RENAL OSTEODYSTROPHY AND VASCULAR CALCIFICATION

描述(申请人提供)：慢性肾脏疾病(CKD)是一种日益严重的流行病，与心血管疾病导致的非常高的死亡率有关。标准的心血管危险因素不能解释与慢性肾脏病相关的风险增加。在慢性肾脏病的研究中发现了新的危险因素：磷、血管钙化和成纤维细胞生长因子23(FGF23)都被纳入新的慢性肾脏病-矿物性骨病(CKD-MBD)综合征。CKD-MBD的原因是未知的，直到最近的进展源于这项申请的前一个资助期，并且没有针对心血管风险的治疗方法。在最初，CKD-MBD的特点是发展中的骨营养不良，刺激血管钙化和刺激循环中的骨细胞蛋白水平。我们发现，CKD-MBD是由于肾脏循环中Wnt抑制剂的产生增加和c-klotho功能的改变所致。在动脉粥样硬化和糖尿病刺激的血管钙化背景下的早期CKD模型中，我们发现残留肾脏中DKK-1的产生增加，循环中的DKK-1、硬化素和c-klotho增加。用单抗中和DKK-1可促进骨形成，纠正骨营养不良，防止CKD刺激的血管钙化(VC)，并增加主动脉和肾脏膜c-klotho的表达。此外，成骨转录因子RUNX2在主动脉中受到抑制，血管平滑肌收缩蛋白表达增加。血浆c-klotho和FGF23水平升高不受DKK-1中和影响，但FGF23水平经磷酸盐结合治疗后降至正常。磷酸盐结合疗法对血管钙化没有影响，但结合DKK-1抗体，完全治疗了CKD-2小鼠特有的CKD-MBD。目前应用的目的是询问在CKD早期治疗CKD-MBD是否改善心血管预后。在第一个目标中，我们将使用我们的血管钙化模型和Alport综合征小鼠模型来研究Wnt抑制剂DKK-1中和对血管僵硬的影响。目的二是研究Wnt抑制剂DKK-1中和对慢性肾功能不全患者存活和心功能的影响。在第三个目标中，将分析早期控制磷酸盐稳态和FGF23是否会增加中和Wnt抑制剂DKK-1治疗CKD-MBD的效果。拟议研究的成功完成将提供临床前的概念证据，证明治疗和预防CKD-MBD可以改善CKD患者的心血管结果，这是一项重大创新，为临床试验铺平了道路。

DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a growing pandemic associated with very high mortality rates due to cardiovascular disease. Standard cardiovascular risk factors do not account for the increased risk associated with CKD. Novel risk factors discovered in the study of CKD: phosphorus, vascular calcification, and fibroblast growth factor 23 (FGF23) are all incorporated in the new chronic kidney disease - mineral bone disorder (CKD-MBD) syndrome. The cause of the CKD-MBD was unknown until recent progress stemming from the previous funding period of this application, and there was no therapy addressing cardiovascular risk. In its inception, the CKD-MBD is characterized by a developing osteodystrophy, stimulation of vascular calcification and stimulation of osteocytic protein levels in the circulation. We have found that the CKD-MBD is caused by increased renal production of circulating Wnt inhibitors and changes in c-klotho function. In a model of early CKD in the background of atherosclerosis and diabetes stimulated vascular calcification, we demonstrated increased production of Dkk-1 in the remnant kidney and increased circulating Dkk-1, sclerostin and c-klotho. Neutralization of Dkk-1 by a monoclonal antibody stimulated bone formation rates, corrected the osteodystrophy, prevented CKD stimulated vascular calcification (VC), and increased the expression of membrane c-klotho in the aorta and kidney. In addition, the osteoblastic transcription factor, RUNX2 was inhibited in the aorta, and vascular smooth muscle contractile protein expression was increased. Increased plasma c-klotho and FGF23 levels were not affected by Dkk-1 neutralization, but FGF23 levels were reduced to normal by phosphate binder therapy. Phosphate binder therapy had no effect on vascular calcification, but combined with the Dkk-1 antibody the CKD-MBD as characterized in the CKD-2 mice was completely treated. The aims of the current application ask whether the treatment of the CKD-MBD in early CKD, improves cardiovascular outcomes. In aim one, the effects of neutralization of the Wnt inhibitor, Dkk-1, on vascular stiffness will be studied using our vascular calcification model and murine model of Alport's syndrome. In aim two, the effects of neutralization of the Wnt inhibitor, Dkk-1, on survival and cardiac function in CKD will be studied. In aim three, the question of whether, early control of phosphate homeostasis and FGF23 add to the effects of treating the CKD-MBD with neutralization of the Wnt inhibitor, Dkk-1, will be analyzed. The successful completion of the proposed studies will provide preclinical proof of concept that treatment and prevention of the CKD-MBD improves cardiovascular outcomes in CKD, a major innovation, paving the pathway to clinical trials.