Prevention and management of acute kidney injury (acute renal failure) in children

INTRODUCTION — Acute kidney injury (AKI) is defined as the abrupt loss of kidney function that results in a decline in glomerular filtration rate (GFR), retention of urea and other nitrogenous waste products, and dysregulation of extracellular volume and electrolytes. The term AKI has largely replaced acute renal failure (ARF) as it more clearly defines kidney dysfunction as a continuum rather than a discrete finding of failed kidney function. Pediatric AKI presents with a wide range of clinical manifestations from a minimal elevation in serum creatinine to anuric kidney failure, arises from multiple causes, and occurs in a variety of clinical settings.

The prevention, management, and outcomes of AKI in children are presented in this topic review. The clinical manifestations and diagnosis of AKI in children and the approach to AKI in newborns are presented separately. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis" and "Neonatal acute kidney injury: Pathogenesis, etiology, clinical presentation, and diagnosis".)

PREVENTION OF ACUTE KIDNEY INJURY

Proven measures — General measures to prevent AKI include:

●Fluid administration in some settings, such as hypovolemia

●Avoidance of hypotension by providing inotropic support in critically ill children following adequate volume repletion (see "Shock in children in resource-abundant settings: Initial management", section on 'Clinical and physiologic targets')

●Readjustment and substitution of nephrotoxic medications based on close monitoring of kidney function and drug levels

Fluid administration — Fluid administration in the following settings has successfully prevented AKI:

●Prerenal AKI due to hypovolemia – In children with a history and physical findings consistent with hypovolemia, administration of an intravenous (IV) fluid bolus with normal saline (10 to 20 mL/kg over 30 minutes) may prevent more severe intrinsic AKI. The bolus can be repeated twice if necessary, until urine output is re-established. Fluid challenge is contraindicated in patients with obvious volume overload or heart failure.

●At-risk patients for AKI – Volume expansion with IV normal saline has been successful in preventing AKI in patients at risk for AKI with the following conditions (see "Possible prevention and therapy of ischemic acute tubular necrosis", section on 'Optimizing volume status and maintaining hemodynamic stability'):

•Hemoglobinuria and myoglobinuria (see "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on 'Volume administration')

•Administration of potential nephrotoxins including:

-Aminoglycosides (see "Pathogenesis and prevention of aminoglycoside nephrotoxicity and ototoxicity", section on 'Prevention')

-Amphotericin B (see "Amphotericin B nephrotoxicity", section on 'Prevention')

-Radiocontrast media (see "Prevention of contrast-associated acute kidney injury related to angiography", section on 'Fluid administration')

-Cisplatin (see "Cisplatin nephrotoxicity", section on 'Intravenous saline')

-IV administration of acyclovir (see "Acyclovir: An overview", section on 'Acute renal failure')

•Tumor lysis syndrome (see "Tumor lysis syndrome: Prevention and treatment", section on 'Prevention')

•Surgical procedures, in which there is a reduction in the intravascular volume during either the intraoperative or postoperative period (see "Pathogenesis and etiology of ischemic acute tubular necrosis", section on 'Surgery' and "Intraoperative fluid management", section on 'Hypovolemia')

Nephrotoxin management — Because nephrotoxins are an important risk factor for pediatric AKI, monitoring serum creatinine (ie, measure of kidney function) and drug level (if possible) is important, as it enables appropriate adjustment of drug dosing based on the knowledge of altered pharmacokinetics in early AKI and substitution of equally efficacious but less nephrotoxic drugs [1]. In addition, clinicians should also monitor drug efficacy and toxicity. However, readjustment of drugs is often challenging as kidney function changes and if drug monitoring is not available, as discussed below. (See 'Drug management' below and "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Nephrotoxins'.)

Studies have shown the impact of effective nephrotoxin management with decreasing AKI duration when systematic daily serum creatinine monitoring was put into practice for children who received multiple nephrotoxic medications using an electronic health record [2-4]. A follow-up report showed nephrotoxic medication exposure rate decreased by 38 percent, and the incidence of AKI rate decreased by 64 percent [3].

Unproven pharmacologic agents — Several pharmacologic agents including mannitol, loop diuretics, low-dose dopamine, fenoldopam, atrial natriuretic peptide, and N-acetylcysteine (NAC) have been studied in the prevention of AKI. However, none of these agents have been shown to be of proven benefit. (See "Possible prevention and therapy of ischemic acute tubular necrosis".)

●Mannitol – Experimental animal studies suggested that mannitol might be protective by causing a diuresis (thereby minimizing intratubular cast formation) and by acting as a free radical scavenger (thereby minimizing cell injury). In the clinical setting, the efficacy of mannitol for prevention of AKI is inconclusive, and its use can result in significant side effects including volume expansion, hyperosmolality, pulmonary edema, and AKI. Its use for prevention of AKI is not recommended. (See "Complications of mannitol therapy", section on 'Complications'.)

●Loop diuretics – Loop diuretics such as furosemide induce a diuresis by reducing active NaCl transport in the thick ascending limb of the loop of Henle. It has been proposed that the ensuing decrease in energy requirement may be protective of renal tubule cells, which may be faced with a decrease in energy delivery due to renal hypoperfusion or injury. However, the available evidence does not support the routine use of diuretics as a preventive measure for AKI, and in some settings, diuretic use was associated with an increase in serum creatinine. In a retrospective analysis of 914 children admitted to a pediatric intensive care unit (PICU), furosemide was the most commonly administered nephrotoxic agents and its use was associated with a two-fold greater risk of developing AKI after adjusting for other factors [5]. As a result, the routine use of loop diuretics to prevent AKI is not recommended. (See "Possible prevention and therapy of ischemic acute tubular necrosis", section on 'Experimental and unproven measures for the prevention of ischemic ATN'.)

●Dopamine – The routine use of dopamine for prevention of AKI is not recommended, based on evidence from prospective randomized studies of adult patients at risk for AKI that did not show a beneficial renoprotective effect of "low-dose" dopamine. In addition, there are significant side effects of dopamine therapy including tachycardia, arrhythmias, myocardial ischemia, and intestinal ischemia. (See "Possible prevention and therapy of ischemic acute tubular necrosis", section on 'Experimental and unproven measures for the prevention of ischemic ATN'.)

●Fenoldopam – Fenoldopam is a potent, short-acting, selective dopamine A-1 receptor agonist that increases renal blood flow and decreases systemic vascular resistance [6]. Data are limited in the use of this agent in children at risk for AKI.

•In a small retrospective study of 13 critically ill children receiving fenoldopam, a significant increase in urine output and a reduction in blood urea nitrogen (BUN) within 24 hours were noted [7].

•In a small, prospective, single-center randomized, double-blind, controlled trial of 80 children undergoing cardiac surgery requiring cardiopulmonary bypass, patients who received fenoldopam compared with those treated with placebo had lower urinary neutrophil gelatinase-associated lipocalin and cystatin C levels (AKI biomarkers) at the end of surgery, and 12 hours after admission into the PICU [8]. There was also a reduction in the use of diuretics (furosemide) and vasodilators (phentolamine) in the fenoldopam group (odds ratio 0.22, 95% CI 0.07-0.7).

Similar results have been reported in adults. However, because of the heterogeneity amongst studies and inability to verify changes in glomerular filtration rate, the benefits of fenoldopam must be confirmed in large randomized, controlled trials prior to routine recommendation of this agent for the prevention of AKI. (See "Possible prevention and therapy of ischemic acute tubular necrosis", section on 'Experimental and unproven measures for the prevention of ischemic ATN'.)

●Natriuretic peptides – Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) block tubular reabsorption of sodium and vasodilate the afferent arteriole. The renoprotective effects of these agents have been evaluated primarily in trials of adults undergoing cardiac surgery. (See "Possible prevention and therapy of ischemic acute tubular necrosis", section on 'Experimental and unproven measures for the prevention of ischemic ATN'.)

Pediatric data for the renoprotective effects of natriuretic peptides are limited. In a small retrospective study of 20 children with decompensated heart failure, recombinant human b-type natriuretic peptide (nesiritide) resulted in increased urine output and decreased serum creatinine concentrations [9]. Because of the paucity of data, the routine use of natriuretic peptides for prophylaxis against AKI is not recommended.

●NAC – NAC is a free radical scavenger antioxidant agent that counteracts the deleterious effects of reactive oxygen species in the generation of tubular injury and also has vasodilatory properties. In adults, several meta-analyses have demonstrated NAC did not provide any additional benefit to placebo in the prevention of AKI in adults following surgery. Although data regarding the use of oral NAC in prevention of contrast-nephropathy in adults are equivocal, NAC is often administered to high-risk patients undergoing a radiologic study that requires the administration of radiocontrast media, as it is a well-tolerated drug with minimal side effects. (See "Prevention of contrast-associated acute kidney injury related to angiography", section on 'Acetylcysteine' and "Prevention of contrast-associated acute kidney injury related to angiography" and "Possible prevention and therapy of ischemic acute tubular necrosis", section on 'Experimental and unproven measures for the prevention of ischemic ATN'.)

While NAC is commonly used in children for treatment of acetaminophen toxicity and other forms of acute liver failure, there are no data for its renoprotective effects in the pediatric population. The routine use of NAC for AKI prophylaxis in children is therefore not recommended, with the possible exception of judicious use in children at high risk for contrast-induced nephropathy.

Prevention of contrast nephropathy — However, we use NAC in conjunction with IV hydration to prevent contrast-induced nephropathy in children who have chronic kidney disease (glomerular filtration rate [GFR] <60 mL/min/1.73m²) and a history of contrast-induced AKI in the past, or when the patient is already on two nephrotoxins and contrast will be the third nephrotoxin to be used. Our protocol includes IV hydration with D5W and NaHCO₃ (70 meq/L) at 2400 mL/m² body surface area for six hours prior to and continuing through two hours after contrast administration, and the administration of NAC 12 mg/kg given either IV or orally every 12 hours for four total doses (one dose prior to and three doses after contrast administration). The efficacy of this approach has not been systematically studied.

For children with chronic kidney disease (GFR <60 mL/min/1.73m²) and no history of contrast-induced AKI in the past, we use the IV hydration with D5W and NaHCO₃ protocol but do not routinely add NAC.

MANAGEMENT OF ACUTE KIDNEY INJURY — The basic principles of the general management of the child with AKI include:

●Specific treatment of the underlying cause (see "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Etiology and pathogenesis')

●Fluid management

●Electrolyte management

●Nutritional support

●Adjustment of drug dosing

●Kidney replacement therapy

●Specific pharmacologic therapies

In general, prompt consultation and referral to a pediatric nephrologist are recommended for the management of intrinsic AKI, especially in the critically ill child.

Fluid management — The fluid status of the child varies depending on the underlying cause, comorbid conditions, and possible previous therapy. Accurate initial assessment is required to determine if the child is hypovolemic, euvolemic, or hypervolemic, and guides initial fluid management. Subsequent fluid therapy is based on careful follow-up with accurate records of fluid input and output, body weights, physical examinations (eg, blood pressure and pulse), and additional invasive monitoring as needed.

Hypovolemia — A child with a clinical history and physical examination consistent with hypovolemia requires emergent intravenous (IV) fluid therapy given as a normal saline bolus (10 to 20 mL/kg over 30 minutes, repeated twice as needed) in an attempt to restore kidney function and prevent the progression of prerenal AKI to intrinsic AKI. If urine output does not increase and kidney function fails to improve with the restoration of intravascular volume (ie, no decrease in serum creatinine and blood urea nitrogen), bladder catheterization is recommended to confirm anuria. At this point, other forms of invasive monitoring, such as measuring central venous pressure, may be required to adequately assess the child's fluid status and help guide further therapy.

Euvolemia — In euvolemic children, ongoing fluid losses (insensible fluid [300 to 500 mL/m² per day], urine, and gastrointestinal losses) should be balanced by administered fluids including medications and nutrition. Insensible water losses are higher in febrile children and lower in ventilated children due to decreased respiratory losses.

Hypervolemia — On the other hand, a child with signs of fluid overload (edema, heart failure, and pulmonary edema) requires fluid removal and/or fluid restriction.

Furosemide — A trial of furosemide may be attempted to induce a diuresis and convert AKI from an oliguric to a nonoliguric form, thereby simplifying fluid and nutritional management. However, loop diuretic therapy does not significantly alter the natural course of AKI. The dissociation between increasing the urine output and not affecting the course of AKI with diuretic therapy probably reflects the ability of the diuretic to enhance the urine output in those few nephrons that are still functioning. However, there is no effect on nonfunctioning nephrons, and as a result, there is no effect on the course of the kidney failure. (See "Possible prevention and therapy of ischemic acute tubular necrosis", section on 'No role for diuretics'.)

If a trial of furosemide is used, it should be given as a single high-dose bolus (2 to 5 mg/kg/dose up to a maximum of 200 mg/dose) to children in the early stages of oliguric AKI with hypervolemia (ie, oliguria of less than 24 hours duration). If the diuretic bolus is effective, a continuous infusion of furosemide (0.1 to 0.3 mg/kg per hour) may be started. Furosemide should be promptly discontinued if the bolus doses do not result in a diuretic response within two hours of bolus administration. The risk of ototoxicity and renal toxicity from furosemide use in this setting is significant due to potential elevated serum levels. Care should also be taken to avoid hypotension from overuse of diuretic therapy as this might result in further kidney injury and, in some cases, increase mortality. Loop diuretics should not be used as prolonged therapy for established AKI but given for a short length of time for volume control in responsive patients, because of the risk of adverse effects.

Critically ill children — In critically ill children, the degree of fluid overload is an independent risk factor for mortality, irrespective of severity of illness [10-12].

●In a study of 297 children who received continuous kidney replacement therapy from the Prospective Pediatric Continuous Renal Replacement Therapy Registry Group, mortality rates for patients who developed fluid overload greater than 20 percent, between 10 and 20 percent, and less than 10 percent were 66, 43, and 29 percent, respectively [10]. After adjusting for severity of illness and intergroup differences, there was a 3 percent increase in mortality for each 1 percent increase in severity of fluid overload.

●In a prospective study in 370 critically ill children, 64 (17.3 percent) developed early fluid overload, defined as fluid accumulation of ≥5 percent in the first 24 hours after admission to a PICU [13]. Early fluid overload was associated with an increased risk of AKI and mortality. The association of early fluid overload with mortality remained significant after adjustment for AKI and illness severity.

As discussed above, in children with AKI, the fluid status should be determined. We utilize the equation from the 2007 updated American College of Critical Care Medicine Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock as follows [14]:

Renal replacement therapy (RRT) should be considered for critically ill children with AKI when fluid overload exceeds 10 percent with multiorgan failure, oliguric despite diuretic therapy, or require large volumes of fluids (nutrition, blood products, or fluid overload), is performed for those with fluid overload greater than 15 percent, uremic or with life-threatening metabolic abnormalities. (See "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy", section on 'Indication and timing for kidney replacement therapy'.)

Electrolyte management — Electrolyte abnormalities are common complications of AKI. In general, electrolyte disturbances are asymptomatic and require a high index of suspicion and routine monitoring for early detection. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Other laboratory findings'.)

General measures to reduce or prevent electrolyte abnormalities in children with AKI include the following:

●Patients with oligo-anuric AKI should not receive potassium or phosphorus unless they exhibit significant hypokalemia or hypophosphatemia.

●Sodium intake should be restricted to 2 to 3 mEq/kg per day to prevent sodium and fluid retention with resultant hypertension.

●Children with polyuric AKI are at risk for electrolyte losses, which may need to be replaced. Ongoing replacement therapy in such patients can be guided by monitoring plasma and urinary electrolytes.

Therapy for specific electrolyte problems is discussed in the following sections.

Hyperkalemia — Hyperkalemia is the most common electrolyte complication, and is potentially life-threatening due to cardiac arrhythmia (waveform 1). Children with hyperkalemia may often be asymptomatic. In those who are symptomatic, findings are usually nonspecific and include malaise, nausea, and muscle weakness.

As a result, potassium levels need to be monitored in children with AKI, especially in those who are anuric or oliguric. Treatment is based on the severity of hyperkalemia (table 1 and algorithm 1).

The management of hyperkalemia in children is discussed separately. (See "Management of hyperkalemia in children".)

Metabolic acidosis — An elevated anion gap metabolic acidosis is common in AKI and is secondary to the impaired renal excretion of acid, and the impaired reabsorption and regeneration of bicarbonate. In addition, acid production is frequently increased, especially in critically ill patients due to shock or sepsis. Hyperventilation by the patient resulting in respiratory alkalosis may provide some correction of the acidosis but aggressive mechanical ventilation should be avoided, as hyperventilation results in compromise to cerebral blood flow with the potential for ischemia resulting in worse outcomes. Other measures to treat metabolic acidosis include IV fluid therapy using lactated Ringer solution or adding acetate to IV fluids, or the addition of sodium citrate to enteral fluids, with care taken to avoid hypocalcemia.

Although there is controversy regarding the use of sodium bicarbonate because of its adverse effects, administration of sodium bicarbonate should be initiated in life-threatening situations. (See "Approach to the child with metabolic acidosis", section on 'Intravenous bicarbonate therapy'.)

Hyperphosphatemia and hypocalcemia — In patients with hyperphosphatemia, oral phosphate binders and dietary restriction of phosphorus are commonly used to decrease intestinal absorption of phosphorus. IV administration of calcium gluconate should be considered if hypocalcemia is severe and/or if bicarbonate therapy is required for severe acidosis and hyperkalemia. (See "Overview of the management of acute kidney injury (AKI) in adults", section on 'Hyperphosphatemia'.)

Hypertension — Hypertension is a common complication in children with AKI. Several contributing factors may cause an elevation in blood pressure including fluid overload and renin-mediated hypertension, often seen in children with glomerulonephritis. Initial management is typically administration of a diuretic. Subsequent management is determined by the severity of hypertension, cause of hypertension, and response to initial therapy (such as diuretics). (See "Initial management of hypertensive emergencies and urgencies in children", section on 'Initial treatment' and "Nonemergent treatment of hypertension in children and adolescents", section on 'Antihypertensive drugs'.)

Nutritional support — AKI is associated with marked catabolism, and aggressive nutritional support is crucial to enhance the recovery process. Adequate nutrition includes normal maintenance requirements and supplemental calories to address the catabolic needs of the patient. However, the optimal nutritional requirements and nutrient intake composition in AKI remain uncertain, and are based largely on expert opinion [15]. Nutrient needs of patients with AKI are highly heterogeneous, depending on etiology, catabolic rate, acute and chronic comorbidities, and RRT modalities. No validated guidelines for the nutritional management of the critically ill child with AKI are currently available. It has been suggested that a caloric intake of approximately 30 percent above the maintenance requirements should provide adequate calories in most children with AKI without a substantial risk of overfeeding. Thus, infants should receive at least 120 Kcal/kg per day, and in older children, nutritional intake should be at least 150 percent of maintenance needs. Tight glucose control is recommended, especially since hyperglycemia and insulin resistance are common in critically ill children and associated with AKI and longer length of PICU stays [16].

In critically ill children, AKI is associated with abnormal amino acid synthesis and increased protein catabolism. In addition, renal replacement therapy results in amino acid losses, which often leads to negative nitrogen balance when a standard intake of 1.5 g/kg of protein is provided [17]. Therefore, it has been recommended that daily protein intake should be increased to a minimum of 3 g/kg per day in critically ill children with AKI, and additional amino acid supplementation (approximately 20 percent) should be given to children on hemodialysis or continuous renal replacement therapy to compensate for amino acid loss [18,19]. Some experts suggest that protein intake should be targeted to maintain blood urea nitrogen (BUN) at the 40 to 80 mg/dL range as an indication of positive nitrogen balance [20].

If feasible, the enteral route is preferred over the parenteral route for nutritional support. Enteral feeding promotes gut mucosal integrity, restores immune responses, prevents gut atrophy, reduces the risk of nosocomial infection, and is more cost-effective [21]. Total parenteral nutrition (TPN) should be considered only if enteral feeding cannot be established after five to seven days in the PICU or if the child is severely malnourished. In a multicenter randomized trial involving 1440 critically ill children, patients in whom TPN was withheld for one week versus those who received earlier TPN had lower rates of infection and RRT, and shorter durations of mechanical ventilation, and PICU and hospital stay [22]. If adequate protein and calorie nutrition cannot be achieved, because of fluid restriction, RRT should be instituted early in the course of the illness. (See "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy", section on 'Indication and timing for kidney replacement therapy'.)

Drug management — Pharmacologic management of children with AKI is best accomplished by close collaboration and consultation with trained pharmacology and pharmacy teams, and nephrologists. Drug management in children with AKI includes:

●Avoidance of nephrotoxic drugs as they may worsen the injury and delay recovery of function.

●Dosing adjustment of renally excreted drugs – Doses of renally excreted medications may require adjustment to avoid toxic accumulation of drugs and their metabolites and to prevent worsening of AKI. When AKI is first identified, the provider should estimate the GFR (calculator 1), or, if AKI is in an early stage and Cr is rising, assume GFR is <10 mL/min 1.73 m². The next step is to review the patient's medication list to determine if dosing adjustments are warranted based on the estimated GFR. Dose reductions are generally necessary for renally excreted drugs when GFR falls below 50 mL/min per 1.73 m². Medication dosing should be revisited regularly throughout the child's illness and readjustments should be made as warranted if kidney function improves or declines. In addition, drug levels should be routinely monitored for medications for which therapeutic monitoring is available (eg, vancomycin, aminoglycosides, enoxaparin, and digoxin). More information is available on the separate drug monographs within the program.

Drug dosing in the setting of AKI is complicated by the following factors [23-25]:

●Pharmacokinetic changes in patients with impaired kidney function include decreases in protein binding, drug metabolism, and potential changes in the volume of distribution due to fluid overload.

●Accurate determination of kidney function in the acute setting is challenging. Although serum creatinine is the most commonly used measurement for renal clearance, it only accurately reflects stable kidney function. As a result, it is an imprecise measure of renal clearance in the acute setting. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Serum creatinine'.)

●Many drugs are significantly cleared by kidney replacement therapies. Clearance varies among the renal replacement modalities.

●Drug monitoring helps to maintain therapeutic levels while preventing drug toxicity. However, for most drugs, monitoring is not available, and in this setting, adequate concentrations for efficacy can only be inferred from clinical response, and there is no ability to determine if these levels are approaching toxicity.

Kidney replacement therapy — The common indications for acute kidney replacement therapy (RRT) in AKI include:

●Fluid overload that is unresponsive to diuretics and is a hindrance to provision of adequate nutrition and other aspects of standard of care, such as administration of medications and blood products.

●Hyperkalemia (serum or plasma potassium >6.5 mEq/L) unresponsive to nondialytic therapy. (See "Management of hyperkalemia in children".)

●Uremia defined as a BUN between 80 to 100 mg/dL.

●Serious and potentially life-threatening complications due to fluid overload such as pulmonary edema, heart failure, and hypertension that is refractory to pharmacologic therapy.

RRT modalities include hemodialysis (HD), peritoneal dialysis (PD), and continuous RRT. The RRT choice depends on the clinical status of the patient, the expertise of the clinician, and the availability of appropriate resources [26-28].

●HD requires central vascular access, specialized equipment and technical personnel, anticoagulation (except in patients with coagulopathy), and the ability to tolerate a large extracorporeal volume. The advantage of hemodialysis in the setting of AKI lies in its ability to rapidly correct imbalances in fluid, electrolyte, and acid-base status.

●The advantages of PD include ease of performance and no requirement for specialized equipment, personnel, or systemic anticoagulation. Peritoneal dialysis is frequently the therapy of choice in neonates and small infants.

●Continuous RRT is especially useful in patients with hemodynamic instability and multiorgan dysfunction, since it allows continuous management of fluid overload without significant fluid shifts that may occur with HD.

RRT in children with AKI is discussed in greater detail separately. (See "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy".)

Specific pharmacologic therapies for established acute kidney injury — Over the past couple of decades, several drugs including fenoldopam and atrial natriuretic peptide have demonstrated benefit in animal models of AKI. However, translational research efforts in humans have not yielded satisfactory results to date. This may be attributed, at least in part, to the delay in initiating therapies imposed by the imprecision of currently available AKI biomarkers. When early structural AKI markers are identified and used in clinical practice, it will be easier to ascertain whether these therapies are beneficial in the treatment of pediatric AKI. The current statuses of these interventions for the treatment of established AKI are reviewed separately. (See "Possible prevention and therapy of ischemic acute tubular necrosis".)

PROGNOSIS AND OUTCOME OF ACUTE KIDNEY INJURY — Pediatric AKI is associated with increased short- and long-term mortality and long-term morbidity.

In-hospital mortality — AKI in hospitalized children is associated with increased short-term mortality compared with those without AKI. However, reported mortality rates vary across studies due to the lack of a consensus AKI definition, different clinical settings, and various geographic locations.

In a meta-analysis of 60 studies from countries around the world, the reported mortality among hospitalized children with AKI was 11 percent and increased with AKI severity [29].

The mortality rate associated with AKI is higher than that in hospitalized children without AKI. As an example, in a prospective study of 1367 pediatric ICU admissions from three tertiary care centers in the Kingdom of Saudi Arabia, in-hospital mortality was six-fold greater among patients with AKI compared with those without AKI after adjustment for age, sex, and underlying diagnosis [30].

In-hospital mortality rates vary by underlying severity of disease [31]. Among children who develop AKI outside of the intensive care unit (ICU) setting, reported mortality ranges from 1.5 to 9.5 percent [32,33]. In contrast, in the ICU setting, mortality rates associated with AKI are dramatically higher, up to 30 to 44 percent [32-36].

In general, the highest mortality rates are seen in infants [37], patients who have multiorgan failure [38], or those receiving kidney replacement therapy [37,39,40]. This was best illustrated by a retrospective analysis of hospital coding data from a large United States multicenter dataset of 2,644,263 hospitalized children that reported an overall in-hospital mortality rate among children with AKI of 15.3 percent [32]. Mortality rates were much higher among infants (31 percent), children requiring critical care (33 percent), and children requiring dialysis (27 percent).

Long-term outcomes — Multiple observational studies suggest that AKI is a risk factor for long-term morbidity and mortality.

●Morbidity – Observational studies report that survivors of pediatric AKI are at risk for chronic kidney disease (CKD) including hypertension and kidney failure, although data are inconsistent [37,41-51]. In particular, children requiring dialysis for AKI are at risk for subsequent death and CKD as illustrated by a retrospective study using a large administrative dataset for all children hospitalized in Ontario from 1996 to 2017 [52]. In this study of 1688 survivors who required dialysis for AKI, outcomes at a median 9.6 years included death (n = 113, 6.7 percent), kidney failure (n = 44, 2.6 percent), hypertension (n = 174, 12.1 percent), de novo CKD (n = 213, 13.1 percent), and repeat episode of AKI (n = 237, 14 percent).

●Mortality – Observational studies of children with AKI during hospitalization have reported long-term mortality rates from nine to 22 percent within two to five years [41,42,53]. As an example, in a retrospective cohort study of 418 children undergoing surgical correction of congenital heart disease, 22 percent of those with AKI died during a two-year follow-up [53]. In multivariable analysis, the most significant contributor to risk of long-term mortality was in-hospital AKI. In a separate multicenter pooled analysis of 3476 children with AKI due to hemolytic-uremic syndrome, death or kidney failure (chronic kidney disease [CKD] stage 5, formerly referred to as end-stage kidney disease) occurred in 12 percent of patients at a mean follow-up of 4.4 years [42].

FOLLOW-UP — Long-term follow-up is necessary based on the long-term morbidity for children who survive an episode of moderate or severe AKI. Our approach is to follow all children with moderate to severe AKI (stage 2 and above) (table 2) and those who received kidney replacement therapy at least annually for five years, and continued follow-up until adulthood if any evidence of chronic kidney disease (CKD) is detected. Widely available interventions for modifiable risk factors (such as hypertension and proteinuria) hold promise for prevention of CKD progression in these high-risk populations. (See "Chronic kidney disease in children: Overview of management", section on 'Slow progression of chronic kidney disease'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute kidney injury in children".)

SUMMARY AND RECOMMENDATIONS

●Prevention

•Proven measures for prevention of acute kidney injury (AKI) include vigorous fluid administration in patients at high risk for developing AKI, adequate fluid repletion in those with hypovolemia, avoidance of hypotension in critically ill children by providing inotropic support as needed, and readjustment of nephrotoxic medications based on close monitoring of kidney function and drug levels if available. (See 'Proven measures' above.)

•The efficacy of mannitol, loop diuretics, low-dose dopamine, fenoldopam, natriuretic peptides, and N-acetylcysteine (NAC) for the prevention of AKI is unproven, and significant adverse effects are associated with mannitol, loop diuretics, and dopamine. As a result, we do not suggest that any of these pharmacologic agents be routinely used in children with acute AKI (Grade 2C). (See 'Unproven pharmacologic agents' above.)

●Management – Management of a child with AKI includes the following:

•Specific treatment of the underlying cause. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Etiology and pathogenesis'.)

•Fluid management is crucial in children with AKI. Accurate initial assessment determines if the child is hypovolemic, euvolemic, or hypervolemic and guides fluid therapy. (See 'Fluid management' above.)

-Hypovolemia – A child with a clinical history and physical examination consistent with hypovolemia requires immediate intravenous (IV) fluid therapy (ie, normal saline bolus) in an attempt to restore kidney function and prevent the progression of prerenal AKI to intrinsic AKI. (See 'Hypovolemia' above.)

-Euvolemia – In euvolemic children, ongoing fluid losses (insensible fluid [300 to 500 mL/m² per day], urine, and gastrointestinal losses) need to be balanced with administered fluids. (See 'Euvolemia' above.)

-Hypervolemia – A child with signs of fluid overload requires fluid removal and/or fluid restriction. A trial of furosemide may be attempted to convert AKI from an oliguric to nonoliguric form in a child with oliguric AKI and hypervolemia. Early consideration for kidney replacement therapy is essential in the critically ill child with AKI and hypervolemia. (See 'Hypervolemia' above.)

•The following general measures prevent or reduce electrolyte abnormalities in children with AKI. (See 'Electrolyte management' above.)

-Patients with oliguria or anuria should not receive potassium or phosphorus.

-Sodium intake should be restricted to 2 to 3 mEq/kg per day to prevent sodium and fluid retention with resultant hypertension.

-In children with polyuric AKI, electrolyte losses may need to be replaced.

•Hyperkalemia is the most common electrolyte complication and is potentially life-threatening due to cardiac arrhythmia (waveform 1). As a result, potassium levels should be monitored in children with AKI. Treatment is based on the severity of hyperkalemia (table 1 and algorithm 1). (See 'Hyperkalemia' above and "Management of hyperkalemia in children".)

•Metabolic acidosis is a common abnormality in children with AKI. Although there is controversy regarding the use of sodium bicarbonate because of its adverse effects, administration of sodium bicarbonate should be initiated in life-threatening situations. (See 'Metabolic acidosis' above and "Approach to the child with metabolic acidosis", section on 'Intravenous bicarbonate therapy'.)

•Hypertension is a common complication of AKI. Therapy is based on the severity and cause of hypertension. (See 'Hypertension' above.)

•AKI is associated with marked catabolism, and nutritional support is required to enhance the recovery process. Adequate nutrition includes normal maintenance requirements and supplemental calories to address the catabolic needs of the patient. The caloric intake for infants is at least 120 Kcal/kg per day and, in older children, is at least 150 percent of maintenance needs. (See 'Nutritional support' above.)

•Drug management in children with AKI includes avoidance of nephrotoxic agents and dosing readjustment of renally excreted drugs based on residual kidney function. (See 'Drug management' above.)

•Indications for kidney replacement therapy in AKI include clinically significant fluid overload unresponsive to diuretic therapy, hyperkalemia that is unresponsive to nondialytic therapy, and uremia. (See 'Kidney replacement therapy' above and "Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy", section on 'Indication and timing for kidney replacement therapy'.)

●Prognosis

•Pediatric AKI is associated with increased mortality, especially in patients who are critically ill and/or require kidney replacement therapy. (See 'In-hospital mortality' above.)

•Children with AKI are at long-term risk for developing chronic kidney disease (CKD), including end-stage kidney disease, and have a higher risk of long-term mortality. Patients with moderate to severe AKI should be followed annually to detect signs of CKD (eg, hypertension and proteinuria). (See 'Follow-up' above and 'Long-term outcomes' above.)