Nephronophthisis: Current clinical spectrum and molecular pathogenesis

Nephronophthisis (NPH) is a ciliopathy primarily affecting renal tubules and interstitial tissue, ultimately progressing to end-stage kidney disease (ESKD). The clinical spectrum of NPH is broad and can be classified according to the age at onset into infantile, juvenile, adolescent, and late-onset forms. Histopathologically, NPH is characterized by corticomedullary cysts, tubular atrophy, interstitial fibrosis, and cystic dilatation of distal tubules. The kidneys may appear normal in early stages but gradually shrink with disease progression. More than 20 causative genes have been identified, with NPHP1 being the most common. These genes encode proteins that localize predominantly to the ciliary transition zone and basal body, where they regulate ciliary structure and signaling. Loss of ciliary function disrupts epithelial polarity, intracellular trafficking, and signal transduction, leading to tubular injury and fibrosis. When extrarenal organs such as the retina, liver, or central nervous system are affected, the condition is defined as nephronophthisis-related ciliopathies (NPH-RC). This review summarizes the current understanding of NPH classification, clinical features, and molecular mechanisms. Here, we highlighted recent advances in genetic discoveries, pathogenic signaling pathways, and therapeutic strategies, including gene therapy and targeted molecular interventions.