Acute Kidney Injury in Children

Acute kidney injury (AKI) is the sudden decrease in kidney capacity function, resulting in a decrease in glomerular filtration and ultimately an increase in serum creatinine level. AKI can be associated with multiple complications, including azotemia (elevated blood urea nitrogen [BUN] level), electrolyte abnormalities (hyperkalemia, acidosis, hyperphosphatemia, etc.), and fluid accumulation.

Over the past 10 years, understanding of the epidemiology, risk factors, outcomes, and treatment of children with ARI has expanded significantly. This review provides an in-depth update on AKI with special attention to definition, renal physiology, epidemiology, outcomes, diagnosis, and treatment.

Advancing understanding of the epidemiology and impact of ARI in children has been driven by the development and use of consensus definitions of ARI. This evolution began with the RIFLE criteria (Risk, Injury, Failure Stage, Loss and Final Stage), (1) which was adapted to form the pediatric RIFLE criteria. (2) This was followed by the definition of the Acute Kidney Injury Network. (3)

The Kidney Disease: Improving Global Outcomes (KDIGO) consortium has consolidated these criteria and presented the current consensus definition of AKI. (4) The KDIGO definition of AKI is based on an absolute increase in serum creatinine or a change in urine output. This definition captures the spectrum of mild to severe AKI, which is associated with adverse outcomes. At this time, in practice and research, the KDIGO definition should be used to define ARF in children. (5)

The KDIGO definition of AKI is anchored to changes in the serum creatinine level from a baseline value (usually a stable level over the previous 3 months) and/or a decrease in urine output. The 2 common practices used if the reference value of the creatinine level is unknown include the use of the high normal level based on laboratory standards or retrospective calculation based on an estimated glomerular filtration rate (GFR) of 100 to 120 ml/ min/1.73 m 2 .

The increase in serum creatinine level in ARF is due to a decrease in GFR. Currently, a change in creatinine level remains the gold standard for diagnosing AKI, but serum creatinine has a variety of weaknesses as a biomarker.

Most importantly, the increase in serum creatinine level is delayed until 48 hours after damage to the kidney has already occurred, and serum creatinine represents a marker of function and not injury . Additional challenges with serum creatinine are that it varies with age, sex, and nutritional status. There are currently multiple novel injury biomarkers under investigation that appear to predict subsequent AKI.

Urine output represents the second component of the KDIGO definition of ARI. The Worldwide Assessment of Acute Kidney Injury, Angina Renal and Epidemiology (AWARE) study, a multinational evaluation of ARF in pediatric critical care, showed that the addition of urine output criteria identified clinically relevant cases of ARF associated with adverse outcomes. that would have gone unnoticed using only criteria based on serum creatinine. (6)(7)

The diagnosis of ARF in newborns deserves special consideration and discussion.

The main challenges with defining AKI in this population come from the presence of maternal creatinine in the baby’s bloodstream after birth and postnatal changes in the newborn’s GFR. In parallel with the development of standardized definitions of ARF for older populations, a consensus definition of neonatal ARF has been developed.

The modified KDIGO neonatal AKI criteria are the agreed definition of neonatal AKI, supported by multidisciplinary experts from the National Institute of Diabetes and Digestive and Kidney Diseases - sponsored by the Neonatal ARI workshop in 2013. ( 8)(9)(10) This KDIGO modified neonatal AKI staging system is based on an increase in the serum creatinine level from a previous trough. This staging system was studied in single-center studies and validated in the international Assessment of the International Epidemiology of Acute Global Kidney Injury in Neonates (AWAKEN) study. (eleven)

Prior to the use of standardized definitions, there were limited data on the precise incidence and prevalence of pediatric ARF. Sutherland et al (12) used International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis codes for ARI and reported an incidence of 3.9 per 1,000 pediatric admissions.

Another study using retrospective data from electronic health records (EHRs) estimated that AKI occurred in at least 5% of all hospitalized children who were not critically ill. (13) A population-based study in Norway from 1999 to 2008 using ICD-10-CM codes to identify ARI in children under 16 years of age found an incidence of 3.3 cases per 100,000 children. (14)

The multicenter, international, prospective AWARE study was a landmark epidemiological study of ARF in critically ill, hospitalized patients. (6) Kaddourah et al examined 4,683 patients, aged between 3 months and 25 years, from 32 PICUs in participating centers. (6)(7) AKI occurred in 26.9% of participants (n = 1,261), and severe AKI (KDIGO stage 2 or 3) in 11.6% of participants (n 5,543). In this study, severe AKI was associated with an incremental risk of death by day 28 and increased use of renal replacement therapy (RRT) and mechanical ventilation.

Outside of the ICU population, some of the most recent data comes from several health systems that use electronic alerting devices (e-alerts).

A recent retrospective cross-sectional study analyzing the incidence of ARF using an electronic alert algorithm based on serum creatinine in 6 hospitals in England reported an incidence of 10.8%, with the majority of patients diagnosed with ARF being younger than 6 years. and they had stage 1 ARF. (15)

A prospective national cohort study using the Welsh electronic ARI reporting system reported an incidence of 77.3 ARI cases per 100,000 person-years, with 84% of all ARIs being stage 1. (16)

A large study of more than 1.5 million children cared for in the Northern California Kaiser Permanente health system between 2008-2016 showed an estimated incidence of community ARI of 0.7 cases per 1,000 person-years, and two-thirds of cases were not associated with an ICU stay. (17)

There is limited data on the global burden of ARI, particularly from low- and middle-income countries (LMICs). In the 0by25 Global Snapshot study, 80% of ARI cases identified occurred in the LMIC community compared to 20% in high-income countries (HICs). (18)

Children in high-income countries were younger and mostly suffered from ARI due to hypotension, post-surgical complications, or dehydration. In LMICs, the most common causes of AKI included infection, nephrotoxic medications, and primary kidney diseases.

A systematic review and meta-analysis of large cohort studies from 2004 to 2012 by Susantitaphong and colleagues (19) showed pooled incidence rates of ARI in children of 33.7% (95% confidence interval [CI], 26.9). %–41.3%), with a mortality rate associated with ARF of 13.8% (95% CI, 8.8%-21.0%). However, more than 80% of the included studies came from PIAs.

Normal renal function encompasses biochemical homeostasis, maintenance of fluid balance, regulation of blood pressure, and endocrinological control of processes such as erythropoiesis and bone mineral balance.

Kidney dysfunction can cause disorders in any or all of these areas.

In the setting of AKI, the clinical focus generally focuses on fluid/electrolyte concentration balance and changes in renal clearance, although other problems related to renal function may also occur.

The kidneys receive between 20% and 25% of cardiac output, which is distributed to the nephrons of the kidney, entering the glomeruli through the afferent arterioles and leaving through the efferent arterioles.

Transmembrane pressure across each glomerulus generates a cell-free glomerular filtrate, which then passes through the renal tubule. During tubular transit, water and other molecules are reabsorbed and/or secreted into the tubular fluid, according to homeostatic needs, to generate final urine, which leaves the kidneys for excretion.

Complex regulatory systems control total filtration in all glomeruli (GFR), free water balance, and biochemical balance. In low-volume states, urine output decreases under the influence of neurohumoral systems, including the renin-angiotensin-aldosterone axis, to limit further volume loss and maintain intravascular volume.

In excess volume, the opposite occurs. Tubuloglomerular feedback adjusts GFR through variations in glomerular perfusion pressure based on renal tubular chloride flux.

The urinary biochemical content varies depending on the interaction of the active and passive transport systems in the renal tubule. Osmolar balance depends on the interference involving hypothalamic monitoring and pituitary excretion of antidiuretic hormone (ADH) and the interface between specialized renal tubular epithelial cells and the renal medullary interstitium.

Therefore, normal urine output and kidney function come from a complex balance of interactions between specialized epithelia and endothelial structures in the kidney, cellular transport mechanisms, macrovascular and microvascular blood flows, and engineered neurohumoral signaling and monitoring systems. to maintain homeostasis.

The traditional categorization of ARF into prerenal (i.e., low perfusion), postrenal (i.e., urinary obstruction), and intrinsic (i.e., kidney-related) is a useful heuristic, but it oversimplifies the complex physiology seen in kidney dysfunction. In particular, the term prerenal AKI has fallen out of use in favor of the newer term— functional AKI —which better supports the implication that low urine output in some settings is appropriate and adaptive rather than evidence of injury. or dysfunction.

> Functional IRA

Functional ARF is due to reduced blood flow to the kidney.

Reduced renal perfusion may also be observed in states of volume depletion (hemorrhage, gastrointestinal tract losses, urinary losses). Fluid redistribution leading to suboptimal renal perfusion may occur due to low levels of oncotic pressure in the vascular compartment (e.g., hypoalbuminemia due to nephrotic syndrome, liver disease, protein-losing enteropathy) or increased leakage. capillary (e.g., systemic inflammation, sepsis).

Systemic vasodilation or poor vascular tone often seen in critical illness may have similar effects on renal perfusion. Poor renal perfusion may also be seen with low cardiac output due to underlying cardiac disease or due to increased resistance to flow (abdominal compartment syndrome, renal artery stenosis). Previously healthy children with functional ARF may have a single cause of low effective circulating volume. On the other hand, ARF in hospitalized children may have a multifactorial origin.

Reduction in renal blood flow stimulates a cascade of compensatory mechanisms, including activation of the reninangiotensin-aldosterone system, increased sympathetic tone, release of ADH, and release of prostaglandins by the local paracrine system.

The local effect of prostaglandins leads to afferent arteriolar vasodilation, which helps maintain blood flow and glomerular filtration in the underperfused kidney. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen in volume-depleted children may worsen ARF by preventing this compensatory afferent arteriolar vasodilation. At the same time, angiotensin II causes efferent arteriolar constriction, and disruption of this mechanism by angiotensin-converting enzyme inhibitors predisposes these patients to functional ARF.

Activation of the renin-angiotensin-aldosterone system and release of ADH lead to increased sodium and urea reabsorption, respectively, which, together with water reabsorption, leads to oliguria and the characteristic urinary findings in functional ARF.

Functional AKI is usually easily reversible with improved perfusion.

This is seen with oliguria in volume depletion that is quickly corrected with volume expansion. Whether functional ARF decreases with simple maneuvers may depend on the patient’s overall clinical condition and whether the underlying physiology is adaptive or maladaptive.

> Post-renal ARF

Postrenal ARF is rare in pediatrics and is due to processes that obstruct the flow of urine. These include those resulting from local mass effect (bilateral ureteral obstruction or urethral obstruction by a tumor), nephrolithiasis, or clots in the bladder.

> Intrinsic IRA

Intrinsic AKI refers to direct renal parenchymal damage or dysfunction.

This can be seen in conditions that cause tubular, interstitial, glomerular, or vascular damage; exposure to nephrotoxins; and AKI from critical illnesses associated with multiple organ dysfunction. AKI frequently occurs in tertiary care centers that care for patients with multisystem diseases. Understanding of the mechanisms underlying intrinsic ARF continues to evolve.

> ARI in sepsis . Multiple factors interact in sepsis to cause ARF. Older concepts of renal hypoperfusion leading to ischemic injury and “acute tubular necrosis” are not well supported by histological studies that fail to show necrosis in the kidneys of patients who died with septic ARF. (20) (21)

Animal models of sepsis do not show a universal reduction in renal blood flow, and some models indicate that renal blood flow may be increased in sepsis, not reduced, due to a hyperdynamic state with elevated cardiac output. (22) Furthermore, other models of renal underperfusion, such as cardiac arrest (23) and the process of kidney harvest for transplantation, do not always result in significant AKI. Gene activation patterns in septic ARF appear to differ from those observed in functional ARF, (24) suggesting different physiological pathways. AKI in sepsis is clearly more complicated than previously imagined.

ARF in sepsis is likely due to an interaction between the body’s responses and maladaptive mechanisms to the disease. Systemic inflammation, including the elaboration of reactive oxygen and nitrogen species, causes local changes in renal blood flow and tubular injury. Alterations in microvascular flow patterns, possibly exacerbated by inflammation associated with microthrombus formation, reduce glomerular pressure, while changes in renal tubules cause autoregulatory systems to decrease glomerular perfusion. This interaction of mechanisms leads to lower GFR and oliguria. (25)

Several interactive processes have been proposed that would cause this sequence of events. Receptors on neutrophils recognize pathogen-associated molecular patterns made by infectious agents and damage-associated molecular patterns released from injured cells. This recognition leads neutrophils to produce reactive oxygen and nitrogen species, cytokines and chemokines, which, together with the molecular patterns associated with pathogens and damage, can enter the renal microcirculation.

In response, blood may divert away from the glomeruli, leading to reduced glomerular perfusion and a fall in GFR. Activated neutrophils can also cause renal tubular cell injury (loss of polarity, changes in energy utilization, cell cycle arrest), further inhibiting normal renal function. (26)

The endothelium can suffer direct damage with inflammation, leading to endothelial cell dysfunction, loss of protective glycocalyx (the gel-like layer that covers the luminal surface of vascular endothelial cells), changes in vascular permeability, and release of more reactive molecules. (27) (28) Although further details remain to be clarified, the simple model of hypoperfusion leading to renal cell injury and subsequent AKI is clearly insufficient to explain the complex interactions underlying renal dysfunction in sepsis. (29)

> ARI in heart diseases . Patients with significant cardiac dysfunction, such as heart failure, may develop kidney complications. Cardiorenal syndrome ( CRS) was originally defined as renal dysfunction that occurred in association with decompensated heart failure and its treatment. The SCR concept has been expanded to encompass a spectrum of cardiac and renal disorders in acute or chronic settings characterized by mutual deterioration. (30)

Acute subtypes of CRS begin with primary cardiac dysfunction leading to AKI (CRS type 1) or with AKI leading to cardiac decompensation (CRS type 3). CRS types 2 and 4 are analogous chronic disorders; In CRS type 2, primary chronic cardiac dysfunction leads to a sustained reduction in renal function and CRS type 4 is characterized by chronic kidney disease (CKD) leading to chronic cardiac dysfunction.

CRS type 5 begins with noncardiac, nonrenal systemic disease that later leads to heart-kidney deterioration. Autoregulatory maladaptation and inflammation, as in sepsis, can occur in CRS with deleterious effects on the heart and kidney. Venous congestion is also a complicating factor, initiated either by heart failure or oliguria and exacerbating the dysfunction of both organs.

> IRA in other configurations . Glomerular and vascular causes of intrinsic AKI are more common in previously healthy children. The timing and clinical presentation often suggest isolated glomerulonephritis (GN) (e.g., postinfectious GN [PIGN]) or multisystem autoimmune diseases affecting the kidney (e.g., IgA vasculitis [formerly Henoch-Schönlein purpura]. or systemic lupus erythematosus [SLE]). Vascular etiologies include microangiopathic conditions (hemolytic uremic syndrome, thrombotic microangiopathy, and thrombotic thrombocytopenic purpura) and systemic vasculitides affecting medium and large vessels.

Acute interstitial nephritis ( AIN) is most commonly due to drug exposure, although it can also be caused by systemic autoimmune disorders (SLE, Sjögren’s syndrome, sarcoidosis) and infections; AIN also occurs in tubulointerstitial nephritis with uveitis syndrome.

The timing is unpredictable with AIN and can develop within 3 to 5 days after being re-exposed to a harmful medication or can occur weeks or months after an exposure. Medications can cause AKI in ways other than AIN. Exposure to nephrotoxins is now recognized as a common cause of intrinsic AKI, particularly in hospitalized patients.

Angiotensin-converting enzyme inhibitors and NSAIDs can cause AKI by blocking renal vascular autoregulation. Other medications that can cause AKI include aminoglycosides, amphotericin, calcineurin inhibitors (cyclosporine, tacrolimus), and chemotherapeutic agents (cisplatin, ifosfamide, methotrexate). Endogenous elements such as hemoglobin and myoglobin, observed in patients with massive hemolysis or rhabdomyolysis, can obstruct the tubules and/or cause direct toxicity to the kidney.

A complete history and physical examination are essential to making the diagnosis of ARF and determining the underlying cause. A systematic approach is important to identify potential functional, intrinsic, and obstructive causes. Based on history, one may be able to delineate risk factors for functional ARF.

There may be a history of volume loss (gastroenteritis, hemorrhage), circulatory volume redistribution (nephrotic syndrome, sepsis), low cardiac output, or conditions that cause increased resistance to renal blood flow (massive edema and abdominal compartment syndrome) renal artery stenosis ). Additional clues on the history and physical examination include recent illness/sore throat (PIGN), rash, arthralgia/arthritis (SLE), gross hematuria, or exposure to a new or known nephrotoxic medication.

Prenatal history in neonates with suspected postrenal ARF may provide details of fetal ultrasound abnormalities, such as large bladder, hydronephrosis, or oligohydramnios, which in turn suggest bladder outlet obstruction or posterior urethral valves in a male infant.

Accurate assessment of urine output over the preceding days can help categorize the patient as having oliguria (defined as urine output <1 mL/kg per hour) or not. This can also define the severity of the ARI. As discussed above, elevation of creatinine level can be delayed up to 48 hours after kidney damage has occurred. Therefore, episodes of hypotension, hypoxia, sepsis, surgery, and drug exposures that occurred in the previous 48 to 72 hours must be considered.

Initial laboratory evaluation of AKI should include an electrolyte panel, BUN, serum creatinine, urinalysis, urine sodium, urine urea nitrogen (NU), urine creatinine, and renal ultrasound. Urine studies can allow differentiation between functional AKI and intrinsic AKI. Fractional excretion of sodium (EF Na ) and fractional excretion of urea (EF urea ) can be calculated as follows:

EF Na = (Urinary Na * Serum Creatinine) * 100%

               (Serum Na * Urinary Creatinine)

EF Urea = (urinary NU * Serum Creatinine) * 100%

               (BUN * Urinary creatinine)

Typical laboratory findings of functional ARF include normal urinalysis, concentrated urine (osmolality >500 mOsm/kg), EF Na less than 1% (<2% in newborns), EF urea less than 35%, urinary sodium less than 20 mEq/L (<20 mmol/L) and a ratio of BUN (mg/dL) to creatinine (mg/dL) greater than 20. Loss of the concentrating ability of urine is classically observed in the tubular dysfunction of some forms of intrinsic ARF. A positive result for blood on the urine dipstick without microscopic evidence of red blood cells warrants further evaluation for hemoglobinuria (hemolysis) or myoglobinuria (rhabdomyolysis).

Urinalysis with microscopy may show findings associated with conditions such as acute tubular injury (“muddy” granular casts) or GN (red blood cell casts). GNs may have additional findings, including hematuria and proteinuria.

A history of a recent upper respiratory tract infection (typically pharyngitis 2 to 3 weeks prior) or skin infections 4 to 6 weeks prior with these urinary findings may suggest PIGN. These patients should have their serum complement levels evaluated and may show low levels of C3 and normal levels of C4. IgA nephropathy may present with a more recent upper respiratory tract infection (2 to 3 days previously) and gross hematuria (sympharyngitic GN) with normal complement levels.

The presence of systemic signs and symptoms such as rash or arthritis and a urinalysis consistent with GN suggests SLE (low levels of C3 and C4) and requires additional antibody testing (antinuclear and anti-double-stranded DNA antibodies).

Pulmonary renal syndrome presents with pulmonary signs and symptoms such as cough, hemoptysis, chest x-ray infiltrates, and active GN. Causes of pulmonary renal syndrome often include the presence of antiproteinase 3 antibodies, microscopic polyangiitis (perinuclear ANCA, often with the presence of antimyeloperoxidase antibodies), eosinophilic granulomatosis (perinuclear ANCA), and antiglomerular basement membrane antibody disease. Although a kidney biopsy may not be necessary in a classic PIGN, it is important to confirm the diagnosis and to guide treatment of the other GN because the degree of renal involvement in a variety of these syndromes dictates the extent of treatment.

Rapidly progressive GN, defined by steadily increasing BUN and creatinine levels, can be seen in any of the GNs. Rapidly progressive GN requires urgent evaluation, including renal biopsy, and prompt treatment to prevent irreversible progression of kidney disease.

Allergic interstitial nephritis may be associated with fever, rash, and eosinophilia. However, the classic triad is seen in less than 15% of patients. Patients usually have a urine sediment with occasional white blood cell casts, but no red blood cell casts.

Eosinophils can be observed in the urine, but their presence lacks sensitivity and specificity for the diagnosis of interstitial nephritis. The degree of proteinuria can be variable; Nephrotic range proteinuria may be observed in patients with interstitial nephritis associated with NSAIDs. The diagnosis of AIN can only be confirmed with a kidney biopsy.

Hemolytic uremic syndrome should be suspected in patients with ARF in the setting of recent diarrheal illness, low platelet count, and hemolytic anemia.

A peripheral blood smear with schistocytes can confirm hemolysis. Atypical hemolytic uremic syndrome caused by non-diarrheal infections (Streptococcus pneumoniae, Bordetella pertussis, Haemophilus influenzae, human immunodeficiency virus, cytomegalovirus, influenza H1N1) or genetic abnormalities in the complement system can be difficult to recognize and treat.

Renal ultrasound may provide limited information in intrinsic AKI. Kidney size may provide clues to the acuity or chronicity of renal dysfunction, with larger kidneys suggesting active inflammation and small-for-age kidneys suggesting a chronic process.

Ultrasound may also show the nonspecific finding of increased echogenicity. Ultrasound is essential for the diagnosis of obstructive ARF, where it can show unilateral or bilateral hydronephrosis. This may also provide clues to the site of obstruction, with bilateral hydronephrosis and/or hydroureters suggesting distal obstruction. If an obstructive process is diagnosed, the obstruction should be relieved immediately.

> Renal angina

Renal angina is a risk stratification construct that combines patient risk factors and early signs of kidney injury (fluid overload and change in creatinine level) for the prediction of severe AKI (stage 2 or 3) on the day 3 from the ICU. (31) Renal angina is a conceptual framework to identify evolving ARF and does not suggest physical symptoms.

It is evaluated by calculating the renal angina index (RAI), which is usually performed 12 hours after admission to an ICU. Patients receive a risk score and an injury score, which are multiplied to calculate the IAR, with a score of 8 or more being positive for renal angina. An IAR less than 8 has a high negative predictive value for severe AKI on day 3.

In a single-center study, Menon et al (32) reported that 32.6% of patients tested positive for renal angina on day 0 of ICU admission. Positive renal angina status on day 0 was associated with a higher incidence of AKI on ICU day 3 (23.1% vs 2.9%; p < 0.001). In the AWARE study, IAR demonstrated a better prediction of severe ARF than serum creatinine elevation from baseline (adjusted odds ratio, 3.21; 95% CI, 2.20–4.67). (33)

> Biomarkers

Traditionally, AKI biomarker research has sought to recapitulate the success of troponin in detecting myocardial infarction. However, unlike myocardial infarction, which primarily represents an ischemic injury, ARF is a syndrome with multiple phenotypes and etiologies and is caused by multiple heterogeneous mechanisms. Therefore, a single biomarker is unlikely to be appropriate for AKI.

Although creatinine is the most commonly used diagnostic marker for AKI, it is a marker of kidney function, not kidney injury.

In recent years, biomarkers of structural injury (e.g., neutrophil gelatinase-associated lipocalin [NGAL], tissue inhibitor of metalloproteinases-2, insulin-like growth factor-binding protein 7, and insulin-like growth factor-1 kidney injury) have been studied for the prediction, early detection, and diagnosis of subclinical ARF. (34) NGAL is one of the most studied AKI biomarkers in children. (3. 4)

In a cohort of 71 children after cardiopulmonary bypass, Mishra et al (35) demonstrated that the NGAL level controlled 2 hours after the start of extracorporeal circulation was an independent predictor of AKI in multivariate analysis (area under the receiver curve operating characteristic, 0.99845). Other studies have demonstrated the usefulness of NGAL in the early diagnosis of AKI, particularly after cardiac surgery. However, its performance has been less optimal in more heterogeneous populations because elevated levels of NGAL can be observed in multiple non-ARI-like conditions, including urinary tract infections, sepsis, and malignancy.

A trial of the combined tissue inhibitor of metalloproteinases-2 and insulin-like growth factor binding protein 7 is approved by the Food and Drug Administration (FDA) for use in adults and is commercially available.

Functional and damage biomarkers can be combined to identify different ARI phenotypes as proposed by the 10th and 23rd Acute Illness Quality Initiative consensus. (36) (37) Using a combination of function and damage biomarkers allows for earlier diagnosis and better delineation of AKI syndrome. It is important to understand that ARF as a syndrome is dynamic and patients can transition between subtypes.

> Stress test with furosemide

A recent advance in the early diagnosis and stratification of children at risk for ARF is the development of a renal function test that serves to identify patients at highest risk for severe and progressive ARF.

The furosemide stress test represents one such test and uses a single dose of furosemide in patients with stage 1 or 2 ARF followed by close monitoring of urine output for 6 hours. In studies of adults, a urine output of less than 200 mL in the first 2 hours after furosemide was shown to predict adverse outcomes (stage 3 AKI, need for renal supportive therapy, increased mortality). (38) (39)

A small, single-center series in children after cardiac surgery has suggested that furosemide stress testing can be used in children and neonates. (40) (41)

Further studies in children are necessary to define clinically relevant thresholds for furosemide stress testing in children. The Trial in AKI Using NGAL and Fluid Overload to Optimize CRRT Use (Approach 2) is an ongoing trial evaluating the impact of urinary biomarker mobilization and furosemide stress testing to improve outcomes in children at risk. of suffering from severe ARF. (42)

> Leveraging EHR systems

With the widespread use of EHRs, it has become feasible to use EHRs for clinical decision support systems. These include automated real-time alerts and diagnostic or therapeutic care packages. (16) (43)

ARF is well suited for e-alerts because it has a consensus definition and is easily diagnosed from discrete, readily available data (creatinine level and urine output). These alerts can be used to identify patients with ARI or people at high risk of ARI. Although electronic alerts have been shown to improve the recognition and diagnosis of AKI, there are limited data on outcomes in pediatric patients.

Electronic alerts may work best when combined with a standardized management care plan.

The first step in the treatment of children presenting with oliguria, hemodynamic instability, or hypotension is restoration of intravascular volume.

An initial bolus of isotonic fluids (20 mL/kg) should be administered rapidly and repeatedly according to pediatric advanced life support algorithms.

Isotonic fluids are used for acute volume expansion (normal saline, lactated Ringer’s, and balanced electrolyte solutions; albumin 5%; packed red blood cells). The clinical scenario drives the choice of fluids.

In recent years there has been increasing data suggesting a potential benefit of balanced electrolyte solutions compared to isotonic sodium chloride in improving renal function and decreasing the incidence of AKI. (44) (45) Recent work in children has suggested that intravenous fluid-related hyperchloremia is an independent risk factor for the development of AKI in children with sepsis. (46)

Children with underlying or suspected cardiac disease were generally given smaller initial fluid boluses (10 mL/kg) to decrease the risk of iatrogenic volume overload. During fluid resuscitation, it is essential to perform serial evaluations to detect signs of response (lower heart rate, improved blood pressure, improved capillary refill, urine output) and fluid overload (pulmonary or peripheral edema).

After fluid resuscitation, initiation of vasopressor support should be considered; Such support may be necessary sooner for those who have obvious fluid overload. Once the patient has been adequately resuscitated with fluids, a trial of time-limited diuretics (furosemide) may be considered if the patient remains oliguric. (4)

In children who remain oliguric after intravascular volume resuscitation, conservative methods of fluid management can be used by restricting fluids to insensible losses (300 to 500 mL/m 2 per day) plus replacement output to avoid subsequent volume overload. .

Pediatricians have been leaders in medicine in recognizing the deleterious effect of fluid accumulation on outcomes and the development of the disease state of fluid overload in children with and without ARF. (47) (48) (49) (50)

Classically, the term fluid overload has been used in the literature to denote a state of positive fluid balance, but this terminology is biased because it assumes that all fluid accumulation is pathological. In 2022, the pediatric consensus Acute Illness Quality Initiative sought to standardize terminology describing fluid balance; The terms daily fluid balance , accumulated fluid balance , and percent accumulated fluid have been proposed to describe fluid status in patients at risk of fluid overload . (51)

Fluid balance is an objective measure of fluid accumulation or loss based on cumulative intakes and outputs or changes in weight. Fluid overload represents a pathological state distinct from positive fluid balance with clinically observable adverse consequences. No single threshold can be used to describe fluid overload; rather, it is unique to the pathophysiology, the population, and the timing. To monitor the development of fluid overload, it is important to monitor the patient’s fluid balance and describe it daily as a vital sign in high-risk patients.

Individuals with AKI may present with various electrolyte disturbances, including hyponatremia and hyponatremia. hyperkalemia, metabolic acidosis and hyperphosphatemia.

Excessive sodium intake above the typical requirements in healthy children (2 to 3 mEq/kg per day) should be avoided to prevent high blood pressure and other complications of sodium overload. Potassium and phosphorus should be retained from fluids and restricted in the diets of children with ARF. Depending on serum levels, children with ARF may require intermittent replacement because low potassium (cardiac conduction abnormalities) and phosphorus (poor muscle contraction) levels may have adverse effects.

Hyperkalemia is one of the most serious complications of ARF. It can present with nonspecific symptoms, including fatigue, nausea, tingling, weakness, and even paralysis. Cardiac conduction abnormalities and arrhythmias are the most serious manifestations of hyperkalemia. Electrocardiogram (ECG) changes may occur when potassium levels are 6.5 to 7.0 mEq/L (6.5 to 7.0 mmol/L), but there is significant variability.

Potassium levels resulting in ECG changes fluctuate with acuity, associated electrolyte abnormalities (hypocalcemia, hypomagnesemia), and disease pathophysiology (tumor lysis syndrome, rhabdomyolysis). Typical initial ECG findings are spiked T waves. Other changes include a widened QRS complex, flattened P waves, and a prolonged PR interval. Untreated hyperkalemia can lead to life-threatening arrhythmias.

An ECG should be obtained in patients with potassium levels greater than 6 mEq/L (>6 mmol/L). In patients with potassium levels of 5.5 to 6.5 mEq/L (5.5 to 6.5 mmol/L) and adequate urine output without ECG abnormalities, one may consider treatment with a potassium-binding resin. potassium in the gastrointestinal tract (sodium polystyrene sulfonate) or a bolus of saline with furosemide.

If there are ECG changes, a potassium level greater than 7.0 mEq/L (>7.0 mmol/L), or a rapidly rising potassium level, hyperkalemia should be considered life-threatening and treated more aggressively. Initial rapid treatment measures include intravenous calcium gluconate, which acts to stabilize the cardiac membrane potential and limit the risk of arrhythmia, but does not reduce potassium levels. This may be followed by the administration of β 2 agonists , sodium bicarbonate and/or insulin with glucose.

It is essential to understand that these agents do not eliminate potassium from the body, but are simply temporary measures that act by displacing potassium intracellularly.

β 2 -agonists , such as albuterol, can be administered by nebulizer and have been shown to reduce potassium level by 1 mEq/L (1 mmol/L) (their use may need to be avoided in patients with underlying cardiac disease ). Insulin given with glucose drives potassium into cells by increasing the activity of sodium/potassium ATPase.

Sodium bicarbonate increases extracellular pH, resulting in the movement of hydrogen ions into the extracellular space with a shift of potassium ions intracellularly, and administration of sodium bicarbonate may be considered if there is an underlying acidosis. Trials evaluating sodium bicarbonate therapy in adults with hyperkalemia have not demonstrated efficacy, but this remains to be studied in children.

Along with these temporary measures, efforts should be made to eliminate potassium from the body, including the administration of loop diuretics with fluid boluses and sodium polystyrene sulfonate. Sodium polystyrene sulfonate should be avoided in neonates or children with underlying intestinal pathology. If these measures fail, or in the case of severe, life-threatening hyperkalemia, RRT should be considered.

The acidosis associated with AKI is classically described as anion gap acidosis. Except for the treatment of acidosis associated with hyperkalemia, the use of bicarbonate is reserved for severe acidosis. Administration of bicarbonate in these circumstances requires diligent monitoring because this may cause ionized hypocalcemia, as calcium is exchanged in plasma proteins for hydrogen ions. In severe cases, tetany may result from ionized hypocalcemia related to excessive bicarbonate supplementation.

Severe hyperphosphatemia can develop in AKI, particularly in pathological states characterized by high cellular turnover (tumor lysis syndrome, rhabdomyolysis). More commonly, hyperphosphatemia associated with AKI can be prevented or managed conservatively by limiting intake. Calcium and ionized calcium levels should be closely monitored in cases of severe hyperphosphatemia because intravascular binding of calcium to excess phosphorus can cause ionized hypocalcemia.

Contrast use

Radiocontrast agents have long been considered a cause of nephrotoxin-related AKI. However, the risk of AKI in patients exposed to intravenous iodinated contrast media has been exaggerated. Newer iso-osmolar agents appear to be less nephrotoxic, and overall concern about radiocontrast AKI has decreased. Both contrast-associated AKI (any AKI within 48 hours of contrast administration) and contrast-induced AKI (AKI caused by contrast administration) may be seen. (52)

Contrast-induced AKI is not common and may be seen in people with preexisting renal dysfunction. A patient should not be denied intravenous contrast due to concern for AKI in situations where information obtained from the contrast study could have therapeutic implications.

> Medications

Medications remain a common and increasingly recognized cause of ARI in children. Drug-associated AKI may occur secondary to tubular injury, tubular obstruction by crystals or cylinders containing drugs and their metabolites, and interstitial nephritis. Other reasons for an increase in creatinine level after drug exposure include drugs that can block tubular secretion of creatinine (e.g., cimetidine, trimethoprim, tyrosine kinase inhibitors) and drugs that cause hemodynamic changes in the glomerular blood flow.

Drug dosing is also affected in the setting of AKI due to changes in drug clearance due to alterations in glomerular system and renal tubular function, non-renal drug metabolism, or change in drug pharmacokinetics due to complications such as volume overload or metabolic acidosis. Dose adjustments in AKI can be difficult due to the challenges of assessing renal function while it changes rapidly. Drug selection and dosing in ARF requires periodic reassessment of renal function and trajectory, clinical response, availability of alternative therapies, and therapeutic drug monitoring.

> Nutrition

AKI is commonly characterized nutritionally by a catabolic state. Protein requirements in these children may be up to 3 g/kg per day of amino acids with a concomitant caloric requirement of 125% to 150% of that of healthy children and infants. To provide adequate protein, one typically allows BUN levels up to 40 to 80 mg/dL (14.28–28.56 mmol/L) in children with ARF.

One may consider limiting protein intake as a short-term or temporary measure to control BUN level, but this should not be used for long periods. Recent literature has shown that critically ill children with ARI often do not receive adequate nutrition. (53) RRT is indicated if adequate nutritional or metabolic balance cannot be achieved through conservative measures. Children receiving RRT have amino acid requirements of up to 3 to 4 g/kg per day. (54)

> Renal replacement therapy

RRT is considered when conservative measures to manage the ARF have failed or are unlikely to be sufficient. Indications for RRT in children with ARF include refractory acidosis, fluid overload, hyperkalemia, uremia (usually a BUN level >100 mg/dL [>35.70 mmol/L] or symptomatic), or an inability to provide adequate nutrition .

In recent years, the association between fluid accumulation and the development of the pathological state of fluid overload with adverse outcomes in critically ill children and newborns has become clear. In single- and multicenter studies, fluid overload has consistently been shown to be the most common indication for RRT in children. (55) Multiple studies have shown that a greater degree of fluid overload at the start of RRT was associated with increased mortality. (47) (48) (49) (56) (57)

RRT modalities include peritoneal dialysis, hemodialysis, and continuous RRT. The choice of modality depends on the center’s specific experience and resources, patient characteristics, and indications. Peritoneal dialysis is generally well tolerated and easily performed, but does not provide precise management of volumes or high clearance rates. Intermittent hemodialysis (typically for 3 to 4 hours) provides high clearance, but short, intermittent sessions make fluid removal difficult in critically ill patients.

In recent years, continuous RRT has become the most commonly used modality in critically ill children when resources are available. Continuous RRT provides advantages because it allows precise metabolic and volume control over a 24-hour period. The continuous nature of the therapy allows for improved nutritional support and more successful fluid removal. It is the most resource-intensive modality of renal support therapy and requires significant nursing support and care at the ICU level.

AKI has been independently associated with poor short- and long-term health.

It is related to a higher risk of rehospitalization, recurrent AKI, lower quality of life, and CKD. (58) (59) (60) Studies have reported proteinuria, hypertension, and reduced GFR after AKI. (61) (62) (63) Although this association is well understood, it is less clear whether AKI causes CKD or whether it highlights a lack of renal reserve or pre-existing renal dysfunction.

The KDIGO guidelines recommended a 3-month follow-up for all patients who developed AKI to evaluate the presence of CKD. However, most long-term studies show follow-up rates of less than 50%. Children who develop AKI require long-term observation and follow-up, with the intensity of post-AKI care depending on several factors, including the severity of AKI, recovery of kidney function, and other comorbidities.

Understanding of ARI in children has advanced over the last decade. It has become obvious that ARF is not a single disease limited to the kidneys, but rather a systemic syndrome that can affect multiple organs. The use of new tools such as AKI risk stratification models, biomarkers, and electronic alerts allows us to consider a dynamic and multidimensional approach, which can further improve the characterization and phenotyping of AKI. AKI management remains supportive, but these tools may also enable predictive enrichment and personalized management of pediatric AKI in the future.

The present review proposes the term acute kidney injury to represent the spectrum of clinically significant kidney damage. This entity continues to be poorly recognized and underdiagnosed in hospitalized pediatric patients, which is why different novel ARI risk stratification tools, biomarkers and electronic alerts are proposed to improve the approach to this pathology. It is highlighted that nephrotoxic medications are a modifiable risk factor for ARF that must be taken into account. On the other hand, carrying out adequate long-term follow-up of patients with ARF will reduce and prevent sequelae such as chronic kidney disease, hypertension, recurrent ARF and proteinuria.