Research Involving RaDaR: Nephrotic Syndrome - NephroS/ NURTuRE Studies. Liz Colby Project Manager, University of Bristol

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1 Research Involving RaDaR: Nephrotic Syndrome - NephroS/ NURTuRE Studies Liz Colby Project Manager, University of Bristol

2 What is Nephrotic Syndrome? Breakdown of the glomerular filtration barrier Massive loss of essential circulating proteins Heavy proteinuria Hypoalbuminemia Oedema In most cases the underlying mechanism is unknown - Genetics: Runs in families, >50 associated genes - Immune mediated: response to immunosuppressant's, circulating factor - Other?

3 Questions in Nephrotic Syndrome Current treatment is empirical and often unsuccessful Current classification is based on observational responses to therapies (low rates of response) Disease needs reclassification management strategies based on molecular investigations Single Gene Disorder Circulating Factor Disease INS population?other mechanism

4 NS Research RaDaR Clinical information on INS patients patients NephroS The National Study of Nephrotic Syndrome 1066 patients Allows patient samples to be collected including: - Blood (Plasma/Serum/DNA for genetics) - Urine - Biopsy material

5 NephroS Recruitment Total Accrual for Child Sites (n=588) Stoke 6 Norfolk and Norwich 1 Exeter 6 Walsall Manor Hospital 1 Russells Hall- Dudley group 2 Wolverhampton 6 Ashford and St Peters 9 Bath 4 Swindon 2 Taunton 4 Guys and St Thomas' 25 Southampton 32 Nottingham 61 Newcastle 11 Manchester 75 Liverpool 39 Leeds 78 GOSH 41 Glasgow 19 Cardiff 13 Bristol Childrens 51 Birmingham Total Accruals for Adult Sites (n=478) Nottingham Lister Preston (Lancashire) Epsom & St. Helier Walsall Manor Hospital Cumberland Infirmary York Truro Royal Cornwall Oxford (Churchill) New Cross Wolverhampton Norfolk and Norwich Stoke Edinburgh Shrewsbury and Telford Coventry and Warwickshire Manchester Newcastle Birmingham Plymouth Glasgow Exeter/Devon Cardiff Adults Colchester Hammersmith Sunderland NBT Southmead Expanded to: SRNS SSNS

6 Benefits of the NephroS Approach 1. A comprehensive collection of all UK NS patients 2. Detailed genetic analysis 3. Ability to discover podocyte specific biomarkers directly linked to patient disease activity Circulating factor disease

7 Research at a Glance Simultaneous sequencing of 24 genes associated with steroid-resistant nephrotic syndrome. McCarthy HJ1, Bierzynska A, Wherlock M, Ognjanovic M, Kerecuk L, Hegde S, Feather S, Gilbert RD, Krischock L, Jones C, Sinha MD, Webb NJ, Christian M,Williams MM, Marks S, Koziell A, Welsh GI, Saleem MA; RADAR the UK SRNS Study Group. Clin J Am Soc Nephrol Apr;8(4): doi: /CJN Epub 2013 Jan 24. Demonstrated the utility and efficiency of Next Generation Sequencing in this patient population: Inexpensive Reliable and reproducible Quick Diagnostic potential Revealed phenotypically unexpected variants

8 Availability of NGS technology is now changing clinical practice All known genes for SRNS tested (currently 50 genes, with new genes added) Rapid turnaround (4-6 weeks) 600 per patient

9 Whole Exome Sequencing Exome sequencing of 187 SRNS paediatric patients 48 (27%) patients had either a previously described mutation or a variant that is probably disease causing. 80 % of those were in the 4 commonest genes (Nephrin, Podocin, WT1 and LAMB2) 14/187 (7.5%) patients had likely pathogenic variants identified in rare genes that would not routinely be screened under recent testing practice Currently genome sequencing the NephroS cohort Bierzynska, A. et al Apr 2017 In : Kidney International. Bierzynska, A. et al May 2017 In : Journal of the American Society of Nephrology. 28, 5, p

10 Summary of Genetic Screening of UK Cohort Steroid resistant NS (defined by KDIGO guideline) Primary steroid resistance 131/181 (72.4%) Exclude clear secondary forms or other specific histological diagnosis 181* patients Next Generation Sequencing (156/181) Presumed steroid resistance (familial/congenital) 25/181 (13.8%) Secondary steroid resistance 25/181 (13.8%) Next generation sequencing (25/181) Initial steroid sensitivity can be a predictor of post transplant recurrence Monogenic 48/156 (30.8%) Non-monogenic/unknown 108/156 (69.2%) Monogenic 0/25 (0%) Post-transplant recurrence risk 0/25 (0%) Post-transplant recurrence risk 11/23 (47.8%) Post-transplant recurrence risk 4/5 (80%) Ding, W. Y.et al 7 Feb 2014 In : Journal of the American Society of Kidney International Nephrology. in press

11 Biomarker Circulating Factor Using plasma samples from patients with active disease, to directly test the effects on human podocytes in the laboratory Changes in cell behaviour from paired relapse/remission samples from same patient Harris, J. J. et al. Apr 2013 In : Journal of Pathology. 229, 5, p

12 NURTuRE m of Industry Investment Fund dedicated research nurses in larger renal units Advance the recruitment ability of the patient registry, >800 NS patients First UK national renal biosample repository as proposed in the UK Renal Research Strategy - strategic resource for fundamental and translational research. High quality research sampling. Links to National Databases RaDaR and NHS Digital

13 Location Hospitals 1. Birmingham Birmingham Children s Hospital Queen Elizabeth Hospital 2. Bristol Bristol Royal Children s Hospital 3. Cardiff University Hospital of Wales Noah s Ark Children s Hospital for Wales 4. Derby Royal Derby Hospital 5 5. Glasgow Queen Elizabeth Hospital Royal Hospital for Children 9 6. Leeds St. James University Hospital Leeds Children s Hospital 7. London Royal Free Hospital Manchester Royal Manchester Children s Hospital 9. Newcastle Royal Victoria Infirmary 10. Nottingham Nottingham University Hospital Queen s Medical Centre 11. Salford Salford Royal Hospital 12. Sheffield Northern General Hospital 88 NS patients to date Potential other sites 13. London Hammersmith Hospital (Imperial) 14. York York Hospital

14 MRC Stratified Medicine Grant Success!! 3.1 million over 4 years Seeks to use the valuable samples and clinical data collected in NURTuRE-NephroS: - Deep analysis of patient DNA, blood and biopsy samples - Generate new data and methods that will allow us to redefine the diagnostic categories of NS - Proved individualised diagnostic tests and new therapies.

15 International RaDaR and NURTuRE/ NephroS MRC Foundation Awards Grant Set up RaDaR and NURTuRE/ NephroS in 4 International Sites: - India: Bangalore, New Delhi - South Africa: Johannesburg - Egypt: Cairo Accurate estimations of incidence, outcomes, and responses to current therapies. Population of Nephrotic Patients is higher in these countries? Differences between ethnicities and environments (possible NS triggers?) Rapidly test larger populations

16 Thanks! Genetic epidemiology (Ania Koziell, Ian Day, Graham Lord) Teams recruiting to RaDaR/ NephroS / NURTuRE Patients and their families