What is a comprehensive work-up for atypical Hemolytic Uremic Syndrome (aHUS) in patients, including those with potential genetic predispositions or a family history of aHUS?

Comprehensive Work-up for Atypical HUS

All patients with suspected atypical HUS require immediate comprehensive laboratory evaluation including complete blood count with peripheral smear, hemolysis markers (LDH, haptoglobin, indirect bilirubin), renal function tests, ADAMTS13 activity, STEC testing, complement studies (C3, C4, CH50, AP50), and genetic testing of complement pathway genes—with treatment initiated immediately without waiting for genetic results. 1, 2

Initial Diagnostic Laboratory Panel

Core Diagnostic Triad Confirmation

• Obtain complete blood count with platelet count to document thrombocytopenia (<150,000/mm³ or 25% reduction from baseline) 1
• Examine peripheral blood smear for schistocytes, burr cells, or helmet cells indicating microangiopathic hemolysis—though absence should not exclude early diagnosis due to low sensitivity 1, 3
• Measure hemoglobin levels, noting that near-normal values may indicate dehydration rather than absence of anemia 1
• Assess renal function with urinalysis for hematuria and/or proteinuria, plus serum creatinine (≥1.0 mg/dL in children <13 years; ≥1.5 mg/dL in individuals ≥13 years; or ≥50% increase over baseline) 1

Hemolysis Markers (Mandatory)

• Measure LDH levels (elevated), haptoglobin (reduced or absent), and indirect bilirubin (elevated) immediately 1, 3
• Obtain direct and indirect Coombs tests—both must be negative to confirm non-immune hemolytic anemia 1, 3
• Measure reticulocyte count to confirm hemolysis 2

Critical Differential Diagnosis Testing

Urgent ADAMTS13 Testing

• Measure ADAMTS13 activity urgently when thrombotic microangiopathy is confirmed, as severely deficient activity (<10 IU/dL) indicates TTP requiring immediate plasmapheresis rather than aHUS 1, 3
• All patients enrolled in aHUS studies were required to have ADAMTS13 activity >5% 4

STEC-HUS Exclusion

• Obtain stool culture and Shiga toxin testing to identify Shiga toxin-producing E. coli (most commonly O157 serotype) 1, 3
• If stool testing is negative but HUS is present, perform serologic testing for STEC (CDC-validated testing for serogroups O157 and O111) 1
• Note that short duration of diarrhea or simultaneous onset of diarrhea and HUS suggests aHUS rather than STEC-HUS 1

Complement System Evaluation

Complement Levels

• Measure C3, C4, CH50 (classical pathway), and AP50 (alternative pathway) to assess complement activation 1, 3
• Serial complement measurements help assess disease activity and guide treatment decisions, particularly when extending C5 inhibitor administration intervals 1

Anti-Complement Antibodies

• Test for anti-factor H antibodies, as approximately 10% of aHUS patients have functional CFH deficiency due to autoantibodies 1, 5

Comprehensive Genetic Testing

Next-Generation Sequencing Panel

• Perform genetic testing in all suspected aHUS cases through next-generation sequencing of complement genes: CFH, CFHR1-5, C3, CD46 (MCP), CFI, THBD, DGKE, and CFB 1, 2, 6
• Include multiplex ligation-dependent probe amplification of genes: CFH, CFHR1, CFHR2, CFHR3, CFHR4, and CFHR5 1
• Results should ideally be available within a few months, though treatment must not be delayed while awaiting results 1, 2

Critical Understanding of Genetic Results

• Recognize that 40-50% of aHUS cases have no detectable mutation, yet can still be diagnosed with aHUS based on clinical and laboratory criteria 1, 6, 7
• In 50-60% of cases, a causal genetic variant can be identified in complement pathway genes or occasionally in coagulation cascade genes 8, 6
• Most genetic forms have autosomal dominant inheritance with incomplete penetrance 8, 7

Special Population Genetic Testing

• When aHUS presents in infants <1 year old, test for mutations in complement-unrelated genes (DGKE, WT1) and inborn errors of cobalamin metabolism (MMACHC) 1

Monitoring Protocol During Acute Phase

Serial Laboratory Monitoring

• Perform daily monitoring of hemoglobin, platelet counts, electrolytes, BUN, and creatinine during the at-risk period 1
• Monitor white blood cell count with differential, as high WBC with neutrophil predominance often occurs in STEC infections progressing to HUS 1
• Continue monitoring until platelet count begins to increase or stabilize with resolved/resolving symptoms 1

Clinical Monitoring

• Monitor for signs of volume overload, elevated blood pressure, and increasing creatinine requiring management in centers capable of handling acute renal failure 1
• Assess for neurological symptoms; if present, obtain neurological consultation, electroencephalogram (EEG), and brain MRI 1

Additional Considerations

Family History and Genetic Counseling

• Document family history of aHUS, as familial cases show higher prevalence of mutations in SCR20 of CFH and more severe disease than sporadic cases 6
• Provide genetic counseling once diagnosis is confirmed due to possible genetic transmission 2
• In living donor kidney transplant evaluation, perform sequential genetic testing of affected individual followed by donor candidate 8

Genotype-Phenotype Correlations for Prognosis

• CFH or THBD mutations are associated with earliest onset and highest mortality 6
• MCP mutations are associated with best prognosis and lowest recurrence after kidney transplantation 6
• CFI mutations are associated with poor response to plasma therapy 6
• Genotype influences clinical evolution, response to plasma therapies, and recurrence after transplantation 6, 7

Critical Pitfalls to Avoid

• Never delay treatment with complement inhibitors while waiting for genetic test results if aHUS is suspected and STEC-HUS is excluded 2
• Do not exclude aHUS diagnosis based on absence of schistocytes on initial smear due to low sensitivity in early disease 1
• Do not exclude aHUS diagnosis when no genetic mutation is identified, as up to 50% of cases have no detectable mutation 1, 6
• Avoid platelet transfusions unless there is life-threatening bleeding, as they can worsen microangiopathic thrombosis 2
• Recognize that up to 50% of aHUS cases may not have all three clinical signs (hemolytic anemia, thrombocytopenia, renal involvement) clearly present at disease onset 1
• In post-transplant patients, do not exclude TMA diagnosis based on absence of marked thrombocytopenia or significant anemia, as 13% lack significant platelet reduction and 38% lack significant anemia or thrombocytopenia 1