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Table of Contents
SYMPOSIUM: CRITICAL POINT OF CARE BIOMARKERS IN EMERGENCY CARE
Year : 2014  |  Volume : 4  |  Issue : 3  |  Page : 238-246

Bedside biomarkers in pediatric cardio renal injuries in emergency


Department of Pediatrics, Division of Pediatric Nephrology, Postgraduate Institute of Medical Education and Research Associated Dr. Ram Manohar Lohia Hospital, New Delhi, India

Date of Web Publication23-Sep-2014

Correspondence Address:
Abhijeet Saha
Department of Pediatrics, Division of Pediatric Nephrology, Room no 406, PGIMER Building, PGIMER and Dr RML Hospital, New Delhi - 201 010
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2229-5151.141457

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   Abstract 

Point of care testing (POCT) using biomarkers in the emergency department reduces turnaround time for clinical decision making. An ideal biomarker should be accurate, reliable and easy to measure with a standard assay, non-invasive, sensitive and specific with defined cutoff values. Conventional biomarkers for renal injuries include rise in serum creatinine and fluid overload. Recently, neutrophil gelatinase associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), cystatin C, interleukin-18 (IL-18) and liver fatty acid binding protein (L-FABP) have been studied extensively for their role in acute kidney injury associated with various clinical entities. Biochemical markers of ischaemic cardiac damage commonly used are plasma creatine kinase and cardiac troponins (cTn). Clinically valuable cardiac markers for myocardial injury in research at present comprise BNP/NT-proBNP and to a lesser extent, CRP, which are independent predictors of adverse events including death and heart failure. Current status of point of care biomarkers for diagnosis and prognostication of renal and cardiac injuries in pediatric emergency care is appraised in this review.

Keywords: Biomarkers, cardiac, children, emergency, renal


How to cite this article:
Singhal N, Saha A. Bedside biomarkers in pediatric cardio renal injuries in emergency. Int J Crit Illn Inj Sci 2014;4:238-46

How to cite this URL:
Singhal N, Saha A. Bedside biomarkers in pediatric cardio renal injuries in emergency. Int J Crit Illn Inj Sci [serial online] 2014 [cited 2019 Oct 21];4:238-46. Available from: http://www.ijciis.org/text.asp?2014/4/3/238/141457


   Introduction Top


The term biomarker (acronym for biological marker) is used to define a characteristic that can be measured and evaluated as normal biological process, pathological process or pharmacological response to therapeutic intervention. [1] A good biomarker in medicine should act as an aid to improve the quality of care for patients with a specific disease. Thus, in accordance with the principles of Evidence-Based Laboratory Medicine, significant improvement in the diagnosis, prognosis and/or treatment of the disease with detection of a new marker has to be demonstrated before accepting it in clinical practice. [2] In addition, from the biological point of view, a good "biomarker" should be a protein that originates from the injured cells in a quantity proportional to the mRNA expression. The appearance of the biomarker should be temporally related to the inciting stimulus and its expression should rapidly decay when the acute phase of injury has terminated. [3]

Biomarkers can be used for point of care testing at the bedside to aid in early intervention. Newly available point-of care testing (POCT) presents an opportunity to add important clinical information to the emergency triage process to help identify patients who need immediate care. The core principle underlying point-of-care measurement has been described as reducing turnaround time without compromising the quality of information on which clinical decisions for patients are based. [4] An ideal biomarker should be accurate, reliable and easy to measure with a standard assay, non-invasive, reproducible, sensitive and specific with defined cutoff values. [5] Current status of point of care biomarker tests used for diagnosis and prognostication of renal and cardiac injuries in pediatric emergency care is appraised in this review.


   Renal Biomarkers in Pediatric Emergency Top


Frequently used "biomarkers" include: Height, a biomarker of growth (biologic process); proteinuria, a biomarker of disease severity in IgA nephropathy (disease progression); urine dipstick for nitrites in urinary tract infection (diagnostic); anti-glomerular basement membrane antibodies in patients with Goodpasture's syndrome (therapeutic response). Current biomarkers of AKI include rise in serum Creatinine (the main biomarker), urinary casts, or clinical markers of renal dysfunction (fluid overload/oliguria). [6]

A classification system has been proposed to standardize the definition of acute kidney injury in adults. A modified RIFLE criteria (pRIFLE) has been developed to characterize the pattern of acute kidney injury in critically ill children. Because pRIFLE focuses on glomerular filtration rate (GFR), a modification (Acute Kidney Injury Network; AKIN) categorizes severity by rise in creatinine in Stage I to III [Table 1]. [7],[8]
Table 1: Two recent definitions of acute kidney injury: Pediatric risk, injury, failure, loss, end-stage kidney disease criteria and the acute kidney injury network staging

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AKI remains associated with high morbidity and mortality, despite progress in medical care. [9] The acute injury to the kidney begins inducing molecular modifications that subsequently evolve into cellular damage. The cells start to produce biomarkers of injury and only subsequently does the clinical picture of the syndrome develop with the typical sign and symptoms.

Currently, AKI is typically diagnosed by measuring rise in serum creatinine. However, creatinine is an unreliable and insensitive indicator during early, acute changes in kidney function as its concentrations may not change until about 50% of kidney function has been lost and a steady state of injury has been reached, which may require several days. The use of serum creatinine thus cannot detect and quantify renal damage during the early, crucial stages of AKI when active interventions have the highest potential for improving outcome. This has prompted the search for urine and serum biomarkers that may significantly improve outcome and reduce mortality if they are able to indicate AKI hours after an insult, in comparison with the days it may take serum creatinine to rise substantially. These biomarkers will lead to earlier diagnosis, improved prognostication of outcome in terms of need for renal replacement and/or mortality. [10]

Several AKI biomarkers have been found, of which four have been tested and found promising in ongoing clinical trials; neutrophil gelatinase-associated lipocalin (NGAL), Kidney Injury Molecule -1 (KIM-1), Interleukin-18 (IL-18) and Liver Fatty Acid Binding Protein (L-FABP). [11] These biomarkers are increased in the urine within 12 hours of renal dysfunction.


   Ngal Top


Neutrophil gelatinase-associated lipocalin (NGAL), a 25 kDa protein produced by injured epithelia of the distal nephron, is one of the most promising new markers of renal epithelial injury. [12] It was initially identified by Allen and Venge in 1989 from human neutrophils and was seen to be expressed at very low concentrations in several human tissues, including kidney, trachea, lungs, stomach and colon. Low NGAL levels are thus detectable in the systemic circulation in healthy individuals. In the kidney, NGAL is filtered in the glomerulus and luminal NGAL is readily reabsorbed in proximal tubule by a megalin-dependent pathway allowing only low levels of NGAL to be detectable in the urine of normal individuals. [13]

Immediately following acute kidney injury, NGAL is massively up regulated in the distal part of the nephron leading to increased urinary and plasma NGAL levels due to both apical and basolateral secretion from nephron epithelia. Impaired proximal tubular reabsorption due to tubular injury may further potentiate increased NGAL levels in urine. [14],[15] NGAL is rapidly induced in kidney tubule cells within hours of ischaemic injury. Its early appearance in the urine and serum though independent of the glomerular filtration rate, is highly predictive of a fall in GFR, which might happen several days later.

A study in mice showed marked urinary NGAL increase within 2 hours of renal injury much before other conventional markers of AKI. [16] A recent prospective study for early identification of AKI after pediatric cardiac surgery showed that in children who subsequently developed a 50% or greater elevation in serum creatinine (which was detectable only 2-3 days after the surgery), serum NGAL concentrations increased by more than 20-fold within 2 h of cardiopulmonary bypass. [17] A similar study on children post cardiopulmonary bypass surgery (CPB) showed that in the non-AKI group, there was a small but statistically significant increase in plasma NGAL at 2 h after CPB, which normalized back to baseline levels at the 12 h and 24 h time points. In marked contrast, in patients who subsequently developed AKI there was a robust threefold increase in plasma NGAL at 2 h after CPB, which persisted at the 12 h and 24 h time. For plasma NGAL at 2 h after CPB, sensitivity and specificity were optimal at the 150 ng/ml cut-off, with an AUC of 0.96 in this study. [18] However, with the present evidence, these cut-off values cannot be accepted as the standard for all populations.

NGAL is also being evaluated as a follow up marker to differentiate between prerenal and intrinsic AKI to guide management. Urine and serum NGAL levels were significantly higher in intrinsic AKI patients than in prerenal AKI patients but SCr levels were not significantly different in the two groups in a recent study. [19]

In sepsis, NGAL is produced from the injured kidney and also from leucocytes and liver. Wheeler at al showed that serum NGAL was significantly increased within the first 24 h of admission to the Pediatric Intensive Care Unit (PICU) in critically ill children with septic shock compared to both healthy controls and critically ill children with Systemic Inflammatory Response Syndrome (SIRS). In addition, serum NGAL was found to be significantly increased within the first 24 h and remained high at day 3 following admission to the PICU in critically ill children who developed AKI compared to critically ill children that did not develop AKI. [20] In contrast, plasma NGAL (pNGAL) and urinary NGAL (uNGAL) levels were found to correlate poorly with urine microscopy in septic AKI compared to non-septic AKI by Bagshaw et al.[21] In a study by Di Nardo et al., uNGAL levels were found to be significantly increased in patients with septic AKI compared with septic patients without AKI, while sNGAL levels were not significantly different between septic patients with and without AKI pointing that uNGAL is a better marker than pNGAL in children with AKI with sepsis. [22] However, the utility of NGAL as a marker for AKI with concomitant sepsis needs further evaluation.

NGAL has also been studied as a marker of likely AKI in children with urinary tract infections. Petrovic et al., demonstrated that levels of uNGAL were significantly higher in subjects with longer duration of inflammation than in subjects with shorter duration of inflammation; thereby stating that uNGAL is sensitive to the state of infection. [23] In a multicenter, prospective study in Turkey, both uNGAL and uNGAL/Cr were found to be excellent indicators for predicting UTI in children, with high sensitivity, specificity and AUC value in the absence of AKI and chronic kidney disease. [24] NGAL reduces bacterial growth by preventing bacterial iron uptake and consuming the ambient iron. Expression of NGAL increases as part of the immune response to remove bacteria in the early stage of infection. [25]

Both serum and urinary NGAL levels are predictors of acute renal damage as described in various studies. Results from a study in children with chronic renal diseases indicate a significant correlation between serum and urinary NGAL levels. [26] Another large study with 632 participants supported these findings and found no significant difference between plasma and urine NGAL values. [27]

Evaluation of pNGAL and uNGAL in children with hypertension without any clinical evidence of nephropathy showed that there was a positive correlation between uNGAL and the index of mean SBP measured. There was a positive correlation between sNGAL and albumin creatinine ratio (ACR) thereby creating a hypothesis that combination of high serum levels of NGAL and high but normal ACR may eventually be a prognostic factor for the future development of microalbuminuria and chronic kidney disease in hypertensive children with normoalbuminuria [28] The utility of pNGAL and uNGAL in children with hypertensive emergencies and urgencies is an area which requires further research.

NGAL has also been extensively studied in critically ill neonates. Hoffman et al., showed that urinary levels of NGAL were elevated in critically ill neonates treated with hypothermia (HT) or Extracorporeal Membrane Oxygenation (ECMO) when compared to healthy newborns. In addition, the urinary levels of NGAL with cut-off values >1,005 ng/mg UCr in combination with FGF-2 improved the specificity for the identification of AKI but isolated NGAL levels did not identify patients with AKI. [29] Previous studies have also stated that NGAL may have utility as an early sensitive screening marker for newborns at high risk for renal injury. [30]

Plasma NGAL may also be altered in other conditions such as chronic kidney disease (CKD), chronic hypertension, systemic infections and inflammatory conditions. However, the increase in plasma NGAL in these situations is generally much less than in intrinsic AKI. Both uNGAL and pNGAL at present have limitations preventing their use as specific markers for AKI and further research is needed to identify various confounding variables.


   Kim 1 Top


KIM-1 is a type-1 transmembrane glycoprotein whose gene and protein are not expressed in the normal kidney. It is specifically upregulated in proximal tubule cells after ischemic or nephrotoxic AKI. [31] It has in its extracellular portion, a novel six-cysteine immunoglobulin-like domain i.e. ectodomain which is cleaved from the transmembrane domain during renal tubular injury and excreted in urine. This protein domain is stable at room temperature in urine allowing detection for use as a biomarker. KIM-1 has properties of a phosphatidylserine receptor that confers on epithelial cells the ability to recognize and phagocytose dead cells that are present in the post-ischemic kidney and are causing obstruction of the tubule lumen that characterizes AKI. [32]

KIM-1 mRNA was first detected 24-48 h after ischemic events in mice. Subsequent studies in adults suggested that KIM-1 can discriminate patients with different types of acute tubular necrosis (hospitalized patients, critically ill patients, patients with acute graft rejection) from those without AKI. [33] In hospitalized patients with established AKI, urinary KIM-1 levels predicted adverse clinical outcomes such as dialysis requirement and mortality. [34] One of the few pediatric studies showed that in children undergoing cardiopulmonary bypass who developed AKI 1-3 days post-surgery, urine KIM-1 concentrations were significantly increased 12 h post operatively. [35] KIM -1 has the potential of being an excellent marker of AKI in the pediatric emergency setting.


   Cystatin C Top


Cystatin C (CysC) is a small, non-glycosylated (13-kDa) endogenous protein produced in all nucleated human cells at a constant production rate which remains unaltered in the presence of inflammation. [36],[37] CysC is freely filtered through the glomerular membrane and is not secreted by the tubule, reabsorbed back into the serum or catabolized in the proximal tubule. Therefore its serum levels reflect the glomerular filtration rate.

CysC can accurately detect renal dysfunction 24 - 48 h before creatinine as its levels become abnormally high when GFR decreases to 88-95 ml/min per 1.73 m2. [38] Moreover, CysC plasma levels being independent of the muscle mass, are superior to Cr as a marker of renal function in patients with muscle loss. [39] In a recent study in Iran, CysC was found to have a significantly higher diagnostic accuracy than Cr for AKI with AUC (area under ROC curve) for serum Cr and CysC 0.55 and 0.93, respectively. [40] In this study, the cut-off value for CysC was determined to be 0.6 mg/l. Similarly, Villa et al., [41] and Delanaye et al., [42] also found a higher CysC sensitivity to detect creatinine clearance of less than 80 ml/min per 1.73 m 2 as compared to creatinine. However, the use of cystatin C as a marker of AKI is limited at present due to non-availability of well-established cut-off values.


   Interleukin -18 Top


IL-18 is an 18-kDa pro-inflammatory cytokine that is induced and cleaved in the proximal tubule and subsequently detected in the urine following ischemic AKI in animal models. [43] Urinary IL-18 levels have been found to be markedly elevated in patients with established AKI but not in subjects with urinary tract infection, chronic kidney disease, nephrotic syndrome, or prerenal azotemia. [44] Parikh et al., in early studies on IL-18 demonstrated that urinary IL-18 was significantly up regulated about 12 h prior to the increase in serum creatinine in patients with acute respiratory distress syndrome who develop AKI. [45] A subsequent pediatric study in children undergoing CPB who developed AKI, urinary IL-18 levels increased at around 6 hours and peaked at over 25-fold at 12 h post CPB. [46] Analysis of IL-18 as a biomarker of AKI in pediatric intensive care in general was done by Washburn et al., who found that peak urine IL-18 concentrations increased with worsening AKI severity in critically ill children (non-cardiac) but performed poorly as an early predictor of AKI. [47] IL-18 appears to be unaffected by chronic kidney disease or urinary tract infections but may be influenced by other common coexisting variables, such as endotoxemia and immunologic injury. Further, studies are however essential to characterize IL-18, an inflammatory marker as a biomarker for AKI and to assess its utility independent of the effect of systemic inflammation.


   Liver Type Fatty Acid Binding Protein (L-FABP) Top


L-FABP is a 14-kDa protein expressed by the proximal tubule cells, which binds, helps to transport and facilitates metabolism of urinary filtered free fatty acids. It appears to play a reno-protective role, potentially via anti-oxidant effects of binding fatty-acid oxidation products. [48],[49] Early studies in adults pointed towards the role of L-FABP as a promising early AKI biomarker of contrast-induced nephropathy. [50] Subsequently in a study of adult hospitalized patients, L-FABP discriminated between AKI/non-AKI with an AUC of 0.93, was found to be higher in patients with established AKI, compared to several non-AKI hospitalized groups and healthy controls and was associated with adverse hospital outcomes. [51] Portilla et al., studied urinary L-FABP in 40 children undergoing cardiopulmonary bypass surgery and found that L-FABP concentrations rose significantly at 4 and 12 h in both patients with and without AKI but this rise was significantly higher in children who subsequently developed AKI. [52] In patients with septic shock and AKI, urinary L-FABP measured at admission was significantly higher in the non-survivors than in the survivors, with an AUC for mortality prediction of 0.99. [53] L-FABP is also altered in the setting of CKD thus inciting further research to validate it as a biomarker to identify early renal damage in populations with varied renal reserve.


   Aki Biomarker Combinations Top


With the present evidence, it is appropriate to state that there is no single perfect AKI biomarker. A combination of biomarkers may be necessary to provide the best diagnostic and prognostic information in a context-specific manner. Recent studies have explored this possibility.

In a study examining biomarkers for the prediction of AKI following elective cardiac surgery, urinary NGAL concentrations measured at the time of admission to the ICU predicted the subsequent development of AKI with an AUC of 0.773 and outperformed other biomarkers including α1-microglobulin and cystatin C.[54] Serial measurements of multiple urinary biomarkers after pediatric cardiac surgery have revealed a sequential pattern for the appearance of AKI biomarkers, with NGAL and L-FABP being the earliest responders (with 2-4 hours after initiation of cardiopulmonary bypass) and KIM-1 and IL-18 representing the intermediate responders (increased 6-12 hours after surgery). [55]

Current multicenter studies of multiple biomarkers will help determine which combinations best predict AKI and its outcomes in a context dependent manner. Considering this is a rapidly evolving area of interest, ongoing functional genomic and proteomic analyses may also reveal additional biomarkers that further advance this field in the near future.


   Cardiac Biomarkers in Pediatric Emergency Top


Biochemical markers of ischaemic cardiac damage have been used in adults for over half a century. The earliest markers used were Aspartate Transaminase (AST), plasma creatine kinase (CK), lactate dehydrogenase (LDH) and then cardiac Troponin (cTn) in the late 1980s. In 2000, guidelines for the diagnosis of AMI (Acute myocardial injury) were changed with the new definition suggesting cTn as the preferred biomarker. [56] Because of the recommendations to use only cTn assays, there has been development of high-sensitivity troponin assays (hs-cTn) to increase the sensitivity for detection of myocardial injury. Other clinically valuable cardiac markers for use in patients with myocardial injury comprise Brain natriuretic peptide (BNP/NT-proBNP) and to a lesser extent, CRP, which are independent predictors of adverse events including death, heart failure and possibly recurrent ischaemia. [57]


   Cardiac Troponins Top


The troponin complex consists of troponins C, I and T. Of these, cardiac troponin T (cTnT) and I (cTnI) are normally only present in cardiac muscle. They are expressed throughout ventricular and atrial tissue. Detection of circulating serum levels of cTnI in the general population has been rare. Proposed mechanisms leading to cTn release in heart failure are cardiomyocyte damage caused by inflammatory cytokines or oxidative stress, subendocardial ischaemia and apoptosis. Neurohumoral activation may also play a role in cTn release. [58]

The measurement of cardiac troponin concentrations in the blood is a key element in the evaluation of patients with suspected acute coronary syndromes, according to current guidelines and contributes importantly to the ruling in or ruling out of acute myocardial infarction in adults.

Cardiac troponins have the advantages of higher specificity and sensitivity than does the muscle brain (MB) fraction of creatine kinase. In addition, troponins have a large diagnostic window, because rapid release of the cytosolic fraction is followed by prolonged myofibrillar degradation. [59] High sensitivity troponin assays allow for early detection of cTn release.

In children without preexisting heart disease, cut off level of cTnT required to exclude myocarditis was studied. Using a cutoff value of 0.01 ng/mL or greater as a positive test, cTnT had a sensitivity of 100%, with a negative predictive value of 100% and a specificity of 85%, with positive predictive value of 37%. [60]

Brown et al., evaluated children presenting to emergency with chest pain and found that troponin levels were increased (≥0.1ng/ml) in 17% subjects of which 48% cases were attributed to a primary cardiac diagnosis with the most common discharge diagnosis of myocarditis or pericarditis. [61] In a study evaluating myocardial dysfunction in pediatric septic shock, systolic and/or diastolic dysfunction was significantly associated with troponin I level (P = 0.007). [62]

In a pilot study on pediatric multisystem trauma patients admitted to the ICU, Sangha et al., demonstrated that 27% patients had elevated TnI levels, suggesting possible myocardial injury. Moreover, patients with elevated TnI were more severely injured than patients with normal TnI levels. [63] Evaluation of cardiac troponin I (cTnI) in children with congenital heart defects showed that cTnI release is more frequently associated with pressure than volume overload and it resolves after treatment in most children. [64] Which of the 2 troponins, cTnT or cTnI is a better marker of cardiac damage still remains an unanswered question warranting further research.cTn and hs-cTn assays have the potential to act as primary point of care biomarkers for assessment of congestive cardiac failure, myocarditis, myocardial dysfunction in pediatric septic shock and post traumatic myocardial injury in children.


   Brain Natriuretic Peptide Top


There are 3 major natriuretic peptides: Atrial natriuretic peptide (ANP) synthesized in the atria, brain natriuretic peptide (BNP) synthesized in the ventricles and C-type natriuretic peptide synthesized in the brain. Human BNP is synthesized as a 134-amino acid (aa) precursor protein (preproBNP) and subsequently processed during secretion to form a 108-aa peptide, proBNP. proBNP is processed to form the 76-aa N-terminal peptide (i.e. NT-proBNP) and then the biologically active 32-aa C-terminal peptide (i.e. BNP). [65] BNP and NT-proBNP have been studied as biomarkers for the diagnosis and prognostication of cardiac dysfunction. NT-BNP seems to be the most stable natriuretic peptide and its concentration is 10 times higher compared with BNP, which potentially makes it easier to devise a stix test for bedside testing in the future.

BNP is secreted from the cardiac ventricular myocytes in response to an increase in ventricular wall tension and is related to left ventricular filling pressures. It is stable in whole blood for 24 hours at 20°C and is not significantly influenced by exercise and position of the patient thereby making it a valid additional marker for ventricular dysfunction. BNP and NT-proBNP concentrations are age dependent in the first week of life. Recent data indicate that plasma BNP concentrations are very high during the first 4 days of life and then peptide values fall rapidly during the first week with a further slower progressive reduction throughout the first month of life. [66] After the first month of life, BNP concentrations remain steady, without any significant changes, from 31 days to 12 years of age. The high levels in the neonate are possibly due to physiological water loss that occurs in the first week of life and the cessation of peptide clearance by the placenta at birth. [67],[68] The normal adult range of NT-proBNP is 0-300ng/l and a value of ≥450 ng/l is suggestive of heart failure. At present, there is no defined normal range for children. Heart failure is likely when the level is >450 ng/l. [69] The results of the study by Lin et al., indicated that an NT-proBNP level >598 ng/l was predictive of a diagnosis of pediatric heart failure. [70]

Levels of BNP have been widely used to predict prognosis and outcome of treatment in adult patients with chronic congestive heart failure (CHF). However, its utility in the pediatric age group is still evolving. In a study in Germany, children with CHF showed significantly higher plasma NT-BNP levels than controls. A correlation was found between plasma NT-BNP levels and the severity of the clinical symptoms of heart failure and between plasma NT-BNP levels and the ejection fraction in patients with impaired ventricular function. [71] Tan et al., retrospectively analysed the relationship between BNP levels and outcome (no readmission; readmission within 60 days; death within 60 days) in 82 children with overt heart failure admitted to the intensive care unit. BNP plasma level >760 pg/ml were related with a higher risk of readmission or death. [72] In a recent study, an increased NT-proBNP level was present in 95% of the 80 children who were diagnosed with heart failure according to the modified Ross criteria and the NT-proBNP levels varied significantly among cases of mild, moderate and severe heart failure. [73] In a prospective study by Prince et al., BNP levels were significantly higher in patients with adverse outcome and BNP level >300 pg/ml was a strong hallmark of cardiac morbidity and mortality. [74] BNP has been shown to be able to discriminate between cardiac and pulmonary causes of respiratory distress. [75],[76] Koulouri et al. and Cohen et al., documented significantly higher BNP plasma levels in patients with CHF than in those with lung diseases. [77],[78]

Several studies have evaluated the role of BNP in children with congenital heart diseases (CHD). Koch et al., found a strong negative correlation between left ventricular systolic function and BNP plasma concentrations. [79] A recent study indicated that the diagnostic accuracy of BNP for CHD is lower in the first 3 days after birth, while after the second week, the accuracy increases significantly and progressively. [65] The pathophysiology of the cardiac defect also influences the levels of BNP. In general, various studies indicate that BNP concentrations are higher in neonates and children with CHD characterized by left ventricular volume overload (such as ventricular septal defects and patent ductus arteriosus) compared to those with right ventricular volume overload or pressure overload (such as tetralogy of Fallot, pulmonary valve and pulmonary artery stenosis). [80] Moreover children with complex CHDs show higher levels of BNP compared to those with simple cardiac defects. [81]

The role of BNP as a prognostic marker in children with CHD undergoing cardiac surgery has also been evaluated. Koch et al., reported that BNP increased significantly with a peak in the first 2 days after surgery, followed by a significant decrease in plasma BNP and then a second peak about 5 days after surgery. [82] Several studies reported that pre-operative (basal condition) BNP/NT-pro-BNP is an accurate marker of peri-operative outcome in these patients and values are correlated directly with time spent in the intensive care unit, the number of days of mechanical ventilation, the dose of catecholamines, the duration of cardiopulmonary bypass and cardiac troponin-T concentrations. [83] It is important to note that BNP and NTproBNP values are correlated with the degree of cardiac load, thereby making them helpful non-invasive, low-cost, simple tools for the follow up of patients with more complex congenital heart defects.

Few studies on patients receiving anthracycline therapy for pediatric malignancies have reported mean BNP levels significantly higher in patients with 'cardiac dysfunction' than in the 'normal' group thereby suggesting a possible role of BNP and NTpro-BNP as early markers of anthracycline-induced cardiac damage. [84],[85],[86],[87] Recent studies have suggested a pathological role of BNP in maintaining the patency of ductus arteriosus (PDA) after birth; therefore, BNP levels have been proposed as a screening tool for significant PDA in premature neonates, especially in cases in which Doppler echocardiography is not easily available. [88],[89]

The role of BNP has also been evaluated in pediatric cardiomyopathy. Kim et al., demonstrated that the serum NT-proBNP level at 3 months after diagnosis of dilated cardiomyopathy predicted an adverse outcome during a 6 m follow-up on treatment with a serum NT-proBNP level at 3 m >681 pg/ml being associated with a more adverse outcome. [89]

In the future, plasma BNP and NT-proBNP can be promising biomarkers for point of care assessment of acute CHF, overload states in CHDs, septic shock and anthracycline induced cardiac damage and to assess prognosis in pediatric CHF.


   C-Reactive Protein Top


CRP was originally discovered by Tillett and Francis in 1930 and since it reacted with the C polysaccharide of Pneumococcus, it received its name. It is a member of the pentraxin family involved with acute immune responses. [90] It enhances local expression of multiple cell surface adhesion molecules thus playing a role in inflammation. In adults, increased high sensitivity CRP (hs-CRP) concentrations have been found to be associated with endothelial dysfunction in patients with coronary artery disease. [91] Recently, there has been a surge of studies of adults showing a direct association between slightly increased baseline hs-CRP serum concentrations and the risk of developing cardiovascular disease. A study in Spain in 2008 showed that hs-CRP levels are significantly increased in obese children and adolescents with metabolic syndrome in comparison with the group without metabolic syndrome thereby, postulating that hs-CRP could be a useful tool for the early detection of cardiovascular risk factors among this population. [92]


   Galectin 3 Top


Galectin-3 is a protein involved in cell adhesion, cell activation, chemo-attraction, cell growth, cell differentiation, fibroblast activation and apoptosis. It has been proposed as a novel biomarker of heart failure. De Boer et al., found galectin-3 to be a significant predictor of the composite of mortality and hospitalization in a group of heart failure patients. [93] Furthermore, combined galectin-3 and BNP levels increased the prognostic value over either biomarker alone.


   ST-2 Top


ST-2 is a member of the interleukin-1 receptor family and is involved in the process of ventricular remodeling. ST-2 may be up-regulated in cardiac myocytes and fibroblasts subjected to mechanical stress. Previous studies in adults have demonstrated that ST-2 was an independent predictor of mortality in patients with acute CHF. [94] This creates a hypothesis for future research on the role of ST-2 in myocardial dysfunction in the pediatric population.

 
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