BTS 2014 Report: Protecting the allograft – preventing and treating chronic antibody-mediated rejection

Maria Dalby reporting from the annual British Transplantation Society meeting in Glasgow by Anthony Dorling, King’s College London – Chronic rejection is a major cause of graft failure beyond one year post-transplantation. Premature loss of renal transplants has remained largely constant in recent years despite the introduction of new drugs and protocols [1]. Research carried out at the King’s College London centre under the supervision of Professor Tony Dorling suggests that targeting cellular rather than antibody-mediated mechanisms may be a rational approach to treating and preventing rejection and improving long-term outcomes.

Although graft half-lives have improved as a result of enhanced survival in the immediate post-transplant period, long-term graft attrition rates remain largely unchanged at around 6% annually [1]; in the UK, an estimated 3% of prevalent renal transplant patients return to dialysis each year [2]. The majority of cases of late graft failure are due to immune-mediated causes, including sensitisation and antibody-mediated microcirculation injury [3]. There is a wealth of data linking the development of DSA with graft failure, most importantly a study carried out at the Charité hospital in Berlin which monitored more than 1,000 renal transplant recipients over a median follow-up period of five years, and found that DSA produced even long after transplantation are detrimental to graft outcome [4]. However, it is important to bear in mind that the association between antibodies and chronic rejection is not the same as causation. Professor Dorling pointed out that whilst antibodies may be comparatively easy to measure, their presence is just the tip of a huge iceberg of underlying immune effector mechanisms. Based on this rationale, the team at King’s College London hypothesised that it may be possible to detect evidence of cellular mechanisms involved in antibody-mediated rejection. An initial cohort study involved 15 patients with evidence of sub-clinical antibody-mediated rejection in protocol biopsies. ELISPOT analysis of reactivity to interferon-gamma (IFNγ) produced by CD4+ T-cells in response to donor antigens showed that in 77% of samples where IFNγ was produced, this mechanism was found to be B-cell-dependent [5]. Patients were followed up for  three years post-biopsy and a strong correlation was found between functional deterioration of the graft and cell-mediated immune responses (p=0.032), whereas patients with no detectable donor-specific response remained stable at follow-up. A second cohort involved patients who had for-cause biopsies for proteinuria or increased creatinine levels. This study showed a similar pattern in the response to changes in the T-cell donor reactivity associated with late chronic antibody-mediated rejection, and suggested that targeting cellular immunity can be a means of stabilising graft dysfunction.

The literature contains a large number of reports on enhanced immunosuppressive protocols for stabilising graft function following antibody-mediated rejection. There is data from randomised clinical trials that demonstrate a clinical benefit of adding or substituting tacrolimus [6, 7], as well as a lack of benefit [8]. A number of retrospective studies have shown that adding rituximab is associated with improved outcomes [9-12] although Professor Dorling cautioned against potential publication bias in this series. Professor Dorling is the principal investigator of two randomised controlled multicentre studies which are currently in progress with the aim of documenting therapies that target cellular immunity, namely the OuTSMART study (tacrolimus and MMF) and the RituxiCAN-C4 study (rituximab). The results of these studies will play an important role for overcoming the significant clinical problem of premature graft loss, a problem which is not improving with time.

References

1.         Lamb, K.E., S. Lodhi, and H.U. Meier-Kriesche, Long-term renal allograft survival in the United States: a critical reappraisal. Am J Transplant, 2011. 11(3): p. 450-62.

2.         Ravanan, R., et al., Measures of care in adult renal transplant recipients in the United Kingdom (chapter 11). Nephrol Dial Transplant, 2007. 22 Suppl 7: p. vii138-54.

3.         Einecke, G., et al., Antibody-mediated microcirculation injury is the major cause of late kidney transplant failure. Am J Transplant, 2009. 9(11): p. 2520-31.

4.         Lachmann, N., et al., Anti-human leukocyte antigen and donor-specific antibodies detected by luminex posttransplant serve as biomarkers for chronic rejection of renal allografts. Transplantation, 2009. 87(10): p. 1505-13.

5.         Shiu, K.Y., et al., Chronic Antibody-Mediated Rejection: B-Cell Dependent Alloreactive IFN gamma-Producing CD4+ T Cells Could Be Used as a Biomarker To Determine Responsiveness to Therapy. American Journal of Transplantation, 2012. 12(Meeting abstract): p. 410-410.

6.         Chapman, J.R. and B.J. Nankivell, Nephrotoxicity of ciclosporin A: short-term gain, long-term pain? Nephrol Dial Transplant, 2006. 21(8): p. 2060-3.

7.         Meier, M., et al., Slowing the progression of chronic allograft nephropathy by conversion from cyclosporine to tacrolimus: a randomized controlled trial. Transplantation, 2006. 81(7): p. 1035-40.

8.         Jevnikar, A., et al., Five-year study of tacrolimus as secondary intervention versus continuation of cyclosporine in renal transplant patients at risk for chronic renal allograft failure. Transplantation, 2008. 86(7): p. 953-60.

9.         Billing, H., et al., Successful treatment of chronic antibody-mediated rejection with IVIG and rituximab in pediatric renal transplant recipients. Transplantation, 2008. 86(9): p. 1214-21.

10.        Fehr, T., et al., Rituximab and intravenous immunoglobulin treatment of chronic antibody-mediated kidney allograft rejection. Transplantation, 2009. 87(12): p. 1837-41.

11.        Kamar, N., et al., Incidence and predictive factors for infectious disease after rituximab therapy in kidney-transplant patients. Am J Transplant, 2010. 10(1): p. 89-98.

12.        Rostaing, L., et al., Treatment of symptomatic transplant glomerulopathy with rituximab. Transpl Int, 2009. 22(9): p. 906-13.