Abstract
Introduction:
Numerous studies on acute kidney injury (AKI) following trauma have been performed, and acceptable findings have been reported in the adult population. The present meta-analysis summarizes the studies performed on the pediatric population to evaluate the prevalence of AKI following trauma in this population.
Method:
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.
Key Words: Multiple trauma, pediatrics, acute kidney injury, earthquakes; exercise, rhabdomyolysis
1. Introduction:
Acute kidney injury (AKI) is a serious complication in children and adolescents. It is caused by many different etiologies and if not diagnosed in time, it can quickly progress to chronic kidney disease and dialysis. The prevalence of AKI indicates that about 10% of children admitted to the intensive 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 AKI could be 3.6 times higher (4). However, there is still considerable 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 systematic 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 evaluate the prevalence of AKI in traumatized pediatric patients. For the present study, the MOOSE guideline, a guide for systematic review and meta-analysis in observational research has been used (9). An extensive search of the Medline, Embase, 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 recommended Cochrane Childhood Cancer Group filter was used to find articles related to children (10). Table 1 presents the search strategy for the Medline database.
Table 1.
Search strategy in Medline database
| Database | Search terms |
|---|---|
| MEDLINE (PubMed) |
|
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 mortality. Therefore, the observational studies performed on traumatized children with AKI were included. Exclusion criteria 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 conducting 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 dissertation section of ProQuest database), the researchers performed 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 design, 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 program. All studies were summarized based on the studied outcomes. These outcomes were the prevalence of AKI in traumatized children and its relationship with mortality. Prevalence data were recorded as frequency. For evaluating the prevalence of trauma-related AKI, the “Metaprop_one” command was used and a pooled prevalence with 95% confidence interval (95% CI) was reported. the relationship between trauma-related AKI and children’s mortality, was assessed using the “metan” command and pooled effect size was reported as odds ratio (OR). The presence of heterogeneity 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 finally 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 rhabdomyolysis, or earthquake. These studies included data from 1,052 traumatized children. Table 2 shows a summary of the characteristics of included articles.
Figure 1.
PRISMA flow diagram of the present study. AKI: Acute Kidney injury.
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; Taiwan | Prospective cohort | Exertional Rhabdomyolysis | High school student | 157 | 106 | Not specified | 0 | 0 | 0 |
| Oh; 2011; United States | Retrospective cohort | Exertional Rhabdomyolysis | 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.
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 severity 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).
Table 3.
Risk of bias assessment of included studies according to National Heart, Lung, and Blood Institute Quality Assessment Tool for Observational 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.
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 heterogeneity in the prevalence of AKI, subgroup analysis was performed based on the etiology of AKI. Table 4 shows the findings of this section. Accordingly, the prevalence of AKI after exertional rhabdomyolysis, mild to severe direct trauma, and earthquake-related injuries was 0%, 12.64% and 24.60%, respectively; According to this analysis, there is a significant difference between the prevalence of AKI in terms of trauma etiology (p = 0.038).
Figure 2.
Prevalence of acute kidney injury in traumatized children.
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.
Relationship between trauma-related AKI and mortality in children
In this section, data from 7 studies were entered. The prevalence of mortality following trauma-related AKI in children is low (Table 2). However, the analysis showed that the occurrence 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, caution should be exercised in interpreting the findings of this section (Figure 3).
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.
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 children (p = 0.72) and relationship of trauma-related AKI with children’s mortality (p = 0.154) (Figure 4).
Figure 4.
Assessment of publication bias among included studies. There is no publication bias in the present meta-analysis. AKI: Acute kidney injury.
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 occurrence 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. Although 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 interpreting 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 nature, 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 define 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 definition 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 participants or animals performed by any of the authors.
6.5. Funding
The study was funded and supported by Tehran university of medical sciences (TUMS); Grant no: 98-01-184-42135.
References
- 1.Schneider J, Khemani R, Grushkin C, Bart R. Serum creatinine 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. doi: 10.1097/CCM.0b013e3181cd12e1. [DOI] [PubMed] [Google Scholar]
- 2.Goldstein SL, Devarajan P. Pediatrics: Acute kidney injury leads to pediatric patient mortality. Nat Rev Nephrol. 2010;6(7):393–4. doi: 10.1038/nrneph.2010.67. [DOI] [PubMed] [Google Scholar]
- 3.Harrois A, Libert N, Duranteau J. Acute kidney injury in trauma patients. Curr Opin Crit Care. 2017;23(6):447–56. doi: 10.1097/MCC.0000000000000463. [DOI] [PubMed] [Google Scholar]
- 4.Haines RW, Fowler AJ, Kirwan CJ, Prowle JR. The incidence and associations of acute kidney injury in trauma patients admitted to critical care: A systematic review and meta-analysis. J Trauma Acute Care Surg. 2019;86(1):141–7. doi: 10.1097/TA.0000000000002085. [DOI] [PubMed] [Google Scholar]
- 5.Burmeister DM, Gomez BI, Dubick MA. Molecular mechanisms of trauma-induced acute kidney injury: Inflammatory and metabolic insights from animal models. Biochim Biophys Acta Mol Basis Dis. 2017;1863(10 Pt B):2661–71. doi: 10.1016/j.bbadis.2017.04.011. [DOI] [PubMed] [Google Scholar]
- 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. doi: 10.1038/s41598-019-42147-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. doi: 10.1371/journal.pone.0211001. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Ramirez ME, McQuillan RF. Acute Kidney Injury Secondary to Trauma-Induced Hemolysis: The Need for Increased Awareness and a Preventative Strategy. Am J Kidney Dis. 2017;69(2):320. doi: 10.1053/j.ajkd.2016.08.021. [DOI] [PubMed] [Google Scholar]
- 9.Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA. 2000;283(15):2008–12. doi: 10.1001/jama.283.15.2008. [DOI] [PubMed] [Google Scholar]
- 10.Leclercq E, Leeflang MMG, van Dalen EC, Kremer LCM. Validation of Search Filters for Identifying Pediatric Studies in PubMed. J Pediatr. 2013;162(3):629–34. doi: 10.1016/j.jpeds.2012.09.012. [DOI] [PubMed] [Google Scholar]
- 11.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9. doi: 10.7326/0003-4819-151-4-200908180-00135. [DOI] [PubMed] [Google Scholar]
- 12.National Institutes of Health. National Heart Lung, and Blood Institute. Quality assessment tool for observational cohort and cross-sectional studies. 2014. Available from: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools.
- 13.Bjornstad EC, Muronya W, Smith ZH, Gibson K, Mottl AK, Charles A, et al. Incidence and epidemiology of acute kidney injury in a pediatric Malawian trauma cohort: a prospective observational study. BMC Nephrol. 2020;21(1):1–12. doi: 10.1186/s12882-020-01755-3. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Chen C-Y, Lin Y-R, Zhao L-L, Yang W-C, Chang Y-J, Wu K-H, et al. Clinical spectrum of rhabdomyolysis presented to pediatric emergency department. BMC Pediatr. 2013;13(1):134. doi: 10.1186/1471-2431-13-134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Guardenier A, Peterson B, Hilfiker M, Shellington D. 1170: Acute renal failure in pediatric patients after moderate to severe traumatic brain injury. Crit Care Med. 2015;43(12):294. [Google Scholar]
- 16.Hatamizadeh P, Najafi I, Vanholder R, Rashid-Farokhi F, Sanadgol H, Seyrafian S, et al. Epidemiologic aspects of the Bam earthquake in Iran: the nephrologic perspective. Am J Kidney Dis. 2006;47(3):428–38. doi: 10.1053/j.ajkd.2005.11.019. [DOI] [PubMed] [Google Scholar]
- 17.Iskit SH, Alpay H, Tuğtepe H, Özdemir C, Ayyıldız SH, Özel K, et al. Analysis of 33 pediatric trauma victims in the 1999 Marmara, Turkey earthquake. J Pediatr Surg. 2001;36(2):368–72. doi: 10.1053/jpsu.2001.20719. [DOI] [PubMed] [Google Scholar]
- 18.Lin H, Chie W, Lien H. Epidemiological analysis of factors influencing an episode of exertional rhabdomyolysis in high school students. Am J Sports Med. 2006;34(3):481–6. doi: 10.1177/0363546505281243. [DOI] [PubMed] [Google Scholar]
- 19.Oh JY, Laidler M, Fiala SC, Hedberg K. Acute exertional rhabdomyolysis and triceps compartment syndrome during a high school football camp. Sports Health. 2012;4(1):57–62. doi: 10.1177/1941738111413874. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Prodhan P, McCage LS, Stroud MH, Gossett J, Garcia X, Bhutta AT, et al. Acute kidney injury is associated with increased in-hospital mortality in mechanically ventilated children with trauma. J Trauma Acute Care Surg. 2012;73(4):832–7. doi: 10.1097/TA.0b013e31825ab14f. [DOI] [PubMed] [Google Scholar]
- 21.Talving P, Karamanos E, Skiada D, Lam L, Teixeira PG, Inaba K, et al. Relationship of creatine kinase elevation and acute kidney injury in pediatric trauma patients. J Trauma Acute Care Surg. 2013;74(3):912–6. doi: 10.1097/TA.0b013e318278954e. [DOI] [PubMed] [Google Scholar]