Demethylating Agent Azacitidine on Prevention of Acute Kidney Injury-chronic Kidney Disease Continuum
Status:
Not yet recruiting
Trial end date:
2024-08-30
Target enrollment:
Participant gender:
Summary
Acute kidney injury (AKI) is increasing worldwide in recent years and is a major risk factor
of chronic kidney disease (CKD). AKI, acute kidney disease (AKD) and CKD form a continuum
whereby initial kidney injury leads to ongoing renal injury and eventually end-stage renal
disease if no effective treatment is applied. Nevertheless, there are no useful
pharmacotherapies approved clinically for the treatment of AKI and subsequent CKD.
Our previous studies have confirmed that pericytes are the primary cell source of
scar-producing myofibroblasts. Furthermore, we had demonstrated that significant epigenetic
modification in transcriptome analysis of pericytes develops in different stage of AKI-CKD
continuum. These epigenetic memory made pericytes obtain proliferative and pro-fibrotic
phenotypes in activated status and persist in inactivated status. Demethylation by
azacitidine prevented AKI-CKD transition, and attenuated fibrogenesis induced by a second
adenine-AKI.
Azacitidine has been approved in the United States Food and Drug Administration and European
Union for treatment of adult acute myeloid leukemia (AML), particularly recommended
front-line treatment for older patients with acute myeloid leukemia who are not candidates
for intensive treatment regimens. Dosage of azacitidine in our clinical trial which is
calculated according to our previous study and other animal study and is lower than
chemotherapeutic dose. Low dose azacitidine has demethylation effect and less cytotoxicity.
CSA-AKI is the second commonest cause of AKI in ICU. We plan to initiate a double-blind
randomized controlled trial (RCT) to recruit CSA-AKI patients. The patients will be divided
as azacitidine group and placebo group. Patients in azacitidine group will receive three
doses of low dose azacitidine in one week when AKI is diagnosed. After that, we will follow
up their renal function and urine protein every three month. Primary composite outcomes
include a decline of at least 50% in the estimated GFR, an increase of urine
protein-creatinine ratio (UPCR) over 1000 mg/g, and the development of end stage renal
disease (ESRD). Secondary outcome is overall mortality.