Archives of Academic Emergency Medicine. 2022; 10(1): e89 REV I EW ART I C L E Prevalence and Mortality of Post-traumatic Acute Kidney Injury in Children; a Systematic Review and Meta-analysis Mahmoud Yousefifard1,2, Amirmohammad Toloui1, Seyed Ali Forouzannia3, Neamatollah Ataei2,4, Hasti Hossein1, Amirali Zareie Shab Khaneh5, Maryam Karimi Ghahfarokhi5, Michael E. Jones6, Mostafa Hosseini2,5∗ 1. Physiology Research Center, Iran University of Medical Sciences, Tehran, Iran. 2. Pediatric Chronic Kidney Disease Research Center, Tehran University of Medical Sciences, Tehran, Iran. 3. Men’s Health and Reproductive Health Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 4. Department of Pediatric Nephrology, Children’s Hospital Medical Center, Tehran University of Medical Sciences, Tehran, Iran. 5. Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran. 6. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. Received: July 2022; Accepted: August 2022; Published online: 7 November 2022 Abstract: Introduction: Numerous studies on acute kidney injury (AKI) following trauma have been performed, and ac- ceptable findings have been reported in the adult population. The present meta-analysis summarizes the stud- ies performed on the pediatric population to evaluate the prevalence of AKI following trauma in this population. Methods: The Medline, Embase, Scopus and Web of Sciences databases were searched for articles published until the July, 31, 2021. Two independent reviewers screened observational studies performed on children with physical trauma and AKI related to it. The interested outcomes were the prevalence and mortality of trauma- related AKI in traumatized children. Results: Data of 9 articles were included in the present meta-analysis. The prevalence of trauma-related AKI varied between 0% and 30.30% among included studies. Pooled analysis showed that the prevalence of trauma-related AKI was 9.86% (95% CI: 8.02 to 11.84%). The prevalence of AKI after exertional rhabdomyolysis, direct physical trauma, and earthquake related injuries was 0%, 12.64% and 24.60%, respectively. There was a significant relationship between the prevalence of AKI and trauma etiology (p = 0.038). Moreover, the occurrence of AKI in children with trauma was associated with an increased risk of mortality (OR = 5.55; 95% CI: 2.14 to 13.93). Conclusion: The findings of the present study showed that 9.86% of children develop AKI following trauma, which may increase their risk of death by about 5.5 times. Nevertheless, since none of the studies had adjusted their analyzes for potential confounders, caution should be exercised in interpreting the relationship between trauma-related AKI and mortality. Keywords: Multiple trauma; pediatrics; acute kidney injury; earthquakes; exercise; rhabdomyolysis Cite this article as: Yousefifard M, Toloui A, Forouzannia SA, Ataei N, Hossein H, Zareie A, et al. Prevalence and Mortality of Post- traumatic Acute Kidney Injury in Children; a Systematic Review and Meta-analysis. Arch Acad Emerg Med. 2022; 10(1): e89. https://doi.org/10.22037/aaem.v10i1.1660. 1. Introduction Acute kidney injury (AKI) is a serious complication in chil- dren and adolescents. It is caused by many different etiolo- gies and if not diagnosed in time, it can quickly progress to ∗Corresponding Author: Mostafa Hosseini; Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran; Email: mhossein110@yahoo.com; Tel: +982188989125; Fax: +982188989127, ORCID: 0000-0002-1334-246X. chronic kidney disease and dialysis. The prevalence of AKI indicates that about 10% of children admitted to the inten- sive care unit develop AKI (1). This injury significantly affects patients’ mortality (1, 2). The risk of developing AKI increases in both children and adults following trauma. This is due to direct damage to the kidneys, shock, the use of harmful compounds for the kidneys in the diagnosis and treatment of trauma patients, and the occurrence of rhabdomyolysis (3). Current evidence show that the risk of mortality in traumatized children with This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 2 AKI could be 3.6 times higher (4). However, there is still con- siderable diversity among studies. In the last 20 years, numerous studies have been performed on AKI following trauma, and acceptable findings have been reported in adults (5-8). However, the extent of the problem in children and the effect of AKI on trauma mortality are not well understood. Based on this, the researchers of the present study intended to provide evidence by conducting a system- atic review and meta-analysis on the prevalence of AKI and its relationship with mortality in traumatized children. 2. Methods 2.1. Study design and search strategy The present meta-analysis was designed to summarize the evidence of studies performed on pediatric samples to eval- uate the prevalence of AKI in traumatized pediatric patients. For the present study, the MOOSE guideline, a guide for sys- tematic review and meta-analysis in observational research has been used (9). An extensive search of the Medline, Em- base, Scopus and Web of Sciences electronic databases was conducted for articles published until the end of May 2020. The search strategy was based on keywords related to AKI, trauma and prevalence. To refine the search, the recom- mended Cochrane Childhood Cancer Group filter was used to find articles related to children (10). Table 1 presents the search strategy for the Medline database. 2.2. Inclusion criteria The definition of PECO in the present study was as follows: problem or study population (P): children and adolescents with trauma; exposure (E): exposure to physical trauma; comparisons (C): with non-AKI group; and outcome (O): prevalence of AKI in children with trauma and their mortal- ity. Therefore, the observational studies performed on trau- matized children with AKI were included. Exclusion crite- ria were adult patients, studies performed on non-traumatic AKI, patients without AKI, penetrating injuries, and case- series studies. 2.3. Data collection and quality assessment Two independent researchers collected the data. After con- ducting the search and integrating the findings obtained from databases and searching the gray literature (search in Google and Google Scholar as well as a search in the dis- sertation section of ProQuest database), the researchers per- formed an initial screening in the Endnote program (version 8.0), independently. Title and abstract of each article were studied and if the article was relevant or likely to be relevant, the full text of the study was retrieved and reviewed. The data of these studies were then summarized in a checklist designed based on PRISMA statement guidelines (11). The extracted data included information related to the study de- sign, sample baseline characteristics (age, sex, etc.), number of samples studied, definition of AKI, prevalence of AKI and prevalence of mortality. The articles’ risk of bias was assessed using the National Heart, Lung, and Blood institute Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies (12). In case of any disagreements, the dispute was resolved through discussion with a third reviewer. 2.4. Statistical analysis Analyses were performed using STATA 14.0 statistical pro- gram. All studies were summarized based on the studied out- comes. These outcomes were the prevalence of AKI in trau- matized children and its relationship with mortality. Preva- lence data were recorded as frequency. For evaluating the prevalence of trauma-related AKI, the “Metaprop_one” com- mand was used and a pooled prevalence with 95% confi- dence interval (95% CI) was reported. the relationship be- tween trauma-related AKI and children’s mortality, was as- sessed using the “metan” command and pooled effect size was reported as odds ratio (OR). The presence of heterogene- ity was investigated using the I2 statistics. Since we expected no obvious heterogeneity among studies, a fixed effect model was used for the analyses. In case of heterogeneity, we used random effect model, and performed subgroup analysis to find the source of heterogeneity. Egger’s test and funnel plot were used to examine publication bias. 3. Results 3.1. Summary of studies The search yielded 3311 non-duplicated articles. After the initial full-text screening, 37 articles were reviewed and fi- nally the data of 9 articles were included in the present meta- analysis (Figure 1) (13-21). There were 3 prospective cohort studies and 6 retrospective cohort studies. The etiology of trauma among patients in the included studies were direct physical trauma, exercise-related injuries, exertional rhab- domyolysis, or earthquake. These studies included data from 1,052 traumatized children. Table 2 shows a summary of the characteristics of included articles. 3.2. Risk of bias In the quality control section, it was realized that none of the studies reported the prevalence of AKI in terms of sever- ity of trauma (item 8); Also, the sample size calculation was reported in only one study (item 5). None of the studies adjusted the analyses for potential confounders (item 14). Moreover, the blinding status of the outcome observer was not reported in any of the studies (item 12) (Table 3). This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 3 Archives of Academic Emergency Medicine. 2022; 10(1): e89 3.3. Meta-analysis • Prevalence of trauma-related AKI in children The prevalence of trauma-related AKI varied between 0% and 30.30% among included studies. Pooled analysis showed that the prevalence of trauma-related AKI was 9.86% (95% CI: 8.02 to 11.84%) (Figure 2). To investigate the cause of hetero- geneity in the prevalence of AKI, subgroup analysis was per- formed based on the etiology of AKI. Table 4 shows the find- ings of this section. Accordingly, the prevalence of AKI after exertional rhab- domyolysis, mild to severe direct trauma, and earthquake- related injuries was 0%, 12.64% and 24.60%, respectively; Ac- cording to this analysis, there is a significant difference be- tween the prevalence of AKI in terms of trauma etiology (p = 0.038). • Relationship between trauma-related AKI and mortality in children In this section, data from 7 studies were entered. The preva- lence of mortality following trauma-related AKI in children is low (Table 2). However, the analysis showed that the oc- currence of AKI in traumatized children was associated with an increased odds ratio (OR) of mortality (OR = 5.55; 95% CI: 2.14 to 13.93). Nevertheless, since none of the studies had adjusted their analyzes for potential confounders, cau- tion should be exercised in interpreting the findings of this section (Figure 3). 3.4. Publication bias Egger’s test showed that there wasn’t any publication bias in assessment of the prevalence of trauma-related AKI in chil- dren (p = 0.72) and relationship of trauma-related AKI with children’s mortality (p = 0.154) (Figure 4). 4. Discussion The present meta-analysis summarized the current evidence on the relationship between trauma and the incidence of AKI in children. The findings of the present study showed that 9.86% of children develop AKI following trauma, which may increase their risk of mortality by about 5.5 times. The analyses of the present study showed that the cause of trauma is an important factor in the occurrence of AKI. The prevalence of AKI following exertional rhabdomyolysis is zero percent, while the prevalence increases with injury severity. Therefore, as a report, it can be said that the oc- currence of AKI in children with exertional rhabdomyolysis is very rare, while almost a quarter of children with severe injuries or earthquake victims develop AKI. A finding that calls for more attention in the management of children with trauma, especially those admitted to intensive care units with severe traumas. One of the aims of the present study was to investigate the relationship between the incidence of AKI following trauma in children and adolescents and the pertaining mortality. Al- though the findings of the present meta-analysis showed that the incidence of AKI is associated with an increased risk of death in traumatized children, care should be taken in inter- preting this finding. Risk of bias assessment in the present study showed that none of the studies attempted to adjust the analyzes for potential confounders of mortality in trauma patients and therefore the observed relationship between the incidence of AKI and mortality of traumatized children may be a confounding relationship. Furthermore, the quality of studies was moderate, most studies were retrospective in na- ture, and the blinding of the outcome assessor was unclear. Therefore, in order to accurately determine the prevalence of AKI in children with trauma, it is necessary to design studies with a larger sample size and higher quality. Another limitation in the present study was the difference in the definition of AKI in included studies. For example, in the study of Prodhan et al., they used the pRIFLE criteria to de- fine AKI, and defined all classes of risk, injury, failure, and end-stage as AKI (20). Whereas, in the standard definition, the risk category is not defined as documented AKI. Therefore, to overcome this problem, the risk category was left out to use a similar defini- tion of AKI among included studies. Nonetheless, two studies (18, 19) did not provide the definition of AKI. 5. Conclusion For the first time, the present meta-analysis summarized the existing reports on the relationship between trauma and the incidence of AKI in children. The findings of the present study showed that 9.86% of children develop AKI following trauma, which may increase their risk of death by about 5.5 times. 6. Declarations 6.1. Acknowledgments None. 6.2. Conflict of interest statement The authors declare that they have no conflict of interests. 6.3. Compliance with Ethical Standards This study complies with the declaration of Helsinki and all ethical standards. 6.4. Human and Animal Rights This article does not contain any studies with human partic- ipants or animals performed by any of the authors. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 4 6.5. Funding The study was funded and supported by Tehran university of medical sciences (TUMS); Grant no: 98-01-184-42135. 6.6. Conflict of interest None. References 1. Schneider J, Khemani R, Grushkin C, Bart R. Serum cre- atinine as stratified in the RIFLE score for acute kidney injury is associated with mortality and length of stay for children in the pediatric intensive care unit. Crit Care Med. 2010;38(3):933-9. 2. Goldstein SL, Devarajan P. Pediatrics: Acute kidney in- jury leads to pediatric patient mortality. Nat Rev Nephrol. 2010;6(7):393-4. 3. Harrois A, Libert N, Duranteau J. Acute kidney injury in trauma patients. Curr Opin Crit Care. 2017;23(6):447-56. 4. Haines RW, Fowler AJ, Kirwan CJ, Prowle JR. The inci- dence and associations of acute kidney injury in trauma patients admitted to critical care: A systematic re- view and meta-analysis. J Trauma Acute Care Surg. 2019;86(1):141-7. 5. Burmeister DM, Gomez BI, Dubick MA. Molecular mech- anisms of trauma-induced acute kidney injury: Inflam- matory and metabolic insights from animal models. Biochim Biophys Acta Mol Basis Dis. 2017;1863(10 Pt B):2661-71. 6. Civiletti F, Assenzio B, Mazzeo AT, Medica D, Giaretta F, Deambrosis I, et al. Acute Tubular Injury is Associated With Severe Traumatic Brain Injury: in Vitro Study on Human Tubular Epithelial Cells. Sci Rep. 2019;9(1):6090. 7. Perkins ZB, Captur G, Bird R, Gleeson L, Singer B, O’Brien B. Trauma induced acute kidney injury. PLoS One. 2019;14(1):e0211001. 8. Ramirez ME, McQuillan RF. Acute Kidney Injury Sec- ondary to Trauma-Induced Hemolysis: The Need for In- creased Awareness and a Preventative Strategy. Am J Kid- ney Dis. 2017;69(2):320. 9. 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Downloaded from: http://journals.sbmu.ac.ir/aaem 5 Archives of Academic Emergency Medicine. 2022; 10(1): e89 Table 1: Search strategy in Medline database Database Search terms MEDLINE (PubMed) 1. “Wounds and Injuries”[mh] OR "Injuries"[Subheading] OR “Multiple Trauma”[mh] OR “Hemolysis”[mh] OR “Rhabdomy- olysis”[mh] OR Trauma[tiab] OR Traumas[tiab] OR Multiple Trauma[tiab] OR Polytrauma[tiab] 2. “Prevalence”[mh] OR “Epidemiology”[mh] OR “Incidence”[mh] OR Prevalence[tiab] OR Epidemiology[tiab] OR Inci- dence[tiab] OR incidence rate[tiab] OR epidemiologic[tiab] 3. ("acute kidney injury"[MeSH Terms] OR ("acute"[All Fields] AND "kidney"[All Fields] AND "injury"[All Fields]) OR "acute kidney injury"[All Fields]) OR ("acute kidney injury"[MeSH Terms] OR ("acute"[All Fields] AND "kidney"[All Fields] AND "in- jury"[All Fields]) OR "acute kidney injury"[All Fields] OR ("acute"[All Fields] AND "renal"[All Fields] AND "failure"[All Fields]) OR "AKI"[All Fields]) 4. (Infan* OR newborn* OR new-born* OR perinat* OR neonat* OR baby OR baby* OR babies OR toddler* OR minors OR minors* OR boy OR boys OR boyfriend OR boyhood OR girl* OR kid OR kids OR child OR child* OR children* OR schoolchild* OR schoolchild OR school child[tiab] OR school child*[tiab] OR adolescen* OR juvenil* OR youth* OR teen* OR under*age* OR pubescen* OR pediatrics[mh] OR pediatric* OR paediatric* OR peadiatric* OR school[tiab] OR school*[tiab] OR prematur* OR preterm*) 5. #1 AND #2 AND #3 AND #4 Table 2: The summary of the characteristics of eligible studies Author; year; country Study type Population Age Sample size Number of boys AKI definition AKI Mortality in AKI Mortality in Non-AKI Bjornstad; 2020; Malawi Prospective cohort Mild to severe trauma 8.1 114 42 KDIGO criteria 11 4 6 Chen; 2013; Taiwan Retrospective cohort Trauma and exercise related injury 10.2 12 26 Serum creatinine level of more than the 97.5th percentile 0 0 0 Guardenier; 2015; United States Retrospective cohort Moderate to severe TBI 0-17 years 35 18 pRIFLE 5 0 0 Hatamizadeh; 2006; Iran Retrospective cohort Earthquake victims 0-15 49 Not specified At least 2 reported serum creatinine values of 1.6 mg/dL or greater 14 Not specified Not specified Lin; 2005; Tai- wan Prospective cohort Exertional Rhabdomyoly- sis High school student 157 106 Not specified 0 0 0 Oh; 2011; United States Retrospective cohort Exertional Rhabdomyoly- sis 15.9 43 Not specified Not specified 0 0 0 Iskit; 2001; Turkey Retrospective cohort Earthquake victims 8.8 33 17 Serum creatinine level above 1.2 mg/dL or oliguria 10 0 0 Prodhan; 2012; United States Retrospective cohort Severe ICU admitted trauma 11.6 88 58 pRIFLE 22 7 5 Talving; 2013; United States Retrospective cohort Mild to severe trauma 12.2 521 352 pRIFLE 70 Not specified Not specified AKI: Acute kidney injury; KDIGO: Kidney Disease Improving Global Outcomes; pRIFLE: Pediatric Risk, Injury, Failure, Loss , End Stage Renal Disease; TBI: Traumatic brain injury; ICU: intensive care unit. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 6 Figure 1: PRISMA flow diagram of the present study. AKI: Acute Kidney injury. Figure 2: Prevalence of acute kidney injury in traumatized children. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem 7 Archives of Academic Emergency Medicine. 2022; 10(1): e89 Figure 3: The pooled odds ratio (OR) of mortality following trauma-related acute kidney injury (AKI) in children. The risk of mortality of is higher in traumatized children with AKI compared to non-AKI children. Figure 4: Assessment of publication bias among included studies. There is no publication bias in the present meta-analysis. AKI: Acute kidney injury. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem M. Yousefifard et al. 8 Table 3: Risk of bias assessment of included studies according to National Heart, Lung, and Blood Institute Quality Assessment Tool for Ob- servational Cohort and Cross-Sectional Studies (12) Study Items 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Bjornstad; 2020 Yes Yes Yes Yes Yes Yes Yes No Yes NA Yes NR Yes No Chen; 2013 Yes Yes Yes Yes NR Yes Yes No Yes NA Yes NR NR No Guardenier; 2015 Yes Yes Yes Yes NR Yes Yes No Yes NA Yes NR NR No Hatamizadeh; 2006 Yes Yes Yes Yes NR Yes Yes No Yes NA Yes No NR NA Lin; 2005 Yes Yes Yes Yes NR Yes ND No Yes NA Yes No NR No Oh; 2011 Yes Yes Yes Yes NR Yes ND No Yes NA Yes No NR No Iskit; 2001 Yes Yes Yes Yes NR Yes ND No Yes NA Yes NR No No Prodhan; 2012 Yes Yes Yes Yes NR Yes Yes No Yes NA Yes NR ND No Talving; 2013 Yes Yes Yes Yes NR Yes Yes No Yes NA Yes NR No No Yes: Low risk of bias; No: High risk of bias; NA: Not applicable; ND: Not determined; NR: Not reported. Table 4: The prevalence of acute kidney injury (16) stratified by the etiology of trauma Etiology of AKI Number of studies Prevalence (95% CI) Heterogeneity (p value) Exertional rhabdomyolysis 3 0.00 (0.00 to 0.20) 0.0% (>0.999) All severities 2 12.64 (10.14 to 15.37) 0.0% (>0.999) Moderate to severe rhabdomyolysis in earthquake 4 24.60 (18.81 to 30.86) 0.0% (>0.999) Among subgroups 0.038 CI: Confidence interval. This open-access article distributed under the terms of the Creative Commons Attribution NonCommercial 3.0 License (CC BY-NC 3.0). Downloaded from: http://journals.sbmu.ac.ir/aaem Introduction Methods Results Discussion Conclusion Declarations References