Urinary renal epithelial cells can be used for NPHP1 phenotyping and a personalized therapeutic strategy.

Nephronophthisis (NPHP) is a recessive tubulointerstitial nephropathy and a leading genetic cause of kidney failure in children and young adults. The most common genetic cause is a homozygous deletion of NPHP1, which encodes nephrocystin-1, a protein essential for primary cilium structure and cell junctions. Using personalized medicine and deep phenotyping, we investigated a family with three siblings carrying a homozygous NPHP1 deletion. We compared kidney biopsy tissue and human urine-derived renal epithelial cells (hURECs) from these individuals. Bulk RNA-seq on patient hURECs revealed altered expression in EGFR signalling, extracellular components and adherens junctions, which is consistent with the known roles for nephrocystin-1. Treatment with alprostadil, a proposed NPHP therapy, increased ciliation but worsened ciliary elongation. By contrast, the EGFR kinase inhibitor AG556 rescued of ciliary length and morphology. Transcriptional profiling post-treatment showed AG556 reversed the disease signature more effectively that alprostadil. These findings suggest that EGFR inhibition might offer a more promising therapeutic strategy for NPHP1-associated renal ciliopathy, warranting further testing in in vivo models before clinical application.