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  • Review Article
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New insights into postrenal transplant hemolytic uremic syndrome

Nature Reviews Nephrology volume 7, pages 23–35 (2011)Cite this article

Subjects

Abstract

After renal transplantation, hemolytic uremic syndrome (HUS) may occur either as a recurrent or de novo form. Over the past decade, much effort has been devoted to elucidating the pathogenesis of atypical HUS (aHUS). Approximately 60–70% patients with aHUS have mutations in regulatory factors of the complement system or antibodies against complement factor H. The risk of post-transplant recurrence of aHUS depends on the genetic abnormality involved, and ranges from 15% to 20% in patients with mutations in the gene that encodes membrane cofactor protein and from 50% to 100% in patients with mutations in the genes that encode circulating regulators of complement. Given the poor outcomes associated with recurrence, isolated renal transplantation had been contraindicated in patients at high risk of aHUS recurrence. However, emerging therapies, including pre-emptive plasma therapy and anti-C5 component monoclonal antibody (eculizumab) treatment have provided promising results and should further limit indications for the risky procedure of combined liver–kidney transplantation. Studies from the past 2 years have demonstrated genetic abnormalities in complement regulators in 30% of renal transplant recipients who experienced de novo HUS after renal transplantation. This finding suggests that the burden of endothelial injury in a post-transplantation setting may trigger de novo HUS in the presence of mild genetic susceptibility to HUS.

Key Points

  • Mutations in genes that encode components of the alternative complement pathway (for example, CFH, CFI, MCP, C3 and CFB) and anti-complement factor H antibodies have been identified in 60–70% of patients with atypical hemolytic uremic syndrome (aHUS)

  • Mutations in genes that encode regulatory factors of the complement system (for example, CFH, CFI and MCP) have been identified in 30% of cases of de novo post-transplant hemolytic uremic syndrome (HUS)

  • The risk of aHUS recurrence after renal transplantation varies according to which factor is mutated: the risk is low (∼15%) for mutations in membrane cofactor protein and high (∼80%) for mutations in circulating proteins

  • Post-transplant recurrence of aHUS is associated with a poor outcome; therefore living-donor renal transplantation is currently not recommended in the setting of aHUS

  • The multitude of endothelial aggressors in the post-transplant setting may trigger de novo HUS in patients with mild genetic susceptibility to HUS

  • Innovative therapeutic avenues, including pre-emptive plasma therapy and anti-C5 antibody therapy are extremely promising for the prevention or cure of recurrent aHUS, and should limit the indications for combined liver–kidney transplantation

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Figure 1: Regulated and deregulated activation of the alternative complement pathway.
Figure 2: Paradigm for post-transplant HUS.
Figure 3: Flowchart of investigations that should be undertaken if a patient experiences de novo post-transplant HUS and/or subclinical TMA.

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Acknowledgements

The authors are grateful to M. Essig (Service de Néphrologie, CHU de Limoges, Limoges, France), B. Moulin (Service de Néphrologie et Hémodialyze, Hôpital Civil, Strasbourg, France) and E. Rondeau (Service de Néphrologie, Hôpital Tenon, Paris, France) for providing updated data on the outcomes of their patients transplanted under pre-emptive plasma therapy. We would also like to thank B. Hurault de Ligny (Service de Néphrologie, CHU de Caen, Caen, France), M. Lozano (Department of Hemotherapy and Hemostasis, Hospital Clinic Barcelona, Barcelona, Spain) and J. Nürnberger (University Duisburg-Essen, Essen, Germany) for providing updated data on the late outcomes of their patients treated with eculizumab. The renal transplant department of Hôpital Necker belongs to the Fondation Centaure Network, which supports clinical and basic research in organ transplantation.

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Authors and Affiliations

  1. Service de Transplantation Rénale Adulte, Université Paris Descartes, Hôpital Necker, 161 rue de Sèvres, F-75015, Paris, France

    Julien Zuber, Rebecca Sberro-Soussan & Christophe Legendre

  2. Service de Néphrologie, Hôpital Foch, 40 rue Worth, F-92150, Suresnes, France

    Moglie Le Quintrec

  3. Service de Néphrologie Pédiatrique, Université Paris7-Diderot, Hôpital Robert-Debré, 48 Boulevard Sérurier, F-75019, Paris, France

    Chantal Loirat

  4. Service d'Immunologie Biologique, Hôpital Européen Georges Pompidou, 20 rue Leblanc, F-75015, Paris, France

    Véronique Frémeaux-Bacchi

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  1. Julien Zuber
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  3. Rebecca Sberro-Soussan
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Contributions

All authors contributed substantially to the discussion of this article's content and reviewed/edited the manuscript before submission. J. Zuber and M. Le Quintrec researched data for the article and J. Zuber, C. Loirat, and V. Fremeaux-Bacchi wrote the article.

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Correspondence to Julien Zuber.

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Competing interests

J. Zuber and V. Frémeaux-Bacchi have received honoria from Alexion Pharmaceuticals for invited lectures. C. Loirat has received grant research support from Alexion Pharmaceuticals and has consulted for LFB Biotechnologies (as a member of the board of experts for the development of plasma-derived concentrated complement factor H). C. Legendre is a member of the French Advisory Board for Alexion Pharmaceuticals. M. Le Quintrec and R. Sberro-Soussan declare no competing interests.

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Zuber, J., Le Quintrec, M., Sberro-Soussan, R. et al. New insights into postrenal transplant hemolytic uremic syndrome. Nat Rev Nephrol 7, 23–35 (2011). https://doi.org/10.1038/nrneph.2010.155

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