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The multifaceted role of complement in kidney transplantation

Nature Reviews Nephrology volume 14, pages 767–781 (2018)Cite this article

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Abstract

Increasing evidence indicates an integral role for the complement system in the deleterious inflammatory reactions that occur during critical phases of the transplantation process, such as brain or cardiac death of the donor, surgical trauma, organ preservation and ischaemia–reperfusion injury, as well as in humoral and cellular immune responses to the allograft. Ischaemia is the most common cause of complement activation in kidney transplantation and in combination with reperfusion is a major cause of inflammation and graft damage. Complement also has a prominent role in antibody-mediated rejection (ABMR) owing to ABO and HLA incompatibility, which leads to devastating damage to the transplanted kidney. Emerging drugs and treatment modalities that inhibit complement activation at various stages in the complement cascade are being developed to ameliorate the damage caused by complement activation in transplantation. These promising new therapies have various potential applications at different stages in the process of transplantation, including inhibiting the destructive effects of ischaemia and/or reperfusion injury, treating ABMR, inducing accommodation and modulating the adaptive immune response.

Key points

  • Complement activation in the donor, the graft and the recipient before, during and after transplantation is a major cause of damage to the kidney transplant.

  • Ischaemia and subsequent reperfusion of the graft is the most important mechanism that triggers complement activation; reperfusion is generally regarded as the most detrimental phase of the transplantation process.

  • Following transplantation, complement has a role in innate immunological and inflammatory processes that further damage the graft and result in a gradual decrease in its functional mass.

  • Complement-targeted strategies might have a role in optimizing graft quality as well as in the treatment of antibody-mediated rejection, induction of accommodation and modulation of the adaptive immune response.

  • Promising data from preclinical and clinical studies suggest that complement-targeted therapies could potentially become part of the standard of care for kidney transplantation.

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Fig. 1: Overview of the complement system.
Fig. 2: Hypothetical model of complement-related deterioration in kidney graft function.
Fig. 3: Ischaemia–reperfusion injury in glomerular capillaries.
Fig. 4: Ischaemia-related activation of the lectin pathway in the proximal tubule.
Fig. 5: Antibody-mediated rejection in peritubular capillaries.
Fig. 6: C4d formation and the reactivity of polyclonal anti-C4d antibodies.

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Acknowledgements

The authors thank Deborah McClellan for excellent editorial assistance before the manuscript was submitted. The European Community’s Seventh Framework Programme under the grant agreement n°602699 (DIREKT) has been a major contributor to the authors’ work, which was further supported by grant 2016-2075-5.1 and 2016–04519 from the Swedish Research Council (VR), and by the Deutsche Forschungsgemeinschaft (DFG) grant CRC1149 A01.

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Nature Reviews Nephrology thanks S. Jordan, D. Ricklin and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Authors and Affiliations

  1. Department of Transplantation, Skåne University Hospital, Malmö, Lund University, Lund, Sweden

    Ali-Reza Biglarnia

  2. Institute for Clinical and Experimental Trauma-Immunology, University Hospital of Ulm, Ulm, Germany

    Markus Huber-Lang

  3. Centre of Biomaterials Chemistry, Linnaeus University, Kalmar, Sweden

    Camilla Mohlin & Kristina N. Ekdahl

  4. Department of Immunology, Genetics and Pathology (IGP), Rudbeck Laboratory C5:3, Uppsala University, Uppsala, Sweden

    Kristina N. Ekdahl & Bo Nilsson

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All authors researched the data, made substantial contributions to discussions of the content, wrote the text and reviewed or edited the manuscript before submission.

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Glossary

Endotheliopathy

Disorder of the endothelial layer leading to morphological changes of the glycocalyx, exposure of intercellular adhesion molecules and changes in the global function of the endothelium.

Glycocalyx

A glycoprotein and glycolipid shield that protects the membranes of endothelial cells and other cell types.

Anaphylatoxin

A complement activation product that can induce a substantial inflammatory response. C3a, C4a and C5a are anaphylatoxins.

Nucleophile

A molecule that donates an electron pair to form a new covalent bond.

Inflammasome

A intracellular protein complex that upon activation induces the generation of IL-1β and inflammation.

Alloresponse

An immune response resulting from the recognition of antigens expressed on the surface of cells of non-self origin.

Endopeptidase

A proteolytic enzyme that cleaves peptide non-terminal bonds within a protein substrate.

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Biglarnia, AR., Huber-Lang, M., Mohlin, C. et al. The multifaceted role of complement in kidney transplantation. Nat Rev Nephrol 14, 767–781 (2018). https://doi.org/10.1038/s41581-018-0071-x

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