CHRONIC FETAL HYPOXIA LEADS TO LONG-TERM PROXIMAL TUBULE INJURY IN THE SHEEP KIDNEY

MR SUTHERLAND1,2, KL BRAIN1, KJ BOTTING1, SN AUSTIN-WILLIAMS1, EJ CAMM1, DA GIUSSANI1

1University of Cambridge, Cambridge, United Kingdom; 2Monash University, Clayton, VIC

Aim: To determine the impact of chronic fetal hypoxia, with and without maternal antioxidant treatment, on renal morphology in the adult sheep kidney.

Background: Chronic fetal hypoxia is a common outcome of pregnancy complications such as pre-eclampsia, as well as maternal smoking. The fetal adaptive response to hypoxia includes peripheral vasoconstriction, which reduces renal blood flow and may therefore impair kidney development. Maternal vitamin C (antioxidant) treatment can ameliorate fetal vasoconstriction in hypoxic pregnancies, and therefore has the potential to improve outcomes.

Methods: Welsh mountain ewes carrying singleton female fetuses were exposed to chronic hypoxia (10% O2; H) or normoxia (21% O2; N) from 105-138 days gestation (term=147 days). During this period, half of the ewes received a high dose (200 mg/kg/d) of vitamin C. Lambs (n=6/group) were delivered naturally and grown to 9 months of age (adulthood). Stereological methods were used to determine kidney volume and nephron number. Fibrosis, glomerulosclerosis, and renal tubule morphology were assessed histologically.

Results: Kidney volumes were significantly larger in the hypoxia-exposed sheep (N: 18,381±1,085; N+VitC: 18,741±991; H: 24,286±2,049; H+VitC: 25,097±1,762 mm3; p<0.001), mediated through a markedly increased volume of renal cortical tubules. Fetal hypoxia also resulted in severe proximal tubule injury (brush border loss), and increased levels of glomerulosclerosis and interstitial fibrosis; there was no difference in nephron number between groups. Vitamin C treatment ameliorated medullary fibrosis in the hypoxia-exposed sheep kidneys.

Conclusions: Chronic fetal hypoxia resulted in significant renal tubule pathology in adulthood; maternal vitamin C treatment, however, had little effect on kidney morphology. These findings have important implications for the long-term renal health of individuals born following hypoxic pregnancies.

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