Pediatric acute kidney injury: Indications, timing, and choice of modality for kidney replacement therapy

INTRODUCTION — 

Hospitalized children, especially critically ill children, are at risk for acute kidney injury (AKI). Children with AKI are at greater risk for mortality than those without AKI due to associated complications, including symptomatic uremia, metabolic and electrolyte abnormalities, and fluid overload. The management of children with AKI remains primarily supportive; however, kidney replacement therapy (KRT; ie, dialysis) is often indicated for patients with severe AKI. (See "Prevention and management of acute kidney injury in children", section on 'Management of acute kidney injury'.)

The indications, timing, and modalities for KRT for children with AKI will be reviewed here. KRT in adults with AKI is discussed separately. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)

DEFINITIONS

●Acute kidney injury (AKI) is characterized by a sudden decrease in the ability of the kidneys to maintain adequate electrolyte, acid-base, and fluid homeostasis along with a reduction in glomerular filtration rate [1-3]. Clinically, AKI is manifested as an increase in serum creatinine (SCr), a reduction in urine output (less than 0.5 to 1 mL/kg per hour) that may be refractory to diuretic therapy, or a combination of both [1-3]. In severe AKI, a change in urine output may be identified before any change in serum creatinine; thus it has been proposed that either urine output or SCr can be used to identify and stage AKI [4,5].

Several published criteria are used clinically to classify the severity of pediatric AKI [5,6]. This topic uses the Kidney Disease Improving Global Outcomes (KDIGO) definition and staging based on consensus of pediatric nephrology experts following a systematic review of the literature (table 1). Other definitions used to guide clinical care include pRIFLE (Pediatric Risk, Injury, Failure, Loss, End Stage Renal Disease) (table 2) and Acute Kidney Injury Network and are discussed separately. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Definition'.)

●Kidney replacement therapy (KRT) is treatment that replaces the normal blood-filtering function of the kidneys. Several different modalities of KRT are used in children with AKI, including intermittent hemodialysis (HD), peritoneal dialysis, continuous KRT therapy (ie, continuous venovenous HD, continuous venovenous hemofiltration, continuous venovenous hemodiafiltration) and prolonged intermittent KRT (PIKRT). (See 'Kidney replacement therapy modalities: Overview' below.)

ACUTE KIDNEY INJURY AND MORTALITY: POTENTIAL ROLE OF KIDNEY REPLACEMENT THERAPY — 

AKI and fluid overload are associated with greater morbidity and mortality in pediatric patients [5,7-9]. Mortality is highest in critically ill children, especially infants and those with multiorgan failure and significant fluid overload [5,7,9-16]. Kidney replacement therapy (KRT) prevents and corrects the adverse and potentially life-threatening complications of AKI including symptomatic uremia, metabolic and electrolyte imbalance, and severe fluid overload. Early initiation and effective administration of KRT in AKI improves survival in critically ill pediatric patients [17,18]. Nevertheless, there continues to be a lack of robust evidence-based guidelines regarding the indications for and timing of initiation of KRT in children, as well as the most appropriate KRT modality for pediatric use in various settings.

INDICATION AND TIMING FOR KIDNEY REPLACEMENT THERAPY — 

The decision to begin KRT is based on the severity and complications of AKI and the urgency of the clinical setting.

Urgent indications — Urgent indications include the following:

●Clinically significant fluid overload with evidence of escalating ventilatory support due to pulmonary edema and/or congestive cardiac failure, which is unresponsive to diuretic therapy and fluid restriction (typically seen in patients with >15 percent fluid overload). (See 'Fluid overload' below.)

●Presence of uremic complications such as pericarditis, uremic encephalopathy or unexplained change in mental status, and bleeding. (See "Acute toxic-metabolic encephalopathy in adults", section on 'Uremic encephalopathy' and "Uremic platelet dysfunction".)

●Life-threatening metabolic derangements that are refractory to medical management:

•Severe persistent hyperkalemia – Values typically >6.5 mEq/L that are refractory to medical management or whenever there are associated electrocardiographic changes. (See "Causes, clinical manifestations, diagnosis, and evaluation of hyperkalemia in children", section on 'Symptomatic patients' and "Causes, clinical manifestations, diagnosis, and evaluation of hyperkalemia in children", section on 'Cardiac conduction abnormalities' and "Management of hyperkalemia in children", section on 'Dialysis'.)

•Severe metabolic acidosis (pH <7.1) refractory to medical therapy. (See "Approach to the child with metabolic acidosis", section on 'Acute metabolic acidosis' and "Approach to the child with metabolic acidosis", section on 'Kidney replacement therapy'.)

•Severe persistent hyponatremia is a rare indication for KRT but mainly when associated with fluid overload.

●Removal of toxins or drugs, which are dialyzable, including alcohols, lithium, salicylates, and other drugs. (See "Ethanol intoxication in children: Clinical features, evaluation, and management", section on 'Extracorporeal removal' and "Lithium poisoning", section on 'Role of extracorporeal removal' and "Salicylate (aspirin) poisoning: Management", section on 'Indications for hemodialysis'.)

●Other metabolic derangements including tumor lysis syndrome and hyperammonemia. (See "Enhanced elimination of poisons", section on 'Extracorporeal removal' and "Urea cycle disorders: Management", section on 'Hemodialysis' and "Tumor lysis syndrome: Prevention and treatment".)

Nonurgent indications — For some patients with severe AKI but without one of the conditions listed above, dialysis may be warranted to prevent worsening complications and/or further deterioration of the patient's clinical status. In these cases, the decision to initiate KRT is based primarily on the judgement of clinicians in evaluating the level of impairment, patient factors (age/size, illness acuity, comorbidities, and ongoing needs), and organizational resources including availability of necessary equipment and trained, experienced staff.

Nonurgent indications include:

●Potential risk for clinically significant fluid overload

•Reduced urine output (ie, oligoanuria) nonresponsive to diuretics, with high-volume requirement for administration of nutrition, medications, and/or blood products with evidence of continued deterioration of kidney function.

•Impending fluid overload with tachycardia, hypertension, or escalating ventilatory requirement.

●Refractory electrolytes and acid-base disturbances – Deteriorating electrolyte and acid-base anomalies not responding to supportive management (eg, refractory severe hyperkalemia) but not yet meeting life-threatening values (noted above).

●Elevated blood urea nitrogen (BUN) – In our practice, we consider the use of KRT when the BUN reaches a level between 80 and 100 mg/dL in the context of oliguria without response to diuretics, worsening electrolyte abnormalities, and nutritional need. However, data from adult studies suggest that early initiation of KRT is not beneficial, because the use of BUN as an indicator for KRT is limited by several nonrenal factors that affect BUN measurements. These include hydration status, gastrointestinal bleeding, steroid use, diuretic use, catabolism, and nutritional intake. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Timing of elective initiation'.)

●Serum creatinine (SCr) – Elevated serum creatinine by itself is not an indication for KRT. Increases in SCr often occur late in the course of AKI, and, thus, SCr is an imperfect marker to determine the appropriate timing of KRT [19,20]. SCr is also affected by hydration status and by muscle mass that varies according to the size, nutritional status, and underlying medical comorbidities of the child. Given the limitations associated with serum creatinine as a kidney function biomarker, decisions regarding initiation of KRT should take into account the multiple patient factors and not be based solely on changes in SCr or a cutoff SCr level.

Evidence for kidney replacement therapy initiation and timing — In children, there are sufficient data to provide guidelines to initiate KRT for fluid overload. However, data remain inadequate to support evidence-based guidelines for KRT initiation that include specific measures of uremia and metabolic disturbances. Nevertheless, most pediatric intensivists and nephrologists, including the authors, advocate for earlier implementation of KRT to avoid these late manifestations of AKI.

Fluid overload — Fluid overload is associated with increased mortality, increased length of mechanical ventilation for mechanically ventilated children, increased organ dysfunction, and prolonged intensive care unit (ICU) and hospital stay when controlled for severity of illness in both single center and multicenter pediatric studies [9,21-23]. Observational data suggest that early initiation of KRT is beneficial in children with multiorgan dysfunction and fluid overload [24].

Based on these findings, the American College of Critical Care Medicine Clinical Guidelines for Hemodynamic Support of Neonates and Children with Septic Shock suggest that KRT be considered in pediatric patients with septic shock at risk for worsening significant fluid overload [25]. Once hemodynamic stability is achieved, diuretics or KRT can be used to remove fluid in patients who are >10 percent fluid overloaded and are unable to maintain fluid balance with their native urine output and/or extrarenal losses. The patient's fluid status is evaluated by determining the percent fluid overload using the following equation:

or

KRT is also often used to maintain the fluid status of critically ill children who have oliguria but require high volumes of intravenous fluids, including parenteral nutrition and medications and/or blood products. In this setting, KRT is not used to remove fluid but to prevent further fluid overload, which may lead to worsening respiratory status and cardiac function. Once the patient has achieved a satisfactory level of hemodynamic stability, the process of fluid removal can commence.

Severe acute kidney injury — Although data from adult studies have been inconclusive about the benefits of early KRT, we recommend elective initiation of KRT in pediatric patients with AKI when their kidney injury is severe or unlikely to quickly resolve. The definitions and staging criteria of AKI are based on the degree of glomerular filtration rate reduction or change in serum creatinine (SCr) in addition to the urine output. However, as stated previously SCr is not the ideal biomarker for kidney injury and even with AKI severity staging (based in part on SCr), the likely duration of AKI is difficult to predict and SCr often remains a late biomarker of AKI. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Serum creatinine'.)

Several investigational tools are being studied to see if they can predict the severity of AKI in children and whether KRT should be initiated. However, these tools have not been conclusively validated in the clinical setting and as a result are not used routinely in managing pediatric AKI.

●Novel biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), insulin-like growth factor-binding protein 7, tissue inhibitor of metalloproteinases, kidney injury molecule-1, and interleukin 18 show promise in both their diagnostic and prognostic utility in the setting of AKI and may allow for early intervention prior to the onset of SCr rise, severe metabolic derangements, and fluid overload. These biomarkers and their role in predicting AKI are discussed separately [26-28]. (See "Acute kidney injury in children: Clinical features, etiology, evaluation, and diagnosis", section on 'Biomarkers of acute kidney injury' and "Investigational biomarkers and the evaluation of acute kidney injury", section on 'Diagnostic biomarkers'.)

●Furosemide stress test – Furosemide stress test, which assesses urine output after a weight-based dose of furosemide, has been reported to predict progression of AKI in both adults and children. In one study of 166 children who underwent cardiac surgery, the furosemide stress test was predicative of AKI with lower mean urine flow rate for patients with AKI compared with those without AKI at two hours (2.9 versus 5 mL/kg/hour) and at six hours (2.4 versus 4 mL/kg/hour) [29]. (See "Investigational biomarkers and the evaluation of acute kidney injury", section on 'Furosemide stress test'.)

●Combination of clinical factors – The use of a collection of clinical risk factors and signs of kidney disease has been proposed as a method to identify patients most at risk for developing AKI in the pediatric ICU setting, analogous to assessing myocardial infarction [30]. The risk of AKI (referred to as renal angina index) is based on the presence of established risk factors (eg, mechanical ventilation, history of cardiopulmonary bypass, bone marrow transplantation) and evidence of kidney disease (fluid overload and changes in serum creatinine) [31]. The proposed renal angina criteria stratify patients into moderate-risk, high-risk, and very high-risk patients according to their underlying clinical condition. For each level of preexisting risk factors, there is a threshold of evidence of injury that a patient must meet to be considered to have renal angina (table 3) [31-35].

KIDNEY REPLACEMENT THERAPY MODALITIES: OVERVIEW

Available pediatric modalities — The following modalities are available for the provision of KRT in the pediatric patient with AKI [36-38]:

●Peritoneal dialysis (PD)

●Intermittent hemodialysis (HD)

●Continuous kidney replacement therapies (CKRT), including:

•Continuous venovenous hemodialysis (CVVHD)

•Continuous venovenous hemofiltration (CVVH)

•Continuous venovenous hemodiafiltration (CVVHDF)

●Prolonged intermittent kidney replacement therapy (PIKRT)

Factors in modality selection — All dialysis modalities can remove fluid and clear solutes. For the pediatric patients with AKI, selection of modality is typically based upon local expertise and availability of staff and equipment. However, in selected patients, other factors may need to be considered.

●Size of the patient – This is a major consideration for dialysis modality selection as HD and CKRT may not be feasible in infants and small children <15 kg in weight. Most CKRT machines and hemodialysis machines used in the United States are only approved for patients weighing more than 15 or 20 kg. As a result, machines must be used off-label to dialyze patients who fall below this cutoff. In addition, the extracorporeal volume of these circuits typically exceeds 10 percent of the blood volume of small patients <10 to 12 kg. For these children, packed red blood cells are required to prime the extracorporeal circuit to prevent hemodynamic instability leading to exposure to donated blood [39]. Smaller dialyzers and extracorporeal circuits have been developed but are not universally available. With the development of these new dialysis systems, use of PD for acute KRT is declining in high-resource settings. However, PD remains globally the most common modality used for infants and small children who require KRT. (See "Hemodialysis for children with chronic kidney disease", section on 'Dialyzer' and "Hemodialysis for children with chronic kidney disease", section on 'Extracorporeal circuit' and "Hemodialysis for children with chronic kidney disease", section on 'Small infants'.)

●Dialysis access

•Hemodialysis and CKRT require placement of a large-bore dual lumen central catheter, which is often a challenging option in small children or infants or those with compromised vasculature. For children on extracorporeal membrane oxygenation (ECMO), access for CKRT can be obtained via the ECMO circuit.

•PD, which requires placement of an abdominal catheter, is a viable option for dialysis in children. Important complications of acute PD include dialysate leakage and infection. PD is contraindicated in patients with certain underlying problems, including diaphragmatic hernia, omphalocele, gastroschisis, and necrotizing enterocolitis.

●Hemodynamic instability – Intermittent HD may be difficult to perform in hemodynamically unstable patients. In these patients, CKRT or PD allow for more gradual and sustained solute and fluid removal and less perturbations on the intravascular circulation than intermittent HD.

●Illness severity – The severity of a patient's illness often determines the KRT modality, along with the primary goal of KRT, whether this is clearance, ultrafiltration, or both. The location of the patient may also contribute to the dialysis modality, especially when considering that more KRT modalities are available in the intensive care unit (ICU) compared with general medical units.

●Anticipated duration of KRT – It is important to consider the likely length of KRT. For example, if a child is likely to require chronic dialysis and is a candidate for home therapy, PD might be the preferred initial selected mode of dialysis as it may facilitate transition to chronic KRT.

KIDNEY REPLACEMENT THERAPY MODALITIES: DETAILS AND CLINICAL CONSIDERATIONS — 

Regardless of the modality choice, initiating KRT in a critically ill child requires collaboration among the pediatric nephrologists, intensivists, and other subspecialists. Early discussion and planning will facilitate the process and allow for more rapid intervention, thereby improving survival outcomes and reducing morbidity. All acute dialysis programs can be monitored and assessed through quality improvement programs with specific metrics and outcome indicators [40]. Quality improvement goals have been outlined for adult programs and similar quality improvement programs are now recommended in pediatric programs.

The following sections describe the use of available KRT modalities in pediatrics, including their relative advantages and disadvantages.

Peritoneal dialysis — PD provides gradual continuous solute and water clearance through diffusion and ultrafiltration, although the ability to separate these components is limited with this modality.

●General availability – Many centers have a relatively greater experience and comfort level using PD in pediatric patients compared with the other modalities. PD historically has provided effective therapy for the management of pediatric AKI and continues to provide reasonably cost-effective, efficient therapy. PD is widely available in resource-limited countries because it requires less technological expertise, as it does not require vascular access, less resource allocation, and is more cost effective than CKRT or HD. PD is critical in the treatment for any child with AKI especially in facilities where pediatric HD and CKRT are less accessible [41,42].

●Access – PD does not require vascular access and thus allows critically ill patients to be dialyzed with preservation of vasculature for patients who may require chronic dialysis in the future. Access for PD can be quickly and safely obtained, even in hemodynamically unstable patients, thus allowing for the rapid institution of therapy. Typical access includes Tenckhoff catheters, usually placed in the operating room by pediatric surgeons, or acute PD or adapted PD catheters placed at the bedside percutaneously by experienced clinicians in patients unable to tolerate a surgical placement [43,44].The most common complications of acute PD are dialysate leakage, infection, and catheter obstruction.

●Components of the PD prescription

•Dialysate composition – The composition of dextrose-based peritoneal dialysate solutions available in the United States includes sodium (132 mEq/L), magnesium (0.5 mEq/L), chloride (95 mEq/L), lactate for a bicarbonate source (40 mEq/L), and two different concentrations of calcium (2.5 and 3.5 mEq/L). Modifications customized to the needs of individual patients can be prepared by hospital pharmacies [45,46], although this does increases the risk of prescription errors or introduction of contaminants [47]. The most common supplementation is the addition of sodium to increase the standard composition, typically in hyponatremic or hypotensive infants. Potassium or phosphate which are not included in standard PD formulations may also be required at times. In addition, bicarbonate may be used in patients with hepatic dysfunction who are unable to metabolize lactate.

-Dextrose – Three different dextrose concentrations are available commercially in the United States: 1.5, 2.5, and 4.25% solutions with respective osmolalities of 346, 396, and 485 mOsm/L. The dextrose used in PD dialysate can provide an extra source of carbohydrate nutrition and calories [46,48], but may also lead to hyperglycemia necessitating insulin correction [49].

-Heparin – Heparin is added to the dialysate when fibrin is present in the dialysate or during episodes of peritonitis given the possible antiangiogenic and anti-inflammatory properties [50]. When adding heparin we use the Pediatric International Society for Peritoneal Dialysis guidelines that suggest administrating intraperitoneal heparin at 500 to 1000 units per L until complete resolution of the cloudy effluent to prevent occlusion of the catheter [51].

•Exchange volume – The recommended initial exchange volume in acute pediatric PD is low (10 mL/kg) in order to minimize abdominal pressure that may cause dialysate leakage around the catheter. The volume can be slowly increased to a maximum of 35 to 40 mL/kg. As volume increases, the number of exchanges per day often can be decreased. Strict fluid balance is particularly critical in small children and infants and the use of buretrols allows for precise measurements of in- and outflow when operating a manual and gravity-based system used for these small patients [52].

•Dwell time – The time allowed for exchange of molecules and fluid is often short in pediatric patients. Initial standard dwell time is between 40 and 60 minutes, which is then adjusted based on the patient's fluid status, rate of ultrafiltration (fluid removal), and clinical course. Shorter dwell times can be utilized to increase ultrafiltration (fluid removal), but this may reduce clearance.

•Number of daily exchanges – Number of exchanges per 24 hours depends on the duration of time required for the inflow, dwell, and outflow of dialysate for each exchange. Typically, on initiation, acute PD runs over the entire 24-hour day but, as the exchange volume is increased or the patient is stabilized, the amount of time on dialysis can be reduced.

●Specific clinical settings

•Multiorgan failure – Retrospective pediatric data show that PD can be performed successfully in the setting of multisystem organ failure, including cardiovascular instability requiring vasopressor support [53,54]. However, the ability to provide adequate dosing of dialysis in the AKI setting is problematic when using PD in the most critically ill patients. These patients, who may have severe fluid overload, lactic acidosis, and hypotension, require precise fluid balance with controlled ultrafiltration, but may not have adequate blood flow (cardiac output) to the peritoneum to allow for efficient solute and fluid removal. Pressor agents may alter peritoneal blood flow in septic patients, further diminishing these processes. Thus, in patients with sepsis-induced AKI the beneficial aspects of slow solute clearance and ultrafiltration provided by PD also limit its effectiveness. Patients with preload-dependent cardiac physiology may become unstable with filling and draining [53,55], necessitating the use of tidal PD prescriptions or an alternative modality such as CKRT. Patients with pulmonary compromise may worsen with increased abdominal dialysate volumes that may prevent full diaphragmatic excursion.

•Other conditions – PD can be used to support patients with ventriculoperitoneal shunts, prune-belly syndrome, abdominal surgeries, and ostomies, though these situations may present some technical challenges for catheter placement (eg, thin abdominal wall in patients with prune-belly syndrome) and come with higher risk of catheter malfunctions [56].

●Contraindications – PD is absolutely contraindicated in patients with diaphragmatic defects due to leakage of peritoneal fluid into the pleural cavity or in patients without an intact or closed peritoneal cavity (eg, omphalocele or gastroschisis). It may also be contraindicated in those with significant underlying gastrointestinal pathology such as necrotizing enterocolitis.

●Complications – Complications of PD include:

•Peritonitis – The risk of peritonitis increases when using a PD catheter acutely due to the risk of dialysate leak and thus PD initiation is often delayed, if possible, for 48 to 72 hours or longer to allow for healing and lower the risk of infection and the other PD complications. Peritonitis can enhance dialysate protein loss, compromise nutrition, and permanently damage the peritoneal membrane.

•Catheter malfunction – PD catheter malfunctions are common. They include failure to fill and drain completely and quickly, as well as leakage of peritoneal fluid at the exit site, which can put patients at risk for peritonitis.

•Electrolyte abnormalities – Patients may have significant losses of sodium and other electrolytes especially in infants and children who only receive formula or breast milk feeds. In such cases, where sodium deficit is present, significant hypotension may result. PD is also associated with hyperglycemia and an increase incidence of hypokalemia and hypophosphatemia if these are not added to the dialysate [57].

•Protein loss – Patients on PD also require increased protein intake due to amino acid losses with PD, and they also lose immunoglobulins in the dialysate, making them more susceptible to infection.

•Hydrothorax due to dialysate leakage into the pleural space.

•Hernia due to fluid in the peritoneal space and increased abdominal pressures.

Intermittent hemodialysis — Intermittent HD provides the most efficient solute clearance and ultrafiltration compared with other KRT modalities. However, for children, especially critically ill patients and small children, management should be undertaken by a team (nephrologist, intensive care team, and dialysis nurses) with expertise in administrating HD to children because of specific pediatric issues regarding obtaining vascular access, catheter selection and placement, and dialysis prescription. For small children, centers should have policies for utilizing hemodialysis equipment as the majority of the hemodialysis machines available on the market are only approved for patients greater than 15 or 20 kg.

●Advantages – In the hemodynamically stable patient, no other modality is better suited for rapid and accurate small solute reduction with or without ultrafiltration. Thus, this therapy is particularly important in the pediatric population for the treatment of acute and life-threatening electrolyte abnormalities (eg, hyperkalemia), ingestions (eg, lithium, aspirin), drug toxicity (eg, vancomycin), tumor lysis syndrome, and hyperammonemia [37,58,59].

●HD access – Vascular access is one of the most important components leading to the satisfactory provision of HD.

●HD catheter selection

•Tunneled versus nontunneled – The length of therapy and the urgency of the line placement will often determine if a tunneled or nontunneled HD catheter is placed. Temporary nontunneled catheters can be placed in most children at the bedside by pediatric nephrologists or intensivists. Semipermanent tunneled catheters are usually placed in the operating room by surgeons or interventional radiologists.

•Gauge and length – A wide variety of vascular catheters are available for the pediatric population with different sizes (gauge) and lengths (table 4) [60].

-Catheter sizes range from 6.5 to 14 Fr and are chosen according to the vessel size based on the weight of the child (table 4). Increasing the gauge of the vascular access will allow for higher blood flow rates. However, too large a catheter can lead to obstruction of vessels, resulting in reduced venous return and therefore poor flow through the dialysis circuit. In the United States, the smallest currently available is a 7 Fr double lumen non-tunneled catheter (table 5). However, in preterm infants, even the 7 Fr catheter may be too large, and two smaller single lumen catheters placed at different access sites, including umbilical veins, may be the only option for HD.

-Pediatric catheters are available in different lengths based on the gauge. The selected length is based on optimal line placement of the catheter tip at the junction of the superior vena cava and the right atrium to optimize flows and limit recirculation.

●Access site – Placement in the right internal jugular vein is typically preferred due to lower risk for complication compared with other insertion sites. Disadvantages of placement in the groin include potential exit site contamination and positionality. Subclavian veins should be avoided to preserve these vessels for future use as arteriovenous fistulas in patients who may progress to end-stage kidney disease.

●Components of the HD prescription

•Blood flow rate – Blood flow rate is a significant factor in determining solute clearance in patients as higher flow rates increase diffusive clearance. However, in acutely ill patients with AKI, the risks of higher blood flow and increased clearance must be weighed against instability of the patient's hemodynamic status and their ability to tolerate a higher blood flow rate. The blood flow rate is also dependent on the size and quality of the dialysis access as larger bore catheters will allow a higher blood flow rate without collapsing or causing high negative arterial pressures on the dialysis machine. Typical blood flow rates range from 3 to 10 mL/kg/minute.

•Dialysate flow rate – The rate of dialysate flow also determines clearance in HD but to a lesser extent than the blood flow rate. The dialysate flow rate should be set at a rate of at least 1.5 to 2 times the blood flow rate to maximize bidirectional flow between the blood and dialysate [61].

•Dialysate composition – Dialysate composition is modified based on patient needs mainly to adjust for sodium, potassium, calcium, and bicarbonate levels.

•Dialyzer and tubing size – The small solute clearance characteristics of the dialyzer are determined by the surface area of this dialyzer. Typically, a dialyzer is prescribed with a surface area similar to the patient’s body surface area (table 6).

The extracorporeal circuit is composed of the arterial (inflow) and venous (outflow) lines (tubing) and the dialyzer. The volume of this circuit is restricted by the upper safe limit for extracorporeal blood volume that is dependent on the total blood volume of the patient. A child can tolerate up to a maximum of 10 percent of his or her total blood volume in the extracorporeal circuit, and a safe volume of the circuit is targeted at 8 percent of total blood volume of the child. For small children and infants, extracorporeal volume often exceeds 10 percent of the blood volume of the child and donor red blood cells are used to prime the extracorporeal circuit to prevent hemodynamic instability. Commercially available tubing that varies in volume should be matched to the size of the patient (table 7). For neonates, tubing volume can be as low as 29 mL for standard HD machines.

•Ultrafiltration (fluid removal) – The volume of fluid removal during a short three- to four-hour dialysis run is often very limited, especially if the patient is not hemodynamically stable or small in size.

•Length of dialysis treatment – The duration of a dialysis treatment is determined based on the clearance and/or fluid removal goals.

•Anticoagulation – Unfractionated heparin is the standard anticoagulation method used for intermittent hemodialysis therapy to prevent loss of the dialysis circuit or complications with the hemodialysis catheter. A typical dose of unfractionated heparin is a bolus of 10 to 30 units/kg followed by a continuous infusion at a rate of 10 to 30 units/kg/hour. During short hemodialysis treatments, treatments can be successful with no anticoagulation or with the administration of frequent saline flushes into the circuit.

●Complications

•Line placement complications – During placement of vascular catheters, complications may include blood vessel sclerosis or thrombosis, air emboli, or hemorrhage.

•Infection – As with all central lines, hemodialysis catheters are a potential source of infection introduction.

•Hypotension – Rapid fluid removal may lead to episodes of hypotension or other vital sign instability.

•Neurologic complications (ie, dialysis disequilibrium syndrome) – A range of neurologic manifestations including headache, nausea, blurred vision, restlessness, mental status changes, and/or seizures due to cerebral edema is associated with the initiation of acute HD in the presence of significant uremia (referred to as dialysis disequilibrium syndrome) [62]. (See "Dialysis disequilibrium syndrome".)

●Potential contraindications

•Hemodynamic instability – For patients with hemodynamic instability, PD or CKRT may be better tolerated than HD. Low blood pressure (hypotension) in the critically ill patient will limit the capacity for ultrafiltration and ultimately the ability to provide adequate treatment with HD.

•Large fluid volume requirements – In critically ill patients who are anuric or oliguric and require large fluid volumes for nutrition and/or medications, it may be challenging to adequately remove fluid over the short treatment typically used with HD. As a result, PD or CKRT may be better options for those patients as they allow greater fluid removal that is continuous and gradual than HD.

•Small size – Very small patients (particularly those <10 kg) are not often able to tolerate significant ultrafiltration without hemodynamic instability. Smaller patients on HD also have issues with HD access, large extracorporeal volume, and anemia from blood loss.

The Newcastle Infant Dialysis Ultrafiltration System (NIDUS) Allmed Medical Care Holdings is an HD system developed for infants weighing between 0.8 and 8 kg, uses a single-lumen catheter (down to 4.5 French in size), and is being evaluated for efficacy and safety [63]. The volume of the NIDUS circuit is 10 mL and thus does not require a blood prime. PD would be another option in such cases.

Continuous kidney replacement therapy — CKRT, if available, is the preferred primary modality for KRT in the critically ill, hemodynamically unstable pediatric patient [21]. CKRT includes dialysis and/or filtration treatments that operate in a continuous mode typically performed in the pediatric intensive care unit (ICU) setting.

●Modalities –The following modalities of CKRT are used in children.

•Continuous venovenous hemodialysis (CVVHD) – Predominantly diffusion based solute clearance

•Continuous venovenous hemofiltration (CVVH) – Predominantly convection based solute clearance

•Continuous venovenous hemodiafiltration (CVVHDF) – Provides diffusion and convection based solute clearance

Ongoing research is trying to determine which modality is better suited for specific patient conditions. Convective therapies (CVVH and CVVHDF) provide superior middle molecule clearance compared with diffusive therapy (CVVHD) [64]. These convective modalities are thought to be superior in clearing proinflammatory cytokines and may be beneficial in the treatment of patients with sepsis-related AKI. As an example, the Selective Cytopheretic Device has been shown to deactivate leukocytes within a low ionized calcium environment as with regional citrate anticoagulation when used in tandem with a hemodialyzer in CKRT circuits in adults [65,66]. In a small clinical trial, this device was shown it can be used safely in children with AKI and multiorgan dysfunction. Further investigation is needed to demonstrate that its use would be beneficial for treating pediatric patients with systemic inflammatory response syndrome with AKI.

●Advantages – CKRT mimics native kidney function with its continual ultrafiltration and solute clearance [67,68] and has several advantages over HD and PD in the management of patients with AKI.

•CKRT is more precise in delivering the goals of solute clearance and ultrafiltration than PD. Although PD provides continuous solute clearance and ultrafiltration, the rates of clearance are variable and dependent on the patient's clinical status. CKRT can control ultrafiltration separately from solute removal, which PD cannot, allowing for greater flexibility within the prescription.

•Because ultrafiltration is continuous and can be adjusted to meet the patient's needs with CKRT, there is usually no need for fluid restriction unlike that required in patients managed by HD. CKRT allows for administration of all necessary blood products, large volumes of medications, and adequate nutrition without compromising the volume status of the patient.

•CKRT provides superior uremia control compared with PD [69,70] or HD [71,72].

●CKRT access – Adequate vascular access is essential. Typically, the same principles apply to placement and selection of catheters for CKRT as for HD. (See 'Intermittent hemodialysis' above.)

●Components of the CKRT prescription – Prescription components are similar to those used for intermittent HD and many of the same issues apply to both modalities:

•Blood flow rate – Similar to HD, blood flow rate determines solute clearance with higher flow rates increasing diffusive clearance. Blood flow is dependent on the size and quality of the dialysis access and catheter. As noted above, the balance of higher blood flow and increased clearance must be weighed against the patient's hemodynamics and their ability to tolerate a higher blood flow rate. Typical blood flow rates also range from 3 to 10 mL/kg/minute.

•Dialysate/replacement flow rate – The dialysate flow rate does determine clearance provided by CVVHD and CVVH, but the replacement solution plays a larger role in determining convective clearance in CVVH and CVVHDF. The standard dose for combined dialysate and replacement rate is 2000 mL/1.73m²/hour or 30 to 50 mL/kg/hour though in some cases (eg, hyperammonemia and severe tumor lysis) higher rates of 4000 to 8000 mL/1.73m²/hour may be needed [73,74].

•Dialysate composition – Dialysate or replacement fluids come in a variety of commercially available formulations, but modification based on patient needs is possible [75]. However, because of potential pharmacy compounding errors when manually preparing custom solutions, caution needs to be exercised when performing these alterations [47].

•Size of the dialyzer – Most CKRT machines have an adult and pediatric set for CKRT with limited options for dialyzer size and extracorporeal blood volume. The volume of these circuits is often >10 percent of the blood volume for children who weigh less than 10 kg. Newer devices are available specifically designed for infants and neonates with smaller dialyzer surface area and blood volume (table 8).

•Ultrafiltration – CKRT allows for slow, continuous fluid removal which is often better tolerated in the hemodynamically unstable patients and can be adjusted on an ongoing basis depending on the fluid intake needed for medication and nutrition to attain a daily fluid balance goal.

•Anticoagulation – Anticoagulation is typically required with pediatric CKRT due to the higher risk of clotting due to low blood flow rates through the small caliber catheters and tubing. In rare cases, anticoagulation may not be required in larger patients with high blood flow rates or in patients with coagulopathies (ie, liver failure patients).

Anticoagulation therapy can be provided regionally or systematically. Regional anticoagulation is typically the preferred method of anticoagulation at most pediatric centers, but this choice is highly dependent on patient characteristics and the experience of the center and its staff. (See "Anticoagulation for continuous kidney replacement therapy".)

-Regional anticoagulation – Citrate is the preferred method of regional anticoagulation in pediatric patients. Regional anticoagulation should be considered in pediatric patients with significant bleeding risk, especially central nervous system hemorrhage risk (see "Anticoagulation for continuous kidney replacement therapy"). There are commercial preparations of sodium citrate or anticoagulant citrate dextrose solution designed for CKRT use. However, citrate anticoagulation has several key requirements which must be considered including separate central access for calcium infusion, arterial line for accurate lab draws, dialysate with no calcium and the need to measure ionized calcium levels frequently. Relative contraindications for citrate anticoagulation include liver failure, mitochondrial disorders, and infants as they are at risk of citrate accumulation. Complications with citrate anticoagulation include hypo- or hypercalcemia, hypernatremia, hyperglycemia, and metabolic alkalosis. Regional citrate anticoagulation has shown longer circuit life than heparin in several pediatric studies [76,77]. New protocols are being designed for the use of other regional anticoagulation agents including prostacyclins (eg, epoprostenol) and serine proteinase inhibitors (eg, nafamostat mesylate), which show promising safety and efficacy [78-80].

-Systemic anticoagulation – Unfractionated heparin is the most common form of systemic anticoagulation for CKRT in pediatric patients. A few reports describe use of bivalirudin, especially when CKRT is used in conjunction with extracorporeal membrane oxygenation (ECMO) [81,82]. (See "Anticoagulation for continuous kidney replacement therapy".)

●Complications – CKRT complications are very similar to those of HD including infection and line complications. However, critically ill and hemodynamically unstable patients are often able to tolerate clearance and ultrafiltration better with CKRT versus HD as the therapy is run continuously rather than for short (three- to four-hour) periods of time.

●Challenges – The main disadvantages of CKRT are its complexity and expense, which limit its general availability. While it is an established therapy at many tertiary care hospitals in resource-abundant settings, CKRT requires significant technological expertise and resource allocation, including trained ICU nurses to monitor and adjust CKRT, and pediatric pharmacy support for modification of dialysate composition [38,83].

Other challenges include:

•Central line access – Like HD, adequate vascular access is essential. An additional central line may also be required for the administration of calcium chloride as part of regional citrate anticoagulation protocols.

•Limitations for small infants and neonates – For small infants and neonates, limitations are based on dialyzer and tubing size. In many cases, similar to intermittent HD, donor blood is needed to prime the extracorporeal circuit, which may expose these infants to transfusion risks and hypotension [84,85].

The feasibility and safety of CKRT in critically ill neonates and infants have improved with new technology. This includes dialyzers and tubing sets with lower priming volumes of blood that are able to run accurately at low blood flows between 5 and 50 mL/min via smaller-sized dialysis catheters (table 8) [86,87]. Additionally, new devices have been developed or previously existing devices have been modified to make CKRT safer for neonates and infants. The Cardio-Renal Pediatric Dialysis Emergency Machine (Carpediem) is now approved in several countries, including the United States, for CKRT in patients weighing between 2.5 to 10 kg [86,88,89]. This system has two dialyzer cartridges which have priming volumes of 32 and 41 mL. They have successfully utilized small-bore dialysis catheters (4 to 7 Fr) with blood flow rates as low as 5 mL/min. However, the experience using this system in critically ill patients has been limited to a few tertiary centers.

A multicenter study reported the successful use of modified aquapheresis utilizing the Aquadex FlexFlow System in critically ill pediatric patients as small as 2.6kg [85]. Although this device has a small extracorporeal volume of 33 mL, a blood prime was still needed for patients weighing <4 kg.

•Effect on medications – Careful attention must be paid to medications that a patient is receiving because CKRT may alter the clearance of these drugs, especially those that are of lower molecular weight, water soluble, and not highly protein bound. Close collaboration with a pharmacist knowledgeable about drug dosing is a key component for the care of children receiving CKRT.

Prolonged intermittent kidney replacement therapy — Prolonged intermittent KRT (PIKRT) is defined as intermittent KRT performed over a prolonged time period (6 to 12 hours) using conventional HD machines. Adult trials have shown PIKRT to be more cost effective and have similar efficacy as CKRT. Pediatric studies are limited to one small case series of four patients that reported the use of lower ultrafiltration and blood flow rates with excellent survival [90]. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose", section on 'Prolonged intermittent kidney replacement therapy'.)

Comparisons of modalities — There have been no prospective clinical trials comparing the three modalities (PD, HD, and CKRT) for treatment of children with AKI. Several trials in adults have demonstrated no difference in survival between CKRT and HD. (See "Kidney replacement therapy (dialysis) in acute kidney injury in adults: Indications, timing, and dialysis dose".)

Observational data in children with AKI include the following:

●A retrospective population-based study from the United Kingdom of children who received KRT from 2005 to 2012 reported improved survival with PD compared with CKRT [91].

●In EurAKId, a multicenter European prospective registry of 340 ICU and non-ICU KRT pediatric patients (86 percent with AKI) from 2016 to 2020, 64 percent of patients received CKRT, 14 percent PD, and 14 percent HD [92]. Overall survival was 65 percent, with CKRT patients having the highest mortality, but the difference in modality also correlated with primary disease, comorbidities, and patient age.

●In a retrospective review of 7109 critically ill pediatric KRT patients from 2009 to 2015, 47 percent received CKRT, 36 percent HD, and 18 percent PD [93]. The highest mortality was in CKRT patients (39 percent) compared with HD (10 percent) and PD (12 percent), but the mortality analysis did not control for severity of illness and higher mortality rates were also associated with certain diagnoses.

These retrospective studies are limited by the lack of control for confounding factors, such as severity of illness, underlying etiology of AKI, comorbidities, and patient age/size. This lack of prospective, randomized data has left the unresolved debate about why AKI patients on KRT have higher morbidity and mortality compared with AKI patients treated with conservative measures. We eagerly await the results from larger cohorts of pediatric KRT patients including the Worldwide Exploration of Renal Replacement Outcomes in Kidney Diseases Collaborative, an international multicenter retrospective cohort of pediatric patients who received CKRT for AKI or fluid overload.

Future research is needed to determine the best approach to treat pediatric AKI. In particular, randomized trials that evaluate early initiation of KRT or that compare different approaches to preventing fluid overload and AKI medical management (eg, diuretics) would be vitally important for guiding clinical decision making in children with AKI.

DISCONTINUATION — 

The factors determining when or how KRT should be discontinued (or transitioned to another modality) are even less well described than the factors determining initiation. No clear approach for dialysis step down or discontinuation has been defined for patients with AKI. Just as with initiation, KRT cessation or modality change is influenced by multiple factors such as urine output (including response to diuretic therapy), hemodynamic stability, respiratory, nutritional and volume status, and changes in underlying disease and overall prognosis. Other considerations may include ongoing resource use, staff availability, family/caregiver wishes, and long-term patient needs. For example, if a patient with multiorgan failure has improved and is at the point of extubation, it may be reasonable to change the patient from a continuous therapy to intermittent HD to facilitate patient rehabilitation and transfer from the pediatric intensive care unit (ICU) to the ward.

Guidelines or strategies have not been published regarding transitioning patients off of KRT. Unlike mechanical ventilation weaning, which has been studied extensively, the approach to tapering and discontinuation of KRT is an area for continued investigation.

OUTCOMES — 

Retrospective data demonstrate that the overall survival rates range between 50 and 75 percent in children with AKI who received KRT [9,91,94-97]. Factors that increase mortality include:

●Underlying diseases that cause secondary kidney failure, including bone marrow failure, hepatic failure, oncohematologic and severe pulmonary disease. In addition, stem cell and solid organ transplantation (eg, lung and liver) are associated with poorer survival [9,91,95,98].

●Hypotension at the onset of KRT [94].

●Use of inotropic agents anytime during the course of KRT [94,97].

●Degree of fluid overload present on initiation of KRT [9,22,97].

●Patients under one year of age [91].

Children who received CKRT have an increased risk for chronic kidney disease [99,100], and patients with AKI have been shown to have increased risk of proteinuria and hypertension in addition to chronic kidney disease. Additional studies are needed to determine whether other measures including chronic kidney disease, hypertension, and proteinuria during and after KRT are predictive for long-term outcome.

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

●Acute kidney injury (AKI) and role of kidney replacement therapy (KRT) – For infants and children, AKI is an independent predictor of morbidity and mortality, especially in critically ill patients. KRT may prevent and correct the adverse and potentially life-threatening complications and improve survival. (See 'Acute kidney injury and mortality: Potential role of kidney replacement therapy' above.)

●Indications

•Urgent indications for KRT include (see 'Urgent indications' above):

-Clinically significant fluid overload and evidence of escalating ventilatory requirements (typically seen in patients with >15 percent fluid overload). (See 'Fluid overload' above.)

-Critical illness and persistent hyperkalemia (eg, potassium level >6.5 mEq/L) that is refractory to medical management. Such children are at risk for life-threatening cardiac conduction abnormalities due to hyperkalemia. (See "Causes, clinical manifestations, diagnosis, and evaluation of hyperkalemia in children", section on 'Cardiac conduction abnormalities'.)

-Critical illness and persistent metabolic acidosis that is refractory to medical management.

-Complications due to uremia, including pericarditis, encephalopathy, or unexplained change in mental status and bleeding.

-Exposure to either endogenous or exogenous toxins that are dialyzable and are inadequately excreted by the kidney.

•Nonurgent indications include (see 'Nonurgent indications' above):

-Severe uremia. Although there are insufficient data to support evidence-based guidelines that include quantifiable values for uremia, we suggest that KRT should be initiated early based on a serum blood urea nitrogen (BUN) level between 80 and 100 mg/dL prior to the development of significant signs and symptoms of acute kidney failure rather than delaying dialysis until the child is symptomatic (Grade 2C). (See 'Severe acute kidney injury' above.)

-Oliguria despite diuretic therapy in a patient who requires high volumes of intravenous fluids (eg, for nutrition, medications, and/or blood products).

●Modalities – Several KRT modalities, including peritoneal dialysis, intermittent hemodialysis, and continuous KRT, are available to manage pediatric patients with AKI. PD is the most common modality utilized in pediatric dialysis, particularly in the smallest children. Data are insufficient to recommend one modality over another. Thus, the selection of modality of KRT is based on patient factors (size, underlying illness, ability to obtain access), local expertise and experience, and available resources. (See 'Kidney replacement therapy modalities: Overview' above.)

●Multidisciplinary team – Initiating KRT in a critically ill child requires collaboration among the nephrologists, intensivists, and other subspecialists caring for the child. Early discussion and planning will facilitate the process and allow for more rapid intervention, thereby improving survival outcomes. (See 'Kidney replacement therapy modalities: Details and clinical considerations' above.)

●Outcome – Retrospective data demonstrate the overall survival rates range between 50 and 75 percent in children with AKI who received KRT. Risk factors for mortality include the underlying disease, hypotension, and significant fluid overload at the start of KRT; use of inotropic therapy during KRT; and age under one year. (See 'Outcomes' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Patrick D Brophy, MD, who contributed to earlier versions of this topic review.