Chronic kidney disease (CKD) is an incurable progressive disease with high morbidity and mortality (Kalantar-Zadeh et al., 2021). It is an increasingly underappreciated global public health problem that imposes huge economic and medical burdens on society and health institutions (Eckardt et al., 2013). The current global prevalence of CKD is estimated to range from approximately 11%–13% (Hill et al., 2016). By contrast, the absolute risk of death increased exponentially with a decline in renal function (Tonelli et al., 2006). Patients with CKD are five to ten times more likely to die prematurely than those who progress to end-stage renal disease (ESRD) (Webster et al., 2017). Slowing down the progression of CKD is a global medical priority. Presently, dietary intervention and drug therapy for CKD can maximize the preservation of renal function. However, patients with CKD progress to ESRD, and renal replacement therapy is inevitable (Kalantar-Zadeh et al., 2021). CKD is heterogeneous in terms of risk, etiology, and clinical presentation. It leads to abnormal lipid metabolism and changes in lipid levels, composition, and quality (Ferro et al., 2019), and lipid accumulation in the renal parenchyma may lead to inflammation and fibrosis (Mitrofanova et al., 2023). Dyslipidemia in CKD is primarily caused by increased triglyceride (TG) levels, decreased high-density lipoprotein cholesterol (HDL-C) levels, and changes in low-density lipoprotein cholesterol levels (Hager et al., 2017). Very low-density lipoprotein, HDL, lipid concentration, and the composition of these lipoproteins, as well as TG and fatty acids in all lipoprotein subclasses, are associated with CKD risk (Geng et al., 2024). Thus, lipid metabolism is a crucial area of CKD research.

Publications are representative of the results of scientific research. Bibliometric analysis can be used to analyze the development trend and core influence of a specific scientific field (Chen and Song, 2019). Bibliometrics is mainly analyzed in terms of performance and visualization (Nakagawa et al., 2019; Sabe et al., 2023). There are currently several publications in the fields of CKD and lipid metabolism. However, there have been no systematic bibliometric evaluations of lipid metabolism in patients with CKD. Therefore, we conducted a bibliometric study to comprehensively evaluate the topic hotspots and trends in CKD and lipid metabolism.

From 2004 to 2023, the number of publications on lipid metabolism in CKD gradually increased, indicating that lipid metabolism in CKD will remain a research hotspot in the future. In this study, we provide a comprehensive overview of the progress in lipid metabolism research in CKD through bibliometric analysis, with a focus on future research directions. Globally, the authors, countries, and institutions in this field are primarily concentrated in China and the United States. Vaziri Nosratola D, Levi Moshe, and Zhao Yingyong were the main contributing authors, who were the authors of the top five publications and top ten cited publications. There is also a close collaboration between Vaziri Nosratola D and Zhao Yingyong. The identification of serum metabolites associated with chronic kidney disease progression and the antifibrotic effect of 5-methoxytryptophan (5-MTP) was published in Nature Communications in 2019 and is one of the most cited papers in their collaboration (165 times) (Chen et al., 2019). In this study, the level of 5-MTP decreased with the progression of CKD according to untargeted metabolomics in 2,155 patients with CKD and healthy controls. The efficacy of 5-MTP was further verified in mice with unilateral ureteral obstruction, ischemia/reperfusion injury, and in human kidney cells. The key role of tryptophan hydroxylase-1, an enzyme involved in 5-MTP synthesis, in inhibiting renal inflammation and fibrosis has been confirmed. They also showed that serum acetylcarnitine levels in patients with CKD increased significantly with a decrease in renal function. Acetylcarnitine may facilitate acetyl-CoA uptake into the mitochondrial matrix during FAO. Elevated serum acetylcarnitine levels in patients with CKD can contribute to skeletal muscle IR by promoting the reverse carnitine acetyltransferase reaction, leading to the accumulation of acetyl-CoA in the mitochondria (Miyamoto et al., 2016). In a study using UPLC-HDMS-based lipidomics to detect serum lipid metabolites in 180 patients with advanced CKD and 120 healthy controls, elevated levels of serum total fatty acids, glycerides, and glycerophospholipids were directly correlated with elevated serum triglyceride levels and inversely correlated with estimated glomerular filtration rate (eGFR) levels. Changes in lipid metabolites have also been reported in patients with CKD (Chen et al., 2017). Polyporus umbellatus may play a protective role in renal fibrosis by regulating fatty acyl metabolism (Wang et al., 2021).

Kidney International, a leading journal in the field of kidney disease, has published several articles on lipid metabolism in patients with CKD. The article on Lipotoxicity published by Weinberg JM in the Journal in 2006 was also among the top ten most-cited articles in the field (294 times) (Weinberg, 2006). This review summarizes the related findings on non-renal tissue lipotoxicity and the pathogenesis of renal lipotoxicity in acute and CKD to further promote the development of this field.

The keywords summarize developments in the field. Systemic lipid homeostasis is of great interest in cardiometabolic diseases (Arsenault et al., 2011; Jaffe and Karumanchi, 2024; Maestri et al., 2024). Glucose and lipid metabolism disorders are the major determinants of the development and progression of DKD (Fu et al., 2020; Mori et al., 2021). Our keyword analysis showed that CVD and DKD are hotspots in the study of lipid metabolism in CKD. Dyslipidemia is a major risk factor for CVD (Hager et al., 2017). Elevated triglyceride levels may increase the risk of CVD through excessive free fatty acid release, the production of proinflammatory cytokines and coagulation factors, and fibrinolysis dysfunction (Reiner, 2017). Lipid oxidation promotes atherosclerosis through endothelial dysfunction and inflammation (Gianazza et al., 2019). CKD is a major risk factor for atherosclerotic CVD (Tonelli et al., 2012). Patients with CKD were also associated with a significant cardiovascular risk (OR = 1.69), and approximately 50% of patients with CKD4-5 had cardiovascular disease (Stevens et al., 2007). Its manifestations include coronary artery disease, heart failure, arrhythmias, and sudden cardiac death (Jankowski et al., 2021). CVD was the most common cause of death in patients with CKD3-5. With a decrease in eGFR, the proportion of deaths from heart failure and valvular disease increased significantly (Thompson et al., 2015). Increasing evidence suggests that lipid-lowering therapy can reduce the incidence of cardiovascular events in CKD (Schlackow et al., 2019). DKD is the leading cause of ESRD (Umanath and Lewis, 2018). Abnormal glucose and lipid metabolisms play important roles in the pathogenesis of DKD. In DKD, ectopic lipid accumulation in the kidney exceeds lipid droplet storage and damages podocytes and tubular cells (Yang et al., 2018; Schelling, 2022). Studies have shown that Statins are effective in preventing DKD (Zhou et al., 2023). Therefore, correcting dyslipidemia has great potential to delay the progression of CKD.

According to the keyword trends, inflammation, oxidative stress, and IR were the topics of lipid metabolism. Inflammation is the main pathogenic mechanism underlying CKD, obesity, impaired glucose tolerance, and IR (Brennan et al., 2021), which can lead to glomerulosclerosis, tubular atrophy, and fibrosis. Ectopic lipid deposition in the kidneys can lead to an inflammatory response (Samuel and Shulman, 2012). Studies have shown that DKD is associated with proinflammatory cytokines, such as circulating levels of C-reactive protein, interleukin-6, intercellular adhesion molecule-1, plasminogen activator inhibitor 1, soluble tumor necrosis factor receptor-1 (sTNFR-1), and sTNFR-2 (Groop et al., 2009; Lopes-Virella et al., 2013; Liu et al., 2024). NLRP3 is a prominent target in the study of inflammatory mechanisms. ZDHHC12-mediated palmitoylation promotes NLRP3 degradation via the chaperone-mediated autophagy pathway (Wang and Cui, 2023). Fatty acid synthesis can drive inflammation by activating the NLRP3 inflammasome through palmitoylation (Leishman et al., 2024). In addition, statins can inhibit NLRP3 activation in the kidney to improve cholesterol-induced inflammation and water channel aquaporin 2 (AQP2) expression (Kong et al., 2020). 6-Gingerol plays a crucial protective role in DN by inducing the expression of miRNA-146a and miRNA-223 and inhibiting the TLR4/TRAF6/NLRP3 inflammasome signaling pathway (Aboismaiel et al., 2024). Oxidative stress is also associated with CKD (Kishi et al., 2024). Lipotoxicity is a significant inducer of oxidative stress (Tanase et al., 2022; Chae et al., 2023). Lipid peroxidation can regulate podocyte migration and cytoskeletal structure through redox-sensitive Ras homologous gene family member A signaling (Kruger et al., 2018). The cellular oxidative stress microenvironment can drive fibroblast activation, leading to renal fibrosis (Li et al., 2023). Research on intracellular signal transduction pathways induced by oxidative stress focuses on the kelch-like erythroid cell-derived protein with the CNC homology-associated protein 1(Keap1)- nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, forkhead box O (FoxO) proteins, HIF-1 pathway and the nuclear factor-κB (NF-κB) pathway (Chae et al., 2023). A meta-analysis of 95 studies suggested that antioxidants may reduce cardiovascular events and progression to renal failure and may improve renal function (Colombijn et al., 2023). Increasing trends in IR were associated with a high risk of adverse renal outcomes, and eGFR was independently associated with insulin sensitivity (Akwo et al., 2021; Yang et al., 2022). The exacerbation of IR increases the risk of cardiorenal outcomes in CKD, whereas the endothelin receptor antagonist atrisentan reduces IR (Smeijer et al., 2023). Farnesoid X receptor agonists also improve IR and renal lipid metabolism in db/db mice (Han S. Y. et al., 2021).

Recently, autophagy and cell death have attracted considerable attention in the field of lipid metabolism in CKD. Autophagy affects different renal cell types and significantly affects the maintenance of renal function and homeostasis (He et al., 2014). It may exert a protective effect against cyclosporin-induced metabolic stress in renal proximal tubular epithelial cells (Kimura et al., 2013). Autophagy in endothelial cells and podocytes synergistically protects against diabetes-induced glomerulosclerosis (Lenoir et al., 2015). Lipophagy is selective autophagy that targets lipid droplets for degradation (Laval and Ouimet, 2023). In proximal tubule cell (PTC)-specific Atg5-deficient (atg5-TSKO) mice, lipophagy counteracts prolonged starvation in PTCs to prevent cellular energy depletion (Minami et al., 2017). Lipophagy is involved in ectopic lipid deposition and lipid-related renal injury in DN; however, these changes can be reversed by AdipoRon, an activator of the adiponectin receptor that promotes autophagy (Han Y. et al., 2021). Deficiency of α-klotho, an anti-aging protein in the renal tubular epithelial cell membrane, leads to ubiquitin-mediated adipose triglyceride lipase degradation, which is a common molecular basis for lipolysis and lipophagy (Wang et al., 2023). Autophagy-modifying drugs can be used to prevent or treat kidney disease. Metformin can upregulate adenosine monophosphate-activated protein kinase signaling and induce autophagy (Lin et al., 2019). Autophagy inhibition can activate endoplasmic reticulum stress, leading to podocyte apoptosis (Fang et al., 2014). Cell death is critical in the pathophysiology of CKD. Cholesterol 25-hydroxylase, an enzyme involved in cholesterol metabolism, maintains endothelial cell activity by regulating ADP-ribosylation factor 4, which further improves kidney injury in DKD (Zhang et al., 2024). Necroptosis leads to the release of cellular contents and cytokines that trigger an inflammatory response in adjacent tissues (Kolbrink et al., 2023). TNF-α and interferon-γ can induce necroptosis through two different pathways (Liu et al., 2018). Ferroptosis is a recently discovered form of iron-dependent cell death characterized by the accumulation of lipid peroxides (Li S. et al., 2024). It depends on the convergence of iron, thiol, and lipid metabolic pathways (Bayır et al., 2023). Ferroptosis plays a crucial role in renal fibrosis, which is a key pathological change in CKD (Li S. et al., 2024). The ferroptosis inducers, erastin and RSL3, can induce renal tubular epithelial cell death in vitro (Wang et al., 2020). Ferroptosis inhibitor Ferrostatin-1 (Fer-1) alleviates renal tubular cell death induced by transforming growth factor-beta1 (Kim et al., 2021). In summary, numerous studies exist on the mechanism of lipid metabolism in CKD; however, effective treatment of CKD with related targets must be further studied.

We found that lipid metabolism in IgA nephropathy, membranous nephropathy, and other types of glomerulonephritis has been under-researched. There is significant potential for research on drugs that target renal lipid metabolism therapy (Izumihara et al., 2024). The discovery of peptide drugs for the treatment of CKD has attracted wide attention, with fibroin peptide notably ameliorating adriamycin-induced nephropathy by regulating lipid metabolism through the PANX1-PPARα/PANK1 pathway (Li S. S. et al., 2024). Our study also highlighted traditional Chinese medicine monomers as a promising area for maintaining renal lipid homeostasis, such as hydrangea paniculata coumarins (Chen et al., 2024), Icariside II (Wang et al., 2024), berberine (Qin et al., 2020), etc.

Our study has some limitations. First, the data for this study were only obtained from the WOSCC database, and some articles in non-English, non-research, and reviews were not included. Second, the data in this study were obtained using bibliometric software based on machine learning, and most of the results were obtained using machine algorithms; therefore, some new research ideas may not be presented. Third, the latest high-quality articles could not be included in the statistics, possibly because of insufficient citation frequency due to time constraints.

In this study, we conducted a systematic bibliometric review of CKD and lipid metabolism from 2004 to 2023 to demonstrate the current status and global trends in related fields. China has the most publications and is second only to the United States in H-index and number of citations in this field. The International Journal of Molecular Sciences published the most publications in this field, and Kidney International, the top journal in the field of kidney disease, is also a core publication. CVD and DKD are closely associated with the lipid metabolism of patients with CKD. Additionally, oxidative stress, inflammation, IR, autophagy, and cell death are research hotspots. Future studies should focus on the treatment of CKD with lipid-lowering targets.