Trans-national cohorts of nephrotic syndrome - a unified approach to a global chronic disease

Lead Research Organisation: University of Bristol
Department Name: Clinical Science at North Bristol

Abstract

Kidney disease in Low and Middle income countries is under recognised and severely under resourced. The reasons include lack of clinical expertise, diagnostic capabilities, and even if recognised the means to treat chronic, remitting disease without specialist drugs and technology is rarely possible. The incidence of one of the commonest types of renal disease (in adults and children), idiopathic nephrotic syndrome (INS), appears considerably higher in LMICs than in the developed world. This is likely contributed to by a combination of infectious triggers and genetic background, though other factors remain unknown.
The biological understanding of glomerular disease has been revolutionised in recent years by study of the glomerular podocyte, the specialised cell type that is the primary target of damage in INS. The potential therefore is to use compelling biological advances to develop technologically sophisticated laboratory assays that can rapidly be tested on large local populations of patients in different LMIC settings. This will lead to directly applicable classification of disease according to new molecular and genetic findings, and hence targeted and more effective health care.
This proposal brings together different groups of researchers with different strengths, and will enable knowledge transfer between all partners. The host laboratory in the UK is a world leader in podocyte biology and INS population genetics, and has well-established links with key leaders in nephrology in several LMICs. In the UK we have established in nephrology a national patient registry (www.rarerenal.org) and biorepository, with widespread clinician and patient buy-in that is recognised as innovative
This proposal aims to extend this concept internationally, to build a vibrant and cohesive network of academic centre leads in three LMICs with the UK centre as a hub. Each centre will be helped to build the infrastructure and expertise required to carry out biomarker and clinical trials studies on large and currently poorly understood cohorts of patients.
The downstream benefits will be (i) establish a team of LMIC centres trained consistently in laboratory research/diagnostic techniques and clinical database/biobank establishment (ii) transfer of cutting edge translational biology advances from the UK laboratory (and elsewhere) to establish novel laboratory assays locally (iii) share clinical trials methodology that will maximise impact of laboratory findings from large cohorts of patients. Links to Bristol will then facilitate definitive analysis of large scale molecular data. in this carefully curated population, with a pipeline of sustainable skills development in each centre.

Technical Summary

Kidney disease in LMICs is under recognised and severely under resourced. The incidence of one of the commonest types of renal disease (in adults and children), idiopathic nephrotic syndrome (INS), appears considerably higher in LMICs than in the developed world. This is likely contributed to by a combination of infectious triggers and genetic background, though other factors remain unknown. The biological understanding of glomerular disease has been revolutionised recently by study of the glomerular podocyte, the target cell in INS, alongside significant genetic advances. The field is ripe for translational research on wider patient cohorts to exploit compelling biological hypotheses arising from this work.
This proposal brings together researchers with complementary strengths, and will enable knowledge transfer between all partners. The host laboratory in the UK is a world leader in podocyte biology and INS population genetics, and has well-established links with key leaders in nephrology in several LMICs. In the UK we established a national renal patient registry (www.rarerenal.org) and biorepository, with widespread clinician and patient buy-in that is recognised as innovative.
We propose to extend this concept internationally, to build a vibrant and cohesive network of academic centre leads in three LMICs with the UK centre as a hub. The downstream benefits will be (i) establish a team of LMIC centres consistently trained in laboratory research/diagnostic techniques and clinical database/biobank establishment (ii) a pipeline to transfer cutting edge translational biology advances from the UK laboratory (and elsewhere) to establish novel biomarker assays locally (iii) share clinical trials methodology that will maximise impact of biomarker findings in large cohorts of patients. Links to Bristol will facilitate definitive studies on genomics, transcriptomics, and epigenetics in this carefully phenotyped population, with on going sustainable skills development

Planned Impact

The proposal fits within the UN Sustainable Development goals, particularly sections 3.c to increase health financing and the recruitment, development, training and retention of the health workforce in developing countries, and section 3.8 bringing access to quality essential health-care services and access to safe, effective, quality and affordable essential medicines for all.
Beneficiaries will include:
1. Patients will benefit in several ways. In LMICs there will be web-based - patient specific logins for International RADAR to allow individuals to see their own laboratory results, patient information and information about research. This is currently established and working well for UK patients (www.renalpatientview.org). Future development of qualitative surveys about their health, socio-economic status, etc. will be developed. LMIC clinicians will also have access to latest research initiatives, as well as treatment algorithms and clinical management guidelines (c.f. www.rarerenal.org).
2. Patient organisations and Charities- specific charities and patient organisations such as Kidney Research UK and the nephrotic syndrome trust (NeST) will be involved to help local LMIC organisations to be better able to inform patients about research that will benefit their own disease.
3. Industry - by forming additional partnerships with industrial/pharmaceutical companies, alongside current active partnerships (e.g. Evotec AG, UCB Pharma, Abbvie) we will develop new assays and drug/compound pipelines based on mechanisms in the glomerulus identified within this programme, thus
creating commercial opportunities for a worldwide market.
4. The LMIC economies and population. Renal disease is expensive. In the UK over 2% of NHS budget is spent on 0.1% of the population. Clearly this is not affordable in most LMIC economies, and the inevitable consequence is under-treatment and mortality. Therefore effectively targeting the correct patient groups with more specific therapies, which both limits side effects of powerfully toxic drugs and delays or prevents renal failure, will be a significant step towards reducing costs and preventing illness and death in a young (and economically viable) age group.

Publications

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Ding WY (2019) Big data and stratified medicine: what does it mean for children? in Archives of disease in childhood

 
Description A large international patient cohort has been recruited, with collaborations strengthened and key skills learnt by the LMIC partners.
Plans are in place for analyses of patient derived biosamples, some already performed and some in collaboration with industry partners as in kind contributions
Exploitation Route Use of data and stored biosamples
Exploitation of new laboratory and database skills imparted to LMIC partners
Sectors Digital/Communication/Information Technologies (including Software),Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description IPNA SRNS guideline committee
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact The first international guideline for Steroid Resistant Nephrotic Syndrome - guideline committee funded by IPNA - due to be published in 2019
 
Description MICA: NURTuRE - changing the landscape of renal medicine to foster a unified approach to stratified medicine
Amount £2,561,603 (GBP)
Funding ID MR/R013942/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2018 
End 07/2022
 
Description National Registry for Rare Kidney Diseases (FSGS & MPGN).
Amount £35,000 (GBP)
Funding ID RP45/2008 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2009 
End 12/2012
 
Description National studies of kidney disease in childhood and adolescence
Amount £349,929 (GBP)
Funding ID G0800571 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2009 
End 03/2011
 
Description Personalised immunomonitoring in idiopathic nephrotic syndrome - towards a molecular re-classification of disease
Amount £99,925 (GBP)
Funding ID KKR/Paed2017/04 
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2017 
End 12/2019
 
Description Stratified Medicine
Amount £3,140,000 (GBP)
Funding ID MR/R013942/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2018 
End 05/2022
 
Description Trans-national cohorts of nephrotic syndrome - a unified approach to a global chronic disease
Amount £532,743 (GBP)
Funding ID MR/P024297/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2017 
End 03/2020
 
Title GCRF - national NephroS study 
Description International INS cohort, built by funding from MRC GCRF award 
Type Of Material Biological samples 
Year Produced 2019 
Provided To Others? Yes  
Impact Industry engagement for use and partnerships Evolving plans for research outcomes 
 
Title NURTuRE patient database 
Description National cohorts of CKD and Nephrotic Syndrome. Patient clinical data is stored at the UK Renal Registry via the RaDaR patient registry 
Type Of Material Database/Collection of data 
Year Produced 2019 
Provided To Others? Yes  
Impact Industry investment - £4M to date 
URL http://nurturebiobank.org
 
Description NURTuRE - the National Unified Renal Translational Research Enterprise 
Organisation AbbVie Inc
Country United States 
Sector Private 
PI Contribution I initiated and lead (with Professor Maarten Taal) this national resource and infrastructure. This is a national network of renal research nurses recruiting patients to 2 pilot cohorts, Chronic Kidney Disease (CKD) and Idiopathic Nephrotic Syndrome (INS). Alongside detailed ongoing clinical phenotyping, there is a comprehensive biorepository, with patient samples stored at the UK Biobank in Milton Keynes. Funding has been obtained from a pre-competitive industry partnership (£2.2M to date), and governance is provided independently by Kidney Research UK
Collaborator Contribution I initiated the concept and brought together the partners, in order to establish the funding and governance of this national infrastructure. The formation of a national renal biorepository fits with one of the main objectives of the UK Renal Research Strategy published by the Renal Association.
Impact MRC Stratified Medicine award. Publications in Journal of Kidney Care, Open Journal of Bioresources. Further industry investment. MRC Global Challenges Award.
Start Year 2016
 
Description NURTuRE - the National Unified Renal Translational Research Enterprise 
Organisation Evotec
Country Germany 
Sector Private 
PI Contribution I initiated and lead (with Professor Maarten Taal) this national resource and infrastructure. This is a national network of renal research nurses recruiting patients to 2 pilot cohorts, Chronic Kidney Disease (CKD) and Idiopathic Nephrotic Syndrome (INS). Alongside detailed ongoing clinical phenotyping, there is a comprehensive biorepository, with patient samples stored at the UK Biobank in Milton Keynes. Funding has been obtained from a pre-competitive industry partnership (£2.2M to date), and governance is provided independently by Kidney Research UK
Collaborator Contribution I initiated the concept and brought together the partners, in order to establish the funding and governance of this national infrastructure. The formation of a national renal biorepository fits with one of the main objectives of the UK Renal Research Strategy published by the Renal Association.
Impact MRC Stratified Medicine award. Publications in Journal of Kidney Care, Open Journal of Bioresources. Further industry investment. MRC Global Challenges Award.
Start Year 2016
 
Description NURTuRE - the National Unified Renal Translational Research Enterprise 
Organisation Kidney Research UK
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution I initiated and lead (with Professor Maarten Taal) this national resource and infrastructure. This is a national network of renal research nurses recruiting patients to 2 pilot cohorts, Chronic Kidney Disease (CKD) and Idiopathic Nephrotic Syndrome (INS). Alongside detailed ongoing clinical phenotyping, there is a comprehensive biorepository, with patient samples stored at the UK Biobank in Milton Keynes. Funding has been obtained from a pre-competitive industry partnership (£2.2M to date), and governance is provided independently by Kidney Research UK
Collaborator Contribution I initiated the concept and brought together the partners, in order to establish the funding and governance of this national infrastructure. The formation of a national renal biorepository fits with one of the main objectives of the UK Renal Research Strategy published by the Renal Association.
Impact MRC Stratified Medicine award. Publications in Journal of Kidney Care, Open Journal of Bioresources. Further industry investment. MRC Global Challenges Award.
Start Year 2016
 
Description NURTuRE - the National Unified Renal Translational Research Enterprise 
Organisation UCB Pharma
Department UCB Celltech
Country United Kingdom 
Sector Private 
PI Contribution I initiated and lead (with Professor Maarten Taal) this national resource and infrastructure. This is a national network of renal research nurses recruiting patients to 2 pilot cohorts, Chronic Kidney Disease (CKD) and Idiopathic Nephrotic Syndrome (INS). Alongside detailed ongoing clinical phenotyping, there is a comprehensive biorepository, with patient samples stored at the UK Biobank in Milton Keynes. Funding has been obtained from a pre-competitive industry partnership (£2.2M to date), and governance is provided independently by Kidney Research UK
Collaborator Contribution I initiated the concept and brought together the partners, in order to establish the funding and governance of this national infrastructure. The formation of a national renal biorepository fits with one of the main objectives of the UK Renal Research Strategy published by the Renal Association.
Impact MRC Stratified Medicine award. Publications in Journal of Kidney Care, Open Journal of Bioresources. Further industry investment. MRC Global Challenges Award.
Start Year 2016
 
Description NURTuRE - the National Unified Renal Translational Research Enterprise 
Organisation University of Nottingham
Country United Kingdom 
Sector Academic/University 
PI Contribution I initiated and lead (with Professor Maarten Taal) this national resource and infrastructure. This is a national network of renal research nurses recruiting patients to 2 pilot cohorts, Chronic Kidney Disease (CKD) and Idiopathic Nephrotic Syndrome (INS). Alongside detailed ongoing clinical phenotyping, there is a comprehensive biorepository, with patient samples stored at the UK Biobank in Milton Keynes. Funding has been obtained from a pre-competitive industry partnership (£2.2M to date), and governance is provided independently by Kidney Research UK
Collaborator Contribution I initiated the concept and brought together the partners, in order to establish the funding and governance of this national infrastructure. The formation of a national renal biorepository fits with one of the main objectives of the UK Renal Research Strategy published by the Renal Association.
Impact MRC Stratified Medicine award. Publications in Journal of Kidney Care, Open Journal of Bioresources. Further industry investment. MRC Global Challenges Award.
Start Year 2016
 
Description Retrophin natural history study in nephrotic syndrome 
Organisation Retrophin
Country United States 
Sector Private 
PI Contribution Provision of data from our national nephrotic syndrome database
Collaborator Contribution Data analyst and high level project management
Impact No outcome yet
Start Year 2020
 
Description NURTuRE launch event 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Research nurse and clinician gathering for national patient cohort study
Year(s) Of Engagement Activity 2018,2019
URL http://www.nurturebiobank.org
 
Description Wellcome Trust funded NS patient App development 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Patients, carers and/or patient groups
Results and Impact Patient and carer involvement in developing a patient focussed app, particularly designed to engage young adults and adolescents, to help in disease monitoring, management and patient education
Year(s) Of Engagement Activity 2020,2021