MICA: NURTuRE - changing the landscape of renal medicine to foster a unified approach to stratified medicine

个性化医疗有望改变我们的行医方式，并重新思考新药开发和试验的方式。我们的目标是大胆的。我们希望重塑英国肾脏医学的格局，以便建立疾病特异性队列，与学者，临床医生，患者，慈善机构和行业的合作保持一致，成为实现所有肾脏疾病个性化管理的加速和常规渠道。我们已经取得了突破性的进展，现在建立了实现这一目标的基础设施，现在建议汇集世界领先的学术专业知识，以有效地了解从这些独特的患者群体收集的大量数据。这一建议的典型结果是重新分类一个最困难的，虽然罕见的条件遭受肾脏医学，特发性肾病综合征（INS）。第二个结果是利用开发的基础设施和方法，深入了解最常见的肾脏疾病之一，慢性肾脏疾病（CKD），以便深入了解为什么有些患者比其他患者进展得更快，这是一个关键的未回答的问题。诊断患有罕见疾病的患者通常很脆弱，没有得到充分的照顾，对他们的疾病知之甚少。这在很大程度上是因为各个中心或临床医生看到的病例太少，无法获得最佳管理所需的经验，而且经验积累得太慢。这也是有效研究的一个障碍，因为一个或几个中心的患者太少，无法进行充分的研究。解决办法是在可持续的基础上建立管理良好和全面包容的疾病登记册。随着英国肾脏罕见病登记处RADAR（www.rarerenal.org）的建立，以及类固醇耐药肾病综合征疾病组作为试点组的发展，我们已经为这一愿景迈出了重要的一步，证明了这一举措的巨大潜力。该项目现已扩展到包括所有年龄段的“特发性”肾病综合征（INS）患者。支撑这一愿景下一阶段的一个关键发展是建立国家统一肾脏转化研究企业。这一步的变化涉及英国专门的肾脏研究护士、项目经理、患者团体、慈善机构和学者的基础设施，从而可以常规收集高质量的生物样本和深入的纵向临床数据，可能适用于任何肾脏疾病队列。重要的是，这是基于新的产学合作模式，行业资助了启动项目的大部分资金，并在两个试点队列（INS和慢性肾病（CKD））中占有关键股份。管理由英国最大的肾脏慈善机构Kidney Research UK提供。该提案旨在利用这两个队列中的新力量，特别是INS，根据患者血液和DNA样本的详细遗传和分子筛查对每位患者进行分层。这种重新分类将是自20世纪70年代以来的第一次，并且是基于我们对肾病综合征的生物学理解的突破性进展，基于对肾脏疾病靶细胞的研究，称为足细胞。这将导致对足细胞的靶向治疗，以取代目前的非特异性毒性治疗，使用新的生物制剂。此外，该提案将产生大量的新的CKD数据集，加上创新的分析方法，以证明这种方法如何有潜力在多因素疾病状态下对疾病机制提出迄今为止具有挑战性的见解。这项事业的成功将是定义的改变，INS的研究和管理，以及为临床医生/学者和现有和未来的行业合作伙伴提供任何肾脏疾病未来研究的“橱窗”。

Personalised medicine has the promise of changing the way we practice medicine, and rethinking the way new drugs are developed and trialled. Our objective is bold. We wish to reshape the landscape of kidney medicine in the UK, such that building disease specific cohorts, aligned with partnering of academics, clinicians, patients, charity and industry becomes an accelerated and routine conduit to achieve personalised management for all renal conditions. We have made ground-breaking progress to now establish the infrastructure to achieve this goal, and now propose bringing together world leading academic expertise to productively understand the large amounts of data collected from these unique patient groups. The exemplar outcome of this proposal is to re-classify one of the most difficult, albeit rare conditions suffered in renal medicine, idiopathic nephrotic syndrome (INS). A secondary outcome is to make use of the infrastructure and methodologies developed, to gain insight into one of the commonest kidney scenarios, chronic kidney disease (CKD), in order to make inroads into why some patients progress faster than others, a key unanswered problem.Patients diagnosed with a rare disease are often vulnerable, inadequately cared for and poorly informed about their disease. This comes about largely because individual centres or clinicians see too few cases to gain the requisite experience for optimal management, and experience builds up too slowly. This is also a barrier to effective research, with too few patients available in one or a few centres to carry out adequately powered studies. The solution is well-managed and fully inclusive disease registries, developed on a sustainable basis. We have made a significant start to this vision, with the establishment of the UK renal rare disease registry, RADAR (www.rarerenal.org), and the development of the Steroid Resistant Nephrotic Syndrome disease group as a pilot group demonstrating the immense potential of this initiative. This project has now extended to include all patients with 'idiopathic' nephrotic syndrome (INS), at all ages. A critical development underpinning the next stage of this vision is the establishment of NURTuRE, the National Unified Renal Translational Research Enterprise. The step change involves a UK infrastructure of dedicated renal study nurses, project managers, patient groups, charities and academics, resulting in the routine collection of high quality biosamples, and deep longitudinal clinical data, potentially for any renal disease cohort. Importantly, this is based on a new model of industry-academia partnership, with industry funding the bulk of the kick-off project, with a key stake in the two pilot cohorts, INS and Chronic Kidney Disease (CKD). Governance is provided by the largest UK kidney charity, Kidney Research UK.This proposal aims to exploit the new power within these two cohorts, and in particular within INS, to stratify each patient according to detailed genetic and molecular screening of patient blood and DNA samples. This re-classification will be the first since the 1970s, and is based on ground-breaking advances in our biological understanding of Nephrotic Syndrome, based on study of the target cell of the disease in the kidney, called the podocyte. This will lead to targeted therapy towards the podocyte, to replace current non-specific toxic treatments, using new biological agents.Furthermore, the proposal will generate large new datasets in CKD coupled with innovative analytic methodologies, to demonstrate how this approach has the potential to make hitherto challenging insights into disease mechanism in a multifactorial disease state.The success of this enterprise would be the change in definition, investigation and management of INS, as well as a 'shop window' for future studies in any kidney condition, for both clinicians/academics and for industry partners, existing and future.