Genomic and Developmental Determinants of Nephron Endowment in Paediatric Kidney Disease: Mechanisms, Diagnosis and Therapeutic Perspectives

Nephron endowment is established by approximately the 34th to 36th week of gestation, varies more than tenfold between healthy individuals and cannot be measured directly in a living patient. Congenital anomalies of the kidney and urinary tract (CAKUT), prematurity and intrauterine growth restriction converge on a low endowment as a shared route to hypertension and chronic kidney disease in childhood. This review integrates the genomic control of the nephrogenic niche with its clinical translation. We summarise how glial cell line-derived neurotrophic factor (GDNF)–RET, WNT/β-catenin, BMP, NOTCH and Hippo signalling and transcription factors including SIX2, PAX2, WT1, SALL1, HNF1B and GATA3 regulate progenitor lifespan, with the direction in which nephron number responds to reduced dosage depending on which node of the network is perturbed. The genomic architecture of a reduced endowment spans monogenic and copy number variants, oligogenic burden, common variants and incomplete penetrance, and exome and genome sequencing each leave part of it unread; cellular mechanisms converge on premature progenitor exhaustion. We then address perinatal determinants, whom to test, how to monitor and how to protect the remaining nephrons. Finally, we compare single-cell, spatial, chromatin, organoid and immunohistochemical platforms, appraise urinary biomarkers including extracellular vesicles, microRNAs, epidermal growth factor and uromodulin, and define priorities for genomically informed risk stratification in children.