Clinical Investigations and Therapeutic Perspectives on Metabolic Syndrome following Kidney Transplantation

Chronic kidney disease (CKD) is characterized by progressive structural and functional impairment of the kidneys due to various etiologies, and chronic kidney failure represented the ultimate outcome of kidney-related conditions [1, 2]. CKD has gradually become a worldwide health burden. In 2020, the Lancet published a report on the global epidemiology of CKD, revealing a global CKD patient population of 697.5 million (including 132 million in China). CKD led to 1.2 million deaths worldwide and was expected to increase to 2.2 million deaths by 2040, and this number may rise to 4 million in severe cases [3]. Chronic kidney failure often remained undetected until it reached an advanced stage due to its insidious onset, posing a grave threat to the patient’s well-being, and ultimately, the vast majority of individuals afflicted by this ailment necessitated life-sustaining measures such as dialysis or kidney transplantation. For end-stage kidney failure patients, kidney transplantation was the most optimal approach for enhancing life quality [4]. However, clinical investigation revealed that the long-term life quality of kidney transplantation recipients was unsatisfactory.

The state following kidney transplantation aggregated numerous risk factors for various diseases such as metabolic disturbances in glucose and lipid metabolism, hyperuricemia, and hypertension, which collectively contributed to metabolic syndrome, a clinical syndrome with various metabolic disorders such as obesity, glucose metabolism disturbances, lipid metabolic irregularities, and hypertension. It was discerned that the incidence of various diseases was higher in kidney transplantation recipients than the general population [5]. In comparison to the non-metabolic syndrome group, the occurrence of metabolic syndrome was correlated with an increased risk of graft loss. The jeopardy of graft loss escalated in tandem with the augmented quantity of dysfunctional metabolic syndrome components [6]. Although there might be debates surrounding the definition and diagnosis of metabolic syndrome, it was generally accepted that the components associated with metabolic syndrome served as significant risk factors for cardiovascular and cerebrovascular events [7]. Thus, analyzing the risk factors, early identifying, and intervening with high-risk recipients were of great significance in reducing the incidence of metabolic syndrome after kidney transplantation. This article provided a comprehensive review of the current researches on post-kidney transplantation metabolic syndrome, thus offering a better understanding of metabolic syndrome and enhancing life quality of the recipients.

Metabolic syndrome was not a distinct ailment but rather a constellation of various metabolic risk factors. Although the precise definition of metabolic syndrome remained a subject of debate, it was widely acknowledged that nearly all metabolic aberrations, including but not limited to obesity, lipid disturbances, hypertension, and insulin resistance, were regarded as potential unified pathogenic elements. The incidence of metabolic syndrome was typically threefold than that of diabetes. According to the IDF Diabetes Atlas, as of 2015, the global prevalence of diabetes was 8.8% (415 million), with projections indicating an increase to 10.4% (642 million) by 2040. Consequently, it was estimated that the global prevalence of metabolic syndrome affected approximately one-fourth of the world’s population, suggesting that over one billion people worldwide were presently subject to the influence of metabolic syndrome. Some epidemiological studies have identified that lifestyle habits and socio-economic status significantly influenced the prevalence of metabolic syndrome in gender, age, and racial/ethnic groups [8, 9]. The precise etiology of metabolic syndrome still remained not entirely comprehended [10, 11]. Abdominal obesity and insulin resistance were commonly considered pivotal factors contributing to the development of metabolic syndrome [12]. Genetic susceptibility, pro-inflammatory status, leptin, physical inactivity, adiponectin, thyroid hormones, aging, and more could also serve as pathological elements. Recently, a research reported that macrophages within adipose tissues played a central role in energy metabolism, M1 macrophages promoted hepatic fibrosis and fat synthesis, while anti-inflammatory M2 macrophages exhibited a macrophage restriction defect in a mouse model and resulted in hepatic fibrosis and obesity phenotypes [13]. Endoplasmic reticulum stress represented another pivotal factor in the pathogenesis of metabolic syndrome. In murine experiments, Shan and colleagues demonstrated that endoplasmic reticulum stress induced by a high-fat diet was dependent on the activity of inositol-requiring enzyme 1 alpha (IRE1alpha), an enzyme crucial for sulfur-free protein synthesis. Lack of IRE1alpha activity prevented obesity, insulin resistance, and hepatic fibrosis induced by high-fat diet. IRE1alpha also inhibited M2 macrophages within adipose tissues [14]. Epigenetics appeared to play a more substantial role in promoting metabolic syndrome. Offspring born to parents afflicted by obesity tended to inherit the same condition [15]. As the cellular and molecular mechanisms underlying the pathogenesis of metabolic syndrome remained not entirely elucidated, treatment regimens were yet to be established. Currently available treatment strategies primarily included promoting a physically active and healthful lifestyle or focusing on addressing the individual components of metabolic syndrome [16]. The overarching objective was to mitigate the risks of cardiovascular disease and type 2 diabetes or prevent their onset [17].

The most prevalent postoperative complication in organ transplantation was hypertension. Aberrations in postoperative blood pressure were significantly related to the incidence of cardiovascular events. If left unregulated, they substantially elevated the risk of cardiovascular complications. Scholars have believed that arterial hypertension following kidney transplantation was intricately linked to suboptimal cardiovascular and renal outcomes [18], which was accompanied by kidney function impairment, diminished graft survival rates, and heightened mortality. The proportion of postoperative kidney transplantation recipients with systolic blood pressure exceeding 140 mm Hg (10 mm Hg = 1.33 kPa) ranged from 55.5% to 90.0% [19], leading to approximately 60–70% of transplanted kidneys experiencing varying degrees of impairment. Various factors contributed to hypertension in organ transplantation recipients. Protein encoded by CYP3A5 gene played a significant role in sodium and aldosterone metabolism in kidney, which also amplified the hypertensive effects of calcium channel blockers [20]. Podocalyxin-1 was a pivotal intracellular protein governing the endocytic machinery [21] and played a leading role in regulating the degradation of transforming growth factor-β. In the absence of podocalyxin-1, there was a significant increase in transforming growth factor-β activity in donors, accelerating the abnormal interstitial fibrosis process in transplanted kidneys [21]. This cascade contributed to hypertension and the deterioration of kidney transplantation. Posttransplantation hypertension might be a principal etiology of metabolic syndrome, which, in turn, exacerbated hypertension, forming a deleterious feedback loop [22].

Dyslipidemia was the disorder of lipid metabolism in human body, which was characterized by the abnormal levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), and was regarded as an autonomous risk factor for cardiovascular events. In prospective kidney transplantation candidates, compared to transplantation recipients, there was a significant increase in the prevalence of hypercholesterolemia, increasing from 25% to 60% [23]. The overall elevation in total cholesterol was approximately 27%. The pathogenic mechanisms of posttransplantation dyslipidemia were multifaceted [24, 25]. Factors such as chronic anemia, elevated homocysteine levels, chronic inflammation, proteinuria, diuretics, and β-adrenergic blockers were recognized contributors to lipid abnormalities and cardiovascular diseases. Additionally, sedentariness, the excessive intake of saturated fats, cholesterol, and trans fats were closely associated with lipid disorder [26]. It has been reported that immunosuppressants played a pivotal role in lipid abnormality [27]. Cyclosporine, tacrolimus, sirolimus, everolimus, corticosteroids, as well as a limited quantity of thiopurines and mycophenolic acid were all associated with lipid imbalance. Cyclosporine decreased LDL receptors expression by increasing proprotein convertase subtilisin/kexin type 9 (PCSK9) and inhibited cholesterol transport to the intestines by reducing cholesterol expression [28]. Conducting mechanistic researches to identify effective targets and corresponding medications for kidney transplantation recipients was significant.

Hyperuricemia was a metabolic disorder characterized by excessive uric acid production or reduced excretion due to the abnormal purine metabolism, as well as the elevated blood uric acid levels resulted from the excessive intake of exogenous purines. Hyperuricemia not only impacted kidney transplantation function but also elevated the risk of cardiovascular diseases, which was a significant risk factor affecting the long-term survival of transplanted kidneys. Epidemiological investigations revealed a rising prevalence of hyperuricemia, ranging from 10% to 15% in the general population. In China, the incidence of hyperuricemia has reached 20% in coastal regions and developed cities, reaching the level of developed countries [29, 30]. The incidence of hyperuricemia in kidney transplantation recipients was significantly higher than that of the general population, affecting approximately 40–60% of recipients [31]. Moreover, a study involving 9,589 participants suggested that incorporating uric acid into the definition of metabolic syndrome was crucial when assessing the risk of mortality in kidney transplantation recipients [32]. Although the pathophysiological molecular mechanisms of kidney damage caused by hyperuricemia were not yet fully understood, current researches suggested the involvement of oxidative stress, endothelial dysfunction, renal fibrosis, and inflammation. Extracellular matrix played a pivotal role in the progression of interstitial fibrosis in the kidney, epithelial-mesenchymal transition (EMT) promoted Extracellular matrix production [33]. Researches revealed that the TGF-β/Smad3 pathway played a pivotal role in EMT. Hyperuricemia resulted in EMT and renal tubular injury in mice through the modulation of the Wnt5a/Ror2 or TLR4/NF-κB signaling pathways. EMT has been regarded as a novel therapeutic target owing to its reversibility [34, 35].

Posttransplantation diabetes mellitus (PTDM) denoted the onset of diabetes following organ transplantation. The incidence of PTDM ranged from 2% to 50%. The substantial variation in incidence was attributed to the differing criteria adopted by various research centers and disparities in posttransplantation immunosuppressive regimens [36]. Risk factors for PTDM in kidney transplantation recipients were categorized into 2 classes: transplantation-related, encompassing the use of glucocorticoids, CNIs, viral infections, posttransplantation weight gain, and non-transplantation-related, including gender, age, ethnicity, obesity, family history of diabetes, and metabolic syndrome. The pathogenic mechanisms of PTDM were similar to type 2 diabetes mellitus [37], both exhibiting the decreased insulin sensitivity, augmented peripheral insulin resistance, weakened insulin secretion by pancreatic β cells, and reduced glucose tolerance. Some scholars believed that the evolution and pathogenic mechanisms of PTDM conformed to pre-transplantation β-cell impairment [38]. Pre-diabetic patients might progress to late-stage PTDM. Individuals with normal sugar metabolism might also experience the onset of new diabetes [39]. In summary, post-kidney transplantation patients experienced metabolic disruptions in fundamental substances, including sugars, lipids, proteins, purines, amino acids, electrolytes, posing a significant threat to life quality.

Until now, most researches on immunometabolism focused on how immune cells simultaneously and differentially used nutrients to meet metabolic demands associated with effector function and differentiation states. In essence, environments influenced the metabolism and function of immune cells. The central metabolic program for the activation of innate and adaptive immune cells was glycolysis, often referred to as the Warburg effect [40]. During this activation process, innate immune cells and T cells, which originally mainly relied on oxidative phosphorylation for energy supply, rapidly switched to aerobic glycolysis (Warburg effect) for energy supply, thus quickly meeting the increased energy demands and providing key metabolic substrates. Hence, glucose exerted a significant effect on the metabolism of immune cells, and interfering with the Warburg effect of immune cells will affect their activation, differentiation, and memory formation. Metabolic processes, such as glycolysis and mitochondrial oxidative phosphorylation, governed the transformation of precursor cells into pathogenic and regulatory T (Treg) cells [41]. Helper T cells exhibited the enhanced glycolysis, relying on the glucose transporter protein glucose transporter1 (GLUT1), to facilitate the effector functions of Th1 and Th17 cells [42]. Modulation of GLUT1-mediated glycolysis in Treg cells, in turn, governed the equilibrium between proliferation and suppressive capabilities. It has also been reported that genes encoding amino acid transport proteins were the most upregulated genes after T-cell activation [43], suggesting that amino acid exchange solution was a critical aspect of immune regulation. In other words, apart from glucose, different amino acids also impacted the metabolism of immune cells.

Glutamine exerted multiple biological roles. In proliferating cells, glutamine provided nitrogen elements for amino acid and nucleic acid synthesis and offered carbon elements to replenish tricarboxylic acid (TCA) cycle intermediates, which was the cornerstone of biosynthesis. Experimental evidence indicated that restricting glutamine inhibited the effector function of differentiated CD8⁺ T cells [44]. Restricting glutamine during the activation of CD8⁺ T cells resulted in the differentiation into a long-term, persisting memory phenotype [45]. Metabolic byproducts of glutamine also modulated various cellular functions. Under the influence of MYC, glutamine was metabolized by glutaminase into glutamate, which was further converted into α-ketoglutarate by glutamate dehydrogenase before entering the TCA cycle [46]. α-Ketoglutarate and other metabolic products of the TCA cycle, such as succinate and fumarate, modulated the activity of numerous cellular factors, including epigenetic remodeling and the stability of crucial transcription factors like HIF-1α [47]. Furthermore, T cells and macrophages exhibited the capacity to catabolize glutamine to enhance the generation of ATP [48]. The inhibitory effect of glutaminase (referring to the conversion of glutamine to glutamate) impaired the proliferation and activation of CD4⁺ T cells and CD8⁺ T cells, with minimal interference in the generation of most cellular effector molecules. The same inhibitory action suppressed the differentiation of Th17 cells [49].

Researches have shown that methionine played a crucial role in immune cells. Controlling cellular methionine levels modulated the state of T cells. When T cells were stimulated by antigens, they maintained the transport of methionine into the cells, thus increasing its intracellular concentration, which was the rate-limiting step where intracellular methionine supplied the methyl groups to the targets to be methylated [50]. Methionine provided methyl groups by generating S-adenosyl methionine (SAM). SAM served as the methyl donor for DNA, RNA, and protein methyltransferases [51]. Only T cells with an ample intracellular supply of methionine promoted DNA methylation, protein synthesis, and proliferation. Serine, a nonessential amino acid, enhanced T-cell proliferation and immune function, which was directly absorbed by cells or synthesized de novo from glycolytic metabolite 3-phosphoglycerate (3-PG) [52]. Serine also served as a methyl donor, providing hydroxymethyl as a one-carbon unit of tetrahydrofolate. Intracellular serine accumulation stimulated one-carbon metabolism, leading to the proliferation of crucial Treg cells that underlie self-immune tolerance. The extracellular availability of serine and methionine influenced the proliferation of T lymphocytes through actions related to one-carbon metabolism [53, 54]. Within T cells, the divergence of folate and methionine cycles coupled with the fact that carbon derived from serine did not integrate into the methionine cycle; external methionine may indeed stand as the exclusive origin of the methyl moiety in SAM. This phenomenon significantly affected subsequent methylation reactions. Serine also emerged as a pivotal switch governing the regulation of both T regulatory cells and effector T cells, a factor of substantial importance in the induction of posttransplantation immune tolerance.

It has been reported that supraphysiological levels of arginine suppressed T-cell-mediated cytokine production and enhanced T-cell survival [55]. The consumption of tryptophan impeded the functionality of T cells by activating integrated stress responses [56]. A recent study revealed that the availability of alanine impacted protein synthesis during the early stage of T-cell activation [57]. These findings suggested that various amino acids exerted distinct cell-specific effects on immune cells and provided the potential for targeting amino acid metabolism in different immune cells as a therapeutic approach in human diseases.

In conclusion, immunosuppressive drugs, obesity, diabetes mellitus, hypertension, albuminuria, improper diets, lack of exercises, and age were all risk factors for posttransplantation metabolic syndrome of recipients (Table 1); monitoring these components before and after the operation in kidney transplantation recipients may benefit clinical practices. However, this article exhibited certain limitations. Abdominal circumference data were not included. Although body mass index served as a critical value for diagnosing obesity, abdominal circumference data would enhance the reliability of the results. Additionally, sufficient Asian models were not collected for clinical external validation due to time constraints. In the future, large-scale studies or interventional studies will be conducted to provide a basis for reducing the occurrence of metabolic syndrome after kidney transplantation. Also, targeted corrections of the host’s metabolic environments hold the potential to enhance the induction of immune tolerance by regulating immune cells, and the clinical detection on the changes of amino acid levels in kidney transplantation recipients was necessary.

All authors declare no conflict of interest.

This work was supported by the Natural Science Fund Program of Science and Technology Department of Jilin Province (No. 20220101329JC), Jilin Province College Students Innovation Training Project (No. s202313706036, 2023-JYSC039), Jilin Medical University College Students Innovation Training Project (No. 2024CXXL014), and Science and Technology Program of Education Department of Jilin Province (No. JJKH20230543KJ).

Kejing Zhu and Yuji Jin conceived the idea of this study. Kejing Zhu, Yuji Jin, Cheng Wen, Xinrui Zheng, Zhixiong Li, Yunjian Chen, Yulin Niu, and Wei Pan assisted in the literature search. Yong Jiang wrote the final report. Yingji Ji reviewed and revised the article. Weijian Liu contributed to the revision. All authors read and approved the final manuscript.

Kejing Zhu and Yuji Jin contributed equally to this work.