Nephronophthisis

Nephronophthisis is a group of autosomal recessive tubulointerstitial kidney diseases characterized by tubulointerstitial fibrosis and cystic changes at the corticomedullary junction. It is a leading genetic cause of end-stage renal disease (ESRD) in children and often presents with progressive kidney dysfunction that becomes apparent in childhood or adolescence.

Clinical features commonly include polyuria and polydipsia due to concentrating defects, nocturnal enuresis, growth retardation, and anemia. Blood pressure is often normal in early disease. The kidneys may be small or normal in size, with corticomedullary cysts visible on imaging. Progression to chronic kidney disease and ESRD typically occurs in childhood or adolescence, with timing varying by the disease subtype. Some patients have extrarenal manifestations, most notably retinal dystrophy in Senior-Løken syndrome or involvement of the central nervous system in other ciliopathies such as Joubert syndrome.

Genetically, nephronophthisis is heterogeneous, with mutations in multiple NPHP genes (including NPHP1, NPHP3, NPHP4, IQCB1/NPHP5, CEP290/NPHP6, and others) accounting for different forms. It is part of a broader spectrum of ciliopathies; certain gene mutations can cause nephronophthisis with retinal (Senior-Løken) or brain involvement (Joubert). Inheritance is autosomal recessive, and the gene involved influences age of onset and extrarenal features.

Diagnosis relies on clinical presentation, laboratory findings of progressive CKD with polyuria, imaging showing corticomedullary cysts, and confirmation with genetic testing. Kidney biopsy is rarely required but may show tubulointerstitial nephritis with fibrosis and cystic changes. Treatment is supportive, addressing CKD progression and extrarenal manifestations; ESRD is managed with dialysis or kidney transplantation. The prognosis varies by genotype and presence of extrarenal features.