A Novel Approach to Phosphorus Lowering in Patients with Chronic Kidney Disease

描述（由申请人提供）：慢性肾脏疾病（CKD）非常普遍，与心血管疾病（CVD）密切相关。由于传统的CVD风险因素不能完全解释CKD和CVD之间的联系，因此很可能“非传统”风险 可能涉及CKD中改变的因素。在这些因素中，较高的血清磷（Pi）水平代表一个因果候选人，并可能是可修改的。 较高的血清Pi在动物中诱导动脉钙化、动脉僵硬和左心室肥大。在人类中也观察到类似的结果，较高的Pi水平也与人类CKD、CVD事件和死亡率的发展和进展相关。KDIGO国际临床实践指南建议在正常范围内靶向Pi，并建议使用口服磷结合剂（OPB）。然而，自从这些建议发表以来，研究一直表明，OPB对CKD 3-4期患者的PI降低效果最小，即使剂量和药丸负担非常高，也可能与伤害有关。相比之下，动物研究和人类的初步研究表明，烟酰胺（维生素B3）大大降低了血清Pi水平，并且每天只需1-2片就可以做到。烟酰胺通过不同的机制降低Pi。它不是结合Pi，而是通过下调关键的肠道Pi转运蛋白来阻断肠道Pi吸收。脂质药物烟酸含有烟酰胺和烟酸，我们已经证明它可以降低CKD患者的Pi。然而，单独的烟酰胺可能具有优势。与烟酸不同，它不会引起潮红、肝功能检查异常、高尿酸血症或胰岛素抵抗。烟酰胺在一般人群中有相当多的长期安全性数据，在美国可作为非处方膳食补充剂获得，费用约为2美元/患者/月。因此，烟酰胺可以提供一种容易获得、耐受性良好、廉价且方便的方法来降低CKD患者的血清Pi水平。 然而，烟酰胺降低CKD 3-4期患者Pi的疗效尚不清楚。此外，烟酰胺对矿物质代谢的其他组分（包括尿磷排泄和反调节激素FGF 23、PTH和骨化三醇）的影响尚不清楚。这些因素的变化可能会对CVD，CKD进展和骨骼健康产生影响。因此，烟酰胺尚未准备好在CKD患者中广泛临床使用。必须首先确定降低Pi的功效和对矿物质代谢的其他组分的影响。 我们提出了一项II期、随机双盲、安慰剂对照研究，在150例eGFR 20- 45 ml/min/1.73 m2的患者中进行，接受烟酰胺或安慰剂治疗6个月。我们的主要目的是确定（1）降低Pi的功效，（2）烟酰胺对矿物质代谢其他组分的影响，包括尿磷排泄和Pi调节激素。如果有效且耐受性良好，本研究将通过引入烟酰胺降低CKD 3-4期患者的Pi来快速改变标准治疗。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is highly prevalent and strongly associated with cardiovascular disease (CVD). Because traditional CVD risk factors do not fully explain the link between CKD and CVD, it is likely that "non-traditional" risk factors that are altered in CKD may be involved. Among such factors, higher serum phosphorus (Pi) levels represent a causal candidate, and may be modifiable. Higher serum Pi induces arterial calcification, arterial stiffness, and left ventricular hypertrophy in animals. Similar fidings are observed in humans, and higher Pi levels are also associated with the development and progression of CKD, CVD events and mortality in humans. The KDIGO international clinical practice guidelines recommend targeting Pi within the normal range and recommends using oral phosphorus binders (OPBs) to do so. However, since the recommendations were published, studies have consistently shown that OPBs have minimal efficacy for Pi lowering in CKD stage 3-4, even with very high doses and pill burden, and may be associated with harm. In contrast, animal studies and pilot studies in humans show that nicotinamide (vitamin B3) substantially lowers serum Pi levels, and can do so with only 1-2 pills/day. Nicotinamide reduces Pi through a different mechanism. Rather than binding Pi, it blocks intestinal Pi absorption by down-regulating a key intestinal Pi transporter. The lipid drug niacin contains both nicotinamide and nicotinic acid, and we have shown that it lowers Pi in CKD patients. However, nicotinamide alone may have advantages. Unlike niacin, it does not cause flushing, liver test abnormalities, hyperuricemia, or insulin resistance. Nicotinamide has considerable long-term safety data in the general population, is available over the counter as a dietary supplement in the US, and would cost about $2/patient/month. Thus, nicotinamide may provide a readily available, well-tolerated, inexpensive, and convenient method to lower serum Pi levels in patients with CKD. However, the efficacy of nicotinamide for Pi lowering in CKD stage 3-4 is unknown. Moreover, the effects of nicotinamide on other components of mineral metabolism including urine phosphorus excretion and counter- regulatory hormones FGF23, PTH, and calcitriol are unknown. Changes in these factors may have their own influences on CVD, CKD progression, and bone health. Thus, nicotinamide is not yet ready for widespread clinical use in CKD patients. The efficacy for Pi lowering and effects on other components of mineral metabolism must first be established. We propose a phase 2, randomized double blind placebo controlled study among 150 patients with eGFR 20-45ml/min/1.73m2 treated with nicotinamide or placebo for 6 months. Our primary aims are to determine (1) the Pi lowering efficacy, (2) the effects of nicotinamide on other components of mineral metabolism including urine phosphorus excretion and Pi regulatory hormones. If effective and well tolerated, this study will rapidly alter the standard of care by introducing icotinamide for Pi lowering in CKD stage 3-4.