Abstract: SA-PO428
Transient Hydronephrosis in the Developing Kidney Leads to Long-Term Epigenetic Changes and Increased Susceptibility to Acute Renal Failure in Adulthood
Session Information
- Pediatric Nephrology - II
October 27, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Pediatric Nephrology
- 1600 Pediatric Nephrology
Authors
- Manson, Scott R., Texas Children's Hospital, Houston, Texas, United States
- AF Molina, Carlos, Texas Children's Hospital, Houston, Texas, United States
- Austin, Paul, Texas Children's Hospital, Houston, Texas, United States
Background
The criteria for surgical intervention in patients with congenital urinary obstruction are poorly defined and little is known about the long-term effects of hydronephrosis in the developing kidney. In this study, we evaluated the impact of developmental context on disease progression, the need for intervention, and long-term susceptibility to kidney disease.
Methods
Disease progression was compared in murine models of unilateral ureteral obstruction (UUO) at P1 during nephrogenesis, P14 during the proliferative growth phase, and P60 at maturity. A reversible UUO model (rUUO) was used in neonates to assess the impact of intervention and its timing on long-term outcomes at maturity including growth and maturation, kidney function, and susceptibility to acute renal failure after unilateral ischemic injury (IR/Nx). Disease progression was evaluated by histological methods, functional assessment (serum BUN/Cre), and whole transcriptome analysis (RNA-seq).
Results
While UUO at P60 leads to inflammation and fibrosis, disease progression in neonates is instead characterized by profound developmental deficits. UUO at P1 triggers a 43.8% decrease in nephrogenesis and 35.2% decrease in kidney growth. UUO at P14 results in a 61.6% decrease in proliferation and 26.3% decrease in kidney growth. Impaired renal maturation is prevented by early intervention following rUUO at P14 but not P1 (Recovery/P1 – 27.1%, P14 – 67.1%). Although mice subjected to rUUO at P14 had only minimal differences in kidney weight and function after 12 weeks of recovery, whole transcriptome analysis showed significant changes in the expression of 30.4% of all genes. Furthermore, when these mice were challenged with an IR/Nx protocol that typically has only moderate effects, they strikingly exhibited acute renal failure (SrCre: CON – 1.8, rUUO – 3.1) and low rates of survival (CON – 100.0%, rUUO – 12.5%). [All results are p<0.05]
Conclusion
This study reveals that developmental context has a significant impact on disease mechanisms, long-term outcomes, and treatment strategies. While deficits in nephrogenesis are irreversible, early intervention restores proliferative growth and kidney function. Continued monitoring is required even after recovery as the epigenetic signature remains altered and there is an elevated risk for kidney disease.
Funding
- NIDDK Support