Acute declines in kidney function during blood pressure interventions in CKD

项目摘要 慢性肾脏疾病（CKD）与显著的发病率和死亡率相关：医疗保险花费了980亿美元 2017年CKD治疗费用到目前为止，已经证明可以改善心血管疾病的两种干预措施 降低慢性肾脏病（CKD）的风险或减缓CKD的进展的方法是将收缩压（BP）降低到 <120 mmHg或使用肾素-血管紧张素系统（RAS）阻滞剂。然而，在两次干预期间， 估计肾小球滤过率（eGFR）下降发生在大多数患者中，尤其是如果基线 CKD存在。传统上，这些肾功能的急性下降（例如，血清肌酐增加高达 RAS阻断期间30%）被认为是良性、可逆的，与长期 后遗症，但最近的研究质疑，即使是较小的变化，肾功能， 这些干预可能与长期CVD或肾脏风险有关。很少有研究系统地 量化了血压降低或RAS启动期间eGFR急性下降的幅度， 阈值可能与不良肾脏或CVD结局的较高风险相关。这个问题 重要的是，因为目前，实现适当的BP控制和使用RAS抑制剂在以下方面是次优的： CKD患者，尽管这些干预措施已证明有益处。许多供应商可能会放松BP控制， 在eGFR急性下降时停用RAS抑制剂，尽管专家建议耐受这些药物 变化我们的目标是确定长期的肾脏和心血管疾病的影响的急性变化， 抗高血压治疗期间的eGFR。在目标1中，我们将收集和协调来自已完成的 强化血压控制或RAS抑制的随机试验，以在个体水平的Meta中检查这一问题， 分析基线CKD患者，并确定存在大幅急性下降风险的患者特征 BP治疗期间的肾功能。在目标2中，我们将评估eGFR的急性变化与 和强化降压或RAS启动后ESRD或CVD事件的风险，并探索是否存在 与不良结局相关的eGFR变化幅度。接下来，我们将确定 eGFR的急性变化改变或介导强化降压或RAS治疗对ESRD的影响 或CVD风险（目标3）。最后，我们将开发一种创新工具，1）预测eGFR的进一步变化 持续抗高血压治疗和2）提供ESRD或CVD风险的精确估计， 考虑eGFR发生的变化（目标4）。这一建议意义重大，因为它可以指导 临床决策：如果eGFR的急性下降与不良结局无关，则提供者 应鼓励患者继续这些治疗，无论是否发生急性eGFR变化。 然而，如果eGFR的急性下降与不良结局相关（以及风险开始时的阈值）， 增加低于可接受的阈值），那么对这些干预措施的生物反应可能是 被认为有助于以循证方式指导临床决策并改善护理。

PROJECT ABSTRACT Chronic kidney disease (CKD) is associated with significant morbidity and mortality: Medicare spent 98 billion dollars for CKD care in 2017. To date, the two interventions that have been shown to improve cardiovascular disease (CVD) risk or slow the progression of CKD are intensive lowering of systolic blood pressure (BP) to <120 mmHg or use of renin-angiotensin system (RAS) blockers. However, during both interventions, acute declines in estimated glomerular filtration rate (eGFR) occur in the majority of patients, especially if baseline CKD is present. Traditionally, these acute declines in kidney function (e.g. serum creatinine increases of up to 30% during RAS blockade) have been thought to be benign, reversible, and not associated with long-term sequelae, but more recent studies have questioned whether even smaller changes in kidney function during these interventions could be associated with long-term CVD or renal risk. Few studies have systematically quantified the magnitude of acute decline in eGFR during BP lowering or RAS initiation and if there is a threshold that may be associated with higher risk of adverse renal or CVD outcomes. This question is significant, since currently, achievement of appropriate BP control and use of RAS inhibitors is suboptimal in patients with CKD despite the proven benefits of these interventions. Many providers may relax BP control or stop RAS inhibitors in the face of acute declines in eGFR despite expert recommendations to tolerate these changes. Our objective is to determine the long-term kidney and CVD implications of the acute changes in eGFR during anti-hypertensive therapy. In Aim 1, we will assemble and harmonize data from completed randomized trials of intensive BP control or RAS inhibition to examine this issue in an individual-level meta- analysis of patients with baseline CKD and identify characteristics of patients at-risk for large acute declines in kidney function during BP therapy. In Aim 2, we will evaluate the association between acute changes in eGFR and risk of ESRD or CVD events following either intensive BP lowering or RAS initiation and explore if there is a magnitude of change in eGFR that is associated with adverse outcomes. Next, we will determine whether acute changes in eGFR modify or mediate the effect of either intensive BP lowering or RAS therapy on ESRD or CVD risk (Aim 3). Finally, we will develop an innovative tool that will 1) predict further changes in eGFR with continued anti-hypertensive therapy and 2) provide refined estimates of the risk of ESRD or CVD, accounting for the changes in eGFR that occurred (Aim 4). This proposal is significant as it could guide clinical decision-making: if acute declines in eGFR are not associated with adverse outcomes, then providers should be encouraged to continue these therapies regardless of the acute eGFR changes that occur. However, if acute declines in eGFR are associated with adverse outcomes (and the threshold when risk begins to increase is lower than the accepted threshold), then the biological response to these interventions could be considered to help guide clinical decision-making in an evidence-based fashion and improve care.