Advanced immunological T-cell ageing defined by a very low thymic function identifies patients with substantial increased risk for long-term mortality after kidney transplantation

M.G.H. Betjes, A.W. Langerak, M. Klepper, N.H.R. Litjens

Wednesday 13 march 2019

14:18 - 14:20h at Mauritszaal

Categories: Klinisch, Parallelsessie

Parallel session: Parallelsessie IV - Klinisch I

Background: End-stage renal disease is associated with premature ageing of the T-cell immune system. At the time of kidney transplantation the average biological age of the circulating T cell system is increased by 15-20 years over the calendar age, but inter-individual variation is substantial. The hypothesis was tested that advanced immunological T-cell ageing increases the long-term mortality risk after kidney transplantation.

Methods: Patients from a well-defined cohort (N=210), transplanted with a kidney from a living donor between 2010-2013, were included. All recipients received induction therapy with basiliximab and prednisone/MMF/tacrolimus. Circulating T cells were analyzed before, at 3, 6 and 12 months after transplantation. The number of CD31 expressing naive T cells (identifying recent thymic emigrants, a marker for thymic function), telomere length of CD4⁺and CD8⁺T cells and T-cell differentiation status were assessed by flow cytometry. The results were validated in a cohort of 180 kidney transplant recipients transplanted between 2007-2010.

Results: Thirty recipients (median age 63 year, range 26-78) died during follow-up until sept 2018. The absolute numbers of naive CD4⁺(living:258 cells/ul vs. deceased:101 cells/ul, p=0.001) and naive CD8⁺T cells (living:97 cell/ul vs. deceased:37 cells/ul, p=0.001) were significantly lower in the deceased group prior to transplantation. Numbers of naive CD31⁺T cells were inversely related with increasing age (r=0.56, p<0.001). However, the average numbers of naive CD4⁺CD31⁺and CD8⁺CD31⁺T cells in the deceased patient group was at the level of patients >75 years. In a multivariate proportional hazard analysis including recipient age, the number of naive CD4⁺T cells remained associated with all-cause mortality (HR 0.98, CI 0.98-0.99, p<0.001). The lowered number of naive CD4⁺T cells in the deceased patient group was primarily caused by a decreased thymic function (less CD31⁺naive T cells). In addition, a compensatory increase in CD31^-naive T cells, which is normally observed with age-related loss of thymic function, was not observed. Within the first year after transplantation, the number and characteristics of naive T cells remained remarkably stable. All other immunological parameters were not related to patient survival after transplantation.

Conclusions: Advanced immunological T-cell ageing at time of transplantation, defined by a severe reduction in thymic function, is highly associated with all-cause mortality after kidney transplantation.