Background: The high cardiovascular morbidity and mortality in patients with end-stage kidney disease could be partially caused by extensive cardiovascular calcification. SNF472, intravenous myo-inositol hexaphosphate, selectively inhibits the formation and growth of hydroxyapatite. Methods: This double-blind, placebo-controlled phase 2b trial compared progression of coronary artery calcium volume score and other measurements of cardiovascular calcification by computed tomography scan during 52 weeks of treatment with SNF472 or placebo, in addition to standard therapy, in adult patients with end-stage kidney disease receiving hemodialysis. Patients were randomized 1:1:1 to SNF472 300 mg (n=92), SNF472 600 mg (n=91), or placebo (n=91) by infusion in the hemodialysis lines thrice weekly during hemodialysis sessions. The primary end point was change in log coronary artery calcium volume score from baseline to week 52. The primary efficacy analysis combined the SNF472 treatment groups and included all patients who received at least 1 dose of SNF472 or placebo and had an evaluable computed tomography scan after randomization. Results: The mean change in coronary artery calcium volume score was 11% (95% CI, 7–15) for the combined SNF472 dose group and 20% (95% CI, 14–26) for the placebo group ( P =0.016). SNF472 compared with placebo attenuated progression of calcium volume score in the aortic valve (14% [95% CI, 5–24] versus 98% [95% CI, 77–123]; P <0.001) but not in the thoracic aorta (23% [95% CI, 16–30] versus 28% [95% CI, 19–38]; P =0.40). Death occurred in 7 patients (4%) who received SNF472 and 5 patients (6%) who received placebo. At least 1 treatment-emergent adverse event occurred in 86%, 92%, and 87% of patients treated with SNF472 300 mg, SNF472 600 mg, and placebo, respectively. Most adverse events were mild. Adverse events resulted in discontinuation of SNF472 300 mg, SNF472 600 mg, and placebo for 14%, 29%, and 20% of patients, respectively. Conclusions: Compared with placebo, SNF472 significantly attenuated the progression of coronary artery calcium and aortic valve calcification in patients with end-stage kidney disease receiving hemodialysis in addition to standard care. Future studies are needed to determine the effects of SNF472 on cardiovascular events. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02966028.

Calcification is an undesirable disorder, which frequently occurs in the heart vessels. In general, the formation of calcific vascular lesions involves complex physicochemical and molecular events. Calcification (hydroxyapatite) is initiated by injury and is progressed by promoter factors and/or the deficit of inhibitory signals. Myo-inositol hexakisphosphate (phytate, InsP6) is found in organs, tissues and fluids of all mammals and exhibits an important capacity as a crystallization inhibitor of calcium salts in urine and soft tissues. The levels found clearly depend on the dietary intake but it can also be absorbed topically. In this paper, the capacity of InsP6 as a potential inhibitor of cardiovascular calcifications was assessed in Wistar rats. Three groups were included, a control group, an InsP6 treated group (subjected to calcinosis induction by Vitamin D and nicotine and treated with standard cream with a 2% of InsP6 as potassium salt) and an InsP6 non-treated group (only subjected to calcinosis induction). All rats were fed AIN 76-A diet (a purified diet in which InsP6 is undetectable). Animals were monitorized every 12 hours. After 60 hours of calcinosis treatment, all rats of the InsP6 non-treated group died and the rest were sacrificed. Aortas and hearts were removed. A highly significant increase in the calcium content of aorta and heart tissue was observed in the InsP6 non-treated rats (21 +/- 1 mg calcium/g dry aorta tissue, 10 +/- 1 mg calcium/g dry heart tissue) when compared with controls (1.3 +/- 0.1 mg calcium/g dry aorta tissue, 0.023 +/- 0.004 mg calcium/g heart dry tissue) and InsP6 treated (0.9 +/- 0.2 mg calcium/g dry aorta tissue, 0.30 +/- 0.03 mg calcium/g dry heart tissue) animals. Only InsP6 non-treated rats displayed important mineral deposits in aorta and heart. These findings are consistent with the action of InsP6, as an inhibitor of calcification of cardiovascular system.

The aim of this study was to assess the inhibitory action of phytate in formation of renal calculi. Hypertension (induced by nicotine) combined with hypercalcemia (induced by D vitamin) was used to induce calcification in renal tissue in male Wistar rats that were fed a purified phytate free diet. Phytate non-treated rats developed significant calcium deposits in kidneys and papillae, as well as in kidney tubules and vessels, whereas calcium deposits were absent in control and phytate treated rats. Fragments of hydroxyapatite (HAP) calculi exhibited the capacity to induce the growth of calcium salts on their surfaces. Presence of 1.5 mg/L of phytate in the synthetic urine inhibited the formation of calcium oxalate monohydrate on HAP renal calculi in normocalciuric conditions. The findings show that the action of phytate as a crystallization inhibitor takes place both in the intrapapillary tissue and urine.

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