Etiology, Clinical Profile, and Short-Term Outcome of Children With Acute Kidney Injury

Background: Acute kidney injury (AKI) is a common clinical syndrome in hospitalized children and it imposes heavy burden of mortality and morbidity. In resource-constraint settings, management of AKI is very challenging and associated with adverse outcomes. The aim of this study was to determine the clinico-etiological profile and outcome of AKI. Methodology: This prospective observational study was done at the department of pediatric nephrology and pediatric intensive care unit, National Institute of Child Health, Karachi, Pakistan from December 2020 to May 2021. A total of 130 children aged 1 month to 15 years, diagnosed with AKI irrespective of the underlying cause were included. Detailed medical information of each child including medical history, examination, and baseline investigations were obtained. Clinical and etiological profile of patients was noted. The patients were followed up to three months and the outcome was noted. Results: In a total of 130 children, 82 (63.1%) were male. The mean age was 5.5±4.4 years (ranging between 1 month and 15 years). There were 117 (90.0%) children who were referred from other centers for either dialysis or surgical treatment. Prerenal cause of AKI was found in 66 (50.8%) children, followed by renal 53 (40.8%) and postrenal in 11 (8.5%) cases. Fever and shortness of breath were the most common clinical presenting symptoms in 102 (78.5%) and 100 (76%) cases, respectively. There were 45 (34.6%) cases who were managed conservatively, 80 (61.5%) needed dialysis, while three children were managed with plasmapheresis and two required surgical intervention in the emergency department. At three-month follow-up period, 64 (49.2%) children recovered (including nine with partial recovery), 46 (36.1%) expired, 9 (6.9%) developed end-stage renal disease, while 11 (8.5%) had chronic kidney disease. Conclusion: Sepsis, nephrotoxic drugs, and acute glomerulonephritis were the major causes of AKI at our center. Mortality was high among children presenting with AKI. A relatively high proportion of children with younger age, septic AKI, and presentation in critical condition could be the reasons for this high mortality.


Introduction
Acute kidney injury (AKI) is a common clinical syndrome in hospitalized children and it imposes heavy burden of mortality and morbidity. More than 13 million people suffer from AKI each year and 85% of them live in developing countries [1]. Further, it is estimated that 1.7 million deaths occur each year from AKI and 60% of AKI survivors may experience residual renal abnormalities: proteinuria, hypertension, and reduced glomerular filtration rate (GFR) [2]. Incidence, etiology, and outcome of pediatric AKI are quite variable and depend upon age, geographic region, and clinical setting. A prospective study from India reported the prevalence of AKI in critically ill patients as 6% while development was independently linked with a significantly higher 30-day mortality rate [3]. Global data report mortality rates between 11% and 63% among children with AKI [4,5]. A study from Pakistan reported oliguria/anuria (83.6%), hypertension (37.1%), and severe anemia (17.2%) to be the most common presentations among children with AKI while post-infectious glomerulonephritis (PIGN) and crescentic glomerulonephritis in primary renal, obstructive urolithiasis in postrenal, and sepsis in prerenal were the most common etiologies [6].
Differences exist regarding the most common presentation and etiologies among children with AKI, and it is necessary to analyze the presentation, etiology, and outcome at our institute. National Institute of Child Health (NICH) is one of the largest public sector hospitals in Karachi, Pakistan, where diagnostic facilities and management are provided free of cost. Neonatal intensive care unit and pediatric ICU (PICU) facilities are available, so the young children with AKI who need peritoneal dialysis are mostly referred to our center. This study was designed to prospectively determine the etiology, clinical profile, and treatment outcome of

Inclusion and exclusion criteria
Children aged one month to 15 years, diagnosed with AKI irrespective of the underlying cause were included. Known cases of chronic kidney disease (CKD) or those with congenital anomalies of kidneys and urinary tract were excluded.

Data collection
Institutional Ethical Review Board (IERB) of NICH Karachi approved this study (IERB No: 40/2020). Informed and written consents were acquired from parents/guardians/caregivers of all study participants. Detailed medical information of each child including medical history, examination, and baseline investigations, i.e. complete blood count, urea, creatinine, electrolytes, urinalysis, urine, and blood cultures, and ultrasound of kidneys, ureters, and bladder were obtained. The diagnosis of AKI was based on pRIFLE (Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease) criteria [7]. Estimated GFR was determined by using Schwartz equation [8]. Further workup was done according to need in individual case like complement 3, antinuclear antibody, anti-dsDNA, and renal biopsy. All children with AKI were managed as per institutional protocol. Indications for dialysis were one or more of the following: complete anuria for >24 hours, volume overload, refractory metabolic acidosis, advanced uremia or uremic encephalopathy, and severe electrolyte imbalance. Peritoneal dialysis was the preferred modality in children <10 kg and children with unstable hemodynamics. The patients were monitored daily with serum creatinine and urine output before, during dialysis, and till discharge. The patients were followed up to three months according to clinical status at discharge and laboratory parameters.
For each patient, predesigned proforma was filled recording to relevant details. Severity of AKI at presentation was graded using pRIFLE criteria. Etiology of AKI was grouped as prerenal, renal, and postrenal. Outcome of AKI was measured in terms of mortality, partial recovery (CKD, proteinuria, hypertension, recurrent urinary tract infection, normalization of urinary stream), and need for long-term dialysis to label as end-stage renal disease (ESRD).

Statistical analysis
SPSS version 26.0 (IBM Corp, Armonk, NY) was employed for data analysis. Qualitative data were expressed as frequency and percentages. Quantitative variables were represented as mean and standard deviation. Chisquare test was performed comparing the outcome of children as per pRIFLE criteria considering P <0.05 as significant.

Results
In a total of 130 children, 82 (63.1%) were male and 48 (36.9%) were female with a male-to-female ratio of 1.7:1. The mean age was 5.5±4.4 years (ranging between one month and 15 years). The most common age group was between 5 and 15 years accounting for 46.9% cases followed by 1-5 years of age (29.2%) and infants (23.8%). Majority of the patients, 78 (60.0%), belonged to urban areas. Poor socioeconomic status was noted in 78 (60.0%) children. There were 117 (90.0%) children who were referred from other centers for either dialysis or surgical treatment.

Severity of AKI at presentation
As per pRIFLE criteria, the majority of children were in failure category, 119 (91.5%), at presentation, 9 (6.9%) were in injury, and 2 (1.5%) in risk category.

Discussion
AKI contributes to high childhood morbidity and mortality and increases significant economic burden on the family and healthcare system [9]. Early identification of risk factors can prevent the initiation of disease and enhance prompt diagnosis and treatment [10]. There is very limited local data regarding risk factors and outcome of AKI especially in children <5 years. AKI in the pediatric age group is associated with various etiologies. Etiology and epidemiology of AKI may vary from center to center within a same country. In our cohort of 130 children with AKI, 63% were male, resulting in a male-to-female ratio of 1.7:1, which is quite similar to the ratio of other developing countries [11,12]. In this study, a majority (91.4%) of the children were in failure category at the time of presentation with GFR <35 mL/min/1.73m 2 as per pRIFLE criteria. This presentation with severe disease has been reported from low-income countries [12]. Possible reasons could be lack of early diagnosis, late referral, and financial constraint, which is the major concern in Pakistan where majority of people are poor and come to hospital when the child has developed severe disease.
After reviewing literature on AKI we found wide variation in etiology between developed and developing countries. In developing countries community-acquired AKI is the common cause, whereas it is hospitalacquired AKI in developed countries. This study found that the prerenal etiology of AKI was noted in 50.8%, renal in 40.8%, and postrenal in 8.5%. A prospective study from China reported prerenal causes of AKI among 27.7% cases of AKI [13]. Researchers have reported that the most common cause of AKI in children in developing countries are infections [14]. We reported sepsis and AGE to be the predominant etiologies behind AKI. Data from developed countries have labeled sepsis and AGE as the most common etiologies of AKI [12,15]. This could be due to poor hygiene and lack of sanitation.
A study from Nigeria reported that 75.8% of children had stage 3 AKI at the time of hospitalization. Sepsis (41.8%) and primary kidney disease (29.7%) were the most common causes [16]. In a study published in 2016 from Karachi, the results were different from our study where PIGN and urolithiasis were the most common etiologies behind AKI [6]. Exposure to nephrotoxic drugs has been recognized as a risk factor for pediatric AKI [17]. In our cohort, exposure to nephrotoxic drugs was the most common renal cause of AKI. Notably, vancomycin and captopril were the most important agents.
The outcome of AKI is dependent upon factors like age, etiology, and the time the child presented to the healthcare facility [18]. Studies from India have reported higher rates of mortality among children with AKI ranging from 28.5% to 46.3%, whereas researchers from sub-Saharan Africa reported high rates of mortality as well (34%) [19,20]. In our study, mortality rate was high (35.4%) comparatively similar to that reported from other developing countries. A relatively high proportion of children with younger age, septic AKI, and presentation in critical condition could be the reasons for this high mortality.

Limitations
First, data in this study is from a single pediatric nephrology center; therefore, it does not truly reflect the etiological spectrum of pediatric AKI prevalent throughout the country. Secondly, neonates were excluded from this study since their susceptibility and etiology of AKI are considerably different from older infants and children. Post-cardiac surgery children were not included in this study. Nevertheless, this prospective study describes very relevant information on pediatric AKI spectrum encountered at a large tertiary care referral center in a developing country.

Conclusions
Sepsis, nephrotoxic drugs, and acute glomerulonephritis were the major causes of AKI at our center. Mortality was high among children presenting with AKI. A relatively high proportion of children with younger age, septic AKI, and presentation in critical condition could be the reasons for this high mortality.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethical Review Board (IERB) issued approval 40/2020. Institutional Ethical Review Board (IERB) of National Institute of Child Health Karachi Pakistan approved this study. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.