未经证实:钙异常,磷,PTH,维生素D代谢,骨头,和血管钙化发生在慢性肾脏病矿物骨紊乱(CKD-MBD)。钙化病,涉及痛苦,溃疡性皮肤病变,也是与CKD-MBD相关的主要问题。没有高质量的医疗干预措施来解决这些临床问题。骨ASARM肽是矿化的强抑制剂,并通过抑制肠道的磷酸盐摄取来诱导低磷酸盐血症。我们假设用ASARM肽治疗CKD-MBD大鼠将逆转高磷酸盐血症,减少软组织钙化,预防钙化。
未经评估:为了检验我们的假设,我们评估了合成ASARM肽在接受5/6次全肾切除术(56NEPHREX)的大鼠中的作用,CKD-MBD的啮齿动物模型。所有大鼠均饲喂高磷酸盐饮食(2%Pi)以恶化矿物质代谢缺陷。血清钾的变化,磷酸盐,BUN,肌酐,PTH,评估FGF23和钙对28天ASARM肽输注的响应。此外,骨质量的变化,软组织钙化,ASARM肽处理后研究了肠Npt2b(Slc34a2)的表达。
未经ASSIGNED:接受ASARM肽治疗的56NEPHREX大鼠显示出高磷酸盐血症的重大改善,血尿素氮(BUN),和骨质量与车辆对照相比。此外,ASARM输注56NEPHREX大鼠显示肾脏改善,大脑,和心血管钙化。值得注意的是,与载体对照相比,ASARM肽输注可预防56NEPHREX大鼠皮下内侧血管钙化和钙化样病变的发生。
UNASSIGNED:ASARM肽输注可纠正高磷酸盐血症并改善血管钙化,肾钙化,脑钙化,骨质量,肾功能,56NEPHREX大鼠皮肤矿化异常。这些发现证实了我们的假设并支持ASARM肽治疗CKD-MBD患者的实用性。
Abnormalities in calcium, phosphorus, PTH, vitamin D metabolism, bone, and vascular calcification occur in chronic kidney disease mineral bone disorder (CKD-MBD). Calciphylaxis, involving painful, ulcerative skin lesions, is also a major problem associated with CKD-MBD. There are no quality medical interventions to address these clinical issues. Bone ASARM peptides are strong inhibitors of mineralization and induce hypophosphatemia by inhibiting phosphate uptake from the gut. We hypothesize treatment of CKD-MBD rats with ASARM peptides will reverse hyperphosphatemia, reduce soft-tissue calcification, and prevent calciphylaxis.
To test our hypothesis, we assessed the effects of synthetic ASARM peptide in rats that had undergone a subtotal 5/6th nephrectomy (56NEPHREX), a rodent model of CKD-MBD. All rats were fed a high phosphate diet (2% Pi) to worsen mineral metabolism defects. Changes in serum potassium, phosphate, BUN, creatinine, PTH, FGF23, and calcium were assessed in response to 28 days of ASARM peptide infusion. Also, changes in bone quality, soft-tissue calcification, and expression of gut Npt2b (Slc34a2) were studied following ASARM peptide treatment.
Rats that had undergone 56NEPHREX treated with ASARM peptide showed major improvements in hyperphosphatemia, blood urea nitrogen (BUN), and bone quality compared with vehicle controls. Also, ASARM-infused 56NEPHREX rats displayed improved renal, brain, and cardiovascular calcification. Notably, ASARM peptide infusion prevented the genesis of subdermal medial blood vessel calcification and calciphylaxis-like lesions in 56NEPHREX rats compared with vehicle controls.
ASARM peptide infusion corrects hyperphosphatemia and improves vascular calcification, renal calcification, brain calcification, bone quality, renal function, and skin mineralization abnormalities in 56NEPHREX rats. These findings confirm our hypothesis and support the utility of ASARM peptide treatment in patients with CKD-MBD.