The European Rare Kidney Disease Reference Network


Research Project

Project Title:

Using stem cell technologies to understand human renal tract malformations

Project Type:

Translational research

Disease group(s):

AD structural kidney disorders, Renal malformations

Project Summary:

Lay summary: In this project we will work out why some people are born with abnormal kidneys. We will use the most up-to-date techniques in which ‘stem cells’ are made from peoples’ blood cells. These stem cells are then used to form mini kidneys in a dish. We will compare the growth of mini kidneys made from healthy people with those made from people born with abnormal kidneys and who carry abnormal genes, or ‘mutations’. Our study will allow us to design therapies to make the diseased kidneys grow more normally, eventually allowing people to live free from dialysis and transplantation.

Science summary: Renal malformations account for 45% of children with end stage renal disease (ESRD). Worldwide, renal malformations account for an estimated 16,000-88,000 ESRD children. Moreover, around 20% of young adults with ESRD have malformed kidneys. Heterozygous mutations of hepatocyte nuclear factor 1B (HNF1B) transcription factor are detected in 5-20% of children with renal malformations, with cystic dysplastic kidneys being the characteristic phenotype. This disease is recognised by RaDaR (National Registry of Rare Kidney Diseases). In this project, presented to an interested audience at the 2016 HNF1B UK Patient Information Day, we will apply stem cell technologies to understand how HNF1B mutations generate malformed human kidneys. We will derive induced pluripotent stem cells (iPSCs) from people with cystic dysplastic kidneys and HNF1B mutations. As proof-of-principle, we have initiated this reprogramming protocol in one family. Unaffected family members will serve as controls. We will mutate HNF1B in wild-type cells using gene editing to make matched lines differing only in the HNF1B locus but identical epigenetically and for potential disease modifying genes. Mutant HNF1B cells will be compared with wild-types for abilities to differentiate into mini kidneys using our successful protocols. These include the generation of 3D embryonic organs containing branching collecting ducts and forming nephrons, processes we can quantify. Strikingly, after transplantation, wild-type iPSCs kidney precursors generate vascularised glomeruli. We hypothesise that HNF1B mutant iPSCs will form kidneys containing poorly branched and cystic ducts, with few nephrons. We will evaluate cell signalling defects in mutant iPSC-derived kidneys to identify pathways to target therapeutically. In future, these results will inform drug screening protocols, e.g. via the National Phenotypic Screening Centre, to enhance kidney differentiation and eventually allow people to live without dialysis and transplantation. Critically, our ground-breaking study constitutes a useful template for further research on numerous rare kidney diseases recognised by RaDaR.

Lead principal investigator(s):

Susan Kimber, Manchester


Adrian Woolf, Manchester

Project Period:

01/2017   -   12/2020


Non-profit foundation

Project web page:

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