Skip to main content

Main menu

  • Home
  • Content
    • Published Ahead of Print
    • Current Issue
    • Article Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Program
    • Feedback
    • Reprints
    • Impact Factor
  • ASN Kidney News
  • Other
    • CJASN
    • 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
    • CJASN
    • 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
    • Article Collections
    • JASN Podcasts
    • Archives
    • Saved Searches
    • ASN Meeting Abstracts
  • Authors
    • Submit a Manuscript
    • Author Resources
  • Editorial Team
  • Subscriptions
  • More
    • About JASN
    • Alerts
    • Advertising
    • Editorial Fellowship Program
    • Feedback
    • Reprints
    • Impact Factor
  • ASN Kidney News
  • Follow JASN on Twitter
  • Visit ASN on Facebook
  • Follow JASN on RSS
  • Community Forum
UP FRONT MATTERSEditorials
You have accessRestricted Access

Pulling the Trigger in Atypical Hemolytic Uremic Syndrome: The Role of Pregnancy

Timothy H.J. Goodship and David Kavanagh
JASN May 2010, 21 (5) 731-732; DOI: https://doi.org/10.1681/ASN.2010030308
Timothy H.J. Goodship
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
David Kavanagh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Info & Metrics
  • View PDF
Loading

In the past 15 years, our understanding of the molecular mechanisms that predispose to atypical hemolytic uremic syndrome (aHUS) has increased dramatically.1 A series of studies established that dysregulation of the alternative complement pathway plays a significant role in the pathogenesis of disease in the majority of patients.1,2 Mutations in both complement regulators (factor H, factor I, and membrane co-factor protein) and activators (C3 and factor B) have been described in both familial and sporadic forms. In addition, factor H autoantibodies, which impair the activity of factor H, and mutations in the gene encoding thrombomodulin are now known.3,4

More than one family member is affected in approximately 10% of patients with aHUS. The study of such families reveals a higher prevalence of the aforementioned mutations and indicates that not every individual who carries a mutation manifests the disease.5 The rate of nonpenetrance is approximately 50%, and it has been shown that naturally occurring variability in single-nucleotide polymorphisms and haplotype blocks of the CFH and CD46 genes encoding factor H and membrane co-factor protein, respectively, increase susceptibility to disease. Moreover, multiple concurrent factors such as single-nucleotide polymorphisms, mutations, and autoantibodies may be necessary for disease to manifest in individual families.6

Some event almost always triggers the disease in the majority of patients. aHUS typically presents in childhood, and a history of a preceding nondiarrheal viral infection is common. This is also true of adults and in females of childbearing age the phenotype of aHUS can present late in pregnancy or soon after delivery;7 pregnancy may be the trigger in 10% of all patients with aHUS.8

Fakhouri et al.9 in their article in this issue of JASN provide us with substantial additional information that will be enlightening to all those who are interested in this condition. They confirm in female adults that aHUS associates with pregnancy in 20% of patients, and, in the majority, this occurs postpartum. Complement abnormalities were found in 86% of these patients; this is the highest prevalence reported in any subgroup of aHUS to date. The prognosis for such patients in the 1970s was extremely poor, with a mortality rate of approximately 55%, and of those who survived, approximately 50% required long-term dialysis.10 Mortality has improved since then, but Fakhouri et al. indicate that 76% of patients develop ESRD despite receiving plasma exchange. The prognosis for renal transplantation in these patients is equally gloomy, especially in those who are known to have a factor H mutation, 80% of whom will lose an allograft to recurrent disease within 2 years of transplantation,11 although liver-kidney transplants may do better.12

With the poor prognosis for these patients and their seeming resistance to plasma exchange, are there any other therapeutic maneuvers that might benefit management? Anecdotal reports suggest that the C5 mAb eculizumab may be an effective form of treatment for aHUS,13 and the results of clinical trials currently being undertaken with this agent are awaited eagerly. If eculizumab proves to be effective, then could it be used in pregnancy or postpartum? Recent reports of patients with paroxysmal nocturnal hemoglobinuria showed no adverse effects when used in pregnancy,14 and, in particular, there is no evidence the drug crosses the placenta or is present in breast milk.

What is it about pregnancy, particularly the postpartum period, that increases susceptibility to aHUS? That complement plays a pivotal role in the pathophysiology of pregnancy is well established.15 In particular, complement-mediated placental damage is prevented by trophoblast expression of the complement regulators known as decay-accelerating factor, membrane co-factor protein, and CD59. In the antiphospholipid antibody syndrome, it is excessive activation of the classical pathway with amplification through the alternative pathway that eventually leads to fetal loss.15 Pregnancy is an immunologically privileged condition,16 and levels of most complement proteins increase during pregnancy, subsequently falling after delivery.17 Reversal of these two phenomena early in the postpartum period could decrease the threshold for aHUS.

In both the familial and sporadic forms of aHUS, family members who are at risk for carrying the same complement gene mutation often undergo genetic screening. Women who are found to be carriers and are of potential childbearing age often ask what the risk of pregnancy might be? The study by Fakhouri et al.9 provides additional information to use in counseling such individuals. Twelve of the 21 patients with pregnancy-associated aHUS had at least one previous uncomplicated pregnancy. In the female patients of the Paris aHUS cohort, 44 with a complement gene mutation in total had 103 pregnancies; of these, only 18 (17.4%) were associated with aHUS. This is a level of risk for which many individuals might countenance, especially if in the future there is also an effective treatment.

It a fascinating observation, albeit uncontrolled, that the prevalence of preeclampsia and fetal loss looks to be higher than normal in women in the Paris aHUS cohort who were known to have a complement mutation. This observation supports other studies suggesting that complement may play a role in the pathogenesis of preeclampsia. For instance, elevated maternal levels of the complement activation product Bb in early pregnancy associates with increased risk for preeclampsia.18

There is much still to be learned about the interplay between complement and pregnancy in health and disease. Studies such as those of Fakhouri et al. help us to identify the next set of questions needing answers.

Disclosures

T.H.J.G. is the UK chief investigator of trials of aHUS sponsored by Alexion and acts as a scientific advisor for Taligen Therapeutics and Laboratoire francais due fractionnement et des biotechnologies.

Footnotes

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

  • See related article, “Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations,” on pages 859–867.

  • Copyright © 2010 by the American Society of Nephrology

REFERENCES

  1. 1.↵
    1. Noris M,
    2. Remuzzi G
    : Atypical hemolytic-uremic syndrome. N Engl J Med 361: 1676–1787, 2009
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Sellier-Leclerc A-L,
    2. Fremeaux-Bacchi V,
    3. Dragon-Durey M-A,
    4. Macher M-A,
    5. Niaudet P,
    6. Guest G,
    7. Boudailliez B,
    8. Bouissou F,
    9. Deschenes G,
    10. Gie S,
    11. Tsimaratos M,
    12. Fischbach M,
    13. Morin D,
    14. Nivet H,
    15. Alberti C,
    16. Loirat C
    French Society of Pediatric Nephrology: Differential impact of complement mutations on clinical characteristics in atypical hemolytic uremic syndrome. J Am Soc Nephrol 18: 2392–2400, 2007
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Delvaeye M,
    2. Noris M,
    3. De Vriese A,
    4. Esmon CT,
    5. Esmon NL,
    6. Ferrell G,
    7. Del-Favero J,
    8. Plaisance S,
    9. Claes B,
    10. Lambrechts D,
    11. Zoja C,
    12. Remuzzi G,
    13. Conway EM
    : Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 361: 345–357, 2009
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Skerka C,
    2. Jozsi M,
    3. Zipfel PF,
    4. Dragon-Durey MA,
    5. Fremeaux-Bacchi V
    : Autoantibodies in haemolytic uraemic syndrome (HUS). Thromb Haemost 101: 227–232, 2009
    OpenUrlPubMed
  5. 5.↵
    1. Martinez-Barricarte R,
    2. Pianetti G,
    3. Gautard R,
    4. Misselwitz J,
    5. Strain L,
    6. Fremeaux-Bacchi V,
    7. Skerka C,
    8. Zipfel PF,
    9. Goodship T,
    10. Noris M,
    11. Remuzzi G,
    12. de Cordoba SR
    European Working Party on the Genetics of HUS: The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome. J Am Soc Nephrol 19: 639–646, 2008
    OpenUrlAbstract/FREE Full Text
  6. 6.↵
    1. Rodriguez de Cordoba S
    : aHUS: A disorder with many risk factors. Blood 115: 158–160, 2010
    OpenUrlFREE Full Text
  7. 7.↵
    1. Kaplan BS,
    2. Trompeter RS,
    3. Moake JL
    1. Saltiel C,
    2. Legendre C,
    3. Grunfeld JP,
    4. Descamps JM,
    5. Hecht M
    : Hemolytic uremic syndrome in association with pregnancy. In: Hemolytic Uremic Syndrome and Thrombotic Thrombocytopenic Purpura, edited by Kaplan BS, Trompeter RS, Moake JL New York, Marcel Dekker, 1992, pp 241–254
  8. 8.↵
    1. Caprioli J,
    2. Noris M,
    3. Brioschi S,
    4. Pianetti G,
    5. Castelletti F,
    6. Bettinaglio P,
    7. Mele C,
    8. Bresin E,
    9. Cassis L,
    10. Gamba S,
    11. Porrati F,
    12. Bucchioni S,
    13. Monteferrante G,
    14. Fang CJ,
    15. Liszewski MK,
    16. Kavanagh D,
    17. Atkinson JP,
    18. Remuzzi G
    : Genetics of HUS: The impact of MCP, CFH and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108: 1267–1279, 2006
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. Fakhouri F,
    2. Roumenina L,
    3. Provot F,
    4. Sallee M,
    5. Caillard S,
    6. Couzi L,
    7. Essig M,
    8. Ribes D,
    9. Dragon-Durey MA,
    10. Bridoux F,
    11. Rondeau E,
    12. Fremeaux-Bacchi V
    : Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J Am Soc Nephrol 21: 859–867, 2010
    OpenUrlAbstract/FREE Full Text
  10. 10.↵
    1. Weiner CP
    : Thrombotic microangiopathy in pregnancy and the postpartum period. Semin Hematol 24: 119–129, 1987
    OpenUrlPubMed
  11. 11.↵
    1. Bresin E,
    2. Daina E,
    3. Noris M,
    4. Castelletti F,
    5. Stefanov R,
    6. Hill P,
    7. Goodship THJ,
    8. 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 1: 88–99, 2006
    OpenUrlAbstract/FREE Full Text
  12. 12.↵
    1. Saland JM,
    2. Ruggenenti P,
    3. Remuzzi G
    Consensus Study Group: Liver-kidney transplantation to cure atypical hemolytic uremic syndrome. J Am Soc Nephrol 20: 940–949, 2009
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Nurnberger J,
    2. Witzke O,
    3. Opazo Saez A,
    4. Vester U,
    5. Baba HA,
    6. Kribben A,
    7. Zimmerhackl LB,
    8. Janecke AR,
    9. Nagel M,
    10. Kirschfink M
    : Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med 360: 542–544, 2009
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Kelly R,
    2. Arnold L,
    3. Richards S,
    4. Hill A,
    5. Bomken C,
    6. Hanley J,
    7. Loughney A,
    8. Beauchamp J,
    9. Khursigara G,
    10. Rother RP,
    11. Chalmers E,
    12. Fyfe A,
    13. Fitzsimons E,
    14. Nakamura R,
    15. Gaya A,
    16. Risitano AM,
    17. Schubert J,
    18. Norfolk D,
    19. Simpson N,
    20. Hillmen P
    : The management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab. Br J Haematol 2 11, 2010 [epub ahead of print]
  15. 15.↵
    1. Girardi G,
    2. Bulla R,
    3. Salmon JE,
    4. Tedesco F
    : The complement system in the pathophysiology of pregnancy. Mol Immunol 43: 68–77, 2006
    OpenUrlCrossRefPubMed
  16. 16.↵
    1. Aagaard-Tillery KM,
    2. Silver R,
    3. Dalton J
    : Immunology of normal pregnancy. Semin Fetal Neonatal Med 11: 279–295, 2006
    OpenUrlCrossRefPubMed
  17. 17.↵
    1. Johnson U,
    2. Gustavii B
    : Complement components in normal pregnancy. Acta Pathol Microbiol Immunol Scand 95: 97–99, 1987
    OpenUrl
  18. 18.↵
    1. Lynch AM,
    2. Murphy JR,
    3. Byers T,
    4. Gibbs RS,
    5. Neville MC,
    6. Giclas PC,
    7. Salmon JE,
    8. Holers VM
    : Alternative complement pathway activation fragment Bb in early pregnancy as a predictor of preeclampsia. Am J Obstet Gynecol 198: 385 e1–e9, 2008
    OpenUrlPubMed
PreviousNext
Back to top

In this issue

Journal of the American Society of Nephrology: 21 (5)
Journal of the American Society of Nephrology
Vol. 21, Issue 5
1 May 2010
  • 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 JASN.
Enter multiple addresses on separate lines or separate them with commas.
Pulling the Trigger in Atypical Hemolytic Uremic Syndrome: The Role of Pregnancy
(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
Pulling the Trigger in Atypical Hemolytic Uremic Syndrome: The Role of Pregnancy
Timothy H.J. Goodship, David Kavanagh
JASN May 2010, 21 (5) 731-732; DOI: 10.1681/ASN.2010030308

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Request Permissions
Share
Pulling the Trigger in Atypical Hemolytic Uremic Syndrome: The Role of Pregnancy
Timothy H.J. Goodship, David Kavanagh
JASN May 2010, 21 (5) 731-732; DOI: 10.1681/ASN.2010030308
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
    • Disclosures
    • Footnotes
    • REFERENCES
  • Info & Metrics
  • View PDF

More in this TOC Section

UP FRONT MATTERS

  • Missing Self and DSA—Synergy of Two NK Cell Activation Pathways in Kidney Transplantation
  • The Road Ahead for Research on Air Pollution and Kidney Disease
  • Ensuring the Equitable Advancement of American Kidney Health—the Need to Account for Socioeconomic Disparities in the ESRD Treatment Choices Model
Show more UP FRONT MATTERS

Editorials

  • Promoting Equity in Eligibility for Registration on the Kidney Transplantation Waiting List: Looking beyond eGFRcr
  • In Search of the Optimal Target for Phosphate Control: Episode 1
  • Animal Model of Pregnancy after Acute Kidney Injury Mirrors the Human Observations
Show more Editorials

Cited By...

  • Bivalent and co-operative binding of complement Factor H to heparan sulfate and heparin
  • Factor I Autoantibodies in Patients with Atypical Hemolytic Uremic Syndrome: Disease-Associated or an Epiphenomenon?
  • Attending Rounds: Microangiopathic Hemolytic Anemia with Renal Insufficiency
  • Google Scholar

Similar Articles

Related Articles

  • Pregnancy-Associated Hemolytic Uremic Syndrome Revisited in the Era of Complement Gene Mutations
  • PubMed
  • Google Scholar

Articles

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

Information for Authors

  • Submit a Manuscript
  • Author Resources
  • Editorial Fellowship Program
  • ASN Journal Policies
  • Reuse/Reprint Policy

About

  • JASN
  • ASN
  • ASN Journals
  • ASN Kidney News

Journal Information

  • About JASN
  • JASN Email Alerts
  • JASN Key Impact Information
  • JASN Podcasts
  • JASN 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 - 1046-6673 Online ISSN - 1533-3450

Powered by HighWire