Biomarkers of acute kidney injury in pediatric cardiac surgery☆
Introduction
Acute kidney injury (AKI) is a significant problem in children undergoing cardiac surgery. Approximately 30–50% of these patients suffer from varying degrees of AKI after cardiopulmonary bypass (CPB) [1], [2], [3]. AKI is known to increase the duration of mechanical ventilation and prolong intensive care and hospital stays [2]. It carries a mortality rate as high as 20–79% in children requiring dialysis [4]. Even a minor degree of postoperative AKI, as manifested by only a 0.2–0.3 mg/dL rise in serum creatinine (sCr) from baseline levels, predicts a significant increase in mortality and morbidity [5], [6]. AKI survivors are also at risk for progression to CKD [7], [8], [9].
Defining AKI according to sCr and urine output is not ideal. In fact, sCr measures function, not injury. It may not change until approximately 50% of kidney function has been lost. In addition, sCr level is affected by multiple confounding factors such as age, gender, diet, muscle mass, race, and hydration status. In the early neonatal period, it is a reflection of the mother's renal function more than the infant's. Additionally, sCr levels are influenced by tubular creatinine secretion, by certain drugs and by the Jaffe method for its measurement, especially in neonates with increased serum bilirubin levels. Urine output, another classic diagnostic AKI marker has limited sensitivity [10].
Animal studies have shown that AKI treatments need to be administered soon after injury to be effective [11], [12], [13]. The importance of developing and defining new biomarkers of kidney diseases that can be used for early diagnosis, assessment of severity, and long term prognosis has been emphasized by the American Society of Nephrology and the National Institutes of Diabetes, Digestive and Kidney Diseases (NIDDK). Cardiac biomarkers such as troponins have been shown to be superior to clinical assessment in the diagnosis of myocardial infarction or decompensated heart failure [14]. It is expected, that renal biomarkers will similarly improve the diagnosis of imminent AKI. Early diagnosis of AKI could facilitate early initiation of supportive measures and facilitate trials of novel therapeutic strategies [15], [16].
Many promising candidates as biomarkers for the early diagnosis of AKI, including neutrophil gelatinase-associated lipocalin (NGAL), cystatin C (CysC), kidney injury molecule-1 (KIM-1), liver fatty acid-binding protein (L-FABP), interleukin-6 and -18 (IL-6 and IL-18, respectively), hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF), beta-2 microglobulin (β-2M) and osteopontin, have been recently tested [11], [12], [13], [15], [16], [17], [18]. However, there is heterogeneity in the reported predictive ability of AKI biomarkers. This is in part related to the use of different AKI definitions [19], different types of biomarkers [20], [21], different times of their measurements after CPB [15], or condition of sample storage [22]. Children after cardiac surgery are an ideal type of patient with whom studying of AKI biomarkers is possible without the influence of comorbidities that complicate similar studies in adults, such as diabetes, chronic hypertension, atherosclerosis, and nephrotoxin use.
The aims of this study were to assess the diagnostic validity of serum CysC (sCysC), serum neutrophil gelatinase lipocalin (sNGAL), urine neutrophil gelatinase lipocalin (uNGAL), urine KIM-1(uKIM-1), and urine L-FABP (uL-FABP) to predict AKI presence and severity in children undergoing CPB.
Section snippets
Patients and study design
We performed a prospective study of consecutive children undergoing cardiac surgery using CPB in a single center from March 1st to December 31st, 2011. All patients underwent the CPB by the same team of surgeons in a uniform pre- and postoperative setting despite all having differences in terms of diagnosis. Exclusion criteria included age above 18 years, preexisting AKI or chronic kidney disease (CKD) (e.g.: those with estimated creatinine clearance below age adjusted normal), congenital
Results
One hundred and twenty patients were eligible and 112 of them were enrolled in the study as 8 patients did not have pre-op sCr. There were 65 boys and 47 girls of median age 1.6 (IQR: 0.4–4.7) years. The total number of neonates was 20 (16.8%); of these 14 (70%) were in the non-AKI group. There were 28 infants (25.0%).
The primary outcome, AKI, defined as ≥ 25% decrease in eCCl from baseline values at 48 h postoperatively developed in 18 patients (16.1%). Transient decrease of eCCl (96% within the
Discussion
The association between CPB and AKI is well recognized [28]. However, its complex pathophysiology is not completely understood [11]. In addition, despite encouraging results on AKI treatment in animal studies [13], no specific treatment has yet been successful in humans, primarily due to the lack of the early accurate diagnostic markers. Many new biomarkers offer promise for early AKI diagnosis [13]. Based on the multifactorial etiology of AKI after CPB, it is likely that a panel of biomarkers
Conclusion
Younger age and longer CPB predisposed to AKI, which occurs in 16.1% of children who underwent CPB. Serum cystatin C, and urine NGAL and L-FABP were reliable early predictors for AKI after CPB. They correlated with disease severity and clinical outcome. The perfect AKI predictor at 2 h after surgery is urinary L-FABP, while at 6 and 24 h after surgery, the perfect AKI predictor is uNGAL. There seems to be no convincing evidence that, in addition to uNGAL, or L-FABP, the performance of sNGAL and
Conflict of interest
None.
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Cited by (51)
Acute kidney injury after pediatric cardiac surgery
2019, Pediatrics and NeonatologyChildren as Biomarker Orphans: Progress in the Field of Pediatric Biomarkers
2018, Journal of PediatricsDiagnostic accuracy and prognostic valued of plasmatic Cystatin-C in children undergoing pediatric cardiac surgery
2017, Clinica Chimica ActaCitation Excerpt :In view of crescent evidences in its favors, several authors suggested that cystatin-C should be added to creatinine in the calculation of the CDK-EPI cystatin equation for better estimation of glomerular filtration rate (eGFR), especially in children [1,12–15]. Furthermore, several studies demonstrated that cystatin-C not only is an early AKI marker [1–11], but also it has some prognostic value in children undergoing cardiac surgery [1,7,11]. However, the clinical relevance of cystatin-C is difficult to evaluate in children undergoing cardiac surgery due to differences in pool sizes (from 17 to 345 subjects), age intervals (indeed some studies included also adults), and criteria for AKI definition (AKIN-Acute Kidney Injury-Network, KIDGO-Acute Kidney Injury Work Group-, p_RIFLE-pediatric Risk, Injury, Failure, Loss, end stage renal disease-) [1–7,10,11], and especially incidence of AKI (from 18% to 85%) [2,3,5,9].