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Pharmacologic epigenetic modulators of alkaline phosphatase in chronic kidney disease

Mathias Haarhaus1, Dean Gilham, Ewelina Kulikowski

  • 1Division of Renal Medicine and Baxter Novum, Karolinska Institutet, Karolinska University Hospital, Stockholm Department of Clinical Chemistry, and Department of Experimental and Clinical Medicine, Linköping University, Linköping Diaverum Sweden AB, Stockholm, Sweden Resverlogix Corp. Research and Development, Calgary, Alberta, Canada Division of Nephrology and Hypertension, Harold Simmons Center for Kidney Disease Research and Epidemiology, University of California Irvine, Orange Nephrology Section, Tibor Rubin Veterans Affairs Medical Center, Long Beach Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, California, USA.

Current Opinion in Nephrology and Hypertension
|November 15, 2019
PubMed
Abstract

Insights

Epigenetic therapies targeting alkaline phosphatase (ALP) show promise for chronic kidney disease (CKD) patients. Modulating ALP may improve cardiovascular outcomes and reduce mortality in CKD by addressing multiple disease pathways.

Area of Science:

  • Nephrology
  • Cardiovascular Medicine
  • Epigenetics

Background:

  • Chronic kidney disease (CKD) is linked to premature aging, cardiovascular disease (CVD), and mortality due to metabolic dysregulation.
  • Conventional single-target treatments have not improved CKD patient outcomes.
  • Epigenetic interventions offer a novel approach to simultaneously target multiple CKD-related pathogenetic processes.

Purpose of the Study:

  • To review the role of alkaline phosphatase (ALP) as a predictor of CVD and mortality in CKD.
  • To explore the potential of epigenetic modulation of ALP for treating CVD and metabolic diseases in CKD.
  • To highlight the therapeutic promise of BET inhibitors, such as apabetalone, in managing cardiovascular risk in CKD patients.

Main Methods:

  • Review of experimental studies on epigenetic modulation of ALP using microRNAs and BET protein inhibition.
  • Analysis of clinical trial data for apabetalone in high-risk CVD patients, including those with CKD.
  • Examination of the association between ALP levels and cardiovascular/renal outcomes.

Main Results:

  • Experimental studies demonstrate that epigenetic modulation of ALP can be effective in treating CVD and metabolic diseases.
  • The BET inhibitor apabetalone has shown ALP-lowering potential in Phase II studies.
  • Apabetalone treatment in Phase II studies was associated with improved cardiovascular and renal outcomes in CKD patients.

Conclusions:

  • Alkaline phosphatase (ALP) is a significant predictor of CVD and mortality in the context of CKD.
  • Epigenetic modification of ALP presents a promising therapeutic strategy for CKD.
  • Targeting ALP epigenetically may simultaneously impact multiple pathogenic pathways, potentially improving cardiovascular outcomes in CKD patients.

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