Chronic Kidney Disease and an Accelerated Aging of the Immune System
Chronic kidney disease leads to the state of end stage renal disease, kidney failure, and death. There are presently few options for effective treatment. Like many conditions, chronic kidney disease has a strong inflammatory component. Senescent cells in kidney tissue are implicated in the increasing fibrosis and declining kidney function exhibited by patients, as is the age-related decline of the immune system into an state of chronic inflammation. Kidney function is clearly very important to the function of organs and systems throughout the body, as demonstrated by the accelerated deterioration and increased mortality observed in chronic kidney disease patients.
It seems likely that the relationship between chronic kidney disease and inflammatory immune dysfunction is bidirectional. The degree to which this is mediated by senescent cells and their inflammatory secretions is unclear, but promising results have been achieved in animal studies based on the use of senolytic treatments capable of selectively destroying senescent cells. A human clinical trial is presently underway.
In today's open access paper, researchers ask whether addressing the decline of the immune system associated with chronic kidney disease might at least slow progression of this condition. That leads to a discussion of thymic involution as an important aspect of age-related immune system failure, and a catalog of some of the approaches to thymic regeneration that have been attempted over the past few decades. The thymus is where thymocytes mature into T cells of the adaptive immune system. The thymus atrophies with age, and the supply of new T cells is greatly diminished as a result. Absent reinforcements, the adaptive immune system becomes ever more dysfunctional. This is thought to be an important component of declining immune function in later life.
The chronic kidney disease (CKD) phenotype is very similar to premature ageing. Frailty, osteoporosis, muscle wasting, and cardiovascular disease occur at a younger age in CKD patients. Many factors such as oxidative stress, accumulation of uremic toxins, and inflammation are supposed to contribute to accelerated ageing. The immune system undergoes a similar premature ageing. Patients with end-stage renal disease (ESRD) frequently exhibit T cell lymphopenia and concomitantly have both a marked susceptibility for infections and a decreased response to vaccines suggesting a T cell immune defect. Finally, ESRD patients exhibit a low-grade inflammation status. This association is typical of the "inflammaging" state observed in elderly.
The term immune senescence clusters all the changes that occur in the immune system during ageing. Although this process mainly affects T lymphocytes, all aspects of innate and adaptive immunity are concerned. The ageing of the immune system is a more general concept including two different processes. The first one is what is specifically referred to by immune senescence, which is mainly linked to age-dependent thymic involution leading to reduced immune repertoire diversity and compounded oligo-clonal increase in memory immune cells. Sensitivity to infections, reduced vaccine immunity, and defect in tumour clearance observed in elderly are thought to be at least in part linked to these immune alterations. The second characteristics of aged immunity is inflammaging. Old age is associated with low-grade systemic inflammation. Chronic innate immune activation, pro-inflammatory cytokine profile secretion, and age-induced accumulation of self-reactive T cells contribute to age-related inflammation. Inflammaging is supposed to explain some degenerative disease associated with ageing.
Premature thymic involution is a key component of ESRD-associated immune senescence. It is reported that thymic output decreased with progression of CKD. Thymic output is comparable between 40-year-old uremic patients and 80 year-old non-uremic patients. Our group recently reported that, in ESRD patients, low thymic output was predictive of severe infections. The decrease in recent thymic emigrant cells could be the result of a reduction in the thymic output of naïve T cells and/or of a reduction in homeostatic proliferation. Premature loss of thymic function is likely to explain the decrease in naïve T cells in young patients with ESRD.
However, there are few data documenting potential causes for premature thymic involution during chronic kidney disease. Chronic inflammation is likely to markedly contribute to immune ageing. Of note, a recent study shows that C-reactive protein levels inversely correlates with naïve T cells in haemodialysis patients suggesting either that inflammation and immune senescence evolve in parallel or that one is driving the other one. Activation of innate immunity, characterised by monocyte activation and overproduction of inflammatory cytokines such as IL-6, is a key feature of the CKD immune system. Treating reversible source of inflammation is obviously a goal in CKD patients and such strategy may reduce premature ageing.
Immune senescence has deleterious consequences. Susceptibility to infection, premature cardiovascular disease, and increased cancer incidence are some of the most frequent and serious. A number of measures, from the simplest to the more complex, may be susceptible to reverse immune senescence, especially premature thymic involution.
Firstly, the impact of physical activity in maintaining thymic activity must not be neglected. It is one of the rare therapeutic strategies with consistent results in both animal and human studies. In an immunological ageing mouse model, 4 weeks of free-wheel running increased naïve T lymphocytes and reduced effector ratio of cytotoxic T lymphocytes. Concordant data also exist in humans. Physical activity is often reduced in CKD patients. Sedentary life, socio-economics conditions, comorbidities, and uremia-related asthenia contribute to the reduced physical activity. Although a large number of studies reported the beneficial effects of exercise in CKD patients, no data are available concerning the potential consequences on immune status. However, other benefits of physical exercise in ESRD patients have been largely reported and physical rehabilitation programs should be encouraged in these patients.
Secondly, many hormonal pathways play a role in thymic physiology. However, most of them are impaired during chronic renal failure. The IGF-1-GH pathway interferes with many aspects of thymus biology. The IGF-1-GH axis is profoundly altered in dialysis patients. ESRF patients have increased GH secretion, but normal IGF-1 concentrations, indicating GH resistance. This suggests that GH may be a therapeutic hope to reverse thymopoiesis defect in ESRD patients.
The effects of sex hormones on thymus are well-known. A number of studies demonstrated that sex steroid ablation delay or reverse thymus involution in both animals and humans. Surgical castration is obviously not a therapeutic option in humans, but LHRH analogues use is also associated with thymic rejuvenation. Nevertheless, some studies also suggest that castration-induced thymic rejuvenation is only transient and potentially hazardous. Despite some former results, the use of chemical castration to enhance thymic rejuvenation is consequently not a safe option.
Some cytokines may also promote thymic function. IL-7 is produced by both thymic stromal cells and bone marrow. IL-7 mediates lymphopoiesis of both T cells and B cells, and in the thymus, promotes proliferation, differentiation, and survival of thymocytes. Administration of IL-7 in mice expand both naïve and memory CD4 and CD8 peripheral T cells. IL-22 interacts with IL-2R on the surface of thymic epithelial cells and allows both survival and proliferation of thymocytes. IL-22 administration to mice having received total body irradiation increases both thymocytes and thymic epithelial cell recovery. Limitations in the therapeutic use of IL-22 are based on its dual effects, which strictly depend on the context. The pro-regenerative effects of IL-22 could be counterbalanced by its inflammatory and tumorigenic properties.
KGF belongs to the fibroblast growth factor family. This cytokine is involved in epithelial cell proliferation and differentiation in many tissues, including the thymus. KGF administration to mice enhance thymopoiesis and accelerate thymic recovery after irradiation.. In non-human primates, KGF enhances immune reconstitution after autologous hematopoietic progenitor cell transplantation. More recently, conflicting results made the benefits of KGF less clear. In HIV-infected patients, KGF was not effective in either improving thymic function or rising circulating CD4+ T cells.
Forced expression of FOXN1 in involuted thymus results in thymic regeneration with increased thymopoiesis and naïve T cell output. The structure of the regenerated thymus was very close to young thymus in terms of architecture and gene expression. These results suggests that up-regulation of FOXN1 is sufficient to reverse age-related thymic involution. Further, recombinant FOXN1 protein fused with cell-penetrating peptides increased the number of thymic epithelial cells and enhanced thymopoiesis after hematopoietic stem cell transplantation in mice. All together, these studies suggest that the FOXN1 axis research is a valuable strategy to reverse thymic involution. To date, there are no evaluation of FOXN1 expression during CKD.
The gut microbiota interferes with the immune system lifelong and its dysregulation results in inflammation. Whether microbiota interferes with immune senescence is challenging because the relative part of microbiota and health status are difficult to isolate. Moreover, even when dysbiosis may favour inflammation, inflammation may also promote dysbiosis asking the question of which came first. Dysbiosis is a hallmark of chronic kidney disease. Accumulation of uremic toxins in CKD causes substantial modifications in gut physiology. Evidence suggests that septic inflammation observed in ESRD is at least in part related to a shift toward more inflammatory microbiota.
In conclusion, premature thymic involution and chronic inflammation greatly contribute to increased morbidity and mortality in CKD patients. Mechanisms are likely to be multiple and interlinked. Even when the quest to fountain of youth is a pipe dream, there are many scientific opportunities to prevent or to, at least in part, reverse CKD-related immune senescence. Further studies should precisely define most important pathways driving premature immune ageing in CKD patients and best therapeutic options to control them.