Senescence in Chronic Kidney Disease

Study Overview
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Brief Summary
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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).

Detailed Description
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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.

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

Conditions
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Chronic Kidney Disease

Intervention / Treatment
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* Drug: Group 2: Dasatinib
* Drug: Group 2: Quercetin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 40-80 years Chronic kidney disease estimated glomerular filtration rate (eGFR) 15-45 ml/min/1.73m2 Diabetes mellitus and taking diabetes medications Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Group 1: Observational<br>Observational Only | |
| Active Comparator: Group 2: Dasatinib & Quercetin<br>The drugs dasatinib and quercetin will be used in this arm | Drug: Group 2: Dasatinib<br>* Dasatinib - take one 100 mg tablet by mouth once daily for 3 consecutive days.<br>* Other names: Sprycel;Drug: Group 2: Quercetin<br>* Quercetin - take four 250 mg capsules daily (total 1000 mg daily) for 3 consecutive days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in proportion of senescent cells (representing the total senescent cell burden) present | Assessment of senescence markers in skin, fat, and/or blood at baseline and day 14. | Baseline, Day 14 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in proportion of senescent mesenchymal stem cells present | Assessment of senescence markers in mesenchymal stem cells at baseline and day 14. | Baseline, Day 14 | 
| Change in mesenchymal stem cell function | Assessment of functional studies in mesenchymal stem cells at baseline and day 14. Number of subjects with change in stem cell function related to treatment. | Baseline, Day 14 | 
| Change in Frailty index score | Assessment by Fried and other frailty criteria at baseline and day 14. | Baseline, Day 14 | 
| Change in kidney function | Assessment by estimated and measured glomerular filtration rate at baseline, day 14, month 4, and month 12. | Baseline, Day 14, Month 4, Month 12 |