Background: The increasing popularity of ketogenic diets raises concerns regarding their safety during pregnancy. While mild ketosis is a common metabolic adaptation in gestation, the impact of diet-induced, supraphysiological ketosis on fetal kidney development remains unknown. We aimed to investigate the effects of maternal ketosis on offspring nephrogenesis and long-term kidney outcomes. Methods: Two complementary murine models were employed: maternal exposure to a ketogenic diet or β-hydroxybutyrate supplementation throughout gestation. Offspring were evaluated at birth and during postnatal development. Kidney structure and function were assessed by nephron counts, kidney size, and serum markers of kidney function and injury. Nephron progenitor cell (NPC) dynamics were examined using RNA sequencing, gene set enrichment analysis, immunostaining, and qPCR to assess proliferation and inflammation-related markers. Results: Both the ketogenic diet and the β-hydroxybutyrate supplementation models induced maternal ketosis and reduced offspring nephron number. Offspring exhibited impaired kidney function, more pronounced in the ketogenic diet group. Transcriptomic analysis of NPCs revealed downregulation of cell-cycle and Myc signaling pathways, alongside upregulation of inflammatory pathways, including TNFα/NFκB signaling. Immunostaining confirmed reduced NPC proliferation and c-Myc expression, alongside increased TNFα expression. Although postnatal NPC proliferation partially recovered after reversion to a standard diet, it was insufficient to rescue the nephron endowment deficit. Conclusions: Maternal ketosis disrupted nephrogenesis by suppressing c-Myc signaling and activating inflammatory pathways in NPCs, leading to a congenital nephron deficit and compromised adult kidney function.
Amleh et al. (Wed,) studied this question.