Incidence, risk factors, clinical profile, and determinants (affecting outcome) of new onset acute kidney injury developing in critically Ill patients in pediatric intensive care unit of a tertiary hospital in middle India

Aim/Objectives: To study the incidence, clinical - profile of AKI developing in critically-ill children after admission to PICU, including its risk-factors and determinants affecting patient outcome. Material/Methods: This prospective observational study was conducted at a tertiary teaching hospital (Pt JNM Medical College Raipur, CG, India) over a study period of 12 months (August 2017-July 2018). Those patients who satisfied the inclusion-criteria of having critical-illness requiring PICU admission, age between 1month to 18 years, and developing in-hospital AKI were enrolled; and after obtaining written informed-consent from parents, their basic demographic, clinical details and laboratory reports were entered from case records into predesigned proforma and then data was compiled in Microsoft Excel-Sheet. AKI staging was obtained using pRIFLE criteria (2007) and compared with renal-recovery and patient-survival. SPSS software (version 21) was used for data-analysis and p-value <0.05 was taken for statistical significance. Results: Out of total 1042 critically-ill children admitted during study-period, 103 developed new-onset AKI in PICU (overall incidence 9.8%). Among them, 96 patients died (93.2% cases). Maximum subjects developing in-hospital AKI had three major associated fatal risk-factors like refractory shock (80.5%), severe sepsis (68%) and MODS (62.1%). But only MODS (p=0.002) and refractory-shock (p=0.0001) showed significant association with fatal outcome. Maximum new-onset AKI cases developed within 3 days of PICU admission (62%). No statistically-significant association was observed between different AKI-stages and renal-recovery or patient-survival. Conclusion: Sepsis was common underlying risk-factor for new-onset AKI in critically-ill patients admitted in PICU, while association of MODS and/or refractory shock majorly determined poor survival-outcome. of total 103 study subjects (28%) for dialysis/hemodialysis. dialysis in most of subjects to low GCS, hemodynamic instability and poor resources in the study-setting. Renal Recovery (AKI Reversal) and its determinants in this study: Only 6 (5.8%) patients out of total 103 patients with new onset AKI completely improved with their serum creatinine improved to near baseline and were successfully discharged; while 7 (6.8%) patients were shifted to the ward from PICU with partial renal recovery. Majority of subjects (n=90, 87.4%) showed worsening renal function results over their hospital stay period.


Introduction
Acute kidney injury (AKI) or acute renal failure (ARF), is usually defined as an abrupt decline in renal function, presenting clinically as a reversible acute increase in nitrogenous wastes (blood urea nitrogen and serum creatinine levels) over the course of few hours to weeks. There is trend of significantly higher incidence of AKI amongst critically ill patients of ICUs compared to all patients admitted to any hospital. Recent two studies have reported overall incidence of new-onset AKI in critically sick PICU subjects to be 36% & 25%, while it was only 9% & 5.2% respectively in non critical pediatric admissions [1,2]. In the critically ill patients (both in adults and children), sepsis is the major cause or risk-factor for AKI, accounting for nearly 50% of cases. Sepsis, shock and/or MODS are major determinants of poor outcome as well, as shown by various observational studies [1,3]. Mortality rates in critically ill paediatric patients developing AKI are usually high, ranging between 9% and 67%. [4,5]. Acute renal insult' is currently defined/categorized based on severity of renal compromise based on RIFLE In pRIFLE staging being creatinine-based AKI criteria, serum creatinine values are used to calculate an es creatinine clearance (eCCl or eClCr) by the Schwartz formula: eCCl (ml/min/1.73m2) = k x patient's height (cm)/serum creatinine (mg/dl), where, k is a constant based on patient's gender and age: 'k values' for preterms or low birth weight less t (0.33), for full term less than 1 year (0.45); for 2 13-21 year old males need higher multiplication factor (0.70).
• Baseline and current serum creatinine values are used • If no baseline serum creatinine is available for 3 months prior to current value, assume normal eCCl = 120 ml/min/1.73m 2 for new onset AKI cases.

Statistical Analysis
• All relevant data were entered into predesigned proforma software for windows TM Version 21, IBM • Data was expressed as percentage and mean +/_ SD • Student's t test was used to check the signif • Pearson correlation analysis was performed to check the correlation between two categorical variables.
• Fischer's exact test or Chi square test was used to analyse the significance of differenc data.
• P value <0.05 was considered as statistically significant.

Results:
Incidence of new-onset AKI in the study setting: period, total 1570 patients were admitted in Pediatric intensive care unit (PICU). Those patients who fulfilled the assumed criteria for critical illness (as well as having higher risk of developing AKI) were 1042, but we could finally recruit only 103 of them as study-subjects who actuall Out total 103 subjects having AKI developed in hospital, 58 subjects were male and 45 subjects were female. grouped total 1042 PICU patients into 4 major age (27%), and 12-18 years (15.4%), since clinico vary in different age groups. Amongst these critically sick females were more than male (58% vs 42%). eCCl (ml/min/1.73m2) = k x patient's height (cm)/serum creatinine (mg/dl), where, k is a constant based on patient's gender and age: 'k values' for preterms or low birth weight less t (0.33), for full term less than 1 year (0.45); for 2-12 years of age (0.55), and, while it is (0.55) for 13 21 year old males need higher multiplication factor (0.70).
Baseline and current serum creatinine values are used to calculate a change in eCCl. If no baseline serum creatinine is available for 3 months prior to current value, assume normal eCCl = 120 for new onset AKI cases.
All relevant data were entered into predesigned proforma and analysed (with help of statistician) using Microsoft SPSS Version 21, IBM TM Corp NY and Microsoft excel TM 2007, Microsoft Inc USA. Data was expressed as percentage and mean +/_ SD Student's t test was used to check the significance of difference between two parameters in parametric data. Pearson correlation analysis was performed to check the correlation between two categorical variables. Fischer's exact test or Chi square test was used to analyse the significance of difference between distributions of the P value <0.05 was considered as statistically significant.
onset AKI in the study setting: In this hospital based observational study conducted over one dmitted in Pediatric intensive care unit (PICU). Those patients who fulfilled the assumed criteria for critical illness (as well as having higher risk of developing AKI) were 1042, but we could finally subjects who actually developed new-onset AKI.
Out total 103 subjects having AKI developed in hospital, 58 subjects were male and 45 subjects were female. grouped total 1042 PICU patients into 4 major age-groups: icance of difference between two parameters in parametric data. Pearson correlation analysis was performed to check the correlation between two categorical variables. e between distributions of the In this hospital based observational study conducted over one-year dmitted in Pediatric intensive care unit (PICU). Those patients who fulfilled the assumed criteria for critical illness (as well as having higher risk of developing AKI) were 1042, but we could finally Out total 103 subjects having AKI developed in hospital, 58 subjects were male and 45 subjects were female. We 6 years (13.7%), 6-12 years factors of AKI and underlying-disease pattern pediatric patients having risk for developing new-onset AKI,

Pediatric Review: International Journal of Pediatric Research
Available online at: www.medresearch.in 255|P a g e But, AKI diagnosed in target population was considered to have 'new-onset' only when it developed in-hospital (without pre-existing AKI or CKD), our actual study population-size contracted to include 103 subjects with more male than female (n=58 vs 45) and even there was no significant difference on fractional contribution -26.2%, 21.4%, 26.2% & 25.2% by four different age groups respectively (thus reducing age-bias in this study subjects especially with regard to renal and patient survival outcome).

Major Outcome Variables (with respect to chance of renal-recovery and patient-survival):
AKI Staging In Our Study Subjects: In all age groups, injury and failure was the most common pRIFLE stages at which patients were first time recognized as AKI. As most of worsening patients died at 'failure' stage, thus 'loss and ESRD' stages could not be observed except in single patient who survived with prolonged AKI >4wks and ultimately died of MODS.  Association between AKI staging and recovery was performed using Chi square test. No significant association was detected between these two parameters.
ii. Other multiple factors determining the final patient outcome: various factors could have affected the disease course and were related to high all-cause mortality (see table 6) - Renal Recovery (AKI Reversal) and its determinants in this study: Only 6 (5.8%) patients out of total 103 patients with new onset AKI completely improved with their serum creatinine improved to near baseline and were successfully discharged; while 7 (6.8%) patients were shifted to the ward from PICU with partial renal recovery. Majority of subjects (n=90, 87.4%) showed worsening renal function results over their hospital stay period.

Discussion
The overall annual incidence of new-onset AKI amongst 1042 critically-ill children admitted to PICU of Pt JNM Medical college, Raipur, CG during the study period was 9.8% (n=103). A similar observational study by Mehta P et al [1] reported overall incidence of newonset AKI in critically sick PICU subjects to be 36.1%, while it was only 9% in non-critically ill pediatric subjects. As observed by another study of Krishnamurthy S, et al [2], the incidence of AKI was 5.2% amongst all pediatric patients admitted to wards (including PICU), while it was as high as 25.1% among isolated PICU admissions.
Most number of cases of AKI developed in young infants in our study, but adolescents also contributed comparable number of cases amongst our subjects (around 25% from each age-group) and rather high agewise incidence among adolescents (16.2% versus 5.9%). Weljad Al Jbur, et al observed most significant risk factors of AKI in critically ill children were the younger age group 1 month to 1 year (42.2%) [3]. The clinico-etiological profile of study subjects by affected primary system, majority of cases were having CNS diseases (30.6%) followed by CVS (16%) and respiratory diseases (16.4%),while isolated renal system Pediatric Review: International Journal of Pediatric Research Available online at: www.medresearch.in 259|P a g e disease was least common (3%). Although system-wise, we obtained systemic infections (multisystem-sepsis) at fourth position, but actually overall infection with/ without culture proven septicemia contributed to most common cause of critical illness and AKI in PICU.
Maximum patients developing any stage of AKI were associated with three commonest risk-factors e.g. refractory shock (87.4% cases) followed by sepsis (68%) and MODS (65% cases). Poonam Mehta, et al [1], conducted a similar study and considered most common etiology of AKI to be acute tubular necrosis (ATN) which was associated with sepsis and shock as the chief predisposing conditions. Similarly, sepsis (45.35%) and MODS (40.6%) were the most significant risk factors of AKI in critically ill children in a study by Weljad Al Jbur, et al [3].
Maximum new-onset AKI developed within 3 days of hospital or PICU stay, as seen in 62% of our enrolled subjects. The staging of new-onset AKI by pRIFLE criteria [7] revealed that most common stage during case-detection were having 'injury'/stage-I (44.6%) and 'failure'/stage-F (42.7%) and least patient survived till or could be observed till developing stage 4 criteria of 'renal loss'.
In our study, 28% of all AKI cases had indications for hemodialysis or RRT, although none could receive dialysis therapy due to certain technical and resource constraints (especially lack of pediatric dialysis unit and inadequate provisions even for timely needed acute peritoneal dialysis). Similar to our study setting with RRT facility-limitations, a study by Touza Po P, et alalso concluded that RRT was required in large proportion (60.1%) of cases, although that could not be performed due to very low GCS and hemodynamic status of patients and poor resource [10]. In another study by Bagshaw S M, et al reasons given by them for not starting RRT (not mutually exclusive) were limitations of support, adequate urine output, and plan to observe. Mortality was higher in those not receiving RRT due to limitations [11].
In our study, overall patient-outcome analysis revealed high mortality after new-onset AKI in patients already critically sick at admission and it figured upto 92%.
Although most of deaths (87% mortality) were related to or associated with worsening renal function or nonrecovery AKI, around 5% patient had shown partial improvement to better AKI stage but died due to other co-morbid conditions related to their critical illness.
Among determinants of overall poor AKI-reversal and patient-survival outcome in our setting, major factors were sepsis (72.6%), refractory shock (94.7%), MODS (70.5%), and unavailability of adequate and timely renal replacement therapy. In a similar study by Yegenage T, et al (2010) [12], Sepsis was thecommon cause of acute renal failure in intensive care units (ICU) with mortality rates as high as 60%. Both fatal outcome and worsening AKI stage (or non-recovery from ARF) showed significant association with each of major outcome determinants -MODS (p<0.05) and refractory shock (p<0.05) respectively.

Pediatric Review: International Journal of Pediatric Research
Available online at: www.medresearch.in 260|P a g e Although there were maximum deaths with RIFLE stage 2 (Injury-47%) and stage3 (Failure-42%) accounting for >89% together, no statistically significant association was detected between different AKI staging (by pRIFLE criteria) and AKI recovery/ reversal (Pearson Chi-square, p value=0.117) same as between AKI stages and patient-survival outcome (p value= 0.067).
Further progression of AKI stages to 'Loss'-stage 4 or prolonged AKI (>4 weeks) was documented in numerically single (1%) patient of 103 critically ill study subjects, as most patients died in AKI stage 2 or 3. This would have nullified p-value significance of possible poor outcome trends with progressive AKI stages.

Conclusion
Significant proportion (approximately 10%) of critically ill patients admitted to PICU developed new-onset AKI. Pre-school and adolescent age-group are equally vulnerable to develop AKI during critical illness having any primary disease diagnosis at admission. Major comorbid risk factors for developing AKI and determinants of AKI-worsening (or poor recovery) as well as poor patient-survival outcome in this study were sepsis, refractory shock and MODS. Most patient with AKI stage 2 (injury) and stage 3 (failure) or stage 4 (loss) had high mortality.
What this study adds to existing knowledge: Timely detection of AKI in early stages using pRIFLE or RIFLE criteria amongst all critically ill pediatric patients may help to reduce disease worsening and fatal outcome with timely reno-protective interventions including dialysis/RRT (if needed) along with appropriate management of underlying and co-morbid fatal condition.
Contributions: BNR, SKR and SP conceptualized, designed and analyzed the study. SKR was directly involved in paper writing drafting and will be primary correspondent author. YKV conducted data-collection and helped in analysis and manuscript writing. DA helped in statistical analysis.
Funding: Nil, Conflict of interest: None initiated, Permission from IRB: Yes