Kidney disease is a significant health problem worldwide, affecting an estimated 10% of the global population [1]. The most common forms of kidney disease include chronic kidney disease (CKD) and acute kidney injury (AKI) [2]. However, kidney disease encompasses a diverse group of disorders that vary in their underlying pathophysiology, clinical presentation, and outcomes. These disorders include tubulointerstitial, glomerulonephritis, nephrotic syndrome, polycystic kidney disease, diabetic kidney disease, vascular disease, vasculitis, and congenital kidney disease, among others.

Immunometabolism refers to the interplay between immune and metabolic pathways, which are tightly regulated in normal physiological conditions [7,8,9,10]. In pathological conditions, such as kidney disease, this delicate balance is disrupted, leading to immunometabolic dysregulation. Immunometabolic dysregulation involves various cell types, such as T cells, B cells, macrophages, and dendritic cells, as well as cytokines, chemokines, and metabolic processes, such as oxidative stress, mitochondrial dysfunction, and inflammation [8,11].

Acute kidney injury (AKI) is a complex condition characterized by a rapid loss of renal function [72,73]. Immunometabolic dysregulation has been shown to play an important role in the pathogenesis of AKI [22,74]. This involves an imbalance between pro- and anti-inflammatory cytokines, leading to the activation of innate immune cells and subsequent tissue damage.

Several genes and pathways have been linked to immunometabolic dysregulation in AKI. One of the key pathways involved in the development of AKI is the hypoxia-inducible factor 1-alpha (HIF-1α) pathway [75,76]. Under hypoxic conditions, HIF-1α is stabilized and activates the transcription of genes involved in glycolysis, angiogenesis, and inflammation [77]. Studies have shown that HIF-1α plays a critical role in the development of AKI by promoting glycolysis in immune cells and contributing to the production of pro-inflammatory cytokines [78,79,80]. In addition, HIF-1α can also upregulate glucose transporter 1 (GLUT1), which facilitates glucose uptake in immune cells, and its upregulation has been linked to the development of AKI [80,81]. Moreover, recent studies have suggested that epigenetic modifications, such as DNA methylation and histone modifications, can contribute to the dysregulation of HIF-1α in AKI pathogenesis [82,83,84]. Another important gene involved in immunometabolic dysregulation in AKI is the gene encoding for inducible nitric oxide synthase (iNOS). iNOS is an enzyme that produces nitric oxide (NO), which is a potent regulator of immune cell function [85]. Dysregulation of iNOS has been implicated in the pathogenesis of AKI, with studies showing that iNOS-mediated NO production can contribute to tissue damage in the kidney [86,87,88].

In addition to HIF-1α and iNOS, toll-like receptors (TLRs) are involved in the recognition of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), and their dysregulation has been linked to the development of AKI [89,90]. TLRs can activate nuclear factor kappa B (NF-κB), a transcription factor that regulates the expression of genes involved in inflammation and immune cell activation, and its dysregulation has been shown to contribute to the development of AKI [91,92]. The NLRP3 inflammasome, a multiprotein complex involved in the processing and secretion of pro-inflammatory cytokines, has also been implicated in the development of AKI. Studies have shown that NLRP3 inflammasome activation can contribute to the development of AKI by promoting the secretion of pro-inflammatory cytokines [93,94,95].

Chronic kidney disease (CKD) is a progressive condition characterized by the gradual loss of kidney function over time. Dysregulation of immune cells and metabolism contribute to the accumulation of toxic metabolites, oxidative stress, and fibrosis, which are key contributors to the progression of CKD [105]. One of the key pathways involved in the development of CKD is dysregulated glucose metabolism in immune cells [106,107]. Studies have shown that this dysregulation can lead to the activation of pro-inflammatory pathways, oxidative stress, and endothelial dysfunction, all of which can contribute to the development of CKD [61]. GLUT1 and HIF-1α are two genes that have been implicated in the dysregulation of glucose metabolism in immune cells in the context of CKD [108,109]. Another important pathway involved in CKD is the activation of the NLRP3 inflammasome and subsequent cytokine production. Increased NLRP3 expression has been observed in patients with CKD, and inhibition of the NLRP3 inflammasome has been shown to ameliorate kidney damage in animal models of CKD [110]. Additionally, dysregulated lipid metabolism has been linked to the progression of CKD. Studies have shown that increased levels of FFAs can contribute to the development of CKD by activating inflammatory pathways and inducing oxidative stress [111,112]. In addition to the above-mentioned pathways, other genes involved in immune cell dysregulation in CKD include TLRs, NF-κB, and the renin–angiotensin–aldosterone system (RAAS). TLRs are involved in the recognition of PAMPs and DAMPs, and their dysregulation has been linked to the development of CKD [113,114,115]. NF-κB activation in CKD can be triggered by a variety of stimuli, including oxidative stress, hypoxia, and proinflammatory cytokines, such as TNF-α and IL-1β [116,117]. Furthermore, NF-κB activation is tightly linked to NLRP3 inflammasome activation in CKD. Activation of the NLRP3 inflammasome triggers the activation of NF-κB, which, in turn, leads to the production of more proinflammatory cytokines, creating a positive feedback loop that perpetuates the inflammatory response [118,119]. The RAAS is a hormone system that regulates blood pressure and fluid balance in the body, and its dysregulation has been linked to the development of CKD through its effects on renal hemodynamics and inflammation [120,121,122].

Lupus nephritis is a type of kidney inflammation that occurs as a result of systemic lupus erythematosus (SLE), an autoimmune disease [127]. Immunometabolic dysregulation is one of the key mechanisms underlying the pathogenesis of lupus nephritis [128]. Dysregulated metabolism in immune cells can contribute to the production of autoantibodies and the activation of inflammatory cells, leading to glomerular damage and renal dysfunction [129,130].

Several genes and pathways have been implicated in the dysregulated metabolism in immune cells in the context of lupus nephritis. One of the most studied pathways is the Warburg effect, which is characterized by the preferential use of glycolysis over oxidative phosphorylation in immune cells [131]. The upregulation of glycolysis is thought to be driven by various signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway, the HIF pathway, and the JAK/STAT pathway [132,133]. These pathways have been shown to contribute to the activation of immune cells and the production of autoantibodies in lupus nephritis [133,134,135,136].

The activation of the NLRP3 inflammasome is another key pathway involved in the pathogenesis of lupus nephritis, with the subsequent production of cytokines. The NLRP3 inflammasome contribute to tissue damage in lupus nephritis [137]. Studies have shown that the NLRP3 inflammasome is upregulated in lupus nephritis patients and that its inhibition can ameliorate kidney injury in animal models of lupus nephritis [137,138]. Moreover, dysregulated lipid metabolism has also been implicated in the pathogenesis of lupus nephritis. Studies have shown that increased levels of FFAs can contribute to the activation of immune cells and the production of autoantibodies in lupus nephritis [139,140]. The dysregulation of cholesterol metabolism has also been linked to the development of lupus nephritis. In addition to the above-mentioned pathways, other genes and pathways involved in the dysregulated metabolism in immune cells in lupus nephritis include TLRs, NF-κB, and the IFN pathway. TLRs are involved in the recognition of PAMPs and DAMPs, and their dysregulation has been linked to the activation of immune cells in lupus nephritis [141,142,143]. NF-κB is a transcription factor that regulates the expression of genes involved in inflammation and immune cell activation, and its dysregulation has been shown to contribute to the development of lupus nephritis [144,145]. The type I IFN pathway is another important pathway involved in the activation of immune cells in lupus nephritis, as the overexpression of type I IFN-inducible genes has been observed in lupus nephritis patients [146,147,148].

Diabetic kidney disease is a common complication of diabetes mellitus and a leading cause of end-stage renal disease [150,151,152]. Dysregulated metabolism and inflammation are key factors in the pathogenesis of diabetic kidney disease. Impaired glucose metabolism leads to the accumulation of AGEs in the kidneys, which contribute to renal dysfunction and fibrosis [153]. GLUT1 and HIF-1α are two genes that have been implicated in the dysregulation of glucose metabolism in immune cells in the context of diabetic kidney disease [78,154].

In addition to dysregulated glucose metabolism, dysregulated lipid metabolism in immune cells has also been implicated in the pathogenesis of diabetic kidney disease. Studies have shown that increased levels of FFAs can contribute to the development of diabetic kidney disease by activating inflammatory pathways and inducing oxidative stress [155,156]. In particular, the peroxisome proliferator-activated receptor (PPAR) family of genes, which regulates lipid metabolism, has been shown to play a role in the pathogenesis of diabetic kidney disease [157,158]. The activation of the NLRP3 inflammasome and subsequent production of pro-inflammatory cytokines have been identified as critical drivers of diabetic kidney disease. The NLRP3 inflammasome is a multiprotein complex involved in the processing and secretion of pro-inflammatory cytokines, and its activation has been implicated in the development of diabetic kidney disease [159]. The inflammasome is activated by a variety of stimuli, including high glucose levels and the accumulation of AGEs [160]. The JAK/STAT signaling pathway is involved in many biological processes, including immune responses and inflammation, and has been implicated in the pathogenesis of diabetic kidney disease [161,162,163,164,165,166,167]. Studies have shown that the JAK/STAT pathway is activated in response to pro-inflammatory cytokines and growth factors, and its dysregulation can contribute to the progression of diabetic kidney disease [168]. The suppressor of cytokine signaling (SOCS) family of genes, which negatively regulates JAK/STAT signaling, has been shown to play a role in the development of diabetic kidney disease [169,170].

In conclusion, dysregulated metabolism and inflammation contribute to the development and progression of diabetic kidney disease through various pathways and genes, including dysregulated glucose and lipid metabolism, activation of the NLRP3 inflammasome, and dysregulated JAK/STAT signaling. Further research in this area may provide novel insights into the mechanisms underlying the development of diabetic kidney disease and help identify new therapeutic targets for the treatment of this condition.

Immunometabolic dysfunction plays a critical role in the pathogenesis of PKD. Dysregulated metabolism in immune cells, such as the activation of the Warburg effect, has been implicated in the development and progression of PKD [171,172]. Additionally, studies have shown that immune cells in PKD exhibit increased mitochondrial stress and metabolic alterations, leading to impaired cellular energetics and increased oxidative stress [173].

One recent study has found that the inflammasome pathway, specifically the NLRP3 inflammasome, is activated in PKD, leading to the production of pro-inflammatory cytokines and subsequent cyst growth [174,175]. The activation of the NLRP3 inflammasome has been linked to the accumulation of damaged mitochondria and the release of mitochondrial DNA, which can trigger an inflammatory response in the kidney [23]. Another study has shown that PKD is associated with altered immune cell metabolism and an increased production of ROS. The authors suggest that this metabolic dysfunction may contribute to the activation of the NLRP3 inflammasome and the subsequent production of pro-inflammatory cytokines in PKD [174,176]. Furthermore, recent research has also linked PKD to dysregulated lipid metabolism in immune cells [61]. One study found that PKD is associated with altered lipid metabolism in T cells, leading to increased T-cell activation and subsequent inflammation in the kidney [177].

In summary, immunometabolic dysfunction, including dysregulated metabolism in immune cells, activation of the inflammasome pathway, altered mitochondrial function, and dysregulated lipid metabolism, contributes to the pathogenesis of PKD. These findings suggest that targeting immunometabolic pathways may provide a potential therapeutic strategy for PKD.

Immunometabolic dysregulation has been increasingly recognized as an important contributor to kidney transplant outcomes. The immune response after kidney transplantation involves both the innate and adaptive immune systems, which interact with each other to establish a balance between tolerance and rejection [178,179]. Dysregulated metabolism and inflammation can disrupt this balance, leading to poor transplant outcomes, such as rejection, infection, and chronic allograft dysfunction [180,181].

One key pathway involved in immunometabolic dysregulation after kidney transplantation is the activation of the NLRP3 inflammasome. Studies have shown that activation of the NLRP3 inflammasome in both donor and recipient cells can contribute to the development of acute and chronic rejection [182]. Furthermore, activation of the NLRP3 inflammasome has also been implicated in the development of ischemia–reperfusion injury, a common complication during kidney transplantation [183,184,185]. Dysregulated metabolism in immune cells has also been implicated in poor kidney transplant outcomes. Specifically, the Warburg effect, a phenomenon where immune cells preferentially use glycolysis for energy production instead of oxidative phosphorylation, has been observed in both donor and recipient cells after kidney transplantation [186,187]. This metabolic switch has been associated with increased inflammation and oxidative stress, which can lead to allograft injury and rejection [188,189]. Finally, dysregulation of lipid metabolism in immune cells has also been implicated in poor kidney transplant outcomes [190]. Studies have shown that high levels of triglycerides and low levels of high-density lipoprotein (HDL) cholesterol are associated with an increased risk of acute rejection and chronic allograft dysfunction [191,192]. Dysregulated lipid metabolism in immune cells can also lead to the production of pro-inflammatory cytokines and the activation of the NLRP3 inflammasome [193,194].

In conclusion, immunometabolic dysregulation plays a critical role in kidney transplant outcomes. Dysregulated metabolism and inflammation can disrupt the delicate balance between tolerance and rejection, leading to poor transplant outcomes, such as rejection, infection, and chronic allograft dysfunction. Understanding the mechanisms underlying immunometabolic dysregulation in kidney transplantation may lead to the development of novel therapeutic strategies to improve transplant outcomes.