Recovered Parental Acute Kidney Injury Programs Renal Dysfunction in Adult Offspring

Background: Acute kidney injury (AKI) is a common complication of acute disease which can cause long-term renal and cardiovascular disease. Women have been excluded from these studies as men and the elderly are considered higher risk, which creates a significant gap in our knowledge of the risk of young women for AKI. Young people are more likely to have rhabdomyolysis-induced AKI (RIAKI) due to muscle injury sustained during exercise, combat, and other accidents and are more likely to survive such incidents; therefore, RIAKI is relevant to understanding long-term reproductive impact of AKI. Using a mouse model of RIAKI, we observed that recovered pre-pregnancy parental AKI resulted in later pregnancy complications, including reduced maternal GFR, increased maternal renal fibrosis, and albuminuria, as well as fetal impact including perinatal death and fetal growth restriction. Studies of offspring following other pregnancy complications indicate underdeveloped organs, including the kidney, resulting in adult-onset disease. We hypothesized that RIAKI-related pregnancy complications would cause developmental programming of adult renal disease in the offspring. Methods: Procedures were approved by institutional IACUC. RIAKI was generated via intramuscular injection of 50% glycerol (8 mL/kg) in 8-10 week old C57BL/6 male and female mice while shams were untreated. After documenting recovery from AKI (return to normal glomerular filtration rate (GFR; uL/min/100g body weight)) 2 weeks post-treatment, sham/sham and RIAKI/RIAKI pairings (n=5 each) were established. Pups survived for either 6 months (young adulthood) or 1 year (older adulthood) and weighed weekly for the first 12 weeks, then again at sacrifice. Urine was collected 24h before GFR measurement and collection of blood, heart, and kidneys. Blood pressures were measured at 6 months for 3 days by tail cuff plethysmography. Sodium and potassium were measured by flame emission detection. Retinol binding protein 4 (RBP4), a measure of proximal tubule dysfunction, was assessed by ELISA. Statistics were assessed by one-way ANOVA with post hoc tests. Results: Pups from RIAKI pairs were born smaller (p=0.006) and remained smaller 1 week after birth (p=0.02) regardless of sex, but were significantly similar to sham offspring at 2-12 weeks. Males from RIAKI pairs gained significantly more weight between 6 and 12 months than females (p=0.04); female RIAKI offspring did not differ from shams. Both males and females from RIAKI pairs had reduced GFR compared to shams at 6 months (p=0.02, p=0.02), but only males were affected at 12 months (p=0.03). However, no changes were observed between groups in systolic, diastolic, or mean arterial pressures at 6 months, nor were there differences in sodium or potassium excretion. RBP4 was unchanged in 6 or 12 month urine samples. Heart weight or kidney weight to body weight ratios were not different except kidney weight/body weight was smaller in female offspring of RIAKI pairs compared to shams at 6 months (p=0.04). Conclusions: Offspring of parents with recovered AKI show evidence of programming for renal disease despite never having AKI themselves. RBP4, sodium, and potassium excretion remaining unchanged suggest that this may be due to reduced availability of glomeruli and nephrons rather than tubule dysfunction. Body weight changes in males but not females, and kidney weight differences in females but not males, indicate sex differences in programmed dysfunction, including possible edema in males. Further studies will evaluate body composition, analysis of fecal and urine content, and renal histology. JFH is supported by the NIH NCATS KL2 (KL2TR002370) and the AHA CDA (24CDA1269587). MPH is supported by DOD (W81XWH2010196) and VA Merit (1I01BX004288). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.