Acute kidney injury (AKI) denotes an abrupt impairment of kidney function resulting in the retention of nitrogenous wastes and dysregulation of extracellular volume and electrolytes.
The Kidney Disease Improving Global Outcomes (KDIGO) criteria define AKI by any of the following parameters:
Absolute increase in serum creatinine of ≥ 0.3 mg/dL over 48 hours.
Percentage increase of ≥ 50% (≥ 1.5 times) from baseline in the last 7 days.
Reduction in urine output to less than 0.5 mL/kg/hr for more than 6 hours.
The KDIGO classification stratifies AKI severity into three stages based on the degree of serum creatinine elevation and the duration of oliguria.
Stage
Serum Creatinine Criteria
Urine Output Criteria
1
Increase to 1.5–1.9 times baseline OR ≥ 0.3 mg/dL absolute increase
< 0.5 mL/kg/hr for 6–12 hours
2
Increase to 2.0–2.9 times baseline
< 0.5 mL/kg/hr for ≥ 12 hours
3
Increase to ≥ 3.0 times baseline OR Serum creatinine ≥ 4.0 mg/dL OR Initiation of renal replacement therapy OR eGFR < 35 mL/min/1.73 m²
< 0.3 mL/kg/hr for ≥ 24 hours OR Anuria for ≥ 12 hours
Etiology
The etiology of AKI is broadly classified into three categories: prerenal, intrinsic renal, and postrenal causes.
Category
Key Pathological Mechanism
Common Pediatric Causes
Prerenal AKI
Decreased effective circulating arterial volume leading to renal hypoperfusion.
Neonates are uniquely predisposed to AKI due to a combination of incomplete nephrogenesis and transitional renal hemodynamics.
Prematurity and extremely low birth weight (ELBW) are highly associated with reduced nephron endowment and abnormal function.
Perinatal asphyxia and hypoxic-ischemic encephalopathy alter renal blood flow during the critical transition to extra-uterine life.
Necrotizing enterocolitis (NEC) triggers severe systemic inflammatory responses and hypotension.
Hemodynamically significant patent ductus arteriosus (hs-PDA) and the use of maternal nephrotoxic medications (NSAIDs, ACE inhibitors) significantly impair neonatal renal perfusion.
Pathophysiology
Phases of Acute Kidney Injury
Initiation Phase: Occurs when renal blood flow decreases to a level causing severe cellular ATP depletion, leading to acute tubular injury and a decline in the glomerular filtration rate (GFR).
Extension Phase: Characterized by continued regional hypoxia (especially in the corticomedullary junction) and the triggering of an intense inflammatory cascade, primarily mediated by microvascular endothelial damage and leukocyte infiltration.
Maintenance Phase: Renal tubule injury is established at its maximum severity, GFR stabilizes at its nadir, and cellular repair processes begin.
Recovery Phase: Marked by cellular differentiation, restoration of epithelial polarity, and a gradual return of normal organ function and GFR.
Hemodynamic and Microvascular Alterations
Severe ischemic or toxic insults lead to an imbalance of vasoactive compounds, causing intense renal vasoconstriction.
There is a marked upregulation of vasoconstrictors such as endothelin, adenosine, and components of the renin-angiotensin system, alongside variable alterations in nitric oxide and prostaglandin pathways.
Endothelial damage triggers the loss of the glycocalyx and upregulates adhesion molecules (ICAM-1, P-selectin, E-selectin), promoting leukocyte and platelet adhesion, which leads to microvascular congestion and persistent hypoperfusion.
Tubular and Cellular Injury
Severe ATP depletion impairs the Na+/K+-ATPase pump, leading to cellular swelling, loss of the apical brush border, and disruption of cell polarity.
Oxidative stress via reactive oxygen species (ROS) and the activation of phospholipases result in lipid peroxidation, membrane damage, and apoptosis or necrosis.
Detached, dead, and viable tubular epithelial cells, along with cellular debris, form casts that obstruct the tubular lumen, leading to increased intratubular pressure.
The loss of tubular epithelial integrity allows passive backleak of the glomerular filtrate into the peritubular capillaries, severely reducing the effective GFR.
Clinical Features
Oliguria (urine volume < 0.5 mL/kg/hr) or anuria is a hallmark symptom, though non-oliguric AKI is frequently observed in cases of nephrotoxicity (e.g., aminoglycosides) or interstitial nephritis.
Fluid retention manifests as peripheral edema, ascites, pulmonary edema (causing respiratory distress and orthopnea), and hypertension.
Accumulation of nitrogenous wastes leads to uremic symptoms, including nausea, vomiting, lethargy, encephalopathy, and seizures.
Electrolyte derangements frequently present with arrhythmias or cardiac arrest (due to hyperkalemia), or tetany (due to severe hypocalcemia and hyperphosphatemia).
Specific systemic features may indicate the underlying etiology, such as a purpuric rash and arthritis (IgA vasculitis/SLE), bloody diarrhea (STEC-HUS), or pharyngitis (APSGN).
Diagnostic Evaluation
Urine Analysis and Indices
Microscopic examination of the urine sediment is crucial: muddy brown granular casts suggest acute tubular necrosis (ATN), dysmorphic red blood cells (RBCs) or RBC casts indicate glomerulonephritis, and white blood cells or eosinophils point to acute interstitial nephritis.
Urinary indices differentiate functional, fluid-responsive prerenal azotemia from established intrinsic ATN.
Parameter
Prerenal Azotemia
Acute Tubular Necrosis (ATN)
Urine Sodium
< 20 mEq/L
> 40 mEq/L
Fractional Excretion of Sodium (FeNa)
< 1% (< 2.5% in neonates)
> 2% (> 10% in neonates)
Fractional Excretion of Urea (FeUrea)
< 35%
> 50%
Urine Osmolality
> 400 mOsm/kg
< 350 mOsm/kg
Urine Specific Gravity
> 1.020
< 1.010
Blood Investigations
Complete blood counts (CBC) and peripheral smear are evaluated for microangiopathic hemolytic anemia (schistocytes) and thrombocytopenia, highly suggestive of HUS or thrombotic microangiopathy.
Serum urea, creatinine, and electrolytes (sodium, potassium, calcium, phosphate, magnesium, bicarbonate) are monitored to assess severity and complications.
Immunological workup (Complement C3/C4, ANA, anti-dsDNA, ANCA, ASO titer) is indicated if rapidly progressive glomerulonephritis or systemic vasculitis is suspected.
Imaging and Advanced Diagnostics
Renal ultrasonography with Doppler evaluates kidney size, echogenicity, corticomedullary differentiation, and excludes obstructive uropathy or vascular thrombosis.
A renal biopsy is rarely needed but is indicated for rapidly progressive glomerulonephritis, unexplained prolonged ATN (> 2-3 weeks), suspected acute interstitial nephritis, or unexplained severe AKI.
Furosemide Stress Test: A standard dose of furosemide (1–1.5 mg/kg) is administered to patients suspected of early AKI; a urine output < 200 mL in the first 2 hours predicts progression to severe AKI stages.
Renal Angina Index (RAI): A validated scoring system utilized 12 hours post-ICU admission that multiplies risk factors (e.g., stem cell transplant, mechanical ventilation) by injury markers (fluid overload percentage, SCr rise). A score ≥ 8 strongly predicts severe AKI development.
Novel Biomarkers: Neutrophil gelatinase-associated lipocalin (NGAL), Kidney Injury Molecule-1 (KIM-1), Liver-type Fatty Acid Binding Protein (L-FABP), and IL-18 rise 24-48 hours prior to serum creatinine, allowing early identification of tubular injury. Cell cycle arrest markers like TIMP-2*IGFBP-7 are FDA-approved predictors of imminent AKI in critically ill patients.
Management
General Measures and Fluid Management
A careful review of medications is mandatory to discontinue nephrotoxic agents (aminoglycosides, NSAIDs, contrast media, ACE inhibitors) and to adjust drug dosages based on the estimated GFR.
For prerenal AKI due to volume depletion, prompt intravascular volume expansion with isotonic saline (20–30 mL/kg over 30–60 minutes) is required until effective circulation and urine output are restored.
In euvolemic, oliguric patients, strict fluid restriction is instituted. Daily intake is limited to insensible water losses (300–400 mL/m²) plus urine output and any extrarenal losses.
Loop diuretics (e.g., furosemide) are strictly utilized to manage fluid overload and maintain urine output to facilitate nutritional delivery; they do not improve renal recovery or alter the disease course.
Medical Management of Complications
Electrolyte and acid-base derangements must be managed aggressively to prevent life-threatening cardiovascular and neurological events.
Fluid restriction; Oxygen support; IV Furosemide (2-4 mg/kg); Consider urgent dialysis if refractory.
Hypertension
Target volume control. Symptomatic/Emergency: IV Sodium nitroprusside (0.5–8 µg/kg/min), Labetalol, Esmolol, or Nicardipine infusions. Asymptomatic: Amlodipine, Nifedipine.
Metabolic Acidosis
IV Sodium bicarbonate (if serum bicarbonate < 18 mEq/L or pH < 7.1). Monitor for paradoxical exacerbation of hypocalcemia or fluid overload.
Hyperphosphatemia / Hypocalcemia
Dietary phosphate restriction; Oral phosphate binders (calcium carbonate/acetate, sevelamer). Avoid IV calcium unless symptomatic tetany or hyperkalemia is present, to prevent metastatic calcification.
Kidney Replacement Therapy (KRT)
Indications: KRT is indicated for refractory fluid overload (>10% body weight), severe hyperkalemia (>6.5 mEq/L), severe metabolic acidosis (bicarbonate <10 mEq/L), symptomatic uremia (encephalopathy, pericarditis), and life-threatening intoxications or tumor lysis syndrome.
Peritoneal Dialysis (PD): Feasible in small infants and hemodynamically unstable patients, requires no vascular access or systemic anticoagulation, but is contraindicated in patients with severe abdominal pathology and provides slower solute clearance.
Intermittent Hemodialysis (IHD): Highly efficient for rapid correction of severe hyperkalemia, hyperammonemia, and acute intoxications, but requires specialized vascular access and often induces hemodynamic instability in critically ill pediatric patients.
Continuous Kidney Replacement Therapy (CKRT): Modalities like CVVH, CVVHD, and CVVHDF are the standard of care for hemodynamically unstable patients, allowing precise, continuous volume control, gradual solute clearance, and the safe administration of required parenteral nutrition and medications.
Nutritional Support
Patients with AKI are highly catabolic and require maximization of caloric intake to prevent nitrogenous waste accumulation.
Protein intake must not be excessively restricted; infants require at least 1.0–1.2 g/kg/day (up to 3 g/kg/day during CKRT to account for extracorporeal amino acid losses), alongside strict monitoring of phosphorus and potassium intake.
Prognosis and Long-Term Sequelae
The mortality rate of pediatric AKI is highly dependent on the underlying etiology, ranging from <1% in isolated post-infectious glomerulonephritis to >50% in the setting of multiorgan failure, severe sepsis, or reliance on ECMO.
Incomplete or maladaptive tubular repair, characterized by persistent interstitial inflammation, pericyte loss, and microvascular rarefaction, leads to irreversible tubulointerstitial fibrosis.
Patients surviving an episode of AKI are at a significantly increased risk (up to 8.8-fold) of developing chronic kidney disease (CKD), end-stage renal disease (ESRD), and secondary hypertension in the years following the insult.
Long-term follow-up at 3 months post-discharge and annual evaluations thereafter (monitoring blood pressure, urinalysis for proteinuria, and estimated GFR) are strictly recommended to detect and delay the progression of chronic kidney disease.
