Treatment of complement-mediated hemolytic uremic syndrome (CM-HUS) in adults

Determining the duration of complement blockade requires discussions with the patient about the risk of relapse and the burdens of continuing therapy. Refer to UpToDate for details.

For an individual with a documented pathogenic sequence variant in a complement regulatory gene, stopping complement blockade may be appropriate if there is no personal or family history of similar kidney disease. However, the risk of recurrence is possibly as high as 50%, and resuming complement blockade may not completely restore kidney function.
For an individual with a complement gene sequence variant of uncertain significance (VUS), stopping complement blockade may be appropriate if there is no personal or family history of similar kidney disease. The risk of recurrence is uncertain but probably <50%.
For individuals without a documented pathogenic variant in a complement gene, stopping complement blockade has less risk, but continuation of complement blockade may be appropriate if there is a history of similar kidney disease in the patient or family.
For individuals with anti-CFH antibodies, some experts use immunosuppressive therapy with cyclophosphamide or rituximab.

CM-HUS: complement-mediated hemolytic uremic syndrome; RBC: red blood cell; LDH: lactate dehydrogenase; MAHA: microangiopathic hemolytic anemia; AKI: acute kidney injury; TTP: thrombotic thrombocytopenic purpura; CFH: complement factor H; VUS: variant of uncertain significance.

* Details of diagnosis are discussed in UpToDate; we generally consider the following to be supportive of a diagnosis of CM-HUS:

Personal or family history of kidney disease not explained by another condition.
Thrombocytopenia – Platelet count <100,000/microL or <50% of normal for that individual.
MAHA – Anemia with fragments of RBCs on the peripheral blood smear; increased LDH and indirect bilirubin; decreased haptoglobin.
AKI – Serum creatinine above the upper limit of normal, provided dehydration has been corrected and other obvious causes of AKI have been excluded. Even slight elevations of serum creatinine are clinically important if there is a history of similar kidney disease in the patient or family.
No evidence of another thrombotic microangiopathy (ADAMTS13 activity ≥20%, stool negative for Shiga toxin if diarrhea is present).

¶ If TTP remains a possibility (results of ADAMTS13 activity pending), therapeutic plasma exchange (TPE) may also be appropriate. Anti-complement therapy should be given immediately following each TPE procedure so that the TPE does not remove the complement blocking monoclonal antibody. Eculizumab and ravulizumab are both complement-blocking monoclonal antibodies; they are equally effective as anti-complement therapy and differ only in the dosing interval.

Δ Refer to UpToDate for details of genetic and serologic testing. Genetic test results may take weeks to months to return. Pathogenic sequence variants in the 5 genes listed above are the most clinically important in CM-HUS. Variants in all other genes such as CFHR or THBD typically are not pathogenic. If a sequence variant of uncertain significance (VUS) is identified, manage according to the personal and family history and continue to review information about pathogenicity (from the testing laboratory, complement expert, or a genetics resource such as ClinVar).

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Treatment of complement-mediated hemolytic uremic syndrome (CM-HUS) in adults