Systemic Activation of Inflammasomes and Frailty in Older Candidates to Kidney Transplantation

Overview

Kidney transplantation (KT) benefit-risk ratio assessment is a challenge in a growing population of older patients with end-stage kidney disease. A pre-KT frailty phenotype has been found predictive of post-KT complications, but biological mechanisms of frailty are poorly known is these patients. Frailty is associated with chronic low-grade inflammation in the older general population, possibly through the inflammasome pathway. Our main objective is to assess if systemic activation of inflammasomes is associated with frailty in older candidates to KT.

Kidney transplantation (KT) benefit-risk ratio assessment is a challenge in a growing population of older patients with end-stage kidney disease. Chronic low-grade inflammation is a hallmark of biological aging and is associated with age-related diseases and frailty. Frailty is conceptually defined as an agerelated reduction in physiological reserve increasing vulnerability to stressors. A pre-KT frailty phenotype is associated with post-KT complications, including re-hospitalizations, delayed graft function, delirium and 5-year mortality. Taking pre-KT inflammation into account (serum level of CRP, IL6, sTNFR1) improves prediction of mortality on KT waiting-list, independently of comorbidity. Molecular and cellular pathways of this inflammation are poorly known, and may involve inflammasomes. Inflammasomes are intra-cellular protein complexes whose assembly, upon stress signals, triggers maturation and release of pro-inflammatory cytokines named interleukine (IL)-1 and IL-18. Inflammasomes are involved in locomotor, cognitive and immune aging in mice, and systemic expression of inflammasomes genes is associated with mortality in older humans. Data is lacking about systemic activation of inflammasomes in older patients with end-stage kidney disease. Our main objective is to assess if pre-KT systemic activation of inflammasomes is associated with frailty in older candidates to KT. We will measure systemic activation of inflammasomes in peripheral blood of older candidates to KT using cytokine bead-based multiplex assay, Single Molecule Array, intra-cytoplasmic staining, flow cytometry and RT-qPCR in peripheral blood mononuclear cells. Frailty will be measured using validated standardized criteria. A frailty phenotype is defined by at least 3 of the following criteria: weight loss, exhaustion, muscle weakness, low physical activity, low gait speed.