardiac, renal and nutritional status in order to balance out the complexity of cardiac defects during this period of time before interventional surgery is necessary.

In theory, severe mitral regurgitation can compromise haemodynamics, leading to AKI. However, there was no association between preoperative mitral regurgitation severity or mitral annuloplasty and AKI in the cohort.

Limitations

Firstly, the size of the study cohort was small because ALCAPA is a rare congenital cardiac defect. Secondly, in our analysis daily SCr levels were not measured in most of the patients during their postoperative ICU stay, and the recovery time from AKI could not be determined. Thirdly, the association between aminoglycoside and AKI was not determined in the study cohort, as antibiotic agents were routinely prescribed at our institution 30 min before the operation. LVEF values at the time of diagnoses were not obtained, because more than 50% of patients were diagnosed at their local hospital and then transferred to our hospital for surgical repair. Finally, since a longer time from diagnosis to surgery was found to be a protective factor against developing AKI, further investigations are needed to determine whether this delay reflects a benefit in terms of preoperative heart failure management or if it represents a selection bias for patients with better collateral flow. Another potential source of selection bias lies in patients with severe heart failure due to ALCAPA who do not survive to surgery.

CONCLUSION

The prevalence of AKI by p-RIFLE criteria tends to be comparably higher in paediatric patients after ALCAPA surgical reimplantation—up to 67.4% in our study. Preoperative cardiac dysfunction is suggested to be a main contributor to the development of AKI. The beneficial effect of delaying surgery in some of our cases warrants further investigation, as it is not concordant with standard teaching regarding timing of ALCAPA surgery.

Conflict of interest: none declared.

REFERENCES

Author notes