Born too small or too early : effects on blood pressure, renal function and retinal vascularization in adulthood : experimental and clinical studies

Abstract

Background: Several epidemiological studies the past fifteen years have suggested a connection between fetal growth retardation and later effects on adult health, such as an increased arterial blood pressure and type 2 diabetes mellitus. We studied the effects of fetal growth retardation in an experimental model were pregnant rats where given the synthetic glucocorticoid dexamethasone (DEX). In addition, we also studied renal function and blood pressure control in adult women born either SGA, preterm or normal birth weight controls. In these subjects, we also aimed to characterize the morphology of the retinal arterioles and certain biochemical serum markers.

Material and methods: Pregnant rats were given DEX from day 1. Their off-springs were investigated at the age of 60 days, by blood pressure, glomerular filtration rate (GFR) and sodium excretion rate. In 20 days old offsprings, we estimated the number of kidney glomeruli. Fifty adult women, aged between 23 to 30 years were divided into three groups 1) born full-term, SGA (SGA) (n= 18) 2) born before gestational week 32 (ex-preterm) (n= 15) and 3) controls born fullterm with normal birth weight (comparison group) (n= 17). They performed casual and ambulatory blood pressure measurements (ABPM) during 24-hours, GFR and renal plasma flow (ERPF) were also determined. We estimated the length of the retinal arterioles and number of branching points by digital image analysis. Serum markers of glucose profile (insulin, IGF-I, IGFBP1 and blood glucose) as well as certain biochemical serum markers (Apolipoprotein A, B, adiponectin, IL-6, HCRP) were evaluated.

Results: At birth, the body and kidney weights of DEX treated offsprings were lower compared to control rats. At postnatal day 20, when rephrogenesis is finished, DEX-treated offsprings exhibited fewer nephrons and in adolescence (60 days) they developed increased blood pressure, alburninuria and a decrease in GFR compared to control rats. An increased systolic blood pressure in the ex-preterm women was found (p<0.01) compared to the other groups, in contrast to day-time ABPM (6:00-24:00) where no significant differences in systolic blood pressure between the groups were recorded. Renal function (GFR) in the three groups was normal. Digital image analyses revealed longer retinal arterioles (p<0.01) and fewer retinal branching points (p<0.03), in the ex-preterm subjects in contrast to the other groups. The SGAs were shorter and weighed less compared to the comparison group, although the three groups did not differ in body mass index (BMI). In the SGA group we found lower levels of IGFBP-1 compared to the comparison group (p<0.05). In the SGA group we also found a correlation between daily ABPM (8:00-20:00) and certain biochemical serum markers, correlations not found in the ex-preterm group.

Conclusions: DEX treatment to pregnant rats produced effects on the fetal development of the kidney, and resulted in a lower glomeruli number in DEX offsprings at postnatal day 20 and development of arterial hypertension and renal dysfunction at day 60. The increased systolic blood pressure in the ex-preterm women at single measurements without a corresponding difference in blood pressure between the groups during day-time ABPM indicate an increased arousal to stressfull situations. In addition, the ex-preterms exhibit an abnormal retinal vascularization. The lower IGFBP-1 levels in the SGA group may indicate a higher diurnal insulin secretion, despite normal morning insulin levels, and could be an early sign of insulin resistance in this group. Certain biochemical serum markers, related to cardiovascular disease, correlated to blood pressure only in the SGAs. A possible influence on cardiovascular disease in SGAs has to be further evaluated.