Senescence in Chronic Kidney Disease

Официальное название

Senescence, Frailty, and Mesenchymal Stem Cell Functionality in Chronic Kidney Disease: Effect of Senolytic Agents

Обзор

The study goal is to assess the effect of senescent cell clearance on senescence burden, physical ability or frailty, and adipose tissue-derived mesenchymal stem cell (MSC) functionality in patients with chronic kidney disease (CKD).

Подробное описание

The proposed studies will examine cellular senescence and the effect of senolytic therapy on senescent cell burden, frailty, and adipose-derived mesenchymal stem cell function in individuals with diabetic chronic kidney disease.

Вмешательства

• Препарат Group 2: Dasatinib
  Dasatinib - take one 100 mg tablet by mouth once daily for 3 consecutive days.
• Препарат Group 2: Quercetin
  Quercetin - take four 250 mg capsules daily (total 1000 mg daily) for 3 consecutive days.

Первичные конечные точки

• Change in proportion of senescent cells (representing the total senescent cell burden) present [Срок оценки: Baseline, Day 14]

Вторичные конечные точки (4)

• Change in proportion of senescent mesenchymal stem cells present [Срок оценки: Baseline, Day 14]
• Change in mesenchymal stem cell function [Срок оценки: Baseline, Day 14]
• Change in Frailty index score [Срок оценки: Baseline, Day 14]
• Change in kidney function [Срок оценки: Baseline, Day 14, Month 4, Month 12]

Критерии участия

Критерии включения

• Age 40-80 years
• Chronic kidney disease estimated glomerular filtration rate (eGFR) 15-45 ml/min/1.73m2
• Diabetes mellitus and taking diabetes medications

Критерии исключения

• Concomitant glomerulonephritis,
• Nephrotic syndrome,
• Solid organ transplantation,
• Autosomal dominant or recessive polycystic kidney disease,
• Known renovascular disease,
• Pregnancy,
• Active immunosuppression therapy,
• Hemoglobin A1c≥10% at screening,
• History of active substance abuse (including alcohol) within the past 2 years,
• Current alcohol abuse (>3 alcoholic beverages/day or >21 per week),
• Body weight >150 kg or body mass index>50
• Human immunodeficiency virus infection
• Active hepatitis B or C infection
• Tyrosine kinase inhibitor therapy
• Known hypersensitivity or allergy to dasatinib or quercetin
• Inability to give informed consent
• Uncontrolled systemic lupus erythematosus
• Uncontrolled pleural/pericardial effusions or ascites
• New invasive cancer except non-melanoma skin cancers
• Invasive fungal or viral infection
• Inability to tolerate oral medications
• Total bilirubin>2x upper limit of normal
• Subjects taking medications that are sensitive to substrates or substrates with a narrow therapeutic range for CYP3A4, CYP2C8, CYP2C9, or CYP2D6 or strong inhibitors or inducers of CYP3A4 (e.g. cyclosporine, tacrolimus or sirolimus). If antifungals are absolutely necessary from an infectious disease perspective, then they will be allowed only if the levels are therapeutic.
• Subjects on strong inhibitors of CYP3A4.
• Subjects on therapeutic doses of anticoagulants (Warfarin (Coumadin);Rivaroxaban (Xarleto); Apixaban (Eliquis); Dabigatran (Pradaxa, Prazaxa) or Other).
• Subjects on antiplatelet agents ((Clopidogrel (Plavix); Dipyridamole + Asprin (Aggrenox); Ticagrelor (Brilinta); Prasugrel (Effient); Ticlopidine (Ticlid) or Other) who are unable or unwilling to reduce or hold therapy prior to and during the 3-day drug dosing. Subjects may continue their previous regimen on day 4.
• Subjects on quinolone antibiotic therapy for treatment or for prevention of infections within 10 days
• Subjects taking H2-antagonists or proton pump inhibitors and unwilling to discontinue therapy 1 week prior and 2 weeks following enrollment.
• Corrected QT interval (QTc)>450 msec
• Presence of any condition that the Investigator believes would put the subject at risk or would preclude the patient from successfully completing all aspects of the trial.

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

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 2 центра

• Mayo Clinic Florida — Jacksonville
• Mayo Clinic in Rochester — Rochester

Публикации

• Bian X, Snow ZK, Zinn CJ, Gowan CC, Conley SM, Bratulin AL, Elhusseiny KM, Miller J, Tchkonia T, Kirkland JL, Lerman LO, Hickson LJ. Activin A Antagonism with Follistatin Reduces Kidney Fibrosis, Injury, and Cellular Senescence-Associated Inflammation in Murine Diabetic Kidney Disease. Kidney360. 2025 Mar 28;6(8):1278-1291. doi: 10.34067/KID.0000000776. PMID 40152935
• Hickson LJ, Langhi Prata LGP, Bobart SA, Evans TK, Giorgadze N, Hashmi SK, Herrmann SM, Jensen MD, Jia Q, Jordan KL, Kellogg TA, Khosla S, Koerber DM, Lagnado AB, Lawson DK, LeBrasseur NK, Lerman LO, McDonald KM, McKenzie TJ, Passos JF, Pignolo RJ, Pirtskhalava T, Saadiq IM, Schaefer KK, Textor SC, Victorelli SG, Volkman TL, Xue A, Wentworth MA, Wissler Gerdes EO, Zhu Y, Tchkonia T, Kirkland JL. S PMID 31542391

Идентификаторы

NCT: NCT02848131 · 15-005843

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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