The fate of nephrons in congenital and heritable renal disorders

Most chronic kidney disease in infants and children results from congenital anomalies of the kidneys and urinary tract, including obstructive nephropathy. Although less common, inherited disorders such as polycystic kidney disease (PKD) and cystinosis also lead to progressive tubular injury and nephron loss. At the present time, therapies to slow progression of kidney disease are mainly directed renal interstitial fibrosis, a final common pathway. To target earlier events in congenital renal disorders, we have investigated in animal models the response of the renal proximal tubule, which appears to be particularly susceptible to injury. Unilateral ureteral obstruction (UUO) causes marked oxidative stress and rapid death of proximal tubular cells in the adult mouse, leading to the formation of atubular glomeruli. This occurs also following UUO in the neonate (during completion of nephrogenesis), but tubular cell death is delayed until proximal tubular mitochondrial maturation is complete. In the pcy mutant mouse, a model of autosomal dominant PKD, tubular cysts develop in the neonatal period, and progressively enlarge, eventually causing obstruction of neighboring nephrons and formation of atubular glomeruli. In the ctns mutant mouse with nephropathic cystinosis, injury results from accumulation of cystine crystals. This results in oxidative stress and stimulates flattening (rather than death) of proximal tubular cells (“swan neck deformity”), and onset of the Fanconi syndrome. Progression to severe proximal tubular atrophy and formation of atubular glomeruli develops in later adult life. These studies suggest that early treatment of congenital renal disorders should target protection of proximal tubules from oxidative injury. We are currently investigating the use of antioxidants that are selectively concentrated in mitochondria. Since children with congenital renal disorders are born with a reduced nephron number (which cannot be regenerated), every effort must be made to preserve remaining nephrons throughout adult life. Review Proceedings of the 9 International Workshop on Neonatology · Cagliari (Italy) · October 23-26, 2013 · Learned lessons, changing practice and cutting-edge research Proceedings