Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia
Daily peritoneal administration of sodium pyrophosphate in a dialysis solution prevents the development of vascular calcification in a mouse model of uraemia
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DOI：
10.1093/ndt/gfr039
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发表时间：
2011-10-01
影响因子：
6.1
通讯作者：
Massy, Ziad A.
中科院分区：
文献类型：
--
作者：
Riser, Bruce L.;Barreto, Fellype Carvalho;Massy, Ziad A.
背景终末期肾病（ESRD）患者的高心血管死亡率是提高预期寿命的重要障碍。该人群的独特之处在于血管钙化（VC）的显著发展和侵袭性恶化。焦磷酸盐（PPi）是一种内源性分子，似乎可以天然抑制软组织钙化，但在慢性肾病（CKD）和ESRD中可能会受到抑制。虽然PPi曾被认为是一种有前途的治疗药物，但它在循环中的半衰期很短，这限制了早期的研究。我们测试了通过每日腹膜透析（PD）缓慢、持续地使PPi进入循环和预防VC的可能性。药代动力学研究首先在5/6肾切除术导致肾损伤的大鼠中进行。然后在与CKD重叠的载脂蛋白E基因敲除小鼠模型中进行疗效研究。通过永久性腹膜导管在模拟PD的溶液中输送PPi，但不定时清除用过的透析液。vonKossa染色后进行半定量形态学图像处理，分离内部（内膜）和外部（假定为中膜）病变，用于确定主动脉根部钙化。与静脉推注相比，在PD溶液中递送PPi导致>4小时的更慢、延长的递送。接下来，疗效研究显示，PPi 6天/周PD模拟给药导致内膜和中膜病变中主动脉钙化的剂量依赖性抑制。还记录了对总主动脉钙化的剂量反应效应，在最高剂量下观察到完全抑制。如预期，观察到有限的腹膜导管相关炎症，包括安慰剂治疗对照组。这种炎症反应可能掩盖了较低水平的PPi特异性不良反应，但没有一个被掩盖。我们的研究结果表明，在PD期间给予PPi，可以预防VC的发展，并可能延长ESRD患者的生命。
Background. The high rate of cardiovascular mortality in patients with end-stage renal disease (ESRD) is a significant barrier to improved life expectancy. Unique in this population is the marked development and aggressive worsening of vascular calcification (VC). Pyrophosphate (PPi), an endogenous molecule, appears to naturally inhibit soft tissue calcification, but may be depressed in chronic kidney disease (CKD) and ESRD. Although once thought to be a promising therapeutic, PPi's very short half-life in circulation curtailed earlier studies. We tested the possibility that a slow, continuous entry of PPi into the circulation and prevention of VC might be achieved by daily peritoneal dialysis (PD).Methods. Pharmacokinetic studies were first carried out in rats with renal impairment resulting from a 5/6 nephrectomy. Efficacy studies were then performed in the apolipoprotein E gene knockout mouse model overlaid with CKD. PPi was delivered by means of a permanent peritoneal catheter in a solution simulating PD, but without the timed removal of spent dialysate. von Kossa's staining followed by semiquantitative morphological image processing, with separation of inside (intimal) and outside (presumed medial) lesions, was used to determine aortic root calcification.Results. In comparison to an intravenous bolus, delivery of PPi in a PD solution resulted in a slower, extended delivery over >4 h. Next, the efficacy studies showed that a 6-day/week PD-simulated administration of PPi resulted in a dose-dependent inhibition of aortic calcification in both intimal and medial lesions. A dose-response effect on total aortic calcification was also documented, with a full inhibition seen at the highest dose. A limited peritoneal catheter-related inflammation was observed, as expected, and included the placebo-treated control groups. This inflammatory response could have masked a lower level PPi-specific adverse effect, but none was observed.Conclusions. Our findings suggest potential for PPi, administered during PD, to prevent the development of VC and to potentially extend the life of ESRD patients.