Chronic kidney disease (CKD) is a long-term kidney damage caused by gradual loss of kidney functions. A global health issue, CKD affects up to 16% of the population worldwide. Symptoms are often not apparent, and if untreated, CKD can progress to end-stage kidney disease when the only remedies are dialysis and kidney transplantation. Kidney fibrosis, the end point of nearly all forms CKD, has been object of intense research in the Verderio Edwards’ group at NTU. Renal scar is routinely tested by renal biopsy, the “gold standard” which however is limited by invasiveness and sampling bias; moreover, it only detects CKD when fibrosis is advanced. Urine is a desirable source of CKD biomarkers; in particular, urinary extracellular vesicles (uEVs), which originate from renal cells and carry proteins, nucleic acids, and lipids, are an attractive source of potential rare biomarkers. Combining spatial transcriptomics and molecular profiling data of uEV isolated from CKD patients, this project is aimed at exploring alternative and more effective ways to assess CKD, which ultimately may allow better treatment and facilitate the running of clinical trials.
We will explore new ways to understand and monitor CKD progression. (i) Via GeoMx Digital Spatial Profiling, tubular and glomerular regions of interest will be monitored in kidney biopsies from patients with stable and progressive CKD and from normal control biopsies. Whole tissue images at single cell resolution and spatially resolved data for RNA will be produced enabling unprecedented early evaluation of CKD progression. The prognostic value and usefulness of this approach will be validated by comparing data with those acquired by routine biopsy (histopathological changes of fibrosis). (ii) The cell origin of urinary CKD markers (uEV’s) will be tracked through imaging areas of interest by immunofluorescence staining against these markers. Further, we will perform whole exome sequencing of these areas as a read-out for GeoMx experiments to obtain gene expression data, which will help unravel previously unknown pathogenic mechanisms and help highlight new therapeutic targets. Analytical pipelines are already in place in our laboratories. A selection of patient kidney sections will be obtained from Nurture CKD biorepository or other sources upon ethical consent through our partnership with Royal Derby Hospital.
Thanks to our collaboration with Professors Maarten Taal and Nick Selby, lead Nephrologists and external supervisors in this project, we anticipate that CKD progression will be detected in a previously unseen way, potentially leading to better patient stratification and treatment.
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