Senescence in Chronic Kidney Disease

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

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).

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.

Inclusion Criteria:

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

Exclusion Criteria:

1. Concomitant glomerulonephritis,
2. Nephrotic syndrome,
3. Solid organ transplantation,
4. Autosomal dominant or recessive polycystic kidney disease,
5. Known renovascular disease,
6. Pregnancy,
7. Active immunosuppression therapy,
8. Hemoglobin A1c≥10% at screening,
9. History of active substance abuse (including alcohol) within the past 2 years,
10. Current alcohol abuse (>3 alcoholic beverages/day or >21 per week),
11. Body weight >150 kg or body mass index>50
12. Human immunodeficiency virus infection
13. Active hepatitis B or C infection
14. Tyrosine kinase inhibitor therapy
15. Known hypersensitivity or allergy to dasatinib or quercetin
16. Inability to give informed consent
17. Uncontrolled systemic lupus erythematosus
18. Uncontrolled pleural/pericardial effusions or ascites
19. New invasive cancer except non-melanoma skin cancers
20. Invasive fungal or viral infection
21. Inability to tolerate oral medications
22. Total bilirubin>2x upper limit of normal
23. 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.
24. Subjects on strong inhibitors of CYP3A4.
25. Subjects on therapeutic doses of anticoagulants (Warfarin (Coumadin);Rivaroxaban (Xarleto); Apixaban (Eliquis); Dabigatran (Pradaxa, Prazaxa) or Other).
26. 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.
27. Subjects on quinolone antibiotic therapy for treatment or for prevention of infections within 10 days
28. Subjects taking H2-antagonists or proton pump inhibitors and unwilling to discontinue therapy 1 week prior and 2 weeks following enrollment.
29. Corrected QT interval (QTc)>450 msec
30. 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.