Uremia-associated immunological aging is stably imprinted in the T-cell system and not reversed by kidney transplantation.

The uremia-induced inflammatory environment in end-stage renal disease (ESRD) patients is associated with premature T-cell aging resulting in a defective T-cell immunity. As kidney transplantation (KTx) reduces the pro-inflammatory environment, we hypothesized that KTx would rejuvenate the aged T-cell system. As aging parameters, we determined in 70 KTx recipients the differentiation status by immunophenotyping, thymic output by the T-cell receptor excision circle (TREC) content together with CD31(+) naïve T-cell numbers and the relative telomere length (RTL) as a measure for proliferative history at pre-KTx, 3, 6 and 12 months post-KTx. In addition, T-cell function was determined by measuring the proliferative capacity and percentages of cytokine-producing cells. Directly post-KTx, memory T-cell numbers were diminished but restored to pre-KTx values at 12 months, except for CD4(+) EM T cells. The RTL of (memory) CD4(+) and CD8(+) T cells did not change. In contrast, TREC content and CD31(+) naïve T-cell numbers were stable post-KTx although the RTL of naïve CD4(+) and CD8(+) T cells decreased implying homeostatic proliferation of naïve cells, in response to a temporary decrease in memory cells. The T-cell function was not improved post-KTx. Our findings demonstrate that the uremia-associated aged phenotype is stably imprinted in the T-cell system and not reversed by KTx.

Uremia causes premature ageing of the T cell compartment in end-stage renal disease patients.

BACKGROUND: End-stage renal disease (ESRD) patients treated with renal replacement therapy (RRT) have premature immunologically aged T cells which may underlie uremia-associated immune dysfunction. The aim of this study was to investigate whether uremia was able to induce premature ageing of the T cell compartment. For this purpose, we examined the degree of premature immunological T cell ageing by examining the T cell differentiation status, thymic output via T cell receptor excision circle (TREC) content and proliferative history via relative telomere length in ESRD patients not on RRT. RESULTS: Compared to healthy controls, these patients already had a lower TREC content and an increased T cell differentiation accompanied by shorter telomeres. RRT was able to enhance CD8+ T cell differentiation and to reduce CD8+ T cell telomere length in young dialysis patients. An increased differentiation status of memory CD4+ T cells was also noted in young dialysis patients. CONCLUSION: Based on these results we can conclude that uremia already causes premature immunological ageing of the T cell system and RRT further increases immunological ageing of the CD8+ T cell compartment in particular in young ESRD patients.

Terminally differentiated CD8+ Temra cells are associated with the risk for acute kidney allograft rejection.

BACKGROUND: End-stage renal disease (ESRD) is associated with T-cell dysregulation, leading to a variable degree of lymphopenia and increased T-cell differentiation. This may cause a relevant reduction in T-cell immunity, yielding a lowered risk for acute rejection (AR) of kidney allografts. METHODS: Before kidney transplantation, circulating CD4 and CD8 T-cell differentiation was established by determining the frequency of naive T cells, central memory and effector memory T cells, and the highly differentiated CD8 Temra cells. In addition, the frequency of differentiated T cells without expression of the costimulatory molecule CD28 was measured. RESULTS: In 47 patients of the 185 patients included, a biopsy-proven AR occurred. Compared with healthy controls, T cells of patients with ESRD were significantly more differentiated. Patients with AR showed the least signs of T-cell dysregulation with significantly more T cells, more naive T cells, and less terminal differentiation of memory T cells compared with nonrejecting patients. After multivariate analysis, only the frequency of terminally differentiated CD8 Temra cells (per percent, 4% decrease of risk [P=0.006]; per tertile, 34% decrease in risk [P=0.002]) and the number of human leukocyte antigen mismatches (per mismatch, 33% [P=0.005]) predicted the risk for AR. Functional analysis showed that CD8 Temra cells have a highly proinflammatory and cytotoxic profile. In vitro T-cell proliferation assays did not reveal a suppressor function of these cells. CONCLUSIONS: Advanced ESRD-related T-cell dysregulation that is associated with a relative increase of terminally differentiated CD8 Temra cells protects against AR after kidney transplantation.

Premature aging of circulating T cells in patients with end-stage renal disease.

Progressive loss of renal function is associated with a dysregulation of circulating T cells that may underlie their impaired T-cell immunity. Here we tested whether end-stage renal disease (ESRD)-related T-cell alterations are compatible with the concept of premature immunological aging. Younger patients (25-45 years old) with ESRD were found to resemble older healthy controls (60-80 years old) as they had a significant loss of naive T cells and a relative increase of memory T cells showing progressive terminal differentiation. A significant decrease in the content of T-cell receptor excision circles and telomere length in patients with ESRD confirmed these phenotypic data. The loss of naive T cells in patients with ESRD was associated with an excessive age-related decrease of recent thymic emigrants, indicating a premature decline in thymic function. Additionally, increased homeostatic proliferation of naive T cells was found in patients with ESRD, similar to that of older healthy individuals, with an increased susceptibility for activation-induced apoptosis. Therefore, both decreased thymic output and increased susceptibility of naive T cells for apoptosis may play a role in the loss of naive T cells in ESRD patients. Thus, our results are compatible with premature aging of the T-cell system of patients with ESRD comparable with that of healthy individuals 20-30 years older.

Differential effects of age, cytomegalovirus-seropositivity and end-stage renal disease (ESRD) on circulating T lymphocyte subsets.

The age- and cytomegalovirus (CMV)-seropositivity-related changes in subsets and differentiation of circulating T cells were investigated in end-stage renal disease (ESRD) patients (n = 139) and age-matched healthy individuals. The results show that CMV-seropositivity is associated with expansion of both CD4+ and CD8+ memory T cells which is already observed in young healthy individuals. In addition, CMV-seropositive healthy individuals have a more differentiated memory T cell profile. Only CMV-seropositive healthy individuals showed an age-dependent decrease in CD4+ naïve T cells. The age-related decrease in the number of CD8+ naïve T cells was CMV-independent. In contrast, all ESRD patients showed a profound naïve T-cell lymphopenia at every decade. CMV-seropositivity aggravated the contraction of CD4+ naïve T cells and increased the number of differentiated CD4+ and CD8+ memory T cells. In conclusion, CMV-seropositivity markedly alters the homeostasis of circulating T cells in healthy individuals and aggravates the T cell dysregulation observed in ESRD patients.