aHUS
- Recommendations
1. In patients with suspected atypical hemolytic uremic syndrome (aHUS), the diagnosis should be based on the presence of thrombotic microangiopathy (TMA), defined by the concurrent presence of all three of the following:
· Microangiopathic hemolytic anemia (MAHA)
· Thrombocytopenia
· Acute kidney injury (AKI) (Good practice statement) [12,14–16]
2. We suggest defining MAHA as hemoglobin <10 g/dL with evidence of intravascular hemolysis such as elevated LDH, low/undetectable haptoglobin, or increased reticulocyte count. (Conditional recommendation with moderate grade of evidence) [15,17,18]
3. We suggest that a schistocyte count ≥2% on a peripheral blood smear supports the diagnosis of MAHA. A count ≥1% should raise clinical suspicion of TMA and prompt further evaluation. (Conditional recommendation with moderate grade of evidence) [19–21]
4. We suggest defining thrombocytopenia in suspected aHUS or other thrombotic microangiopathies as a platelet count of less than 150,000/mm³ or a decrease of 25% or more from baseline, even if the absolute value remains within the normal range. (Conditional recommendation with moderate grade of evidence) [17,18,22,23]
5. We suggest defining acute kidney injury in suspected aHUS as a serum creatinine increase of ≥ 1.5 × the upper limit of normal for age and sex. (Conditional recommendation with moderate grade of evidence) [24,25]
6. In patients with suspected aHUS, clinicians should consider urine output < 0.5 mL/kg/h for ≥ 6 hours as supportive of acute kidney injury. (Good practice statement)
7. Measurement of blood urea nitrogen (BUN) may be useful in patients with suspected aHUS as part of routine kidney function assessment. While BUN elevation is nonspecific, it can aid in the evaluation of acute kidney injury (AKI) when considered with other TMA-related laboratory markers such as serum creatinine and hemolysis parameters. (Good practice statement)
8. In patients with suspected aHUS, a direct antiglobulin (Coombs) test may help exclude autoimmune hemolytic anemia as a cause of microangiopathic hemolysis. A negative result supports the diagnosis of thrombotic microangiopathy, including aHUS. (Good practice statement)
9. ANA testing may be performed in patients with suspected aHUS to help exclude autoimmune conditions such as systemic lupus erythematosus that can mimic aHUS. (Good practice statement)
10. Fibrin degradation products (FDPs) or D-dimer levels may be measured to help exclude disseminated intravascular coagulation (DIC) in the differential diagnosis of aHUS. Normal or mildly elevated levels make DIC less likely and support the diagnosis of aHUS. (Good practice statement)
11. We recommend testing for Shiga toxin (Stx) using stool culture and/or ELISA/PCR in all patients with suspected aHUS, especially those with diarrheal prodrome. A positive result confirms STEC-HUS and excludes aHUS (Strong recommendation with moderate grade of evidence) [14,15,18,22,24–26]
12. We recommend measuring ADAMTS13 activity and autoantibodies in all patients with suspected aHUS to exclude thrombotic thrombocytopenic purpura (TTP). A confirmed ADAMTS13 activity level <10% is diagnostic of TTP and excludes aHUS.
Samples should be obtained prior to plasma exchange or transfusion to preserve diagnostic accuracy. (Strong recommendation with moderate grade of evidence) [12,14,15,18,22,24–26]
13. We suggest measuring serum complement levels (C3 and C4) in all patients with suspected aHUS as part of the diagnostic workup. Low C3 or C4 levels support complement pathway involvement but are not diagnostic alone. (Conditional recommendation with moderate grade of evidence) [12–15]
14. We suggest measuring anti–Factor H (CFH) autoantibodies in patients with suspected aHUS, particularly in cases without a clear secondary trigger. Detection of these autoantibodies supports the diagnosis of acquired complement-mediated aHUS and may guide targeted immunosuppressive management. (Conditional recommendation with moderate grade of evidence) [11,13,18,24,27–32]
15. Anti–Factor H autoantibodies are more frequently observed in pediatric aHUS cases, and testing may have a higher diagnostic yield in this population. (Good practice statement)
16. We suggest performing a comprehensive genetic analysis in patients with confirmed or highly suspected atypical hemolytic uremic syndrome (aHUS), particularly in cases without an identified secondary trigger. This testing should evaluate genes encoding complement regulatory proteins such as CFH, CFI, CFB, MCP (CD46), C3, and others. Identification of pathogenic variants supports the diagnosis of complement-mediated aHUS and may inform prognosis and therapeutic decision-making. (Conditional recommendation with moderate grade of evidence) [13,27,33–35]
17. Genetic testing is not mandatory to confirm the initial diagnosis of aHUS, but it can provide valuable information for determining patient management, prognosis, and guiding the duration and intensity of treatment, particularly with C5 inhibitors. (Good practice statement)
18. Blood samples for ADAMTS13 activity, anti–factor H antibodies, and reticulocyte count should be obtained before any plasma therapy or transfusion in suspected aHUS or TMA cases. This ensures accurate diagnostic interpretation and informs appropriate treatment. (Good practice statement)
19. We recommend to start Plasma Exchange (PEX) within 24 hours of clinical suspicion of TMA (Strong recommendation with moderate grade of evidence) [1,35,36]
20. PEX is done using 1.5 plasma volume exchanges of pure FFP in a dose of 60–75 mg/kg/day for 5 consecutive days. (Good practice statement)
21. The tapering schedule is every alternate day for 2 weeks, then twice weekly for 2 more weeks, and eventually once weekly for an additional 4 weeks. (Good practice statement)
22. Once the diagnosis of aHUS is confirmed, we recommend to use anti-C5 therapy as first-line treatment (Strong recommendation with moderate grade of evidence) [1,12,35,37]
23. Use the following table for dosing (Table 4):
Table 4: Ravulizumab weight-based dosing regimen for pediatric patients with PNH or aHUS below 40 Kg
|
Body weight range (Kg) |
Loading dose (mg) |
Maintenance dose (mg)* |
Dosing interval |
|
≥ 10 to < 20 |
600 |
600 |
Every 4 weeks |
|
≥ 20 to < 30 |
900 |
2,100 |
Every 8 weeks |
|
≥ 30 to < 40 |
1,200 |
2,700 |
Every 8 weeks |
* First maintenance dose is administered 2 weeks after loading dose (Good practice statement)
24. Meningococcal vaccine should be given to reduce the infectious risk when anti-C5 therapy is initiated. (Good practice statement)
25. Patients treated with anti-C5 therapy <2 weeks after vaccination should be given daily prophylactic antibiotics for 2 weeks after vaccination. (Good practice statement)
In Patients positive for anti-CFH antibodies:
26. In case of patients with positive anti-CFH antibodies, we recommend to start initial treatment by combining PEX and/or anti-C5 therapy with corticosteroids , with or without additional immunosuppressive agents (Strong recommendation with moderate grade of evidence) [1,27,38–41]
27. Upon the remission of TMA, maintenance therapy is suggested to use corticosteroids ± immunosuppressants. (Good practice statement)
28. If follow-up tests show anti-CFH antibodies are absent, discontinue immunosuppressive therapy. (Good practice statement)
In patients negative for anti-CFH antibodies:
29. We recommend to continue treatment with anti-C5 therapy if genetic mutations identified (CFH, CFI, CFB, or C3 genes) is detected discontinuation is not recommended as relapses are common post-cessation agents (Strong recommendation with moderate grade of evidence) [6,42–44]
30. We suggest to use eculizumab in patients with atypical hemolytic uremic syndrome (aHUS), particularly in the following cases: after kidney transplantation to prevent or treat post-transplant thrombotic microangiopathy (TMA); in patients with active aHUS to improve renal outcomes and prevent dialysis; during perioperative periods to maintain complement inhibition and reduce surgical complications; and in combined organ transplantation to minimize the risk of graft thrombosis and optimize transplant success (Conditional recommendation with moderate grade of evidence) [45–49]