Nephronophthisis and Related Ciliopathies

Abstract

Nephronophthisis (NPHP) is an autosomal recessive cystic kidney disease that constitutes one of the most frequent genetic causes for end-stage kidney disease (ESKD) in the first three decades of life [1-4]. Three clinical forms of NPHP have been distinguished by age of onset of ESKD: infantile [5, 6], juvenile [7], and adolescent NPHP [8], which manifest with ESKD at median ages of 1 year, 13 years, and 19 years, respectively. Initial symptoms are relatively mild with the exception of infantile NPHP type 2. They consist of polyuria, polydipsia with regular fluid intake at nighttime, secondary enuresis, anemia, and growth retardation [8]. A slightly raised serum creatinine is noted at an average age of 9 years, before ESKD invariably develops within a few years (Fig. 1a). Renal ultrasound reveals increased echogenicity (Fig. 1b). Beyond the age of 9 years, cysts appear at the corticomedullary junction within the kidneys of normal or slightly reduced size (Fig. 1b) [9]. Renal histology reveals a characteristic triad of tubular basement membrane disruption, tubulointerstitial nephropathy, and cysts (Fig. 1c) [10, 11]. In nephronophthisis, cysts arise from the corticomedullary junction of the kidneys (Fig. 1b). Because kidney size is normal or slightly reduced, cysts seem to develop ex vacuo through loss of normal tissue. This is in contrast to polycystic kidney disease, where cysts are distributed evenly and lead to gross enlargement of the kidneys [12]. NPHP is part of a broad spectrum of renal cystic/degenerative diseases that often include extrarenal manifestations. Over 90 recessive single-gene causes have been identified. Because the related gene products localize to primary cilia and centrosomes, the term “NPHP-related ciliopathies (NPHP-RC)" is now used for these disorders.