Atypical Hemolytic Uremic Syndrome (aHUS) - AKI Definition and Diagnosis
Diagnostic Criteria for aHUS with AKI
The diagnosis of atypical hemolytic uremic syndrome requires the presence of three core features: microangiopathic hemolytic anemia with schistocytes on peripheral smear, thrombocytopenia (platelets <150,000/mm³), and acute kidney injury, while excluding Shiga toxin-producing E. coli infection and thrombotic thrombocytopenic purpura. 1, 2
Core Clinical Triad
- Microangiopathic hemolytic anemia with characteristic red blood cell fragmentation including schistocytes (>1%), burr cells, or helmet cells on peripheral blood smear 2
- Thrombocytopenia defined as platelet count <150,000/mm³ or 25% reduction from baseline 2
- Acute kidney injury evidenced by hematuria, proteinuria, or elevated creatinine (≥1.0 mg/dL in children <13 years; ≥1.5 mg/dL in individuals ≥13 years; or ≥50% increase over baseline) 2
Critical Diagnostic Caveat
Up to 50% of aHUS cases may not present with all three clinical signs at disease onset, particularly in pediatric patients where thrombocytopenia, anemia, or elevated creatinine may be absent initially. 3, 2 This makes early diagnosis challenging but should not delay treatment when clinical suspicion is high.
Essential Laboratory Workup
Immediate First-Line Tests
- Complete blood count with peripheral blood smear to identify schistocytes, though absence does not exclude early disease due to low sensitivity 3, 2
- Hemolysis markers: elevated LDH, reduced or absent haptoglobin, elevated indirect bilirubin 4, 2
- Direct Coombs test must be negative to confirm non-immune hemolytic anemia 2
- ADAMTS13 activity level to exclude thrombotic thrombocytopenic purpura (TTP); severely deficient activity <10 IU/dL indicates TTP requiring immediate plasmapheresis rather than aHUS 1, 2
- Stool testing for Shiga toxin/verocytotoxin-producing E. coli to exclude STEC-HUS 1, 3
Complement Testing
- C3, C4, CH50 (classical pathway), and AP50 (alternative pathway) to assess complement activation 1, 2
- These levels help characterize disease activity but are not required for diagnosis 2
Genetic Testing
- Next-generation sequencing of complement genes: CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, and CFB 1, 2
- Multiplex ligation-dependent probe amplification of genes CFH, CFHR1-5 2
- Critical point: Genetic mutations are identified in only 50-60% of cases; absence of mutations does not exclude aHUS diagnosis 1, 2
- Testing should be performed but treatment must not be delayed while awaiting genetic results 1, 3
Special Population Considerations
- Infants <1 year old: Test for complement-unrelated genes (DGKE, WT1) and inborn errors of cobalamin metabolism (MMACHC) 2
- Post-transplant patients: 13% lack significant platelet reduction and 38% lack significant anemia or thrombocytopenia despite active TMA 2
Biomarkers for Differential Diagnosis
Urinary NGAL (Neutrophil Gelatinase-Associated Lipocalin)
- Cutoff value of 220-244 μg/g creatinine best differentiates acute tubular necrosis (ATN) from aHUS 4
- NGAL levels in aHUS patients are always much lower than in ATN, even when aHUS has not responded to treatment 4
- Urinary NGAL measured 2 days after fluid challenge performs better than serum NGAL 4
- Limitation: Not widely available in the United States for clinical use 4
AKI Staging in aHUS Context
When aHUS presents with AKI, standard AKI staging criteria apply 4:
- Stage 1: Serum creatinine 1.5-1.9 times baseline 4
- Stage 2: Serum creatinine 2.0-2.9 times baseline 4
- Stage 3: Serum creatinine ≥3.0 times baseline or increase to ≥353.6 μmol/L (≥4.0 mg/dL) or ongoing need for renal replacement therapy 4
Monitoring Protocol During Diagnostic Phase
- Daily monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine during the at-risk period 2
- Serial complement measurements (C3, C4, CH50, AP50) help assess disease activity, though no single test is sufficiently sensitive for detecting early relapses 2
- Monitoring can stop when platelet count begins to increase or stabilize with resolved/resolving symptoms 2
Critical Diagnostic Pitfalls to Avoid
Do Not Delay Treatment for Genetic Testing
Treatment with complement inhibitors (eculizumab or ravulizumab) must be initiated immediately upon clinical suspicion of aHUS after excluding STEC-HUS, without waiting for genetic test results. 1, 3 Genetic mutations are found in only 50-60% of cases, and delay in treatment is associated with increased mortality and morbidity 1.
Do Not Rely on Schistocyte Presence Alone
The absence of schistocytes should not exclude early diagnosis of aHUS due to the low sensitivity of this finding 3, 2. Clinical suspicion with other laboratory markers should guide diagnosis.
Do Not Administer Platelet Transfusions
Platelet transfusions should be avoided unless there is life-threatening bleeding, as they can worsen microangiopathic thrombosis. 1, 3
Distinguish from STEC-HUS
- Typical (STEC) HUS: Onset within 3 weeks after acute or bloody diarrhea 2
- Atypical HUS: No preceding diarrheal illness, or if diarrhea present, it is brief with simultaneous onset of HUS symptoms suggesting aHUS rather than STEC-HUS 2
- Both forms may present with diarrhea in pediatric patients, making this distinction challenging 2
Immediate Treatment Initiation
Once aHUS diagnosis is confirmed (STEC excluded, ADAMTS13 activity normal), complement inhibitor therapy with eculizumab or ravulizumab must be started immediately as aHUS is a medical emergency. 3, 5 The FDA-approved indication for eculizumab specifically states it is for treatment of aHUS to inhibit complement-mediated thrombotic microangiopathy 5.
Meningococcal Vaccination Requirement
- Vaccinate against meningococcal infection (serogroups A, C, W, Y, and B) at least 2 weeks prior to first dose of complement inhibitor when possible 5
- If urgent therapy is required: Provide antibacterial prophylaxis and administer vaccines as soon as possible 5
- Life-threatening meningococcal infections are a serious risk with complement inhibition 5