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

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат Blood sample
  * Immunophenotyping of peripheral lymphocytes, with a focus on proportions of naïve / central memory / effector memory / TEMRA cells, and markers of activation and senescence * Serum inflammatory markers : CRP, IL-6, MCP-1, TNF, sTNFR1 * Single Molecule Array for IL1 and LUMINEX for IL18 in patient's sera * RT-qPCR for inflammasomes genes (NLRP3, NLRC4, NLRC5, AIM2, ASC, casp1, IL1b, IL18) expression among peripheral blood mononuclear cells * Assembly of the inflammasome platform will be measure
• Поведенческое Geriatric assessment standardized
  * Exhaustion (2 standardized questions) * Physical activity \<383 kcal/week (men) or \<270 kcal/week (women), measured using a standardized questionnaire (IPAQ) * 4-meters gait speed, with sex and height-specific cutoffs * Handgrip strength, measured using a dynamometer, with sex and BMI-sp Comorbidity (CIRS-G score ) * Screening for intrinsic capacity decline (first step of ICOPE program, adapted to the study, ) * Physical performance (SPPB score ) * Cognitive functions (MoCA score ), * Depress

Первичные конечные точки

• IL1 [Срок оценки: at recruitment (up to 30 days)]
• IL18 [Срок оценки: at recruitment (up to 30 days)]
• inflammasomes genes [Срок оценки: at recruitment (up to 30 days)]
• inflammasome platform [Срок оценки: at recruitment (up to 30 days)]
• Weight [Срок оценки: at enrollment (Day 0), at recruitment (up to 30 days)]
• Activity [Срок оценки: at enrollment (Day 0), at recruitment (up to 30 days)]
• Gait [Срок оценки: at enrollment (day 0), at recruitment (up to 30 days)]
• Handgrip strength [Срок оценки: at enrollment (day 0), at recruitment (up to 30 days)]

Вторичные конечные точки (12)

• Comorbidity [Срок оценки: at recruitment (up to 30 days)]
• decline [Срок оценки: at recruitment (up to 30 days)]
• Physical performance [Срок оценки: at recruitment (up to 30 days)]
• Cognitive functions [Срок оценки: at recruitment (up to 30 days)]
• Depression [Срок оценки: at recruitment (up to 30 days)]
• Nutrition [Срок оценки: at recruitment (up to 30 days)]
• Snellen test [Срок оценки: at recruitment (up to 30 days)]
• ADL [Срок оценки: at recruitment (up to 30 days)]
• Immunophenotyping [Срок оценки: at recruitment (up to 30 days)]
• CRP [Срок оценки: at recruitment (up to 30 days)]
• IL-6 [Срок оценки: at recruitment (up to 30 days)]
• MCP-1 [Срок оценки: at recruitment (up to 30 days)]

Критерии участия

• Inclusion criteria:

• Age ≥ 70
• Patient candidate to kidney transplantation (during assessment for inscription on the waiting-list, or during waiting time after effective inscription), without absolute contraindication
• Free, informed and written consent signed by the participant and the investigator (at the latest, on the day of inclusion and before any examination required by the research).
• Person affiliated or beneficiary of a social security scheme
• Exclusion criteria:

• Inclusion in an industrial study refusing co-inclusion in our study
• Person under guardianship, assisted decision-making or under temporary guardianship

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Диагностика

Центры проведения

Франция · 3 центра

• CHU de Bordeaux - Hôpital Pellegrin - — Bordeaux
• CHU de Bordeaux, Hôpital Xavier Arnozan- Gérontologie Clinique — Pessac
• CHU de Toulouse - Hôpital Rangueil — Toulouse

Идентификаторы

NCT: NCT06887075 · CHUBX 2022/31

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗