Definition and Classification

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 $\ge$ 0.3 mg/dL over 48 hours.
- Percentage increase of $\ge$ 50% ($\ge$ 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 $\ge$ 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 $\ge$ 12 hours
3	Increase to $\ge$ 3.0 times baseline OR Serum creatinine $\ge$ 4.0 mg/dL OR Initiation of renal replacement therapy OR eGFR < 35 mL/min/1.73 m²	< 0.3 mL/kg/hr for $\ge$ 24 hours OR Anuria for $\ge$ 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.	Dehydration, gastroenteritis, hemorrhage, sepsis, shock, congestive heart failure, nephrotic syndrome, hypoalbuminemia.
Intrinsic Renal AKI	Direct parenchymal damage to glomeruli, tubules, interstitium, or vasculature.	Acute tubular necrosis (prolonged ischemia, sepsis, aminoglycosides, contrast, NSAIDs, hemoglobinuria, tumor lysis syndrome), Glomerulonephritis (APSGN, SLE), Interstitial nephritis, Hemolytic Uremic Syndrome (HUS).
Postrenal AKI	Mechanical obstruction to urinary outflow, requiring bilateral involvement in patients with two kidneys.	Posterior urethral valves, bilateral pelviureteric junction obstruction, urolithiasis, hemorrhagic cystitis, neurogenic bladder, tumors.

Neonatal-Specific Causes

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 $\ge$ 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

Category	Specific Management Strategies
Fluid Management & Resuscitation	• Assess volume status using clinical examination, inferior vena cava (IVC) collapsibility, and lung ultrasound. • For dehydration and hypovolemia, administer 20-30 mL/kg of isotonic saline or Ringer's lactate over 30-45 minutes. • Avoid potassium-containing fluids in patients with oliguria. • In fluid overload, use the AKI regimen: replace insensible losses (300-400 mL/m²) with 5-10% dextrose and replace urine output with normal saline, modifying based on sodium levels. • Aim for a 0.5-1% weight loss per day if overloaded. • Use intravenous (IV) furosemide (2-4 mg/kg) only for the management of fluid overload, not for the prevention of AKI.
Hyperkalemia	• Place the patient on a cardiac monitor and stop all potassium intake. • For ECG changes, administer IV 10% Calcium gluconate (0.5-1 mL/kg, max 20 mL) over 5-10 minutes. • For intracellular shifting, administer Dextrose (0.5-1 g/kg) and Insulin (0.1-0.2 U/kg) over 30 minutes (monitor for hypoglycemia). • Administer nebulized Salbutamol (2.5-5 mg), which can be repeated after 20 minutes. • Administer IV Sodium Bicarbonate (1-2 mL/kg over 15-20 mins) if associated with metabolic acidosis. • To remove potassium, use potassium-binding resins like sodium polystyrene sulfonate (1 g/kg orally, nasogastric, or rectally) or initiate dialysis.
Metabolic Acidosis & Other Electrolytes	• Acidosis: Administer IV or oral Sodium Bicarbonate if pH is <7.2, monitoring closely for fluid overload and hypernatremia. • Hyperphosphatemia: Restrict dietary phosphate and use phosphate binders like calcium carbonate or sevelamer hydrochloride. • Hypocalcemia: Provide oral or IV calcium depending on the severity. • Hyponatremia: Usually dilutional and managed by fluid restriction; use hypertonic saline (3%) cautiously only for symptomatic hyponatremia (e.g., lethargy, seizures).
Hypertension	• Symptomatic: Start Labetalol infusion at 0.25-1 mg/kg/h or Sodium Nitroprusside at 0.5-8 µg/kg/min (do not exceed 48 hours to avoid toxicity) along with IV furosemide (2-4 mg/kg). • Asymptomatic: Give oral nifedipine or amlodipine (0.3-0.5 mg/kg). • Maintain on amlodipine or hydralazine.
Pulmonary Edema	• Administer oxygen and IV furosemide (2-4 mg/kg). • Provide respiratory support (High-Flow Nasal Cannula, Non-Invasive Ventilation, or Mechanical Ventilation) as required.• Initiate dialysis for urgent fluid removal.
Nutrition Support	• Patients are often catabolic and require adequate nutritional support via the enteral route whenever possible. • Provide a minimum of 50-60 Cal/kg (or 20-30 kcal/kg/day), utilizing liberal amounts of carbohydrates and fats. • Protein intake: 0.8-1.2 g/kg/day in infants, and 0.6-0.8 g/kg/day in older children. For non-catabolic AKI without dialysis, provide 0.8-1.0 g/kg/day. • If on dialysis, increase protein to 1.0-1.5 g/kg/day, and up to 1.7 g/kg/day if on continuous renal replacement therapy (CRRT) or if hypercatabolic. • Do not restrict protein purely to delay dialysis, as malnutrition is an independent predictor of mortality. • Supplement water-soluble vitamins and trace elements.
Infections & Medications	• Avoid nephrotoxic agents such as aminoglycosides, NSAIDs, radiocontrast media, and amphotericin B. • Treat infections promptly with non-nephrotoxic antimicrobials, modifying doses based on estimated kidney function (eGFR) or ongoing kidney replacement therapy.
Anemia	• Transfuse Packed Cell Volume (PCV) at 5-10 mL/kg, closely monitoring for fluid overload.
Kidney Replacement Therapy (Dialysis) Indications	• Fluid overload ≥10-15% above baseline that is refractory to diuretics. • Refractory hyperkalemia (K+ > 6.0 mEq/L or ECG changes) despite medical management. • Severe metabolic acidosis (pH < 7.2) worsening despite bicarbonate therapy. • Symptomatic dysnatremia or signs of uremia (encephalopathy, blood urea > 160-200 mg/dL). • Need to create space for essential fluid intake like blood products and nutrition.
Dialysis Modalities	• Peritoneal Dialysis (PD): Often the initial choice in sick neonates and children due to technical simplicity, no need for anticoagulation, and hemodynamic stability, though it has slower clearance and a risk of peritonitis. • Intermittent Hemodialysis (IHD): Best for hemodynamically stable patients needing rapid fluid and toxin removal, but carries a risk of hypotension. • Continuous Renal Replacement Therapy (CRRT): Ideal for hemodynamically unstable patients, those with liver failure, or raised intracranial pressure, allowing slow, continuous removal of fluid and toxins. • Sustained Low-Efficiency Dialysis (SLED): Serves as an effective alternative to CRRT in resource-constrained scenarios, maintaining hemodynamic stability and potentially avoiding anticoagulation.

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.