Premature aging of both CD4 regulatory T (Treg) and CD4 responder-T (Tresp) cells in patients with end-stage renal disease (ESRD) is expected to affect the success of later kidney transplantation. Both T-cell populations are released from the thymus as inducible T-cell co-stimulator-positive (ICOS ) and ICOS recent thymic emigrant (RTE) Treg/Tresp cells, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS and ICOS RTE Treg/Tresp cells into ICOS  CD31 or ICOS  CD31 memory Treg/Tresp cells and examined whether diverging pathways affected the suppressive activity of ICOS and ICOS Treg cells in co-culture with autologous Tresp cells. Compared with healthy controls, we found an increased differentiation of ICOS RTE Treg/Tresp cells and ICOS RTE Treg cells through CD31 memory Treg/Tresp cells into CD31 memory Treg/Tresp cells in ESRD and dialysis patients. In contrast, ICOS RTE Tresp cells showed an increased differentiation via ICOS mature naive (MN) Tresp cells into CD31 memory Tresp cells. Thereby, the ratio of ICOS Treg/ICOS Tresp cells was not changed, whereas that of ICOS Treg/ICOS Tresp cells was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS and ICOS RTE Tresp cells proceeded, whereas that of ICOS RTE Treg cells ceased and that of ICOS RTE Treg cells switched to an increased differentiation via ICOS MN Treg cells. Consequently, the ratios of ICOS Treg/ICOS Tresp cells and of ICOS Treg/ICOS Tresp cells decreased significantly, reducing the suppressive activity of Treg cells markedly. Our data reveal that an increased tolerance-inducing differentiation of ICOS and ICOS Treg cells preserves the functional activity of Treg cells in ESRD patients, but this cannot be maintained during long-term renal replacement therapy.