Ovine fetal renal development impacted by multiple fetuses and uterine space restriction

Abstract

Intrauterine growth restriction (IUGR) from uteroplacental dysfunction causes impaired nephrogenesis and ultimately hypertension, but it is unknown whether IUGR caused by insufficient space for placental development seen in uterine anomalies and/or multifetal gestation exerts the same effects. Fetal renal development and metabolism were studied in an ovine space-restriction model by combining unilateral horn surgical ligation and/or multifetal gestation. Reduced placental attachment sites and placental weight per fetus defined space-restricted (USR) v. control nonrestricted (NSR) fetuses. Space-restricted fetuses exhibited evidence for decreased plasma volume, with higher hematocrit and plasma albumin at gestational day (GD) 120, followed by lower blood pO2, and higher osmolarity and creatinine at GD130, P < 0.05 for all. By combining treatments, fetal kidney weight relative to fetal weight was inversely related to both fetal weight and plasma creatinine levels, P < 0.05 for both. At GD130, space-restricted fetal kidney weights, cortical depths and glomerular generations were decreased, P < 0.05 for all. Space-restricted kidneys underwent an adaptive response by prolonging active nephrogenesis and increasing maculae densa number, P < 0.05 for both. The major renal adaptations in space-restricted IUGR fetuses included immaturity in both development and endocrine function, with evidence for impaired renal excretory function.

Figure 1. Relationships Between Fetal Kidney Weight, Body Weight and Renal Function

NSR (X) and USR (solid circles) fetuses are both shown in the figure. a. In fetuses at both GD120 and GD130, weight of kidneys expressed proportionate to body weight (g/kg) on vertical axis was inversely proportional to fetal weight (kg) on horizontal axis (F=28.67, R²= -0.38, P<0.0001). The figure includes both groups. The relationship between these variables in NSR is equal in strength to that of USR, and the relationship strengthened by including NSR samples, and with minimal change in the line of identity. b. In fetuses at both GD120 and GD130, fetal plasma creatinine (mg/dL) on the vertical axis was indirectly related to weight of kidneys expressed proportionate to body weight (g/kg) on horizontal axis (F=14.75, R²= -0.337, P<0.001). The figure includes both groups. Although the observed relationship in NSR alone is not significant (P=0.055), the relationship is strengthened by including NSR samples, and with minimal change in the line of identity. 254x190mm (72 x 72 DPI)

Figure 2. Relationship between Fetal Microscopic Morphometry and Renal Function

NSR (X) and USR (solid circles) are both shown in the figure. a. In fetuses at both GD120 and GD130, cortical depth (μm2) on vertical axis was directly related with glomerular generations on horizontal axis, F=20.67, R²= +0.293, P<0.0001. The figure includes both groups. Although the relationship in NSR only is not significant (P=0.5), the line of identity is strengthened and better defined by inclusion of the NSR samples. b. In fetuses at both GD120 and GD130, fetal plasma creatinine (g/dL) on the vertical axis was indirectly related with glomerular generations on the horizontal axis, F=23.90, R²= -0.461, P<0.0001. The figure includes both groups. Although the relationship in NSR only is not significant (P=0.16), the line of identity is strengthened and better defined by inclusion of the NSR samples. c. In fetuses at both GD120 and GD130, fetal plasma creatinine (g/dL) on the vertical axis was indirectly related with cortical depth (μm) on the horizontal axis, F=14.31, R²= -0.338, P<0.001. The figure includes both groups. Although the relationship in NSR is not significant (P=0.9), the line of identity is strengthened and extended by inclusion of the NSR samples.

Figure 3. Nephrogenic Zone in Nonrestricted (NSR) and Restricted (USR) Kidneys at GD120 and GD130

Shown are representative examples of renal capsular areas in Gomori trichrome stain sections. Bars indicate 100 microns. a. GD120 NSR, b. GD120 USR, c. GD130 NSR and d. GD130 USR kidneys at 20X demonstrating that S- and C-shaped bodies of the active nephrogenic zone were common in the GD120 USR fetuses (arrows), but not in the NSR group. By GD130, nephrogenesis was complete in both NSR and USR groups.

Figure 4. Glomeruli and Maculae Densa in NSR and USR Kidneys at GD130

Shown are representative H&E examples. Bars indicate 25 microns. a. GD130 NSR and b. GD130 USR fetuses at 100X demonstrating glomeruli (asterisk) greater numbers of cells in the maculae densa (arrows) as seen by quantitative point counting, P<0.05.