Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology

User menu

  • Subscribe
  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
American Society of Nephrology
  • Other
    • JASN
    • Kidney360
    • Kidney News Online
    • American Society of Nephrology
  • Subscribe
  • My alerts
  • Log in
  • My Cart
Advertisement
American Society of Nephrology

Advanced Search

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Podcasts
    • Subject Collections
    • Archives
    • ASN Meeting Abstracts
    • Saved Searches
  • Authors
    • Submit a Manuscript
    • Author Resources
    • Reprint Information
  • Trainees
    • Peer Review Program
    • Prize Competition
  • About CJASN
    • About CJASN
    • Editorial Team
    • CJASN Impact
    • CJASN Recognitions
  • More
    • Alerts
    • Advertising
    • Reprint Information
    • Subscriptions
    • Feedback
  • ASN Kidney News
  • Visit ASN on Facebook
  • Follow CJASN on Twitter
  • CJASN RSS
  • Community Forum
Diagnostic & Therapeutic Corner
You have accessRestricted Access

Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome

David Kavanagh, Anna Richards, Veronique Fremeaux-Bacchi, Marina Noris, Timothy Goodship, Giuseppe Remuzzi and John P. Atkinson
CJASN May 2007, 2 (3) 591-596; DOI: https://doi.org/10.2215/CJN.03270906
David Kavanagh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Anna Richards
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Veronique Fremeaux-Bacchi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marina Noris
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Timothy Goodship
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Giuseppe Remuzzi
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John P. Atkinson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data Supps
  • Info & Metrics
  • View PDF
Loading

The past decade has seen the identification of mutations in the genes for complement factor H (CFH) (1–6), membrane co-factor protein (MCP) (7–12), and factor I (CFI) (9,13–15) as predisposing factors for the development of atypical hemolytic uremic syndrome (aHUS). With this increased understanding of the genetic basis of aHUS and its implications for patient treatment, particularly transplantation, has come an increasing demand for genetic screening. A full analysis for mutations in all three of these complement proteins is expensive and time-consuming. A rational system is required to optimize the timely delivery of results and to reduce the cost of screening. We suggest some proposals that are based on our own experience with aHUS and our review of the relevant literature.

The strategy that we propose (Figure 1) involves an initial screen that is based on protein levels (either serum levels or surface expression). This offers a rapid mechanism to identify the likely gene involved. In those in whom normal levels of complement regulators are found, we propose screening genes on the basis of their order of frequency of mutation detection (CFH, approximately 30%; MCP, approximately 10%; CFI, 2 to 5%) (15). Furthermore, mutations cluster in certain exons of the genes that code for the protein (60% of CFH mutations cluster in complement control protein modules 19 and 20; 90% of MCP mutations in control protein modules 1 to 4; 60% of CFI mutations in the serine protease domain) (15). By screening these regions first, cost and detection time can be minimized.

   Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

Flow diagram demonstrating screening strategy in atypical hemolytic uremic syndrome (aHUS). Our suggested screening strategy in aHUS involves a three-tier approach. Level 1 investigations provide a quantitative assessment of protein concentrations by radioimmunodiffusion assay (RIDA) or FACS. Level 2 investigations provide a genetic assessment of complement genes using direct fluorescence sequencing and mixed ligation-dependent probe amplification (MLPA). The level 1 screen may demonstrate low levels of a protein and thereby suggest the mutated gene. Confirmatory level 2 genetic testing of the corresponding gene can then be undertaken. If this testing is negative at level 2, then a guide to further evaluation is presented in level 3, which is based largely on the frequency of mutations in each of the three genes in patients with aHUS. In those with normal protein expression, we suggest screening genes on the basis of frequency of mutation detection and on the clustering of mutations in certain exons of the genes (as is shown for level 2). Because of the high frequency of genomic rearrangements in the gene for complement factor H (CFH), we favor performing MLPA in addition to sequencing of control protein modules 19 and 20 initially. A possible alternative in patients with normal protein expression is to screen for the gene for factor I (CFI) after CFH, because of their greater relevance of a mutation to transplantation than is the case for the gene for membrane co-factor protein (MCP). However, mutations in CFI are much rarer than mutations in MCP. SP, serine protease domain.

Serum Measurement

When possible, blood should be taken for CFH or CFI measurement before plasma infusion/exchange is commenced. If blood is taken in a convalescent period, then it should be at least 2 wk after the last infusion of plasma to ensure that the levels measured are from natively synthesized proteins.

Serum C3 and C4 levels generally will form part of a basic complement screen. In almost all cases of aHUS, C4 levels are normal (9). Low C3 levels are commonly seen in patients with mutations in CFH, CFI, and MCP (9). However, this is not a sensitive screening test, and normal C3 levels do not exclude the presence of mutations in complement regulatory proteins (15). In those with mutations in CFH, approximately 50% have normal C3 levels. For CFI, this figure is 40% and for MCP approximately 70% (15). There is also a group with low C3 levels (approximately 30%) and no mutations in MCP, CFH, or CFI (9). This group likely represents a cohort with mutations in an as-yet-unidentified complement gene.

CFH and CFI Levels

Because most cases of CFH-associated HUS have a heterozygous mutation in CFH (15), patients in whom the mutant protein is not expressed would be expected to have a 50% level. Factor H serum levels, however, vary considerably, and the range changes with age (neonates 170 to 397 μg/ml; adults 242 to 759 μg/ml) (16). Most children reach adult levels by 1 yr of age. It therefore is essential that an age-matched control panel be established in a reference laboratory to give interpretable results. No significant difference in CFH levels has been shown between genders (16).

From the reports to date, serum measurement of CFH will detect approximately 25% of patients with mutations in CFH (15). As with CFH, there are differences in CFI concentration according to age (neonate 15 to 55 μg/ml; adults 39 to 100 μg/ml) (16). Again, most children reach adult levels by 1 yr of age. Serum measurement will be low in approximately 40% of mutations in CFI (15).

Commercially available radioimmunodiffusion assay kits for CFI and CFH are available and give reliable results on serum or plasma. Serum generally is preferred, and it should be collected and stored frozen as the laboratory does for C3 and C4 assays.

MCP Levels

FACS analysis of peripheral blood mononuclear cells provides a quick and relatively cheap screening option for MCP mutations. From currently available data, screening in this manner will detect approximately 75% of mutations (12). The mean fluorescence intensity in patients and family carriers of a heterozygous mutation should be approximately 50% of the normal range. Rare carriers of either compound heterozygous or homozygous MCP mutations show almost absent MCP signal by FACS (9,10,12).

There is a modest (approximately 20%) variation in MCP expression level on peripheral blood mononuclear cells using serial measurements up to 5 d after venipuncture (unpublished observations). When possible, blood should be examined at a standard number of days after collection and be compared with wild-type controls that were collected and stored under similar conditions. We recommend that blood be stored for no more than 5 d at 4°C before FACS analysis.

Genetic Analysis of the Genes for CFH, CFI, and MCP

Screening for mutations by serum levels or cell surface expression will fail to detect low protein levels in 25 to 75% of mutations. Genetic analysis therefore also is required.

Genetic screening for mutations has most frequently been performed using either denaturing HPLC or single-strand conformation polymorphism. Both of these options are relatively inexpensive but are not sensitive. In addition, these techniques do not reveal the position of a mutation, and further confirmatory direct sequencing is required (17).

Sequencing PCR amplicons is now becoming the method of choice for mutation screening. Although it can be expensive, it is the most sensitive method available (17).

The CFH gene consists of 23 exons. Primers for mutation screening of CFH using single-strand conformation polymorphism, denaturing HPLC, and direct sequencing have been reported (3–6,18). The primers chosen will reflect whichever technology is available and optimized in the laboratory of choice. Furthermore, it is vital that the primers chosen be able to differentiate between CFH and the factor H–related proteins, especially CFHL1 (19). Errors have been made as a result of use of nonspecific primers, and this is a vital component of the screening process because the majority of CFH mutants cluster in the region of maximal CFHL1 homology (19,20). For this reason, it may be prudent to adopt the primers that already are used and verified by one of the recognized groups in this area.

CFI has 13 exons, and MCP has 14 exons. Primers for mutation screening for CFI and for MCP using direct sequencing again have been reported by several groups who are experienced in this field (9,10,13,14).

Genomic Rearrangements

The genes for CFH and MCP, as well as many other complement regulatory genes, all are tightly linked in a region that is known as the regulators of complement activation (RCA) cluster on chromosome 1q32. The RCA cluster arose by several large genomic duplications. These duplications have resulted in a high degree of sequence identity between the gene for CFH and the genes for the five factor H–related proteins (CFHL1 through 5) (21,22). These large genomic duplications predispose to gene conversion events and genomic rearrangements (23).

Unambiguous evidence of a role for gene conversion in generation of CFH mutants in aHUS was provided by Heinen et al. (24). In that study, the Goodship group described two patients with conclusive evidence of gene conversion and another nine patients in whom a CFH mutation could have arisen by gene conversion. This type of mutation can be detected by genomic sequencing.

The Goodship group also described a large genomic rearrangement in CFH that resulted in a hybrid gene in which exons 1 to 21 are derived from CFH and exons 22 and 23 are derived from CFHL1 (25). Subsequent analysis of a large panel of patients with aHUS revealed similar deletions of exons 22 and 23 with formation of a hybrid gene in an additional three of 80 patients. Such a change accounts for approximately 5% of mutations in aHUS in this series. This is of particular importance when screening patients for mutations in CFH, because large genomic rearrangements of this type would not be detected by genomic sequencing using CFH-specific primers. Because these individuals lacked CFH exons 22 and 23 on one allele, the specific primers would amplify only exons 22 and 23 of CFH on the normal allele. The sequencing therefore would seem normal.

Given the high frequency of genomic rearrangements in CFH, it is recommended that all patients be screened with multiplex ligation–dependent probe amplification. No data yet exist for genomic rearrangements in MCP and CFI, however, multiplex ligation–dependent probe amplification of these genes should be considered in those in whom a mutation has not been discovered (17).

Combined Mutations

When screening for mutations in complement regulators, it also should be noted that in several cases, individuals have had mutations in two complement regulators (9,11,26). This raises the question of whether after the identification of a mutation in one complement regulator, efforts should be made to seek out another predisposing gene. The small number of cases with multiple mutations discovered so far makes genotype–phenotype correlations difficult to derive. We believe that when a mutation has been identified in either CFH or CFI, which are poor prognostic indicators for successful renal transplantation, there is no clinical utility in searching for another mutation. In those in whom an MCP mutation has been identified, which has a better prognosis for renal transplantation, there may be an argument for screening CFH and/or CFI to exclude mutations in these genes that would adversely affect transplant outcome.

Autoantibodies

In those without detectable mutations in CFH, CFI, or MCP, autoantibodies to CFH have been identified in a small percentage of cases (approximately 6%) (27). An ELISA with purified human factor H–coated plates to capture anti-CFH antibodies is used.

Interpreting Results

Functional Significance of Mutations

Mutation screening of CFH, MCP, and CFI is challenging because many distinct disease-associated mutations are individually rare. In most cases, interpreting the functional significance of nonsense mutations, large gene rearrangements, frameshift mutations, and obvious splice junction mutations is clear-cut. However, a significant proportion of variants consist of missense mutations of unknown functional significance.

Functional studies have been performed for all MCP mutations that are associated with aHUS (reviewed in reference [12]) and for many CFH mutations (reviewed in reference [15]). Functional analysis of CFI mutations are awaited. These functional analyses have only been undertaken in a research situation and are too costly and time-consuming to be used in a diagnostic screening service.

In a diagnostic screening service, where functional analysis is not practical, a probability of significance is assigned to a missense mutant. This can be done by comparison with orthologous complement sequences, examination of the site of the mutation within the functional domains of the protein, and examination of the chemical difference in amino acid changes and how they would fit in available protein structures. This assignment often is far from absolute. Consequently, for many missense mutations, laboratories that specialize in these tests will need to be contacted so that they can assist in defining the functional significance of the change.

Predisposing Genes

When interpreting the results of screening, it also should be noted that the mutations reported in the genes for CFH, MCP, and CFI in aHUS are increasingly believed to be predisposing rather than directly causal (i.e., this is not a predictable single gene disorder, e.g., adult polycystic kidney disease I and II).

Testing for predisposing mutations is a challenging issue. The general problem with predictive testing on the basis of a predisposing factor (as opposed to a causative mutation) is that, by definition, it is one of only several risk factors required for disease penetrance. Predictions that are based on a single risk factor in unaffected individuals are hazardous. From currently available data, the penetrance of disease for all mutations is approximately 50%. The degree of penetrance is thought to be determined by risk haplotypes in the RCA cluster (11,28,29) and by exposure to environmental triggers (e.g., infection, drugs) (9); consequently, the risk cannot be quantified for a given individual. In an unaffected family member with a mutation in a complement regulatory protein, screening may allow monitoring during periods of increased risk (e.g., pregnancy, infections) and will allow avoidance of known precipitants of disease, such as the oral contraceptive pill.

Management of aHUS

In those who have mutations and have developed aHUS, genotype–phenotype correlations can be seen. Those with MCP mutations have milder disease than those with either CFH or CFI mutations, and many recover without plasma therapy (9). This information is of limited use clinically because, at first presentation, the predisposing mutant will be unknown and will take many weeks to identify. Plasma therapy therefore will have been instigated long before a mutation has been identified. As treatment strategies to inhibit complement activation or enhance complement regulation come into clinical use, screening for mutations in patients with relapsing disease may become indicated.

Renal Transplantation

The real utility of genetic screening is in those who already are on renal replacement as a result of aHUS and wish to be considered for a renal transplant. Renal transplantation is complicated by recurrence of aHUS in the allograft in >50% of cases. Historically, it was not possible to identify the subgroup of patients who did not have recurrent aHUS after transplantation. The characterization of the underlying molecular defect in aHUS has now revealed two distinct subgroups. For those with mutations in serum complement regulators (CFH/CFI), recurrence is very common. There have been 28 recurrences in 36 patients who had CFH mutations and received a renal transplant, and all six patients who had CFI mutations and received renal transplants have experienced recurrence. However, for those with mutations in the membrane-bound regulator MCP, recurrence was very rare, with only one recurrence in 10 transplants (30,31).

Living-Related Renal Transplantation

Live-donor renal transplantation also carries a poor prognosis; moreover, in four reported cases, the donors themselves have gone on to develop HUS within 1 yr of donation (32). Many centers do not recommend live-related transplantation because of the risk for recurrence in the recipient and of de novo disease in the donor.

Genotyping of the donor and recipient should be undertaken when live donation is to be considered. This will not, of course, prevent the risk for the donor in those with an unknown genetic basis.

Combined Liver/Kidney Transplantation

Genotyping also is important when considering aHUS patients for combined liver and renal transplants. Because CFH and CFI both are synthesized in the liver, combined liver and renal transplantation seems to be a logical form of treatment. Although the initial three reports (33–35) that described this for CFH-associated HUS had a poor outcome, with two of three dying, a more recent report using plasma exchange preoperatively was successful (36). Unless functioning CFH is already present in the recipient, complement activation will result in rapid failure of the graft (36).

Conclusion

We propose a method for screening for mutations in complement regulatory proteins in patients with aHUS. We believe that the evidence suggests that all patients who have aHUS and are being considered for renal transplantation should undergo screening for mutations in complement regulators. This will allow patients and clinicians to make informed decisions regarding listing for transplantation, on the basis of the risk for recurrence and its not inconsiderable consequent morbidity and mortality. Screening of unaffected family members has limited clinical utility unless they are being considered as living-related kidney donors. A useful source of guidance for genetic screening in aHUS is GeneTests, an National Institutes of Health–funded Web site that provides information on commercial and research-based testing for various genetic disorders (http://www.genetests.org).

Disclosures

None.

Footnotes

  • Published online ahead of print. Publication date available at www.cjasn.org.

  • D.K., A.R., V.F.-B., M.N., T.G., and G.R. are members of the European Working Party on the Genetics of HUS.

  • Copyright © 2007 by the American Society of Nephrology

References

  1. ↵
    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 Int53 :836– 844,1998
    OpenUrlCrossRefPubMed
  2. Richards A, Buddles M, Donne R, Kaplan B, Kirk E, Venning M, Tielemans C, Goodship J, Goodship T: Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition. Am J Hum Genet68 :485– 490,2001
    OpenUrlCrossRefPubMed
  3. ↵
    Caprioli J, Bettinaglio P, Zipfel P, Amadei B, Daina E, Gamba S, Skerka C, Marziliano N, Remuzzi G, Noris M: The molecular basis of familial hemolytic uremic syndrome: Mutation analysis of factor H gene reveals a hot spot in short consensus repeat 20. J Am Soc Nephrol12 :297– 307,2001
    OpenUrlAbstract/FREE Full Text
  4. Neumann H, Salzmann H, Bohnert-Iwan B, Manuelin T, Skerka C, Lenk D, Bender B, Cybulla M, Riegler P, Konigsrainer A, Neyer U, Bock A, Widmer U, Franke G, Zipfel PF: Haemolytic uraemic syndrome and mutations of the factor H gene: A registry based study of German speaking countries. J Med Genet40 :676– 681,2003
    OpenUrlAbstract/FREE Full Text
  5. Perez-Caballero D, Gonzalez-Rubio C, Gallardo M, 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 Genet68 :478– 484,2001
    OpenUrlCrossRefPubMed
  6. ↵
    Dragon-Durey M-A, Fremeaux-Bacchi V, Loirat C, Blouin J, Niaudet P, Deschenes G, Coppo P, Fridman W, Weiss E: Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: Report and genetic analysis of 16 cases. J Am Soc Nephrol15 :787– 795,2004
    OpenUrlAbstract/FREE Full Text
  7. ↵
    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 A100 :12966– 12971,2003
    OpenUrlAbstract/FREE Full Text
  8. Noris M, Brioschi S, Caprioli J, Todeschini M, Bresin E, Porrati F, Gamba S, Remuzzi G: Familial haemolytic uraemic syndrome and an MCP mutation. Lancet362 :1542– 1547,2003
    OpenUrlCrossRefPubMed
  9. ↵
    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 C, Liszewski M, Kavanagh D, Atkinson J, Remuzzi G: Genetics of HUS: The impact of MCP and CFH mutations on clinical presentation, response to treatment, and outcome. Blood108 :1267– 1279,2006
    OpenUrlAbstract/FREE Full Text
  10. ↵
    Fremeaux-Bacchi V, Moulton EA, Kavanagh D, Dragon-Durey M-A, Blouin J, Caudy A, Arzouk N, Cleper R, Francois M, Guest G, Pourrat J, Seligam R, Fridman WH, Loirat C, Atkinson JP: Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J Am Soc Nephrol17 :2017– 2025,2006
    OpenUrlAbstract/FREE Full Text
  11. ↵
    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 Genet14 :703– 712,2005
    OpenUrlCrossRefPubMed
  12. ↵
    Richards A, Liszewski M, Kavanagh D, Fang C, Moulton E, Fremeaux-Bacchi V, Remuzzi G, Noris M, Goodship T, Atkinson JP: Implications of the initial mutations in membrane cofactor protein (MCP; CD46) leading to atypical hemolytic uremic syndrome. Mol Immunol44 :111– 122,2006
    OpenUrlCrossRefPubMed
  13. ↵
    Kavanagh D, Kemp E, Mayland E, Winney R, Duffield J, Warwick G, Richards A, Ward R, Goodship J, Goodship T: Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J Am Soc Nephrol16 :2150– 2155,2005
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Fremeaux-Bacchi V, Dragon-Durey M-A, Blouin J, Vigneau C, Kuypers D, Boudailliez B, Loirat C, Rondeau E, Fridman W: Complement factor I: A susceptibility gene for atypical haemolytic uraemic syndrome. J Med Genet41 :e84 ,2004
    OpenUrlFREE Full Text
  15. ↵
    Kavanagh D, Goodship THJ, Richards A: Atypical haemolytic uraemic syndrome. Br Med Bull77–78 :5– 22,2006
    OpenUrl
  16. ↵
    de Paula P, Barbosa J, Junior P, Ferriani V, Latorre M, Nudelman V, Isaac L: Ontogeny of complement regulatory proteins: Concentrations of factor H, factor I, C4b-binding protein, properdin and vitronectin in healthy children of different ages and in adults. Scand J Immunol58 :572– 577,2003
    OpenUrlCrossRefPubMed
  17. ↵
    Goodship T, Fremeaux-Bacchi V, Atkinson J: Genetic testing in atypical HUS and the role of membrane cofactor protein (MCP; CD46) and factor I. In: Complement and Kidney Disease, edited by Zipfel PF, Basel, Birkhauser Verlag,2005 , pp111– 127
  18. ↵
    Richards A, Goodship J, Goodship T: The genetics and pathogenesis of haemolytic uraemic syndrome and thrombotic thrombocytopenic purpura. Curr Opin Nephrol Hypertens11 :431– 436,2002
    OpenUrlCrossRefPubMed
  19. ↵
    Buddles M, Donne R, Richards A, Goodship J, Goodship T: Complement factor H gene mutation associated with autosomal recessive atypical hemolytic uraemic syndrome. Am J Hum Genet66 :1721– 1722,2000
    OpenUrlCrossRefPubMed
  20. ↵
    Ying L, Katz Y, Schlesinger M, Carmi R, Shalev H, Haider N, Beck G, Sheffield V, Landau D: Complement factor H gene mutation associated with autosomal recessive atypical haemolytic uraemic syndrome. J Hum Genet65 :1538– 1546,1999
    OpenUrlCrossRef
  21. ↵
    Male D, Ormsby R, Ranganathan S, Giannakis E, Gordon D: Complement factor H: Sequence analysis of 221kb of human genomic DNA containing the entire fH, fHR1 and fHR3 genes. Mol Immunol37 :41– 52,2000
    OpenUrlCrossRefPubMed
  22. ↵
    Zipfel PF, Jokiranta TS, Hellwage J, Koistinen V, Meri S: The factor H protein family. Immunopharmacology42 :53– 60,1999
    OpenUrlCrossRefPubMed
  23. ↵
    Lupski J, Stankiewicz P: Genomic disorders: Molecular mechanisms for rearrangements and conveyed phenotypes. PLoS Genet1 :e49 ,2005
    OpenUrlCrossRefPubMed
  24. ↵
    Heinen S, Sanchez-Corral P, Jackson M, Strain L, Goodship J, Kemp E, Skerka C, Jokiranta T, Meyers K, Wagner E, Robitaille P, Esparza-Gordillo J, Rodriguez de Cordoba S, Zipfel P, Goodship T: De novo gene conversion in the RCA gene cluster (1q32) causes mutations in complement factor H associated with atypical hemolytic uremic syndrome. Hum Mutat27 :292– 293,2006
    OpenUrlCrossRefPubMed
  25. ↵
    Venables JP, Strain L, Routledge D, Bourn D, Powell H, Warwicker P, Diaz-Torres ML, Sampson A, Mead P, Webb M, Pirson Y, Jackson MS, Hughes A, Wood KA, Goodship JA, Goodship TH: Atypical haemolytic syndrome associated with a hybrid complement gene. PLoS Med3 :e431 ,2006
    OpenUrlCrossRefPubMed
  26. ↵
    Esparza-Gordillo J, Goicoechea de Jorge E, Garrido C, Carreras L, Lopez-Trascasa M, Sanchez-Corral P, Rodriguez de Cordoba S: Insights into hemolytic uremic syndrome: Segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol Immunol43 :1769– 1775,2006
    OpenUrlCrossRefPubMed
  27. ↵
    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 Nephrol16 :555– 563,2005
    OpenUrlAbstract/FREE Full Text
  28. ↵
    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 disease. Hum Mol Genet12 :3385– 3395,2003
    OpenUrlCrossRefPubMed
  29. ↵
    Fremeaux-Bacchi V, Kemp E, Goodship J, Dragon-Durey M, Strain L, Loirat C, Deng H, Goodship T: The development of atypical HUS is influenced by susceptibility factors in factor H and membrane cofactor protein: Evidence from two independent cohorts. J Med Genet42 :852– 856,2005
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Kavanagh D, Goodship TH: Membrane cofactor protein and factor I: Mutations and transplantation. Semin Thromb Haemost32 :155– 159,2006
    OpenUrlCrossRefPubMed
  31. ↵
    Bresin E, Daina E, Noris M, Castelletti F, Stefanov R, Hill P, Goodship T, Remuzzi G: Outcome of renal transplantation in patients with non-Shiga toxin-associated haemolytic syndrome: Prognostic significance of genetic background. Clin J Am Soc Nephrol1 :88– 99,2006
    OpenUrlCrossRefPubMed
  32. ↵
    Donne R, Abbs I, Barany P, Elinder C-G, Little M, Conlon P, Goodship T: Recurrence of hemolytic uremic syndrome after live related renal transplantation associated with subsequent de novo disease in the donor. Am J Kidney Dis40 :E22 ,2002
    OpenUrlCrossRefPubMed
  33. ↵
    Cheong H, Lee B, Kang H, Hahn H, Suh H, Ha I, Choi Y: Attempted treatment of factor H deficiency by liver transplantation. Pediatr Nephrol19 :454– 458,2004
    OpenUrlCrossRefPubMed
  34. Remuzzi G, Ruggenenti P, Codazzi D, Noris M, Caprioli J, Locatelli G, Gridelli B: Combined kidney and liver transplantation for familial haemolytic uraemic syndrome. Lancet359 :1671– 1672,2002
    OpenUrlCrossRefPubMed
  35. ↵
    Remuzzi G, Ruggenenti P, Colledan M, Gridelli B, Bertani A, Bettinaglio P, Bucchioni S, Sonzogni A, Bonanomi E, Sonzogni V, Platt J, Perico N, Noris M: Hemolytic uremic syndrome: A fatal outcome after kidney and liver transplantation performed to correct factor H gene mutation. Am J Transplant5 :1146– 1150,2005
    OpenUrlCrossRefPubMed
  36. ↵
    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 Transplant6 :1948– 1952,2006
    OpenUrlCrossRefPubMed
View Abstract
PreviousNext
Back to top

In this issue

Clinical Journal of the American Society of Nephrology
Vol. 2, Issue 3
May 2007
  • Table of Contents
  • Table of Contents (PDF)
  • Index by author
View Selected Citations (0)
Print
Download PDF
Sign up for Alerts
Email Article
Thank you for your help in sharing the high-quality science in CJASN.
Enter multiple addresses on separate lines or separate them with commas.
Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome
(Your Name) has sent you a message from American Society of Nephrology
(Your Name) thought you would like to see the American Society of Nephrology web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome
David Kavanagh, Anna Richards, Veronique Fremeaux-Bacchi, Marina Noris, Timothy Goodship, Giuseppe Remuzzi, John P. Atkinson
CJASN May 2007, 2 (3) 591-596; DOI: 10.2215/CJN.03270906

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Screening for Complement System Abnormalities in Patients with Atypical Hemolytic Uremic Syndrome
David Kavanagh, Anna Richards, Veronique Fremeaux-Bacchi, Marina Noris, Timothy Goodship, Giuseppe Remuzzi, John P. Atkinson
CJASN May 2007, 2 (3) 591-596; DOI: 10.2215/CJN.03270906
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like

Jump to section

  • Article
    • Serum Measurement
    • CFH and CFI Levels
    • MCP Levels
    • Genetic Analysis of the Genes for CFH, CFI, and MCP
    • Genomic Rearrangements
    • Combined Mutations
    • Autoantibodies
    • Interpreting Results
    • Conclusion
    • Disclosures
    • Footnotes
    • References
  • Figures & Data Supps
  • Info & Metrics
  • View PDF

More in this TOC Section

  • Dialysis in Intensive Care Unit Patients with Acute Kidney Injury: Continuous Therapy is Superior
  • Therapeutic Monitoring of Mycophenolate Mofetil
Show more Diagnostic & Therapeutic Corner

Cited By...

  • The role of complement in kidney disease
  • Characterization of a New DGKE Intronic Mutation in Genetically Unsolved Cases of Familial Atypical Hemolytic Uremic Syndrome
  • Thrombotic microangiopathy and indications for therapeutic plasma exchange
  • Combined Complement Gene Mutations in Atypical Hemolytic Uremic Syndrome Influence Clinical Phenotype
  • Nephrology Quiz and Questionnaire: 2009
  • Liver-Kidney Transplantation to Cure Atypical Hemolytic Uremic Syndrome
  • Google Scholar

Similar Articles

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Articles

  • Current Issue
  • Early Access
  • Subject Collections
  • Article Archive
  • ASN Meeting Abstracts

Information for Authors

  • Submit a Manuscript
  • Trainee of the Year
  • Author Resources
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • CJASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About CJASN
  • CJASN Email Alerts
  • CJASN Key Impact Information
  • CJASN Podcasts
  • CJASN RSS Feeds
  • Editorial Board

More Information

  • Advertise
  • ASN Podcasts
  • ASN Publications
  • Become an ASN Member
  • Feedback
  • Follow on Twitter
  • Password/Email Address Changes
  • Subscribe

© 2021 American Society of Nephrology

Print ISSN - 1555-9041 Online ISSN - 1555-905X

Powered by HighWire