Abstract
Cardiovascular calcification (CVC) is a progressive complication of chronic kidney disease and a predictor of CV events and mortality. The use of biomarkers to predict CV risk and activities of potential or current treatment drugs in these patients could have a crucial impact on therapeutic approaches. Our aim was to develop a novel assay for measurement of the rate of calcium phosphate crystallization in human plasma and provide a tool to evaluate the effects of crystallization inhibitors. The efficacy of inhibitors was determined by adding inhibitory compounds (polyphosphates, fetuin-A, sodium thiosulfate or citrate) to control samples. The assay was additionally validated for SNF472, an experimental formulation of phytate being developed for the treatment of calciphylaxis and CVC in patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD). The method was repeatable and reproducible. The plasma crystallization rate was reduced up to 80% in a concentration-dependent manner following treatment with inhibitors in vitro, among which SNF472 was the most potent. This method appears beneficial in evaluating and discriminating between inhibitory activities of compounds such as polyphosphates on calcium phosphate crystallization, which present a novel therapeutic approach to treat CVC in ESRD patients.
Highlights
Calcification is the normal process of calcium salt deposition in body tissues occurring due to the presence of supersaturated or metastable salt solutions in biological fluids[1, 2]
Since polyphosphates protect against crystallization and are the mainstay of Cardiovascular calcification (CVC) treatments[27, 29, 35,36,37], the key objective of this study was to develop a novel and rapid in vitro/ex vivo method to evaluate of calcium phosphate crystallization in plasma samples containing calcification inhibitors and validate its potential as a pharmacodynamic assay for use in both non-clinical and clinical settings
Validation of the spectrophotometric PD assay in human plasma
Summary
Calcification is the normal process of calcium salt deposition in body tissues occurring due to the presence of supersaturated or metastable salt solutions in biological fluids[1, 2]. Chronic kidney disease (CKD) and calciphylaxis are disorders that develop as a consequence of disturbances in calcium and phosphate metabolism, and involve inflammatory processes in which levels of circulating calcification inhibitors, such as fetuin-A3, matrix-Gla protein[4, 5], pyrophosphate and osteopontin, are reduced while promoters of calcification are increased. No approved therapies are currently available for the treatment or reduction of HAP accumulation in CVC, there are evidences from randomized clinical trials of decreasing the progression of CVC in ESRD These treatments include non-calcium-based phosphate binders to reduce hyperphosphatemia[14], as well as calcimimetics to treat sHPT15. Subsequent clinical studies demonstrated associations of this nanoparticle marker with CVC and mortality, graft failure after renal transplantation and aortic stiffness[32,33,34] This method lacked the ability to evaluate the effectiveness of potential therapeutic agents, such as polyphosphates (pyrophosphate, bisphosphonates or phytate). Since polyphosphates protect against crystallization and are the mainstay of CVC treatments[27, 29, 35,36,37], the key objective of this study was to develop a novel and rapid in vitro/ex vivo method to evaluate of calcium phosphate crystallization in plasma samples containing calcification inhibitors and validate its potential as a pharmacodynamic assay for use in both non-clinical and clinical settings
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