CHICKADEE Cohort Study to Chart Kidney and Cardiovascular Trajectories in Children After Congenital Heart Surgery
核心洞察
A multi-center prospective cohort study (CHICKADEE) will enroll 300 children aged 4–16 years, 4–12 years after their first cardiac surgery requiring cardiopulmonary bypass, to characterize the natural history of hypertension (搜索) and kidney disease in congenital heart disease (搜索).
The study integrates 24-hour ambulatory blood pressure monitoring, novel glomerular and tubular biomarkers, proteomics, and genetic characterization to detect subclinical kidney injury and identify risk factors beyond traditional measures.
Prior data show hypertension (搜索) (12%–17%), albuminuria (8%), and chronic kidney disease (搜索) (21%–30%) emerge in childhood after cardiac surgery, yet only 4% of affected children are evaluated by a pediatric nephrologist.
A team of pediatric nephrologists, cardiologists, and epidemiologists has launched a multi-center prospective cohort study to provide the first comprehensive assessment of kidney and cardiovascular health trajectories in children with congenital heart disease (搜索) (CHD). The CHICKADEE study (Congenital Heart disease In Children: Kidney-AssociateD Conditions with Epidemiologic Endpoints) aims to close a critical knowledge gap: to date, no prospective studies have comprehensively characterized the incidence, progression, and mechanisms of kidney disease in children with CHD beyond five years post-surgery.
CHD is the most common birth defect, affecting approximately 2.4 million individuals in the United States, including 1 million children and 1.4 million adults. One in four children with CHD undergoes cardiac surgery, and with advances in surgical techniques and perioperative care, over 90% now survive to adulthood. This improvement in survival has shifted clinical focus toward understanding and preventing long-term complications that affect quality of life and longevity.
The Under-Recognized Burden of Kidney Disease in CHD
Among long-term complications, kidney disease has emerged as a critical yet under-recognized threat. Multiple studies demonstrate that individuals with CHD face substantially elevated risks of hypertension (搜索), chronic kidney disease (搜索) (CKD), and premature death. In adults with CHD, hypertension prevalence reaches 47%, while the risks of hypertension and CKD are increased 1.4-fold and 3.4-fold respectively compared to the general population.
The investigators' previous work suggests that the kidney disease burden observed in adults with CHD has its origins in childhood. In pediatric CHD populations, they identified a high burden of albuminuria (8%), hypertension (搜索) (12%–17%), and CKD (21%–30%) following cardiac surgery. Children with hypoplastic left heart syndrome (搜索) (HLHS) face particularly severe risks, with 35% developing hypertension and 9% progressing to kidney failure during long-term follow-up.
Several perioperative factors predict these adverse outcomes, including age less than 3 months at surgery, surgical complexity, need for perioperative dialysis, and cumulative number of cardiac surgeries. These findings strongly suggest that the excess burden of kidney disease in adults with CHD begins during childhood, although the natural history remains poorly characterized.
A Documented Care Gap
Despite compelling evidence of risk, kidney complications in children with CHD remain under-diagnosed and under-treated. In the pediatric TRIBE-AKI cohort, while 17% had hypertension (搜索) and 13% had CKD, only 4% had been evaluated by a pediatric nephrologist. This care gap is particularly concerning given that early intervention with RAAS inhibitors and lifestyle modifications can effectively control blood pressure and albuminuria, potentially limiting kidney disease progression.
Accurate blood pressure assessment in pediatric patients presents a unique challenge. Ambulatory blood pressure monitoring (ABPM), the gold standard for pediatric hypertension (搜索) diagnosis, captures circadian patterns and identifies masked hypertension that clinic measurements miss. A pilot study revealed ABPM abnormalities in 11 of 23 children with CHD, the most common being loss of nocturnal blood pressure dipping, highlighting the inadequacy of routine clinic measurements for comprehensive cardiovascular risk assessment.
Study Design and Cohort
The CHICKADEE study has a targeted recruitment of 300 children, 4–16 years old, 4 to 12 years after their first cardiac surgery requiring bypass. Of the 300 participants, the investigators aim for at least 15% (45 of 300) with single ventricle cardiac lesion and at least 35% (105 of 300) with a history of cyanotic CHD, approximately evenly distributed at each site.
Recruitment encompasses children across a wide range of estimated glomerular filtration rates (eGFRs) at enrollment, but patients with advanced CKD (eGFR < 20 ml/min/1.73m²) or end stage kidney disease (ESKD) are excluded. Children with congenital anomalies of the kidney and urinary tract (CAKUT) are not excluded, as CAKUT is more common in children with CHD. Exclusion criteria include history of non-bypass surgery, prior heart transplant, ventricular assist device support, or listing for transplant.
The study comprises a partnership across three clinical sites—Yale University (搜索) (New Haven, CT), Cincinnati Children's Hospital Medical Center (Cincinnati, OH), and Seattle Children's Hospital (Seattle, WA)—with a Data Coordinating Center and Central Lab at Johns Hopkins University (搜索) (Baltimore, MD). The start of the recruitment period was March 1, 2025, with participant recruitment and data collection estimated to be completed by December 2027 and results expected by June 2028.
Outcome Measures and Methodological Innovation
The primary outcomes include hypertension (搜索), CKD, and microalbuminuria. Hypertension is defined as the presence of abnormal ABPM or the use of antihypertensive agents. CKD is defined as eGFR < 90 mL/min/1.73 m² or a urine albumin to creatinine ratio >30 mg/g, with GFR estimated using the recent "Under 25" (U25) equations validated for children and young adults based on serum creatinine and cystatin C. Microalbuminuria is defined by KDIGO guidelines as a urine albumin to creatinine ratio >30 mg/g.
The study will use the Society of Thoracic Surgeons/European Association for Cardio-Thoracic Surgery (STAT) score to classify surgical complexity, and will define CHD severity using consensus guidelines. AKI events will be classified by KDIGO criteria as hemodynamic, intrinsic, obstructive, or indeterminate.
A key innovation is the integration of novel biomarkers to characterize subclinical kidney injury in the absence of changes in GFR. The investigators hypothesize that higher plasma TNFR1 (搜索) and TNFR2 (搜索), higher urine KIM-1 (搜索), and lower urine EGF (搜索) and uromodulin (搜索) concentrations will be associated with primary outcomes. Untargeted proteomic measurements will also be assessed, leveraging recent advances that enable measurement of over 10,000 proteins to identify mechanistic pathways and therapeutic targets.
Genetic characterization is a further focus. While genetic factors contribute to approximately 40% of CHD cases, their role in kidney disease susceptibility remains unexplored. In a systematic review, the investigators identified 47 genes that could be pathogenic or highly probable risk factors potentially linking CHD to kidney disease, including 11 genes encoding ciliary proteins—structures critical for both cardiac and kidney development.
Clinical Significance
A detailed understanding of the incidence of hypertension (搜索), albuminuria, and CKD in CHD may allow strategies that target early detection. Earlier CKD detection after CHD surgery may prompt cardiovascular risk reduction interventions to promote cardiovascular health and improve quality of life. The investigators note that recent findings in adults have shown that hypertension and CKD in childhood are independent risk factors for these same outcomes in adulthood and are associated with increased risk of mortality.
The CHICKADEE cohort will demonstrate the ability to overcome traditional challenges in recruitment, sample collection, biomarker measurement, and outcome ascertainment in this understudied group of children at increased risk of kidney complications. The findings are expected to facilitate improved clinical monitoring, stimulate hypotheses for clinical trials, and inform clinical management guidelines.