Nephronophthisis

Nephronophthisis (NPHP) is a group of autosomal recessive cystic kidney diseases that represent the most common genetic cause of end-stage renal disease (ESRD) in children and young adults. The disease primarily affects the kidneys, where it causes progressive tubulointerstitial fibrosis, tubular basement membrane disruption, and the formation of corticomedullary cysts. Nephronophthisis belongs to the broader category of ciliopathies — disorders caused by dysfunction of primary cilia — and is caused by mutations in over 20 different NPHP genes, including NPHP1 (the most commonly affected gene, accounting for approximately 20% of cases), NPHP2 (INVS), NPHP3, NPHP4, and others. Three clinical forms are recognized based on age of onset of end-stage renal disease: infantile nephronophthisis (presenting in the first few years of life), juvenile nephronophthisis (the most common form, with ESRD typically occurring around age 13), and adolescent/adult nephronophthisis (with ESRD occurring around age 19 or later). Key symptoms include polyuria (excessive urination), polydipsia (excessive thirst), secondary enuresis (bedwetting), growth retardation, and progressive chronic kidney disease. Notably, the disease often presents insidiously, with bland urinary sediment and absence of significant proteinuria or hypertension until late stages, which can delay diagnosis. Kidneys are typically normal-sized or small, distinguishing nephronophthisis from polycystic kidney diseases. In approximately 10-20% of cases, nephronophthisis occurs as part of a syndromic condition with extrarenal manifestations. These include Senior-Løken syndrome (with retinal degeneration/retinitis pigmentosa), Joubert syndrome (with cerebellar vermis hypoplasia), Bardet-Biedl syndrome, Meckel-Gruber syndrome, and other ciliopathies involving hepatic fibrosis, skeletal anomalies, or situs inversus. There is currently no specific treatment to halt or reverse the progression of nephronophthisis. Management is supportive and includes treatment of chronic kidney disease complications such as anemia, growth failure, electrolyte imbalances, and metabolic bone disease. Renal replacement therapy (dialysis or kidney transplantation) is ultimately required when ESRD develops. Importantly, nephronophthisis does not recur in transplanted kidneys. Genetic testing and counseling are essential components of care for affected families.

Common questions about Nephronophthisis