SYMPOSIUM: NEPHROLOGY

Acute kidney injury

Wesley Hayes Martin Christian

Abstract
The denition and classication of acute kidney injury (AKI) in children has become clearer over the last decade. The paediatric RIFLE criteria stratify AKI in children into ve groups (R risk, I injury, F failure, L loss of kidney function, E end stage renal disease) enabling earlier recognition and intervention. This article reviews the denition, classication, causes and management of AKI as relevant to the general paediatrician. Common causes of AKI in neonates and children are reviewed including E. Coli associated haemolytic uraemic syndrome, hypoxic ischaemic insults and medication related kidney injury. Initial management of acute kidney injury and its complications is outlined in the context of the role of the general paediatrician and factors which should prompt discussion with a tertiary paediatric nephrologist. The outcome and complications of kidney injury are discussed and future directions in the eld considered.

Keywords acute kidney injury; acute renal failure; acute tubular necrosis (ATN); dialysis; haemolytic uraemic syndrome (HUS); renal replacement therapy

There is no standardized denition of AKI in adult or paediatric patients; rather, diagnosis currently relies on changes in serum creatinine concentration as a surrogate marker of glomerular ltration rate (GFR). This is increasingly recognized to be an insensitive and delayed measure of reduced kidney function following AKI. In due course, novel early biomarkers of AKI may allow for detection prior to changes in serum creatinine. A multidimensional classication system which grades AKI severity in children, the paediatric modied RIFLE criteria, has been shown to be a useful independent predictor of the need for intensive care, length of hospital stay and death. The system straties AKI in children into ve groups (R risk, I injury, F failure, L loss of kidney function, E end stage renal disease) as shown in Table 1. It is particularly useful in children admitted to PICU. The distinction between oligo-anuric AKI and injury in which normal urine output is maintained can be useful as studies have demonstrated substantially greater morbidity and mortality with oligo-anuric renal injury. Children with AKI due to hypoxic/ ischaemic insults, haemolytic uraemic syndrome and glomerulonephritis are more likely to demonstrate oliguria whereas normal urine output is usually maintained in AKI caused by nephrotoxic insults.

Causes of AKI
The major causes of AKI in children are listed in Table 2. These can be thought of anatomically as pre-renal (hypoperfusion), intrinsic renal and post-renal (urinary outow obstruction). We will briey consider each of these three categories in turn. Pre-renal AKI When kidney perfusion is compromised due to hypovolaemia or reduced cardiac output, compensatory mechanisms act to preserve glomerular perfusion. These include catecholamine secretion, activation of the renineangiotensinealdosterone axis and local generation of prostaglandins. In pre-renal AKI these compensatory mechanisms are overwhelmed with resultant impairment in glomerular perfusion and ltration and thus reduced kidney function. Whilst this impairment is initially reversible with resolution of adequate renal perfusion, sustained

Introduction
The term acute kidney injury (AKI) is now used in place of acute renal failure. This is more than a simple change in terminology. The traditional concept of acute renal failure was unhelpful for a number of reasons: its diagnosis was imprecise and it was frequently used to describe an anuric, dialysis dependent state. By the time such a state is recognized, benecial interventions are signicantly delayed which is known to increase mortality in critically ill children on PICU. Over the last decade much progress has been made in early recognition of kidney injury and intervention prior to the development of oliguria. The concept of AKI has been key to these developments. This article gives a brief overview of AKI in children with consideration of some common causes of AKI, its recognition, management and long-term outcome.

Paediatric RIFLE criteria

eGFRa Risk Injury Failure Loss Decrease by 25% Decrease by 50% Decrease by 75% or <35 ml/min/1.73m2 Persistent failure >4 weeks Persistent failure >3 months Urine output <0.5 ml/kg/h for 8 h <0.5 ml/kg/h for 16 h <0.3 ml/kg/h for 24 h or anuric for 12 h

Denition and classication of AKI

AKI is intrinsic renal cell injury which can result in a wide spectrum of clinical manifestations ranging from an asymptomatic mild elevation in serum creatinine through to anuric renal failure.

Wesley Hayes MEng MBBChir MRCPCH is a Paediatric Nephrology Registrar at the Nottingham Childrens Hospital, QMC Campus, Derby Road, Nottingham, UK. Conict of interest: none. Martin Christian MD FRCPCH is Consultant Paediatric Nephrologist at the Nottingham Childrens Hospital, QMC Campus, Derby Road, Nottingham, UK. Conict of interest: none.

End stage
a

Estimated GFR calculated using the HaycockeSchwartz formula: eGFR (ml/ min/1.73m2) [40 height (cm)]/[serum creatinine (mmol/l)].

Table 1

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SYMPOSIUM: NEPHROLOGY

The major causes of AKI in children

Pre-renal
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Hypovolaemia  Haemorrhage  Severe dehydration e GI losses e Salt wasting e Diabetes insipidus  Third space losses e Burns e Sepsis e Nephrotic syndrome

myoglobin). The sudden loss of glomerular ltration, by a number of mechanisms including hypoperfusion, tubular obstruction from casts and debris, tubular back leak and activation of glomerular bypass, is a successful adaptive response as on-going glomerular ltration would result in massive loss of water and electrolytes. Once established, patients may remain anuric for 1e2 weeks or even longer. The recovery phase is due to regeneration of tubular epithelial cells. Recovery is often associated with polyuria during which salt and water losses can be excessive. The extent of recovery of renal function depends on the nature and extent of tubular injury; in most cases a return of normal renal function is seen. Haemolytic uraemic syndrome (HUS): HUS is a triad of microangiopathic haemolytic anaemia, thrombocytopenia and AKI. 90% of childhood HUS is caused by verocytotoxin (shiga-like toxin)-producing bacteria, commonly E. Coli O157:H7. Less commonly, infection with Streptococcus pneumoniae can induce HUS through exposure of T-antigen on the surface of red blood cells by the action of neuraminidase, a bacterial enzyme. Rarely, HUS is related to atypical causes such as complement pathway dysregulation. The underlying pathological process in HUS is endothelial cell inammation, swelling and detachment with resultant activation of the coagulation cascade and platelet activation and consumption. Glomerular endothelium is particularly susceptible to this inammatory process resulting in a thrombotic microangiopathy within the kidney with a clinical picture of AKI. The peak age of presentation of verocytotoxic E. Coli (VTEC) HUS is 1e5 years. HUS usually develops around the fourth day of bloody diarrhoea but ranges from 1 to 10 days after onset of diarrhoea. AKI often manifests abruptly with oliguria or anuria and hypertension related to uid overload but there may be co-existent ATN from severe diarrhoea and a careful uid balance assessment of these children is essential. Children appear pale from haemolytic anaemia which can be rapid and severe. In addition to AKI other systems may be affected by the endothelial inammatory process and some cases of HUS are associated with myocarditis, cerebral involvement (seizures, reduced consciousness) and pancreatic involvement (acute onset diabetes mellitus). Diagnosis is conrmed with bloods showing haemolytic anaemia (schistocytes on blood lm) with thrombocytopenia and elevation in serum creatinine. Elevated white cell count may be present and is a marker of disease severity. Conrmation of VTEC by serology or stool culture is necessary to exclude atypical forms of HUS which are rare and require specialist management. Management of HUS should always be discussed with a paediatric nephrologist as AKI often requires renal replacement therapy. Early uid resuscitation with normal saline is benecial in dehydrated patients. Antibiotics, NSAIDs, anti-motility agents and opiate analgesia should be avoided as they have been shown to worsen outcome. Close monitoring of serum electrolytes and uid balance is essential. Rapid reduction in serum sodium concentration can result in seizures. Caution is needed with blood transfusion due to signicant risk of hyperkalaemia and uid overload. For further advice on the management of bloody diarrhoea refer to the document The management of acute bloody diarrhoea potentially caused by vero cytotoxin producing Escherichia Coli in

Other factors which impair renal perfusion  Reduced cardiac output (impaired ventricular function)  Vasodilatation (warm shock) Hypoxic/ischaemic  Prolonged pre-renal injury of any cause  Severe hypoxic insult e.g. HIE in neonates Toxins  Medication (aminoglycosides, NSAIDs, acyclovir, amphotericin)  Exogenous toxins (ethylene glycol, methanol)  Endogenous toxins (rhabdomyolysis e myoglobinuria)  Tumour lysis syndrome (precipitation of uric acid crystals) Vascular insults  Renal vein/artery thrombosis  Cortical necrosis  Haemolytic uraemic syndrome Rapidly progressive glomerulonephritis Congenital anomalies of the kidney and urinary tract Acquired urethral obstruction  Stricture  Phimosis

Intrinsic renal

Post renal

Table 2

pre-renal insults will result in intrinsic renal injury in the form of acute tubular necrosis (ATN) which is discussed below. Pre-renal injury can therefore progress to intrinsic renal injury if the underlying cause is not promptly recognized and corrected. Intrinsic renal injury Intrinsic renal injury represents the majority of AKI in children. Underlying causes are diverse and include hypoxic ischaemic insults leading to ATN, medication related toxicity and primary disorders such as haemolytic uraemic syndrome. Acute tubular necrosis (ATN): ATN is a common cause of AKI. ATN is renal tubular cell injury or death resulting from hypoxia/ ischaemia or nephrotoxins (drugs or endogenous toxins such as

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children. A guide for primary care, secondary care and public health practitioners available at www.hpa.org.uk/webc/HPAwebFile/ HPAweb_C/1309968515827. For those children who require dialysis, the average time to recovery of renal function is 1e2 weeks and this has practical consequences for families who may live at some distance from their regional paediatric renal unit. The majority of children with VTEC related HUS recover normal renal function in the short term, however in a signicant minority there can be a late development of hypertension, proteinuria and chronic kidney disease therefore all patients need long-term follow up throughout childhood. It is usual practice to measure glomerular ltration rate (GFR) formally at least once during follow-up. In those adolescents with normal GFRs and absence of proteinuria or hypertension, it is our practice to discharge back to primary care with a caveat to continue annual blood pressure monitoring and urinalysis. Post renal AKI AKI secondary to post-renal urinary obstruction is rare in children but occurs more commonly in infants as a result of urethral obstruction (most commonly from posterior urethral valves) or bladder leak, bilateral ureteric obstruction (e.g. from a developmental anomaly of the urinary tract or mass) or unilateral ureteric obstruction in a single kidney.

All infants who have renal vein thrombosis should undergo follow-up investigations for pro-thrombotic tendencies. Neonates are at risk of AKI from toxic damage to renal tubules caused by medication, commonly aminoglycoside antibiotics and aciclovir. Aminoglycoside induced AKI is related to the dose and duration of therapy and the level of renal function prior to starting the medication. Serum creatinine may continue to rise after discontinuation of the antibiotic due to ongoing tubular injury from high parenchymal levels. Medication related AKI is reversible in most cases following discontinuation of the causal agent. AKI in the neonatal period is associated with a signicant risk of mortality with a rate of 42.6% reported in a study of 472 patients in 2010. Risk factors for mortality included ventilation, hypervolaemia, congenital heart disease and metabolic acidosis. The risk of long-term renal impairment in neonates with AKI has not been reported.

AKI in the context of multiorgan dysfunction syndrome

AKI can occur as part of multiorgan dysfunction syndrome (MODS) which is often related to sepsis in children. The development of AKI in this context is associated with increased mortality risk and early initiation of renal replacement therapy is thought to be benecial. The mechanisms underlying AKI in MODS are compromised renal perfusion due to systemic hypotension and dysregulation of intrinsic renovascular feedback mechanisms, inammation related to systemic inammatory response syndrome and toxic injury from endotoxins and other peptides. Early recognition of AKI and prompt initiation of renal supportive therapy (when necessary) improve outcome of patients with MODS. Indications for renal supportive therapy include hyperkalaemia, uid overload, refractory acidosis and severe uraemia. Choice of therapy depends on the expertise of the team caring for the child but continuous haemoltration associated therapies are now frequently used in preference to acute peritoneal dialysis.

AKI in neonates
Assessment of AKI in the neonatal period is more challenging than in children due to the difculty in dening a serum creatinine level which represents normal kidney function. Nephron development continues until 34 weeks gestation and kidney function matures during infancy as part of normal physiological development. Assessment and management of AKI in neonates is important despite the above challenges as they are at risk from a number of potential insults, including perinatal hypoxic ischaemic insults, sepsis, vascular insults such as renal vein or artery thrombosis related to umbilical catheters, cortical necrosis and medication related toxicity from aminoglycoside antibiotics. Hypoxic ischaemic insults can result in AKI in neonates. This is usually reversible ATN however in prolonged severe insults cortical necrosis ensues. In addition to elevations in creatinine and urea, thrombocytopenia may be present due to microvascular injury. Renal ultrasound is initially normal but may show renal atrophy in due course. Babies with cortical necrosis need follow up as chronic renal damage can ensue. Renal artery thrombosis is strongly associated with the presence of an umbilical artery catheter and patent ductus arteriosus. Risk factors for renal vein thrombosis include dehydration, hypoxic insults, polycythaemia and cyanotic heart disease. Both renal arterial and venous thromboses can present with gross or microscopic haematuria, thrombocytopenia, oliguria and hypertension. Ultrasound conrms a lack of renal perfusion in arterial thrombosis and reversed end diastolic ow in venous thrombosis. Specic therapy includes treating the underlying risk factor and preventing extension of the clot. In unilateral renal vein thrombosis with extension into the IVC anticoagulation with low molecular weight heparin for 3 months is recommended. In bilateral renal vein thromboses, thrombolysis with tissue plasminogen activator followed by anticoagulation is recommended.

Management of AKI
The immediate risks common to all children with AKI are life threatening hyperkalaemia or other metabolic derangement (e.g. acidosis, hyponatraemia, hypocalcaemia), uid overload and hypertension. Careful monitoring of uid status and serum biochemistry are essential to determine if and when renal replacement therapy will be required. As children with AKI present to local paediatric centres, it is essential that the general paediatrician is condent to make a suitable clinical assessment and knows when to ask for help from his or her regional paediatric nephrologist. The importance of the working partnership between local paediatric centres and tertiary paediatric nephrology services is emphasized in the recent RCPCH document Improving the standard of care of children with kidney disease through paediatric nephrology networks. Role of the paediatrician or neonatologist Assessment and management of uid status: assessment of uid status comprises a combination of urine output, blood pressure, clinical examination, change in patient weight and serum biochemistry. In neonates and infants changes in serum sodium concentration are particularly helpful as hyponatraemia

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often reects uid overload. In oliguric children without clinical uid overload, a uid bolus may stimulate urine output. Children with uid overload or who remain oliguric despite uid challenge will require a uid input regimen which reects losses e insensible losses, usually 20 ml/m2/h, plus replacement of urinary and other losses (e.g. gastric losses, diarrhoea) should achieve this. Fluid management of the oligo-anuric child is summarized in Table 3. These are initial management steps. If the response is poor or unexpected there should be early discussion with a paediatric nephrologist. Management of hyperkalaemia: AKI impairs clearance of potassium and can result in life threatening hyperkalaemia. Initial management includes the use of salbutamol and insulin to drive extracellular potassium into cells. Bicarbonate is useful for this purpose if there is metabolic acidosis but care must be taken if there is hypocalcaemia as this will worsen with the administration of bicarbonate. Calcium gluconate is helpful in stabilizing myocardium. Calcium or sodium resonium binds potassium in the gut helping minimize absorption but takes over 24 h to be effective and is therefore less useful in the acute setting. Driving urine output with furosemide in oliguric children can aid potassium clearance. Hyperkalaemia in association with oligo-anuria is an absolute indication for dialysis. Management of other metabolic derangement: the kidney plays a key role in acidebase homeostasis through reabsorption of ltered bicarbonate and excretion of dietary or endogenous acids. Failure of these processes in AKI can result in marked metabolic acidosis which compounds hyperkalaemia by impairing intracellular potassium uptake. Severe acidosis can compromise myocardial function. Correction of acidosis with intravenous sodium bicarbonate can improve hyperkalaemia and myocardial function. Anaemia in AKI: the haemolytic anaemia associated with HUS can be rapid and severe. Most children with HUS require at least one blood transfusion. This is given most safely in a paediatric nephrology unit where there is access to dialysis if needed from the uid and potassium load of the blood. The administration of erythropoietin may reduce the requirement for blood in children with HUS. Medications in AKI: medication dosing must often be altered for patients with AKI with avoidance of nephrotoxic medication and dose reduction in those which are renally excreted. Guidance on

dosing based on eGFR is available but discussion with a pharmacist is advised. Role of the paediatric nephrologist Renal replacement therapy: in some cases of AKI, renal replacement therapy is needed to control uid overload, hyperkalaemia and acidosis. The modality of renal replacement therapy used depends on several factors including feasibility of vascular or peritoneal dialysis access, the haemodynamic stability of the patient and the expertise of the team caring for the child. Continuous renal replacement therapy (CRRT) in the form of continuous haemodialysis, continuous haemoltration or continuous haemodialtration is delivered on PICU. CRRT is often used in critically ill patients on PICU as it minimizes haemodynamic perturbations associated with intermittent haemodialyis. Peritoneal dialysis and intermittent haemodialysis can be performed on a paediatric nephrology unit.

Outcome and follow up

Recent studies report mortality rates up to 40% for infants and children with multiple organ dysfunction syndrome who receive acute renal replacement therapy on paediatric intensive care units. Many children with AKI recover normal renal function with no apparent long-term consequences. In some individual diseases, for example HUS, there are signicant long-term sequelae including the late development of proteinuria, hypertension or chronic kidney disease (CKD). Children who do not regain normal renal function are followed-up on discharge to monitor blood pressure, urinalysis and renal function. Formal quantication of kidney function with 51 Cr-EDTA GFR measurement, usually performed after 1 year, is helpful to assess the degree of residual renal impairment.

Future developments in AKI

Much progress has been made in the last decade to facilitate earlier detection and management of AKI with introduction of the pRIFLE criteria. Despite this, current recognition of AKI in the clinical context relies on elevation of serum creatinine and changes in urine output, markers which change hours to days after kidney injury has occurred. Much research effort is currently directed towards identication and evaluation of novel biomarkers of kidney injury which may allow earlier detection and intervention similar to troponin in myocardial ischaemia. The application of functional genomics and proteomics to the study of AKI has enabled the identication of several serum and

Fluid management of the oligo-anuric child

Clinical assessment Initial management Further management Hypovolaemic or dehydrated Fluid bolus 10 ml/kg 0.9% saline then reassess Repeat bolus up to twice more if clinically hypovolaemic Euvolaemic Fluid bolus 10 ml/kg 0.9% saline Consider Furosemide 3e5 mg/kg Fluid overloaded Furosemide 3e5 mg/kg Needs dialysis. Consider venesection of 5 ml/kg in extremis as temporizing measure if symptomatic with pulmonary oedema

Table 3

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urinary biomarkers including neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), and interleukin (IL)-18. The sensitivity of NGAL in urine and plasma in early detection of AKI has been demonstrated in early studies. Combinations of biomarkers may prove useful with evolution of AKI biomarker panels. Large clinical studies are still needed to demonstrate the association of these novel markers with clinical outcomes. During the German outbreak of HUS, several adult patients with severe multi-system disease were treated with the monoclonal antibody eculizumab. There have also been separate case reports of its use in children with VTEC HUS. Eculizumab is effective in some patients with atypical HUS where it prevents over-activation of the alternate complement pathway. These recent reports have now raised the question of the role of the complement pathways in typical HUS and further knowledge in this area may result in newer novel treatments that might potentially remove the need for dialysis and prevent severe multi-system effects. The long-term consequences of AKI in childhood are not known and recent publications have suggested that the development of CKD into adulthood is more common than previously thought. There is a need for long-term follow-up studies of childhood and neonatal AKI survivors but individual patients should ideally be followed throughout childhood. A

Askenazi DJ, Ambalavanan N, Goldstein SL. Acute kidney injury in critically ill newborns: what do we know? What do we need to learn? Pediatr Nephrol (Berlin, Germany) 2009 Feb; 24. ISSN: 0931-041X: 265e74. PMID: 19082634. Hsu CW, Symons JM. Acute kidney injury: can we improve prognosis? Pediatr Nephrol (Berlin, Germany) 2010 Dec; 25. ISSN: 1432-198X: 2401e12. PMID: 20379746. Improving the standard of care of children with kidney disease through paediatric nephrology networks. Report of a working party of Royal College of Paediatrics and Child Health. British Association for Paediatric Nephrology, NHS Kidney Care, 2011.

Practice points
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FURTHER READING Andreoli SP. Acute kidney injury in children. Pediatr Nephrol (Berlin, Germany) 2009 Feb; 24. ISSN: 0931-041X: 253e63. PMID: 19083019.

All children with AKI should have a thorough assessment made of their uid balance status on presentation with a careful history and examination There should be early discussion between general paediatricians and regional paediatric nephrologists, especially if there is oligo-anuria The long-term renal consequences of AKI in children are not well documented. All children with AKI should be follow-up as out-patients. A formal GFR at 1 year may be a useful predictor of long-term renal function but even when this is normal, arrangements should be made for on-going surveillance of blood pressure and urinalysis

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