Expression of Angiogenesis-Related Factors in Lungs of Patients with Congenital Diaphragmatic Hernia and Pulmonary Hypoplasia of Other Causes

Abstract

Twin-to-twin transfusion syndrome (TTTS) is caused by uneven shunting of blood between monochorionic twins, resulting in polycythemia in the recipient twin and growth restriction, anemia, and oliguria in the donor twin. Recent reports have described loss of proximal convoluted tubules in the kidneys of TTTS donor twins. In order to elucidate the pathogenesis of tubular deficiency in TTTS, we have reviewed the renal pathology in 25 twin pairs with autopsy-proven TTTS. Loss of differentiated proximal tubules, associated with atrophy of medullary tubules, was identified in 12/25 donor twins. In seven of these cases (all > 23-wk gestational age), the kidneys showed diffuse or partial tubular atrophy without evidence of cell death, similar to previously reported patterns. In five cases (all between 18- and 22-wk gestation), proximal and medullary tubules showed active injury characterized by markedly increased apoptosis, cell detachment, and intraluminal cell debris associated with calcifications. Tubular apoptosis tended to be more prevalent in donor fetuses with greater inter-twin body weight discordance, consistent with a more severe degree of TTTS. These results extend the spectrum of tubular alterations in TTTS to include an early stage of active apoptotic injury. The temporal distribution of injury patterns suggests that apoptotic injury of proximal and medullary tubules may be a precursor to partial or diffuse tubular atrophy. We speculate that the risk for development of tubular apoptosis in TTTS depends on the severity and timing of the hemodynamic imbalance, whereby early mid-trimester fetuses may be more vulnerable.

Effect of VEGF on the branching morphogenesis of normal and nitrofen-induced hypoplastic fetal rat lung explants

“…Studies using autopsy specimens showed enhanced expression of VEGF in CDH patients on the endothelial and medial smooth muscle cells of the pulmonary arteries and the bronchial epithelium compared to the normal controls [13], whereas others observed no difference in the localization of VEGF expression between those 2 groups [14]. However, its temporospatial expression of VEGF in the human fetus with and without CDH remains unclear because acute or chronic postnatal respiratory distress may influence its expression before the patients died [15].…”

Gene expression analysis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia

“…In rat lungs with CDH, a decreased expression of NOS and NOS activity has also been found [31]. This combination of a decreased number of vascular branches, increased adventitia and medial thickness of the pulmonary arterial walls, and pulmonary vascular hyperreactiviy might result in persistent pulmonary hypertension in CDH patients [1,5,54]. We found a decreased expression of several genes involved in angiogenesis and vascular tone regulation.…”

“…Endothelial NOS was also decreased, consistent with previous results [31], as well as angiotensin receptor 1 and angiotensin II receptor associated protein (Agtr1 and Agtrap). However, the expression pattern of VEGF and eNOS in immunohistochemistry studies of lungs of CDH patients was no different to controls [54].…”

Short-Term Postnatal Renal Function in Twin Anemia-Polycythemia Sequence

“…Lenclen et al [14] also reported an increased incidence of renal failure in TTTS twins treated with amnioreduction (20%, 6/30) but made no distinction between donors and recipients. The etiology and pathology of renal injury in TTTS was evaluated in detail by De Paepe et al [6] who reviewed the renal pathology in 25 fetal twin pairs. The authors showed that donor twins had a high prevalence of tubular loss, involving both proximal and medullary tubules.…”

“…In TTTS, various renal complications have been reported in donor twins, including renal cortical necrosis and fibrosis, transient renal insufficiency, acute renal failure requiring long-term peritoneal dialysis or permanent tubular dysfunction with polyuria due to renal dysgenesis [6]. In TAPS, knowledge on biochemical differences between donors and recipients is sparse.…”