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).
| . | Age, sex . | Mutation . | TMA episodes . | Renal manifestations . | Extrarenalmanifestations . | Other medical conditions . | Treatment of TMA episode and outcome . |
|---|---|---|---|---|---|---|---|
| 1 | 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 |
| 2 | 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 | ||||
| 3 | 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 |
| 4 | 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 | ||||
| 5 | 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, sex . | Mutation . | TMA episodes . | Renal manifestations . | Extrarenalmanifestations . | Other medical conditions . | Treatment of TMA episode and outcome . |
|---|---|---|---|---|---|---|---|
| 1 | 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 |
| 2 | 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 | ||||
| 3 | 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 |
| 4 | 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 | ||||
| 5 | 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 |
| Case . | Complement protein and function studies . |
|---|---|
| 1 | No abnormalities |
| 2 | Elevated AH50, sC5b-9 Low C3, fH |
| 3 | Elevated sC5b-9 Low C3 |
| 4 | Elevated AH50 |
| 5 | Not done |
| Case . | Complement protein and function studies . |
|---|---|
| 1 | No abnormalities |
| 2 | Elevated AH50, sC5b-9 Low C3, fH |
| 3 | Elevated sC5b-9 Low C3 |
| 4 | Elevated AH50 |
| 5 | 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.
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
Asterisk with author names denotes non-ASH members.
This feature is available to Subscribers Only
Sign In or Create an Account Close Modal