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

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.

Renal disease is often complex and chronic with variable phases of activity, resulting in advances in therapies being slow and difficult to introduce systematically. We have realised a sustainable national infrastructure, NURTuRE (National Unified Renal Translational Research Enterprise, nurturebiobank.org), kick-start funded by an industry/academic consortium partnership (£2.05M) to systematically permit recruitment of any patient with kidney disease to participate in research lifelong. Crucially, this includes meticulous biosample collection from every patient, protocolled to stringent industry standards. NURTuRE establishes a national network of research nurses to recruit patients into two pilot cohorts of kidney disease (1) a rare disease, idiopathic nephrotic syndrome (INS) and (2) a common condition, chronic kidney disease (CKD), held within an established registry. We are recruiting 1000 INS and 3000 CKD patients over 2 years (2017-19). This proposal will assemble a unique dataset from those cohorts, combining analysed biomarkers with detailed temporal clinical and routine biochemical data. By the end of the funding period the aim is to achieve a paradigm shift in mechanism-based stratification for INS, and additionally establish proof of principle that this resource can yield rich datasets for discovery of stratification paradigms in CKD.
The platform is based on solid momentum over the last 7 years, of having established in the UK firstly a renal rare disease registry (RaDaR) based on substantial core infrastructure, under the governance of the UK Renal Association, with a Rare Disease Committee, and RaDaR operational management board. Additionally the IT is based within the established UK Renal Registry, and linked to Renal Patient View, both NHS embedded organisations.
The proposal aims to achieve the first re-classification of INS in decades, as well as advancing mechanism based endotypes of CKD which can be built upon in future studies

Realising the objective of this programme of research will benefit the following groups:
1. Patients with kidney disease and cliinicians as this project will result in disease stratification based diagnostic and prognostic categories based on clinical/genetic/biomarker/'omic' profile, superseding current therapeutic response or observational categories. This work will also enable the design of interventional trials (working with existing and future industry partners) to introduce novel drugs/biologics to clinical practice. These are based on mechanistically derived stratification algorithms to determine inclusion criteria with the highest likelihood of success

2. Renal scientists. This project will result in a repository of highest quality samples and deep clinical/genotypic/biomarker/'omic' data for research and industry based cooperative strategies in INS and CKD. For renal scientists with interests in other disease areas the development of NURTuRE provides a complete UK platform for disease cohort building, stratification and interventional trials in nephrology

3. Industry - by forming partnerships with industrial/pharmaceutical companies we will develop new assays and drug/compound pipelines thus creating commercial opportunities for a worldwide market. This project will also establish and showcase a dynamic and adaptable infrastructure for clinical research with which to engage with industry and academic partners
The NURTuRE resource is already attracting the serious attention of several large Pharma companies for investment. At the present time, three companies are in negotiations with the Project Development Team, including the extension of current cohorts and development of new renal disease cohorts for future use.

4. Other scientists. This work will lead to the Development and application of 'machine learning' methodologies for integrating large datasets
This will have applications across disease spectra, in all specialities

5. The UK economy. Renal disease is expensive. Over 2% of NHS budget is spent on 0.1% of the population. Renal disease is expensive. Over 2% of NHS budget is spent on 0.1% of the population. The overall cost of treating CKD in England has been estimated at £1.4 billion/year and development of biomarkers to identify rates of progression would transform the ability to trial emerging therapies such as novel anti-fibrotics, and thereby introduce new agents into clinical care. Annual incidence of CKD attributed to INS is increasing (0.2% to 2.3%) The current protocol for INS management is indiscriminate high dose steroids. Of resistant patients, only 30% will respond to 2nd/3rd line immunosuppression, the rest suffer long-term morbidity and renal failure requiring dialysis/transplantation. Identification of 'non-responders' by recently introduced genetic panel screening has been estimated to save £68,900 per patient pre-dialysis (figure submitted in UKGTN approval) by avoidance of unnecessary investigations and treatment. Stratification proposed in the non-genetic cohort aims to transform response rates with new biologics/agents, and prevention of CKD.

6. Patient organisations and Charities- the embedding of specific charities and patient organisations such as Kidney Research UK and the nephrotic syndrome trust (NeST) within NURTuRE will better enable them to inform patients about research that will benefit their own disease.
Patients have been centrally involved in the design, and rollout of NURTuRE, and will continue to benefit from advising national research strategies, and on individual levels by having access to their own data and disease specific information (e.g. nurturebiobank.org, rarerenal.org)

7. The general public. The other non-academic beneficiaries will be the public: we are committed to public engagement on many levels, and the PIs have many years of experience between them of addressing lay groups including patients, carers and the general public.