# Acute Kidney Injury and Hemolytic Uremic Syndrome

## Introduction

Acute kidney injury (AKI) is defined as a sudden decline in kidney function resulting in the inability to maintain fluid, electrolyte, and acid-base homeostasis. In children, AKI has shifted from being primarily a surgical or nephrology concern to a condition frequently encountered across all pediatric subspecialties, particularly in critically ill patients. Hemolytic uremic syndrome (HUS) is the most common cause of AKI in previously healthy young children and represents a thrombotic microangiopathy with a classic triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury.

## Acute Kidney Injury

### Definition and Staging (KDIGO Criteria, Pediatric-Modified)

| KDIGO Stage | Serum Creatinine | Urine Output |
|-------------|-----------------|-------------|
| Stage 1 | 1.5-1.9x baseline | <0.5 mL/kg/hr for 6-12 hours |
| Stage 2 | 2.0-2.9x baseline | <0.5 mL/kg/hr for ≥12 hours |
| Stage 3 | ≥3.0x baseline OR ≥4.0 mg/dL OR initiation of RRT | <0.3 mL/kg/hr for ≥24 hours OR anuria ≥12 hours |

Stage 1 is defined as serum creatinine 1.5-1.9 times baseline or urine output less than 0.5 mL/kg/hr for 6-12 hours. Stage 2 is serum creatinine 2.0-2.9 times baseline or urine output less than 0.5 mL/kg/hr for 12 hours or more. Stage 3 is serum creatinine 3.0 times baseline or greater, creatinine 4.0 mg/dL or greater, initiation of renal replacement therapy, or urine output less than 0.3 mL/kg/hr for 24 hours or more or anuria for 12 hours or more. For neonatal AKI, neonatal-modified KDIGO criteria are increasingly used, and baseline creatinine reflects maternal levels in the first 48 hours.

### Etiology

Prerenal AKI is the most common type in children and results from decreased renal perfusion with intact renal parenchyma. Causes include dehydration (gastroenteritis being the most common overall), hemorrhage, sepsis, heart failure, and burns. A FENa less than 1% and BUN-to-creatinine ratio greater than 20:1 suggest a prerenal etiology. Prerenal AKI is responsive to volume resuscitation; if there is no improvement after adequate rehydration, intrinsic renal disease should be considered.

Intrinsic renal AKI involves damage to the glomeruli, tubules, interstitium, or vasculature. Acute tubular necrosis (ATN) is the most common intrinsic cause and results from prolonged prerenal states or nephrotoxic medications (aminoglycosides, NSAIDs, amphotericin B, cisplatin, contrast agents). Glomerulonephritis encompasses post-infectious GN, lupus nephritis, IgA nephropathy, and ANCA-associated vasculitis. Interstitial nephritis is often drug-induced (penicillins, cephalosporins, NSAIDs, PPIs) and classically presents with fever, rash, eosinophilia, and sterile pyuria. Vascular causes include HUS, renal vein thrombosis, and bilateral renal artery thrombosis.

Postrenal (obstructive) AKI results from obstruction of urinary flow. Posterior urethral valves are the most common obstructive cause in neonatal males. Other causes include ureteropelvic junction obstruction, neurogenic bladder, renal calculi, and tumors. Renal ultrasound is the first-line imaging study to evaluate for hydronephrosis, and urgent decompression (bladder catheterization, nephrostomy, or ureteral stenting) is required.

<image>Diagram categorizing the causes of acute kidney injury in children into prerenal, intrinsic renal, and postrenal etiologies, with the most common causes highlighted for each category and arrows showing pathophysiologic mechanisms: decreased renal perfusion for prerenal, direct parenchymal damage for intrinsic, and urinary tract obstruction for postrenal, with corresponding diagnostic clues (FENa, urinalysis findings, ultrasound features)</image>

### Clinical Presentation

Oliguria (less than 0.5 mL/kg/hr) or anuria is common, though non-oliguric AKI is increasingly recognized. Fluid overload manifests as edema, hypertension, pulmonary edema, and weight gain. Electrolyte derangements include hyperkalemia (the most immediately life-threatening), hyponatremia, hyperphosphatemia, and hypocalcemia. Metabolic acidosis with a high anion gap develops from retained organic acids and uremic toxins. Uremic symptoms include nausea, vomiting, lethargy, encephalopathy, and pericarditis in severe cases.

### Management

The underlying cause must be identified and treated, whether through volume resuscitation for prerenal AKI, discontinuation of nephrotoxins, or relief of obstruction. Fluid management should match intake to output plus insensible losses, with restriction if the patient is oliguric or anuric with volume overload. Hyperkalemia (K+ greater than 6.0 mEq/L or ECG changes) requires cardiac membrane stabilization with calcium gluconate 100 mg/kg IV, intracellular shift with insulin (0.1 U/kg) plus dextrose (0.5 g/kg), nebulized albuterol, and sodium bicarbonate if acidotic, and potassium removal with sodium polystyrene sulfonate (Kayexalate) 1 g/kg PO/PR, patiromer, or dialysis. Metabolic acidosis is treated with sodium bicarbonate for pH less than 7.2 or symptomatic acidosis. Hypertension is treated with IV labetalol, hydralazine, or nicardipine for hypertensive urgency or emergency. Adequate caloric intake should be maintained with restriction of potassium, phosphorus, and sodium while avoiding excessive protein restriction. Nephrotoxic medications must be avoided, and all drug dosing should be adjusted for renal function.

### Renal Replacement Therapy (RRT) Indications

Indications for RRT include refractory hyperkalemia despite medical management, severe metabolic acidosis (pH less than 7.1) unresponsive to bicarbonate, volume overload with pulmonary edema or respiratory failure unresponsive to diuretics, uremic complications (encephalopathy, pericarditis, coagulopathy), and toxic ingestion of a dialyzable substance (methanol, ethylene glycol, lithium, salicylates). Continuous renal replacement therapy (CRRT) is preferred in hemodynamically unstable children, intermittent hemodialysis is used for stable patients, and peritoneal dialysis is an option in younger children and resource-limited settings.

## Hemolytic Uremic Syndrome (HUS)

### Classification

Typical (diarrhea-associated, D+ HUS) accounts for 90% of pediatric HUS and is caused by Shiga toxin-producing Escherichia coli (STEC), most commonly serotype O157:H7. Atypical HUS (aHUS) is a complement-mediated thrombotic microangiopathy caused by dysregulation of the alternative complement pathway, which may be genetic (mutations in complement regulatory proteins: CFH, CFI, MCP, CFB, C3) or acquired (anti-CFH antibodies). Secondary HUS is associated with pneumococcal infection (Streptococcus pneumoniae producing neuraminidase), HIV, medications (calcineurin inhibitors, quinine), malignancy, or transplant.

### Typical HUS: Pathophysiology and Clinical Course

The illness begins with bloody diarrhea (hemorrhagic colitis) from STEC infection, typically acquired from undercooked ground beef, unpasteurized dairy, contaminated produce, or person-to-person spread. Shiga toxin enters the systemic circulation and binds to Gb3 receptors on renal endothelial cells, causing endothelial injury and activation of the coagulation cascade. The resulting thrombotic microangiopathy features fibrin deposition in glomerular capillaries that causes mechanical shearing of red blood cells (producing schistocytes), platelet consumption, and microvascular occlusion. HUS develops 5-10 days after onset of diarrhea in approximately 15% of children with STEC O157:H7 infection. Peak age is 6 months to 5 years.

### Clinical Features of Typical HUS

Microangiopathic hemolytic anemia presents with hemoglobin often less than 8 g/dL, schistocytes on peripheral smear, elevated LDH, low haptoglobin, elevated indirect bilirubin, and a negative direct Coombs test. Thrombocytopenia is common, with platelet count often less than 60,000/mcL, and petechiae and bleeding may occur. AKI manifests as oliguria or anuria, elevated creatinine, hematuria, and proteinuria, with approximately 50-60% of patients requiring dialysis. Extrarenal involvement includes CNS manifestations (seizures, encephalopathy, stroke in 20-25%), pancreatic complications (insulin-dependent diabetes, pancreatitis), GI complications (colonic necrosis, perforation, intussusception), and cardiac involvement (myocarditis).

<image>Peripheral blood smear illustration showing the characteristic findings of hemolytic uremic syndrome: fragmented red blood cells (schistocytes including helmet cells and triangular cells), reduced platelet numbers, and a normal white blood cell, alongside a cross-section of a glomerular capillary showing endothelial swelling, fibrin deposition, platelet thrombi, and red blood cell fragmentation in the narrowed lumen</image>

### Management of Typical HUS

Supportive care is the mainstay, as no specific pharmacologic therapy has proven benefit. Careful IV hydration is essential to avoid dehydration (which is associated with worse outcomes) while managing volume overload from oliguria. RBC transfusions are given for symptomatic anemia (hemoglobin less than 6-7 g/dL) and should be administered slowly to avoid volume overload. Platelet transfusions are generally avoided unless there is active life-threatening bleeding or before an invasive procedure, as platelet transfusion may worsen thrombotic microangiopathy. Dialysis is initiated as indicated for standard AKI indications, with 50-60% of children with typical HUS requiring temporary dialysis. Antibiotics are contraindicated for STEC infection because they are associated with increased risk of HUS progression through increased Shiga toxin release. Antimotility agents (loperamide) are also contraindicated in bloody diarrhea as they prolong toxin exposure. Eculizumab is not routinely used for typical HUS but may be considered for severe extrarenal manifestations, particularly severe CNS involvement.

### Atypical HUS

Atypical HUS is complement-mediated, caused by mutations in complement regulatory proteins or anti-CFH antibodies. It does not present with a diarrheal prodrome (or if diarrhea is present, it is not from STEC). It may present at any age, including the neonatal period and adulthood. Eculizumab (anti-C5 monoclonal antibody) is the first-line treatment, as it blocks terminal complement activation and has dramatically improved outcomes (preventing ESRD in more than 80% of patients). Meningococcal vaccination is mandatory before eculizumab initiation due to increased risk of Neisseria meningitidis infection. Plasma exchange may be used as a bridge to eculizumab or when eculizumab is unavailable. Genetic testing for complement mutations and screening for anti-CFH antibodies are essential.

### Prognosis

Typical HUS has a mortality rate of less than 5% in developed countries with good supportive care. Seventy to eighty percent of patients recover renal function completely, though 25% may have long-term sequelae including hypertension, proteinuria, and CKD. Atypical HUS historically had a poor prognosis, with 50% progressing to ESRD, but outcomes have dramatically improved with eculizumab.

## Clinical Pearls

Prerenal azotemia from dehydration is the most common cause of AKI in children and is reversible with appropriate volume resuscitation. Hyperkalemia is the most immediately life-threatening electrolyte derangement in AKI, and ECG monitoring with stepwise management is essential. Antibiotics and antimotility agents should not be given to children with suspected STEC infection, as both increase the risk of HUS. Typical HUS is a clinical diagnosis based on the triad of microangiopathic hemolytic anemia, thrombocytopenia, and AKI following a diarrheal prodrome. Platelet transfusions should be avoided in HUS unless there is life-threatening hemorrhage. Atypical HUS requires complement-directed therapy with eculizumab, and genetic testing and meningococcal vaccination are essential components of management.

## References

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