Hemodynamic mechanisms of impaired recovery and progression of renal disease following AKI in preexisting CKD states

有强有力的证据表明，急性肾损伤(AKI)会显著增加慢性肾脏疾病的风险 (CKD)和终末期肾病(ESRD)。如果慢性肾脏病患者发生AKI，预后显著。 更糟。临床和基础科学研究都报告说，先前存在的慢性肾脏病损害了急性肾损伤和急性肾损伤的康复 加速了先前存在的CKD的进展。然而，导致这种AKI-CKD的机制 相互作用仍然鲜为人知。在这方面，最近的两项临床研究表明，给药 急性心肌梗死恢复期应用肾素-血管紧张素系统(RAS)抑制剂显著降低死亡率和慢性肾脏病 进步。因此，急性心肌梗死后的危重窗口期给予抗高血压治疗(AHT) 可能会改善康复并降低CKD进展的风险。因此，这一提议检验了这样的假设 先前存在的CKD状态AKI后高血压的发展或恶化损害了肾小管的恢复 并且是随后进展为终末期肾病的主要原因。一种新的AKI-CKD联系的大鼠模型 我们已经展示了从AKI中受损的恢复以及随后快速发展为ESRD的情况 临床环境将在拟议的研究中使用。第一个目标是研究高血压的作用。 并增加肾脏血压传递以促进肾脏炎症，周细胞功能障碍， 在先前存在的CKD状态下，从AKI恢复过程中微血管稀疏和缺氧。我们建议 缺氧会阻碍受损的肾小管上皮细胞再分化和恢复功能的能力。为了测试这一点， 我们将在AKI后1周开始实施RAS依赖和独立的AHT，以评估 它们改变肾周细胞密度、毛细血管密度、缺氧和肾小管分化状态的程度。 与我们的初步数据一致，我们预计，降低血压本身将缓解微血管 稀疏缺氧，促进肾小管上皮细胞再分化，减少纤维化的发展 在从AKI恢复期间。我们还将使用多重ELISA细胞因子阵列来确定不同的能力 AHT减轻急性肾损伤大鼠肾组织促炎细胞因子的产生 CKD。AIM 2的研究将长期在有意识的人群中使用黄金标准血压测量 用仪器化的大鼠研究AKI后血压即使轻微上升的程度 已有CKD的大鼠参与了CKD的进展。新的分析方法也将是 用于评估AKI后数周清醒大鼠的肾血流自动调节。这些研究 使用创新的动物模型以及生理、生化和免疫学方法来检查 导致康复受损并迅速进展为终末期肾病的机制知之甚少 Aki在先前存在的CKD的设置中。除了提供对临床AKI-CKD关系的新见解外，这些 实验可能导致新的治疗策略或治疗靶点，可以用来改善 在这些高危人群中，从AKI中恢复并降低CKD进展的后续风险。

There is strong evidence that acute kidney injury (AKI) significantly increases the risk of chronic kidney disease (CKD) and end-stage renal disease (ESRD). If AKI occurs in patients with CKD, the prognosis is significantly worse. Both clinical and basic science studies report that preexisting CKD impairs recovery from AKI and AKI accelerates the progression of preexisting CKD. However, the mechanisms contributing to such AKI-CKD interactions remain poorly understood. In this regard, two recent clinical studies indicate that administration of renin-angiotensin system (RAS) inhibitors during recovery from AKI significantly reduces mortality and CKD progression. Thus, administration of anti-hypertensive therapy (AHT) during a critical window following AKI may improve recovery and reduce the risk of CKD progression. As such, this proposal tests the hypothesis that the development or worsening of hypertension following AKI in preexisting CKD states impairs tubule recovery and is the major cause of the subsequent progression to ESRD. A novel rat model of the AKI–CKD nexus that we have shown recapitulates the impaired recovery from AKI and subsequent rapid progression to ESRD in the clinical setting will be used in the proposed studies. The first aim will investigate the role of hypertension and increased renal blood pressure transmission to promote renal inflammation, pericyte dysfunction, microvascular rarefaction, and hypoxia during recovery from AKI in preexisting CKD states. We propose that hypoxia hinders the ability of injured tubular epithelial cells to redifferentiate and regain function. To test this, we will administer RAS dependent and independent AHT’s beginning 1 week following AKI to assess the extent to which they alter renal pericyte density, capillary density, hypoxia, and tubular differentiation status. Consistent with our preliminary data, we anticipate that reducing BP, per se, will mitigate microvascular rarefaction and hypoxia, promote tubular epithelial cell redifferentiation, and reduce the development of fibrosis during recovery from AKI. We will also use multiplex ELISA cytokine arrays to determine the ability of different AHT’s to mitigate renal pro-inflammatory cytokine production during recovery from AKI in rats with preexisting CKD. Studies in Aim 2 will utilize gold standard blood pressure measurements in conscious, chronically instrumented rats to investigate the extent to which even modest increases in blood pressure following AKI in rats with preexisting CKD contribute to the progression of CKD. Novel analytical methodologies will also be used to assess renal blood flow autoregulation in conscious rats over several weeks after AKI. These studies employ an innovative animal model and physiological, biochemical, and immunological approaches to examine the poorly understood mechanisms contributing to impaired recovery and the rapid progression to ESRD after AKI in settings of preexisting CKD. In addition to providing novel insights into the clinical AKI-CKD nexus, these experiments may lead to new treatment strategies or therapeutic targets that could be used to improve recovery from AKI and reduce the subsequent risk of CKD progression in this at-risk population.