---
title: "CHICKADEE study protocol: kidney outcomes and hypertension after pediatric congenital heart diseas"
id: "plos-one-9-the-congenital-heart-disease-in-children-kidney-associated-conditions-with"
canonical_url: "https://medichelpline.com/clinical-feed/plos-one-9-the-congenital-heart-disease-in-children-kidney-associated-conditions-with"
content_type: "clinical_feed_article"
specialty: "Nephrology"
source_name: "PLOS ONE (Medicine)"
source_url: "https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639"
published_at: "2026-08-20T14:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# CHICKADEE study protocol: kidney outcomes and hypertension after pediatric congenital heart diseas
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/plos-one-9-the-congenital-heart-disease-in-children-kidney-associated-conditions-with
- **Specialty:** [Nephrology](https://medichelpline.com/clinical-feed/nephrology.md)
- **Primary Source:** PLOS ONE (Medicine)
- **Source URL:** [Original Journal Publication](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639)
- **Published At:** 2026-08-20T14:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The CHICKADEE study is a multi-center prospective cohort protocol designed to characterize **kidney disease** and **hypertension** in children several years after cardiac surgery for **congenital heart disease (CHD)**. - The study plans to enroll 300 children aged 4–16 years, recruited 4–12 years after their index CHD surgery, across three clinical sites with stratification by CHD severity and enrichment for **hypoplastic left heart syndrome (HLHS)** and other single-ventricle defects. - Primary endpoints include prevalent and incident **hypertension**, **chronic kidney disease (CKD)**, and kidney failure assessed years after cardiac surgery. - Phenotyping includes standardized clinical assessments, echocardiography, **ambulatory blood pressure monitoring (ABPM)**, and both targeted and untargeted proteomic biomarker discovery; a biorepository will be created to support ancillary studies. - The protocol emphasizes the need to address under-recognition and under-treatment of kidney complications in pediatric CHD, noting prior pediatric cohorts with elevated rates of albuminuria, hypertension, and CKD and low referral rates to pediatric nephrology. - The study highlights high-risk subgroups, notably single-ventricle physiology and **Fontan** patients, whose unique hemodynamics may predispose to kidney injury. - The protocol recognizes limitations of routine clinic blood pressure measurement and supports ABPM for detecting masked hypertension and nocturnal non-dipping patterns previously observed in CHD cohorts. - The study will leverage proteomic advances (measurement of >10,000 proteins) to discover mechanistic pathways and therapeutic targets and considers genetic contributors to CHD-related kidney risk, noting 47 candidate genes identified in prior review, including ciliary genes. - Funding source is the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK135518). Details on some operational elements and analytic plans beyond those reported in the source were not provided in the protocol summary.
## Clinical Analysis & Structured Key Points
[ Skip to main content ](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#main-content) Advertisement * [plos.org](https://plos.org/) * [Create account](https://community.plos.org/registration/new) * [Sign in](https://journals.plos.org/user/secure/login?page=%2Fplosone%2Farticle%3Fid%3D10.1371%2Fjournal.pone.0356639) * * About * Browse * Publish * [](https://journals.plos.org/plosone/ "PLOS One") * Search [advanced search](https://journals.plos.org/plosone/search) * [Browse Topics](https://journals.plos.org/plosone/subjectAreaBrowse) Browse Subject Areas ? Click through the PLOS taxonomy to find articles in your field. For more information about PLOS Subject Areas, click [here](https://github.com/PLOS/plos-thesaurus/blob/master/README.md "Link opens in new window"). [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639) [](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639) * 0 [Save](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639#savedHeader) [Total Mendeley and Citeulike bookmarks.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639#savedHeader) * 0 [Citation](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639#citedHeader) [Paper's citation count computed by Dimensions.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639#citedHeader) * 12 [View](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639#viewedHeader) [PLOS views and downloads.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639#viewedHeader) * 0 [Share](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639#discussedHeader) [Sum of Facebook, Twitter, Reddit and Wikipedia activity.](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639#discussedHeader) Open Access Study Protocol # The Congenital Heart Disease in Children: Kidney-Associated Conditions with Epidemiologic Endpoints (CHICKADEE) study: Study design and protocol * Jason H. Greenberg , Contributed equally to this work with: Jason H. Greenberg, Derek K. Ng Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Supervision, Writing – original draft, Writing – review & editing * E-mail: jason.greenberg@yale.edu Affiliations Division of Nephrology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America, Department of Medicine, Clinical and Translational Research Accelerator, Yale University School of Medicine, New Haven, Connecticut, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0001-5874-1109 ](https://orcid.org/0000-0001-5874-1109 "ORCID Registry") ⨯ * Derek K. Ng , Contributed equally to this work with: Jason H. Greenberg, Derek K. Ng Roles Conceptualization, Formal analysis, Funding acquisition, Investigation, Methodology, Project administration, Writing – review & editing Affiliations Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America, Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ⨯ * Eyal Sagiv, Roles Conceptualization, Investigation, Methodology, Writing – review & editing Affiliation Division of Cardiology, Department of Pediatrics, University of Washington and Seattle Children’s Hospital, Seattle, Washington, United States of America ⨯ * Mark Mitsnefes, Roles Investigation, Methodology, Resources, Writing – review & editing Affiliation Division of Nephrology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0000-0002-9904-0250 ](https://orcid.org/0000-0002-9904-0250 "ORCID Registry") ⨯ * Addison Gearhart, Roles Investigation, Methodology, Project administration, Writing – review & editing Affiliation Division of Cardiology, Department of Pediatrics, University of Washington and Seattle Children’s Hospital, Seattle, Washington, United States of America ⨯ * Lucy Mulqueen, Roles Investigation, Methodology, Project administration, Resources, Writing – review & editing Affiliation Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America ⨯ * Olyvia J. Hanken-Arlen, Roles Investigation, Methodology, Project administration, Resources, Writing – review & editing Affiliation Division of Nephrology, Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, United States of America [ ![ORCID logo](https://journals.plos.org/resource/img/orcid_16x16.png) https://orcid.org/0009-0001-2258-2844 ](https://orcid.org/0009-0001-2258-2844 "ORCID Registry") ⨯ * Henon Gebre, Roles Investigation, Methodology, Project administration, Writing – review & editing Affiliation Division of Cardiology, Department of Pediatrics, University of Washington and Seattle Children’s Hospital, Seattle, Washington, United States of America ⨯ * Ilham Boutahri, Roles Investigation, Methodology, Project administration, Resources, Writing – review & editing Affiliation Division of Nephrology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America ⨯ * Allen D. Everett, Roles Investigation, Methodology, Project administration, Writing – review & editing Affiliation Division of Pediatric Cardiology, Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, United States of America ⨯ * Joseph T. Flynn, Roles Investigation, Methodology, Project administration, Writing – review & editing Affiliation Division of Nephrology, Department of Pediatrics, University of Washington and Seattle Children’s Hospital, Seattle, Washington, United States of America ⨯ * Chirag R. Parikh Roles Conceptualization, Funding acquisition, Investigation, Methodology, Project administration, Resources, Writing – original draft, Writing – review & editing Affiliation Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ⨯ # The Congenital Heart Disease in Children: Kidney-Associated Conditions with Epidemiologic Endpoints (CHICKADEE) study: Study design and protocol * Jason H. Greenberg, * Derek K. Ng, * Eyal Sagiv, * Mark Mitsnefes, * Addison Gearhart, * Lucy Mulqueen, * Olyvia J. Hanken-Arlen, * Henon Gebre, … * Ilham Boutahri, * Allen D. Everett ![PLOS](https://journals.plos.org/resource/img/logo-plos-full-color.svg) x * Published: August 20, 2026 * * [Article](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639) * [Authors](https://journals.plos.org/plosone/article/authors?id=10.1371/journal.pone.0356639) * [Metrics](https://journals.plos.org/plosone/article/metrics?id=10.1371/journal.pone.0356639) * [Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0356639) * [Media Coverage](http://plos.altmetric.com/details/doi/10.1371/journal.pone.0356639) * [Abstract](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#abstract0) * [Introduction](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#sec005) * [Methods](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#sec027) * [Discussion](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#sec026) * [References](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#references) * [Reader Comments](https://journals.plos.org/plosone/article/comments?id=10.1371/journal.pone.0356639) * [Figures](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639) ## Abstract ### Background Congenital heart disease (CHD) is the most common structural birth defect affecting 1% of live births. With improvements in medical and surgical management, there are now more than 2 million children and adults in the United States with CHD, a number that continues to grow. Children who undergo cardiac surgery for CHD face elevated risks of hypertension, chronic kidney disease (CKD), kidney failure, and premature mortality—complications that are more prevalent in those with single ventricle physiology and increase as they get older. Although emerging evidence suggests that the excess burden of CKD observed in adults with CHD originates in childhood, these complications remain under-recognized because they are understudied in pediatric populations and represent a critical missed opportunity for evaluation and early intervention. ### Objectives This multi-center prospective cohort study aims to characterize the epidemiology, risk factors, and mechanisms of CKD and hypertension in children several years after CHD surgery, with a particular focus on complex CHD conditions. ### Methods We aim to enroll 300 children, 4 to 16 years old, across three clinical sites, 4 to 12 years after their initial CHD surgery. The cohort will be stratified by CHD severity with enrichment for hypoplastic left heart syndrome and other single-ventricle defects. Primary outcomes include prevalent and incident hypertension, CKD, and kidney failure. The study will feature comprehensive phenotyping of kidney health through standardized clinical assessments, echocardiographic characterization, ambulatory blood pressure monitoring, and novel biomarker discovery using both targeted and untargeted proteomic approaches. A biorepository will be established to facilitate future ancillary studies. ### Significance This study addresses critical knowledge gaps in pediatric cardio-nephrology by providing the first comprehensive and collaborative longitudinal assessment of kidney outcomes in children with CHD-a population largely excluded from existing pediatric nephrology cohorts. The study aims to inform risk stratification, enable early detection strategies, and guide development of targeted interventions to preserve long-term kidney health in this vulnerable and growing population. ## Figures ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.t001) ![Table 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.t002) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.g003) ![Table 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.t001) ![Table 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.t002) ![Fig 1](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.g001) ![Fig 2](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.g002) ![Fig 3](https://journals.plos.org/plosone/article/figure/image?size=inline&id=10.1371/journal.pone.0356639.g003) **Citation:** Greenberg JH, Ng DK, Sagiv E, Mitsnefes M, Gearhart A, Mulqueen L, et al. (2026) The Congenital Heart Disease in Children: Kidney-Associated Conditions with Epidemiologic Endpoints (CHICKADEE) study: Study design and protocol. PLoS One 21(8): e0356639. https://doi.org/10.1371/journal.pone.0356639 **Editor:** Jennifer Tucker, PLOS: Public Library of Science, UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND **Received:** July 22, 2026; **Accepted:** August 4, 2026; **Published:** August 20, 2026 **Copyright:** © 2026 Greenberg et al. This is an open access article distributed under the terms of the [Creative Commons Attribution License](http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. **Data Availability:** For Study Protocols: No datasets were generated or analysed during the current study. All relevant data from this study will be made available upon study completion. **Funding:** This study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (R01DK135518). **Competing interests:** The authors have declared that no competing interests exist. ## Introduction ### The growing population of children with CHD Congenital heart disease (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 [[1](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref001),[2](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref002)]. 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 remarkable improvement in survival has shifted clinical focus toward understanding and preventing long-term complications that affect quality of life and longevity. ### Kidney disease in CHD Among these 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, chronic kidney disease (CKD), and premature death [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref003)–[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref006)]. 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 [[7](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref007),[8](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref008)]. These sobering statistics underscore an urgent need to understand when and how these complications develop. ### Evidence for childhood origins of kidney disease Our previous work suggests that the kidney disease burden observed in adults with CHD has its origins in childhood. In pediatric CHD populations, we identified a high burden of albuminuria (8%), hypertension (12%-17%), and CKD (21%-30%) following cardiac surgery [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref003),[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref006)]. Children with hypoplastic left heart syndrome (HLHS) face particularly severe risks, with 35% developing hypertension and 9% progressing to kidney failure during long-term follow-up [[3](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref003)–[5](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref005)]. 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 [[9](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref009),[10](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref010)]. ### The care gap: Under-recognition and under-treatment 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 and 13% had CKD, only 4% had been evaluated by a pediatric nephrologist [[6](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref006)]. 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 [[11](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref011)]. ### Challenges in diagnosis and monitoring **_Blood Pressure Assessment:_** Accurate blood pressure assessment in pediatric patients presents a unique challenge. Ambulatory blood pressure monitoring (ABPM), the gold standard for pediatric hypertension diagnosis, captures circadian patterns and identifies masked hypertension, conditions that clinic measurements miss [[12](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref012)]. Our pilot study revealed ABPM abnormalities in 11 of 23 children with CHD, the most common being loss of nocturnal blood pressure dipping [[13](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref013)]. These findings highlight the inadequacy of routine clinic measurements for comprehensive cardiovascular risk assessment. **_High-Risk Populations:_** Children with single-ventricle physiology, particularly those with HLHS undergoing Fontan palliation, require special consideration. Worldwide there are now over 47,000 patients living with a Fontan circulation and aging into adulthood. Their unique hemodynamics characterized by elevated central venous pressure, reduced cardiac output, and neurohormonal activation place them at risk for kidney injury. Understanding how these physiological derangements affect kidney health is essential for developing targeted interventions to prevent premature morbidity and mortality. ### Beyond traditional risk factors **_Biomarker Innovation_ :** Traditional kidney function assessment using serum creatinine and albuminuria provides limited insight into ongoing injury and repair processes. Novel biomarkers reflecting diverse pathways—glomerular health, tubular injury, inflammation, and fibrosis—offer opportunities for earlier detection and mechanistic understanding. Recent advances in proteomic technology now enable measurement of over 10,000 proteins potentially identifying mechanistic pathways and therapeutic targets. **_Genetic Contributions_ :** While genetic factors contribute to approximately 40% of CHD cases, their role in kidney disease susceptibility remains unexplored [[14](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref014)–[17](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref017)]. In a systematic review, we 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 [[17](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref017)–[21](https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0356639#pone.0356639.ref021)]. Genetic testing is often clinically available, and these data may provide important contextual data for understanding risk of CKD and identify subgroups for closer monitoring. ### The imperative for action To date, no prospective studies have comprehensively characterized the incidence, progression, and mechanisms of kidney disease in children with CH
## Related Clinical Research

- [Long-term Renal Outcomes After Neonatal and Pediatric Renal Vein Thrombosis](https://medichelpline.com/clinical-feed/medrxiv-15-renal-outcomes-in-survivors-of-neonatal-and-pediatric-renal-vein-thrombosis.md)
- [Early detection of declining kidney function in a Sri Lankan working-age cohort](https://medichelpline.com/clinical-feed/medrxiv-4-detecting-early-loss-of-kidney-function-in-a-sri-lankan-cohort-study-of-working.md)
- [Atherosclerosis in Chronic Kidney Disease: Early Prevention Matters](https://medichelpline.com/clinical-feed/kidney-international-21-atherosclerosis-in-chronic-kidney-disease-early-prevention-is-better-than-late-treatment.md)
- [Use Of Kidney-Preserving Medications In Breastfeeding](https://medichelpline.com/clinical-feed/kidney-international-63-use-of-kidney-preserving-medications-in-breastfeeding.md)
- [Nintedanib-Linked Glomerular Endothelial Injury and Secondary Collapsing FSGS: SGLT2 Inhibitor as](https://medichelpline.com/clinical-feed/pubmed-42674550.md) (DOI: 10.1111/nep.70274)

## Navigation
- [← Back to Nephrology Feed](https://medichelpline.com/clinical-feed/nephrology.md)
- [← All Clinical Specialties](https://medichelpline.com/clinical-feed.md)
## Medical & Regulatory Disclaimer

> [!CAUTION]
> MedicHelpline content is structured for research, educational, and professional discovery purposes. It does not constitute individual medical advice, clinical diagnosis, or treatment recommendations.
> Always verify dosing, contraindications, and regulatory alerts against official product labeling and primary regulatory sources before clinical decision-making.