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

NCT ID: NCT06887075

Last Updated: 2025-03-20

Basic Information

• Recruitment Status: NOT_YET_RECRUITING
• Clinical Phase: NA
• Total Enrollment: 60 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-04-15
• Study Completion Date: 2027-02-15

Brief Summary

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.

Detailed Description

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.

Conditions

Chronic Kidney Failure; Frailty; Aging; Inflammation

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: DIAGNOSTIC
• Blinding Strategy: NONE

Study Groups

Frail Patients

Frailty will be measured clinically using reference criteria in the general population and validated in Kidney Transplantation (KT), i.e. predictive of post-KT complications: delayed recovery of graft function, graft function, early re-hospitalization, occurrence of post-operative confusion, mortality.

Fragile patients present at least 3 out of 5 criteria

Group Type: ACTIVE_COMPARATOR

Blood sample

Intervention Type: BIOLOGICAL

• 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 measured in monocytes using intra-cellular staining of the ASC protein and flow cytometry

Geriatric assessment standardized

Intervention Type: BEHAVIORAL

• 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 ),
• Depression (GDS-15 score ),
• Nutrition (MNA score )
• Sensory functions (Snellen test for vision, HHIES questionnaire for hearing) -- Dependency in activities of daily living (ADL and IADL scores)

non frail patients

Patients will be considered non-fragile if they present 0 to 2 criteria

Group Type: ACTIVE_COMPARATOR

Blood sample

Intervention Type: BIOLOGICAL

• 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 measured in monocytes using intra-cellular staining of the ASC protein and flow cytometry

Geriatric assessment standardized

Intervention Type: BEHAVIORAL

• 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 ),
• Depression (GDS-15 score ),
• Nutrition (MNA score )
• Sensory functions (Snellen test for vision, HHIES questionnaire for hearing) -- Dependency in activities of daily living (ADL and IADL scores)

Interventions

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 measured in monocytes using intra-cellular staining of the ASC protein and flow cytometry

Intervention Type: BIOLOGICAL

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 ),
• Depression (GDS-15 score ),
• Nutrition (MNA score )
• Sensory functions (Snellen test for vision, HHIES questionnaire for hearing) -- Dependency in activities of daily living (ADL and IADL scores)

Intervention Type: BEHAVIORAL

Eligibility Criteria

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

• Minimum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Hospital, Bordeaux

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Florent GUERVILLE, MD

Role: PRINCIPAL_INVESTIGATOR

University Hospital, Bordeaux

Locations

CHU de Bordeaux - Hôpital Pellegrin -

Bordeaux, France, France

CHU de Bordeaux, Hôpital Xavier Arnozan- Gérontologie Clinique

Pessac, France, France

CHU de Toulouse - Hôpital Rangueil

Toulouse, France, France

Countries

France

Central Contacts

Florent GUERVILLE, MD

Role: CONTACT

florent.guerville@chu-bordeaux.fr

05 57 65 65 53 ext. +33

Facility Contacts

Lionel COUZI, MD, PhD

Role: primary

lionel.couzi@chubordeaux.fr

0556796107 ext. +33

Florent GUERVILLE, MD

Role: primary

florent.guerville@chubordeaux.fr

05 57 65 65 13 ext. +33

Aliénor Galinier, MD

Role: primary

galinier.al@chutoulouse.fr

0561323379 ext. +33

Other Identifiers

CHUBX 2022/31

Identifier Type: -

Identifier Source: org_study_id