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 during periods of glucose deficiency.

Until recently, KBs carried a negative clinical stigma as they are key modulators in pathological conditions such as diabetic and alcoholic ketoacidosis [2]. However, accumulating evidence from both cellular and animal models has suggested a protective role of KBs in the development of kidney diseases and cardiovascular diseases (CVDs) [3,4]. For example, daily subcutaneous administration of β-hydroxybutyrate for one month reduced pro-inflammatory cytokine levels including interleukin 1-β and tumor necrosis factor-α, as well as reactive oxygen and nitrogen species levels in the kidney of aged mice [3]. Similarly, in mice with ischemia/reperfusion injury, β-hydroxybutyrate infusion reduced mitochondrial stress in the myocardium [4].

On the other hand, data from clinical studies have been conflicting. While higher levels of KBs have been linked to a higher risk of CVDs and all-cause mortality [5], [6], [7], β-hydroxybutyrate infusion was reported to have beneficial hemodynamic effects in patients with heart failure and reduced ejection fraction [8]. Moreover, in patients with chronic kidney disease (CKD) who are at high risk of developing CVD, sodium glucose co-transporter 2 inhibitors (SGLT2is) have been postulated to provide cardiorenal benefits to patients with CKD by inducing nutritional ketosis [9]. However, the association between KB levels and adverse kidney outcomes has not been previously investigated in clinical studies.

Hence, this study aimed to investigate whether plasma total KB levels were associated with adverse kidney outcomes and death.