An integrated immunological-pharmacological approach to improve long-term allograft function

Improving the long-term outcome is the main challenge after kidney
transplantation, because 40% of the transplants are lost within 10 years. This
may be due to high intra-patient variability (IPV) to tacrolimus (Tac). It is
already known that 71% of the patients who lost their graft expressed a high
Tac IPV profile. Therefore, optimized exposure to Tac may improve renal
function and will inhibit the anti-donor immune response. Remarkably, the
connection between high Tac IPV profile and T-cell and B-cell functions leading
to graft lost is unknown. We hypothesize that low immunosuppression levels due
to high IPV profile triggers the expansion of memory T-cells and memory B-cells
resulting in the development of chronic renal allograft dysfunction (CRAD)
threatening transplant and patient survival. Identification of patients at risk
for CRAD will enable timely adjustment of immunosuppressive drugs aiming to
prevent graft loss after transplantation.

The main aims of the present study:
1. Define the causality between low immunosuppression, i.e. high IPV, and
anti-donor T-cell and B-cells immune responses
2. Set a robust benchmark for CRAD
3. Improve the knowledge of the biological mechanisms resulting in this CRAD

This is an investigator-driven, observational study investigating the
anti-donor T-cell and B-cell immune response 5-6 years after kidney
transplantation in relation to Tac IPV. Tac IPV between 6-12 months after
transplantation will be calculated and correlated with graft failure and
immunological parameters. The hypothesis is that a high Tac IPV leads to
periods of under-immunosuppression which triggers the expansion of
donor-specific T-cells and B-cells resulting in CRAD.

During a regular follow-up visit at the outpatient clinic between 5 and 6 years
after transplantation blood will be drawn to determine kidney function and
trough levels of immunosuppressive drugs as part of clinical care. At this same
time point additional blood will be sampled for the present study. No risk is
involved in participation of the study. The included patients do not benefit
from participation, even though they will contribute to identify patients at
risk to lose their graft due to CRAD in future.