What is the most likely cause of a patient with markedly elevated creatine phosphokinase (~4500 U/L), acute kidney injury (serum creatinine ~7.8 mg/dL) with anuria, severe thrombocytopenia (~50 ×10⁹/L), low complement levels, 1‑2 % schistocytes on peripheral smear, and altered mental status, while all blood cultures are negative?

Atypical Hemolytic Uremic Syndrome (aHUS)

This clinical presentation is most consistent with atypical hemolytic uremic syndrome (aHUS), a thrombotic microangiopathy characterized by the triad of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury, with complement dysregulation as the underlying pathophysiology. 1

Key Diagnostic Features Supporting aHUS

The constellation of findings creates a highly specific pattern:

• Thrombotic microangiopathy (TMA) triad is complete: The presence of schistocytes (1.8%), thrombocytopenia (50,000/μL), and severe AKI with anuria (creatinine 7.8 mg/dL) establishes the diagnosis of TMA 1

• Low complement levels are pathognomonic for complement-mediated aHUS: Both C3 and C4 depression indicates alternative complement pathway activation, which is the hallmark of aHUS and distinguishes it from other TMAs 1

• Elevated CPK (4,500 U/L) indicates systemic microvascular injury: While CPK >1,000 U/L confirms rhabdomyolysis 2, this moderate elevation in the context of TMA more likely reflects systemic tissue ischemia from widespread microvascular thrombosis rather than primary muscle injury 1

• Negative blood cultures exclude infection-triggered HUS: The absence of bacterial infection, particularly Shiga toxin-producing E. coli, shifts the diagnosis toward atypical (complement-mediated) rather than typical (infection-triggered) HUS 1

• Neurological involvement (irritability) indicates CNS microangiopathy: Altered mental status reflects cerebral microvascular thrombosis, a known complication of systemic TMA that can progress to seizures or stroke 1

Differential Diagnosis Considerations

While aHUS is most likely, several conditions warrant brief consideration:

• Thrombotic thrombocytopenic purpura (TTP) typically presents with more severe neurological symptoms and fever, with ADAMTS13 activity <10% (which should be tested but was not mentioned) 1

• Rhabdomyolysis-induced AKI alone would not explain thrombocytopenia, schistocytes, or low complement levels; CPK of 4,500 U/L is also relatively modest for causing severe AKI (typically requires >75,000 U/L for >80% AKI risk) 2

• Disseminated intravascular coagulation (DIC) would show prolonged PT/PTT and low fibrinogen, which are not mentioned and are typically normal in aHUS 1

Immediate Management Algorithm

Step 1: Urgent complement blockade with eculizumab

• Eculizumab 900-1,200 mg IV should be administered immediately, as delay increases risk of irreversible organ damage and death 1
• In the case report of a neonate with identical presentation (low C3, schistocytes 9%, platelets 49,000, AKI requiring dialysis), eculizumab produced complete hematologic remission within 2 weeks and renal recovery within 48 hours 1

Step 2: Initiate renal replacement therapy for anuria

• Continuous renal replacement therapy (CRRT) is indicated for anuria, severe uremia (creatinine 7.8 mg/dL), and likely hyperkalemia 3
• RRT should be started for definitive indications: severe hyperkalemia >6.0 mmol/L with ECG changes, refractory volume overload, or uremic complications 3

Step 3: Avoid plasma exchange unless TTP cannot be excluded

• Plasma exchange is ineffective in complement-mediated aHUS and may delay definitive treatment 1
• If ADAMTS13 testing is pending and TTP remains in the differential, plasma exchange can be initiated but should not delay eculizumab 1

Step 4: Discontinue all nephrotoxic medications

• Immediately withdraw NSAIDs, ACE inhibitors, ARBs, aminoglycosides, and any contrast agents 3
• Hold diuretics given anuria 3

Step 5: Monitor for complications

• Check potassium urgently and treat if >6.0 mEq/L with calcium gluconate, insulin/dextrose, and consider dialysis 3
• Monitor for intestinal perforation and skin necrosis from systemic TMA, as occurred in the reported case 1
• Assess for worsening neurological status requiring intubation 1

Critical Pitfalls to Avoid

• Do not delay eculizumab while awaiting genetic testing: Complement gene mutations (CFH, CFI, MCP) and anti-CFH antibodies may be negative, yet patients still respond to complement blockade 1

• Do not attribute AKI solely to rhabdomyolysis: CPK of 4,500 U/L is insufficient to cause creatinine 7.8 mg/dL with anuria; the TMA is the primary driver of renal failure 2, 4

• Do not stop eculizumab after initial response: The infant case required ongoing eculizumab every 3 weeks to maintain remission, demonstrating the need for long-term complement suppression 1

• Do not use bicarbonate for rhabdomyolysis when pH ≥7.15: Two randomized trials showed no benefit and identified risks including sodium overload and increased lactate 3

Prognosis and Long-Term Management

• With eculizumab, complete hematologic and renal recovery is achievable: The case report demonstrated normalization of creatinine from dialysis-dependent AKI to 0.2 mg/dL (eGFR 110 mL/min/1.73 m²) with sustained treatment 1

• Without complement blockade, mortality and ESRD rates exceed 50%: Systemic TMA causes multi-organ failure including intestinal perforation, skin necrosis, and irreversible renal damage 1

• Lifelong eculizumab may be required: The 14-month-old infant remained disease-free only with continued therapy every 3 weeks 1