Accurate Measurement of Renal Function in Cirrhosis

描述（由申请人提供）： 随着美国慢性B型和C型肝炎感染流行的恶化，肝硬化发病率的上升导致显著的和不断增长的发病率和死亡率。可用于移植的肝脏数量有限，这意味着适当分配这些宝贵的资源比以往任何时候都更加重要。肾功能不全是肝硬化患者死亡率最重要的危险因素之一，如MELD移植优先评分中包括血清肌酐（Cr）所反映的，但在肝硬化患者中，肾功能的测量非常不准确。基于Cr和最近的半胱氨酸蛋白酶抑制剂C（CysC）的GFR估计值高估了肾功能，导致临床管理不善和次优移植优先级。在过去的十年中，我们已经开发了3D MR成像和分析工具，用于测量肾小球滤过率（GFR），使用低剂量的Gd造影剂，并在不到10分钟的额外MR表时间。由于其发展为肝细胞癌的倾向，肝硬化患者接受常规成像筛查;在成像检查中，MRI已被证明对早期恶性肿瘤最敏感。我们建议在常规肝脏MRI检查中，可以获得准确的GFR测量值，以确定肾病患者的肾脏状态。我们的初步MR GFR测量，使用修改后的2D协议，显示出密切的协议与参考99 mTc-DTPA清除率值在前列腺癌。广泛的长期目标：开发并测试一种易于实施的方法，用于准确测量接受常规肝脏MRI检查的肾病患者的肾功能。具体目标/方法：（1）开发和完善一种快速MRI方法，以测量单肾和总肾小球滤过率（GFR），该方法可与常规筛查肝脏MR检查联合进行。在15名受试者中，我们将比较两种方法定量Gd浓度的准确性，进行Gd剂量优化研究，并检查房室模型分析的稳健性。(2)在197例受试者的肾衰竭人群中，验证快速MR GFR方法与参考放射性核素清除方法相比对单肾和总GFR的准确性。我们将比较MR GFR估计值与传统的基于Cr和CysC的估计值（3）开发并提供用户友好的图形用户界面供公众使用，以便在标准的常用计算机平台上快速（< 5分钟）分析MR肾造影数据。在结论中，我们的研究极有可能表明，MR肾成像可以快速准确地提供GFR的准确测量，并且当添加到常规肝脏MRI时，可以忽略不计的额外费用。该项目将对人类健康产生重大影响，通过改善对肾病患者的管理，提高风险分层和基于MELD的肝移植优先顺序的准确性，并通过准确监测肾功能降低移植后发病率和死亡率，此外还对更广泛的肾病风险患者人群产生重大影响。 公共卫生相关性： 拟议的项目将对改善慢性肝炎和肝硬化等肝病患者的保健非常重要，这些患者通常会患肾病，但往往诊断不足。利用我们提出的新型磁共振成像（MRI）技术，可以比现有方法更准确地测量肾功能，并且可以将其整合到肝癌的常规MRI筛查方案中，而增加的时间和成本可以忽略不计。这种更准确的测量的潜在影响包括更好地管理肾病患者和改善移植的优先级，以及更广泛地改善对更广泛的有肾脏疾病风险的患者人群的诊断。

DESCRIPTION (provided by applicant): With the worsening epidemic of chronic hepatitis B and C infections in the U.S., the rising incidence of cirrhosis is causing significant and growing morbidity and mortality. The limited number of livers available for transplantation means appropriate allocation of these precious resources is more critical than ever. Renal dysfunction is one of the most important risk factors for mortality in cirrhotics, as reflected by the inclusion of serum creatinine (Cr) in the MELD priority score for transplantation, and yet measures of renal function are highly inaccurate in cirrhosis. Estimators of GFR based on Cr and, more recently, cystatin C (CysC), overestimate renal function, leading to clinical mismanagement and suboptimal transplant prioritization. Over the past decade, we have developed 3D MR imaging and analysis tools for measuring glomerular filtration rate (GFR) using low doses of Gd contrast material and in less than 10 min of additional MR table time. Because of their propensity to develop hepatocellular carcinoma, cirrhotic patients undergo routine imaging for screening; of the imaging tests, MRI has proven most sensitive for early malignancy. We propose that during routine liver MRI, accurate measurements of GFR can be obtained for determining renal status in cirrhotic patients. Our preliminary MR GFR measurements, using a modified 2D protocol, show close agreement with reference 99mTc-DTPA clearance values in cirrhotics. Broad long term objectives: To develop and test an easily- implementable method for accurately measuring renal function in cirrhotic patients undergoing routine liver MRI. Specific Aims/Methods: (1) To develop and refine a fast MRI method to measure single kidney and total glomerular filtration rate (GFR) that can be performed in conjunction with routine screening liver MR exams. With 15 subjects, we will compare accuracy of two methods for quantifying Gd concentration, perform a Gd dose optimization study, and examine the robustness of compartmental models of analysis. (2) To validate the accuracy of fast MR GFR methods compared with reference radionuclide clearance methods for single kidney and total GFR in a cirrhotic population of 197 subjects. We will compare MR GFR estimates with conventional Cr and CysC-based estimates (3) To develop and offer for public use a user-friendly graphical user interface to enable rapid (< 5 min) analysis of MR renography data on standard, commonly available computer platforms. At its conclusion, our study is highly likely to show that MR renography can provide accurate measures of GFR quickly and accurately, and with negligible added costs when added to routine liver MRI. This project would have a high impact on human health by improving the management of cirrhotic patients, increasing the accuracy of risk stratification and MELD-based liver transplantation prioritization, and by reducing post-transplantation morbidity and mortality through the accurate monitoring of renal function, in addition to significant implications for the broader population of patients at risk for renal disease. PUBLIC HEALTH RELEVANCE: The proposed project will be important for improving the health care of patients with liver diseases such as chronic hepatitis and cirrhosis, in whom kidney disease commonly develops but is frequently underdiagnosed. With the novel magnetic resonance imaging (MRI) technique that we propose, kidney function can be measured more accurately than available with existing methods, and can be integrated into the routine MRI screening protocol for liver cancer with negligible added time and costs. Potential implications of this more accurate measurement include better management of cirrhotic patients and improved prioritization for transplants as well as, more broadly, improved diagnosis of the broader population of patients who are at risk for developing kidney disease.