Maternal Ketosis during Gestation: Implications for Fetal Kidney Development and Long-Term Kidney Health

Background: Maternal ketosis is a metabolic state that can be encountered during normal pregnancy, gestational diabetes, and due to the growing popularity of ketogenic diets. While ketone bodies in the physiological range facilitate energy supply to the fetus, emerging data suggest potential adverse fetal outcomes of increased ketosis. This study investigates the impact of maternal ketosis during gestation on fetal kidney development and nephrogenesis, a critical determinant of lifelong renal health. Methods: Two murine models evaluated the effects of maternal ketosis on kidney development: a ketogenic diet regimen and exogenous beta-hydroxybutyrate (BHB) supplementation in drinking water. Nephron endowment was quantified in adulthood, and renal function was assessed by blood urea levels. Nephron progenitor cells were isolated via fluorescence-activated cell sorting from transgenic reporter mice, and RNA-sequencing analyzed transcriptomic profiles. Alterations in gene expression pathways were validated through immunofluorescence, western blot, and qPCR. Results: Both maternal ketosis models exhibited significantly reduced nephron endowment at birth and adulthood compared to the control group, indicative of impaired nephrogenesis. The reduction in nephron number in the ketogenic group was associated with compromised long-term renal function in adulthood, as was measured by elevated blood urea levels. Transcriptomic analyses revealed decreased proliferative capacity of nephron progenitors, with downregulation of the MYC pathway and concomitant upregulation of inflammatory response genes. These findings were consistently validated across multiple complementary techniques. Conclusion: This study provides compelling evidence that maternal ketosis during gestation adversely impacts fetal kidney development and long-term renal function. Reduced nephron progenitor proliferation, decrease MYC expression and heightened inflammatory signaling, emerges as an underlying mechanism. These findings underscore the importance of monitoring and managing maternal ketosis to protect fetal nephrogenesis and lifelong kidney health.