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Developmental Context has a Significant Impact on Disease Progression in the Obstructed Kidney and Potential Treatment Strategies
Julio J. Geminiani, M.D., Scott R. Manson, Ph.D., Gino J. Vricella, M.D., Qiusha Guo, Ph.D., Paul F. Austin, M.D..
Washington University, Saint Louis, MO, USA.

BACKGROUND:
A key research goal is to develop adjuvant therapies capable of improving surgical outcomes in patients with obstructive uropathies. While most studies have examined disease progression in the mature kidney, it is likely that there are significant differences in the developing kidney which have important implications for the treatment of congenital urinary tract obstruction. In this study, we compared the pathogenesis of obstruction-induced renal injury during each of the critical stages of kidney development.
METHODS:
Disease progression was examined in chronic and reversible murine models of unilateral ureteral obstruction (UUO) at several developmental time points: (1) P1, during nephrogenesis/nephron maturation and corresponding to the third trimester in humans, (2) P14, during the proliferative growth phase and corresponding to 1-2 years of infancy in humans, and (3) P60, in the mature kidney. Renal pathology was assessed by using standard histological techniques and immunostaining for molecular markers of key processes in kidney development and the pathogenesis of renal injury.
RESULTS:
Urinary obstruction leads to impaired renal maturation as demonstrated by a 35.2% and 26.3% decrease in kidney growth following UUO at P1 and P14, respectively. This is paralleled by a dramatic decrease in the proliferation of tubular epithelial cells in the developing kidney (56.2% decrease at P1; 61.6% decrease at P14) which contrasts the 5.4-fold increase in reparative proliferation in the tubules following UUO at P60. Furthermore, there is a 48.4% and 45.3% increase in the susceptibility of the kidney to apoptosis following UUO at P1 and P14 when compared to the obstructed kidney at P60, respectively. There are also significant differences in the injury responses in the developing kidney. Following UUO at P60, there is a 4.3-fold increase in proliferating cells in the renal interstitium corresponding with the expansion of fibroblast and inflammatory cell populations. In contrast, there is no significant increase in proliferating interstitial cells following UUO at either P1 or P14. Similarly, while there is a 6.4-fold increase in renal fibrosis following UUO at P60, there is no significant renal fibrosis following UUO at either P1 or P14. This finding was confirmed by using 4 different standard techniques for quantifying renal fibrosis. [All results are n=5-10, p<0.05]
CONCLUSIONS:This study reveals that developmental context has a significant impact on the pathogenesis of obstruction-induced renal injuries. In the developing kidney, urinary obstruction results in profound developmental deficits mediated by decreases in proliferation and increases in apoptosis. Additionally, there is a distinct absence of the activation of inflammatory interstitial cell populations and renal fibrosis. This contrasts the mature kidney where chronic inflammation and renal fibrosis drive disease progression. These findings suggest that the treatment of patients with obstructive uropathies can be optimized by tailoring therapeutic strategies that are specific to the developmental context. More aggressive surgical intervention at early developmental stages may be necessary to prevent impaired renal maturation. Additionally, it may be beneficial to design adjuvant therapies to stimulate proliferation and minimize apoptosis at early stages of development while targeting inflammation and fibrosis at later stages of development.


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