Long-term metabolic effects of kidney events with intensive SBP control

一项具有里程碑意义的研究--收缩压干预试验（SPRINT）表明， 收缩压（SBP）降低（SBP目标<120 vs <140 mmHg）降低了死亡风险， 无糖尿病但心血管风险高的人群中的主要心血管事件。在最近的一份出版物中， 我们注意到，SPRINT中SBP的强烈降低导致肾小球滤过率的相对平均下降， 6个月时的滤过率（eGFR）（强化vs标准）为− 3.31 ± 0.30 mL/min/1.73 m2。重症 SBP组发生慢性肾脏病（CKD）的风险也高3.5倍。 控制糖尿病心血管风险的行动血压（ACCORD-BP）试验使用了2 × 2 析因设计，以测试与SPRINT相同的SBP干预以及强化与标准血糖 对照组（糖化血红蛋白<6% vs 7.0 - 7.8%）2型糖尿病（T2DM）患者。在我们 ACCORD-BP数据分析，强化组与标准SBP组的比较显示， 在ACCORD-BP中，加强SBP干预导致更明显的早期平均eGFR下降， CKD的累积发病率相对于SPRINT的增加更大（交互作用p值<0.001）。 由于血压降低导致的eGFR下降可能具有明显的临床和公众影响。 与其他条件导致的eGFR下降相比，我们假设 与内源性肾病的进展有关。由于随访时间太短，无法确定 急性、早期eGFR下降/CKD事件对硬终点的长期影响，来自两种样本的储存标本 研究提供了一个机会，研究对反映关键结果领域的代谢标志物的平行影响 炎症/铁代谢以及骨和矿物质代谢/血管钙化。 在此，我们建议检查急性早期eGFR下降/事件的长期代谢影响， SPRINT和ACCORD-BP中的CKD。对目标1的分析将涉及以下方面急剧变化的后果： SBP干预导致的eGFR和新发CKD以及GFR变化的后果 由于其他因素，包括肾脏疾病的自然病程。目标2将使用现代因果模型 技术，以解决eGFR和CKD事件的急性变化的后果，特别是由于 加强SBP干预。 当前提案将阐明强化SBP是否会导致eGFR和CKD事件的变化 降低导致改变的代谢环境。在SPRINT之前，没有如此密集的随机对照试验水平证据 SBP控制在<120 mm Hg可提高生存率并降低心血管事件的风险。而 SPRINT的发现是新颖的和重要的，人们担心SPRINT对肾脏的影响 干预该提案旨在解决这一深刻的公共卫生主题的知识差距 意义

The Systolic Blood Pressure Intervention Trial (SPRINT), a landmark study demonstrated that intensive systolic blood pressure (SBP) lowering (SBP target <120 versus <140 mmHg) reduced the risk of death and major cardiovascular events in persons without diabetes but at high cardiovascular risk. In a recent publication, we noted that intensive SBP lowering in SPRINT resulted in a relative mean decline in estimated glomerular filtration rate (eGFR) (intensive versus standard) of −3.31 ± 0.30 mL/min/1.73 m2 by 6 months. The intensive SBP group also had a 3.5-fold higher hazard of incident chronic kidney disease (CKD). The Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial used a 2 X 2 factorial design to test the same SBP intervention as SPRINT as well as intensive versus standard glycemic control (glycated hemoglobin < 6% versus 7.0 to 7.8%) in persons with type 2 diabetes mellitus (T2DM). In our analysis of ACCORD-BP data, comparisons of the intensive vs. standard SBP groups showed that the intensive SBP intervention in ACCORD-BP led to an even more pronounced early mean eGFR decline and a greater increase in the cumulative incidence of CKD relative to SPRINT (interaction p-value <0.001). It is possible that the decline in eGFR due to blood pressure lowering may have distinct clinical and public health consequences compared with the decline in eGFR due to other conditions, which we have presumed to be related to progression of intrinsic kidney disease. As the follow-up periods are too short to determine the long-term effects of acute, early eGFR decline/incident CKD on hard endpoints, stored specimens from both studies provide an opportunity to study parallel effects on metabolic markers reflecting key outcome domains of inflammation/ iron metabolism and bone and mineral metabolism/ vascular calcification. Herein we propose to examine the long-term metabolic implications of acute, early eGFR decline/incident CKD in SPRINT and ACCORD-BP. The analyses of Aim 1 will address consequences of acute changes in eGFR and incident CKD that are due to the SBP interventions as well as consequences of changes in GFR due to other factors including the natural course of kidney disease. Aim 2 will use modern causal modeling techniques to address the consequences of acute changes in eGFR and incident CKD that are specifically due to the intensive SBP intervention. The current proposal will clarify whether changes in eGFR and incident CKD noted with intensive SBP lowering result in an altered metabolic milieu. Prior to SPRINT, there was no RCT level evidence that intensive SBP control to a goal of <120 mm Hg prolongs survival and reduces the risk of cardiovascular events. While SPRINT findings are novel and significant, there are concerns about the kidney effects of the SPRINT intervention. This proposal seeks to address this knowledge gap in a topic of profound public health significance.