Greater Thymic Atrophy Correlates with More Rapid Progression of Chronic Kidney Disease

It is the nature of becoming older that diverse and quite different age-related conditions proceed in parallel, linked by the contributions of shared underlying mechanisms, such as chronic inflammation, or mitochondrial dysfunction. Individuals age at different rates, largely the result of lifestyle choices and environmental factor such as exposure to persistent pathogens such as herpesviruses. In any given individual, however, different aspects of aging often appear correlated, as they are the results of deeper processes of damage and dysfunction.

The thymus is a small organ in which thymocytes produced in the bone marrow mature into T cells of the adaptive immune system. Active thymic tissue is slowly replaced with fat over later life, and the declining production of new T cells contributes to the age-related dysfunction of an immune system consisting ever more of worn, exhausted, malfunctioning, and senescent cells. Chronic kidney disease is most often a downstream consequence of diabetes and/or raised blood pressure, but rising numbers of senescent cells in older individuals are implicated in the fine details of its pathology, such as fibrosis, the production of scar-like excess collagen deposition that is disruptive of tissue structure and function.

Consider a correlation between the degree of thymic involution and the severity and progression of chronic kidney disease. These are very different issues, but both impacted by mechanisms such as the chronic inflammatory signaling characteristic of old age. In today's open access paper, researchers present data illustrating this correlation in a study population with chronic kidney disease. Correlation doesn't necessarily imply any direction of causation; both issues might contribute to the other, or be more independent outcomes of shared underlying mechanisms. The researchers here favor the idea that immune dysfunction contributes to a worsened progression of chronic kidney disease, however.

Decreased thymic output predicts progression of chronic kidney disease

In this study, we explored the impact of T cell senescence on the renal prognosis and mortality of patients with chronic kidney disease (CKD). We found that decreased recent thymic emigrant (RTE) T cells, which corresponds to decreased thymic output, was associated with CKD progression and high mortality, and an increase in highly differentiated CD28-CD4+ T cells, which increases with age, tended to be associated with CKD progression. Thymic atrophy is a characteristic of an aging immune system and has been implicated in age-related diseases such as infection, malignancy, atherosclerosis, and CKD. However, epidemiologic data are limited in patients with non-dialysis-dependent CKD. To our knowledge, this is the first study to demonstrate the impact of decreased thymic output on renal prognosis and all-cause mortality in patients with non-dialysis-dependent CKD.

An immunological model has been constructed using epidemiological and immunological data to show that an age-related decrease in thymic output is associated with the development of infectious diseases and malignancies. Decreased RTE in renal transplant patients increases all-cause mortality. In dialysis patients, decreased RTE is associated with death caused by infection, and decreased naive T cell count due to thymic atrophy increase all-cause mortality. Furthermore, our results are consistent with previous findings showing that shorter telomeres in peripheral blood leukocytes worsen renal prognosis and mortality, because the decrease in naive T cell counts due to thymic atrophy is compensated by increased T cell division, thereby shortening telomeres.

There are three potential mechanisms by which decreased thymic output contributes to CKD progression and increased mortality. (a) Low thymic output reduces the diversity of TCR repertoire and may reduce the clearance of senescent cells by immune cells. (b) When the number of newly produced naive T cells decreases, homeostatic proliferation maintains the peripheral T cell count. However, homeostatic proliferation increases the percentage of dysfunctional memory-type T cells in mice. These T cells secrete inflammatory chemokines involved in chronic tissue inflammation, delay kidney tissue repair after acute kidney injury, and may be associated with CKD progression. (c) Thymic atrophy may reflect a systemic state of aging. As aging progresses, local and systemic inflammation induced by senescent-associated secretory phenotype (SASP) causes organ damage, which may cause thymic atrophy and decreases kidney function, and increase mortality. Conversely, the presence of CKD decreases thymic output, increasing the susceptibility to further progression of CKD and high mortality.


Let's make an ex vivo thymus.

Posted by: Matt at February 25th, 2023 1:40 PM

It boggles my mind that in 2023, 33 years after the first gene therapy trial, we still don't have a safe and effective way of targeting a gene therapy to the Thymus.

Posted by: Jimofoz at February 26th, 2023 7:21 AM

Why regenerate the thymus? Reprogramming other still replicating cells to take over thymic function is just around the corner.

Posted by: Jones at February 27th, 2023 5:09 AM

One question that has been concerning me and more so with these observations is how does low thymic activity effect the abilities of senolytics, i.e. D+Q, fisetin, etc., to clear senescent cells? Or do they work independently of the thymus and are perhaps even more important for folks with a declining thymus?
And, further, which best target senescent cells in the kidney?

Posted by: ShrinkingThymus at February 27th, 2023 5:12 PM
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