The role of alloantibodies in causing hyperacute rejection after kidney transplantation was initially recognized in positive crossmatch recipients.1 Subsequently, the significance of preformed antibodies in organ transplantation was identified, and pretransplant measurement of these antibodies is now used as the main method to assess sensitization status.2
However, the importance of antibodies after transplantation was only recently defined. In the last decade, monitoring for such antibodies has gained more attention in the transplant community, given their association with chronic rejection and lower graft survival.3–5 HLA-specific antibodies are usually detectable by flow cytometric crossmatch or solid-phase immunoassays.
The frequency of anti-HLA antibodies detected after kidney transplantation is extremely variable—partly due to the timing posttransplant, presensitization status, and the measurement methods used—ranging between 1.6% and 60%.6
The presence of donor-specific antibodies (DSAs) is now widely used to support a diagnosis of antibody-mediated rejection (AMR), in conjunction with pathological evidence of immune-mediated injury and C4d deposition on allograft biopsy.7
Although some studies have suggested that posttransplant monitoring of patients for de novo anti-HLA antibodies might be helpful in predicting acute or chronic rejection8,9 and in identifying patients at risk for poor graft outcome,9–12 the role of such monitoring has not been established, nor have the appropriate therapies to remove detected antibodies been determined.
Predicting Acute Rejection
Gill et al screened 70 transplant recipients without preformed antibodies for the development of anti-HLA antibody at seven time points within the first posttransplant year.13 De novo DSA was found in 11 recipients but did not predate clinically evident rejection episodes. Therefore, detection of anti-HLA antibodies did not help to predict the risk of rejection in the study.
Cooper et al screened 244 kidney and kidney/pancreas recipients for de novo antibodies at 1, 6, 12, and 24 months (protocol screening) or when clinically indicated (non-protocol measurement).14 Only three of 19 patients with acute rejection had donor-specific antibody detected before the rejection episode, whereas 49 of 52 patients with DSA detected by protocol screening had no subsequent clinically apparent acute rejections.
The results of these studies suggest that periodic DSA screening is not an effective way to identify acute rejection risk in patients who do not have evidence of anti-HLA antibodies before transplantation.
A single-center study of a more frequent DSA screening protocol (Days 7, 14, 30, 60, 90, 120, 150, 180, 270, and 365) found contrary results, however.15 In the study, Piazza et al were able to identify donor-specific antibody one to 10 days before rejection in nine of 18 patients.
Multiple studies have investigated the association of donor-specific antibodies with graft outcome. Terasaki et al16 and Mao et al10 both reported inferior graft outcomes in patients who had DSA at various points after transplantation. Lachmann et al11 showed higher prevalence of DSA in patients with graft loss versus patients with functioning graft. These findings not only confirm the association of donor-specific antibodies with worse graft outcomes but also suggest that monitoring for DSA can identify patients at risk for graft loss.
However, in most studies, DSAs were checked either by retrospective analysis of stored sera or by single measurement of DSA and subsequent monitoring of clinical outcome. Moreover, patient clinical status at the time of antibody testing was not reported.
To overcome this problem and determine whether donor-specific antibody itself is responsible for poor outcomes or if the association of DSA with acute rejection is the major factor, Cooper et al compared graft outcomes in DSA-positive and DSA-negative patients without pretransplant donor-specific antibody.14 After excluding patients with acute rejection, the relationship between graft survival and donor-specific antibodies disappeared, suggesting that the negative effects of DSA on graft outcome were primarily due to previous or intercurrent clinically apparent acute rejection.
Conversely, Piazza et al reported worse kidney function and higher graft loss in patients with DSA regardless of acute rejection.15
Alloantibodies can be removed from the patient's circulation by plasmapheresis or immunoadsorption, and they can be suppressed by intravenous immunoglobulin, either alone or in combination with plasmapheresis.17–19 However, these treatments might not prevent de novo antibody production, and patients remain at increased risk for antibody rebound, especially if they experience infection or under-immunosuppression.
Newer therapeutic strategies combine these treatments with the anti-CD20 antibody rituximab20 or the proteasome inhibitor bortezomib,21,22 based on the rationale that depletion of B lymphocytes and plasma cells may reduce donor-specific antibody production.
Moreover, as complement activation plays an important role in the terminal effects of antibodies, addition of a monoclonal antibody such as eculizumab, which blocks complement activation, would be a reasonable addition to the currently established treatment.23 As more data are accumulated, a better understanding of how to construct treatment paradigms will emerge.
With emerging new therapies to reduce antibody level, screening and monitoring DSA strength might be more justified in the near future. Clinical trials assessing the effectiveness of immunosuppression protocols should include HLA antibody testing.
However, in nonsensitized kidney transplant recipients with relatively stable kidney function, the role of routine anti-HLA antibody monitoring is unclear, particularly considering the relatively low prevalence of donor-specific antibodies and the lack of effective treatment.
Patel R, Terasaki PI. Significance of the positive crossmatch test in kidney transplantation. N Engl J Med
Terasaki PI, Kreisler M, Mickey RM. Presensitization and kidney transplant failures. Postgrad Med J
Kerman RH, Orosz CG, Lorber MI. Clinical relevance of anti-HLA antibodies pre and posttransplant. Am J Med Sci 1997;313:275-278.
Christiaans MH, Overhof-de Roos R, Nieman F, van Hooff JP, van den Berg-Loonen EM. Donor-specific antibodies after transplantation by flow cytometry: relative change in fluorescence ratio most sensitive risk factor for graft survival. Transplantation
Monteiro F, Mineiro C, Rodrigues H, de Paula FJ, Kalil J. Pretransplant and posttransplant monitoring of anti-HLA class I IgG1 antibodies by ELISA identifies patients at high risk of graft loss. Transplantation Proc
Akalin E, Pascual M. Sensitization after kidney transplantation. Clin J Am Soc Nephrol 2006;1:433-440.
Racusen LC, Colvin RB, Solez K, et al. Antibody-mediated rejection criteria—an addition to the Banff 97 classification of renal allograft rejection. Am J Transplantation 2003;3:708-714.
Hourmant M, Cesbron-Gautier A, Terasaki PI, et al. Frequency and clinical implications of development of donor-specific and non-donor-specific HLA antibodies after kidney transplantation. J Am Soc Nephrol
Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplantation 2004;4:438-443.
Mao Q, Terasaki PI, Cai J, et al. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplantation 2007;7:864-871.
Lachmann N, Terasaki PI, Budde K, et al. Anti-human leukocyte antigen and donor-specific antibodies detected by Luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation
Lee PC, Zhu L, Terasaki PI, Everly MJ. HLA-specific antibodies developed in the first year posttransplant are predictive of chronic rejection and renal graft loss. Transplantation
Gill JS, Landsberg D, Johnston O, et al. Screening for de novo anti-human leukocyte antigen antibodies in nonsensitized kidney transplant recipients does not predict acute rejection. Transplantation
Cooper JE, Gralla J, Cagle L, Goldberg R, Chan L, Wiseman AC. Inferior kidney allograft outcomes in patients with de novo donor-specific antibodies are due to acute rejection episodes. Transplantation
Piazza A, Poggi E, Borrelli L, et al. Impact of donor-specific antibodies on chronic rejection occurrence and graft loss in renal transplantation: posttransplant analysis using flow cytometric techniques. Transplantation
Terasaki PI, Ozawa M, Castro R. Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplantation 2007;7:408-415.
Zachary AA, Montgomery RA, Ratner LE, et al. Specific and durable elimination of antibody to donor HLA antigens in renal transplant patients. Transplantation 2003;76:1519-1525.
Jordan SC, Tyan D, Stablein D, et al. Evaluation of intravenous immunoglobulin as an agent to lower allosensitization and improve transplantation in highly sensitized adult patients with end-stage renal disease: report of the NIH IG02 trial. J Am Soc Nephrol
Stegall MD, Gloor J, Winters JL, Moore SB, Degoey S. A comparison of plasmapheresis versus high-dose IVIg desensitization in renal allograft recipients with high levels of donor-specific alloantibody. Am J Transplantation 2006;6:346-351.
Beimler JH, Morath C, Schmidt J, et al. Successful deceased-donor kidney transplantation in crossmatch-positive patients with peritransplant plasma exchange and rituximab. Transplantation 2009;87:668-671.
Trivedi HL, Terasaki PI, Feroz A, et al. Abrogation of anti-HLA antibodies via proteasome inhibition. Transplantation
Everly MJ, Everly JJ, Susskind B, et al. Bortezomib provides effective therapy for antibody- and cell-mediated acute rejection. Transplantation 2008;86:1754-1761.
Stegall M, Diwan T, Burns J, et al. Prevention of acute humoral rejection with C5 inhibition. Paper presented at: American Transplant Congress; May 30-June 3, 2009; Boston, MA.