Award Title: SuperResPath-Renal: Quantitative super-resolution technology for a fast, de-centralised clinical diagnosis of renal pathologies
Funder: Department of Health and Social Care

Abstract: Background  Renal pathologies are the most common primary cause of nephrotic syndrome. For diagnosis, a renal biopsy is examined at different levels, including high-resolution electron microscopy (EM) to detect glomerular ultrastructural changes imperceptible by histology. EM is the most expensive single test in histopathology labs, limiting diagnosis of renal pathologies with long turnaround times (2-3 weeks). NHS England spent around £1.45 billion on chronic kidney disease (2009-10), with an average 70% of renal biopsies needing EM studies for diagnosis, costing around £300 each.   Aims and Research question  Our project aims to combine super-resolution microscopy with advanced data analysis to establish a de-centralised and rapid (2-5 days) platform for routine renal pathology assessment. We intend to detect multiple glomerular podocyte markers in biopsy samples using high-precision dSTORM imaging for an improved renal histopathology diagnosis and patient outcome.   Methods  Formalin-fixed paraffin-embedded tissue samples will be imaged using ONI s Nanoimager microscope, with cutting-edge super-resolution imaging technology. Machine-learning algorithms will allow detection of features of interest to be imaged with dSTORM to visualise key fluorescently-labelled renal proteins. Multi-parametric cluster-based data analysis will provide a read-out for diseased tissues.  Timelines  Phase I will validate and optimise the protocol to stain tissue samples for dSTORM imaging, phase II will integrate imaging and automated data analysis into a turn-key workflow, phase III will see the clinical application of ONI's super-resolution microscope into NHS histopathology labs. Our technology should be patient-ready in 3 years.   Anticipated impact and dissemination   Our technology will allow a larger portion of renal biopsies to be examined, increasing diagnostic sensitivity and specificity, benefiting patients. Replacing EM and reducing labour costs could save money to the NHS (>£10M across UK pathology units, 3 years post-project). Adoption will be ensured through conference presentations, publications, demonstrations at NHS pathology units, and with public and patient involvement.

Lay Abstract: Kidneys are the organs that filter the blood and produce urine. Conditions are usually identified (diagnosed) by doing a kidney biopsy, a procedure that takes a piece of kidney tissue for examination under a microscope (instrument used to see objects which are too small to be seen by naked eye). Currently, electron microscopes are the only tool able to detect tiny nanoscale (a nanometre is a millionth of a millimetre) changes in kidney tissue. Detecting these tiny changes allows experts to diagnose specific kidney diseases, like Minimal Change Disease and Focal Segmental Glomerulosclerosis (scarring). These affect two components of the kidney filtration barrier: podocytes (cells wrapped around blood vessels) and basement membrane (sitting between cells and vessels).  In the last 10 years, a new class of light microscopy that enables imaging at the nanoscale has emerged: super-resolution microscopy, which is able to resolve structures too small to see with normal light microscopes. This type of microscopy can be used to visualise the really small kidney structures that are affected in these diseases. The company Oxford Nanoimaging (ONI) has built one of the world s first desktop super-resolution microscopes, which can sit on a laboratory bench and make advanced imaging more easily usable in clinical practice. The technology can measure data of multiple single molecules (groups of atoms bonded together) with great accuracy.  We recognised the need for a faster, simpler, cheaper test that studies the entire kidney biopsy in detail rather than a small part of it. This would increase diagnostic quality and give advantages to patients and the NHS, such as a shorter time to diagnosis in just 2-5 days. To achieve this we will test and confirm a range of kidney markers in renal tissue using the ONI microscope. This information will then be used to build a computer programme for automated imaging analysis (a software to extract data from digital images).  Presentations at conferences, publications and technology demonstrations at pathology units and hospitals will encourage adoption. We will engage patients, researchers and clinicians across Leeds Teaching Hospital, to ensure an informed strategy through discussions. Public members will be engaged during the Leeds University open days, National Pathology day and the Thackray Medical Museum.  Once commercialised (on sale to hospitals), our super resolution microscope could be used to diagnose other diseases and become a routine NHS test.

Research Activity Codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health Categories: RENAL AND UROGENITAL