Abu-Snieneh Asmahan, Gurt Irina, Abedat Suzan, Lotan Chaim, Glikson Michael, Shuvy Mony
Heart Institute, Cardiovascular Research Center, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Jesselson Integrated Heart Center, Shaare Zedek Medical Center and Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Front Nephrol. 2024 Aug 6;4:1385705. doi: 10.3389/fneph.2024.1385705. eCollection 2024.
Renal failure associated aortic valve calcification (AVC) is the result of hyperphosphatemia and hyperparathyroidism. Calcimimetics is an effective tool for management of secondary hyperparathyroidism. Our goal was to evaluate the effect of the medical intervention with calcimimetic R568 on the AVC process.
The experimental design consisted of administering a uremia-inducing phosphate-enriched diet to rats for six weeks. Rats received a daily R568 injection at different times. Biochemical analysis demonstrated increased urea (34.72 ± 3.57 . 5.18 ± 0.15 mmol/L, <0.05) and creatinine (293.93 ± 79.6 . 12.82 ± 1.56 µmol/L, <0.05). R568 treatment markedly reduced parathyroid hormone (PTH) levels in both treated groups (192.63 ± 26.85, 301.23 ± 101.79 . 3570 ± 986.63 pg/mL, <0.05), with no impact on serum calcium and phosphate. von Kossa staining showed increase in AVC in uremic rats compared to control (1409 ± 159.5 . 27.33 ± 25.83, <0.05). AVC was not affected by R568 in both groups (3343 ± 2462, 1593 ± 792 . 1409 ± 159.5, NS). Similarly, the inflammatory marker CD68 was elevated in uremic rats (15592 ± 3792 . 181.8 ± 15.29, <0.01), and was not influenced by R568 treatment (8453 ± 818.5, 9318 ± 2232 . 15592 ± 3792, NS). Runt-related transcription factor 2 (Runx2), the regulator of osteoblast differentiation, was upregulated in uremic rats (23186 ± 9226 . 3184 ± 2495), that accompanied by elevated levels of Osteopontin (158395 ± 45911 . 237.7 ± 81.5, <0.05) and Osteocalcin (22203 ± 8525 . 489.7 ± 200.6, <0.05). R568 had no impact on osteoblastic markers (Runx2: 21743 ± 3193, 23004 ± 10871 . 23186 ± 9226, NS; osteopontin: 57680 ± 19522, 137116 ± 60103 . 158395 ± 45911, NS; osteocalcin: 10496 ± 5429, 8522 ± 5031 . 22203 ± 8525, NS).
In an adenine-induced uremic rat model, we showed that short-term R568 therapy had no effect on AVC. Treatment with R568 decreased PTH levels but had no effect on high phosphate levels. Regression of AVC necessitates not only a decrease in PTH levels, but also a decline in phosphate levels. To achieve improved outcomes, it is advisable to consider administering a combination of R568 with other medications, such as calcium supplements or phosphate binders. Additional studies are required for further evaluation of the potential treatment of chronic kidney disease (CKD)-associated AVC.
肾衰竭相关的主动脉瓣钙化（AVC）是高磷血症和甲状旁腺功能亢进的结果。拟钙剂是治疗继发性甲状旁腺功能亢进的有效工具。我们的目标是评估拟钙剂R568的药物干预对AVC进程的影响。
实验设计为给大鼠喂食诱导尿毒症的高磷饮食六周。大鼠在不同时间接受每日一次的R568注射。生化分析显示尿素（34.72±3.57. 5.18±0.15 mmol/L，<0.05）和肌酐（293.93±79.6. 12.82±1.56 µmol/L，<0.05）增加。R568治疗显著降低了两个治疗组的甲状旁腺激素（PTH）水平（192.63±26.85，301.23±101.79. 3570±986.63 pg/mL，<0.05），对血清钙和磷无影响。冯·科萨染色显示，与对照组相比，尿毒症大鼠的AVC增加（1409±159.5. 27.33±25.83，<0.05）。两组中R568均未影响AVC（3343±2462，1593±792. 1409±159.5，无显著性差异）。同样，尿毒症大鼠的炎症标志物CD68升高（15592±3792. 181.8±15.29，<0.01），且不受R568治疗影响（8453±818.5，9318±2232. 15592±3792，无显著性差异）。成骨细胞分化调节因子 Runt相关转录因子2（Runx2）在尿毒症大鼠中上调（23186±9226. 3184±2495），同时骨桥蛋白（158395±45911. 237.7±81.5，<0.05）和骨钙素（22203±8525. 489.7±200.6，<0.05）水平升高。R568对成骨细胞标志物无影响（Runx2：21743±3193，23004±10871. 23186±9226，无显著性差异；骨桥蛋白：57680±19522，137116±60103. 158395±45911，无显著性差异；骨钙素：10496±5429，8522±5031. 22203±8525，无显著性差异）。
在腺嘌呤诱导的尿毒症大鼠模型中，我们发现短期R568治疗对AVC无影响。R568治疗可降低PTH水平，但对高磷水平无影响。AVC的消退不仅需要降低PTH水平，还需要降低磷水平。为了取得更好的效果，建议考虑将R568与其他药物联合使用，如钙剂或磷结合剂。需要进一步研究以评估其对慢性肾脏病（CKD）相关AVC的潜在治疗作用。
