Pathophysiology of congenital diaphragmatic hernia IV: Renal hyperplasia is associated with pulmonary hypoplasia

Abstract

The hypothesis of this article is that growth of the fetal lung is stimulated by a pulmonary growth factor (PGF) produced by the kidneys, which is modulated by a feedback signal from the lungs, a pulmonary-derived renotropin (PDR). In the fetus with pulmonary hypoplasia (PH), the lungs may maximally stimulate this feedback loop to release more PDR, resulting in continual stimulation of the kidneys and renal enlargement. If such a schema plays a role in the pathophysiology of PH, newborn infants with congenital diaphragmatic hernia (CDH) or chronic amniotic fluid leak (CAFL) should have enlarged kidneys. To investigate this hypothesis, we created models of CDH in fetal lambs and CAFL in fetal rabbits, and then analyzed lung (Lu) and kidney (K) growth. When compared to controls, newborn CDH lambs had significantly smaller lungs and larger kidneys. The lungs were hypoplastic as defined by either decreased lung weight/body weight ( LuW BW ), lung DNA/body weight ( Lu DNA BW ), or lung total protein/body weight ( LuTP BW ) ( P < .01). Renal hyperplasia was confirmed by KW BW , K DNA BW ( P < .01), and KTP BW ( P < .05). An inverse relationship between lung size and kidney size could be described by the equation KW BW = 1.04 − 0.12 LuW BW ( r = −.75). The CAFL model in newborn rabbits produced severe oligohydramnios when compared with controls ( P < .01). This resulted in fetuses with smaller lungs and larger kidneys as compared with those of controls. The lungs were significantly smaller and more hypoplastic than controls when compared by LuW ( P < .01), LuW BW ( P < .01), Lu DNA BW ( P < .05), and Lu TP BW ( P < .01). The kidneys were significantly larger and more hyperplastic than controls as judged by the similar criteria ( P < .01). In addition, the earlier in gestation the operation was performed, the greater was the effect on the kidneys and lungs. These data support our hypothesis and demonstrate that significant renal enlargement is associated with PH. The presumed mechanisms of renal enlargement associated with PH and the relation to amniotic fluid volume are discussed. If such a PGF and PDR can be isolated, the diagnostic and therapeutic implication for fetuses with PH are considerable.