Deep, Akash

Gist, Katja M.

Soranno, Danielle E.

Zappitelli, Michael

Frontiers in Pediatrics

PubMed

Danielle E. Soranno

Akash Deep

Katja M. Gist

Michael Zappitelli

Directory of Open Access Journals

EDITORIAL
published: 15 November 2021
doi: 10.3389/fped.2021.792210
Frontiers in Pediatrics | www.frontiersin.org 1 November 2021 | Volume 9 | Article 792210
Edited and reviewed by:
Michael L. Moritz,
University of Pittsburgh, United States
*Correspondence:
Danielle E. Soranno
danielle.soranno@
childrenscolorado.org
Specialty section:
This article was submitted to
Pediatric Nephrology,
a section of the journal
Frontiers in Pediatrics
Received: 09 October 2021
Accepted: 18 October 2021
Published: 15 November 2021
Citation:
Soranno DE, Deep A, Gist KM and
Zappitelli M (2021) Editorial: Acute
Kidney Injury: It’s Not Just Acute, and
It’s Not Just the Kidneys.
Front. Pediatr. 9:792210.
doi: 10.3389/fped.2021.792210
Editorial: Acute Kidney Injury: It’s Not
Just Acute, and It’s Not Just the
Kidneys
Danielle E. Soranno 1*, Akash Deep 2, Katja M. Gist 3 and Michael Zappitelli 4
1 Section of Pediatric Nephrology, Departments of Pediatrics, Bioengineering and Medicine, University of Colorado, Aurora,
CO, United States, 2Department of Child Health, NHS Foundation Trust, King’s College Hospital, London, United Kingdom,
3Division of Pediatric Cardiology, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States, 4Division
of Nephrology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, Canada
Keywords: acute kidney injury, pediatric nephrology, Continuous Renal Replacement Therapies (CRRT), diabetes
mellitus, Artificial Intelligence-AI, metabolic bone disease, critical care nephrology
Editorial on the Research Topic
Acute Kidney Injury: It’s Not Just Acute, and It’s Not Just the Kidneys
Acute kidney injury (AKI) occurs in ∼20, 30, and 40–60% of pediatric patients in pediatric,
neonatal and cardiac intensive care units, respectively (1, 2). Twenty years ago, AKI in hospitalized
children was considered an unfortunate consequence of illness, but ultimately self-limited without
direct impacts on patient outcomes. Extensive research in the last 15 years revealed that AKI
in hospitalized children is associated with greater hospital resource utilization, morbidity and
hospital mortality (1, 3). Shockingly, many episodes of pediatric hospital-acquired AKI continue
to go unrecognized (4). More recently, emerging evidence suggests that children surviving
hospitalization with an AKI episode may be at substantially higher risk than children without AKI,
for developing long-term chronic kidney disease (CKD) and hypertension and long-termmortality
(5). This literature has contributed to a paradigm shift that AKI increases risk for poor long-
term outcomes, warranting efforts to improve detection, management and secondary prevention
of permanent sequelae.
The goals of this collection of 9 manuscripts are to provide an update on best practices for
detection, management, and follow-up of pediatric AKI, and perspectives on the deleterious short-
and long-term systemic sequelae of AKI in the context of evolving clinical, epidemiologic and
fundamental AKI research.
In Impact of Acute Kidney Injury on Critically Ill Children and Neonates, authors Leghrouz and
Kaddourah provide an overview of the recent shifts in AKI definition, now centering on the KDIGO
defined criteria using either a rise in serum creatinine, and/or a reduction in urine output. The
authors highlight the importance of measuring urine output in order to recognize oliguric AKI for
improved diagnostic precision. The review also provides a summary of the impact of AKI following
hematopoietic stem cell transplant and emerging data on children with multisystem inflammatory
syndrome as a result of the SARS-CoV-2 pandemic.
In Acute Kidney Injury in Critically Ill Children Is not all Acute: Lessons Over the Last 5
Years, Hessey et al. reviewed the last 5 years of peer-reviewed literature exploring the long-term
outcomes of pediatric AKI. The summary provides an overview of the advancements and remaining
challenges in investigating long-term outcomes after critical illness in hospitalized children. It also
highlights the importance of implementing standardized follow-up of kidney health and outcomes
after an episode of severe AKI. This aligns with recent recommendations in the neonatal and
pediatric response to the Acute Disease Quality Initiative (ADQI) 22 guidance document (6).
Soranno et al. Editorial: After the Acute and Beyond the Kidneys
In A Precision Medicine Approach to Biomarker Utilization
in Pediatric Sepsis-Associated Acute Kidney Injury, authors
Odum et al. reframe sepsis-associated AKI as a heterogeneous
disease process. They provide a framework approach to utilizing
biomarkers for prognostic enrichment and precision medicine to
decluster the sepsis phenotype into distinctive pathophysiologies
for targeted therapeutic clinical trials. This manuscript highlights
the need to improve our understanding of AKI phentoypes for
which future therapeutic targets might be considered.
In Continuous Renal Replacement Therapy in Critically Ill
Children in the Pediatric Intensive Care Unit: A Retrospective
Analysis of Real-Life Prescriptions, Complications, and
Outcomes, Buccione et al. present new data from a 6-year
single center retrospective study evaluating outcomes after
CRRT therapy in pediatrics. Their data reports that fluid
overload was the predominant indication for CRRT initiation
(>60% of cases) and identifies catheter size <8 French and
lack of citrate regional anticoagulation as predictors of early
discontinuation of treatment. With a mean follow-up time
of 3.5 years, only 42% of the patients who survived did
not have any long-term kidney sequelae, including CKD
or proteinuria.
In Two to Tango: Kidney-Lung Interaction in Acute Kidney
Injury and Acute Respiratory Distress Syndrome, Alge et al.
provide a thorough review of the basic science and clinical data
surrounding the development of AKI-mediated lung injury and
the role that lung injury plays in affecting kidney function. The
review highlights the complexity of identifying the bidirectional
effects of hemodynamic alterations in critical illness, resulting
from acute lung disease as well as from AKI.
In A review on the application and limitations
of administrative health care data for the study of
acute kidney injury epidemiology and outcomes in
children, Ulrich et al. summarize the opportunities and
limitations of leveraging “big data” in administrative
health repositories to investigate pediatric AKI outcomes.
While big data research offers unique and unprecendented
opportunities to evaluate pediatric AKI with large
sample sizes, there is a need to validate these data
for defining pediatric kidney outcomes and limiting
associated biases.
In For Whom the Bell Tolls: Acute Kidney Injury and
Electronic Alerts for the Pediatric Nephrologist, authors Nguyen
and Menon review best practices for AKI alerts, and how
they can be implemented to hasten the diagnosis and optimize
management in pediatric AKI. These AKI alerts and tools tie
in with broader efforts within the nephrology community to
utilize artificial intelligence and machine learning to improve
outcomes in patients with AKI. The review provides examples
of early applications of alert tools in pediatric AKI, including
a nephrotoxic-mediated AKI stewardship program, which has
been shown to reduce the rate, severity and duration of
nephrotoxic AKI (7, 8).
In Acute kidney injury in pediatric diabetic kidney disease,
Piani et al. describe the pathophyisiology of AKI and its
relation to diabetic kidney disease in children with types
I and II diabetes mellitus. Children with diabetes are at
an increased risk for developing AKI, and after an episode
of AKI, they are at higher risk of developing diabetic
kidney disease and CKD. The review also summarizes the
increased risk of severe COVID-19 disease in patients with
diabetes mellitus.
In Acute Kidney Injury and Pediatric Bone Health,
authors Hegde et al. review the current literature on fracture
risk after AKI, the mechanisms of dysregulation in bone
metabolism in AKI, and suggest areas for future research,
particularly with regard to skeletal growth in pediatric patients
after AKI.
As the overall survival of critically ill pediatric patients
improves, there are increasing survivors of childhood AKI.
With these perspectives in mind, future research is required to
explore the long-term impact of pediatric AKI on population
health, health care costs, and how pediatric providers within
varying healthcare contexts, can potentially improve care
delivery with a goal to optimize their patients’ outcomes later
in life.
AUTHOR CONTRIBUTIONS
DS, AD, KG, and MZ contributed to the editorial writing and
revision process. All authors contributed to the article and
approved the submitted version.
REFERENCES
1. Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL, Investigators A.
Epidemiology of acute kidney injury in critically ill children and young
adults. N Engl J Med. (2017) 376:11–20. doi: 10.1056/NEJMoa161
1391
2. Jetton J, J Boohaker L, Sethi S, Wazir S, Rohatgi S, Soranno DE, et al.
Incidence and outcomes of neonatal acute kidney injury (AWAKEN):
a multicentre, multinational, observational cohort study. Lancet
Child Adolesc Health. (2017) 1:184–94. doi: 10.1016/S2352-4642(17)30
069-X
3. Silver SA, Long J, Zheng Y, Chertow GM. Cost of acute kidney injury
in hospitalized patients. J Hosp Med. (2017) 12:70–6. doi: 10.12788/jhm.
2683
4. Roy JP, Goldstein SL, Schuh MP. Under-recognition of neonatal
acute kidney injury and lack of follow-up. Am J Perinatol.
(2020). doi: 10.1055/s-0040-1716841. [Epub ahead of print].
5. Sigurjonsdottir VK, Chaturvedi S, Mammen C, Sutherland SM. Pediatric acute
kidney injury and the subsequent risk for chronic kidney disease: is there cause
for alarm? Pediatr Nephrol. (2018) 33:2047–55. doi: 10.1007/s00467-017-3
870-6
6. Macedo E, Bihorac A, Siew ED, Palevsky PM, Kellum JA, Ronco
C, et al. Quality of care after AKI development in the hospital:
Consensus from the 22nd Acute Disease Quality Initiative (ADQI)
conference. Eur J Intern Med. (2020) 80:45–53. doi: 10.1016/j.ejim.2020.0
4.056
7. Goldstein SL. Medication-induced acute kidney injury. Curr Opin Crit Care.
(2016) 22:542–5. doi: 10.1097/MCC.0000000000000355
Frontiers in Pediatrics | www.frontiersin.org 2 November 2021 | Volume 9 | Article 792210
Soranno et al. Editorial: After the Acute and Beyond the Kidneys
8. Goldstein SL, Dahale D, Kirkendall ES, Mottes T, Kaplan H, Muething
S, et al. A prospective multi-center quality improvement initiative
(NINJA) indicates a reduction in nephrotoxic acute kidney injury in
hospitalized children. Kidney Int. (2020) 97:580–8. doi: 10.1016/j.kint.2019.1
0.015
Conflict of Interest: The authors declare that the research was conducted in the
absence of any commercial or financial relationships that could be construed as a
potential conflict of interest.
Publisher’s Note: All claims expressed in this article are solely those
of the authors and do not necessarily represent those of their affiliated
organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may
be made by its manufacturer, is not guaranteed or endorsed by the
publisher.
Copyright © 2021 Soranno, Deep, Gist and Zappitelli. This is an open-access article
distributed under the terms of the Creative Commons Attribution License (CC BY).
The use, distribution or reproduction in other forums is permitted, provided the
original author(s) and the copyright owner(s) are credited and that the original
publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these
terms.
Frontiers in Pediatrics | www.frontiersin.org 3 November 2021 | Volume 9 | Article 792210


Editorial: Acute Kidney Injury: It's Not Just Acute, and It's Not Just the Kidneys

IUPUIScholarWorks

EDITORIALpublished: 15 November 2021doi: 10.3389/fped.2021.792210Frontiers in Pediatrics | www.frontiersin.org 1 November 2021 | Volume 9 | Article 792210Edited and reviewed by:Michael L. Moritz,University of Pittsburgh, United States*Correspondence:Danielle E. Sorannodanielle.soranno@childrenscolorado.orgSpecialty section:This article was submitted toPediatric Nephrology,a section of the journalFrontiers in PediatricsReceived: 09 October 2021Accepted: 18 October 2021Published: 15 November 2021Citation:Soranno DE, Deep A, Gist KM andZappitelli M (2021) Editorial: AcuteKidney Injury: It’s Not Just Acute, andIt’s Not Just the Kidneys.Front. Pediatr. 9:792210.doi: 10.3389/fped.2021.792210Editorial: Acute Kidney Injury: It’s NotJust Acute, and It’s Not Just theKidneysDanielle E. Soranno 1*, Akash Deep 2, Katja M. Gist 3 and Michael Zappitelli 41 Section of Pediatric Nephrology, Departments of Pediatrics, Bioengineering and Medicine, University of Colorado, Aurora,CO, United States, 2Department of Child Health, NHS Foundation Trust, King’s College Hospital, London, United Kingdom,3Division of Pediatric Cardiology, Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States, 4Divisionof Nephrology, Department of Pediatrics, Hospital for Sick Children, Toronto, ON, CanadaKeywords: acute kidney injury, pediatric nephrology, Continuous Renal Replacement Therapies (CRRT), diabetesmellitus, Artificial Intelligence-AI, metabolic bone disease, critical care nephrologyEditorial on the Research TopicAcute Kidney Injury: It’s Not Just Acute, and It’s Not Just the KidneysAcute kidney injury (AKI) occurs in ∼20, 30, and 40–60% of pediatric patients in pediatric,neonatal and cardiac intensive care units, respectively (1, 2). Twenty years ago, AKI in hospitalizedchildren was considered an unfortunate consequence of illness, but ultimately self-limited withoutdirect impacts on patient outcomes. Extensive research in the last 15 years revealed that AKIin hospitalized children is associated with greater hospital resource utilization, morbidity andhospital mortality (1, 3). Shockingly, many episodes of pediatric hospital-acquired AKI continueto go unrecognized (4). More recently, emerging evidence suggests that children survivinghospitalization with an AKI episode may be at substantially higher risk than children without AKI,for developing long-term chronic kidney disease (CKD) and hypertension and long-termmortality(5). This literature has contributed to a paradigm shift that AKI increases risk for poor long-term outcomes, warranting efforts to improve detection, management and secondary preventionof permanent sequelae.The goals of this collection of 9 manuscripts are to provide an update on best practices fordetection, management, and follow-up of pediatric AKI, and perspectives on the deleterious short-and long-term systemic sequelae of AKI in the context of evolving clinical, epidemiologic andfundamental AKI research.In Impact of Acute Kidney Injury on Critically Ill Children and Neonates, authors Leghrouz andKaddourah provide an overview of the recent shifts in AKI definition, now centering on the KDIGOdefined criteria using either a rise in serum creatinine, and/or a reduction in urine output. Theauthors highlight the importance of measuring urine output in order to recognize oliguric AKI forimproved diagnostic precision. The review also provides a summary of the impact of AKI followinghematopoietic stem cell transplant and emerging data on children with multisystem inflammatorysyndrome as a result of the SARS-CoV-2 pandemic.In Acute Kidney Injury in Critically Ill Children Is not all Acute: Lessons Over the Last 5Years, Hessey et al. reviewed the last 5 years of peer-reviewed literature exploring the long-termoutcomes of pediatric AKI. The summary provides an overview of the advancements and remainingchallenges in investigating long-term outcomes after critical illness in hospitalized children. It alsohighlights the importance of implementing standardized follow-up of kidney health and outcomesafter an episode of severe AKI. This aligns with recent recommendations in the neonatal andpediatric response to the Acute Disease Quality Initiative (ADQI) 22 guidance document (6).Soranno et al. Editorial: After the Acute and Beyond the KidneysIn A Precision Medicine Approach to Biomarker Utilizationin Pediatric Sepsis-Associated Acute Kidney Injury, authorsOdum et al. reframe sepsis-associated AKI as a heterogeneousdisease process. They provide a framework approach to utilizingbiomarkers for prognostic enrichment and precision medicine todecluster the sepsis phenotype into distinctive pathophysiologiesfor targeted therapeutic clinical trials. This manuscript highlightsthe need to improve our understanding of AKI phentoypes forwhich future therapeutic targets might be considered.In Continuous Renal Replacement Therapy in Critically IllChildren in the Pediatric Intensive Care Unit: A RetrospectiveAnalysis of Real-Life Prescriptions, Complications, andOutcomes, Buccione et al. present new data from a 6-yearsingle center retrospective study evaluating outcomes afterCRRT therapy in pediatrics. Their data reports that fluidoverload was the predominant indication for CRRT initiation(>60% of cases) and identifies catheter size <8 French andlack of citrate regional anticoagulation as predictors of earlydiscontinuation of treatment. With a mean follow-up timeof 3.5 years, only 42% of the patients who survived didnot have any long-term kidney sequelae, including CKDor proteinuria.In Two to Tango: Kidney-Lung Interaction in Acute KidneyInjury and Acute Respiratory Distress Syndrome, Alge et al.provide a thorough review of the basic science and clinical datasurrounding the development of AKI-mediated lung injury andthe role that lung injury plays in affecting kidney function. Thereview highlights the complexity of identifying the bidirectionaleffects of hemodynamic alterations in critical illness, resultingfrom acute lung disease as well as from AKI.In A review on the application and limitationsof administrative health care data for the study ofacute kidney injury epidemiology and outcomes inchildren, Ulrich et al. summarize the opportunities andlimitations of leveraging “big data” in administrativehealth repositories to investigate pediatric AKI outcomes.While big data research offers unique and unprecendentedopportunities to evaluate pediatric AKI with largesample sizes, there is a need to validate these datafor defining pediatric kidney outcomes and limitingassociated biases.In For Whom the Bell Tolls: Acute Kidney Injury andElectronic Alerts for the Pediatric Nephrologist, authors Nguyenand Menon review best practices for AKI alerts, and howthey can be implemented to hasten the diagnosis and optimizemanagement in pediatric AKI. These AKI alerts and tools tiein with broader efforts within the nephrology community toutilize artificial intelligence and machine learning to improveoutcomes in patients with AKI. The review provides examplesof early applications of alert tools in pediatric AKI, includinga nephrotoxic-mediated AKI stewardship program, which hasbeen shown to reduce the rate, severity and duration ofnephrotoxic AKI (7, 8).In Acute kidney injury in pediatric diabetic kidney disease,Piani et al. describe the pathophyisiology of AKI and itsrelation to diabetic kidney disease in children with typesI and II diabetes mellitus. Children with diabetes are atan increased risk for developing AKI, and after an episodeof AKI, they are at higher risk of developing diabetickidney disease and CKD. The review also summarizes theincreased risk of severe COVID-19 disease in patients withdiabetes mellitus.In Acute Kidney Injury and Pediatric Bone Health,authors Hegde et al. review the current literature on fracturerisk after AKI, the mechanisms of dysregulation in bonemetabolism in AKI, and suggest areas for future research,particularly with regard to skeletal growth in pediatric patientsafter AKI.As the overall survival of critically ill pediatric patientsimproves, there are increasing survivors of childhood AKI.With these perspectives in mind, future research is required toexplore the long-term impact of pediatric AKI on populationhealth, health care costs, and how pediatric providers withinvarying healthcare contexts, can potentially improve caredelivery with a goal to optimize their patients’ outcomes laterin life.AUTHOR CONTRIBUTIONSDS, AD, KG, and MZ contributed to the editorial writing andrevision process. All authors contributed to the article andapproved the submitted version.REFERENCES1. Kaddourah A, Basu RK, Bagshaw SM, Goldstein SL, Investigators A.Epidemiology of acute kidney injury in critically ill children and youngadults. N Engl J Med. (2017) 376:11–20. doi: 10.1056/NEJMoa16113912. Jetton J, J Boohaker L, Sethi S, Wazir S, Rohatgi S, Soranno DE, et al.Incidence and outcomes of neonatal acute kidney injury (AWAKEN):a multicentre, multinational, observational cohort study. LancetChild Adolesc Health. (2017) 1:184–94. doi: 10.1016/S2352-4642(17)30069-X3. Silver SA, Long J, Zheng Y, Chertow GM. Cost of acute kidney injuryin hospitalized patients. J Hosp Med. (2017) 12:70–6. doi: 10.12788/jhm.26834. Roy JP, Goldstein SL, Schuh MP. Under-recognition of neonatalacute kidney injury and lack of follow-up. Am J Perinatol.(2020). doi: 10.1055/s-0040-1716841. [Epub ahead of print].5. Sigurjonsdottir VK, Chaturvedi S, Mammen C, Sutherland SM. Pediatric acutekidney injury and the subsequent risk for chronic kidney disease: is there causefor alarm? Pediatr Nephrol. (2018) 33:2047–55. doi: 10.1007/s00467-017-3870-66. Macedo E, Bihorac A, Siew ED, Palevsky PM, Kellum JA, RoncoC, et al. Quality of care after AKI development in the hospital:Consensus from the 22nd Acute Disease Quality Initiative (ADQI)conference. Eur J Intern Med. (2020) 80:45–53. doi: 10.1016/j.ejim.2020.04.0567. Goldstein SL. Medication-induced acute kidney injury. Curr Opin Crit Care.(2016) 22:542–5. doi: 10.1097/MCC.0000000000000355Frontiers in Pediatrics | www.frontiersin.org 2 November 2021 | Volume 9 | Article 792210Soranno et al. Editorial: After the Acute and Beyond the Kidneys8. Goldstein SL, Dahale D, Kirkendall ES, Mottes T, Kaplan H, MuethingS, et al. A prospective multi-center quality improvement initiative(NINJA) indicates a reduction in nephrotoxic acute kidney injury inhospitalized children. Kidney Int. (2020) 97:580–8. doi: 10.1016/j.kint.2019.10.015Conflict of Interest: The authors declare that the research was conducted in theabsence of any commercial or financial relationships that could be construed as apotential conflict of interest.Publisher’s Note: All claims expressed in this article are solely thoseof the authors and do not necessarily represent those of their affiliatedorganizations, or those of the publisher, the editors and the reviewers.Any product that may be evaluated in this article, or claim that maybe made by its manufacturer, is not guaranteed or endorsed by thepublisher.Copyright © 2021 Soranno, Deep, Gist and Zappitelli. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Pediatrics | www.frontiersin.org 3 November 2021 | Volume 9 | Article 792210

http://dx.doi.org/10.3389/fped.2021.792210

Editorial: Acute Kidney Injury: It's Not Just Acute, and It's Not Just the Kidneys

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