Uremia-associated T-cell aging with regard to kidney transplantation

Abstract

The research described in this thesis focused on the prematurely aged T-cell compartment in end-stage renal disease (ESRD) patients, in the context of kidney transplantation (KT). Loss of renal function induces a pro-inflammatory environment which is strongly associated with immune deficiency. It is assumed that retention of uremic toxins and cytokines are underlying the oxidative stress and inflammation in ESRD patients. This causes chronic activation of the immune system, including T cells which results in a lymphopenic T-cell number and a dysfunctional T-cell immunity. The typical uremia-associated changes in the peripheral T-cell compartment are reminiscent of age related changes in healthy individuals. Recently, it has been demonstrated that the biological age of the peripheral T-cell system of ESRD patients is approximately 20 to 30 years older compared to an age-matched healthy individual. This prematurely aged immune system offers at least a partial explanation for the increased susceptibility for infections, reduced vaccination response, increased prevalence of malignancies and also constitutes a non-classical risk factor for cardiovascular diseases. KT is considered the best option to regain renal function for ESRD patients. However, immunosuppressive medication is needed to prevent rejection of the graft but introduces an increased risk for infections and cancers post-KT. Currently, immune suppressive medication is targeted on through levels of calcineurin inhibitors, mycophenolate mofetil (MMF) and fixed doses of steroids. However, over- and under immunosuppression is frequently observed. The degree of uremia-associated immunological ageing could be an important parameter in the assessment of the amount of immunosuppression needed, thereby leading to a strategy of personalized immune suppression. The clinical relevance of T-cell ageing in the field of allograft rejection and infections is examined in this thesis.