Available online 4 March 2024, 101527

Author links open overlay panel, , , , , , , , ABSTRACTAims

Although cellular and animal models have suggested a protective effect of ketone bodies (KBs), clinical data are still lacking to support these findings. This study aimed to investigate the association of KB levels with incident chronic kidney disease (CKD) and death.

Methods

This was a prospective cohort study of 87,899 UK Biobank participants without baseline CKD who had plasma levels of β-hydroxybutyrate, acetoacetate, and acetone levels measured at the time of enrollment. The main predictor was plasma total KB, which was the sum of the aforementioned three KBs. The primary outcome was a composite of incident CKD, or all-cause mortality. Secondary outcomes included the individual components of the primary outcome.

Results

During a median follow-up of 11.9 years, a total of 8,145 primary outcome events occurred (incidence rate 8.0/1,000 person-years). In the multivariable Cox model, a 1-standard deviation increase in log total KB was associated with a 7% [adjusted hazard ratio (aHR), 1.07; 95% confidence interval (CI), 1.05-1.10] higher risk of the primary outcome. When stratified into quartiles, the aHR (95% CI) for Q4 versus Q1 was 1.18 (1.11-1.27). This association was consistent for incident CKD (aHR, 1.04; 95% CI, 1.01-1.07), and all-cause mortality (aHR, 1.10; 95% CI, 1.07-1.13). Compared with Q1, Q4 was associated with a 12% (aHR 1.12; 95% CI 1.02-1.24) and 26% (aHR 1.26; 95% CI 1.15-1.37) higher risk of incident CKD and all-cause mortality, respectively.

Conclusions

Higher KB levels were independently associated with higher risk of incident CKD and death.

Section snippetsINTRODUCTION

Ketone bodies (KB) serve as an important alternative metabolic energy source in the fasting state [1]. Ketogenesis predominantly occurs in the liver, where free fatty acids are converted to two major KBs: β-hydroxybutyrate and acetoacetate. Circulating levels of serum KBs are determined by the balance of their rates of production and utilization. The KBs can be utilized by extrahepatic tissues through the process of ketolysis, which produces energy,1 and provides an alternative energy source

Study Cohort

The UK Biobank is a large-scale, prospective, observational, population-based cohort consisting of 502,536 participants aged 37-73 years from England, Scotland, and Wales between 2006 and 2010. The rationale, design, and protocol summary are described elsewhere [10]. Exclusion criteria were as follows: 1) missing data on sex or race; 2) missing data of baseline estimated glomerular filtration rate (eGFR) or proteinuria; 3) missing data on baseline β-hydroxybutyrate or acetoacetate; 4) baseline

Baseline Characteristics

After excluding participants according to the pre-specified exclusion criteria, a total of 87,899 participants were enrolled in this study (Figure S1; see supplementary materials associated with this article on line). Baseline characteristics of the final study population, categorized according to plasma total KB level quartiles, are presented in Table 1. The mean age was 56 years, and 45,902 (52%) participants were male. The median plasma total KB level was 62 μmol/L, and the mean baseline

DISCUSSION

In this large population-based cohort study of individuals without established CKD, higher plasma KB levels, as indicated by both higher quartiles of log-transformed KB levels and log-transformed KB levels in its continuous form, were independently associated with higher risk of incident CKD and death. A 1-SD log increase in total KB was associated with a consistently higher risk of the primary composite outcome and secondary outcomes. Compared to Q1, higher quartiles of log-transformed KB were

ACKNOWLEDGEMENTS

None.

FUNDING

None.

AUTHORS’ CONTRIBUTIONS

C.Y.J. and S.H.H contributed to the research idea and study design; C.Y.J., H.B.K., H.W.K., and S.H.H. were involved in data acquisition; C.Y.J. and S.H.H. were responsible for data analysis/interpretation, drafting and revision of the manuscript; G.Y.H., B.K., J.T.P., T.H.Y., and S.W.K. were responsible for supervision or mentorship. Each author contributed important intellectual content during manuscript drafting or revision and accepts accountability for the overall work by ensuring that

CRediT authorship contribution statement

Chan-Young Jung: Writing – original draft, Formal analysis, Data curation, Conceptualization. Hee Byung Koh: Data curation. Ga Young Heo: Data curation. Byounghwi Ko: Formal analysis, Data curation. Hyung Woo Kim: Supervision. Jung Tak Park: Supervision. Tae-Hyun Yoo: Supervision. Shin-Wook Kang: Supervision. Seung Hyeok Han: Writing – review & editing, Project administration, Formal analysis, Data curation, Conceptualization.

Declaration of competing interest

Dr. Han reports serving as a subeditor of Nephrology and servicing as a scientific advisor and member of the Korean Society of Nephrology. All remaining authors have nothing to disclose.

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