Acute or Chronic Antibody-Mediated Rejection and Long-term Outcomes Following Transplantation

Reducing De Novo Donor-Specific Antibody Levels During Acute Rejection Diminishes Renal Allograft Loss

Everly MJ, Everly JJ, Arend LJ, et al
Am J Transplant. 2009;9:1063-1071

Anti-Human Leukocyte Antigen and Donor-Specific Antibodies Detected by Luminex Posttransplant Serve as Biomarkers for Chronic Rejection of Renal Allografts

Lachmann N, Terasaki PI, Budde K, et al
Transplantation. 2009;87:1505-1513

Summary

The first study, by Everly and colleagues, was a retrospective single-center analysis of 52 kidney transplant recipients with biopsy-proven acute rejection diagnosed between January 1, 2003, and October 1, 2007. Of these,16 (31%) tested positive for de novo donor-specific antibody (DSA) according to the Luminex Single Antigen bead assay.

Thirteen of 13 of those patients (81%) were also positive for the C4d stain. Univariate analysis of risk factors for graft loss demonstrated significance for black race, delayed graft function, cytotoxic panel-reactive antibody level > 20% (current) or > 50% (peak), de novo DSA, C4d positivity, and retransplantation. Multivariate analysis identified only de novo DSA detection (6.6-fold increase in risk for allograft loss; P = .02) to be significant. Patients with DSA at the time of acute rejection had a 5-year graft survival rate of 42%, compared with 89% in those without DSA (P = .005). Of the 3 graft losses in patients without DSA, all cases were positive for C4d, suggesting that donor-specific non-human leukocyte antigen (HLA) antibodies may have been responsible for allograft injury. Patients with a > 50% reduction in DSA within 14 days of diagnosis and treatment experienced better graft survival (P = .04).

On the basis of these findings, the authors concluded that the presence of de novo DSA detected during acute rejection is associated with reduced graft survival, but prompt DSA reduction was associated with improved graft survival. In addition, DSA alone and not C4d predicted allograft loss, suggesting that treatment of DSA is indicated regardless of C4d status.

The second study, conducted in Germany by Lachmann and colleagues, was also a retrospective single-center analysis of 1014 deceased donor kidney transplant recipients who had been monitored in a cross-sectional manner for the development of HLA antibodies using Luminex Single Antigen beads.

HLA antibodies were detected in 30% of patients (median of 5 years posttransplant with stable renal allograft function), whereas DSA was identified in 31% of antibody-positive patients. Patients were subsequently monitored for a mean of 5.5 years. Most (74%) of the HLA antibody was directed against class 1 antigens, and patients with HLA antibodies were younger, were more often female, had undergone retransplantation more frequently, and had a lower estimated glomerular filtration rate than patients who were HLA antibody negative.

Although the prevalence of HLA antibodies among patients with functioning grafts after 5.5 years of testing was 25%, 48% of patients with failed grafts were HLA antibody positive (P ≤ .001). The incidence of DSA was 21.2% in patients with failed grafts vs 6.0% in those with functioning grafts after 5.5 years of follow-up testing (P ≤ .001). The 5.5-year kidney graft survival rates for patients with DSA, those with non-DSA, and those without HLA antibodies were 49%, 70%, and 83%, respectively.

In a prospective analysis of 195 patients who had no detectable HLA antibody on repeated tests, the survival probability was 94% vs 79% among patients who developed de novo HLA antibody after the first testing (P = 0.05). In a multivariate Cox proportional hazards model, the hazard ratio for graft loss in the presence of HLA antibody was 3.1 (95% confidence interval, 2.3-4.1; P ≤ .001).

On the basis of these findings, the authors concluded that late production of HLA antibody is detrimental to graft outcome and that posttransplant HLA antibody monitoring may be indicated to improve long-term outcomes by identifying a population that might benefit from interventions that target antibody-mediated rejection.

The presence of donor-specific HLA antibody leading to a positive cross-match is associated with the highest risk for graft loss and is generally considered a contraindication to transplantation. Patients may develop preexisting antibodies because of previous sensitizing events (blood transfusion, pregnancy, previous transplant), antibody-mediated disease states, or certain types of infections.

The importance of antibody-mediated rejection has been fueled by advances in antibody detection (solid-phase assays such as enzyme-linked immunosorbent assay and Luminex flow beads); the introduction of C4dstaining of renal allograft biopsy specimens; and the implementation of new technologies directed against antibody/B lymphocytes, such as plasmapheresis, intravenous immune globulin, immunoabsorption with protein A, splenectomy, anti-B-cell agents (rituximab, alemtuzumab, rabbit antithymocyte globulin, bortezomib), and maintenance immunosuppressants, such as tacrolimus and mycophenolate.

Although anti-HLA antibodies appear to be the most immunogenic, major histocompatibility complex class 1 chain-related gene A antigens and minor histocompatibility antigens may also play a role in causing chronic allograft damage. Despite the development of novel and more potent immunosuppressive agents, the long-term graft survival of transplanted organs has improved only marginally in the past 2 decades. This observation may be partly explained by the discovery of the importance of humoral immunity as newer immunosuppressive regimens have become more effective at suppressing cellular immunity.

The above 2 studies clearly demonstrate the importance of monitoring for HLA antibody in general and DSA in particular, either in patients with acute rejection or in those with stable graft function years after transplantation. The ability to detect and potentially treat acute or chronic antibody-mediated rejection may provide the key for improving long-term outcomes after transplantation.

Abstract

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