The Fate of Nephrons in Congenital Obstructive Nephropathy: Adult Recovery is Limited by Nephron Number

Abstract

Background: Pediatric chronic kidney disease (CKD) is most often due to congenital anomalies of the kidneys and urinary tract (CAKUT), and obstructive nephropathy is the leading cause. Progression to renal failure, however, is more likely to develop in adulthood than childhood (Wuhl, CJASN 8: 67–74, 2013). Frequently associated with CAKUT, reduced nephron number (NN) at birth is an independent risk factor for adult CKD. Methods: To determine the role of NN in progression of congenital obstructive nephropathy, wild-type (WT) and reduced NN mice (Os/+) were subjected to sham operation or partial unilateral ureteral obstruction (UUO) in the first 2 days of life (prior to completion of nephrogenesis). To assess the impact of NN on recovery, additional WT and Os/+ mice underwent release of UUO at 7 days. All kidneys were harvested at 3 weeks (weaning) or 6 weeks (adulthood). Glomerular number and area, glomerulotubular junction integrity, proximal tubular volume fraction, and interstitial fibrosis were measured by histomorphometry. Results: In the obstructed kidney, UUO caused additional nephron loss in Os/+ but not WT mice. Glomerular growth from 3 to 6 weeks was impaired by ipsilateral UUO and was not preserved by release in WT or Os/+. Proximal tubular growth was impaired and interstitial collagen was increased by ipsilateral UUO in all mice. These were attenuated by release of UUO in WT mice but were not restored in Os/+ mice. In the contralateral kidney of Os/+ mice, UUO decreased proximal tubular growth and increased interstitial collagen which were prevented by release of obstruction. Conclusions: Congenital partial UUO impairs glomerular and proximal tubular growth, and causes additional nephron loss in mice with reduced NN. Release of UUO does not improve glomerular growth regardless of NN, and does not preserve tubular mass when NN is reduced. Because tubular injury and fibrosis develop in both kidneys of adult mice with UUO and reduced NN, timely release of UUO benefits all remaining nephrons. Children with CAKUT should be followed throughout adulthood regardless of earlier surgical intervention.