Below the Waterline—The Danger of De Novo Donor‐Specific HLA Antibodies

Advances in immunosuppression have dramatically lowered rates of acute cellular rejection but have impacted less on rates of long-term renal allograft survival (1). This could be because of (1) late immunoreactivity against the allograft, (2) the nephrotoxicity of calcineurin inhibitors and/or (3) the development of opportunistic infections. In this issue, Dr. Wiebe and coinvestigators from the University of Manitoba provide strong evidence for the importance of the first possibility by a longitudinal analysis of circulating HLA antibodies, renal histology and clinical outcome (2). Advances in solid phase multiplex assays have provided transplant physicians with an unprecedented ability to detect donor-specific HLA antibodies (DSAs). However, it has not been clear whether these ultrasensitive techniques to detect DSAs have any pathologic significance or clinical utility posttransplantation. Furthermore, the risk factors that predispose one patient to develop DSAs as compared to another have not been clearly defined. The paper byWiebe et al. sheds light on the pathologic significance of de novo DSA (dnDSA) and discusses potential risk factors for their development. The paper demonstrates that the detection of dnDSAs by sensitive solid-phase assays has adverse prognostic implications and raises several new questions. A major finding of the paper is that in a low-risk population on a modern immunosuppressive regimen (i.e. mainly Caucasian, primary transplant recipients with low panel reactive antibody levels) dnDSAs as detected by solid phase assays develop at a surprisingly high rate of 15% over a mean period of 6 years. Furthermore, the 10-year survival rate of patients with dnDSAs is inferior (59%) compared to patients that do not develop dnDSAs (96%). An obvious conclusion from these data is that the development of dnDSAs has poor prognostic implications and although this may be true, the challenge is to use this information. Should the development of dnDSAs be used as a standard endpoint in clinical immunomodulation trials as a potential marker of long-term dysfunction of an allograft? Although this may be a helpful approach to determine if one immunomodulatory approach may be more beneficial than another for a group of people, it is more difficult to know what to do when faced with a patient who has developed dnDSA. From the data in the paper, it is unclear whether every dnDSA has equal pathogenicity. The authors acknowledge that there seem to be groups of patients with different pathologic responses to the development of a dnDSA. Some patients experience acute allograft dysfunction and these patients seem to have higher rates of mixed cellular and antibody rejection as compared to a group of patients with stable allograft function and no dnDSA. Other patients have more indolent damage and these seem to have less activation of the complement system as evidenced by lower rates of diffuse C4d deposition and milder histologic evidence of rejection. Finally, some patients seem to have no allograft dysfunction as evidenced by stability of serum creatinine or lack of significant proteinuria and although these patients had no findings of rejection by light microscopy, they did have evidence of activation of the complement system as indicated by C4d staining and presence of mild peritubular capillaritis. The authors argue that although renal function may seem stable in these patients, the histologic changes suggest that progressive damage is occurring that will not remain clinically silent for long, a conclusion also reached in a study on 3-month protocol biopsies in sensitized patients (3). However, it seems that some patients can do quite well even after developing dnDSA. Thus, a future challenge is to identify and determine which antibodies are more pathogenic. Among the current approaches under evaluation to address this issue are tests for complement fixation (C1q) (4) and analysis of subclasses of IgG (5). One would expect that evidence of tissue injury would be valuable in this assessment either by morphology, immunopathology or gene expression (6). Other questions arise from this paper. How should patients that have developed dnDSA be treated? Randomized controlled clinical trials will be needed to reveal the optimal management and whether new immunosuppressive agents, eculizumab or belatacept, will be useful in treatment or prevention of chronic antibody-mediated rejection. Should allocation strategies be reevaluated in light of lowering rates of dnDSA production by better HLA-DR matching? This paper is an important first step in identifying the issues. Chronic antibody-mediated rejection is a challenge for diagnosis, because the disease evolves slowly (years), has fluctuating pathology (e.g. C4d) and has a variable course. Not all cases have detectable C4d or DSA at any particular time. Despite these limitations, it is clear that dnDSA can be the first sign to damage below the waterline in otherwise stable patients and deserves further attention by the transplant community.