Current Trends in Immunosuppressive Strategies After Renal Transplantation

The prognosis for graft survival following renal transplantation in the modern era is very impressive. This is well illustrated by Figure 1, from the Collaborative Transplant Study, which is a voluntary registry collecting data from participating units across the world. Although there is likely to be some positive selection bias, the number of patients whose data are analysed must mean that the results reflect current experience. As Figure 1 illustrates, there is a trend of early graft loss so that by six months post-grafting graft survival is approximately 93%, and after the end of the first year approximately 3% of grafts are lost annually.

This good performance means that it has become increasingly difficult to demonstrate any impact of new immunosuppressive agents (or combination of agents) on graft survival. In part, this is because only a proportion of graft losses is due to an immunologically mediated ‘rejection process’. It has become necessary to focus on early proxy measures that influence either graft survival – such as the rate of acute rejection – or factors such as dyslipidaemia or hypertension, which are likely to influence patient survival in the long term. As well as these quasi-hard end-points, there has been increasing interest in exploring the drug-associated side effects as well as other influences on the patient’s compliance with the invariably complex treatment regimens. In the large, pivotal, randomised controlled studies that form the basis for regulatory approval of the majority of immunosuppressive drugs used in chronic management, the rate at which patients discontinued the studies because of side effects varied from 3 to 17%.^1-3 These proportions may not reflect current experience as in trials any new symptoms are likely to be attributed to the ‘trial drug’, and so exaggerate the apparent sideeffect profile. However, there is little doubt that morbidity associated with therapy is considerable.

In the rest of this commentary I will draw attention to some of the critical issues currently influencing immunosuppressive strategies in renal transplant units. I will not cover agents used off-label, nor will I discuss agents that are not in widespread clinical use.

One key theme is that clinicians are now better placed than ever before to offer evidence-based tailoring of immunosuppressive therapy to fit any particular patient. A second general point is that, in the past, as new immunosuppressive agents were developed the approach was generally to add them to existing regimens while reducing the dose of the older agents. Many patients received a calcineurin inhibitor as well as anti-T-cell antibodies, or an antimetabolite as well as prednisolone. Currently, however, there is substantially more interest in reducing the immunosuppressive burden and attempting drug withdrawal.