Disease name and synonyms
Definition
Epidemiology
Clinical Description
Gender and age at onset
Triggering events
Presenting features
Pathogenesis
Complement and its regulation
Complement dysregulation in aHUS
CFH mutations
CFH mutation | CFI mutation | MCP mutation | C3 mutation | CFB mutation | THBD mutation | Anti -CFH Ab | None | |
---|---|---|---|---|---|---|---|---|
Decreased C3 concentration
(< 2SD)
(% patients)
| 30-50% | 20-30% | 0-27% | 70-80% | 100% | 50% | 40-60% | up to 20% |
Protein level or expression | ||||||
---|---|---|---|---|---|---|
C4 | C3 | CFH | CFI | CFB | MCP | |
CFH
mutation
| N | Normal (decreased) | Normal (decreased) | Normal | Normal (decreased) | Normal |
CFI
mutation
| N | Normal (decreased) | Normal | Normal (decreased) | Normal (decreased) | Normal |
MCP
mutation
| N | Normal (decreased) | Normal | Normal | Normal | Decreased (normal) |
CFB
mutation
| N | Decreased | Normal | Normal | Normal (decreased) | Normal |
C3
mutation
| N | Decreased | Normal | Normal | Normal (decreased) | Normal |
THBD
mutation
| N | Normal or decreased | ND | ND | ND | Normal |
Anti-CFH Ab
| N | Decreased (normal) | Normal (decreased) | Normal | Normal (decreased) | Normal |
Gene or subgroup | Frequency in aHUS | Minimal age at onset | Risk of death or ESRD at 1st episode or within < 1 y | Risk of relapses | Risk of recurrence after renal transplantation | Plasma therapy indicated | |
---|---|---|---|---|---|---|---|
Children | Adults | ||||||
CFH
| 20-30% | Birth | any age | 50-70% | 50% | 75-90% | Yes |
CFI
| 4 -10% | Birth | any age | 50% | 10-30% | 45-80% | Yes |
MCP
| 5 -15% | > 1 y | any age | 0-6% | 70-90% | < 20% | Questionable |
C3
| 2 -10% | 7 m | any age | 60% | 50% | 40-70% | Yes |
CFB
| 1-4% | 1 m | any age | 50% | 3/3 not in ESRD | 100% | Yes |
THBD
| 3 -5% | 6 m | rare | 50% | 30% | 1 patient | Yes |
Anti-CFH Ab
| 6% | Mostly 7-11 y | 30-40% | 40-60% | Yes if high Ab titer | Yes (+ IS) |
Anti-CFH autoantibodies
MCP mutations
CFI mutations
CFB mutations
C3 mutations
Thrombomodulin mutations
Combined mutations
In conclusion
Familial aHUS, incomplete penetrance and genetic variability
Genotype-phenotype correlations
Diagnostic methods
Plasma or membrane complement Proteins | Plasma concentration (mg/L) (- 2 to + 2 SD) or membrane expression | Technique | Laboratory | Interpretation |
---|---|---|---|---|
C3
| 660-1250 | Nephelometry | Basic complement screen | Severe complement consumption through the alternative pathway indicated by very low plasma levels of C3 and CFB. Frequently, there is only an isolated moderate decrease of C3 level with normal CFB level |
CFB
| 93-380 | Nephelometry | Specialized diagnostic | |
CFH
| 330-680 (no international standard) | ELISA | Specialized diagnostic | CFH or CFI less than 60% of normal are compatible with quantitative deficiency |
CFI
| 40-80 (no international standard) | ELISA (or radial immunodiffusion) | Specialized diagnostic | |
Anti-CFH Ab
| Screening | ELISA | Specialized diagnostic | The title is expressed in Arbitrary Units (AU) |
MCP
| Mean fluorescent intensity (MFI) | FACS (a) with anti- MCP phycoerythrin -conjugated antibodies | Specialized diagnostic | No MCP expression is detected in patients with homozygous MCP deficiency. The MFI in patients of heterozygous MCP deficiency is around 50% of the normal range |
Gene | Location | Method of choice for mutation screening | Number of exons |
---|---|---|---|
CFH
| RCA, Chr 1q32 | Direct sequencing analysis | 22 |
CFI
| Chr 4q25 | Direct sequencing analysis | 13 |
MCP
| RCA, Chr 1q32 | Direct sequencing analysis | 14 |
C3
| Chr 19p13.3 | Direct sequencing analysis | 42 |
CFB
| Chr 6p21.3 | Direct sequencing analysis | 18 |
THBD
| Chr 20p11.2 | Direct sequencing analysis | 1 |
Age at onset | Complement abnormality to screen first |
---|---|
Birth to < 12 months ± decreased C3 | CFH , CFI, C3 mutation |
> 1 year + normal C3 | MCP decreased expression/mutation |
> 1 year + decreased C3 | CFH, CFI, C3 mutation |
7-11 years ± decreased C3 | Anti-CFH antibodies |
Differential Diagnosis
Age at onset and clinical presentation | Probable diagnosis | Investigations to confirm diagnosis |
---|---|---|
Neonatal period
Severe jaundice Porto colour urine without major hematuria Consanguineous family and/or similar symptoms or neonatal death in siblings | Congenital TTP (Upshaw-Schulman syndrome) | ADAMTS 13 deficiency (< 10%) without anti-ADAMTS 13 antibobies Mutation in ADAMTS13 (autosomal recessive) |
Neonatal period-< 6 months
Failure to thrive, feeding difficulties, hypotonia ± developmental delay Consanguineous family | Methyl-malonic aciduria-associated HUS | Hyperhomocysteinemia, hypomethioninemia, methyl-malonic aciduria Mutation in MMACHC (autosomal recessive) |
< 2 years
Fever Invasive S.pneumoniae infection (proven or suspected): pneumonia, meningitis, septicaemia, especially if empyema or subdural collection | HUS due to Streptococcus pneumoniae | False positive Coombs test Positive cultures (blood, CSF) or PCR Positive T-activation test (exposure of the Thomsen-Friedenreich antigen on red blood cells) supports the diagnosis |
> 6 months-5 years
Diarrhea ± melena during the last 2 weeks Endemic region of STEC or Shigella dysenteriae infection | STEC-HUS (Shigella dysenteriae- HUS in endemic regions) | Stool or rectal swab: culture for STEC (Mac Conkey for 0157:H7); PCR for Stx Serum: anti-LPS antibodies against the most common serotypes in the local country |
Adolescents and adults
Fever Central nervous system manifestations No or mild renal involvement Autoimmune context (SLE, APLS, thyroiditis) | Immune TTP | ADAMTS 13 deficiency (< 10%) with anti-ADAMTS13 antibodies |
From birth to adolescence and adult age
No prodromic diarrhea or prodromic diarrhea but any of the following: - age < 6 months or > 5 years - insidious onset - relapse of HUS - suspicion of previous HUS - previous unexplained HUS - post-transplant HUS - pregnancy (post-partum) HUS - non synchronous familial HUS | Complement-aHUS | Complete investigation of the complement system |
Patients identified as having aHUS require full biological investigation (Table 8)
Investigations | |
---|---|
1. STEC infection | Stool or rectal swab: culture for STEC (Mac Conkey for 0157:H7); PCR for Stx Serum: anti-LPS antibodies against the most common serotypes in the local country |
2. Disorders of complement regulation | C3, C4 (plasma/serum) Factor H, Factor I, Factor B (plasma/serum) Anti-factor H autoantibodies MCP (surface expression on leucocytes (polynuclear or mononuclear leucocytes by FACS) Gene mutation analysis in factor H, factor I, MCP, C3, factor B |
3. ADAMTS13 deficiency inherited or acquired classification | Plasma ADAMTS13 activity or dosage (Elisa) ± inhibitor |
4. Cobalamin metabolism:methyl malonic aciduria | Plasma amino-acid chromatography (high homocysteine, low methionine); urine organic acid chromatography (methyl-malonic aciduria) ± mutation analysis in MMACHC gene |
5. HIV | Serology |
6. Pregnancy, HELLP syndrome | Pregancy test, liver enzymes. Investigate as in 2 and 3 |
7. Miscellaneous | Antinuclear antibody, lupus anticoagulant, anti-phospholipid antibodies |
Genetic Counselling and Prenatal Diagnosis
Management Including Treatment
Supportive treatment
Plasmatherapy
Plasmatherapy in patients with CFH mutation
Plasmatherapy in patients with CFI mutation
Plasmatherapy in patients with MCP mutation
Plasmatherapy in patients with C3, CFB or THBD mutation
Plasmatherapy and immunosuppressive drugs in aHUS with anti-CFH antibodies
Recommendations for the practice
The limits of plasmatherapy
Renal transplantation: indications, risks and new issues
The risk of post-transplant recurrence of aHUS according to complement abnormality
Living-related kidney donation is not recommended
Prevention/rescue of post-kidney transplant aHUS recurrence
Avoidance of calcineurin inhibitors
Plasmatherapy to rescue or prevent post- kidney transplant aHUS recurrence
Combined liver-kidney transplantation to cure aHUS
Complement inhibitors: the new treatment in 2010-2011
Eculizumab
Clinical experience with eculizumab in aHUS
Reference | Mutation | Age at onset of HUS, evolution and response to plasmatherapy | Age at eculizumab initiation | Response to plasmatherapy of HUS episode at eculizumab initiation | Serum creatinine level at eculizumab initiation | Delay of hematological and renal improvement after initiation of eculizumab | Delay until complete remission of HUS after initiation of eculizumab | Protocol | Evolution of HUS Last Screat (follow-up under eculizumab) |
---|---|---|---|---|---|---|---|---|---|
Gruppo et al 2009 [155] R. Gruppo PC | NI | < 8 days 3 relapses over 11 m, PI sensitive | 19 m | PE resistant | 265 μmol/L | 2 days | 10 days | Complete protocol | Remission 35 μmol/L (2 y 4 m) |
Fremont et al 2009 [156] | CFH | 4 y | 4 y | PE partially sensitive | 80 μmol/L | ND | 2 weeks | Complete protocol | Remission 26 μmol/L (10 weeks) |
Mache et al 2009 [157] | NI | 17.8 y PE sensitive 3 relapses at PE tapering | 17.11 y | PE resistant | 690 μmol/L | ~ 3 days (platelets increase) | 5 days (hematologic remission) | Single dose | Relapse at 2w ESRF |
Kose et al 2010 [158] | NI | 18 y | 18 y | PE resistant | ~310 μmol/L | 1 day | ~ 7 days | Single dose | Relapse at 2m ESRF |
Lapeyraque et al 2010 [159] AL. Lapeyraque PC | CFH S1191L V1197A | 7 m 11 relapses over 5.4 y, PE/PI sensitive | 6 y | PI resistant | 108 μmol/L | A few days | 1 week | Complete protocol | Remission 44 μmol/L (1 y 3 m) |
Prescott et al 2010 [160] HC. Prescott PC | CFI p.A258T | 47 y PE sensitive Relapse 2 w after PE cessation | 47 y | PE resistant | 610 μmol/L | - 7 days (Screat decrease) - 49 days (platelets normalization) | ~1.5 m | Complete protocol | Remission 230 μmol/L (7 m) |
Ohanian et al 2011 [161] | ND | 50 y | 50 y | No plasmatherapy | 600 μmol/L | - 4 days (LDH decrease) - 10 days (Screat decrease) | ~ 1.5 m | Complete protocol | Remission 198 μmol/L (2.5 m) |
Reference | Gene | Previous transplantations | Age and post-tx course before eculizumab initiation | Delay from recurrence to eculizumab initiation | Screat at eculizumab initiation μmol/L | Delay until platelet increase/hemolysis resolution/Screat decrease under eculizumab | Protocol | Recurrence after eculizumab cessation (delay) | Evolution under eculizumab Last Screat (follow-up under eculizumab) |
---|---|---|---|---|---|---|---|---|---|
Nurnberger 2009 [162] J.Nurnberger PC | CFH Y475S | 1st tx: recurrence at 5 w, PE resistant, graft loss | 37 y, 2nd tx Recurrence at 6 w PE resistant | 5 days | 132 | 2 days/6 days/24 h | Single dose | Likely but not biopsy proven (21 m). Graft loss. | / |
Chatelet 2009 [121] 2010 [163] V.Chatelet PC | C3 R570Q | 1st tx: recurrence at 5 m, graft loss after 2 y | 43 y, 2nd tx Recurrence at 3 y PE sensitive/dependent | 14 m | 320 | A few days/a few days/~1 month | Complete protocol | NA | 2 recurrences of hemolytic anemia when injections delayed by 6-8 days 230 μmol/L (2 y 5 m) |
Legault 2009 [164] | ND | No | 34 y, 1st tx Recurrence at 1 m and 5 m, PE sensitive initially, then resistant | 9 m | 323 | ND/ND/4 weeks | Complete protocol | NA | Remission 238 μmol/L (6 m) |
Davin 2010 [137] JC. Davin PC | CFH S1191L | 1st tx: recurrence at day 3, graft loss 2nd tx under prophylactic PE: recurrence at 10 w, graft loss | 17 y, 3rd tx Preventive PE Recurrence at 4 m, rescue (PE intensification) Plasma intolerance at 10 m | 10 m | 131 | NA (in remission at eculizumab initiation) | Complete protocol | NA | Remission 130 μmol/L (1 y 10 m) |
Larrea 2010 [165] M.Lozano PC | NI | No | 22 y, 1st tx Recurrence at day 12 PE resistant | 9 days | 415 | 36 h/36 h/3 days | Single dose | Yes (11.5 m) Eculizumab resumed | Remission 177 μmol/L (5 m) Graft loss after 2nd eculizumab cessation (humoral rejection) |
Zuber 2010 [131] J. Zuber PC | CFH | 1st tx: recurrence, graft loss | 24 y, 2nd tx Preventive PI/PE Recurrence at day 1 PE resistant | 4 days | 500 | 24 h/24 h/3 days | Complete protocol | NA | Remission 62 μmol/L (9 m) |
Al-Akash 2010 [166] SI. Al-Akash PC | C3 R570W | 1st tx: recurrence at 4 y, graft loss 2nd tx: recurrence at 2 m, graft loss | 15 y, 3rd tx Preventive PE Recurrence at 2 m, PE partially sensitive | ~20 days | 220 | A few days | Complete protocol | NA | Remission 115 μmol/L (1 y 5 m) |
Zimmerhakl 2010 [167] M.Riedl PC | CFH W1183C | No | 10 y, 1st tx Preventive PE | Preventive eculizumab | ~ 45 | NA | Complete protocol | NA | No recurrence 44 μmol/L (2 y 1 m) |
Weitz 2011 [168] | CFH E1198 stop | No | 7 y, 1st tx | Preventive eculizumab | NA (dialysis) | NA | Complete protocol | NA | No recurrence Normal Screat (7 m) |
Nester 2011 [169] | Hybrid CFH | No | 12 y, 1st tx Preventive PE | Preventive eculizumab | NA (dialysis) | NA | Complete protocol | NA | No recurrence 80 μmol/L (4 m) |