The Aging Kidney Anatomy Study

 描述(由申请人提供)：只有被认为患有严重肾病的患者才会接受肾脏活检以评估结构病理学。已经花费了大量的努力来确定肾脏病理的新的生物标志物，但肾脏病理在多大程度上预测了没有严重肾病的患者的不良结局尚不清楚。这项更新建议将通过详细说明无严重肾病患者的肾脏活检和CT扫描中与年龄相关和亚临床疾病相关的结构性病理来填补这一关键知识空白。将分析基于活检(肾硬化症和肾单位肥大)和CT扫描(皮质体积、表面粗糙度、囊肿)的结构病理和形态；以及肾单位数量(从活检和CT估计)，以确定它们与不良肾脏结局的关系。将研究三个未被定义为严重肾病的互补人群：活体肾脏捐赠者，与这些活体肾脏捐赠者配对的肾移植接受者，以及肿瘤肾切除患者。这些特定人群也将从这一发现中受益最多。通过确定慢性肾脏疾病(CKD)风险最高的捐赠者，肾脏捐赠者的选择和捐献后监测将得到改善。由于选择有限，肾移植接受者通常会尽可能接受任何捐赠的肾脏，但同种异体移植失败的一个主要决定因素是活体捐赠者的年龄。确定在较老的同种异体移植物中预测肾衰竭风险的结构发现是改善肾移植受者管理的必要步骤。在肾肿瘤患者中，决定是完全(根治)还是部分切除 根据非肿瘤性肾脏病理学预测的肾功能衰竭的风险，肾切除术与监测相比，将会被告知。这项研究的假设是：1)肾硬化、肾单位肥大和肾单位数目减少独立于年龄、肾功能和(CKD)危险因素预测不良的肾脏结局，2)肾脏的CT扫描检测到潜在的肾脏病理，并可用于预测不良的肾脏结局。1.在3,000名活体肾捐献者中，肾硬化、肾单位体积增大、肾单位数目减少(如植入肾活检和供体前CT扫描所确定的)预示着在供体后3-6个月和供体后5-20年肾小球滤过率(GFR)降低、残余GFR(RGFR)降低、蛋白尿和高血压。2.在与这些捐赠者匹配的3000名肾移植受者中，供体肾脏中相同的基线结构发现预测了死亡审查的移植物丢失(肾衰竭)、全原因移植物丢失(肾衰竭或死亡)、GFR下降、蛋白尿以及随后的常规活检中间质纤维化的增加。3.在1,000名肿瘤肾切除患者中，同样的肾脏结构表现预示着肾功能衰竭、非癌症死亡率和较低的rGFR(随访GFR/肾切除前GFR)。

 DESCRIPTION (provided by applicant): Only patients thought to have a severe nephropathy undergo a kidney biopsy to assess structural pathology. Much effort has been expended to identify new biomarkers for kidney pathology, but the extent to which kidney pathology predicts adverse outcomes in patients without a severe nephropathy is unknown. This renewal proposal will fill this key knowledge gap by detailing the age-related and subclinical disease-related structural pathology on renal biopsy and CT scan of patients without a severe nephropathy. Structural pathology and morphology based on biopsy (nephrosclerosis and nephron hypertrophy) and computed tomography (CT) scans (cortical volume, surface roughness, cysts); and nephron number (estimated from biopsy and CT) will be analyzed to determine how they relate to adverse kidney outcomes. Three complementary populations not defined by a severe nephropathy will be studied: living kidney donors, kidney transplant recipients paired to these living donors, and tumor nephrectomy patients. These specific populations will also benefit most from the findings. Kidney donor selection and post-donation monitoring will be improved by identifying donors at highest risk for chronic kidney disease (CKD). Kidney transplant recipients usually take any donated kidney they can due to limited options, but a major determinant of allograft failure is the age of the living donor. Determining the structural findings in older allografts that predict kidney failure risk is a needed step to improved management of kidney recipients. In patients with a renal tumor, decisions regarding a complete (radical) versus partial nephrectomy versus monitoring would be informed by the risk for kidney failure as predicted by non-tumor kidney pathology. The study hypotheses are that 1) nephrosclerosis, nephron hypertrophy, and reduced nephron number are predictive of adverse kidney outcomes independent of age, kidney function, and (CKD) risk factors, and 2) CT scans of the kidneys detect this underlying renal pathology and can be used to predict adverse kidney outcomes. Three Specific Aims test these hypotheses: 1. In 3,000 living kidney donors, nephrosclerosis, larger nephron size, and decreased nephron number (as determined by implantation renal biopsy and pre-donation CT scan) are predictive of lower glomerular filtration rate (GFR), lower residual GFR (rGFR), proteinuria, and hypertension at 3-6 months after donation and at 5-20 years after donation. 2. In the 3,000 kidney transplant recipients matched to these donors, the same baseline structural findings in the donor kidney are predictive of death-censored graft loss (kidney failure), all-cause graft loss (kidney failure or death), GFR decline, proteinuria, and increased interstitial fibrosis on ensuing protocol biopsies. 3. In 1,000 tumor nephrectomy patients, these same kidney structural findings are predictive of kidney failure, non-cancer mortality, and lower rGFR (follow-up GFR/pre-nephrectomy GFR).