In this study, we identified a significant association between elevated RC levels and the prevalence of CKD in the general Chinese population. This association remained independent of demographic factors, education, residency, lifestyle, and traditional cardiovascular risk factors. Additionally, a non-linear correlation between RC and the risk of prevalent CKD was observed, and influenced by serum LDL-C levels. In the analysis of discordant/concordant LDL-C and RC groups, it was determined that RC played a smaller role in the cholesterol-related pathogenesis of CKD compared to LDL-C. The findings shed light on the pathophysiology of RC in CKD, indicating a correlation between elevated serum levels of RC and the interaction of LDL-C in the progression of CKD. Specifically, this association was attributed to the pro-inflammatory state serving as a mediator.
Several studies have observed inconsistencies in the relationship between CKD and RC. He et al.14 identified a significant inverse correlation between RC levels and eGFR in a U.S. population. The risk of CKD progressively increased across RC quartiles in a cohort comprising a general population of middle-aged and elderly individuals of Chinese descent.12 In contrast, Rysz-Gorzynska et al.15 did not observe significant differences in levels of very VLDL-C or IDL-C between individuals with CKD and those with normal kidney function. Additionally, a non-independent relationship was noted between declining kidney function and VLDL-C in a prospective cohort study with CKD.16 These discrepancies may stem from variations in population demographics, geographical region, sample size, analytical methods, and confounding variables.
In our study, we observed an “inverted U-shape” curve in the association between serum RC levels and the risk of CKD. Understanding and recognizing this non-linear trend is paramount in the context of clinical management of CKD, as it suggests a potential threshold effect where the influence of RC on the development or progression of the disease may not be uniform across all levels of cholesterol. After adjusting for LDL-C level as a confounder, the decreased section of the RCS curve became flat. Elevated RC levels were associated with increased TG enrichment of LDL particles, particularly in small, dense LDL particles with an extended half-life in circulation.26 We hypothesized that LDL-C may exert a dominant effect in the relationship between RC and the risk of CKD. It was further elucidated that serum RC levels have less impact than LDL-C in contributing to the pathogenesis of CKD, according to the LDL-C and RC discordance/concordance group. With new-generation TG and RC lowering medications, such as apoC3 and ANGPTL3 inhibitors,27 currently under evaluation, transitioning to a novel strategy that separately considers each component may be the most prudent course of action.26 In clinical practice, it is essential to simultaneously consider the levels of both RC and LDL to ensure a dynamic balance.
The influence of RC on the development and progression of CKD involves various complex processes. Historical evidence suggested that RC induced pro-inflammatory activation of the endothelium and low-grade inflammation, both of which contribute to atherosclerosis.28 Our investigation revealed that the relationship between RC and CKD was partially mediated by WBC count and hs-CRP concentrations, suggesting that RC was frequently associated with a pro-inflammatory state because of its highly atherogenic nature and unique physicochemical properties. The inflammatory state plays a crucial role in the onset and progression of CKD, impacting the quality of life and prognosis of individuals with CKD.29 The hydrolysis of apolipoprotein C (ApoC), triglycerides, and cholesterol within RC under physiological conditions leads to the production of free fatty acids (FFAs) and glycerol. Zewinger et al.30 found that elevated levels of ApoC3 in plasma were associated with a notable increase in markers of systemic inflammation, such as hs-CRP, in patients with CKD. Furthermore, in humanized mouse models, ApoC3 activated human monocytes in vivo to promote kidney injury in an NLRP3 and caspase-8-dependent manner30 (Fig. 5).
In CKD, the upregulation of fatty acid protein transporters and CD36 results in the excessive accumulation of FFAs in kidney cells and lipid droplets (LDs), causing kidney lipotoxicity.6 Moreover, the increased activity of fatty acid-binding proteins (FABPs) in CKD patients enhances the transportation of FFAs to the mitochondria for further oxidation. Conversely, the decreased expression of carnitine palmitoyltransferases (CPT1 and CPT2) leads to reduced fatty acid oxidation, ineffective NADH production, decreased electron transport chain (ETC) activity, resulting in mitochondrial dysfunction and subsequent mitochondrial DNA (mtDNA) instability. This instability activates the cGAS-STING pathway, triggering NF-κB activation6,31(Fig. 5). An important strength of this study lies in our examination of the intermediary role of inflammation in systemic lipid metabolism disorders. This contributes to the selection of anti-inflammatory medications and lipid-lowering drugs for nephrologists to halt the progression of CKD, reduce proteinuria, and mitigate the risk of cardiovascular disease.
In most Chinese institutions, the direct measurement of RC using nuclear magnetic resonance or ultracentrifugation is impractical in clinical practice due to its time-consuming, expensive, and radioactive nature. In our study, we assessed the RC value due to its convenience, minimal time requirement, and established reliability, as it has been widely used in large cohort studies.12,32–34 This assessment may be sufficient for predicting and determining treatment strategies in actual clinical settings.
limitations
The current study acknowledges several limitations. Firstly, the cross-sectional design precludes the establishment of causal relationships between RC and CKD. It remains uncertain whether dyslipidemia causes kidney problems or if it is a metabolic consequence. Additionally, as the data was solely derived from the CHNS study in China, the generalizability of our findings to individuals of diverse ethnic backgrounds remains uncertain, potentially constraining their applicability. In conclusion, while our comprehension of RC and CKD advances in recent years, we strongly advocate for ongoing research to explore the occurrence and underlying mechanisms of RC in CKD, including systemic lipid levels or cellular lipid metabolism disorders.