Abstract
Chronic kidney disease impacts a large percentage of the global population. Chronic kidney disease-mineral bone disorder is the broad term describing alterations in key circulating factors involved in mineralization, ectopic calcification, and bone abnormalities. Cardiovascular complications, involving vascular calcification are one of the leading causes of death in this patient population. Plasma levels of pyrophosphate, a potent inhibitor of ectopic mineralization, are low in chronic kidney disease and end-stage kidney disease patients. These data suggest that correction of pyrophosphate levels could stand out as a crucial therapeutic goal to mitigate vascular calcifications and reduce cardiovascular mortality. The primary enzyme responsible for the generation of plasma pyrophosphate is ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We therefore evaluated INZ-701, a recombinant human ENPP1-Fc fusion protein, in an adenine-induced rat model of chronic kidney disease. Our investigation revealed that INZ-701 administration resulted in significantly lower levels of calcification in the vasculature and soft tissues. Moreover, INZ-701 treatment significantly prevented the osteoid volume increase observed in vehicle treated rats, addressing another critical clinical manifestation of chronic kidney disease-mineral bone disorder. These results underscore the potential of INZ-701 to reduce vascular calcification and bone mineralization abnormalities in chronic kidney disease.
Lay Summary
As the kidneys shut down, concentrations of minerals such as calcium and phosphate become imbalanced leading to calcification of blood vessels and weak bones. Calcification of the blood vessels leads to cardiovascular disease and is the leading cause of death for those with kidney failure. Here we describe a rat model of kidney failure that mimics key clinical symptoms. We show that treatment with INZ-701, a drug which prevents genetic forms of vascular calcification and weak bones, reduced calcification of blood vessels and bone abnormalities in a rat model of kidney failure.
Accepted manuscriptsAuthor notes
Present address: TOXPLUS Monitoring LLC, 677 Citadel Drive, Westmont, IL 60559, USA
Present address: Rallybio, 234 Church Street, Suite 1020, New Haven, CT 06510, USA.
