Demethylating Agent Azacitidine on Prevention of Acute Kidney Injury-chronic Kidney Disease Continuum

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.

Previous studies of the investigators have confirmed that pericytes are the primary cell source of scar-producing myofibroblasts. Furthermore, the investigators 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 clinical trial is calculated according to previous 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. The investigators 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, the investigators 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.