Abstract

Background: Atypical HUS is a rare disorder caused by uncontrolled activation of the alternative pathway of complement. It presents with thrombotic microangiopathy (TMA), renal insufficiency and in 20% of cases extrarenal manifestations. Most cases of aHUS result from a genetic defect.

Methods: We conducted a retrospective chart review of all adult patients with TMA assessed by our apheresis service between January 1, 2010 and December 31, 2013. Complement genetics studies included screening CFI, CFH, CFB, MCP/CD46, CFHR5, C3 and THBD/CD141 genes and were performed at The Hospital for Sick Children, Toronto, Canada. Complement protein and function studies (CH50, AH50, C3d, sC5b-9, C3, factor H, factor I, and anti-CFH antibody) were performed at the University of Heidelberg, Germany.

Results: During the study period, 65 patients with TMA were assessed. On clinical and laboratory grounds, 16 patients (25%) were diagnosed with aHUS. 15 patients underwent complement genetics studies and 10/15 (73%) had no disease causing mutations identified.

Data on 5 patients with genetic abnormalities are summarized in Table 1. All patients were women, mean age 33 years. 4 patients (80%) had extra-renal manifestations. Mean PLT count nadir during acute episode was 40xE9/L. In most TMA episodes, therapeutic plasma exchange (TPE) resulted in a partial response (normalization/stabilization of thrombocytopenia and/or LD and/or creatinine) (Table 1). Due to limited access to eculizumab, the drug was not consistently used. 3 patients (2, 3 and 5) had low C3 and normal C4, a pattern classically described in aHUS. 4 patients underwent additional complement protein studies during acute episode (Table 2).

Abstract 4186. Table 1.
Age, sexMutationTMA episodesRenal manifestationsExtrarenalmanifestationsOther medical conditionsTreatment of TMA episode and outcome
20 F polymorphism vs. disease-causing mutation in CFH gene, c.3148A>T (p.Asn1050Tyr)  1st and only episode Peak Cr 104 Retinal hemorrhages, headache, hypertensive emergency, abdominal pain, elevated liver enzymes Dyskeratosis congenita, alloBMT Partial response to TPE
Response to eculizumab
Died of sepsis 
43 F  unknown mutation in CFHR5 gene, c.1412G>A (p.Gly471Glu)  1st episode ESRD, dialysis
Living related kidney transplant 8 yrs post 1st episode 
Cardiomyopathy, mitral regurgitation Crohn's disase Partial response to TPE
No renal recovery 
2nd episode TMA recurrence in graft, ESRD, dialysis Pulmonary hemorrhage  Partial response to TPE, steroids, eculizumab (single dose)
No renal recovery
Most recent follow-up: TMA free, on dialysis, awaiting 2nd transplant 
29 F variant of unknown significance in C3 gene, c.1685C>T (p.Ser562Leu) predicted to be benign 1st and only episode Cr 650, Required hemodialysis Central retinal artery occlusion, abdominal pain, effusions, seizures, hypertensive emergency Adult Onset Still's Disease Partial response to TPE
Partial response to Eculizumab (single dose)
Most recent follow-up: TMA free, Cr 95 
33 F  disease-causing mutation in CFHR5 gene, c.1135G>C (p.Val379Leu) 1st episode  Not available Hypertensive emergency Pulmonary embolus, cardiac arrest Blood pressure control, improved 
2nd episode Peak Cr 345 Hypertensive emergency, headache, small bowel ischemia, pancreatitis, effusions  Partial response to TPE
Most recent follow-up: TMA free, Cr 89 
42 F  disease-causing mutation in CFI gene, c.949C>T (p.Arg317Trp) and variant of unknown significance in C3 gene (c.193A>C p.Lys65Gln)  1st episode Peak Cr 200 Hypertension Hypo-thyroidism Complete response to TPE, steroids 
2nd episode Peak Cr 700, dialysis not required   Complete response to TPE, steroids 
3rd episode Peak Cr unknown, Dialysis required   Complete response to TPE, steroids 
4th episode Peak Cr 533   Partial response to TPE, steroids
Hematologic response to Rituximab, splenectomy
TMA free, Cr 175
Started on eculizumab 1 year ago
Most recent follow-up: TMA free, Cr 117 
Age, sexMutationTMA episodesRenal manifestationsExtrarenalmanifestationsOther medical conditionsTreatment of TMA episode and outcome
20 F polymorphism vs. disease-causing mutation in CFH gene, c.3148A>T (p.Asn1050Tyr)  1st and only episode Peak Cr 104 Retinal hemorrhages, headache, hypertensive emergency, abdominal pain, elevated liver enzymes Dyskeratosis congenita, alloBMT Partial response to TPE
Response to eculizumab
Died of sepsis 
43 F  unknown mutation in CFHR5 gene, c.1412G>A (p.Gly471Glu)  1st episode ESRD, dialysis
Living related kidney transplant 8 yrs post 1st episode 
Cardiomyopathy, mitral regurgitation Crohn's disase Partial response to TPE
No renal recovery 
2nd episode TMA recurrence in graft, ESRD, dialysis Pulmonary hemorrhage  Partial response to TPE, steroids, eculizumab (single dose)
No renal recovery
Most recent follow-up: TMA free, on dialysis, awaiting 2nd transplant 
29 F variant of unknown significance in C3 gene, c.1685C>T (p.Ser562Leu) predicted to be benign 1st and only episode Cr 650, Required hemodialysis Central retinal artery occlusion, abdominal pain, effusions, seizures, hypertensive emergency Adult Onset Still's Disease Partial response to TPE
Partial response to Eculizumab (single dose)
Most recent follow-up: TMA free, Cr 95 
33 F  disease-causing mutation in CFHR5 gene, c.1135G>C (p.Val379Leu) 1st episode  Not available Hypertensive emergency Pulmonary embolus, cardiac arrest Blood pressure control, improved 
2nd episode Peak Cr 345 Hypertensive emergency, headache, small bowel ischemia, pancreatitis, effusions  Partial response to TPE
Most recent follow-up: TMA free, Cr 89 
42 F  disease-causing mutation in CFI gene, c.949C>T (p.Arg317Trp) and variant of unknown significance in C3 gene (c.193A>C p.Lys65Gln)  1st episode Peak Cr 200 Hypertension Hypo-thyroidism Complete response to TPE, steroids 
2nd episode Peak Cr 700, dialysis not required   Complete response to TPE, steroids 
3rd episode Peak Cr unknown, Dialysis required   Complete response to TPE, steroids 
4th episode Peak Cr 533   Partial response to TPE, steroids
Hematologic response to Rituximab, splenectomy
TMA free, Cr 175
Started on eculizumab 1 year ago
Most recent follow-up: TMA free, Cr 117 

Table 2.
CaseComplement protein and function studies
No abnormalities 
Elevated AH50, sC5b-9
Low C3, fH 
Elevated sC5b-9
Low C3 
Elevated AH50 
Not done 
CaseComplement protein and function studies
No abnormalities 
Elevated AH50, sC5b-9
Low C3, fH 
Elevated sC5b-9
Low C3 
Elevated AH50 
Not done 

Conclusions: 33% of patients diagnosed with aHUS had abnormalities detected on genetic studies. Extrarenal manifestations were common and, in most cases, TPE resulted in only a partial response. Only 3 patients had a classically described pattern of low C3 and normal C4. The utility of extensive complement protein studies requires further study.

Disclosures

Pavenski:Alexion Pharmaceuticals: Honoraria. Licht:Alexion Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

Author notes

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Asterisk with author names denotes non-ASH members.