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Review Article

An update and review of acute kidney injury in pediatrics


Rajit K. Basu, MD; Prasad Devarajan, MD; Hector Wong, MD; Derek S. Wheeler, MD
Objectives: To inform the pediatric intensivist of recent advancements in acute kidney injury diagnosis and management. Data Sources: Studies were identied from MEDLINE (OVID), PubMed, and the Cochrane Library for topics relevant to acute kidney injury. We also reviewed bibliographies of relevant studies. Data Extraction, Synthesis, and Outline Review: Because of the lack of prospective trials, a majority of information is extracted from observational and retrospective data. The pathophysiology section reviews acute kidney injury mechanisms and highlights data regarding distal injury from experimental acute kidney injury. The epidemiology section focuses on incidence and outcomes of acute kidney injury, highlighting new strategies for diagnosis. The management section cites studies investigating hemodynamic optimization, nutrition, and uid management, including the indications and impact of continuous renal replacement therapy in uid overload. Conclusions: There is limited data-driven evidence in pediatrics regarding effective therapy for acute kidney injury, a significant problem in the pediatric intensive care unit extending length of stay, ventilator days, and overall mortality. Sublethal kidney injury may be contributing to overall morbidity. We conclude that prospective clinical trials are needed to evaluate specic diagnostic aids, such as biomarkers, and therapeutic strategies, such as early initiation of continuous renal replacement therapy in children with uid overload. (Pediatr Crit Care Med 2011; 12: 339 347) KEY WORDS: acute kidney injury; children; intensive care; epidemiology; pathophysiology; management; renal replacement therapy

cute kidney injury (AKI) is increasingly recognized as a cause of increased morbidity in critically ill children and adults, and damage to the kidney, a central mediator of homeostasis in the body, affects patient survival (1 4). AKI is now known to be an independent risk factor for mortality, and research pursues optimization of diagnosis, management, and outcome (5). The list of putative causes of AKI in pediatrics is long (6) (Table 1); however, the true etiology is likely multifactorial, related to a combination of several factors, such as ischemia and reperfusion injury, disruption of renal vasomotor homeostasis, hypoxic and oxidative stress, and cytokine-driven effects. The kidney is central to numerous realtime homeostatic control mechanisms, including water balance, electrolyte han-

From the Divisions of Critical Care (RKB, HW, DSW) and Nephrology (PD), Department of Pediatrics, Cincinnati Childrens Hospital and Medical Center, University of Cincinnati, Cincinnati, OH. The authors have not disclosed any potential conicts of interest. For information regarding this article, E-mail: rajit.basu@cchmc.org Copyright 2011 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: 10.1097/PCC.0b013e3181fe2e0b

dling, erythropoiesis, vascular tone, acid base status, and regulation of normal glucose metabolism; however, AKI diagnosis is based on downstream readouts. The laboratory indicator, decreased glomerular ltration rate, factors in urine and plasma solute concentration and is the accepted reection of nephron function. Calculations of glomerular ltration rate (Table 2) rely on serum creatinine and are often unreliable because of variability within age groups, gender, metabolic state, body composition, and excretion by the kidney itself (79). Denitions of oliguria, the bedside indicator for AKI diagnosis, also are varied. Although clinicians have shown that sick kidneys affect morbidity independently and synergistically with multi-organ disease, study of the impact of kidney injury is limited by having to use these markers of failure. Also unfortunate is the mirrored variability between diagnosis and treatment, which is largely reactive and can differ from patient to patient (10, 11). AKI represents a serious burden to the pediatric patient population (12). We focus this narrative review on evidencebased AKI research, highlighting disturbing epidemiologic trends for pediatric AKI, novel detection strategies, the role of AKI as an independent causative agent of injury, and available evidence-based

data regarding management and outcomes. Much further research in basic science and in prospective trials is needed to improve outcome for pediatric patients with this signicant afiction.

METHODS
An electronic search was performed in January 2010 using the PubMed, Ovid, MEDLINE, and Cochrane databases for the following search terms: acute kidney injury, renal ischemia, pediatrics, RIFLE (risk, injury, failure, loss, end stage), Acute Kidney Injury Network, epidemiology, renal replacement therapy, and outcomes. Inclusion criteria were adult and pediatric articles from 2000 to 2010 in the English language. All retrospective pediatric AKI studies performed from 2000 to 2010 were included. Additionally, heavily cited articles within our search results were considered for inclusion.

Etiology of AKI
Traditional AKI causes are stratied into location of injury relative to the kidney. The diseases that t into pre-renal and intrinsic renal share the commonality that they alter the regional perfusion of, and subsequent oxygen delivery to, the kidney. Post-renal injury refers to antegrade urine ow disruption from the kidney. The pathophysiology of AKI in the intensive care unit, however, is much more complex and multifactorial.

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Table 1. Common classications and etiologies for pediatric acute kidney injury (6) Classication Prerenal Intrinsic renal Etiology Intravascular volume depletion Acute tubular necrosis (vasomotor nephropathy) Hypoxic-ischemic insults Sepsis/toxin-mediated: endogenous and exogenous Multiple organ dysfunction syndrome-driven Interstitial nephritis: drug-induced and idiopathic Tumor lysis syndrome (uric acid nephropathy) Glomerulonephritis Vascular thrombosis Cortical necrosis Hemolytic uremic syndrome Cortical dysplasia or hypoplasia Obstructive uropathy: ureteral or urethral obstruction Solitary kidney obstruction

Postrenal

Table 2. Formulas for calculation of glomerular ltration rate Eq Eq 1: Cockcroft-Gault ( 7) Eq 2: Modied diet in renal disease (9) Eq 3: Schwartz formula (for children) (8) Formula GFR [fr](140 age) weight(fd)0.8 SCr GFR 186.3 SCr 1.154 age 0.203 1.212 (if AfricanAmerican) 0.742 (if female) GFR (k height)/SCr Notes Denominator: (0.85 SCr in females); weight in kilograms

0.413

Eq, equation; GFR, glomerular ltration rate; SCr, serum creatinine.

Table 3. Extrinsic and intrinsic responses to altered renal perfusion (13) Response Extrinsic Juxtaglomerular apparatus stimulation Arteriolar smooth muscle vasoconstriction Mesangial cell retraction Sympathoadrenal activation Efferent arteriolar vasoconstriction Renin-angiotensin-aldosterone axis activation Angiotensin II activation Arteriolar vasoconstriction Aldosterone release Prostaglandin formation Phospholipase-A2 formation Renal venodilation Atrial natriuretic peptide stimulation Renal arterial vasodilation Intrinsic Renal myocyte stimulation Arteriolar vasodilation Tubular epithelial cell stimulation Angiotensin inhibition

Altered Renal Perfusion. The kidneys receive a high percentage (20% to 25%) of the cardiac output at any moment. Aberrations in the intricate regulatory mechanism in place to maintain renal perfusion pressure (Table 3) lead to injury such as acute tubular necrosis (13). Pediatric kidney transplant recipients of organs with increased ischemic times during harvest have increased rates of acute tubular necrosis (14), as do patients with long cross-

clamp times during cardiopulmonary bypass (CPB) (15, 16). Direct effects on renal blood ow in the microvasculature of the vasa recta occur in sickle cell disease, rhabdomyolysis, hemolytic uremic syndrome, and tumor lysis syndrome. Vasomotor Nephropathy. AKI occurs by stress-mediated glomerular endothelial release of vasoactive substances, proteases, reactive oxygen species, and nitric oxide. For example, the factor XII plasma contact system, coagulation cascades, and complement pathways are activated in renal endothelium during CPB (17, 18). Sepsis and AKI. Sepsis causes AKI in up to 50% of cases (19, 20). Although the precise mechanism remains unclear, a gamut of cytokines is implicated, as are circulating lymphocytes, T cells, and native kidney tubular epithelial and endothelial cells. Interestingly, septic AKI does not appear to be ischemiadependent, because it can occur in hyperdynamic renal blood ow (21). Aberrant Oxygen Homeostasis. A natural degradation in oxygen tension exists from the level of the renal artery to the counter-current mechanism in the vasa recta (Fig.), making the kidney highly susceptible to both hypoxic and oxidative injury during ischemiareperfusion (22). Experimental ischemia leads to renal dysoxia, a situation also seen in sepsis, in which renal cells are unable to utilize oxygen for energy, regardless of oxygen availability (23).

Nephrotoxins and AKI. Nephrotoxic medications in the intensive care unit contribute to nearly 25% of AKI cases (3, 4). Common offenders include aminoglycoside antibiotics, nonsteroidal anti-inammatory agents, radioopaque contrast, and immunosuppressives such as calcineurin inhibitors (24, 25). Associated Syndromes. AKI is seen in conjunction with pulmonary, hepatic, and cardiac failure (26, 27). The increased mortality reported with these dual-axis syndromes underscores the kidneys centrality to host survival. Although exact mechanisms are unknown, they all are almost certainly linked to aberrations in blood ow distribution and to endothelial activation (28 30). Isolated AKI. In complex cases, isolated renal injury is difcult, if not impossible, to identify and without concomitant uid overload or electrolyte mishandling it is not felt to be signicant. However, laboratory evidence shows that isolated AKI affects remote organ homeostasis and host morbidity. A wide set of regulatory genes and inammatory mediators are altered during isolated renal ischemia and can lead to increased pulmonary capillary permeability (31, 32), decreased active uid transport out of alveoli (33), and T-cell trafcking in rats (34). Left ventricular systolic performance is reduced (35) and blood brain barrier permeability increases after renal ischemia (36). In these experiments, distal changes were found before any overt signs of renal injury, highlighting a renal distress state during which a host may be primed to further injury. Further work aims to identify a phenotype to this distress state, its downstream ramications, and whether it is reversible.

Epidemiology of AKI in the Intensive Care Unit


Diagnosis. A review of nearly 30 studies conducted over 25 yrs showed that no two studies used the same criteria to dene AKI (37). To amend this variability, the Acute Dialysis Quality Initiative group standardized the denition of AKI in 2002 using the RIFLE criteria, a mnemonic for three levels of severity, risk, injury, and failure, and two outcomes, loss and end-stage kidney disease (38). Based on glomerular ltration rate, serum creatinine values, and urine output plotted against time of admission, RIFLE marks progressive degrees of injury in both intensive care unit and non-intensive care unit adult patients. In 2004, the Acute Kidney Injury Network devised strata that dened AKI based on time in relation to absolute creatinine increase, percentage increase, or documented oliguria, broadening the window for time of AKI diagnosis and creating an automatic failure designation for any patient administered renal replacement therapy (39). Although Acute Kidney Injury Network criteria have shown close approximations to RIFLE stratications of patients (40, 41), both schemes

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equate specic changes in serum creatinine to specic worsening of oliguria, an assumption yet to be prospectively proven. Incidence and Outcome. Within the new strata (Table 4), it is clear that the incidence of AKI is considerable in adults and children and outcomes can be severe. Increases in RIFLE and Acute Kidney Injury Network criteria correlate with increased morbidity. Adults. Before the validation of the new classication schemes, reported incidence in adults varied from 7% to 25% (42, 43). Hoste et al (44) now report that 18% to 63% of all adult hospitalized patients have some degree

of AKI, up to 67% for intensive care patients, which increases mortality in sepsis, trauma, burn, transplantation, and acute respiratory distress syndrome, is an independent risk factor for mortality (with odds ratios as high as 4.8), and independently increases hospital costs, length of stay, and ventilator days. The incidence of AKI after CPB in adults ranges from 30% to 50% and increases mortality to nearly 80% in some reports (45, 46). AKI also leads to end-stage renal disease in a signicant portion of adults (47). Pediatrics. The reported incidence of AKI in pediatric populations varies from 1% to

Figure 1. Degradation in oxygen tension through renal cortex and medulla (22). The cortex has an ample blood supply and is generally well-oxygenated. The medullary ray areas are devoid of glomeruli and are supplied by venous blood ascending from the medulla. The medulla has a low blood supply and is poorly oxygenated but is responsible for concentration of the urine. Medullary hypoxia results from the countercurrent exchange of oxygen within the vasa recta and from the consumption of oxygen by the medullary thick ascending limbs. Renal medullary hypoxia is an obligatory part of the process of urinary concentration. Reproduced with permission from Brezis and Rosen (22).

82% (Table 5), with a recent study nding an incidence of 339 of 3,396 ( 10%) patients admitted to the pediatric intensive care unit (48). Using a modication of the RIFLE criteria (pediatric RIFLE), approximately 50% of pediatric patients studied had some degree of kidney injury early in their hospital stay (mean time to pediatric RIFLE stratum, 3.3 3.1 days; 82% diagnosed within 7 days) (49). In a study of nearly 4,000 critically ill children, AKI increased mortality and lengthened intensive care stay four-fold (48). AKI increases mortality with multi-organ failure, marrow or solid organ transplantation, extracorporeal membrane oxygenation, or acute respiratory distress syndrome from 10% to 57.1% (12, 50 51). AKI has a high risk of death independent of Pediatric Risk of Mortality II scores in these patients (49). AKI affects between 2.7% and 28% of children after CPB and has a notable increased morbidity risk, including longer duration of ventilation and overall length of stay (52, 53). For these children, even a small creatinine increase of 25% is a high risk factor for AKI (54). Finally, at 3- to 5-yr follow-up, 40% to 50% of pediatric patients who had AKI show signs of chronic renal insufciency, indicating that sublethal injury permanently alters the renal bed (55). Biomarkers. RIFLE, pediatric RIFLE, and Acute Kidney Injury Network criteria have limited real-time/pre-injury utility because they rely on creatinine and urine output. Accordingly, the search is on for a real-time markers of AKI that would allow for rapid and reliable diagnosis, theoretically providing a therapeutic advantage to intensivists akin to troponins in myocardial infarction (56). Many candidate biomarkers of AKI have been identied (Table 6) (57, 58). Serum cystatin C levels show high correlation to established AKI and are used by some urologists as a marker of disease progression after kidney transplantation (59). Kidney injury molecule-1, interleukin-18, and liver fatty acid-binding protein have been shown to be associated with kidney ischemia (60, 61). Clinical studies indicate urine and serum neutrophil gelatinase-associated li-

Table 4. Current criteria used for diagnosis of acute kidney injury Scheme RIFLE (38) Stage R I F L E R I F L E 1 2 3 Creatinine Criteria 1 1.5 or 2 glomerular ltration rate 25% 1 2 or 2 glomerular ltration rate 50% 1 3 or serum creatinine 350 mol/L Persistent failure 4 wks Persistent failure 3 mos eCCl 2 25% eCCl 2 50% eCCl 2 75% or eCCl 35 mL/min/1.73m2 Persistent failure 4 wks Persistent failure 3 mos 1 0.3 mg/dL or 1 to 150%200% baseline 1 to 200%300% baseline 1 to 300% baseline or 4.0 mg/dL with an acute 1 of 0.5 mg/dL Urine Output Criteria 0.5 mL/kg/hr for 6 hrs 0.5 mL/kg/hr for 12 hrs 0.3 mL/kg/hr for 24 hrs or anuria for 12 hrs 0.5 mL/kg/hr for 8 hrs 0.5 mL/kg/hr for 16 hrs 0.3 mL/kg/hr for 24 hrs or anuria for 12 hrs 0.5 mL/kg/hr for 6 hrs 0.5 mL/kg/hr for 12 hrs 0.3 mL/kg/hr for 24 hrs or anuria for 12 hrs

Pediatric RIFLE (49)

AKIN (39)

RIFLE, risk, injury, failure, loss, end stage; AKIN, Acute Kidney Injury Network; eCCl, estimated creatinine clearance.

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Table 5. Incidence of pediatric acute kidney injury in the past 20 yrs Renal Replacement Therapy (%) 40 (1.4%) 25 (2.3%) 14 (5.1%)

Authors Giuffre et al (105) Kist-van Holthe tot Echten et al (106) Michael et al (83)

Year 1992 2001 2004

Population After CPB After CPB Stem cell

n 2782 1075 272

Mean Age (yrs)

AKI Criteria

Incidence (%) 44 (1.6%) 180 (17%) 26 (9.6%)

Mortality (%) 27 (61.4%)

Cr doubling 13 5 Diagnosis made by attending nephrologist (glomerular ltration rate) Cr 1.5 mg/dL Continuous renal replacement therapy requirement Cr doubling Cr doubling Serum blood urea nitrogen 20 mg/dL pRIFLE Cr doubling Cr doubling Continuous renal replacement therapy requirement Cr doubling pRIFLE Cr doubling pRIFLE pRIFLE RIFLE Cr 1.5 mg/dL

10 (38.5%)

Agras et al (107) Pltz et al (108)

2004 2005

Neonatal intensive care unit Septic shock

45 22 4.0

31% in preterm 7 (31.8%)

24.4% 4 (57.1%)

Skippen and Krahn (52) Mishra et al (109) Mathur et al (110)

2005 2005 2006

After CPB After CPB Neonatal intensive care unit Intubated PICU PICU After CPB PICU

101 71 200 2.1

11 (11%) 20 (28%) 52 (26%)

70.2%

Akcan-Arikan et al (49) Bailey et al (111) Dent et al (112) Kendirli et al (113)

2007 2007 2007 2007

150 985 120 332

6.4 6.0 4.9 9.6

6.4 5.7 0.7 7.4

123 (82%) 44 (4.5%) 45 (37%)

11 (8.9%) 7 (0.7%) 21 (6.3%)

18 (14.6%) 12 (27.3%) 14 (66.7%)

Bennett et al (62) Pltz et al (114) Nguyen et al (115) Palmieri et al (116) Zappitelli et al (54) Schneider et al (48) Askenazi et al (51)

2008 2008 2008 2009 2009 2010 2010

After CPB Intubated PICU After CPB Burn After CPB PICU Nonsurvivor neonates administered extracorporeal membrane oxygenation Nonsurvivor children administered extracorporeal membrane oxygenation

198 103 106 123 390 3396 2175

4.8 6.1 4.3

0.5 5.5 5.5

2.8 4.7 4.37.5 mos 030 days

99 (51%) 60 (58%) 32 (30.2%) 56 (45.5%) 140 (35.9%) 339 (10%)

6 (6%)

17 (17%) 5 (8.9%) 30%32% 19% vs 3.9% without acute kidney injury

Askenazi et al (51)

2010

1962

Cr

1.5 mg/dL

32.3% vs. 12% without acute kidney injury

AKI, acute kidney injury; CPB, cardiopulmonary bypass; PICU, pediatric intensive care unit; Cr , serum creatinine; RIFLE, risk, injury, failure, loss, end stage; pRIFLE, pediatric RIFLE staging criteria. Reported incidence of acute kidney injury in select pediatric studies.

pocalin as highly sensitive, specic, and predictive of AKI in many different disease processes (62, 63). A recent meta-analysis demonstrated high neutrophil gelatinase-associated lipocalin sensitivity in AKI for a value of serum neutrophil gelatinase-associated lipocalin 150 ng/mL (64). In pediatrics, neutrophil gelatinase-associated lipocalin has been studied after CPB, after nephrotoxin administration and contrast nephropathy, in sepsis, and in cardiorenal syndrome. Urine neutrophil gelatinase-associated li-

pocalin concentrations 50 g/mL predict AKI in children after CPB with high sensitivity and specicity (62). Diagnostic Adjuncts. Other real-time modalities are being tested for AKI diagnosis. Minute-to-minute variations in somatic nearinfrared spectroscopy numbers may be correlative with low perfusion states, including pediatric emergency department patients with hypovolemia (65, 66). Imaging modalities such as blood oxygen level-dependent magnetic resonance imaging have been used in adults to de-

termine changes in renal parenchymal oxygenation (67). Adult urine PO2 levels, assumed to mirror changes in renal oxygenation, have been correlated to AKI (68). AKI is clearly a major contributor to overall morbidity and mortality in hospitalized patients. Although stratication strata continue to advance as epidemiologic tools, biomarker research seeks to deliver intensivists real-time and sensitive tests of even subtle kidney injury, injury that may have more consequences than simply signaling the kidneys own death knell.

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Table 6. Quality biomarkers currently undergoing study for acute kidney injury (58) Etiology Cardiopulmonary bypass Intensive care unit Nephrotoxin Pediatric cardiopulmonary bypass Pediatric intensive care unit Hemolytic uremic syndrome Established Acute Kidney Injury Serum cystatin C Serum cystatin C Urine NGAL Early Detection Serum/urine NGAL, urine interleukin-18 Urine NGAL, serum cystatin C Urine NGAL, kidney injury molecule-1, L-FABP Urine NGAL Prediction of Severity

Serum cystatin C Urine NGAL, interleukin-18 Urine interleukin-18, cystatin C Urine NGAL

NGAL, neutrophil gelatinase-associated lipocalin. High-performing biomarkers for acute kidney injury based on performance in high-quality individual trials in which outcome measure was either sensitivity or specicity of the test ( 0.75), area under the receiver-operating characteristic curve ( 0.75), or likelihood ratio ( 2). Adapted with permission from Parikh et al (58).

Management
Development of management parameters in AKI is limited by the multifactorial etiology of the disease process and by the paucity of prospectively validated data. Thus, although universally based on limiting future injury, patient management is quite heterogeneous. Maintaining Renal Perfusion. To limit ischemic injury, attempts are made to modulate renal perfusion pressure and to optimize renal preload. The use of renal vasodilators to increase renal perfusion has not demonstrated improved outcomes. Adult studies of low-dose, or renal-dose, dopamine have failed to show benet and actually may even be harmful (69, 70). Low-dose dopamine in children has not been effective at improving outcomes either (6, 71). Fenoldopam, a selective dopamine agonist, increases renal blood ow and may reduce mortality and the need for renal replacement therapy (RRT) in adults (72) but has not signicantly improved AKI outcomes in children (73, 74). No consensus exists regarding the appropriate balance of uids, diuresis, and dialysis to use in AKI. In response to hypoperfusion, many patients may receive total uid doses to reach central venous pressure and mean arterial pressure targets that result in total body water overload (75, 76). Intravenous uids are medicines prescribed and administered like all other drugs, and warning signs of overdose should be heeded before every dose. A study of 3,000 adult patients revealed a link between positive uid balance and mortality in AKI (77). The Prospective Pediatric Continuous Renal Replacement Therapy Registry Group (Prospective Pediatric CRRT), studying a sample of 116 children, retrospectively found increased uid administration to be independently associated with mortality in children started on CRRT (78). Crystalloid or Colloid Infusions. In the adult population, studies have compared albumin to saline (SAFE study [79]) and hydroxyethyl starches to saline (SOAP study [80]) for resuscitation. Neither demonstrated clear benet in colloid over crystalloid infusions. There was no survival difference in 7,000

patients between recipients of albumin or saline (SAFE). Conicting correlations between AKI and the use of starches for resuscitation during sepsis have been reported. There have been no published studies relating type of uid used in pediatric resuscitation and AKI incidence or outcomes. Diuretics. Reducing uid overload with diuresis can limit the use of renal replacement therapy but has not been proven to improve outcomes of AKI. Adults. The use of diuretics in adults with AKI has been associated with an increased risk of death and has shown no benet in recovery of kidney function (81, 82). There is also no evidence of a mortality benet in using diuretics to convert oliguric AKI into nonoliguric AKI. Several trials involving recombinant atrial natriuretic peptide have shown conicting results. Pediatrics. Data regarding augmentation of urine output in pediatric AKI using diuretics are limited to bone marrow transplantation and after bypass (74, 83). The use of natriuretic peptides has been attempted in patients with AKI and cardiorenal syndrome (84). Brain natriuretic peptide (nesiritide), described in children with decompensated heart failure, increases diuresis but its effect on isolated AKI is not known (85). Continuous RRT. Other than emergent dialytic therapy for electrolyte disturbance or ingested toxins, controversies abound with regard to the proper timing of initiation, dose, route, and duration of continuous RRT (CRRT) in AKI. Prospective adult data based on blood urea nitrogen value cutoffs are heterogeneous for timing of initiation and outcome. The mortality for adults started on CRRT is nearly 60% in some studies (86 88). In pediatrics, the percent uid overload has been used as an initiating trigger and is calculated as uidfollows: uid overload [( uidIN 100. OUT)/admission weight] Retrospective study of 21 children receiving CRRT for AKI suggested that the degree of uid overload at time of CRRT initiation was signicantly lower in survivors than in nonsurvivors (16.4% vs. 34%) (89). In a larger study of 113 children with multiple organ dysfunction syn-

drome started on CRRT, median percent uid overload was signicantly lower in survivors compared to nonsurvivors (7.8% vs. 15.1%), independent of severity of illness (90). Even more recently, in 297 patients, percent uid overload was again signicantly lower in survivors vs. nonsurvivors (12.5% vs. 23.0%) (91). DiCarlo (92) initiated CRRT for ten children with acute respiratory distress syndrome after bone marrow transplantation regardless of presence of AKI in a prospective observational study, with an 80% survival rate. The mortality for children started on CRRT is 10% to 57.1% (Table 7). Although Prospective Pediatric CRRT data suggest that 10% to 15% uid overload is the signal for CRRT or peritoneal dialysis initiation, this has yet to be prospectively proven. Further, it has yet to be demonstrated that children administered CRRT for AKI have better outcomes than those without such therapy. RRT Dose and Modality. A large recent study with meticulous documentation of actual doses received demonstrated no improvement in kidney function or mortality outcome in adults receiving high-intensity CRRT (35 mL/kg/hr) vs. low-intensity CRRT (20 mL/kg/ hr) or intermittent hemodialysis (87). The few outcomes studies performed in pediatrics investigating the effects of RRT dosage and modality are retrospective. The Prospective Pediatric CRRT in 2007 demonstrated no difference in overall outcomes based on modality or dose of CRRT used (93). Although another study showed some improvement in outcome using convective CRRT modes for bone marrow transplantation patients, many centers only offer one mode of CRRT delivery, and thus study applicability is limited. Peritoneal Dialysis. Peritoneal dialysis can be efcacious in uid overload and offers advantages for younger children, including simplicity, less invasiveness, and improved hemodynamic tolerance (94). Peritoneal dialysis is generally safe and effective in children after CPB, with some investigators utilizing it as a prophylactic therapy as well (95). CRRT for Immunomodulation. CRRT has been used in septic adults with the intention of altering levels of circulating cytokines and inammatory mediators (96, 97). Modications of

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Table 7. Mortality in pediatric renal replacement therapy since 2000 Mean Age (yrs) 6.2 8.8 0.9 6.3

Authors Bunchman et al (117) Goldstein et al (89)

Year 2001 2001

n 226 21

Notable Etiologies CV shock 47 (20.8%) BMT 26 (11.5%) Sepsis 11 (52.3%) CV shock 4 (19%) CV shock 27 (42.9%) Sepsis 10 (15.9%) All patients had acute respiratory distress syndrome Orthotopic heart transplantation 18 (15.9%) BMT 16 (14.2%)

Mortality 104 (46%) 12 (57.1%)

Conclusions Pressor requirement is signicant 16.4% FO in survivors vs. 34% in nonsurvivors Peritoneal dialysis use can be effective Early initiation in BMT acute respiratory distress syndrome aids survival 7.8% FO in survivors vs. 15.5% in nonsurvivors

Flynn et al (118) DiCarlo et al (92)

2002 2003

63 10 10.7

31 (49%) 1 (10%)

Foland et al (90)

2004

113

9.6

44 (39%)

Gillespie et al (119) Goldstein et al (78)

2004 2005

77 116

5.1 8.5

5.7 6.8 Sepsis 47 (39.2%) CV shock 24 (20%) CV shock 22 (41.5%) Sepsis 8 (15.4%) 56 (48.3%)

10% FO has 3.02 mortality risk than 10% FO Greater uid overload and central venous pressure worsen outcome Prognosis depends on hemodynamics Ventilation and airway pressure worsen outcome 7.3% FO in survivors vs. 22.3% in nonsurvivors 12.5% FO in survivors vs. 23.0% in nonsurvivors Nonsurvivors (39.7%) received more continuous renal replacement therapy than survivors (16.0%)

Fernndez et al (120) Hui-Stickle et al (1) Flores et al (93) Hayes et al (121)

2005 2005 2008 2009

53 77 51 76 5.5 6.7 11.2 5.8

17 (32.1%) 31 (41.3%) 28 (55%) 34 (44.7%)

Only BMT patients (51/370) BMT 12 (15.8%) Sepsis 9 (11.8%) Sepsis 95 (32%) Oncologic 71 (23.9%) Neonates administered extracorporeal membrane oxygenation who died Children administered extracorporeal membrane oxygenation who died

Sutherland et al (91)

2010

297

8.5

7.0

128 (43.1%)

Askenazi et al (51)

2010

2175

030 days

863 (39.7%)

Askenazi et al (51)

2010

816

487 (58.9%)

Nonsurvivors (58.9%) received more continuous renal replacement therapy than survivors (30.8%)

CV, cardiogenic; BMT, bone marrow transplantation; FO, uid overload at time of initiation. Reported mortality in renal replacement therapy in select pediatric studies.

CRRT have not improved outcomes for such patients. To date, literature does not support the use of CRRT for sepsis without AKI. In summary, few prospectively validated data exist regarding the effect of CRRT on outcomes. Although some data suggest that early and aggressive CRRT initiation may be benecial in children with uid overload, the questions that need to be objectively addressed are the denitions of early and aggressive. We as practitioners must continually weigh the inherent risks associated with initiating RRT, including placement of large venous catheters and creating signicant hemodynamic and thermal shifts in children with unstable conditions, against the possible benets, which, to this point, have been only retrospectively demonstrated.

Oxidative and Inammatory Homeostasis. The kidney has derangements in oxygen homeostasis during AKI. Although prospective study of CPB patients demonstrated that anemia is independently associated with AKI, the risks of increased volume and blood viscosity must be balanced against the presumed benet of increased oxygen-carrying capacity. Studies of N-acetylcysteine and dexamethasone therapies to limit oxidative and inammatory damage in AKI after CPB showed conicting results (98 101). The use of nephrotoxins such as aminoglycoside antimicrobials, nonsteroidal anti-inammatory drugs, radiocontrast media, antifungal agents, and immunosuppressive drugs are associated with high rates of AKI and must be diligently constrained (102).

Nutritional Support. Nutrition in adult AKI is important and minding macronutrient and micronutrient requirements is vital to outcome (50). Optimizing nutrition in pediatric AKI patients can be challenging, and Bunchman (10) recommends using a metabolic cart to determine the amount of nutrition necessary. CRRT may reduce uid concerns when optimal nutrition, using renoprotective and anabolic formulas, is desired. Recent large, prospective, randomized, control trials suggest that tight glucose control increases overall mortality and also show no difference in the number of adult patients requiring RRT based on glycemic control strategy (103). A prospective pediatric study demonstrated morbidity improvements in children receiving intensive insulin therapy,

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but no effects on outcomes with AKI or dialysis were seen (104).

CONCLUSIONS
The management of AKI in pediatrics is complex and challenging. Our understanding and ability to detect renal distress and its possible autocrine and endocrine effects are in their infancy. Biomarkers may improve our management if early detection actually affects outcomes. To date, therapy of AKI revolves around optimizing renal perfusion pressure and oxygenation through a combination of judicious uid prescription, inotropy, and RRT while attending to proper nutrition and avoidance of additional nephrotoxins. However, pediatric intensivists have limited consensus or best-practice parameters to follow, as little prospective evidence is available. Kidney injury is likely incremental, more temporally proximal than uid overload and anuric failure, and likely causes more signicant distal harm than previously appreciated. The impact of AKI on critically ill children is signicant and demands prospective study if we are to nd effective therapies and improve outcomes.

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