Out of control: accelerated aging in uremia

Abstract

Next to a high morbidity, patients with end-stage renal failure (ESRD) suffer from a complex spectrum of clinical manifestations. Both the phenotype of patients with ESRD as well as the pathophysiology of uremia show interesting parallels with the general aging process. Phenotypically, patients with ESRD have an increased susceptibility for both cardiovascular as well as infectious disease and show a reduction in functional capacity as well as muscular mass (sarcopenia), translating into a high prevalence of frailty also in younger patients. Pathophysiologically, the immune dysfunction, telomere attrition and the presence of low-grade inflammation in uremic patients also show parallels with the aging process. System models of aging, such as the homeodynamic model and reliability theory of Gavrilov may also have relevance for ESRD. The reduction in the redundancy of compensatory mechanisms and the multisystem impairment in ESRD explain the rapid loss of homeodynamic/homeostatic balance and the increased susceptibility to external stressors in these patients. System theories may also explain the relative lack of success of interventions focusing on single aspects of renal disease. The concept of accelerated aging, which also shares similarities with other organ diseases, may be of relevance both for a better understanding of the uremic process, as well as for the design of multidimensional interventions in ESRD patients, including an important role for early rehabilitation. Research into processes akin to both aging and uremia may result in novel therapeutic approaches.

The Relevance of Geriatric Impairments in Patients Starting Dialysis: A Systematic Review

“…A significant percentage of patients accepted for RRT is now .75 years old, ranging from 17% to 45% (1). In addition, patients with ESRD are prone to accelerated aging (2). Underlying mechanisms, such as inflammation and microvascular damage, contribute to both decline of kidney function and development of impairment across other physiologic domains.…”

Aging and uremia: Is there cellular and molecular crossover?

“…As a group, ESKD patients have a morbidity and mortality profile similar to that of the geriatric population, and the pathophysiology of the uremic syndrome has interesting parallels with the aging process. Based on these thoughts it has been posited that kidney failure results in accelerated, pathological aging [1] . Indeed there are striking ana logies between the effects of aging and uremia on the structure and function of the heart and vasculature, with similar changes seen in pulse contour, pulse wave velocity, and impedance, and similar structural abno rmalities with wall thickening, decreased elastin, and increased collagen content [2] .…”

“…In the original study that developed this definition, 6.9% of participants ≥ 65-year-old were classified as frail; in a more recent study of dialysis patients 44% of those under 40yearold were found to be frail [10] . Cognitive impairment is also highly prevalent in the dialysisdepe ndent population and occurs in comparatively young patients [1,11] . Whilst much has already been written about the intriguing similarities that appear to exist between the aging process and CKD [1,8,12,13] , comparatively little work has been undertaken looking at the cellular and molecular hallmarks of aging in the context of the known evidence concerning uremiainduced cellular and molecular pathways.…”

“…Cognitive impairment is also highly prevalent in the dialysisdepe ndent population and occurs in comparatively young patients [1,11] . Whilst much has already been written about the intriguing similarities that appear to exist between the aging process and CKD [1,8,12,13] , comparatively little work has been undertaken looking at the cellular and molecular hallmarks of aging in the context of the known evidence concerning uremiainduced cellular and molecular pathways. Therefore in this review, in order to try and fill this perceived gap in the literature, we have first briefly outlined what the main cell death pathways are and by what means these processes interact with each other, followed by an analysis of published research concerning the mechanisms of aging and uremiainduced cell death and their common molecular pathways and cellular characteristics.…”

Clinical Trials Targeting Aging and Age-Related Multimorbidity

“…Deficits in functional outcomes, such as slower gait speed or lower cognitive function, may be important (22). Intermediate metabolic risk factors, such as impaired glucose tolerance, markers of inflammation, or renal insufficiency (23,24) and evidence of unhealthy behaviors, such as low physical activity or obesity (25), may also be considered.…”