A Phase III, Randomised, Single-site Trial on the Minimisation of Immunosuppression In Elderly Renal Transplant Recipients.

Older kidney transplant recipients are at increased risk of infection and death from infectious causes compared to younger transplant recipients, and despite knowledge of age related immunological changes, the immunosuppressive protocol for older recipients was not yet adjusted. Our provisional data suggest that standard dose immunosuppression in the older patients results in more infections and fewer rejection episodes. Achieving a better balance by reducing risk of infection would be highly desirable. Defining age-specific target drug levels and doses should therefore be tested in a formal trial to establish its validity.

Transplant recipients are especially at risk from viral and opportunistic infections; CMV is a particular problem, as infections can be both donor-derived or due to re-activation of latent virus in the recipient. In the transplant population, CMV infection can cause significant morbidity, including bone marrow suppression, pneumonitis, colitis, retinitis and encephalitis, and as a consequence, increased mortality. However, as this will be measured prospectively, it can also be utilised as a marker of the degree of ( over) immunosuppression in our patients.

There are no current recommendations regarding optimal dose or target drug levels, and importantly, no age-specific standards. This trial could provide some specific recommendations.

There is an increasing body of evidence that demonstrates age-related changes to the immune system, termed immunosenescence, characterized by reduced responsiveness to both newly and previously encountered antigens. In transplantation, it is thought that such immunosenescence may influence both the immune response of the recipient and the immunogenicity of the donor organ. Understanding if this is in any way related to physical frailty may be helpful in informing patients of risk of transplantation.

Donor-derived cell-free DNA (dd-cfDNA) detected in the plasma of transplant recipients has been increasingly reported as a noninvasive biomarker of acute rejection(AR)-with transplant organ damage leading to release of more of the donor DNA into the bloodstream. A recent systematic review showed that all but one of 48 relevant studies reported significant elevations of dd-cfDNA at the time of biopsy-proven AR (BPAR), with successful treatment of AR resulting in restoration of dd-cfDNA levels back to baseline. Furthermore, a rise in dd-cfDNA can be detected before the clinical manifestations of rejection, with elevated levels seen up to a month or more before diagnosis of BPAR in some studies. Using the stability of the marker( a lack of rise) as a means of customising therapy has not been attempted, and our study could provide the rationale for this strategy.