Levels of the Endogenous Nephrotoxin Adenine in Healthy Humans and Effects of Diet

Background: Recent publications indicate that endogenous adenine is likely in the causative pathway for kidney disease in humans and urine adenine/creatinine ratio (UAdCR) is a mechanistic biomarker for ESKD in prospective studies of patients with DKD. However, adenine level in urine of healthy individuals has not been well studied. It is also not known if adenine levels vary according to age, gender, and body mass index (BMI). To shed light on these we conducted two separate studies. Methods: In one study (Healthy Study), we determined adenine concentrations using validated HPLC-MS/MS analysis in random urine samples collected from apparently healthy individuals (n=122, age 18-89 yrs) without diabetes and hypertension and with eGFR >90 mL/min/1.73m2. We also performed a post-hoc analysis of the KETO Study (NCT05071287) data that randomized 60 individuals (age 25-82 yrs) with eGFR of >60 mL/min/1.73m2 to either low-fat or keto diet for 6 months with primary outcome of weight change. Results: In the Healthy Study, mean±SD urine adenine/creatinine ratio (µM/mM) in females (n=60; 0.052 ± 0.065) was significantly higher compared to males (n=62; 0.010 ± 0.012, P = 0.0016). Similar significant difference was noted in the KETO Study. Urine adenine level did not correlate with age in either study. In the KETO Study, BMI declined in both males and females at 3-Mon and 6-Mon compared to Baseline values (P for all <0.01) but did not correlate with UAdCR. Compared to Baseline, UAdCR level declined significantly only in females at 6-Mon (0.06 ± 0.01 vs 0.03 ± 0.05, P=0.04). There was no correlation of eGFR or UACR with the UAdCR. Conclusion: Reduction in urine adenine/creatinine ratio observed in females was similar with both type of diets, suggesting that weight reduction by diet may be reno-protective. Further work is warranted to explore mechanistic pathway for higher urine adenine/creatinine ratio in females and clinical implications of these novel findings.