Adiposity and kidney disease: observations from large blood-based prospective cohorts across a wide range of different populations

英国肾脏研究所2013年的患者调查发现，“预防肾脏疾病”和“特定肾脏疾病的原因”是肾脏研究的第二和第三个优先事项，仅次于“找到治疗肾脏疾病的方法”。这个团契的重点显然符合这些优先事项。我最近完成的一项研究使用了英国140万成年人的数据，结果表明超重和肥胖是英国肾脏疾病的主要原因。对这些人进行了7年的跟踪调查，几乎每100人中就有1人出现永久性严重肾损伤，每1000人中就有1人需要透析或肾移植。与瘦人相比，超重的人永久性严重肾损伤的风险中等增加（他们的风险增加了约30- 40%），但中度肥胖者（即那些身体质量指数[BMI]在30- 35kg/m2之间的人）的风险增加了一倍，严重肥胖者（BMI超过35kg/m2）的风险增加了三倍。在英国和世界范围内，糖尿病是严重肾损伤的常见原因，也是肥胖可能导致永久性肾损伤的机制之一。然而，这项研究发现，无论是否患有糖尿病，以及血压控制良好的人，体重超标都会增加肾脏损伤的风险。考虑到超重和肥胖在英国是多么普遍，这些数据表明，英国成年人中至少有三分之一的永久性严重肾脏损伤可能是由于超重或肥胖造成的，尽管有现代治疗糖尿病和高血压的方法，肥胖仍然是严重肾脏疾病的主要原因。因此，我的总体研究目标是研究超重或肥胖以及腹部脂肪沉积（即中心性肥胖）在多大程度上增加了大范围人群发生暂时性、永久性和/或进行性肾损害的风险，然后探索潜在的因果机制。这项研究将通过一些世界上最大的人口研究来完成，这些研究测量了人们的体重和体脂，收集了血液的基因，然后对他们进行多年的跟踪调查，看看肾脏问题是否以及如何发展。在研究过程中需要以下步骤：1。完成3项大型人群研究（中国嘉道里生物银行、英国生物银行和墨西哥城前瞻性研究）中超过100万人中新发肾病患者的识别和确认。评估体重和中心性肥胖如何预测发生不同肾脏疾病的风险。确认肥胖是肾脏疾病的一个因果危险因素，然后关注潜在的机制，其中存在一些争议。这项工作将包括在研究中使用新的基于基因的计算方法。从长远来看，这些研究将能够将不同类型的肥胖和肾脏疾病如何影响被认为与这两种疾病相关的其他疾病的风险联系起来，包括心脏病、感染和癌症。除了个人发展和形成一个专注于肥胖、糖尿病和肾脏疾病的新研究项目外，该奖学金的主要应用和好处包括：扩展肾脏医生的专业知识，他们已经知道如何设计和进行大型试验，并使他能够使用专业基因分析来测试肾脏疾病的风险因素是否代表一个可能的原因，而不是与肾脏疾病有关。这确保了未来的临床试验将测试最好的问题；2 .为英国生物银行、中国嘉道里生物银行和墨西哥城前瞻性研究用户定义可靠的肾脏结局；为制药行业提供了新的和重要的机会来测试生物途径是否可以减少或增加肾脏疾病的风险。

The Kidney Research UK 2013 patient survey identified 'prevention of kidney disease' and 'cause of specific kidney diseases' as the second and third priority for renal research after 'finding a cure for kidney disease'. This fellowship focus demonstrably aligns with these priorities. Work I have recently completed using data of 1.4 million adults in England showed that being overweight and obese is a key cause of kidney disease in the UK. Tracking these people for 7 years, nearly 1-in-100 developed permanent serious kidney damage and 1-in-1000 required dialysis or a kidney transplant. Compared to lean people, those who were overweight were at moderately increased risk of permanent serious kidney damage (their risk was increased by about 30- 40%), but risk was doubled among those who were moderately obese (ie, those who had a body-mass index [BMI] between 30-35 kg/m2) and was tripled among those with severe obesity (BMI above 35kg/m2). Diabetes is a common cause of serious kidney damage in the UK and worldwide, and is one of the mechanisms by which obesity may cause permanent kidney damage. Nevertheless, this study found that excess weight increased the risk of kidney damage by a similar amount in people with or without diabetes, and also in people who had 'well-controlled' blood pressure. Taking into account how common overweight and obesity are in the UK, these data suggested that at least one-third of all permanent serious kidney damage in adults in the UK could be due to being overweight or obese, and that despite modern treatments for diabetes and raised blood pressure, obesity remains a major cause of serious kidney disease. My overall research aim is therefore to study by how much being overweight or obese and deposition of fat in the abdomen (ie, central obesity) increase the risk of developing temporary, permanent and/or progressive kidney damage across a wide range of populations, and then explore the potential causal mechanisms. This will be done using some of the world's largest population studies which have measured people's weight and body fat and collected blood for genetics, then followed them for many years to see if and how kidney problems develop. The following steps in the research process are necessary:1. Completing the identifying and confirming of people who develop new kidney disease in over 1 million people assessed and then followed in 3 large population studies (China-Kadoorie Biobank, UK Biobank and the Mexico City Prospective Study).2. Assessing how body weight and central obesity predict the risk of developing different kidney diseases.3. Confirming adiposity is a causal risk factor for kidney disease, and then focusing on potential mechanisms, where there is some controversy. This work will include use of novel gene-based computational methods in the studies.Long-term, these studies will be capable of relating how different types of obesity and kidney disease affect risk of other diseases thought to be associated with both conditions, including heart disease, infection and cancer.Key applications and benefits of this fellowship, beyond personal development and the formation of a new research program focused on obesity, diabetes and kidney disease, include providing: 1. Extending the expertise of a kidney doctor who already has knowledge of how to design and conduct large trials, and providing him with the ability to use specialist genetic analyses to test whether risk factors for kidney disease represent a probable cause, rather than an association with kidney disease. This ensures future clinical trials will test the best questions;2. Defining reliable kidney outcomes for UK Biobank, China-Kadoorie Biobank and Mexico City Prospective Study users;3. Providing new and major opportunities for the pharmaceutical industry to test whether biological pathways may reduce or increase risk of kidney diseases.