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The impact of donor-specific anti-HLA antibodies on late kidney allograft failure

Nature Reviews Nephrology volume 8, pages 348–357 (2012)Cite this article

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Abstract

Despite improvements in outcomes of renal transplantation, kidney allograft loss remains substantial, and is associated with increased morbidity, mortality and costs. Identifying the pathologic pathways responsible for allograft loss, and the attendant development of therapeutic interventions, will be one of the guiding future objectives of transplant medicine. One of the most important advances of the past decade has been the demonstration of the destructive power of anti-HLA alloantibodies and their association with antibody-mediated rejection (ABMR). Compelling evidence exists to show that donor-specific anti-HLA antibodies (DSAs) are largely responsible for the chronic deterioration of allografts, a condition previously attributed to calcineurin inhibitor toxicity and chronic allograft nephropathy. The emergence of sensitive techniques to detect DSAs, together with advances in the assessment of graft pathology, have expanded the spectrum of what constitutes ABMR. Today, subtler forms of rejection—such as indolent ABMR, C4d-negative ABMR, and transplant arteriopathy—are seen in which DSAs exert a marked pathological effect. In addition, arteriosclerosis, previously thought to be a bystander lesion related to the vicissitudes of aging, is accelerated in ABMR. Advances in our understanding of the pathological significance of DSAs and ABMR show their primacy in the mediation of chronic allograft destruction. Therapies aimed at B cells, plasma cells and antibodies will be important therapeutic options to improve the length and quality of kidney allograft survival.

Key Points

  • Antibody-mediated rejection (ABMR) is now recognized as an underestimated culprit in many failing organs, superseding the historical dogma that calcineurin-inhibitor toxicity was the leading cause of graft failure

  • New populations of kidney transplant recipients with donor-specific anti-HLA antibodies (DSAs) have created new forms of disease and a new model for studying the natural history of ABMR

  • ABMR is a process that occurs at different time points with a continuum between acute and chronic damage

  • ABMR can be indolent but this muted form ultimately progresses to graft loss

  • Compelling evidence shows that C4d-negative ABMR does exist and produces injury to the graft

  • Arteriosclerosis is accelerated in ABMR and vasculitis may be associated with DSAs

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Figure 1: The natural history of antibody-mediated allograft deterioration.
Figure 2: Features of subclinical or indolent ABMR, which is typically diagnosed in protocol biopsies performed at 3 months or 1 year after transplantation in kidney transplant recipients who have preformed DSAs and are receiving potent immunosuppressive conditioning.
Figure 3: Fluctuations in C4d status during the first year after transplantation.
Figure 4: DSA-mediated acceleration of arteriosclerosis.

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Authors and Affiliations

  1. Department of Kidney Transplantation, Necker Hospital, UMR-S970, 75015, Paris, France

    Alexandre Loupy

  2. Department of Histolopathology, Georges Pompidou European Hospital, 26 rue Edouard Jacques, 75014, Paris, France

    Gary S. Hill

  3. Comprehensive Transplant Center, Kidney Transplant Program and Transplant Immunotherapy Program, Cedars-Sinai Medical Center, 8635 West 3rd Street, Suite 490W, Los Angeles, 90048, CA, USA

    Stanley C. Jordan

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The authors contributed equally to all aspects of this manuscript.

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Correspondence to Stanley C. Jordan.

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Competing interests

S. C. Jordan declares associations with the following companies: CSL Behring (grant/research support; patent holder/applicant), Genentech (grant/research support). The other authors declare no competing interests.

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Loupy, A., Hill, G. & Jordan, S. The impact of donor-specific anti-HLA antibodies on late kidney allograft failure. Nat Rev Nephrol 8, 348–357 (2012). https://doi.org/10.1038/nrneph.2012.81

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