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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Inflammation; Frailty; Aging; Chronic Kidney Failure
• Intervention / Treatment: Biological: Blood sample; Behavioral: Geriatric assessment standardized

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Florent GUERVILLE, MD; Phone Number: +33 05 57 65 65 53; Email: florent.guerville@chu-bordeaux.fr

Study Locations

• France
  • Bordeaux, France, 33076
    • CHU de Bordeaux - Hôpital Pellegrin -
    • Contact: Lionel COUZI, MD, PhD; Phone Number: +33 0556796107; Email: lionel.couzi@chubordeaux.fr
    • Contact: Lionel COUZI, MD; PhD
  • Pessac, France, 33600
    • CHU de Bordeaux, Hôpital Xavier Arnozan- Gérontologie Clinique
    • Contact: Florent GUERVILLE, MD; Phone Number: +33 05 57 65 65 13; Email: florent.guerville@chubordeaux.fr
    • Contact: Florent GUERVILLE, MD
  • Toulouse, France, 31059
    • CHU de Toulouse - Hôpital Rangueil
    • Contact: Aliénor Galinier, MD; Phone Number: +33 0561323379; Email: galinier.al@chutoulouse.fr
    • Contact: Aliénor Galinier, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Diagnostic
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: 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	Biological: 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; Behavioral: 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)
Active Comparator: non frail patients; Patients will be considered non-fragile if they present 0 to 2 criteria	Biological: 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; Behavioral: 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)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
IL1	Single Molecule Array for IL1	at recruitment (up to 30 days)
IL18	LUMINEX for IL18 in patient's sera	at recruitment (up to 30 days)
inflammasomes genes	RT-qPCR for inflammasomes genes (NLRP3, NLRC4, NLRC5, AIM2, ASC, casp1, IL1b, IL18) expression among peripheral blood mononuclear cells	at recruitment (up to 30 days)
inflammasome platform	Assembly of the inflammasome platform will be measured in monocytes using intra-cellular staining of the ASC protein and flow cytometry	at recruitment (up to 30 days)
Weight	Frailty phenotype : Weight loss (unintentional, >4,5 kg during past year)	at enrollment (Day 0), at recruitment (up to 30 days)
Activity	Frailty phenotype : Physical activity <383 kcal/week (men) or <270 kcal/week (women), measured using a standardized questionnaire (IPAQ)	at enrollment (Day 0), at recruitment (up to 30 days)
Gait	Frailty phenotype : 4-meters gait speed, with sex and height-specific cutoffs	at enrollment (day 0), at recruitment (up to 30 days)
Handgrip strength	Frailty phenotype : Handgrip strength, measured using a dynamometer, with sex and BMI-specific cutoffs	at enrollment (day 0), at recruitment (up to 30 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comorbidity	Comorbidity : Cumulative Illness Rating Scale (CIRS-G score)	at recruitment (up to 30 days)
decline	Screening for intrinsic capacity decline : first step of ICOPE program, adapted to the study	at recruitment (up to 30 days)
Physical performance	Physical performance : Short Physical Performance Battery (SPPB) score. The SPPB (Short Physical Performance Battery) is the sum of scores on three criteria: the balance test, the walking speed test and the chair lift test. This test assesses an individual's physical performance. The sum of the scores for all the tests gives an overall performance score. A score below 8 indicates a risk of sarcopenia (or age-related muscular dystrophy).	at recruitment (up to 30 days)
Cognitive functions	Cognitive functions : Score Montreal Cognitive Assessment (MoCA) score The Montreal Cognitive Assessement (MoCA) is the most sensitive rapid assessment test, providing the most comprehensive evaluation (attention, concentration, executive functions, memory, language, capacitive-vesuo-constructive, abstraction, calculation, orientation) cognitive functions. It is tending to replace the MMSE in clinical practice. A score of 26 (25 if cultural level ≤3 = primary diploma = CEP) is considered abnormal.	at recruitment (up to 30 days)
Depression	Depression : Geriatric Depression Scale (GDS-15 score) 0 - 5 points: normal 5-10 points: mild to moderate depression 11-15 points: severe depression	at recruitment (up to 30 days)
Nutrition	Nutrition : Mini Nutritional Assessment (MNA score); 12-14 points: MNA score indicates normal nutritional status.; 8-11 points: the MNA score indicates a risk of malnutrition.; 0-7 points: MNA score indicates malnutrition.	at recruitment (up to 30 days)
Snellen test	Sensory functions : Snellen test for vision	at recruitment (up to 30 days)
ADL	Dependency in activities of daily living : Activities of Daily Living ADL The original ADL scale scores each of the 6 items in 0/1, with 1 corresponding to independence and 0 to dependence. The total score ranges from 0 to 6. An overall score can be calculated, ranging from 0 (totally dependent) to 6 (best possible independence).	at recruitment (up to 30 days)
Immunophenotyping	Immunophenotyping of peripheral lymphocytes, with a focus on proportions of naïve / central memory / effector memory / TEMRA cells, and markers of activation and senescence	at recruitment (up to 30 days)
CRP	Serum inflammatory markers : CRP	at recruitment (up to 30 days)
IL-6	Serum inflammatory markers : IL-6	at recruitment (up to 30 days)
MCP-1	Serum inflammatory markers : MCP-1	at recruitment (up to 30 days)
TNF	Serum inflammatory markers : TNF	at recruitment (up to 30 days)
sTNFR1	Serum inflammatory markers : sTNFR1	at recruitment (up to 30 days)
HHIES questionnaire	Sensory functions : Hearing Handicap Inventory for the Elderly Screening (HHIES) questionnaire for hearing. The higher the score, the greater the likelihood of hearing loss	at recruitment (up to 30 days)
IADL	Dependency in activities of daily living : IADL scores	at recruitment (up to 30 days)

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Florent GUERVILLE, MD, University Hospital, Bordeaux

Study record dates

Study Major Dates

• Study Start (Estimated): April 15, 2025
• Primary Completion (Estimated): February 15, 2027
• Study Completion (Estimated): February 15, 2027

Study Registration Dates

• First Submitted: January 22, 2025
• First Submitted That Met QC Criteria: March 14, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: March 14, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Keywords: Frailty; Kidney transplantation; Older persons; Inflammasomes; End-stage kidney disease; Immune aging; Chronic low-grade inflammation
• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Renal Insufficiency, Chronic; Frailty; Inflammation; Renal Insufficiency; Kidney Failure, Chronic
• Other Study ID Numbers: CHUBX 2022/31

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No