Renin Gene Expression in Fetal Kidneys of Pregnancies Complicated by Twin-Twin Transfusion Syndrome

Abstract

Twin-twin transfusion syndrome (TTTS) complicates one in five monochorionic pregnancies and is generally associated with high mortality and morbidity. One twin (the recipient) grows appropriately and has polyhydramnios while the other (the donor) may have a reduced growth velocity and severe oligohydramnios. The disparities in amniotic fluid volumes represent differences in fetal urine output. These differences occur secondary to hemodynamic changes, in which the vascular arrangement of placental anastomoses in TTTS leads to unidirectional flow from the donor to the recipient twin. A better understanding of the pathophysiology may contribute to improved management of this morbid condition. We studied three consecutive prospectively diagnosed stillborn twin pairs affected by early-onset TTTS. Renin gene expression was studied in sections of fetal kidneys with immunocytochemistry using a renin antiserum and with in situ hybridization using riboprobes complementary to renin mRNA, and renin-secreting cells (RCC) were counted. The overall maturation of the renal cortex was assessed by the percentage of immature glomeruli. The donor twin kidneys were smaller than those of the recipients, but the maturation of the renal cortex was not significantly different (28.2% immature glomeruli in the donor and 24.4% in the recipient kidney). The donor kidney showed increased renin gene expression with hyperplastic juxtaglomerular apparatuses (JGAs) that contained excess RCCs (median 20.02 [25th-75th centiles, 5.4, 25.1 RCCs per 100 glomeruli]). In contrast, the recipient kidney was virtually devoid of these cells (0.04 [0, 0.36] RCCs per 100 glomeruli; P < 0.05). In the donor kidney, increased renin release may, by a local action, contribute to renal vasoconstriction and oliguria. Increased renin and/or angiotensin II in the blood passing through the placental anastomoses may, by an endocrine action, suppress renin synthesis in the recipient kidney, thereby increasing renal blood flow and causing polyuria and polyhydramnios. These changes in the renal RAS could thus contribute to the pathogenesis of TTTS. The renal renin changes noted here may represent a contributory or compensating mechanism, the success of which may dictate the overall survival of the twin pregnancy and allow better understanding of the pathophysiology and perhaps therapy that may be employed in this condition.

Blood pressures in newborns with twin–twin transfusion syndrome

“…[13][14][15]23,27 In contrast, the current data show a decrease in BP during the first 12 h of life in recipients. A similar evolution of BP has been reported by Cordero et al 23 in a 28 and restoration of renal renin expression in the recipient, which was totally inhibited in utero, 8,9 should take many hours. Indeed, after 12 h of life, recipient's BP increased progressively.…”

“…9,10 The concept has recently been further supported by reports showing in donors and recipients similarly markedly elevated cord blood plasma levels of renin and angiotensin II (and in one case report of aldosterone), 7,10 whereas renal renin protein and mRNA expression are downregulated in the recipient's kidney and upregulated in the donor's kidney. 8,9 The recipient is therefore exposed to RAS hormones secreted by the donor and transferred via placental shunts. The action of the RAS on vascular smooth muscle cells could lead to vasoconstriction and further volume retention in the recipient who is already hypervolemic, resulting in hypertension.…”

“…Investigators have suggested a role for other elements such as increased circulating endothelin and activation of the renin-angiotensin system (RAS) in the donor twin, resulting in the transfer of significant amounts of circulating vasoactive elements such as angiotensin II to the recipient through the placental vascular anastomoses. [5][6][7][8][9][10] It is therefore postulated that transfer of volume and of vasoactive elements could lead to significant elevation of blood pressure (BP) in recipients as well as to CBH. 9,10 One study has indirectly evaluated BP during fetal life and indeed suggested elevated BP in the recipient twin.…”

Paradoxic Activation of the Renin-Angiotensin System in Twin-Twin Transfusion Syndrome: An Explanation for Cardiovascular Disturbances in the Recipient

“…We first demonstrated that renal expression of renin was up-regulated in donors and down-regulated in recipient twins (11). This phenomenon, since confirmed by others (16), could be interpreted initially as a physiologic adaptation to hypovolemia in the donor and hypervolemia in the recipient. However, we have speculated that this adaptation then could go on to become deleterious, particularly to the recipient, who could be exposed to the transfer of a variety of molecules produced by the donor via intertwin vascular anastomoses, including vasoactive RAS hormones (15).…”

Twin-Twin Transfusion Syndrome

“…24,25 Human studies suggest additional plausible mechanisms for discordant PWV in childhood survivors of TTTS such as the finding of increased endothelin levels in recipient fetuses compared with their codonor and control subjects 26 and recipient neonatal hypertension. 27 The finding of renin gene and protein expression in donor kidneys 28,29 but not in those of their cotwins suggests that the renin-angiotensin system is activated in the donor but not the recipient. This may be one explanation for the relatively lower PWV seen in some of the recipients in group 1 in addition to increased deposition of elastin in the fetal aorta associated with increased volume flow.…”