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Atypical Hemolytic-Uremic Syndrome

Synonyms: Familial Hemolytic-Uremic Syndrome, Hereditary Hemolytic-Uremic Syndrome, aHUS, Atypical HUS. Includes: C3-Related Atypical Hemolytic-Uremic Syndrome, CD46-Related Atypical Hemolytic-Uremic Syndrome, CFB-Related Atypical Hemolytic-Uremic Syndrome, CFH-Related Atypical Hemolytic-Uremic Syndrome, CFHR1 and CFHR4-Related Atypical Hemolytic-Uremic Syndrome, CFHR3 and CFHR1-Related Atypical Hemolytic-Uremic Syndrome, CFI-Related Atypical Hemolytic-Uremic Syndrome, DGKE-Related Atypical Hemolytic-Uremic Syndrome, THBD-Related Atypical Hemolytic-Uremic Syndrome

, PhD, , MD, , Biol Sci D, and , MD.

Author Information
, PhD
IRCCS – Istituto di Ricerche Farmacologiche Mario Negri
Clinical Research Center for Rare Diseases Aldo e Cele Daccò
Transplant Research Center Chiara Cucchi de Alessandri e Gilberto Crespi
Bergamo, Italy
, MD
IRCCS – Istituto di Ricerche Farmacologiche Mario Negri
Clinical Research Center for Rare Diseases Aldo e Cele Daccò
Bergamo, Italy
, Biol Sci D
IRCCS – Istituto di Ricerche Farmacologiche Mario Negri
Clinical Research Center for Rare Diseases Aldo e Cele Daccò
Bergamo, Italy
, MD
IRCCS – Istituto di Ricerche Farmacologiche Mario Negri
Clinical Research Center for Rare Diseases Aldo e Cele Daccò
Division of Nephrology and Dialysis
Azienda Ospedaliera, Papa Giovanni XXIII
Bergamo, Italy

Initial Posting: ; Last Update: August 8, 2013.

Summary

Disease characteristics. Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. Typical (acquired) HUS is triggered by infectious agents such as strains of E. coli (Stx-E. coli) that produce powerful Shiga-like exotoxins, whereas atypical HUS (aHUS) can be genetic, acquired, or idiopathic (of unknown cause). Onset of atypical HUS ranges from prenatal to adulthood. Individuals with genetic atypical HUS frequently experience relapse even after complete recovery following the presenting episode. Sixty percent of genetic aHUS progresses to end-stage renal disease (ESRD).

Diagnosis/testing. Atypical HUS is considered genetic when two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded, or when disease-causing mutation(s) are identified in one of the ten genes in which mutations are known to be associated with aHUS, irrespective of familial history. The genes:

  • CFH (encoding complement factor H and accounting for ~30% of aHUS;
  • CD46 (MCP) (encoding membrane cofactor protein and accounting for ~12% of aHUS);
  • CFI (encoding complement factor I; ~5%-10% of aHUS),
  • C3 (encoding the third component of complement C3; ~5% of aHUS);
  • CFB (encoding complement factor B; rare);
  • THBD (encoding thrombomodulin; ~3%-5% of aHUS);
  • DGKE (encoding diacylglycerol kinase; ~27% of aHUS manifesting before age 1 year)
  • CFHR3, CFHR1, and CFHR4; deletions involving CFHR1 and CFHR3 or CFHR1 and CFHR4 account for ~5%-15% of aHUS.

Management. Treatment of manifestations: Eculizumab (a human anti-C5 monoclonal antibody) to treat aHUS and to induce remission of aHUS refractory or dependent to plasma therapy; plasma manipulation (plasma infusion or exchange) to reduce mortality; however, plasma resistance or plasma dependence is possible. Plasma manipulation and eculizumab therapy may not be beneficial to those with aHUS caused by mutations in DGKE. Treatment with ACE inhibitors or angiotensin receptor antagonists helps to control blood pressure and reduce renal disease progression. Bilateral nephrectomy when extensive renal microvascular thrombosis, refractory hypertension, and signs of hypertensive encephalopathy are not responsive to conventional therapies, including plasma manipulation. Renal transplantation may be an option, although recurrence of disease in the graft limits it usefulness.

Prevention of primary manifestations: Plasma exchange prophylaxis may prevent disease recurrences in those with mutation in CFH.

Prevention of secondary complications: Eculizumab therapy may prevent thrombotic microangiopathic events and prophylactic treatment may prevent post-tranplantation aHUS recurrence; vaccination against Neisseria meningitidies, Streptococcus pneumonia, and Haemophilus influenza type B is required prior to eculizumab therapy; prophylactic antibiotics may be needed if vaccination against Neisseria meningitidies is not possible at least two weeks prior to eculizumab therapy.

Surveillance: Serum concentration of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin: (1) every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for those with normal renal function or chronic renal insufficiency as they are at risk for relapse; and (2) in relatives with the mutation following exposure to potential triggering events.

Agents/circumstances to avoid: Those with known aHUS should avoid if possible pregnancy and the following drugs that are known precipitants of aHUS: anti-cancer molecules (including mitomycin C, cisplatin, daunorubimicin, cytosine arabinoside); immunotherapeutic agents (including cyclosporin and tacrolimus); and antiplatelet agents (including ticlopidine and clopidogrel). Plasma therapy is contraindicated in those with aHUS induced by Streptococcus pneumoniae because antibodies in the plasma of adults may exacerbate the disease.

Pregnancy management: Women with a history of aHUS are at increased risk for aHUS flare during pregnancy and even a greater risk in the post-partum period; the risk for pregnancy-associated aHUS (P-aHUS) is highest during the second pregnancy. Women with complement dysregulation should be informed of the 20% risk for P-aHUS, and any pregnancy in these women should be closely monitored.

Evaluation of relatives at risk: While it is appropriate to offer molecular genetic testing to at-risk relatives of persons in whom disease-associated mutations have been identified, predictive testing based on a predisposing factor (as opposed to a causative mutation) is problematic as it is one of only several risk factors required for disease causation.

Other: Live-related renal transplantation for individuals with aHUS should also be avoided in that disease onset can be precipitated in the healthy donor relative. Evidence suggests that kidney graft outcome is favorable in those with CD46 and DGKE mutations but not in those with CFH, CFI, C3, THBD, or CFB mutations; however, simultaneous kidney and liver transplantation in young children with aHUS and CFH mutations may correct the genetic defect and prevent disease recurrence.

Genetic counseling. Predisposition to atypical HUS (aHUS) is inherited in an autosomal recessive or autosomal dominant manner with incomplete penetrance. Rarely digenic inheritance and uniparental isodisomy are observed.

Autosomal recessive inheritance: Heterozygotes (carriers) are usually asymptomatic; however, rarely carriers have developed aHUS in adulthood. At conception, each sib of an individual with autosomal recessive aHUS has a 25% chance of inheriting two disease-causing mutations, a 50% chance of inheriting one mutation and being a carrier, and a 25% chance of inheriting neither mutation.

Autosomal dominant inheritance: Some individuals diagnosed with autosomal dominant aHUS have an affected parent or an affected close relative, but in the majority the family history is negative because of reduced penetrance of the disease-causing mutation in an asymptomatic parent, early death of a parent, late onset in a parent (or close relative), or a de novo mutation in the proband. Each child of an individual with autosomal dominant aHUS has a 50% chance of inheriting the mutation.

In both genetic types, clinical severity and disease phenotype often differ among individuals with the same mutations; thus, age of onset and/or disease progression and outcome cannot be predicted. Prenatal diagnosis for pregnancies at increased risk is possible if the disease-associated mutation(s) have been identified in the family.

Diagnosis

Clinical Diagnosis

Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs.

Typical (acquired) HUS is triggered by infectious agents such as strains of E. coli (Stx-E. coli) that produce powerful Shiga-like exotoxins (Stx), and manifests with diarrhea (D+HUS), often bloody. However, approximately 25% of children with typical HUS do not have diarrhea. Typical HUS may subside when the underlying condition has been treated or removed. Typical HUS is not known to be associated with any genetic predisposition.

Atypical HUS (aHUS) can be genetic, acquired, or idiopathic (of unknown cause). Individuals with aHUS frequently relapse even after complete recovery from the presenting episode; thus, aHUS is sometimes referred to as recurrent or relapsing HUS. Relapsing HUS is more likely to be genetic. The final outcome of aHUS is usually death or permanent renal or neurologic impairment.

Atypical HUS is considered genetic in the following situations:

  • Two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded;

    OR
  • Disease-causing mutation(s) are identified in one of the ten genes known to be associated with aHUS, irrespective of familial history.

Genetic atypical HUS can be multiplex (i.e., familial; two or more affected family members) or simplex (i.e., a single occurrence in a family).

Atypical HUS is considered acquired when an underlying environmental factor such as drugs, systemic disease, viral agents, or bacterial agents that do not result in Shiga-like exotoxins (Stx) can be identified.

Atypical HUS is considered idiopathic when no trigger (genetic or environmental) is evident.

Testing

Laboratory testing

Typical and atypical HUS. The following are laboratory hallmarks of both typical HUS and atypical HUS:

  • Thrombocytopenia that is usually severe
    • Platelet count should be less than 150,000/mm3 to establish the diagnosis. In most cases, platelet counts are below 60,000/mm3.
    • Platelet survival time is reduced, reflecting enhanced platelet disruption in the circulation.
    • Giant platelets may be seen in the peripheral smear, a finding consistent with secondary activation of thrombocytopoiesis.
  • Microangiopathic hemolytic anemia that is usually severe
    • Hemoglobin concentrations lower than 10 mg/dL are reported in 99% of cases and lower than 6.5 mg/dL in 40% of cases.
    • Serum lactate dehydrogenase (LDH) concentrations are increased (>460 U/L), often at very high levels, reflecting not only hemolysis, but also diffuse tissue ischemia.
    • Hyperbilirubinemia (mainly unconjugated), reticulocytosis, circulating free hemoglobin, and low or undetectable haptoglobin concentrations are additional nonspecific indicators of accelerated red cell disruption and production.
    • Detection of fragmented red blood cells (schistocytes) with the typical aspect of burr or helmet cells in the peripheral smear together with a negative Coombs test (with the exception of Streptococcus pneumoniae-associated HUS) are needed to confirm the microangiopathic nature of the hemolysis.
  • Acute renal insufficiency
    • Serum concentration of creatinine greater than 97th centile for age
    • Serum concentration of urea (BUN) greater than 97th centile for age

Typical HUS. The following are characteristic findings during acute illness in typical but not in atypical HUS:

  • Shiga toxins in the stools (by the Vero cell assay)

    AND/OR
  • Serum antibodies against Shiga toxin (by enzyme-linked immunosorbent assay [ELISA]) and/or LPS (lipopolysaccharides) (O157, O26, O103, O111, and O145, by ELISA)

The detection of free fecal STEC (Shiga toxin-producing E. coli) can be made by commercial immunoassays and requires only a few hours [Gianviti et al 2003].

Note: STEC isolation and detection of LPS antibodies are not routinely available and require a few days to complete.

Complement studies

  • Serum C3 and C4 concentrations can be used to monitor complement activation or dysregulation; however, these markers are not disease specific. Plasma concentrations of Bb (cleaved Factor B) can be used to evaluate the activation of the alternative pathway of complement. Plasma levels of the soluble membrane attack complex (sMAC) that includes sC5b-9 can be measured as an index of activation of the terminal complement cascade.
  • CFH, CFI, and CFB serum concentrations and surface expression of membrane cofactor protein (MCP) (encoded by CD46) in peripheral leukocytes should also be evaluated as they may give an indication of the underlying genetic mechanism.

Serum anti-CFH IgG autoantibodies . Five percent to 10% of individuals with aHUS have serum anti-CFH IgG autoantibodies even though plasma CFH antigen levels and analysis of CFH are normal. In about 90% of such individuals, deletion of the adjacent genes CFHR1 and CFHR3 was detected on both chromosomes. These genes encode factor H-related proteins 1 and 3, respectively, which share structural and functional similarities to factor H. The mechanism underlying the association between deletion of CFHR1 and CFHR3 and factor H antibody formation is not understood [Dragon-Durey et al 2004, Zipfel et al 2007].

Three affected individuals positive for anti-CFH autoantibodies were recently found to have no copies of CFHR1 and a single copy of CFHR3 rather than none and a novel deletion incorporating CFHR1 and CFHR4. Thus, these individuals had a CFHR3/CFHR1 deletion on one allele and a CFHR1/CFHR4 deletion on the other allele [Moore et al 2010].This finding suggests that the complete deficiency of factor H-related protein 1 is probably the significant factor associated with the production of factor H autoantibodies in aHUS.

Renal histology (typical and atypical HUS). The common microvascular lesions of HUS consist of vessel (capillary and arteriole) wall thickening with endothelial swelling, which allows accumulation of proteins and cell debris in the subendothelial layer, creating a space between endothelial cells and the underlying basement membrane of affected microvessels. Both the widening of the subendothelial space and intraluminal platelet thrombi lead to a partial or complete obstruction of the vessel lumen. The partial occlusion of the lumen probably disrupts erythrocytes by mechanical trauma, which explains the hemolysis and presence of fragmented and distorted erythrocytes in the blood smear.

In D+HUS the glomeruli are large; the capillaries are distended by red cells and platelet fibrin thrombi that may extend proximally into the afferent arteriole, suggesting that the thrombus is initiated in the glomerular capillaries themselves. Arterial lesions and mesangial changes are not reported, even long after the initial episode of D+HUS [Taylor et al 2004].

In DHUS glomerular thrombosis, intracapillary foamy cells, endocapillary swelling, endocapillary hypercellularity, mesangiolysis, and doubled basement membranes are observed. Arterioles have thrombosis, endothelial swelling, or fibrinoid necrosis. Arteries have intimal swelling with various amounts of hypercellularity and thrombosis [Taylor et al 2004].

Note: (1) In children younger than age two years the lesion is mainly confined to the glomerular tuft and is noted in an early phase of the disease. Glomerular capillary lumina are reduced or occluded. In patent glomerular capillaries packed with red blood cells and fibrin, thrombi occasionally are seen. (2) Examination of biopsies taken several months after disease onset shows that most glomeruli are normal; 20% eventually became sclerotic. (3) Arterial thrombosis does occur but is uncommon and appears to be a proximal extension of the glomerular lesion. (4) In the acute phase, tubular changes include foci of necrosis of proximal tubular cells and presence of red blood cells and eosinophilic casts in the lumina of distal tubules. Occasionally fragmented red blood cells can be detected in the distal tubular lumina. (5) In adults and older children, glomerular changes are different and more heterogeneous than in infants, and the classic pattern of thrombotic microangiopathy is less evident.

Molecular Genetic Testing

Genes. Evidence is emerging that 50%-60% of the atypical HUS (aHUS) is associated with genetically determined alterations of the complement system. Mutations have been found in the following genes [Noris & Remuzzi 2009, Noris et al 2010]:

  • CFH (encoding complement factor H). Intragenic CFH mutations, mostly missense, account for 30% of aHUS (also known as aHUS1). Gene rearrangements that inactivate CFH:
  • CD46 (MCP) (encoding membrane cofactor protein). Mutations in CD46 account for an estimated 12% of aHUS (also known as aHUS2). In one child, complete paternal uniparental isodisomy of chromosome 1 with homozygosity for a splice defect of exon 10 resulted in severe deficiency of CD46 expression [Fremeaux-Bacchi et al 2007].
  • CFI (encoding complement factor I). Mutations in CFI account for an estimated 5%-10% of aHUS (also known as aHUS3).
  • CFB (encoding complement factor B). Mutations in CFB have been reported in affected individuals from two Spanish families [Goicoechea de Jorge et al 2007]. Both are gain-of-function mutations that result in either enhanced formation of C3bBb convertase or increased resistance to inactivation by complement regulators. In a US cohort CFB mutations accounted for 4% of aHUS [Maga et al 2010b] (also known as aHUS4).
  • C3 (encoding the third component of complement C3). Mutations in C3 account for an estimated 5% of aHUS (also known as aHUS5).
  • THBD (encoding the anticoagulant protein thrombomodulin). Mutations in THBD account for 3%-5% of aHUS [Delvaeye et al 2009] (also known as aHUS6).
  • DGKE (encoding diacylglycerol kinase). Recessive (homozygous or compound heterozygous) mutations in DGKE account for 27% of aHUS manifesting before age one year (also known as aHUS7) [Lemaire et al 2013].
  • CFHR3, CFHR1, and CFHR4 are contiguous genes (in the order shown) in the regulators of complement activation (RCA) cluster (see Molecular Genetics). Deletion of either CFHR3 and CFHR1 or CFHR1 and CFHR4 is associated with atypical aHUS [Zipfel et al 2007, Dragon-Durey et al 2009, Moore et al 2010].

Digenic inheritance

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Atypical Hemolytic-Uremic Syndrome

Gene Symbol 1 (Phenotype Designation)Proportion of aHUS Attributed to Mutations in This GeneTest Method Mutations Detected 2
CFH (aHUS1)30% Sequence analysis Sequence variants 3, 4
Deletion / duplication analysis 5Exonic or whole-gene deletions
3%-5% CFH/CFHR1 hybrid allele 6
CD46 (aHUS2)12% Sequence analysis Sequence variants 3
Deletion / duplication analysis 5Exonic or whole-gene deletions 7
CFI (aHUS3)5%-10% Sequence analysisSequence variants 3
Deletion / duplication analysis 5Exonic or whole-gene deletions 7
CFB (aHUS4)1%-4%Sequence analysisSequence variants 3
C3 (aHUS5)5%Sequence analysisSequence variants 3
THBD (aHUS6)3%-5%Sequence analysisSequence variants 3
DGKE (aHUS7)27% of cases manifesting at age <1 yrSequence analysisSequence variants 3
CFHR3, CFHR15%-10%Deletion / duplication analysis 5Deletions involving CFHR3 and CFHR1 8
CFHR1, CFHR4Deletion / duplication analysis 5Deletions involving CFHR1 and CFHR4 9

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations; typically, exonic or whole gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

4. Sequence analysis does not detect the CFH/CFHR1 hybrid allele that accounts for approximately 3%-5% of all aHUS.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

6. This hybrid allele, resulting from crossing over between intron 21 of CFH and intron 4 of CFHR1, consists of the first 21 exons of CFH and the last two exons of CFHR1. Deletion analysis detects the hybrid allele, which is not detected by sequence analysis of CFH.

7. Some laboratories offer deletion/duplication analysis for CD46 and CFI. However, no deletions or duplications involving either CD46 or CFI as causative of aHUS have been reported. The clinical utility of such testing is unknown.

8. The allele frequency of the CFHR1 and CFHR3 deletion is 26.5% [Moore et al 2010].

9. The allele frequency of the CFHR1 and CFHR4 deletion is 1.4% among individuals with aHUS [Moore et al 2010].

Testing Strategy

To confirm/establish the diagnosis of genetic aHUS in a proband

  • Measurement of the concentration of CFH and CFI by ELISA methods, measurement of CFB by nephelometry, and evaluation of CD46 protein expression on peripheral blood leukocytes by FACS is recommended in all affected individuals prior to molecular genetic testing because the results of these tests may provide insight into which gene is likely to be mutated.
  • Molecular genetic testing of CFH, CD46, CFI, C3, the CFH/CFHR1 hybrid allele, THBD, and CFB (in the order shown) should be performed in all individuals in whom clinical evaluation and laboratory testing supports the diagnosis of aHUS.
  • For individuals with aHUS presenting before age one year, particularly if the family history reveals consanguinity or evidence of autosomal recessive inheritance, consider sequence analysis of DGKE first.

    Note: (1) No one laboratory test is correlated with the presence or absence of a mutation in one of the genes encoding a complement factor. (2) If only one mutation is identified in CFH, CD46, CFI, or C3, complete sequencing of each gene should be considered to determine if a mutation is present in a second gene, a finding that supports the possibility of digenic inheritance.
  • Search for CFH autoantibodies by ELISA in all affected individuals whether or not a mutation has been identified because CFH autoantibodies have been found in both instances.

    Note: The CFHR3/CFHR1 deletion on both alleles is found in 90% of persons with CFH autoantibodies [Moore et al 2010].

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.

Predictive testing

  • Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutations in the family.
  • Prior to kidney transplantation, predictive testing is important because individuals with mutations in CFH, CFI, CFB, C3, and THBD tend to have recurrence of aHUS after renal transplantation [Bresin et al 2006, Noris et al 2010].

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.

Clinical Description

Natural History

Atypical HUS (aHUS) comprises genetic aHUS, acquired (sporadic) aHUS, and idiopathic (of unknown cause) aHUS.

Onset of atypical HUS ranges from prenatal to adulthood [Constantinescu et al 2004, Taylor et al 2004, Sellier-Leclerc et al 2007, Noris et al 2010].

Collectively, aHUS is associated with poor outcome. Fifty percent of acquired aHUS and 60% of genetic aHUS progresses to end-stage renal disease (ESRD) [Ruggenenti et al 2001, Caprioli et al 2003, Caprioli et al 2006, Noris et al 2010].

Genetic (Multiplex and Simplex) Atypical HUS

Currently, genetic atypical HUS accounts for an estimated 60%-70% of all aHUS. Note: The remaining 30%-40% may also be genetic; however, causative mutations in other genes have not yet been identified.

Genetic atypical HUS frequently relapses even after complete recovery following the presenting episode [Ruggenenti et al 2001, Taylor et al 2004], with death or permanent neurologic or renal sequelae being the final outcome in the majority of cases.

It is likely that mutations in CFH, CD46, CFI, CFB, C3, and THBD confer a predisposition to develop aHUS, rather than directly causing the disease, and that a second mutational event in the remaining normal allele is required for full-blown manifestation of the disease. Conditions that trigger complement activation either directly (bacterial and viral infections or sepsis) or indirectly (drugs or certain systemic diseases that cause endothelial insult) may precipitate an acute event in those with the predisposing genetic background [Caprioli et al 2006, Noris et al 2010].

Recessive mutations in DGKE represent a distinctive Mendelian disease: affected individuals present with aHUS before age one year, have persistent hypertension, hematuria, and proteinuria (sometimes in the nephrotic range), and develop chronic kidney disease with age [Lemaire et al 2013].

Multiplex aHUS (i.e., more than one affected individual in the family) accounts for approximately 10% of all aHUS. Both autosomal dominant and autosomal recessive forms of aHUS have been noted.

  • In autosomal recessive aHUS the onset is usually early in childhood. The prognosis is poor, with a mortality rate of 60%-70%. Episodes of aHUS recur frequently.
  • In autosomal dominant aHUS the onset is usually in adulthood. The prognosis is poor, with a cumulative incidence of death or ESRD of 50%-90%.

Sporadic (Acquired) aHUS

Triggers for acquired aHUS include non-enteric bacterial infections, viruses, drugs, malignancies, transplantation, pregnancy, and other underlying medical conditions (scleroderma, anti-phospholipid syndrome, and systemic lupus erythematosus [SLE]). Triggering agents for acquired (sporadic) aHUS differ from those of typical HUS (see Differential Diagnosis, Distinguishing typical HUS from atypical HUS):

  • Infection caused by Streptococcus pneumoniae accounts for 40% of aHUS and 5% of all causes of HUS in children in US. Neuroaminidase produced by Streptococcus pneumoniae removes sialic acids from the cell membranes, exposing Thomsen-Friedenreich antigen to preformed circulating IgM antibodies which bind to this neoantigen on platelet and endothelial cells and cause platelet aggregation and endothelial damage. The clinical picture is usually severe, with respiratory distress, neurologic involvement, and coma; the mortality rate is 12.3% [Copelovitch & Kaplan 2008].
  • Drugs that have been most frequently reported to induce aHUS include the following [Dlott et al 2004]:
    • Anti-cancer agents (mitomycin, cisplatin, bleomycin, gemcitabine). The risk of developing aHUS after use of mitomycin is 2%-10%. The onset is delayed, occurring almost one year after starting treatment. The prognosis is poor, with up to 75% mortality at four months [Dlott et al 2004].
    • Immunotherapeutic agents (cyclosporine, tacrolimus, OKT3, interferon, and quinidine)
    • Antiplatelet agents (ticlopidine, clopidogrel)
    • A variety of common medications, including oral contraceptives and anti-inflammatory agents
  • Cancer-associated aHUS complicates almost 6% of cases of metastatic carcinoma. Gastric cancer alone accounts for approximately half of such cases.
  • Post-transplantation aHUS is being reported with increasing frequency [Ruggenenti et al 2001]. It may occur for the first time in individuals who have not experienced aHUS before (de novo post-transplantation aHUS) or may affect those whose primary cause of ESRD was aHUS (recurrent post-transplantation aHUS; see Treatment of Manifestations). De novo post-transplantation aHUS may occur in individuals receiving transplants of kidneys or other organs because of the use of calcineurin inhibitors or because of humoral (C4b-positive) rejection. Post-renal transplantation aHUS occurs in 5%-15% of patients receiving cyclosporine and in approximately 1% of those receiving tacrolimus.
  • Pregnancy-associated aHUS may occasionally develop as a complication of preeclampsia. Some women progress to a life-threatening variant of preeclampsia with severe thrombocytopenia, microangiopathic hemolytic anemia, renal failure, and liver involvement (HELLP syndrome). Complete remission usually follows prompt delivery.
  • Post-partum aHUS usually manifests in women within three months of delivery. The outcome is usually poor with 50%-60% mortality; residual renal dysfunction and hypertension are the rule in those who survive the acute episode.
  • Underlying medical conditions. Autoimmune disease is one of the underlying medical conditions; autoantibodies to CFH are present in an estimated 6%-10% of individuals [Dragon-Durey et al 2005, Jozsi et al 2007, Noris et al 2010].

Genotype-Phenotype Correlations

The phenotype of aHUS ranges from mild (with complete recovery of renal function) to severe (resulting in ESRD or death) [Noris & Remuzzi 2005]. Although genotype-phenotype correlations are not always straightforward, analysis of published reports reveals that the course and outcome of the disease are influenced by the gene in which mutations occur [Caprioli et al 2003, Neumann et al 2003, Noris & Remuzzi 2005, Caprioli et al 2006, Sellier-Leclerc et al 2007, Noris et al 2010].

CFH. Atypical HUS associated with CFH mutations presents early in childhood in approximately 70% of affected individuals and in adulthood in approximately 30%. Irrespective of the pattern of inheritance, the clinical course is characterized by a high rate of relapse and a 60%-80% rate of death or ESRD following the presenting episode or as a consequence of relapse.

CD46. Atypical HUS associated with CD46 mutations presents mostly in childhood; the acute episode is in general milder than that associated with CFH mutations. Eighty percent of affected individuals experience complete remission. Recurrences are frequent but have little effect on long-term outcome; an estimated 60%-70% of individuals remain dialysis free even after several recurrences. A subgroup of individuals, however, lose renal function either during the first episode or later in life.

CFI. Atypical HUS associated with CFI mutations is variable. The onset is in childhood in 50% of affected individuals. Fifty-eight percent develop ESRD over the long term.

CFB. Atypical HUS associated with CFB mutations is poorly understood, as few affected individuals have been reported.

C3. Atypical HUS associated with C3 mutations presents in childhood in about 50% of individuals. More than 60% of affected individuals develop ESRD over the long term.

THBD. Atypical HUS associated with THBD mutations presents in childhood in about 90% of individuals. More than 50% of patients develop ESRD over the long term.

DGKE. Atypical HUS associated with recessive mutations in DGKE presents before 1 year of age in all affected individuals [Lemaire et al 2013]. Affected individuals show persistent hypertension, hematuria and proteinuria (sometimes in nephrotic range), and develop chronic kidney disease by the second decade of life. Relapsing episodes are reported before age five years. Assessment of complement system shows no abnormality in any affected individual [Lemaire et al 2013].

Digenic inheritance. About 3% of individuals have mutations in two or even three genes encoding complement regulatory proteins. Reports of digenic inheritance include the following:

These findings indicate that CFH, CD46, CFI, and C3 genetic variants could have an additive effect in determining the aHUS phenotype, since the proteins encoded by CFH, CD46, CFI, and C3 interact with each other to control complement activation on host cells.

A few affected individuals with combined homozygous deletion of CFHR3 and CFHR1 and mutations in CFH, CFI, CD46, or C3 have also been reported [Moore et al 2010].

A number of common normal allelic variants described in the regulator of complement activation (RCA) cluster (see Molecular Genetic Pathogenesis) may predispose to aHUS both in individuals with CFH/CD46/CFI mutations and in those without identifiable mutations [Caprioli et al 2003, Esparza-Gordillo et al 2005, Fremeaux-Bacchi et al 2013, FH aHUS Mutation Database].

Understanding of genotype-phenotype correlations could potentially optimize treatment (see Management, Treatment of Manifestations).

Penetrance

The incomplete penetrance of aHUS often found in those with mutation of CFH, CD46, CFI, C3, or THBD indicates that such mutations confer a predisposition to develop aHUS, rather than directly causing the syndrome and that multiple genetic and/or environmental events are required for full-blown disease manifestation.

CFH. A substantial number of individuals with mutation of CFH never develop aHUS. Overall the penetrance of the disease in those with mutation of CFH is 48%. Conditions that trigger complement activation, either directly (bacterial and viral infections) or indirectly by causing endothelial insult (drugs, systemic diseases, pregnancy), precipitate the acute event in approximately 60% of those with mutation of CFH [Caprioli et al 2006, Noris et al 2010]. It is postulated that suboptimal CFH activity in these individuals is sufficient to protect the host from the effects of complement activation in physiologic conditions; however, suboptimal CFH activity is not sufficient to prevent C3b from being deposited on vascular endothelial cells when exposure to an agent that activates complement produces higher-than-normal amounts of C3b.

CD46, CFI, C3, and THBD. Penetrance for mutations in these genes is: CD46: 53%; CFI: 50%; C3: 56%; and THBD: 64% [Caprioli et al 2006, Noris et al 2010].

DGKE. Of nine kindreds analyzed in which mutations in DGKE segregated, 4/18 siblings of index cases had aHUS, consistent with recessive transmission with high penetrance [Lemaire et al 2013]. In these families, all affected individuals were found to have either homozygous or compound heterozygous mutations in DGKE and all healthy siblings were either found to have no pathogenic mutation in DGKE or were carriers of one heterozygous mutation. Thus, the penetrance is very probably complete in those with a recessive form of aHUS associated with mutations in DGKE.

Nomenclature

Typical HUS is also referred to as Shiga-like toxin-associated HUS (Stx-HUS) and D+HUS (diarrhea-positive HUS), although 25% of cases do not manifest diarrhea. Thus, at a minimum a search for free-fecal Shiga toxin (by commercial immunoassays) is recommended even in DHUS.

Atypical HUS (aHUS) is also referred to as non-Shiga-like toxin-associated HUS (non-Stx-HUS) and DHUS (diarrhea-negative HUS). However, the term diarrhea-negative HUS to refer to aHUS is not completely accurate, as 25% of typical HUS does not manifest diarrhea.

Prevalence

Atypical HUS is less common than typical HUS and accounts for only 5%-10% of individuals presenting with findings of HUS [Ruggenenti et al 2001].

According to a recent US study the incidence of aHUS in children is approximately one tenth that of typical HUS, corresponding to an estimated annual incidence of 2:1,000,000 population [Kaplan et al 1998].

Differential Diagnosis

Distinguishing typical HUS from atypical HUS (aHUS). Typical HUS is triggered by infective agents such as certain strains of E. coli that produce the Shiga-like powerful exotoxins (Stx-E. coli).

Typical HUS triggered by Stx-E. coli manifests with a prodrome of diarrhea (D+HUS), often bloody. However, approximately 25% of typical HUS is diarrhea negative. During an acute episode, identification of Shiga toxins in the stools (by the Vero cell assay) and/or serum antibodies against Shiga toxin (by enzyme-linked immunosorbent assay [ELISA]) and/or LPS (O157, O26, O103, O111, and O145, by ELISA) distinguishes typical HUS (D+HUS or DStx+HUS) from aHUS (DStxHUS).

In its most common presentation, typical HUS manifests as an acute disease and 80%-90% of individuals recover without sequelae, either spontaneously (as in most cases of childhood typical HUS) or after plasma infusion or exchange (as in adult or severe forms of typical HUS) [Ruggenenti et al 2001].

Typical HUS usually subsides when the underlying condition is treated or removed.

Distinguishing atypical HUS from thrombotic thrombocytopenic purpura (TTP). Atypical HUS and TTP share a common pathologic lesion (thrombotic microangiopathy) but have different clinical manifestations. In aHUS the lesions and clinical symptoms are mainly localized in the kidney, whereas the pathologic changes of TTP are more extensively distributed, probably reflecting the systemic nature of the underlying defect. Clinically, TTP manifests mainly with central nervous system symptoms, but renal insufficiency has been reported.

Approximately 80% of TTP is triggered by deficient activity of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor (VWF) multimers soon after their secretion by endothelial cells. ADAMTS13 deficiency can be constitutive, as a result of homozygous or compound heterozygous mutations in ADAMTS13; or acquired, as a result of the presence of an inhibitory antibody. Evaluation of ADAMTS13 activity in serum or plasma is performed by several specialized laboratories using different tests based on the capability of the protease to cleave standard VWF multimers in vitro. One such test is the collagen binding assay. In large clinical studies, deficiency of ADAMTS13 activity was found in individuals with TTP but not in those with either typical or atypical HUS [Galbusera et al 2006]. This observation generated the hypothesis that TTP is caused by a deficiency of ADAMTS13 activity, whereas atypical HUS is unrelated to mutation of ADAMTS13.

The exception to the above hypothesis occurs when ADAMTS13 and CFH mutations are observed in the same individual.

  • Of two sisters with thrombotic microangiopathy, one presented with neurologic symptoms only and the other with superimposed severe renal impairment [Noris et al 2005]. Both had complete ADAMTS13 deficiency resulting from two heterozygous ADAMTS13 mutations; however, the sister who developed chronic renal failure also had a heterozygous CFH mutation that was not present in her sister, who had neurologic symptoms only. Thus, it was hypothesized that CFH haploinsufficiency had a role in determining the renal complications superimposed on the systemic disease caused by ADAMTS13 deficiency.
  • Other affected individuals with both ADAMTS13 and CFH mutations have been reported [Zimmerhackl et al 2007].

Distinguishing aHUS from dense deposit disease / membranoproliferative glomerulonephritis type II (DDD/MPGN II). DDD/MPGN II typically occurs in children age five to 15 years who manifest with one of the following: hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome, or nephrotic syndrome. DDD/MPGN II is associated with alternative pathway complement activation usually caused by C3 nephritic factors, IgG autoantibodies that stabilize the alternative C3 convertase (C3bBb). Diagnosis of DDD/MPGN II requires electron microscopy and immunofluorescence studies of a renal biopsy [Walker et al 2007]. Electron microscopy demonstrates dense transformation of the glomerular basement membrane (GBM) that occurs in a segmental, discontinuous, or diffuse pattern in the lamina densa. The precise composition of these altered areas remains unknown. Immunofluorescence should be positive for C3, usually in the absence of immunoglobulin deposition.

Spontaneous remissions are uncommon in DDD/MPGN II. Approximately half of affected individuals develop ESRD within ten years of diagnosis. Other findings can include visual impairment late in the disease, acquired partial lipodystrophy, and other autoimmune diseases including diabetes mellitus type 1 and celiac disease. Mutations in CFH, C3, FHR5, and LMNA have been implicated in the pathogenesis of DDD/MPGN II.

DDD/MPGN II has been reported in individuals with CFH deficiency. In contrast to individuals with aHUS, persons with DDD/MPGN II generally have homozygous or compound heterozygous CFH mutations that cause severely reduced CFH protein levels [Dragon-Durey et al 2004]. However, the rare cases of aHUS associated with homozygous mutations in CFH and very low levels of circulating CFH protein can blur the distinction between HUS and DDD/MPGN. Furthermore, this overlap in phenotypes is evident in those few individuals who have a mixed diagnosis of aHUS and DDD/MPGN in the same biopsy or in biopsies taken at different points in time [Bresin et al 2007].

Distinguishing aHUS from cobalamin C (cblC) disease. Cobalamin C (cblC), caused by mutations in MMACHC, is characterized by abnormal vitamin B12 metabolism, manifest as metabolic acidosis, methylmalonic aciduria, homocystinuria, hematologic abnormalities, and, on occasion, aHUS [Geraghty et al 1992, Van Hove et al 2002]. Inheritance is autosomal recessive. See Disorders of Intracellular Cobalamin Metabolism.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Current guidelines for the initial assessment and early management of children with aHUS have been published [Ariceta et al 2009] (full text).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with atypical hemolytic-uremic syndrome (aHUS), the following evaluations are recommended:

  • Renal function
    • Creatinine clearance (i.e., glomerular filtration rate [GFR])
    • Serum concentration of creatinine resources
    • Urinalysis
  • Hematologic status
    • Platelet count
    • Erythrocyte count
    • Search for schistocytes in the blood smear
    • Leukocyte count
  • Other
    • Serum LDH concentration
    • Haptoglobin
    • Serum C3 and C4 concentrations
    • Plasma concentrations of Bb and sC5b-9
  • Measure serum concentrations of CFH and CFI
  • Assessment of CD46 expression on leukocytes
  • Testing for CFH autoantibodies because affected individuals who have autoantibodies could benefit from an immunosuppressive therapy (see Treatment of Manifestations)
  • Medical genetics consultation

Treatment of Manifestations

Eculizumab, a human anti-C5 monoclonal antibody registered for the treatment of paroxysmal nocturnal hemoglobinuria [Brodsky et al 2008], has been shown to induce remission of acute episodes of aHUS refractory to plasma therapy [Gruppo & Rother 2009] and is now widely used as a first line therapy to treat aHUS.

In two prospective phase 2 clinical trials using eclizumab for a median of 64 and 62 weeks, respectively, in 37 individuals with aHUS, Eclizumab resulted in increased platelet counts and significant improvement in all secondary end points, with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR) [Legendre et al 2013]. In trial 1, 4/5 affected individuals treated with Eclizumab were able to discontinued dialysis. Eculizumab was also associated with improvement in health-related quality of life. No cumulative toxicity of therapy or serious infection-related adverse events, including meningococcal infections, was observed through the extension period.

Eculizumab should be considered as a first-line therapy when the diagnosis of aHUS is unequivocal, since this treatment has the potential to rescue renal function when administered early after onset of the disease [Zuber et al 2012a, Fakhouri et al 2013].

  • In children with a first episode of aHUS eclizumab therapy avoids the complications associated with apheresis and central venous catheters.
  • In adults, eculizumab can be used as a first-line therapy when the aHUS diagnosis is undisputable, although plasma therapy should be used as a first-line therapy if uncertainty in the diagnosis warrants further investigation.
  • Evidence of plasma resistance or dependance should lead to a prompt shift to eculizumab therapy [Zuber et al 2012a].

Note: (1) A small number of reports have suggested that eculizumab could also reverse extra-renal aHUS-related organ failure, including neurologic involvement and digital ischemia [Ariceta et al 2012, Ohanian et al 2011]; (2) individuals with mutations in DGKE may not benefit from treatment with eculizumab [Zuber et al 2012a]; (3) a number of important issues require further study, including the appropriate duration of treatment according to an individual's genetic background and medical history, and a cost-efficacy analysis.

Plasma infusion or exchange. The mortality rate for aHUS dropped from 50% to 25% after plasma manipulation (plasma infusion or exchange) was introduced [Lara et al 1999]. A consistent number of individuals with aHUS respond to plasma treatment [Lara et al 1999, Caprioli et al 2006].

Debate continues as to whether plasma infusion and/or plasma exchange is effective in the treatment of acute episodes. It has been proposed that plasma exchange is more effective than plasma infusion because it removes potentially toxic substances from the blood; in one study the efficacy of plasma exchange was shown to be superior to that of plasma infusion [Ruggenenti et al 2001]. However, persons treated with plasma exchange were given larger amounts of plasma than those treated with plasma infusion alone; when equivalent volumes of plasma were given, the two treatments appeared to be equally effective. In situations that limit the amount of plasma that can be provided with infusion alone (e.g., renal insufficiency, heart failure), plasma exchange should be considered the therapy of choice [Ruggenenti et al 2001].

Plasma exchange usually involves exchanging one plasma volume (40 mL/kg) per session. Treatment can be intensified by increasing the volume of plasma replaced. Twice-daily exchange of one plasma volume is probably the treatment of choice for those with refractory disease in order to minimize the recycling of infused plasma.

Plasma infusion is the first-line therapy when plasma exchange or eculizumab therapies are not available. In plasma infusion 30-40 mL/kg of plasma is administered initially, followed by 10-20 mL/kg/day. Plasma infusion should be used to treat or prevent recurrent episodes.

Platelet count and serum LDH concentration are the most sensitive markers for monitoring response to plasma therapy. Plasma treatment should be continued until platelet count and serum LDH concentration remain normal after therapy is discontinued. Discontinuation of plasma therapy is the only way to know if complete remission has been achieved. Immediate exacerbation of disease activity, principally manifested by falling platelet count that requires the resumption of daily plasma therapy, occurs in 29%-82% of patients after treatment is discontinued. Thus, many cycles of stopping and resuming plasma therapy may occur, in which case therapy with eculizumab should be considered.

Genetic characterization of persons with aHUS has the potential to optimize the treatment:

  • CFH. Plasma infusion or exchange has been used in patients with aHUS and CFH mutations with the rationale of providing normal CFH to compensate for the genetic deficiency, as CFH is a circulating plasma protein. In published studies, some patients with CFH mutations did not respond at all to plasma therapy and died or developed ESRD. Others required infusion of plasma at weekly intervals in order to raise CFH plasma levels enough to maintain remission [Landau et al 2001].

    Stratton and Warwicker [2002] were able to induce sustained remission in a patient with a CFH mutation by three months of weekly plasma exchange in conjunction with intravenous immunoglobulins. One year after discontinuation of plasma therapy, the patient remained disease free and dialysis independent.

    In the authors' series [Caprioli et al 2006, Noris et al 2010], approximately 60% of patients with CFH mutations treated with plasma underwent either complete or partial remission (hematologic normalization with renal sequelae). However, the remaining patients did not respond at all to plasma and 20% died during the acute episode.
  • CD46. The rationale for using plasma in patients with CD46 mutations is not so clear, since the CD46 protein (also known as MCP) is a transmembrane protein and, theoretically, plasma infusion or plasma exchange would not compensate for the MCP defect. Published data indicate that the majority (80%-90%) of patients undergo remission following plasma infusion or exchange [Richards et al 2003, Caprioli et al 2006]; however, complete recovery from the acute episode was also observed in 100% of patients not treated with plasma [Noris et al 2010]. The decision whether or not to treat with plasma should be based on the clinical severity of the acute episode.
  • CFI. Theoretically one should expect a good response to plasma therapy in patients with CFI mutations because CFI (like CFH) is a circulating protein; the results, however, suggest that a larger quantity of plasma is required to provide sufficient wild-type CFH or CFI to compensate for the genetic deficiency [Caprioli et al 2006]. Indeed, remission was achieved in only 25% of episodes treated with plasma in persons with CFI mutations [Noris et al 2010].
  • CFB. Few data are available on response of individuals with CFB mutations to treatment with plasma. Only one of three treated individuals underwent remission [Goicoechea et al 2007].
  • C3. Response to plasma treatment in persons with C3 mutations was comparable (57%) to that in persons with CFH mutations [Noris et al 2010]. It is hypothesized that plasma exchange could remove mutant hyperactive C3 and also provide regulatory plasma proteins to counteract complement activation induced by mutant C3.
  • THBD. Plasma treatment induced disease remission in about 80% of acute episodes in persons with THBD mutations [Noris et al 2010].
  • DGKE. Absence of evidence linking DGKE deficiency to the complement cascade and relapses of acute aHUS in affected individuals with mutations in DGKE while receiving plasma therapy suggest that this treatment may not benefit individuals with DGKE mutations [Zuber et al 2012a].
  • CFH- autoantibodies. In individuals with anti-CFH autoantibodies, plasma treatment induced complete or partial remission (normalization of hematologic parameters with renal sequelae) of 75% of episodes [Noris et al 2010]. Persons with anti-CFH autoantibodies benefit from treatment with steroids or other immunosuppressants in conjunction with plasma exchange.

Treatment with ACE inhibitors or angiotensin receptor antagonists helps to reduce renal disease progression to end-stage renal failure, while at the same time controlling blood pressure levels.

Bilateral nephrectomy has been performed on rare occasion in a small number of individuals with extensive microvascular thrombosis at renal biopsy, refractory hypertension, and signs of hypertensive encephalopathy, in whom conventional therapies including plasma manipulation are not adequate to control the disease (i.e., persistent severe thrombocytopenia and hemolytic anemia). Follow-up has been excellent in some patients [Remuzzi et al 1996].

Plasma-resistant/plasma-dependent disease. Some patients with aHUS are plasma resistant (i.e., they do not achieve remission despite plasma therapy); some become plasma dependent, experiencing disease relapse as soon as plasma infusion or exchange is stopped. The following treatments are ineffective:

  • Splenectomy, which induces remission in some persons with plasma-resistance, is ineffective and actually increased morbidity and mortality in others.
  • Other treatments including antiplatelet agents, prostacyclin, heparin or fibrinolytic agents, steroids, and intravenous immunoglobulins have been attempted in both plasma resistance and plasma dependence with no consistent benefit [Ruggenenti et al 2001].

Renal transplantation is not necessarily an option for aHUS in contrast to typical HUS.

  • In the past, an estimated 50% of individuals with aHUS who underwent renal transplantation had a recurrence of the disease in the grafted organ [Artz et al 2003, Noris & Remuzzi 2005]. Recurrences occur at a median time of 30 days after transplantation (range 0 days to 16 years). However, this data was collected prior to the availability of eculizumab therapy.
  • Eculizumab therapy may be used to treat post-transplantation aHUS recurrence, as reported in individuals with mutations in CFH, C3, and CFI [Zuber et al 2012b].
  • Eculizumab prophylactic therapy may also prevent post-transplantation aHUS recurrence (see Prevention of Secondary Complications).

Molecular genetic tests could help to define graft prognosis; thus, all affected individuals should undergo such testing prior to transplantation.

  • CFH. In patients with CFH mutations the graft outcome is poor. Recurrence rate ranges from 30% to 100% (depending on the survey) and is significantly higher than in patients without CFH mutations [Neumann et al 2003, Noris & Remuzzi 2005, Bresin et al 2006, Noris & Remuzzi 2010]. As CFH is mainly produced by the liver, kidney transplantation does not correct the CFH genetic defect in these patients.

    Simultaneous kidney and liver transplantation has been performed in two young children with aHUS and CFH mutations with the objective of correcting the genetic defect and preventing disease recurrence [Noris & Remuzzi 2005]. However, following transplantation both children experienced premature irreversible liver failure. The first child recovered after a second uneventful liver transplantation. This child, who had had monthly recurrences of aHUS before transplantation, had no symptoms of aHUS for more than two years following transplantation. The second child expired after primary non-function of the liver graft followed by multiorgan failure.

    In six other patients with CFH mutations and in one child with digenic mutations (one in CFH and one in CFI) who received simultaneous kidney and liver transplantation [Saland et al 2006, Saland et al 2009, Noris et al 2010], good renal and liver function were recorded at two-year follow-up. In these individuals extensive plasma exchange was given prior to surgery to provide enough normal CFH to prevent damage to the liver graft.
  • CD46. Kidney graft outcome is favorable in patients with CD46 mutations: four patients have been successfully transplanted with no disease recurrence [Noris & Remuzzi 2005, Noris et al 2010]. The strong theoretic rationale is that because the CD46 protein (MCP) is a transmembrane protein that is highly expressed in the kidney, transplantation of a kidney expressing normal MCP corrects the defect.
  • CFI, C3, and CFB. As CFI, CFB, and C3 are plasma proteins, one could speculate that aHUS may recur in the transplanted kidney, resulting in graft failure. The few data available support this hypothesis as graft failures secondary to recurrences occurred in 70% of patients with CFI mutations and in one patient with a CFB mutation. The percentage of graft failure was slightly lower (50%) in patients with C3 mutations [Noris et al 2010].
  • THBD. One patient with THBD mutations had disease recurrence in the kidney graft, which is unexpected because thrombomodulin, like CD46, is an endothelial transmembrane protein. However, a soluble thrombomodulin form circulates in plasma and has functional activities similar to those of membrane-bound thrombomodulin. It is possible that the grafts were not sufficiently protected against complement activation because of dysfunctional soluble thrombomodulin in persons with THBD mutations [Noris et al 2010].
  • DGKE. Three individuals with autosomal recessive aHUS caused by mutations in DGKE received cadaveric renal transplantation at ages two, 19, and 21 years [Lemaire et al 2013]. Two allografts have survived two years and four years, till last observation, whereas the other failed after six years due to chronic rejection. Importantly, there were no aHUS recurrences after transplantation. On the basis of these findings, it seems that renal transplantation can be efficacious and safe in individuals with aHUS caused by mutations in DGKE.
  • CFH autoantibodies. The transplant outcome is rather good in those patients: of five persons with anti-CFH autoantibodies, only one had disease recurrence and lost the graft [Noris & Remuzzi 2010].

Prevention of Primary Manifestations

Plasma exchange prophylaxis has been shown to prevent disease recurrences in persons with mutation of CFH [Davin et al 2008].

Prevention of Secondary Complications

Eculizumab

  • Eculizumab has a greater efficacy than plasma therapy in the prevention of thrombotic microangiopathic events, with earlier intervention associated with a greater clinical benefit [Legendre et al 2013].
  • Eculizumab can be used as a prophylactic treatment to prevent post-transplantation aHUS recurrence in those at moderate to high risk of recurrence, as defined below [Nester et al 2011, Weitz et al 2011, Krid et al 2012, Zuber et al 2012b]:
    • Individuals with mutations in CFH, C3, and CFB or those who have the CFH-CFHR1 hybrid allele have a high risk of recurrent disease [Zuber et al 2012b].
    • Individuals with anti-CFH antibodies, mutations in CFI, mutations of unknown functional significance and/or no identified mutations have a moderate risk of recurrent disease [Zuber et al 2012b].

The major adverse effect of eculizumab is the increased risk for meningococcal infection [Rother et al 2007].

  • Vaccination against Neisseria meningitides (tetravalent vaccine A, C, Y, W135) is mandatory two weeks before administration of eculizumab.
  • In those who are not vaccinated two weeks prior to therapy with eculizumab, daily prophylactic antibiotics (for example, oral penicillin or a macrolide) should be administered for two weeks after vaccination.
  • Since currently available vaccines do not cover all N. Meningitidis strains, a few countries require continuous antibiotic prophylaxis throughout eculizumab treatment.

In children treated with eculizumab, vaccination against Streptococcus pneumonia and Haemophilus influenza type B infections is also required.

Surveillance

Individual with known aHUS. Measure serum concentration of hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, and C4, and haptoglobin:

  • Every month in the first year after an aHUS episode, then every three to six months in the following years, particularly for persons with normal renal function or chronic renal insufficiency as they are at risk for relapse. Note: Individuals with ESRD usually do not relapse.
  • Every two weeks for those rare individuals with homozygous CFH mutations that result in very low or undetectable levels of the CFH protein

Note: The proposed time intervals for checking hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3, C4, and haptoglobin are suggestions (based on the Authors' experience); each center may follow different guidelines based on their own experience.

At-risk relative of an individual with aHUS

  • Offer molecular genetic testing to at-risk family members of persons in whom disease-associated mutations have been identified.
    • For relatives who are identified to have the family-specific mutation, monitor hemoglobin, platelet count, and serum concentrations of creatinine, LDH, C3 and C4, and haptoglobin) when exposed to potential triggering events such as severe infections, inflammation, and pregnancy.
    • For relatives who do not have the family-specific mutation, no monitoring is needed.
  • For relatives of persons in whom disease-associated mutations have NOT been identified, no monitoring is needed.

Agents/Circumstances to Avoid

Discontinue cyclosporine or tacrolimus when aHUS develops following challenge with the medication.

Fresh frozen plasma should be avoided (i.e., plasma therapy is contraindicated) in persons with aHUS induced by Streptococcus pneumoniae because plasma from an adult contains antibodies against the Thomsen-Friedenreich antigen, which may exacerbate the disease. It is preferable to transfuse washed red blood cells or platelets. There is no evidence that plasmapheresis is of value [Copelovitch & Kaplan 2008].

Individual with known aHUS. An individual with known aHUS should avoid if possible the following known potential precipitants of aHUS, especially any that are known to have triggered aHUS (see Clinical Description, Sporadic aHUS).

  • Pregnancy
  • Drugs:
    • Some anti-cancer molecules, including mitomycin C, cisplatin, daunorubimicin, cytosine arabinoside
    • Immunotherapeutic agents, including cyclosporin and tacrolimus
    • Antiplatelet agents, including ticlopidine and clopidogrel
    • Some common medications such as oral contraceptives, anti-inflammatory agents

Unaffected mutation-positive relatives of an individual with aHUS should avoid known precipitants of aHUS (see Clinical Description, Sporadic aHUS.

Evaluation of Relatives at Risk

Molecular genetic testing should be offered to at-risk family members of persons in whom disease-predisposing mutations have been identified.

Note: Testing of family members needs to be done with caution because the family-specific mutations are predisposing (not causative) and, thus, are only one of several risk factors required for disease causation. Predictions based on a single risk factor in unaffected individuals are unreliable. From currently available data, the penetrance of disease for all mutations is approximately 50%. The degree of penetrance is thought to be determined by: (1) common normal allelic variants of CFH and CD46 [Caprioli et al 2003]; (2) risk haplotypes in RCA (see Molecular Genetic Pathogenesis) cluster [Esparza-Gordillo et al 2005]; and (3) exposure to environmental triggers (e.g., infection and drugs. Therefore, the risk cannot be quantified for a given individual.

For relatives who have the family-specific predisposing mutation, the following are appropriate:

  • Monitoring when exposed to potential triggering events such as severe infections, inflammation, and pregnancy (see Surveillance)
  • Avoiding known precipitants of aHUS (see Clinical Description, Sporadic aHUS)

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Women with a history of aHUS are at increased risk for aHUS flare during pregnancy and an even greater risk in the post-partum period.

  • Fakhouri et al [2010] conducted a retrospective study to assess the presentation and outcomes of women with pregnancy-associated HUS (P-aHUS) and observed that P-aHUS occurred in 21 of 100 adult women with aHUS, with 79% presenting post-partum.
  • Treatment consisted mainly of plasma exchange (15 of 18, 83%), and the outcomes were poor:
    • 62% reached end-stage renal disease by one month after presentation and 76% by last follow-up.
    • The risk for P-aHUS was highest during a second pregnancy.
    • Complement abnormalities were found in 18 of the 21 adult women with P-aHUS. Pregnancies in affected women with complement abnormalities were complicated by fetal loss and preeclampsia in 4.8% and 7.7%, respectively.

On the basis of these results, women with complement dysregulation should be informed of the 20% risk for P-aHUS, and any pregnancy in these women should be closely monitored.

Preventive treatment with aspirin and/or plasma infusions during pregnancies in women with previous manifestations of aHUS remains a matter of debate. As for eculizumab, the precautionary principle discourages the administration of any new drugs in pregnant women, however the preliminary experience gained from pregnant women with paroxysmal nocturnal hemoglobinuria who had been treated with eculizumab suggest a risk-benefit balance leading towards the use of eculizumab [Kelly et al 2010].

Therapies Under Investigation

Research efforts are aimed at identifying more specific approaches that may interfere with the primary cause of microangiopathy in the different forms of aHUS.

  • For aHUS associated with CFH mutations:
    • Specific replacement therapies with recombinant CFH protein could become a viable alternative to plasma treatment.
    • Efforts are also ongoing to isolate plasma fractions enriched in CFH protein that could provide the patient with sufficient active molecules while minimizing the risk of allergy and fluid overload associated with standard plasma infusion therapy. A CFH protein concentrate under development for clinical use has recently achieved Orphan Drug designation by European Medicines Agency (EMEA) and FDA.
  • The discovery of mutations in three different complement-regulatory genes provides sufficient evidence to undertake clinical trials using complement inhibitors that block the activation of C3 [Kirschfink 2001]. Studies on other complement-regulatory genes would help to clarify the molecular determinants underlying the pathogenesis of aHUS and potentially improve management and therapy.
  • Advances in vector safety and transfection efficiency may eventually make gene therapy a realistic option.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Predisposition to atypical HUS (aHUS) is inherited in an autosomal recessive manner or in an autosomal dominant manner with incomplete penetrance [Caprioli et al 2006].

Rare digenic inheritance occurs [Esparza-Gordillo et al 2006] and one case of uniparental isodisomy has been reported [Fremeaux-Bacchi et al 2007].

Risk to Family Members — Autosomal Recessive Inheritance

Parents of a proband

  • The parents of a child with autosomal recessive aHUS are obligate heterozygotes and therefore carry a single copy of a disease-causing mutation.
  • Heterozygotes (carriers) are usually asymptomatic. CFH, CD46, CFI, CFB, C3, and THBD mutations are usually inherited from unaffected parents. Rare cases of carriers who have developed aHUS in adulthood have also been reported [Caprioli et al 2006].

Sibs of a proband

  • At conception, each sib of an individual with autosomal recessive aHUS has a 25% chance of inheriting two disease-causing mutations, a 50% chance of inheriting one mutation and being a carrier, and a 25% chance of inheriting neither mutation.
  • Heterozygotes (carriers) are usually asymptomatic.
  • Clinical severity and disease phenotype often differ among individuals with the same mutations; thus, age of onset and/or disease progression and outcome cannot be predicted.

Offspring of a proband. The offspring of an individual with autosomal recessive aHUS are obligate heterozygotes (carriers) for a disease-causing mutation and will likely be asymptomatic.

Note: Because individuals known to be homozygous have not yet reached reproductive age, whether offspring of these individuals will be affected is currently unknown.

Carrier Detection

Carrier testing for family members at risk for autosomal recessive aHUS is possible if the disease-causing mutations have been identified in the proband.

Risk to Family Members — Autosomal Dominant Inheritance

Parents of a proband

  • Some individuals diagnosed with autosomal dominant aHUS have an affected parent or other close relative, but the majority of cases are simplex (i.e., a single occurrence in a family).
  • In simplex cases of aHUS the CFH mutation was either inherited from a healthy parent or, more rarely (5 individuals reported) occurred as a de novo mutation in the proband [Perez-Caballero et al 2001, Neumann et al 2003, Noris et al 2010]. Similarly, in simplex cases of aHUS the CD46, CFB, C3, or THBD mutation was inherited from a healthy parent [Noris et al 2010].
  • Family history may be negative because of reduced penetrance of the disease-causing mutation in an asymptomatic parent, early death of a parent, late onset in a parent (or close relative), or a de novo mutation in the proband.
  • If both parents are unaffected and a disease-causing mutation is identified in the proband, molecular genetic testing should be offered to both parents. If a disease-causing mutation is identified in a parent, the parent is at risk of developing aHUS and of transmitting the disease-causing mutation to other offspring.
  • Clinical severity and disease phenotype often differ among individuals with the same mutations; thus, age of onset and/or disease progression and outcome cannot be predicted.

Sibs of a proband

  • The risk to the sibs of the proband depends on the genetic status of the parents.
  • If a parent of the proband is affected, has a positive family history, or has a disease-causing mutation, the risk to the sibs of inheriting the mutation is 50%.
  • Clinical severity and disease phenotype often differ among individuals with the same mutations; thus, age of onset and/or disease progression and outcome cannot be predicted.
  • If the disease-causing mutation found in the proband cannot be detected in DNA extracted from the leukocytes of either parent, the risk to the sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband

  • Each child of an individual with autosomal dominant aHUS has a 50% chance of inheriting the mutation.
  • Clinical severity and disease phenotype often differ among individuals with the same mutations; thus, age of onset and/or disease progression and outcome cannot be predicted.

Other family members of a proband. The risk to other family members depends on the status of the proband's parents. If a parent is affected or is a carrier of a disease-causing mutation, his or her family members may be at risk and molecular genetic testing should be offered.

Risk to Family Members — Digenic Inheritance

Digenic aHUS is caused by the simultaneous presence of one mutation in each of two complement-regulatory genes (see Molecular Genetic Testing).

Parents of a proband

  • The parents are obligate heterozygotes.
  • Heterozygotes (carriers) are usually asymptomatic.

Sibs of a proband

  • At conception, each sib has a 25% chance of inheriting both mutations, a 50% chance of inheriting one mutation and being a carrier, and a 25% chance of inheriting neither mutation.
  • Heterozygotes (carriers) are usually asymptomatic.

Offspring of a proband. All offspring are obligate carriers of one of the mutations.

Other family members of a proband. Other family members may be at risk and molecular genetic testing should be offered.

Carrier Detection

Carrier testing for family members at risk for digenic aHUS is possible if the disease-causing mutations have been identified in the family.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Precipitation of aHUS in renal donors. In two families, renal transplantation precipitated disease onset in the previously healthy donor [Donne et al 2002]. Subsequent molecular genetic testing revealed that one of the donors had a CFH mutation that put him at risk for aHUS. Thus, molecular genetic testing is recommended before live related donation to avoid the risk of triggering disease in the donor.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks' gestation. The disease-predisposing allele(s) must be identified in the family before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Medline Plus
  • National Kidney and Urologic Diseases Information Clearinghouse (NKUKIC)
    3 Information Way
    Bethesda MD 20892-3580
    Phone: 800-891-5390 (toll-free); 866-569-1162 (toll-free TTY)
    Fax: 703-738-4929
    Email: nkudic@info.niddk.nih.gov
  • A.R.M.R. Foundation (Fondazione Aiuti per la Ricerca sulle Malattie Rare)
    Italy
    Email: segretriapresidenza@armr.it; presidenza@armr.it
  • American Kidney Fund
    11921 Rockville Pike
    Suite 300
    Rockville MD 20852
    Phone: 866-300-2900
    Email: helpline@kidneyfund.org
  • Fondazione ART Onlus
    Via Palestro, 20
    Milano 20121
    Italy
    Phone: +39 02 76317311
    Fax: +39 02 76317311
    Email: info@artrapianti.org
  • National Kidney Foundation (NKF)
    30 East 33rd Street
    New York NY 10016
    Phone: 800-622-9010 (toll-free); 212-889-2210
    Fax: 212-689-9261
    Email: info@kidney.org
  • International Network and Registry for TMA
    Email: trachtma@lij.edu
  • International Registry of Recurrent and Familial HUS/TTP
    Mario Negri Institute for Pharmacological Research
    Clinical Research Center for Rare Diseases "Aldo e Cele Daccò"
    Villa Camozzi - Via Camozzi, 3
    Ranica 24020
    Italy
    Phone: +39 35 4535304
    Fax: +39 35 4535373
    Email: raredis@marionegri.it

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Atypical Hemolytic-Uremic Syndrome: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Atypical Hemolytic-Uremic Syndrome (View All in OMIM)

120700COMPLEMENT COMPONENT 3; C3
120920CD46 ANTIGEN; CD46
134370COMPLEMENT FACTOR H; CFH
134371COMPLEMENT FACTOR H-RELATED 1; CFHR1
138470COMPLEMENT FACTOR B; CFB
188040THROMBOMODULIN; THBD
217030COMPLEMENT FACTOR I; CFI
235400HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 1; AHUS1
601440DIACYLGLYCEROL KINASE, EPSILON, 64-KD; DGKE
605336COMPLEMENT FACTOR H-RELATED 3; CFHR3
605337COMPLEMENT FACTOR H-RELATED 4; CFHR4
612922HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 2; AHUS2
612923HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 3; AHUS3
612924HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 4; AHUS4
612925HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 5; AHUS5
612926HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 6; AHUS6

Molecular Genetic Pathogenesis

In 1998 Warwicker et al studied three families with aHUS and established linkage in the affected individuals to the regulator of complement activation (RCA) gene cluster on human chromosome 1q32, which encodes two complement-regulatory proteins (CFH [Warwicker et al 1998] and CD46 [Noris et al 2003, Richards et al 2003]) and five factor H-related proteins (CFHR1-5 [Monteferrante et al 2007, Zipfel et al 2007, Moore at al 2010]).

Because an association between familial HUS and CFH abnormalities had been reported previously, the first examined candidate gene in this region was factor H (CFH). CFH is a plasma glycoprotein that plays an important role in the regulation of the alternative pathway of complement. It serves as a cofactor for the C3b-cleaving enzyme, factor I (encoded by CFI) in the degradation of newly formed C3b molecules and controls decay, formation, and stability of the C3b convertase C3bBb. The CFH glycoprotein consists of 20 homologous short consensus repeats (SCRs). The complement-regulatory domains needed to prevent fluid phase alternative pathway amplification have been localized within the N-terminal SCR1-4 [Rodriguez de Cordoba et al 2004].

The inactivation of surface-bound C3b is dependent on the binding of the C-terminal domain of CFH protein to polyanionic molecules that increases CFH protein affinity for C3b and exposes its complement-regulatory N-terminal domain. The C-terminal domain contains two C3b-binding sites, located in SCR12-14 and SCR19-20, and three polyanion-binding sites, located in SCR7, SCR13, and SCR19-20 [Jozsi et al 2004]. However, the C3b- and the polyanion-binding sites located in SCR19-20 are required for CFH to inactivate surface-bound C3b, since deletion of this portion of the molecule renders CFH protein incapable of blocking complement activation on sheep erythrocytes.

Abnormalities in two additional genes encoding for complement-regulatory proteins have been recently involved in predisposition to aHUS. Two independent reports described mutations in CD46, encoding membrane cofactor protein (MCP), in affected individuals of four families [Noris et al 2003, Richards et al 2003]. MCP is a widely expressed transmembrane glycoprotein that serves as a cofactor for CFI protein to cleave C3b and C4b deposited on the host cell surface [Goodship et al 2004]. MCP has four extracellular N-terminal SCRs important for their inhibitory activity, followed by a serine-threonine-proline rich domain, a transmembrane domain, and a cytoplasmic tail. To date, about 50 CD46 mutations in aHUS have been reported, with a mutation frequency of 10%-15% among all aHUS [FH aHUS Mutation Database]. Evaluation of mutant protein expression and function showed either severely reduced protein expression on the cell surface or reduced C3b-binding capability and/or capacity to block complement activation [Caprioli et al 2006, Noris et al 2010].

About 30 mutations in CFI, which encodes a plasma serine protease that cleaves and inactivates C3b and C4b, have been reported in individuals with aHUS, with a frequency of 5%-10% depending on the study [Fremeaux-Bacchi et al 2004, Kavanagh et al 2005, Caprioli et al 2006, Noris et al 2010]. All are heterozygous mutations, 80% cluster in the serine-protease domain and may either cause reduced protein secretion or result in mutant proteins with decreased cofactor activity. However, studies on the p.Gly261Asp mutation revealed no alteration of CFI serum concentration or functional defect in CFI [Nilsson et al 2007].

Gain-of-function mutations in the gene encoding complement factor B (CFB), a zymogen that carries the catalytic site of the complement alternative pathway convertase, have been found in two families from a Spanish HUS cohort [Goicoechea de Jorge et al 2007]. Mutants have excess C3b affinity and form a hyperactive C3 convertase that is resistant to dissociation, enhancing C3b formation.

About 5% of persons have heterozygous mutations in C3, usually with low C3 levels [Fremeaux-Bacchi et al 2008, Noris et al 2010]. Most mutations reduce C3b binding to CFH and MCP, which severely impairs degradation of mutant C3b.

More recently, about 5% of persons with aHUS have been found to have heterozygous mutations in THBD [Noris et al 2010, Delvaeye 2009]. Cells expressing these variants are less efficient in degrading C3b and in generating activated thrombin-activatable fibrinolysis inhibitor (TAFI), a plasma carboxypeptidase B that cleaves C3a and C5a.

Genetic variants of CFHR5 that have been identified may play a secondary role in the pathogenesis of HUS [Monteferrante et al 2007].

Complete absence of both CFHR1 and CFHR3 proteins was detected in about 10% of aHUS [Zipfel et al 2007, Moore at al 2010]. CHR1/CFHR3 plasma deficiency is associated in the large majority of cases with the formation of anti-CFH autoantibodies. These antibodies bind both to CFHR1 and to the CFH C-terminal [Moore et al 2010], reduce CFH binding to C3b and enhance alternative pathway dependent lysis of sheep erythrocytes without influencing fluid-phase cofactor activity. The causal link between CFHR1-R3 deletion and CFH autoantibodies is still unknown.

More recently, three affected individuals positive for anti-CFH autoantibodies were found to have no copies of CFHR1 but a single copy of CFHR3 and a novel deletion incorporating CFHR1 and CFHR4. In these individuals a CFHR3/CFHR1 deletion was present on one allele and a CFHR1/CFHR4 deletion on the other allele, suggesting that the complete deficiency of factor H-related protein 1 was probably the significant factor associated with the production of factor H autoantibodies in aHUS [Moore et al 2010].

In 2013, recessive mutations in DGKE cosegregating with aHUS were identified in nine unrelated kindreds, defining a distinctive Mendelian disease. Loss of DGKE function may result in a prothrombotic state [Lemaire et al 2013] and seems critical to the normal function of podocytes [Ozaltin et al 2013].

CFH

Normal allelic variants. CFH is approximately 100 kb long. It comprises 23 exons.

Pathologic allelic variants. See Table 2.

Table 2. Selected CFH Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.3572C>Tp.Ser1191LeuNM_000186​.2
NP_000177​.2
c.3590T>Cp.Val1197Ala
CFH and CFHR1 hybrid allele

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

The list of published and unpublished mutations within CFH is continuously updated in the FH aHUS Mutation Database.

Since the first report by Warwicker et al [1998], a number of studies have been performed, describing more than 100 different CFH mutations in individuals with aHUS [Saunders et al 2006]. The vast majority of CFH mutations in individuals with aHUS are heterozygous and cause either single amino acid changes or premature translation terminations that primarily cluster in the C-terminus domains and are commonly associated with normal CFH protein plasma levels. A minority of the mutations result in the production of a truncated protein or impaired secretion of protein [Perez-Caballero et al 2001, Richards et al 2001, Caprioli et al 2006].

A heterozygous hybrid allele of CFH and CFHR1, derived from a crossing over between intron 21 of CFH and intron 4 of CFHR1 (CFH-related 1), was found in five persons with aHUS [Venables et al 2006]. The hybrid allele consists of the first 21 exons of CFH (encoding short consensus repeats [SCRs] 1-18 of CFH) and the last two exons of CFHR1 (encoding SCR4 and SCR5 of CFHR1). The frequency of this heterozygous hybrid allele in aHUS is estimated to be approximately 3%-5%.

A novel heterozygous hybrid allele of CFH and CFHR1, derived from a crossing over between intron 22 of CFH and intron 5 of CFHR1 has been recently found in two persons with aHUS [Maga et al 2010a]. The novel hybrid allele consists of the first 22 exons of CFH (encoding SCRs 1-19) and the last exon of CFHR1 (encoding SCR5 of CFHR1).

The frequency of this novel heterozygous hybrid allele in aHUS is estimated to be 1.5% [Maga et al 2010a].

Because CFH exon 22 (SCR19) and CFHR1 exon 5 (SCR4) encode identical proteins, the deletion found by Venables and the deletion found by Maga produce identical fusion proteins despite different non-homologous allelic recombination (NHAR) sites.

Normal gene product. Mainly synthesized by the liver, the complement factor H (CFH) protein is a 150-kd single-chain plasma glycoprotein and consists of 20 homologous structural domains called SCRs (short consensus repeats), each of which comprises approximately 60 amino acids.

Abnormal gene product. Expression and functional studies demonstrated that CFH proteins with aHUS-associated mutations (deriving from point mutations, gene conversion, and a hybrid allele) have a severely reduced ability to interact with polyanions and with surface-bound C3b [Jozsi et al 2004], resulting in a lower density of mutant CFH molecules bound to endothelial cell surface and a diminished complement-regulatory activity on the cell membrane [Jozsi et al 2004]. In contrast these mutants have a normal capacity to control activation of the complement in plasma, as indicated by their retention of normal cofactor activity in the proteolysis of fluid-phase C3b.

The majority of CFH mutations are heterozygous and cluster in the exons that encode for the C-terminal portion of the protein. A minority of the mutations result in the production of a truncated protein or impaired secretion of protein [Perez-Caballero et al 2001, Richards et al 2001, Caprioli et al 2006].

Interestingly, the protein product of the hybrid CFH/CFHR1 is identical to another CFH mutant allele with two mutations in cis configuration, p.[Ser1191Leu;Val1197Ala], which arises by gene conversion between CFH and CFHR1 and whose protein product lacks surface complement-regulatory activity.

See Molecular Genetic Pathogenesis.

CD46

Normal allelic variants. CD46 is an estimated 43 kb long. It comprises 14 exons.

Pathologic allelic variants. The majority of CD46 mutations are heterozygous and cluster in the exons encoding the four N-terminal extracellular short consensus repeats (SCRs). No deletions or duplications involving either CD46 or CFI as causative of aHUS have been reported.

The list of published and unpublished mutations within CD46 is continuously updated in the FH aHUS Mutation Database.

Normal gene product. CD46 encodes the membrane cofactor protein (MCP), with is a widely expressed transmembrane glycoprotein composed of four extracellular SCRs followed by a serine-threonine-proline rich region, a transmembrane domain, and a cytoplasmic tail.

Abnormal gene product. CD46 mutations generally result in either reduced MCP expression or impaired C3b binding capability [Noris et al 2003, Richards et al 2003, Caprioli et al 2006]. See Molecular Genetic Pathogenesis.

CFI

Normal allelic variants. CFI is approximately 63 kb long. It comprises 13 exons.

Pathologic allelic variants. See Table 3. The majority of CFI mutations cluster in the exons that encode the serine-protease domain. No deletions or duplications involving either CD46 or CFI as causative of aHUS have been reported.

Table 3. Selected CFI Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.782G>Ap.Gly261AspNM_000204​.2
NP_000195​.2

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

The list of published and unpublished mutations within CFI is continuously updated in the FH aHUS Mutation Database.

Normal gene product. Mainly produced by the liver, complement factor I (CFI) protein is an 88-kd plasma serine-protease with a modular structure. It is a heterodimer and consists of a non-catalytic 50-kd heavy chain linked to a catalytic 38-kd light chain by a disulphide bond.

Abnormal gene product. Approximately 60% of the mutations result in low CFI levels or low CFI activity, the functional significance of the others remains to be determined [Fremeaux-Bacchi et al 2004, Caprioli et al 2006]. See Molecular Genetic Pathogenesis.

CFB

Normal allelic variants. CFB is an estimated 6 kb long. It comprises 18 exons.

Pathologic allelic variants. See Table 4.

Table 4. Selected CFB Pathologic Allelic Variants

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.858C>Gp.Phe286LeuNM_001701​.2
NP_001701​.2
c.967A>Gp.Lys323Glu

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Two heterozygous mutations in affected members of two Spanish pedigrees, c.858C>G and c.967A>G, have been reported [Goicoechea de Jorge et al 2007].

Normal gene product. CFB encodes complement factor B, a 90-kd protein consisting of three domains: a three-module complement control protein, a von Willebrand factor A domain, and a C-terminal serine protease domain that adopts a default inactive (zymogen) conformation.

Abnormal gene product. In affected members of two Spanish pedigrees, two gain-of-function heterozygous mutations, p.Phe286Leu and p.Lys323Glu, were found to result in enhanced formation of the C3bBb convertase and increased resistance to inactivation by complement regulators, respectively [Goicoechea de Jorge et al 2007].

C3

Normal allelic variants. C3 is an estimated 42.8 kb long. It comprises 41 exons.

Pathologic allelic variants. The majority of C3 mutations are heterozygous. Mutations are spread all over the gene; however, a hot spot is evident in the thioester-containing (TED) domain.

Normal gene product. C3 encodes complement component C3. Mainly produced by the liver, C3 is the pivotal component of the complement system. The mature protein is made by 1641 amino acids that form a beta chain and an alpha chain. C3 is processed by proteolytic cleavage by enzymatic complexes, the C3 convertases, into the anaphylatoxin C3a and the C3b fragment that deposits on cell surfaces causing the activation of the complement cascade. The alpha and beta chains form 13 domains including eight homologous domains called macroglobulin (MG) domains, the linker domain (LNK), the anaphylatoxin (ANA) domain, the CUB domain, the thioester-containing (TED) domain, and finally the C345c domain.

Abnormal gene product. Most mutations reduce C3b binding to CFH and MCP, which severely impairs degradation of mutant C3b [Frémeaux-Bacchi et al 2008]

See Molecular Genetic Pathogenesis.

THBD

Normal allelic variants. THBD is approximately 4.03 kb long; it comprises a single exon.

Pathologic allelic variants. All THBD mutations are heterozygous and cluster in the lectin-like domain and in the serine-threonine (ST)-rich peptide.

Normal gene product. Thrombomodulin is a 557-amino-acid endothelial glycoprotein that is anchored to the cell by a short cytoplasmic tail and a single transmembrane domain that is followed by a ST-rich domain. A series of six epidermal growth factor-like repeats are required for thrombin-mediated generation of activated protein C, which has anticoagulant and cytoprotective properties, and the generation of activated TAFI, which has C3a degrading and C5a-degrading properties. Farthest from the transmembrane domain is the lectin-like domain, which confers resistance to proinflammatory stimuli, including endotoxin. Thrombomodulin facilitates complement inactivation by CFI in the presence of CFH.

Abnormal gene product. Cells expressing these variants are less efficient in degrading C3b and in generating activated TAFI, a plasma carboxypeptidase B that cleaves C3a and C5a [Delvaeye et al 2009].

DGKE

Normal allelic variants. DGKE (NM_003647.2) is approximately 34 kb long; it comprises 12 exons.

Pathologic allelic variants. All DGKE mutations are recessive (homozygous or compound heterozygous) and are distributed throughout the gene.

Normal gene product. Diacylglycerol kinase-epsilon is a 64-kd intracellular lipid kinase comprised of 567 amino acids that phosphorylates and inactivates arachidonic acid-containing diacylglycerol (AA-DAG) to the corresponding phosphatidic acid (NP_003638.1). AA-DAG is major signaling molecule that activates protein kinase C (PKC). PKC, in turn, increases the production of various prothrombotic factors in endothelial cells. DGKE is found in endothelium, platelets and podocytes.

Abnormal gene product. Loss of DGKE may result in sustained AA-DAG signaling, causing a prothrombotic state [Lemaire et al 2013], and seems critical to the normal function of podocytes [Ozaltin et al 2013].

CFHR3, CFHR1, and CFHR4

Normal allelic variants. CFHR3, CFHR1, and CFHR4 (previously known as CFHL3, CFHL1, and CFHL4, respectively) are contiguous genes that occur in this relative order on chromosome 1 at 1q31-q32.1. These genes are in the regulators of complement activation (RCA) cluster (see Molecular Genetic Pathogenesis). Each comprises six exons; reference sequences are NM_021023.5, NM_002113.2, and NM_006684.4.

Pathologic allelic variants. Deletion involving CFHR3 and CFHR1 or CFHR1 and CFHR4 is associated with atypical aHUS [Moore et al 2010, Zipfel et al 2007]. Deletions occur by non-allelic homologous recombination between regions of high sequence identity [Moore et al 2010].

Normal gene product. Like the human complement factor H (CFH), the factor H-related proteins, CFHR3, CFHR1, and CFHR4 are exclusively composed of highly-related short consensus repeats (SCRs), each of which contains four cysteine residues and additional conserved amino acids.

  • CFHR3 encodes a secreted protein which belongs to the complement factor H-related protein family.
  • CFHR1 encodes a secreted protein which belongs to the complement factor H protein family. It binds to Pseudomonas aeruginosa elongation factor Tuf together with plasminogen, which is proteolytically activated.
  • Both CFHR3 and CFHR4 enhance the cofactor activity of factor H in C3b inactivation.

Abnormal gene product. Individuals with aHUS who are homozygous for these alleles typically have factor H autoantibodies [Moore et al 2010].

References

Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Published Guidelines/Consensus Statements

  1. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Van de Kar N, Vandewalle J, Zimmerhackl LB, Zimmerhackl LB (2009) Guideline for the investigation and initial therapy of diarrhea-negative hemolytic uremic syndrome. Available online. 2009. Accessed 8-6-13. [PubMed: 18800230]

Literature Cited

  1. Abrera-Abeleda MA, Nishimura C, Smith JL, Sethi S, McRae JL, Murphy BF, Silvestri G, Skerka C, Jozsi M, Zipfel PF, Hageman GS, Smith RJ. Variations in the complement regulatory genes factor H (CFH) and factor H related 5 (CFHR5) are associated with membranoproliferative glomerulonephritis type II (dense deposit disease). J Med Genet. 2006;43:582–9. [PMC free article: PMC2564553] [PubMed: 16299065]
  2. Ariceta G, Besbas N, Johnson S, Karpman D, Landau D, Licht C, Loirat C, Pecoraro C, Taylor CM, Van de Kar N, Vandewalle J, Zimmerhackl LB, Zimmerhackl LB. Pediatr Nephrol. 2009;24:687–96. [PubMed: 18800230]
  3. Ariceta G, Arrizabalaga B, Aguirre M, Morteruel E, Lopez-Trascasa M. Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am J Kidney Dis. 2012;59:707–10. [PubMed: 22196848]
  4. Artz MA, Steenbergen EJ, Hoitsma AJ, Monnens LA, Wetzels JF. Renal transplantation in patients with hemolytic uremic syndrome: high rate of recurrence and increased incidence of acute rejections. Transplantation. 2003;76:821–6. [PubMed: 14501861]
  5. Ault BH, Schmidt BZ, Fowler NL, Kashtan CE, Ahmed AE, Vogt BA, Colten HR. Human factor H deficiency. Mutations in framework cysteine residues and block in H protein secretion and intracellular catabolism. J Biol Chem. 1997;272:25168–75. [PubMed: 9312129]
  6. Baracho GV, Nudelman V, Isaac L. Molecular characterization of homozygous hereditary factor I deficiency. Clin Exp Immun. 2003;131:280–6. [PMC free article: PMC1808620] [PubMed: 12562389]
  7. Bergeron-Sawitzke J, Gold B, Olsh A, Schlotterbeck S, Lemon K, Visvanathan K, Allikmets R, Dean M. Multilocus analysis of age-related macular degeneration. Eur J Hum Genet. 2009;17:1190–9. [PMC free article: PMC2729805] [PubMed: 19259132]
  8. Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, Jablonski M, Renault N, Rameix-Welti MA, Loirat C, Sautés-Fridman C, Villoutreix BO, Blom AM, Fremeaux-Bacchi V. Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int. 2010;77:339–49. [PubMed: 20016463]
  9. Botto M, Fong KY, So AK, Barlow R, Routier R, Morley BJ, Walport MJ. Homozygous hereditary C3 deficiency due to a partial gene deletion. Proc Nat Acad Sci. 1992;89:1957–61. [PubMed: 1350678]
  10. Botto M, Fong KY, So AK, Koch C, Walport MJ. Molecular basis of polymorphisms of human complement component C3. J Exp Med. 1990;172:1011–7. [PMC free article: PMC2188593] [PubMed: 1976733]
  11. Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship TH, Remuzzi G. Outcome of renal transplantation in patients with non-Shiga toxin-associated hemolytic uremic syndrome: prognostic significance of genetic background. Clin J Am Soc Nephrol. 2006;1:88–99. [PubMed: 17699195]
  12. Bresin E, Mossali C, Caprioli J, Rota S, Kirschfink M, Noris M, Remuzzi G. A young girl with MPGN/HUS and a heterozygous CFH-mutation. Mol Immunol. 2007;44:3970.
  13. Bresin E, Rurali E, Caprioli J, Sanchez-Corral P, Fremeaux-Bacchi V, Rodriguez de Cordoba S, Pinto S, Goodship TH, Alberti M, Ribes D, Valoti E, Remuzzi G, Noris M, Noris M. J Am Soc Nephrol. 2013;24:475–86. [PMC free article: PMC3582207] [PubMed: 23431077]
  14. Brodsky RA, Young NS, Antonioli E, Risitano AM, Schrezenmeier H, Schubert J, Gaya A, Coyle L, de Castro C, Fu CL, Maciejewski JP, Bessler M, Kroon HA, Rother RP, Hillmen P. Multicenter phase 3 study of the complement inhibitor eculizumab for the treatment of patients with paroxysmal nocturnal hemoglobinuria. Blood. 2008;111:1840–7. [PubMed: 18055865]
  15. Caprioli J, Castelletti F, Bucchioni S, Bettinaglio P, Bresin E, Pianetti G, Gamba S, Brioschi S, Daina E, Remuzzi G, Noris M. Complement factor H mutations and gene polymorphisms in haemolytic uraemic syndrome: the C-257T, the A2089G and the G2881T polymorphisms are strongly associated with the disease. Hum Mol Genet. 2003;12:3385–95. [PubMed: 14583443]
  16. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, Mele C, Bresin E, Cassis L, Gamba S, Porrati F, Bucchioni S, Monteferrante G, Fang CJ, Liszewski MK, Kavanagh D, Atkinson JP, Remuzzi G. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood. 2006;108:1267–79. [PMC free article: PMC1895874] [PubMed: 16621965]
  17. Constantinescu AR, Bitzan M, Weiss LS, Christen E, Kaplan BS, Cnaan A, Trachtman H. Non-enteropathic hemolytic uremic syndrome: causes and short-term course. Am J Kidney Dis. 2004;43:976–82. [PubMed: 15168377]
  18. Copelovitch L, Kaplan BS. Streptococcus pneumoniae-associated hemolytic uremic syndrome. Pediatr Nephrol. 2008;23:1951–6. [PubMed: 17564729]
  19. Davin JC, Strain L, Goodship TH. Plasma therapy in atypical haemolytic uremic syndrome: lessons from a family with a factor H mutation. Pediatr Nephrol. 2008;23:1517–21. [PMC free article: PMC2459233] [PubMed: 18483746]
  20. Delvaeye M, Noris M, De Vriese A, Esmon CT, Esmon NL, Ferrell G, Del-Favero J, Plaisance S, Claes B, Lambrechts D, Zoja C, Remuzzi G, Conway EM. Mutations in thrombomodulin in hemolytic uremic syndrome. N Engl J Med. 2009;361:345–57. [PMC free article: PMC3530919] [PubMed: 19625716]
  21. Dlott JS, Danielson CF, Blue-Hnidy DE, McCarthy LJ. Drug-induced thrombotic thrombocytopenic purpura/hemolytic uremic syndrome: a concise review. Ther Apher Dial. 2004;8:102–11. [PubMed: 15255125]
  22. Doggen CJM., Kunz G, Rosendaal FR, Lane DA, Vos HL, Stubbs PJ, Cats VM, Ireland H. A mutation in the thrombomodulin gene, 127G to A coding for ala25-to-thr, and the risk of myocardial infarction in men. Thromb Haemost. 1998;80:743–8. [PubMed: 9843165]
  23. Donne RL, Abbs I, Barany P, Elinder CG, Little M, Conlon P, Goodship TH. Recurrence of hemolytic uremic syndrome after live related renal transplantation associated with subsequent de novo disease in the donor. Am J Kidney Dis. 2002;40:E22. [PubMed: 12460067]
  24. Dragon-Durey MA, Blanc C, Marliot F, Loirat C, Blouin J, Sautes-Fridman C, Fridman WH, Frémeaux-Bacchi V. The high frequency of complement factor H related CFHR1 gene deletion is restricted to specific subgroups of patients with atypical haemolytic uraemic syndrome. J Med Genet. 2009;46:447–50. [PubMed: 19435718]
  25. Dragon-Durey MA, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Herman Fridman W, Weiss L. Heterozygous and homozygous factor h deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol. 2004;15:787–95. [PubMed: 14978182]
  26. Dragon-Durey MA, Loirat C, Cloarec S, Macher MA, Blouin J, Nivet H, Weiss L, Fridman WH, Fremeaux-Bacchi V. Anti-Factor H autoantibodies associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16:555–63. [PubMed: 15590760]
  27. Esparza-Gordillo J, Goicoechea de Jorge E, Buil A, Carreras Berges L, Lopez-Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum Mol Genet. 2005;14:703–12. [PubMed: 15661753]
  28. Esparza-Gordillo J, Jorge EG, Garrido CA, Carreras L, Lopez-Trascasa M, Sanchez-Corral P, de Cordoba SR. Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol. 2006;43:1769–75. [PubMed: 16386793]
  29. Faioni EM, Franchi F, Castaman G, Biguzzi E, Rodeghiero F. Mutations in the thrombomodulin gene are rare in patients with severe thrombophilia. Br J Haematol. 2002;118:595–9. [PubMed: 12139752]
  30. Fakhouri F, Frémeaux-Bacchi V, Loirat C (2013) Atypical hemolytic uremic syndrome: From the rediscovery of complement to targeted therapy. Eur J Intern Med. doi:pii: S0953-6205(13)00136-2.
  31. Fakhouri F, Roumenina L, Provot F, Sallée M, Caillard S, Couzi L, Essig M, Ribes D, Dragon-Durey MA, Bridoux F, Rondeau E, Frémeaux-Bacchi V. Pregnancy-associated hemolytic uremic syndrome revised in the era of complement gene mutations. J Am Soc Nephrol. 2010;21:859–67. [PMC free article: PMC2865741] [PubMed: 20203157]
  32. Frémeaux-Bacchi V, Dragon-Durey MA, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman WH. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet. 2004;41:e84. [PMC free article: PMC1735822] [PubMed: 15173250]
  33. Frémeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, Moghal N, Kaplan BS, Weiss RA, Lhotta K, Kapur G, Mattoo T, Nivet H, Wong W, Gie S, Hurault de Ligny B, Fischbach M, Gupta R, Hauhart R, Meunier V, Loirat C, Dragon-Durey MA, Fridman WH, Janssen BJ, Goodship TH, Atkinson JP. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood. 2008;112:4948–52. [PMC free article: PMC2597601] [PubMed: 18796626]
  34. Frémeaux-Bacchi V, Sanlaville D, Menouer S, Blouin J, Dragon-Durey MA, Fischbach M, Vekemans M, Fridman WH. Unusual clinical severity of complement membrane cofactor protein-associated hemolytic-uremic syndrome and uniparental isodisomy. Am J Kidney Dis. 2007;49:323–9. [PubMed: 17261436]
  35. Frémeaux-Bacchi V, Fakhouri F, Garnier A, Bienaimé F, Dragon-Durey MA, Ngo S, Moulin B, Servais A, Provot F, Rostaing L, Burtey S, Niaudet P, Deschênes G, Lebranchu Y, Zuber J, Loirat C. Clin J Am Soc Nephrol. 2013;8:554–62. [PMC free article: PMC3613948] [PubMed: 23307876]
  36. Galbusera M, Noris M, Remuzzi G. Thrombotic thrombocytopenic purpura--then and now. Semin Thromb Hemost. 2006;32:81–9. [PubMed: 16575682]
  37. Geraghty MT, Perlman EJ, Martin LS, Hayflick SJ, Casella JF, Rosenblatt DS, Valle D. Cobalamin C defect associated with hemolytic-uremic syndrome. J Pediatr. 1992;120:934–7. [PubMed: 1593355]
  38. Gianviti A, Tozzi AE, De Petris L, Caprioli A, Rava L, Edefonti A, Ardissino G, Montini G, Zacchello G, Ferretti A, Pecoraro C, De Palo T, Caringella A, Gaido M, Coppo R, Perfumo F, Miglietti N, Ratsche I, Penza R, Capasso G, Maringhini S, Li Volti S, Setzu C, Pennesi M, Bettinelli A, Peratoner L, Pela I, Salvaggio E, Lama G, Maffei S, Rizzoni G. Risk factors for poor renal prognosis in children with hemolytic uremic syndrome. Pediatr Nephrol. 2003;18:1229–35. [PubMed: 14593522]
  39. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, Lopez-Trascasa M, Sanchez-Corral P, Morgan BP, Rodriguez de Cordoba S. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A. 2007;104:240–5. [PMC free article: PMC1765442] [PubMed: 17182750]
  40. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet. 2006;38:458–62. [PMC free article: PMC2921703] [PubMed: 16518403]
  41. Goodship TH, Liszewski MK, Kemp EJ, Richards A, Atkinson JP. Mutations in CD46, a complement regulatory protein, predispose to atypical HUS. Trends Mol Med. 2004;10:226–31. [PubMed: 15121049]
  42. Gruppo RA, Rother RP. Eculizumab for congenital atypical hemolytic uremic syndrome. N Engl J Med. 2009;360:544–6. [PubMed: 19179329]
  43. Heinen S, Sanchez-Corral P, Jackson MS, Strain L, Goodship JA, Kemp EJ, Skerka C, Jokiranta TS, Meyers K, Wagner E, Robitaille P, Esparza-Gordillo J, Rodriguez de Cordoba S, Zipfel PF, Goodship TH. De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum Mutat. 2006;27:292–3. [PubMed: 16470555]
  44. Jozsi M, Manuelian T, Heinen S, Oppermann M, Zipfel PF. Attachment of the soluble complement regulator factor H to cell and tissue surfaces: relevance for pathology. Histol Histopathol. 2004;19:251–8. [PubMed: 14702193]
  45. Jozsi M, Strobel S, Dahse HM, Liu WS, Hoyer PF, Oppermann M, Skerka C, Zipfel PF. Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood. 2007;110:1516–8. [PubMed: 17495132]
  46. Kaplan BS, Meyers KE, Schulman SL. The pathogenesis and treatment of hemolytic uremic syndrome. J Am Soc Nephrol. 1998;9:1126–33. [PubMed: 9621299]
  47. Kavanagh D, Kemp EJ, Mayland E, Winney RJ, Duffield JS, Warwick G, Richards A, Ward R, Goodship JA, Goodship TH. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16:2150–5. [PubMed: 15917334]
  48. Kelly R, Arnold L, Richards S, Hill A, Bomken C, Hanley J, Loughney A, Beauchamp J, Khursigara G, Rother RP, Chalmers E, Fyfe A, Fitzsimons E, Nakamura R, Gaya A, Risitano AM, Schubert J, Norfolk D, Simpson N, Hillmen P. The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol. 2010;149:446–50. [PubMed: 20151973]
  49. Kirschfink M. Targeting complement in therapy. Immunol Rev. 2001;180:177–89. [PubMed: 11414360]
  50. Krid S, Roumenina LT, Beury D, Charbit M, Boyer O, Frémeaux-Bacchi V, Niaudet P. Renal transplantation under prophylactic eculizumab in atypical hemolytic uremic syndrome with CFH/CFHR1 hybrid protein. Am J Transplant. 2012;12:1938–44. [PubMed: 22494769]
  51. Kunz G, Ireland HA, Stubbs PJ, Kahan M, Coulton GC, Lane DA. Identification and characterization of a thrombomodulin gene mutation coding for an elongated protein with reduced expression in a kindred with myocardial infarction. Blood. 2000;95:569–76. [PubMed: 10627464]
  52. Landau D, Shalev H, Levy-Finer G, Polonsky A, Segev Y, Katchko L. Familial hemolytic uremic syndrome associated with complement factor H deficiency. J Pediatr. 2001;138:412–7. [PubMed: 11241053]
  53. Lara PN Jr, Coe TL, Zhou H, Fernando L, Holland PV, Wun T. Improved survival with plasma exchange in patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome. Am J Med. 1999;107:573–9. [PubMed: 10625026]
  54. Legendre CM, Licht C, Muus P, Greenbaum LA, Babu S, Bedrosian C, Bingham C, Cohen DJ, Delmas Y, Douglas K, Eitner F, Feldkamp T, Fouque D, Furman RR, Gaber O, Herthelius M, Hourmant M, Karpman D, Lebranchu Y, Mariat C, Menne J, Moulin B, Nürnberger J, Ogawa M, Remuzzi G, Richard T, Sberro-Soussan R, Severino B, Sheerin NS, Trivelli A, Zimmerhackl LB, Goodship T, Loirat C. Terminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome. N Engl J Med. 2013;368:2169–81. [PubMed: 23738544]
  55. Lemaire M, Frémeaux-Bacchi V, Schaefer F, Choi M, Tang WH, Le Quintrec M, Fakhouri F, Taque S, Nobili F, Martinez F, Ji W, Overton JD, Mane SM, Nürnberg G, Altmüller J, Thiele H, Morin D, Deschenes G, Baudouin V, Llanas B, Collard L, Majid MA, Simkova E, Nürnberg P, Rioux-Leclerc N, Moeckel GW, Gubler MC, Hwa J, Loirat C, Lifton RP. Recessive mutations in DGKE cause atypical hemolytic-uremic syndrome. Nat Genet. 2013;45:531–6. [PMC free article: PMC3719402] [PubMed: 23542698]
  56. Maga TK, Meyer NC, Belsha C, Nishimura CJ, Zhang Y, Smith RJH. A novel deletion in the RCA gene cluster causes atypical hemolytic uremic syndrome. Nephrol Dial Transplant. 2010a;26:739–41. [PubMed: 20974643]
  57. Maga TK, Nishimura CJ, Weaver AE, Frees KL, Smith RJH. Mutations in alternative pathway complement proteins in American patients with atypical hemolytic uremic syndrome. Hum Mutat. 2010b;31:E1445–60. [PubMed: 20513133]
  58. Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, Seddon JM. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet. 2006;38:1055–9. [PubMed: 16936732]
  59. Maller JB, Fagerness JA, Reynolds RC, Neale BM, Daly MJ, Seddon JM. Variation in complement factor 3 is associated with risk of age-related macular degeneration. Nat Genet. 2007;39:1200–1. [PubMed: 17767156]
  60. Martínez-Barricarte R, Heurich M, Valdes-Cañedo F, Vazquez-Martul E, Torreira E, Montes T, Tortajada A, Pinto S, Lopez-Trascasa M, Morgan BP, Llorca O, Harris CL, Rodríguez de Córdoba S. Human C3 mutation reveals a mechanism of dense deposit disease pathogenesis and provides insights into complement activation and regulation. J Clin Invest. 2010;120:3702–12. [PMC free article: PMC2947238] [PubMed: 20852386]
  61. Monteferrante G, Brioschi S, Caprioli J, Pianetti G, Bettinaglio P, Bresin E, Remuzzi G, Noris M. Genetic analysis of the complement factor H related 5 gene in haemolytic uraemic syndrome. Mol Immunol. 2007;44:1704–8. [PubMed: 17000000]
  62. Moore I, Strain L, Pappworth I, Kavanagh D, Barlow PN, Herbert AP, Schmidt CQ, Staniforth SJ, Holmes LV, Ward R, Morgan L, Goodship TH, Marchbank KJ. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood. 2010;115:379–87. [PMC free article: PMC2829859] [PubMed: 19861685]
  63. Nester C, Stewart Z, Myers D, Jetton J, Nair R, Reed A, Thomas C, Smith R, Brophy P. Pre-emptive eculizumab and plasmapheresis for renal transplant in atypical hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2011;6:1488–94. [PMC free article: PMC3109948] [PubMed: 21617085]
  64. Neumann HP, Salzmann M, Bohnert-Iwan B, Mannuelian T, Skerka C, Lenk D, Bender BU, Cybulla M, Riegler P, Konigsrainer A, Neyer U, Bock A, Widmer U, Male DA, Franke G, Zipfel PF. Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J Med Genet. 2003;40:676–81. [PMC free article: PMC1735586] [PubMed: 12960213]
  65. Nilsson SC, Karpman D, Vaziri-Sani F, Kristoffersson AC, Salomon R, Provot F, Fremeaux-Bacchi V, Trouw LA, Blom AM. A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation. Mol Immunol. 2007;44:1835–44. [PubMed: 17084897]
  66. Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet. 2003;362:1542–7. [PubMed: 14615110]
  67. Noris M, Bucchioni S, Galbusera M, Donadelli R, Bresin E, Castelletti F, Caprioli J, Brioschi S, Scheiflinger F, Remuzzi G. Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. J Am Soc Nephrol. 2005;16:1177–83. [PubMed: 15800115]
  68. Noris M, Caprioli J, Bresin E, Mossali C, Pianetti G, Gamba S, Daina E, Fenili C, Castelletti F, Sorosina A, Piras R, Donadelli R, Maranta R, van der Meer I, Conway EM, Zipfel PF, Goodship TH, Remuzzi G. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin J Am Soc Nephrol. 2010;5:1844–59. [PMC free article: PMC2974386] [PubMed: 20595690]
  69. Noris M, Remuzzi G. Hemolytic uremic syndrome. J Am Soc Nephrol. 2005;16:1035–50. [PubMed: 15728781]
  70. Noris M, Remuzzi G. Atypical-hemolytic uremic syndrome. N Engl J Med. 2009;361:1676–87. [PubMed: 19846853]
  71. Noris M, Remuzzi G. Thrombotic microangiopathy after kidney transplantation. Am J Transplant. 2010;10:1517–23. [PubMed: 20642678]
  72. Ohanian M, Cable C, Halka K. Eculizumab safely reverses neurologic impairment and eliminates need of dialysis in severe atypical hemolytic uremic syndrome. Clin Pharmacol. 2011;3:5–12. [PMC free article: PMC3262387] [PubMed: 22287852]
  73. Ohlin A-K, Marlar RA. The first mutation identified in the thrombomodulin gene in a 45-year-old man presenting with thromboembolic disease. Blood. 1995;85:330–6. [PubMed: 7811989]
  74. Ozaltin F, Li B, Rauhauser A, An SW, Soylemezoglu O, Gonul II, Taskiran EZ, Ibsirlioglu T, Korkmaz E, Bilginer Y, Duzova A, Ozen S, Topaloglu R, Besbas N, Ashraf S, Du Y, Liang C, Chen P, Lu D, Vadnagara K, Arbuckle S, Lewis D, Wakeland B, Quigg RJ, Ransom RF, Wakeland EK, Topham MK, Bazan NG, Mohan C, Hildebrandt F, Bakkaloglu A, Huang CL, Attanasio M. DGKE variants cause a glomerular microangiopathy that mimics membranoproliferative GN. J Am Soc Nephrol. 2013;24:377–84. [PMC free article: PMC3582208] [PubMed: 23274426]
  75. Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, Vera M, Lopez-Trascasa M, Rodriguez de Cordoba S, Sanchez-Corral P. Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet. 2001;68:478–84. [PMC free article: PMC1235280] [PubMed: 11170895]
  76. Remuzzi G, Galbusera M, Salvadori M, Rizzoni G, Paris S, Ruggenenti P. Bilateral nephrectomy stopped disease progression in plasma-resistant hemolytic uremic syndrome with neurological signs and coma. Kidney Int. 1996;49:282–6. [PubMed: 8770981]
  77. Richards A, Buddles MR, Donne RL, Kaplan BS, Kirk E, Venning MC, Tielemans CL, Goodship JA, Goodship TH. Factor H mutations in hemolytic uremic syndrome cluster in exons 18-20, a domain important for host cell recognition. Am J Hum Genet. 2001;68:485–90. [PMC free article: PMC1235281] [PubMed: 11170896]
  78. Richards A, Kathryn Liszewski M, Kavanagh D, Fang CJ, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship TH, Atkinson JP. Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol. 2007;44:111–22. [PubMed: 16882452]
  79. Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, Muslumanoglu MH, Kavukcu S, Filler G, Pirson Y, Wen LS, Atkinson JP, Goodship TH. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci U S A. 2003;100:12966–71. [PMC free article: PMC240728] [PubMed: 14566051]
  80. Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P. The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol. 2004;41:355–67. [PubMed: 15163532]
  81. Rother RP, Rollins SA, Mojcik CF, Brodsky RA, Bell L. Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria. Nat Biotechnol. 2007;25:1256–64. [PubMed: 17989688]
  82. Ruggenenti P, Noris M, Remuzzi G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int. 2001;60:831–46. [PubMed: 11532079]
  83. Saland JM, Emre SH, Shneider BL, Benchimol C, Ames S, Bromberg JS, Remuzzi G, Strain L, Goodship TH. Favorable long-term outcome after liver-kidney transplant for recurrent hemolytic uremic syndrome associated with a factor H mutation. Am J Transplant. 2006;6:1948–52. [PubMed: 16889549]
  84. Saunders RE, Goodship TH, Zipfel PF, Perkins SJ. An interactive web database of factor H-associated hemolytic uremic syndrome mutations: insights into the structural consequences of disease-associated mutations. Hum Mutat. 2006;27:21–30. [PubMed: 16281287]
  85. Sellier-Leclerc AL, Fremeaux-Bacchi V, Dragon-Durey MA, Macher MA, Niaudet P, Guest G, Boudailliez B, Bouissou F, Deschenes G, Gie S, Tsimaratos M, Fischbach M, Morin D, Nivet H, Alberti C, Loirat C. Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol. 2007;18:2392–400. [PubMed: 17599974]
  86. Servais A, Fremeaux-Bacchi V, Lequintrec M, Salomon R, Blouin J, Knebelmann B, Grunfeld JP, Lesavre P, Noel LH, Fakhouri F. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uraemic syndrome. J Med Genet. 2007;44:193–9. [PMC free article: PMC2598029] [PubMed: 17018561]
  87. Servais A, Noël LH, Roumenina LT, Le Quintrec M, Ngo S, Dragon-Durey MA, Macher MA, Zuber J, Karras A, Provot F, Moulin B, Grünfeld JP, Niaudet P, Lesavre P, Frémeaux-Bacchi V. Acquired and genetic complement abnormalities play a critical role in dense deposit disease and other C3 glomerulopathies. Kidney Int. 2012;82:454–64. [PubMed: 22456601]
  88. Stratton JD, Warwicker P. Successful treatment of factor H-related haemolytic uraemic syndrome. Nephrol Dial Transplant. 2002;17:684–5. [PubMed: 11917071]
  89. Taylor CM, Chua C, Howie AJ, Risdon RA. Clinico-pathological findings in diarrhoea-negative haemolytic uraemic syndrome. Pediatr Nephrol. 2004;19:419–25. [PubMed: 14986082]
  90. Thakkinstian A, Han P, McEvoy M, Smith W, Hoh J, Magnusson K, Zhang K, Attia J. Systematic review and meta-analysis of the association between complement factor H Y402H polymorphisms and age-related macular degeneration. Hum Mol Genet. 2006;15:2784–90. [PubMed: 16905558]
  91. Tsukamoto H, Horiuchi T, Kokuba H, Nagae S, Nishizaka H, Sawabe T, Harashima S, Himeji D, Koyama T, Otsuka J, Mitoma H, Kimoto Y, Hashimura C, Kitano E, Kitamura H, Furue M, Harada M. Molecular analysis of a novel hereditary C3 deficiency with systemic lupus erythematosus. Biochem Biophys Res Commun. 2005;330:298–304. [PubMed: 15781264]
  92. Van Hove JL, Van Damme-Lombaerts R, Grunewald S, Peters H, Van Damme B, Fryns JP, Arnout J, Wevers R, Baumgartner ER, Fowler B. Cobalamin disorder Cbl-C presenting with late-onset thrombotic microangiopathy. Am J Med Genet. 2002;111:195–201. [PubMed: 12210350]
  93. Venables JP, Strain L, Routledge D, Bourn D, Powell HM, Warwicker P, Diaz-Torres ML, Sampson A, Mead P, Webb M, Pirson Y, Jackson MS, Hughes A, Wood KM, Goodship JA, Goodship TH. Atypical haemolytic uraemic syndrome associated with a hybrid complement gene. PLoS Med. 2006;3:e431. [PMC free article: PMC1626556] [PubMed: 17076561]
  94. Vyse TJ, Morley BJ, Bartok I, Theodoridis EL, Davies KA, Webster ADB, Walport MJ. The molecular basis of hereditary complement factor I deficiency. J. Clin. Invest. 1996;97:925–33. [PMC free article: PMC507137] [PubMed: 8613545]
  95. Walker PD, Ferrario F, Joh K, Bonsib SM. Dense deposit disease is not a membranoproliferative glomerulonephritis. Mod Pathol. 2007;20:605–16. [PubMed: 17396142]
  96. Warwicker P, Goodship TH, Donne RL, Pirson Y, Nicholls A, Ward RM, Turnpenny P, Goodship JA. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int. 1998;53:836–44. [PubMed: 9551389]
  97. Weitz M, Amon O, Bassler D, Koenigsrainer A, Nadalin S. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr Nephrol. 2011;26:1325–9. [PubMed: 21556717]
  98. Yates JR, Sepp T, Matharu BK, Khan JC, Thurlby DA, Shahid H, Clayton DG, Hayward C, Morgan J, Wright AF, Armbrecht AM, Dhillon B, Deary IJ, Redmond E, Bird AC, Moore AT. Complement C3 variant and the risk of age-related macular degeneration. N Engl J Med. 2007;357:553–61. [PubMed: 17634448]
  99. Zimmerhackl LB, Scheiring J, Prufer F, Taylor CM, Loirat C. Renal transplantation in HUS patients with disorders of complement regulation. Pediatr Nephrol. 2007;22:10–6. [PubMed: 17058051]
  100. Zipfel PF, Edey M, Heinen S, Jozsi M, Richter H, Misselwitz J, Hoppe B, Routledge D, Strain L, Hughes AE, Goodship JA, Licht C, Goodship TH, Skerka C. Deletion of complement factor H-related genes CFHR1 and CFHR3 is associated with atypical hemolytic uremic syndrome. Plos Genet. 2007;3:e41. [PMC free article: PMC1828695] [PubMed: 17367211]
  101. Zuber J, Fakhouri F, Roumenina LT, Loirat C, Frémeaux-Bacchi V, Frémeaux-Bacchi V. Nature reviews. Nephrology. 2012a;8:643–57. [PubMed: 23026949]
  102. Zuber J, Le Quintrec M, Krid S, Bertoye C, Gueutin V, Lahoche A, Heyne N, Ardissino G, Chatelet V, Noël LH, Hourmant M, Niaudet P, Frémeaux-Bacchi V, Rondeau E, Legendre C, Loirat C, Loirat C. Am J Transplant. 2012b;12:3337–54. [PubMed: 22958221]

Chapter Notes

Author Notes

Web: www.marionegri.it

Author History

Elena Bresin, MD (2007-present)
Jessica Caprioli, Biol Sci D; Mario Negri Institute for Pharmacological Research (2007-2013)
Caterina Mele, Biol Sci D (2007-present)
Marina Noris, PhD (2007-present)
Giuseppe Remuzzi, MD (2007-present)

Revision History

  • 8 August 2013 (me) Comprehensive update posted live
  • 10 March 2011 (me) Comprehensive update posted live
  • 20 November 2008 (cd) Revision: deletion/duplication testing for CFI and CD46 available clinically
  • 17 December 2007 (cd) Revision: sequence analysis available for CFB
  • 16 November 2007 (me) Review posted to live Web site
  • 27 March 2007 (mn) Original submission
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