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Background: Patients with end-stage renal disease (ESRD) have an impaired immune response with a prematurely aged T-cell system. Mitogen-activated protein kinases (MAPKs) including extracellular signal-regulated kinase (ERK) and p38, regulate diverse cellular programs by transferring extracellular signals into an intracellular response. T cell receptor (TCR)-induced phosphorylation of ERK (pERK) may show an age-associated decline, which can be reversed by inhibiting dual specific phosphatase (DUSP) 6, a cytoplasmic phosphatase with substrate specificity to dephosphorylate pERK. The aim of this study was to assess whether ESRD affects TCR-mediated signaling and explore possibilities for intervening in ESRD-associated defective T-cell mediated immunity. Results: An age-associated decline in TCR-induced pERK-levels was observed in the different CD4+ (P<0.05), but not CD8+, T-cell subsets from healthy individuals (HI). Interestingly, pERK-levels of CD4+ T-cell subsets from young ESRD patients were in between young and elderly HI. A differentiation-associated decline in TCR-induced ERK and p38 phosphorylation was observed in T cells, although TCR-induced p38 phosphorylation was not significantly affected by age and/or ESRD. Frequencies of TCR-induced CD69-expressing CD4+ T cells declined with age and were positively associated with pERK. In addition, an age-associated tendency of increased expression of DUSP6 was observed in CD4+ T cells of HI and DUSP6 expression in young ESRD patients was similar to old HI. Inhibition of DUSP6 significantly increased TCR-induced pERK-levels of CD4+ T cells in young and elderly ESRD patients, and elderly HI. Conclusions: TCR-mediated phosphorylation of ERK is affected in young ESRD patients consistent with the concept of premature immunological T cell ageing. Inhibition of DUSP6 specific for pERK might be a potential intervention enhancing T-cell mediated immunity in ESRD patients.

The number of elderly patients with end-stage renal disease (ESRD) has increased significantly during the last decade. Elderly ESRD patients are vulnerable to infectious complications because of an aged immune system. Additional immunological ageing effects may be derived from the uraemic environment and cytomegalovirus (CMV) latency. Elderly patients may be affected by these factors in particular, but data in this age group are limited. To assess the degree of immunological ageing and proliferative capacity of T lymphocytes, 49 elderly ESRD patients (defined as aged ≥ 65 years) on the renal transplantation waiting list were recruited and compared to 44 elderly healthy individuals (HI), matched for age and CMV serostatus. CMV latency was associated with more highly differentiated CD4+ and CD8+ T cells in both elderly HI and patients. Elderly CMV seropositive ESRD patients showed a substantial reduction in the number of naive CD4+ and CD8+ T cells compared with age- and CMV serostatus-matched HI. Elderly ESRD patients also showed significantly decreased numbers of central memory CD4+ and CD8+ T cells compared with HI, independently of CMV serostatus. In addition, thymic output and relative telomere length of both CD4+ and CD8+ T cells were decreased in CMV seropositive ESRD patients compared with HI. The proliferative capacity of T cells was similar for patients and HI. Elderly ESRD patients have an advanced aged T cell compartment when compared to age-matched healthy controls, which is driven mainly by CMV latency.