Kidney Week

Abstract: SA-PO252

Correction of Paradoxical Mineralization in Murine CKD-MBD by ENPP1 Enzyme Biologics

Session Information

• CKD-MBD: Basic and Translational
  October 26, 2024 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 501 Bone and Mineral Metabolism: Basic

Authors

• Kato, Hajime, Yale University Department of Pathology, New Haven, Connecticut, United States

Hajime Kato, MD, PhD

• Kim, Hana, Yale University Department of Pathology, New Haven, Connecticut, United States

Hana Kim, APN

• Ishaq, Tayyaba, Yale University Department of Pathology, New Haven, Connecticut, United States

Tayyaba Ishaq, MS

• Sims, Dominique, Yale University Department of Pathology, New Haven, Connecticut, United States

Dominique Sims

• Srivastava, Shivani, Yale University Department of Pathology, New Haven, Connecticut, United States

Shivani Srivastava, PhD

• Stabach, Paul, Yale University Department of Pathology, New Haven, Connecticut, United States

Paul Stabach

• Carpenter, Thomas, Yale University Department of Pediatrics, New Haven, Connecticut, United States

Thomas Carpenter, MD

• O'Neill, W. Charles, Emory University Renal Division, Atlanta, Georgia, United States

W. Charles O'Neill, MD

• Braddock, Demetrios, Yale University Department of Pathology, New Haven, Connecticut, United States

Demetrios Braddock, MD, PhD

Background

Chronic Kidney Disease-Mineral & Bone Disorder (CKD-MBD) is a mineralization disorder characterized by medial arterial calcifications and loss of bone mass, a physiologic process known as ‘Paradoxical Mineralization’. Reduced plasma pyrophosphate (PPi) levels in CKD patients suggest a role for the enzyme producing PPi, ENPP1, in the pathogenesis of this condition.

Methods

To induce CKD-MBD, mice were placed on a high phosphate, high calcium, low magnesium diet with alternating adenine (0.15%, 0.2%, or 0.3%) for 33 weeks, after the method of Jia et al. (BMC Nephrology 2013, 14:116). Following the development of renal failure, animals were dosed weekly with either vehicle or soluble (S-) or bone-targeted (BT-) ENPP1-Fc. At 33 weeks, calcifications in the aorta, subcutaneous tissue, and heart were quantitated chemically, by weight, and by micro-CT, respectively. Bone mineralization was assessed using biomechanical testing of femurs and micro-CT analysis of tibial microarchitecture.

Results

The mice on the adenine diet showed progressive renal failure, characterized by elevated BUN and reduced plasma PPi levels. Both S- and BT-ENPP1 reduced aortic and subcutaneous calcification, comparable to the non-CKD control mice (Fig). Biomechanical testing showed improvements in maximum load, post-yield, and total work in both treatment groups compared with the vehicle CKD cohort. Micro-CT analysis showed improvement in trabecular number and spacing in the ENPP1-treated CKD cohort compared with the vehicle CKD controls. Finally, vehicle-treated CKD mice demonstrated an inverse correlation of vascular calcifications with bone mineralization parameters.

Conclusion

Our studies demonstrate that a modified version of the alternating adenine diet reproduces paradoxical mineralization in CKD-MBD which can be treated with an ENPP1 enzyme therapy, supporting the hypothesis that PPi deficiency may be a pathogenic mechanism driving the paradoxical mineralization in CKD-MBD.

Subcutaneous calcifications of CKD-MBD cohorts at 33 weeks

Funding

• NIDDK Support