AGE-RELATED CHANGES IN RENAL MORPHOLOGY AND FUNCTION IN CHRONIC KIDNEY DISEASE

申请者描述(申请人提供)：本申请是针对PA-09-166《老龄时期的肾功能和慢性肾脏疾病(R21)》而提出的。慢性肾脏病在老龄化人口中是一个日益严重的问题。根据美国肾脏数据系统，老年终末期肾病(ESRD)患者的数量在过去25年中几乎翻了一番。因此，慢性肾脏病构成了相当大的医疗和公共卫生挑战，特别是在老年人口中。CKD是指肾功能下降，表现为肾小球滤过率(GFR)下降。在大约40岁之前，肾小球滤过率似乎是稳定的，然后在大约70%的成年人中，以平均每十年8-10毫升/分钟的速度下降。肾功能下降的病理特征还包括肾小管萎缩、肾小球硬化和间质纤维化。肾血管和血管功能的改变也可能促进CKD的发展。对CKD的病因和病理生理学有了更好的了解，无疑将有助于改进CKD的诊断和干预方法。因此，美国国立卫生研究院专门征集申请，以研究“慢性肾脏病与年龄相关的肾脏形态、病理、结构变化(例如，肾小管萎缩、肾小球硬化、间质纤维化)的关系”。 和功能(例如，肾血流动力学、肾小球滤过率等的变化)。我们假设，结合光学相干断层扫描(OCT)和荧光共聚焦显微镜(FCM)的多模式光学成像平台可以：1)定量测量CKD的结构和功能参数；2)纵向监测与年龄相关的肾脏结构和功能的变化。我们在动物和人类肾脏上的大量初步数据表明，光学成像在体内评估肾脏病理和功能方面具有强大的潜力和前景。我们建议通过以下两个具体目标在动物模型上验证我们的假设：目的1：使用OCT/FCM联合成像建立CKD动物模型，并将肾脏形态和功能参数与CKD的进展进行关联。具体来说，我们将量化OCT的形态测量参数、DOCT的血流动力学参数和FCM的肾小球滤过参数。这些参数将被统计分析，以与CKD相关。目标2：定量研究两者之间的关系 在衰老动物模型上，肾脏形态和功能参数与CKD年龄相关进展之间的关系。具体地说，我们将纵向成像四组动物：青年成年大鼠(3-4个月)、中年大鼠(8-10个月)、老年大鼠(18个月)和衰老大鼠(22-24个月)，并监测CKD的年龄相关进展。在每个时间点，光学成像参数将从多个位置采样，以获得对全球肾脏状况的代表性描述。此外，我们将在每个时间点对多个动物进行成像，以统计研究肾脏结构/功能参数和 慢性肾脏病的年龄相关性进展。

DESCRIPTION (provided by applicant): This application is in response to PA-09-166 "Renal Function and Chronic Kidney Disease (CKD) in Aging (R21)". CKD is a growing problem among the aging population. According to the United States Renal Data System, the number of older patients with end-stage renal disease (ESRD) has almost doubled over the last 25 years. Thus, CKD poses a considerable medical and public health challenge, particularly in the older population. CKD is a decline in renal function defined by decreased glomerular filtration rate (GFR). GFR appears to be stable until about 40 years of age and then declines at an average rate of 8-10 mL/min/per decade in approximately 70% of adults. The decline in renal function is also characterized pathologically by tubular atrophy, glomerulosclerosis, and interstitial fibrosis Alterations in renal vasculature and vascular function may also contribute to the development of CKD. A better understanding of the etiology and pathophysiology of CKD will undoubtedly lead to improved methods in both diagnosis and intervention of CKD. Therefore, NIH is specifically soliciting applications to investigate the "relationship of CKD to age-related changes in renal morphology, pathology, structure (e.g., tubular atrophy, glomerulosclerosis, interstitial fibrosis) and function (e.g., changes in renal hemodynamics, GFR, etc.)." We hypothesize that a multi-modal optical imaging platform combining optical coherence tomography (OCT) and fluorescence confocal microscopy (FCM) can: 1) provide quantitative measurements of structural and functional parameters in CKD; and 2) longitudinal monitor age-related changes in renal structure and function. Our extensive preliminary data on both animal and human kidneys demonstrate the strong potential and promise of optical imaging for evaluating kidney pathology and function in vivo. We propose to test our hypothesis on animal models by pursuing the following two specific aims: Aim 1: Quantitatively image animal model of CKD using combined OCT/FCM and correlate renal morphological and functional parameters with the progression of CKD. Specifically, we will quantify morphometric parameters from OCT; hemodynamic parameters from DOCT; and glomerular filtration parameters from FCM. Those parameters will be statistically analyzed to correlate with CKD. Aim 2: Quantitatively investigate the relationship between renal morphological and functional parameters with age-related progression of CKD on an animal model of aging. Specifically, we will longitudinally image four groups of animals: young adult rats (3-4 months), middle age (8-10 months), old rats (18 months), and senescent rats (22-24 months) and monitor the age-related progression of CKD. At each time point, optical imaging parameters will be sampled from multiple locations to attain a representative description of global kidney status. Furthermore, we will image multiple animals at each time point to statistically investigate the interplay between renal structural/functional parameters and age-related progression of CKD.