RaDaR Research

RDG

Outputs / Exemplars

aHUS

Change in practice: Identification of complement nonresponsive genes for aHUS including EXOSC3, and secondary TMA due to nephrotic syndrome genes and hypertension genes.

Publications:

- Atypical haemolytic uraemic syndrome in the era of terminal complement inhibition- An observational cohort study. Blood 2023

- Assessing the Impact of Prophylactic Eculizumab on Renal Graft Survival in Atypical Hemolytic Uremic Syndrome. Transplantation 2023;107(4):994-1003.

- Safety and impact of eculizumab withdrawal in patients with atypical haemolytic uraemic syndrome: protocol for a multicentre, open-label, prospective, single-arm study. BMJ Open 2022;12(9):e054536.

- Long-term outcomes and response to treatment in diacylglycerol kinase epsilon nephropathy. Kidney Int 2020;97(6):1260-74.

- Hyperfunctional complement C3 promotes C5-dependent atypical hemolytic uremic syndrome in mice. J Clin Invest 2019;129(3):1061-75.

Alport Syndrome

Our close working relationship.

Engagement with an international research community.

Establishment of the Alport Hub (£2.55M from the Stoneygate Trust to create physical and virtual hubs bringing together world-leading researchers to accelerate the discovery and testing of new treatments).

Publications:

- Alport syndrome natural history from the radar registry: associations with gene, variant type and sex. Nephrology Dialysis Transplantation 2023;38(1)

ARPKD/NPHP

Change in sampling technique from invasive kidney biopsy to non-invasive "liquid biopsy" (urine sample).

• Less difficult and distressing for patients to provide samples; more samples provided.
• Increased ability to study inherited kidney disease, in more detail.
• Increased research activity has led to the establishment of dedicated inherited kidney disease clinics.
• Also resulted in significant funding for the labs.

BK Nephropathy

The RDG PPI has contributed to grant applications

Calciphylaxis

Global leadership:

• CACLIPHYX International Chief Investigator and UK PI (Global Phase 3 CTIMP for vascular calcification inhibitor SNF472).
• BEAT-Calci Co-Investigator (Better Evidence and Translation for Calciphylaxis international study).

CKD African Genes

New APOL1 testing available at King's which can be offered to other units.  This will be publicised when 'live'.

Cystinosis 

National Commissioning of the Cystinosis Centres: NHS England » Service specification: Cystinosis diagnosis and co-ordination of management (all ages).

• The Centres will provide coordinated multidisciplinary care which will delay/prevent severe complications, and provide treatment and care for other complications.

National Commissioning of Cystadrops:  NHS England » Mercaptamine hydrochloride viscous eyedrops for corneal cystine deposits in people aged 2 years and over.

• Viscous eyedrops are more effective, require fewer doses, and can be stored at room temperature, compared with aqueous drops.

Most of the RDG members energy has been focussed on setting up the hubs, which are still evolving but will profoundly change practice with anticipated patient benefit.

There is a major phase 1 trial of the “CF10 prodrug” hopefully in 2024, which we will support.

We will be supporting the International Cystinosis Network Europe Conference from 25 – 27 July 2024 in Manchester.

Cystinuria

Approached by several Pharma companies regarding urine chelators.

Improving patient care. A good exemplar of this was the National letter re tiopronin shortage we developed in 2021.

Publications:

- Clinical and Genetic Analysis of Patients with Cystinuria in the United Kingdom. Clinical Journal of American Society of Nephrology (cJASN) Jul 7:1235-45. 2015

- Cystinuria: An overview of challenges and surgical management. Frontiers in Surgery 2022

- Non-contrast computed tomography characteristics in a large cohort of cystinuria patients. World J Urol 2021; 39: 2753-7

- Cystinuria: clinical practice recommendation. Kid Int 2021; 99: 48-58

- Patient experience: Living with cystinuria during the Covid-19 pandemic. J Endolum Endourol 2020;3;1-6

- Evaluation and medical management of patients with cystine nephrolithiasis: a consensus statement. J Endourol 2020; 34: 1103-1110

- Hypertension and renal impairment in patients with cystinuria findings from a specialist cystinuria centre. Urolithiasis 2019; 47: 357-63

- Associating mutations causing cystinuria with disease severity with the aim of providing precision medicine. BMC Genomics 2017; 18:550

- Novel therapy for Cystinuria using Genetic Tools Fr PO602. American Society Nephrology 2023

Fibromuscular Dysplasia

The main developments are the ethical approval of the UK FMD study, Salford Royal Hospital is the sponsor and are uploading patients to this study. 9 other centres (the RaDaR collaborators primarily) are in the process of onboarding.

Hyperoxaluria

Creation of a virtual clinical pathway which is nationally available.

Helping the NHS use high-cost drugs in a cost-effective way.

Making genetic testing quicker and easier.

IgA Nephrothaphy

First questionnaire out to an entire RDG; intention is to send these annually.

Research plans are active and we wish to add QoL data to RaDaR.

We have "virtually" linked RaDaR with the NIHR BioResource and this should reap rewards in the coming years.

Inherited Renal Cancer Syndromes

Extensive recruitment has been achieved at one centre (Cambridge) and other centres are coming on board and are being prioritised.

MPGN, DDD and C3G

Activity in C3G trials slightly outwith RaDaR; work done by RDG group members has led to publications.

Nephrotic Syndrome (Steroid Sensitive & Steroid Resistant SSNS & SRNS)

Publications:

- Exploring the relevance of NUP93 variants in steroid-resistant nephrotic syndrome using next generation sequencing and a fly kidney model. Pediatr Nephrol. 37, (2022).

- PAR-1 signalling and pro-fibrotic effects of podocytes in response to circulating factor in active SRNS plasma (Submitted to Communications Biology)

- A NURTuRE study: Proteomic profiling of kidney biopsy from minimal change disease and focal segmental glomerulosclerosis patients. (submitted to Wellcome Open Research)

- What is circulating factor disease and how is it currently explained?. Pediatr Nephrol (2023)

- Epigenetic mechanisms and nephrotic syndrome: a systematic review. Biomedicines 2023, 11(2), 514

- Paper in press in Nephrology Dialysis and Transplantation: Taal et al; Associations with age and glomerular filtration rate in a referred population with chronic kidney disease: methods and baseline data from a UK multicentre cohort study (NURTuRE-CKD).

- Proteomic signature associated with chronic kidney disease (CKD) progression identified by data-independent acquisition mass spectrometry. Clinical Proteomics (accepted March 2023)

- Podocyte protease actuated receptor 1 stimulation in mice produces focal segmental glomerulosclerosis mirroring human disease signaling events. 18 Mar 2023, (E-pub ahead of print) In: Kidney International.

Tuberous Sclerosis

Development of the first ever UK clinical guidelines for management and surveillance of Tuberous Sclerosis Complex in the NHS, published in 2019. The guidelines capture best practice in clinical care and aim to make it available to all NHS patients with TSC, helping to drive improvements in consistency and quality of care.

Tubulopathy

Publications:

- Long-read sequencing identifies a common transposition haplotype predisposing for CLCNKB deletions. Genome Medicine volume 15 62 (2023)

- Hyperoxaluric acute kidney injury and frontotemporal dementia. The Lancet (2023) (401) 10387 May 2023

- Machine Learning to Identify Genetic Salt-Losing Tubulopathies in Hypokalemic Patients. Kidney International Reports (2022) Dec 2022

- Parathyroid hormone and phosphate homeostasis in patients with Bartter and Gitelman syndrome: an international cross-sectional study. Nephrology Dialysis Transplantation (2022)

- Renal Tubular Acidosis. Pediatric Nephrology (2022) 903-928 Sept 2022

- Distal renal tubular acidosis: ERKNet/ESPN clinical practice points. Nephrology Dialysis Transplantation, (2021) Volume 36, Issue 9, p1585–1596

- Fumaric acid ester–induced renal Fanconi syndrome: evidence of mitochondrial toxicity. Clinical Kidney Journal (2021)

- The management of Sjögren’s syndrome: British Society for Rheumatology guideline scope. Rheumatology (2021) May 14;60(5):2122-2127.