Ketogenic Diet, Serum Ketone Bodies and Risk of End‐Stage Renal Disease in Patients With Diabetic Kidney Disease: A Multi‐Cohort Study

This study aims to explore the effect of the ketogenic diet (KD) on the occurrence of end-stage renal disease (ESRD) and the longitudinal relationship between circulating β-hydroxybutyrate (β-OHB) and kidney outcomes. We used the dietary ketogenic ratio (DKR) to estimate the nutritional ketosis probability of KD and analyzed the association with ESRD using NHANES cross-sectional data by Spearman correlation coefficient and multivariate logistic regression model. We also used the Kaplan-Meier method, Cox regression analysis, and restricted cubic splines (RCS) to analyze the relationship between circulating β-OHB and renal outcomes in the T2DM-DKD longitudinal cohort of West China Hospital. Mendelian randomization (MR) was also employed to evaluate potential causal associations. The cross-sectional analysis revealed that non-ESRD patients had significantly higher baseline age, BMI, serum albumin, and DKR values, with a weak negative correlation between DKR and serum creatinine (ρ = -0.072, p = 0.011). Logistic regression consistently indicated a reduced ESRD prevalence in higher DKR quartiles. In the longitudinal study, elevated β-OHB levels were associated with improved renal survival and a lower risk of ESRD, with RCS analysis identifying the lowest risk at approximately 0.25 mmol/L. MR analyses supported these findings, showing inverse correlations between genetically predicted β-OHB and creatinine (p = 0.007) and cystatin c (p < 0.001). These findings suggest that KD may be associated with a lower incidence of ESRD in DKD patients, with elevated β-OHB levels independently associated with a reduced risk of ESRD, warranting further research to confirm causality and elucidate underlying mechanisms.