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Table of Contents
REVIEW ARTICLE
Year : 2017  |  Volume : 6  |  Issue : 1  |  Page : 6-11

Pediatric acute kidney injury: Appraisal of predictors and prognostic indicators


Pediatric Nephrology Firm, University of Teaching Hospital, Ituku-Ozalla, Enugu, Nigeria

Date of Web Publication15-Sep-2017

Correspondence Address:
Samuel Nkachukwu Uwaezuoke
Honorary Consultant Pediatrician, Pediatric Nephrology Firm, University of Nigeria Teaching Hospital, Ituku-Ozalla, Enugu
Nigeria
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Source of Support: None, Conflict of Interest: None


DOI: 10.12980/jad.6.2017JADWEB-2016-0069

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  Abstract 


Acute kidney injury (AKI) is a major contributor to childhood morbidity and mortality worldwide. In spite of the advances in renal replacement therapy, there has been a minimal reduction in AKI-related morbidity and mortality. Identifying the prognostic indicators and the risk factors that predict disease onset and progression, and instituting appropriate measures will lead to better survival outcomes. This narrative review seeks to appraise the predictors and prognostic indicators of pediatric AKI. Several biomarkers clearly stand out as predictors and prognostic indicators of the acute disease. Some of them are urine angiotensinogen, fibroblast growth factor-23, cystacin C, neutrophil gelatinase-associated lipocalin, tissue inhibitor of metalloproteinase-2 and insulin-like growth factor-binding protein 7. Combining few of these biomarkers with clinical prediction models has improved their predictive and prognostic utility for AKI. Hemodynamic parameters such as indexed systemic oxygen delivery and mean arterial blood pressure have been proved to be reliable in predicting the occurrence and progression of the disease and its outcomes. Miscellaneous predictors and prognostic indicators like AKI definition criteria, presence of co-morbidities, and health-related quality of life assessment have also been documented from evidence-based studies. An understanding and application of these indices will obviously help to reduce AKI mortality in children.

Keywords: Acute kidney injury, Children, Predictors, Prognostic indicators


How to cite this article:
Uwaezuoke SN. Pediatric acute kidney injury: Appraisal of predictors and prognostic indicators. J Acute Dis 2017;6:6-11

How to cite this URL:
Uwaezuoke SN. Pediatric acute kidney injury: Appraisal of predictors and prognostic indicators. J Acute Dis [serial online] 2017 [cited 2021 Apr 13];6:6-11. Available from: http://www.jadweb.org/text.asp?2017/6/1/6/214616




  1. Introduction Top


Acute kidney injury (AKI) in children can be community-acquired or hospital-acquired. In both forms, it is a major contributor to pediatric morbidity and mortality worldwide[1],[2]. AKI is not a single disease but rather a syndrome consisting of several clinical states. Its prognosis essentially depends on the fundamental disease, the severity and duration of renal deterioration, and the patient's premorbid renal status[1]. In spite of the advances in renal replacement therapy (RRT), there has been a minimal reduction in AKI-related morbidity and mortality. Identifying the prognostic indicators and the risk factors that predict disease onset and progression, and instituting appropriate measures will lead to better survival outcomes.

For instance, a group of investigators have identified a more elevated indexed systemic oxygen delivery (DO2I) and mean arterial blood pressure (MAP) as hemodynamic characteristics which are independently linked to a more reduced likelihood of stage I AKI progressing to stage III AKI[3]. A related study by other workers noted that fluid imbalance with excessive fluid administration in stage I AKI was a risk factor for progression to stage III of the acute disease[4]. Using the AKI Network (AKIN) classification, other authors reported that stages II and III AKI, severe acute pancreatitis and multiple organ failure were major prognostic indicators[5]. On the other hand, anemia was not identified as a predictor of AKI deterioration in patients hospitalized in an intensive care unit (ICU) despite the fact that it generally increases the risk of developing the disease[6]. In another retrospective study, employing the minimum value of pre-hospitalization serum creatinine as a reference parameter for renal function resulted in a better predictive ability for AKI mortality within a 60-day period[7]. Although these studies were conducted among adult patients[3],[4],[5],[6],[7], other researchers working on hospitalized Chinese children identified the stage of AKI, blood urea nitrogen at discharge and platelet count as independent prognostic factors for the acute disease[8]. Furthermore, urine biomarkers such as tissue inhibitor of metalloproteinase-2 (TIMP-2) and insulinlike growth factor-binding protein 7 (IGFBP-7) have been reported as reliable predictors of poor prognoses in neonatal and childhood AKI of diverse etiology[9]. In a study, the authors identified significant independent risk factors which could predict the worsening of pediatric AKI as the use of extracorporeal membrane oxygenation, mechanical ventilation or vasopressors, intrinsic renal diseases, sepsis, and age above 1 year[10].

Expectedly, the management of AKI should be guided by the knowledge of prognostic indicators and predictors of renal deterioration which will help to reduce AKI-related morbidity and mortality. This narrative review seeks to appraise these predictors and prognostic indicators of pediatric AKI.


  2. Literature search strategy Top


Using the keywords of acute kidney injury, children, predictors and prognostic indicators, the PubMed database was searched for relevant articles published in the previous 5 years or less. The search initially yielded 539 publications. However, a preponderance of original (research) articles and systematic reviews were retrieved, with emphasis on the literature related to pediatric AKI and the topic. Only few narrative review articles were included in the present review, and some were included through cross referencing.


  3. Biomarkers as predictors and prognostic indicators of AKI Top


The current general clinical severity scores such as Acute Physiology and Chronic Health Evaluation, Sequential Organ Failure Assessment and AKI-specific severity scores are not reliable predictors of renal recovery; hence there is paradigm shift to novel biomarkers which have increasingly been proved to be more reliable alternative tools. Evidence-based reports show that several serum and urinary biomarkers are now dependable diagnostic tools for AKI in children[11]. Interestingly, some of these biomarkers can also serve as both predictors and prognostic indicators of the acute disease[12],[13],[14].

In a pilot study in the United States[15], pre- and post-operative levels of fibroblast growth factor 23 were measured in 19 pediatric patients without chronic kidney disease (CKD) who had undergone cardiopulmonary bypass (CPB). Five of them developed AKI, while the remaining 14 who did not develop AKI were used as controls. The results showed that fibroblast growth factor 23 could function as a pre-operative prognostic indicator of the evolution of AKI post-cardiac surgery. The authors further suggested that identifying AKI-susceptible patients as a pro-active measure would help to accomplish a better management of the acute disease, as well as fluid homeostasis[15].

Elsewhere in Germany, some researchers have demonstrated the prognostic utility of two urine biomarkers in children aged 0–18 years in a prospective cohort study of 133 patients[9]. Their study findings indicated that as diagnostic biomarkers, urine TIMP-2 and IGFBP-7 could predict adverse sequelae in neonatal and pediatric AKI which was caused by heterogeneous factors. Notably, these biomarkers are triggers of G1 cell cycle arrest - a crucial process implicated in AKI. Other investigators have also corroborated the predictive value of the two biomarkers for early AKI following other major surgeries not related to the heart[16]. Apart from serving as a sensitive and specific biomarker for early prediction of AKI post-cardiac surgery in pediatric patients with congenital heart diseases[17], urine TIMP-2 and IGFBP-7 have also been proved to be a predictor of renal recovery after AKI[18], as well as unfavorable long-term outcomes in patients with the acute disease[19]. A recent review showed that these urine biomarkers have equally been validated for the detection of AKI well ahead of clinical features like azotemia and oliguria[20]. This observation is consistent with the report of a study which indicated their diagnostic utility in the detection of patients who were at increased risk of AKI on the first post-operative day following cardiac surgery[21].

Other biomarkers like cystacin C and neutrophil gelatinase- associated lipocalin (NGAL) have also been documented as both diagnostic and prognostic tools[12],[13]. For instance, as a prognostic tool, urine cystacin C/urine creatinine ratio was noted to be a predictor of mortality in hospitalized AKI patients[12]. Another report also indicated that serum cystatin C was a reliable predictor of AKI, pediatric risk, injury, failure, loss, and end-stage kidney disease (pRIFLE) classification and reduced estimated glomerular filtration rate after CPB[22]. In a recent systematic review, NGAL was found to be an effective predictor of sepsis-induced AKI, RRT and AKI-related mortality[23]. Other studies show that urine NGAL can predict renal outcome and mortality in patients with cirrhosis and associated bacterial infections[24], serve as a prognostic biomarker for AKI in hospitalized cirrhotic patients with AKI-prone conditions[13], and predict the severity of contrast-induced AKI in CKD patients undergoing coronary procedures[25]. Nevertheless, in a study which compared urine biomarkers, it was observed that urine IGFBP-7 was a more reliable predictor of renal outcome (renal recovery and AKI severity) than NGAL[26]. The former is a promising novel prognostic biomarker which still requires further evaluation.

In a pioneer study that demonstrated the usefulness of urine angiotensinogen as a prognostic biomarker of AKI after cardiac surgery, elevated urine angiotensinogen/creatinine ratio was found to be associated with unfavorable sequelae in patients with AKI[27]. The investigators specifically noted that the prognostic and predictive power of urine angiotensinogen/creatinine ratio was high in stage I AKI patients among whom it predicted progression to stage III AKI or mortality[27]. In addition, the combination of urine angiotensinogen and renin was able to predict progression to stage III AKI in patients with stage I AKI following cardiac surgery[28]. In a related study, the authors reported that incorporating some novel biomarkers, such as plasma NGAL, matrix metalloproteinase-8, and neutrophil elastase-2, into renal angina index improved their discriminative ability for severe AKI in critically ill pediatric patients[29]. Other researchers observed that combining biomarkers (such as urine NGAL and TIMP-2 and IGFBP-7) with clinical prediction models (such as kinetic estimated glomerular filtration rate) enhanced the differentiation and re-categorization of patients who will get better from AKI or become worse with significant unfavorable renal outcomes[30].

A recently published study which was conducted in the United States among children with AKI after CPB for congenital heart disease showed that some of the novel biomarkers (interleukin 18 and liver-type fatty acid-binding protein) may hold prospects for the prediction of long-term renal sequelae after the acute disease[31]. These urine biomarkers remarkably remain raised seven years after an episode of CPB-AKI and may thus constitute a more sensitive indicator of chronic kidney injury.

One systematic review has highlighted the usefulness of pre- AKI renal function and post-AKI renal function (determined by the traditional biomarker - serum creatinine) in predicting long-term mortality and renal outcome[32]. The authors advocated that future AKI studies should consider these parameters as additional factors which can potentially modify disease prognosis, even though the long-term prognosis of AKI varies depending on etiology and clinical scenario.


  4. Hemodynamic and acid-base parameters as predictors and prognostic indicators of AKI Top


The risk factors for AKI severity and renal deterioration can reliably predict disease outcomes. Attention is gradually being focused on the role of hemodynamic parameters such as MAP and renal oxygen delivery in risk stratification, disease progression and improvement of patient outcome[33]. However, while some researchers have noted that higher MAP and systemic oxygen delivery were renoprotective in early AKI and precluded disease progression[33], others have reported that high MAP did not reduce the risk of post-operative AKI during normothermic CPB, or change the duration of hospitalization and mortality rate[34]. In one study, critically ill patients with early AKI and DO2I > 450 mL/min/m2 within the first 12 h of diagnosing the early stage of the disease had a significantly lower susceptibility of progressing to late disease in comparison to patients with DO2I < 450 mL/min/m2[3].

Interestingly, the findings of another study showed that hyperthermic CPB was an independent predictor of AKI, as avoiding arterial outlet hyperthermia may help to reduce AKI risk[35]. Furthermore, few evidence-based studies indicated that the avoidance of hypotension in stage I AKI, by for instance maintaining MAP at less than 70–75 mmHg, may reduce the incidence of stage III AKI[36],[37]. Some investigators recorded haemodynamic characteristics (DO2I, cardiac index, central venous pressure, MAP), hemoglobin, oxygen saturation, fluid balance and urinary output on the day of diagnosing stage I AKI with subsequent daily documentations until progression to stage III AKI or return to baseline renal function, and observed that an elevated MAP by 5 mmHg between early AKI and late AKI was independently associated with a reduced mortality risk[38]. Conversely, an increase in cumulative fluid balance by > 1 L was noted to be independently associated with a high mortality risk, underscoring the need for therapeutic plan of action to focus on maintaining adequate MAP and avoiding fluid imbalance in order to reduce mortality in critically ill patients with early AKI[38].

Other studies showed that cumulative fluid balance not only influenced AKI outcomes[39],[40], but was also associated with increased likelihood of AKI deterioration over 12–72 h after onset of the acute disease[4]. Specifically, fluid overload is recognized as a key prognostic determinant in patients with AKI; one study suggested that a greater degree of fluid overload predicts a lower possibility of renal recovery that is characterized by non- dependence on RRT[40]. In clinically unstable patients with stage I AKI, a positive fluid imbalance induced by excessive fluid administration is associated with an increased risk of AKI progression and mortality[41]. Furthermore, urine output was noted to be a sensitive and early marker for AKI, and was associated with adverse outcomes in ICU patients as AKI diagnosis occurred earlier in oliguric than in non-oliguric patients[42]. For instance, oliguria of more than 12 h and oliguria of 3 or more episodes predicted a high mortality rate.

In another recent study, some investigators reported that metabolic acidosis (evidenced by low bicarbonate of less than 22 mmol/L) was a potential predictor of mortality in AKI cases which were generated by electronic alerts[43]. In addition, the patients who were reviewed a day or more after AKI alert by the Critical Care and Outreach Team, when compared with their counterparts reviewed within 24 h of the alert, were observed to have a 2.4 times rise in mortality and seven times more probability to require acute dialysis[43].

Given the documented role of hemodynamic parameters in predicting the occurrence of AKI and its outcome, it is not surprising that the use of mechanical ventilation and vasopressors was part of the independent risk factors for disease progression, as reported in the previously mentioned study[10].


  5. Other miscellaneous predictors and prognostic indicators of AKI Top


A recent review has revealed the usefulness of several health- related quality of life (HRQOL) tools in the assessment and management of children with CKD[44]. As a clinical measure, HRQOL assessment aims to improve quality of life outcomes in pediatric patients with CKD. Similarly, this tool has been applied to children with AKI for prognostication. HRQOL measured by Health Utilities Index Mark 3 was an independent predictor of death among survivors of AKI after modifying for clinical risk parameters[45]. Poor ambulation and other HRQOL variables were also linked with increased risk of mortality. Thus, HRQOL may arm clinicians with additional data to help identify patients at high risk of mortality following AKI that required RRT.

Several co-morbid states have also been identified as predictors of recurrent AKI. Apart from a more prolonged AKI duration, some authors have reported these predictors as congestive cardiac failure (primary diagnosis), fulminant hepatic failure, malignancy with or without chemotherapy, acute coronary syndrome, or volume depletion[46].

In one prospective study which aimed to investigate the relationship between the occurrence of AKI according to pRIFLE criteria and unfavorable outcomes in children after cardiac surgery in a tertiary health facility in Brazil, the investigators followed up the subjects during their admission in the pediatric ICU (PICU) or up to the time of mortality. The exposure variable was occurrence of AKI according to pRIFLE criteria which grouped AKI into three categories: R (risk), I (injury), and F (failure). The evaluated outcomes were mortality, duration of mechanical ventilation, and duration of PICU admission. The occurrence of AKI according to pRIFLE criteria was linked to unfavorable outcomes after cardiac surgery[47]. Other workers who assessed the applicability of pRIFLE as a prognostic tool in the ICU reported that the incidence of AKI was not only significant but positively correlated with mortality and the duration of admission in the ICU and outside the intensive care setting[48].

The pRIFLE classification therefore facilitated the definition of AKI, making it a notable predictor of disease prognosis[48]. Nevertheless, the predictive value of RIFLE urine output criteria for the evolution of contrast-induced AKI predicated upon creatinine levels was low, thus limiting its utilization for measuring the effects of treatment interventions on the onset and progression of AKI[49].

One observational study in a children's hospital has indicated that when pRIFLE was used with other definition criteria such as AKIN and Kidney Disease: Improving Global Outcomes, AKI was associated with higher mortality and longer duration of stay within and outside the ICU[50]. The three definition criteria however resulted in disparities in the incidence and staging of the acute disease. The findings of other similar studies appear to be in line with this observation. For instance, the pRIFLE was the most sensitive classification in detecting AKI, especially in infancy, as well as in the early identification of the acute disease in low-risk patients. The AKIN definition was more specific and detected mostly high-risk patients across all age groups. The performance of Kidney Disease: Improving Global Outcomes classification stayed between pRIFLE and AKIN. All the three classifications showed AKI deterioration which was related to mortality[51]. The AKIN classification however correlated better with mortality than the RIFLE criteria did[52].

In a retrospective study conducted in a PICU, stage I AKI when evaluated with pRIFLE criteria could predict prolonged ICU admission, need for prolonged mechanical ventilation, as well as mortality[53]. Another study which evaluated the performance of pRIFLE score for AKI diagnosis and prognosis among infants with congenital heart diseases after cardiac surgery, revealed that the method was seamlessly applied to these patients. The pRIFLE classification showed that AKI incidence was not only high but was also associated with poorer outcomes[54].


  6. Conclusions Top


The role of biomarkers as predictors and prognostic indicators of AKI is now well established despite the differences in sensitivity and specificity. While their employment as novel diagnostics is presently the norm; there is need for more discovery of prognostic biomarkers which can predict disease severity early enough. Combining some of the biomarkers with clinical prediction models has improved their predictive and prognostic utility for AKI. Hemodynamic parameters have equally been proved to be reliable in predicting the occurrence and progression of the acute disease and its outcomes. Miscellaneous predictors and prognostic indicators such as AKI definition criteria, presence of co-morbidities, and HRQOL assessment have also been documented from evidence-based studies. An understanding and application of these indices will obviously help to reduce AKI mortality in children.

Conflict of interest statement

The author reports no conflict of interest.



 
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Abstract
1. Introduction
2. Literature se...
3. Biomarkers as...
4. Hemodynamic a...
5. Other miscell...
6. Conclusions
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