Perfluoroalkyl chemicals, including perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS), are found in all populations worldwide, regardless of geographical location, due to their extensive use (11). The plasma concentrations of these substances exhibit geographical variation (12, 13). According to reports, the levels of per- and poly-fluoroalkyl substances (PFAS) in drinking water are consistent with PFAS exposure (14). Consequently, multiple regulatory entities have established the approved threshold for plasma concentration. For example, the National Food Agency in Sweden and the Environmental Protection Agency in the United States have suggested limits of 90 ng/L and a range of 13 to 1,000 ng/L, respectively (15, 16). PFOA has a long half-life that may last for several years (1.2 to 14.9 years) (17–21). The long half-life of PFOA is primarily due to its significant reabsorption in the renal tubules, which leads to sluggish urine excretion (22). PFAS substances build up in breast milk, liver, and kidneys upon absorption. Upon introduction into the body, perfluorooctanoic acid (PFOA) typically binds to proteins instead of lipids. As a result, it typically accumulates in tissues and organs that have a high protein content (21, 23, 24). Animal studies have demonstrated that PFAS are most highly concentrated in the kidney, liver, and lungs. The human body does not metabolize PFAS, leading to its excretion without any metabolic transformations (13, 22). The reabsorption of PFAS in the kidneys may result in progressive kidney damage over time. Epidemiological studies have demonstrated a correlation between exposure to perfluorooctanoic acid (PFOA) and various forms of kidney disease (25). PFOA exposure causes renal hypertrophy, tissue proliferation, and microvascular dysfunction (26).

Exposure to perfluorooctanoic acid (PFOA) alters many signaling pathways. These pathways include the inflammatory pathway, the oxidative stress pathway, the peroxisome proliferator-activated receptor pathway, DNA methylation, and the autophagy pathway (26). Animal experiments have found that PFOA causes oxidative stress in the kidney and liver. Reactive oxygen species cause oxidation that exceeds the capacity of antioxidant defense system, leading to oxidative stress (26). This leads to detrimental effects on the peroxide of membrane phospholipids, DNA damage and mutation, oxidation and deactivation of proteins and enzymes, and the commencement of the apoptosis process (27). In order to demonstrate the causal relationship between PFAO and oxidative stress, scientists conducted an experiment where they administered an antioxidant known as N-acetylcysteine (NAC). The purpose of this experiment was to observe whether NAC might mitigate or reduce the biomarkers associated with liver and kidney damage caused by PFOA. The authors demonstrated that NAC decreased the biomarkers of PFOA-induced kidney and liver toxicity (28). PFOA has also been shown to activate the nuclear receptor peroxisome proliferator α (PPAR α), which changes how the kidneys work. However, the precise workings of this pathway are still poorly understood (29, 30). PPAR receptors have subtypes, namely PPARα, PPARβ, and PPARγ, which share the same core structure (31). Previous research suggests that the levels of PPARα are elevated in the kidney and adrenal glands. Additional studies have demonstrated that PFOA has the ability to stimulate the activation of mouse and human PPARα and PPARδ/γ in mouse models (32). The immune-damaging effects that PFAO caused in zebrafish kidneys showed that it changed the activity of NF-κB transcription factors, which, in turn, changed the transcription of cytokines. PFOA initially modulates the Toll-like receptors (TLR), hence regulating the MyD88 and NF-κB pathways to govern cytokine transcription and stimulate the immune system in zebrafish (33).

Aluminum (Al) has favorable physical and chemical properties, making it the most widely used element in medicine, industry, and everyday life. The kidney primarily excretes Al, making it the primary location for Al accumulation and, consequently, a major site of Al-induced organ damage. A previous study found that chronic exposure to Al leads to kidney accumulation and, consequently, impairment in kidney function. On the other hand, our understanding of cause of kidney damage of Al remains incomplete. However, it may be because extracellular matrix (ECM) accumulation and apoptosis work together in several different pathogenic mechanisms to cause the injury and progression of kidney disease (34). In a related study, exposure to Al was found to upregulate TGF-β, thus inducing oxidative stress with an attendant increase in apoptosis-related protein expression and subsequent kidney cell apoptosis (35). Another study also showed increased ECM protein expression in animals exposed to Al (36). A recent study on animals showed that Al treatment increased apoptosis and increased TGF-β1 and its downstream Smad2 mediators (34). This suggests that an abnormality in the TGF-1/Smad2 signaling pathway likely causes Al-induced kidney damage. One of the main ways that progressive tubular and interstitial fibrosis occurs is through apoptotic death and the buildup of ECM (37, 38). Arsenic (As) is a noxious metallic element that is abundantly present on our planet and typically forms chemical bonds with oxygen, chlorine, and sulfur. Therefore, it is referred to as an inorganic arsenic (39). Humans are exposed to arsenic through dietary sources, the environment, and contaminated drinking water. Common dietary sources of arsenic, such as fish and other shellfish, may have elevated quantities of this element. In addition, youngsters may come into contact with As (arsenic) as a result of their regular interaction with sand (40–42). Following ingestion, the kidneys play a crucial role in eliminating it, making them a key site for absorption and buildup. Prior animal investigations indicate that glucose transporters GLUT1 (SLC2A1) and GLUT5 (SLC2A5) are likely to have important functions in the uptake of As at the basolateral membrane of the proximal tubular cells as well as at the peritubular capillaries into the proximal tubular cells (43). Additional animal research indicates that aquaporin 3 (AQP3) channels may also take in arsenic (As). Additional transporters potentially essential for arsenic uptake include inorganic anion-transporting peptides, such as OATP2B1 (SLCO2B1). The mechanism by which As exits the kidney is still unclear. However, it is possible that GLUT1 and GLUT5, which have the ability to transport substances in both directions, may play a role in transporting As out of the renal tubular cells (44). In vitro studies demonstrate that arsenic (As) export relies on the interaction between glutathione (GSH) and As, forming a complex. The As-GSH complex is subsequently removed in transportable forms such as As(GS)₃ and MAs(GS)₂ (45). The metal and toxicant extrusion protein (MATE; SLC47A1) is another transporter found on the apical membrane of the proximal tubular cells that export As out of the renal tubular cells (46).

Acute poisoning can cause damage to the tubules and interstitium of the kidneys, leading to hypercalciuria, albuminuria, nephrocalcinosis, and renal papillary necrosis. Internalization of As can lead to alterations in intracellular signaling pathways (47, 48). Exposure to arsenic (As) leads to an increase in the generation of ROS and raises the levels of heme oxygenase (HMOX1), a crucial modulator of heme oxidation and reaction to stress in kidney epithelial cells (49). It also increases the likelihood of developing hypertension, kidney damage, albuminuria, and chronic kidney disease (CKD), ascribed to the death of nephrons and subsequent hyperfiltration in the surviving nephrons (50, 51).

Mercury, a poisonous metal, can be found in several industrial and ecological contexts. It can be found in several organic and inorganic forms. Methylmercury (CH3Hg+) is the predominant form of organic mercury that humans are typically exposed to in the environment (52, 53). Mercury exposure can also happen when people come into contact with polluted water, consume contaminated food, engage in certain occupations, or interact with contaminated soil (54). After 2 weeks of being consumed, the body transforms CH3Hg + into Hg2+ (55). The kidneys are the primary location of mercury accumulation and toxicity, as they are responsible for eliminating both organic and inorganic forms of mercury from the body (47, 56). Exposure to any form of mercury can lead to renal diseases. However, kidney problems caused by Hg2+ conjugates are particularly severe. The first segment of the proximal tubule that is impacted upon exposure is the pars recta, which is particularly vulnerable to the toxic effects of mercury. Minimal amounts of mercury have no impact on the distal nephron segment and the pars convoluta. However, elevated levels can lead to damage and necrosis in these areas (57–59). Observable proof of kidney damage caused by mercury exposure includes alterations in mitochondrial morphology and the presence of pyknotic nuclei (60). After being exposed for a few hours, the cells experience a loss of microvilli, swelling of the mitochondria, and dilation of the endoplasmic reticulum. During the final phases following exposure, the plasma membrane ruptures, resulting in reduced interaction with the basement membrane (60). Prolonged exposure to mercury might also impact the glomeruli leading to glomerular fibrosis and membranous nephropathy (60).

Multiple studies have demonstrated that the gut microbiota affects the nutrition, metabolism, and immune system under physiological settings of the host. On the contrary, diseases such as obesity, diabetes, and cardiovascular diseases, have been linked to microbiome disturbances in the gut. The capacity of the gut microbiota to adapt is crucial for maintaining gut homeostasis, although drastic alterations caused by antibiotics or food might be harmful (2, 82–84). The gut microbiota, as an ecosystem, primarily plays trophic and defensive roles, but it also has several impacts on human physiology. One of these is the ability of commensal bacteria to enhance the intestinal epithelial barrier (8, 85).

In addition to their trophic and defensive activities, the gut microbiota acts as an ecosystem that has several impacts on human physiology. Commensal bacteria perform a variety of functions, one of which is enhancing the intestinal epithelial barrier (8, 86). Protein fermentation by the bacteria is the principal pathomechanism. The process is responsible for the formation of urea solutes such as indoxyl sulfate, p-cresyl sulfate, phenyl sulfate, cholate, hippurate, dimethylglycine, Î3-guanidino-butyrate, glutarate, 2-hydroxy-pentanoate, trimethylamine N-oxide, and phenaceturate. Reduced function of the epithelial barrier has the potential to cause oxidative stress damage to the kidneys by increasing the transfer of uremic toxins made by bacteria. Endotoxemia is common in uremic patients, even when a clinical infection is not present (8, 87, 88).

.The “gut–kidney crosstalk” is about how CKD, the digestive system, and changes in the permeability of the intestinal epithelial barrier affect each other” (2). Gut dysbiosis and subsequent bacterial translocation can lead to chronic systemic inflammation in persons with CKD. It is also known that microbiome dysbiosis can result in cardiovascular disease, insulin resistance, and diabetes mellitus, increasing the risk of CKD. Gut dysbiosis is characterized by the excessive growth of harmful bacteria, leading to the increased release of substances such as LPS, peptidoglycans, bacterial DNA, and outer membrane proteins into the bloodstream of the host. This, in turn, causes prolonged activation of the immune system. The aforementioned harmful substances alter the ability of the intestines to allow substances to pass through and activate the immune system of the intestinal lining. This leads to the creation of substances that cause inflammation, such as interferon-γ (IFN-γ), TNF-α, and IL-6 (89, 90).

Additionally, the uremic milieu that results in elevated expression of TLR2 and TLR4 may be the reason why neutrophils and monocytes from CKD patients exhibit an excessive response to stimulation with lipopolysaccharides (LPS) (2, 87, 90–95).

In order to maintain the balance of the gastrointestinal system, it is crucial to stimulate the development of mucosal immune responses. This is achieved through the activation of pathogen sensors, such as TLRs, NLRs, and RIG-I-like receptors, which are distributed throughout the intestinal lining. These sensors are capable of identifying PAMPs and initiating a series of signaling pathways and molecular processes. As a result, the production of anti-infective cytokines and other defensive molecules in the intestinal mucosa is generated (96).

Dendritic cells, which are adept at presenting antigens, are part of the gut immune system together with intestinal intraepithelial lymphocytes and T lymphocytes in the lamina propria. Numerous immunological and epithelial cells exhibit the important inflammasome family member NLRP3. Reactive oxygen species and toxins from gut bacteria cause the NLRP3 inflammasome to make more IL-1 and IL-18, which are usually activated by caspase-1 downstream effector proteins (2, 96, 97).

Both CKD and the gut microbiome are influenced by one another. The gut microbial composition is greatly affected by chronic kidney disease (CKD) and is highly sensitive to the number of UTs, just as gut dysbiosis can affect kidney function (2, 98). Urease-positive microbes hydrolyze elevated quantities of urea to ammonium hydroxide in the intestinal lumen. The disruption of tight junctions accelerates the subsequent progression of kidney dysfunction. Furthermore, it impairs the IEB and makes it more permeable, which opens the door for bacterial toxins to enter the bloodstream (2, 99–104).

The inflammatory mediators produced by microbiome dysbiosis (IFN-γ, TNF-α, and IL-6) may increase the expression of apolipoprotein A-1 (APOL1). IFN-γ and TNF-α increase the expression of APOL1 in endothelial cells and podocytes (105, 106). The increased expression of G1 and G2 risk variants of APOL1 has been linked to a decline in kidney function and albuminuria (107).

Cellular metabolism has the capacity to generate acrolein, a compound that is commonly found in both the environment and food that we consume. It is an α,β-unsaturated aldehyde that is released during the breakdown of petroleum fuels, biofuel, plastic, paper, and wood (108). Direct contact with this primary constituent of tobacco smoke results in immediate damage to the skin and lungs. Individuals who are at high risk of exposure include cigarette users, firefighters, workers in the acrolein industry, and residents of densely polluted cities (108–110). Cooked, fried, and charred food and beer, wine, rum, and bread are noteworthy sources of acrolein, which is produced when vegetable and animal fats are overheated (111). Cells synthesize acrolein through various metabolic pathways, including the metabolism of polyamines such as spermine and spermidine by amine oxidase, the breakdown of threonine by neutrophil-derived myeloperoxidase, the breakdown of cancer drugs such as cyclophosphamide, and the lipid peroxidation of polyunsaturated fatty acids (PUFAs) (110, 112). Research conducted in vivo and in vitro has shown that acrolein causes oxidative stress, resulting in the rupture of cell membranes, DNA and mitochondria damage, endoplasmic reticulum (ER) stress, and the potential to initiate apoptosis (112, 113). Furthermore, both high and low doses of acrolein, as well as prolonged exposure to acrolein, result in cellular damage through immunological and inflammatory mechanisms. These processes involve (1) enhancing inflammatory responses by activating NF-κB, IL-8, COX-2, IL-1β, IL-6, TNF, IFN-γ, KC, MCP-1, 5-lipoxygenase, LTB4, and MMP, resulting in tissue damage and inflammation (114, 115); and (2) suppressing immune responses by activating NF-κB, TNFα, IL-10, IFN-γ, and GM-CSF, thereby increasing the susceptibility to infections (116, 117).

Acrolein can induce ischemia and reperfusion damage via inflammatory mechanisms (118). Acrolein contributes to the development of diabetic nephropathy by promoting the accumulation of extracellular matrix, increasing the production of angiotensin II (Ang II), activating MAPK signaling pathways that phosphorylate JNK, ERK, or p38, increasing the expression of inflammatory cytokines such as IL-6, IL-1beta, IL-18, and TNF-alpha, and cleaving caspase 9, caspase 3, and PARP (119). Cyclophosphamide and ifosfamide, both used in cancer treatment, undergo metabolism to produce acrolein, which is a significant concern because it induces oxidative stress and can lead to hemorrhagic cystitis (120).

AST-120 is commonly used in CKD patients as an oral charcoal adsorbent to absorb uremic toxins and their derivatives, including IS. Previous studies revealed that AST-120 contributes to changes in the gut microbiome composition, reduces ROS production from endothelial cells, and thus blocks the resultant oxidative stress and inflammation (121, 122). Again, other research reports indicate that AST-120 reduced proteinuria, signs of uremia, and prolonged time to dialysis (121, 123). Nevertheless, recent studies revealed that AST-120 reduced uremic symptoms but did not have much impact on renal function or all-cause mortality (124). Some studies have proven that phosphate binders such as sevelamer can bind uremic toxins, but their effectiveness in removing uremic toxins such as IS and pCS has been inconsistent in other studies (125).

Although some clinical trials have produced encouraging findings, there are currently few studies evaluating the impact of therapies meant to alter the microbiome in individuals with chronic kidney disease. A meta-analysis of studies investigating the effect of prebiotics on renal function revealed that supplementing with fiber markedly reduced serum urea levels. In pilot research, probiotics such as Lactobacillus acidophilus, Bifidobacterium longum, and Streptococcus thermophilus were administered, with favorable results showing significantly lowered blood urea levels. However, subsequent clinical trials failed to validate these findings.

The SYNERGY randomized trial aimed to assess whether symbiotic therapy, involving the combined use of pre- and probiotics, modifies the gut microbiota and lowers blood levels of uremic toxins produced by the microbiome in CKD patients. The findings of the study showed that while blood levels of P-Cresol sulfate (PCS) considerably decreased along with a shift in the microbiota of the stool toward a healthier one, levels of indoxyl sulfate (IS) did not change as a result of the intervention (126).

Scientists recently used gene sequencing to manufacture disease-specific probiotics. For example, the next generation of probiotics (NGP) has shown potential as disease-specific therapeutics and will help us understand the effectiveness and safety of probiotic microorganisms (127, 128). As a result, investigations have shown that nanoprobiotics and nanoprebiotics are effective therapies for dysbiosis (129). Researchers have demonstrated the potential benefits of synbiotic foods, a combination of prebiotic and probiotic foods, for both host organisms and human health (130). The benefits of synbiotic food will have to be examined in people with CKD.

High-amylose maize-resistant protein (HAMRS) is a type 2 starch found in potato, banana, and maize. It is resistant to digestion and reaches the large intestine, where it serves as an energy source for beneficial bacteria such as Bifidobacterium and Lactobacillus (131, 132). Prior studies have demonstrated that HAMRS may slow the advancement of CKD and enhance microbial diversity (131–133). Additionally, animals administered HAMRS exhibited a significant rise in the ratio of Bacteroidetes to Firmicutes. Another study exhibited a reduction in oxidative stress and inflammation (133). Moreover, diets high in fiber were advantageous for decreasing inflammation and overall mortality (134).

Neutrophil–gelatinase-associated lipocalin (NGAL) levels are typically low in healthy tubules; however, NGAL production rises in response to renal tubular epithelial cell injury. Because tubular cells express NGAL due to kidney injury, elevated gene transcription in this chronic disease could suggest ongoing kidney damage. NGAL is an emerging biomarker for kidney injury, including AKI and CKD. Furthermore, there is a direct link between high NGAL levels and albuminuria in people with chronic kidney disease, and NGAL as a biomarker for AKI has been extensively studied. Research into the role of NGAL in kidney injury could lead to novel approaches to treating chronic kidney disease (8, 171–181). Additionally, NGAL is a promising biomarker for CKD and its progression (182).

Several physiological processes rely on matrix metalloproteinases (MMPs), a class of proteolytic enzymes. These include cell differentiation, angiogenesis, inflammation, proliferation, vascular damage, and apoptosis. Collagenases, gelatinases, stromelysins, matrilysins, and other matrix metalloproteinases (MMPs) are among the about 20 varieties of mammalian MMPs. MMPs affect some clinicopathological conditions, including kidney diseases. Inflammation, matrix deposition, fibrosis, and fibroblast/myofibroblast activation, are all stages of CKD that involve multiple matrix metalloproteinases (MMPs) (8, 183, 184) (Table 1).

Many scientists have hypothesized that MMP-7-induced alterations to the extracellular matrix contribute to the onset of chronic kidney disease (CKD). It is possible that MMP-7 has a more important function than other MMPs in the development of kidney diseases (8, 184, 185).

.According to Tan et al., normal mice injected with an MMP-7 expression vector experienced proteinuria. Additionally, removing MMP-7 shielded the mice against glomerular damage and proteinuria (186). As stated earlier, new biomarkers must be created to identify kidney diseases early and determine their prognosis (170). They highlighted the possibility of MMP-7 levels in urine as a non-invasive marker of renal impairment. Furthermore, MMP-7 in urine may be a useful indicator of acute kidney injury, according to some studies (8, 187). Renal fibrosis non-invasively can be detected by measuring urinary MMP-7 levels because urine MMP-7 levels were shown to be positively associated with renal fibrosis scores and inversely associated with renal function, according to research by Zhou et al. (188). Gelatinases MMP-2 and MMP-9 are produced by tubular and glomerular cells, respectively. Research has shown that the activation of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) sets in motion events that cause inflammation, abnormalities in the extracellular matrix, tubular atrophy, and fibrosis (84, 189–191).

Mincle cell receptor is an innate immune protein expressed by macrophages such as monocytes, neutrophils, and dendritic cells, and some types of B cells also upregulate it. It is an innate immunity protein in the cell membrane, and a number of factors trigger its expression (192). The mincle receptor identifies necrotic cells by binding to Sap-130. For instance, mincle, in conjunction with splenic tyrosine kinase (Syk) and caspase recruitment domain proteins, induces an inflammatory response to infections by mycobacterium and fungi is controlled (193).

A study demonstrated that during the early phases of cisplatin-associated acute kidney injury (AKI), mincle cells were produced mainly in the macrophages of the kidney. Using Immunofluorescence techniques, the authors were able to show that macrophages that expressed mincle entered the damaged kidney on the third day after cisplatin was introduced. They noted a rise in serum creatinine on the third day of cisplatin intake. Additionally, an elevation of mincle protein was found on day 1 of the kidney injury. The authors used flow cytometry and immunohistochemistry to demonstrate that macrophages that entered the kidneys (F4/80+ or CD68+) largely created mincle. They discovered that M1 macrophages were responsible for mincle production. Furthermore, a study found an association between AKI and macrophages that express mincle (192), while another research also showed that macrophages deprived of mincle could protect against kidney damage caused by cisplatin. In addition, the researchers showed that adoptive transfer with macrophages lacking mincle greatly decreased AKI (192). Again, through both gain-of-function and loss-of-function reactions, it was found that regulating the expression of mincle in macrophages can have an effect on the degree of AKI. Largely, M1 macrophage mincle expression is a critical trigger for acute kidney injury (AKI). This could potentially slow down the progression of AKI to CKD. A recent study (2024) found that macrophages and neutrophils expressed mincle throughout the transition from AKI to CKD, revealing its impact on the process. The authors demonstrated a substantial elevation of mincle level on day 1 of AKI and another elevation on day 14. These mincle-laden neutrophils and macrophages promoted kidney tissue inflammation by secreting tumor necrosis factor (TNF). They also discovered that mincle-deficient mice had no significant renal injury or fibrosis (194). Thus, mincle may become a future therapeutic target for the prevention of AKI transitioning to CKD.

Antioxidants such as edaravone, which lowers ROS levels, and ebselen, a glutathione peroxidase mimetic, have shown promising results in studies involving kidney disease models, improving renal function, lowering lipid peroxidation, and increasing endothelial and epithelial cell survival (126).

Various lipid-soluble tocopherols in vitamin E stop lipid peroxidation chain reactions and remove oxygen-free radicals. They do this by entering the plasma membrane (195). Vitamin E-rich foods contain antioxidant-rich such as α-tocotrienols (196). CKD patients do not have enough α-tocotrienol (197). Extra α-tocotrienol supplementation for end-stage kidney disease or dialysis patients reduces heart disease risk and oxidative stress and boosts antioxidants such as SOD, Gpx, and CAT (198). Some studies found no mortality benefits from high-dose vitamin E, whereas others found an increased prostate cancer risk. Trolox (± − 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid), a chemical comparable to α-tocopherol, helps eliminate free radicals more effectively. Due to its significant water solubility, studies have shown it can treat acute renal damage resulting from ischemia reperfusion (199). Combining α-tocopherol and Trolox may be more effective due to fast-acting qualities of Trolox and sustained scavenging abilities of α-tocopherol (200).

Omega-3 polyunsaturated fatty acids such as docosahexaenoic and eicosapentaenoic acids are anti-inflammatory and antioxidant (201). These compounds boost glutamyl-cysteinyl ligase and glutathione reductase (202). Eicosapentaenoic and docosahexaenoic acidtherapy decreases inflammation and oxidative stress, increasing kidney function and reducing renal fibrosis risk (201).

N-acetyl cysteine (NAC) decreases oxidative stress and boosts cell glutathione (203). Research on NAC therapy for CKD is unclear. Uremic toxins cause endothelial damage, whereas NAC therapy reduces NF-κB upregulation, which requires reactive oxygen species (203). In end-stage kidney disease and dialysis patients, NAC lowered serum 8-isoprostane and IL-6 (204, 205). Studies have shown that allopurinol protects against diseases where oxidative stress plays a role in their pathogenesis (206). Treatment of diabetic patients with allopurinol reduced high uric acid levels, albuminuria, and tubulointerstitial damage (207).

The kidneys have elevated concentrations of CoQ9 and CoQ10 due to their strong dependence on aerobic metabolism and high mitochondrial density (208). CoQ10 has two primary antioxidant roles: directly preventing lipid peroxidation and indirectly interacting with α-tocopherol to prevent lipid peroxidation (209). In a study conducted by Ishikawa et al. (210), it was discovered that CoQ10 supplementation had a positive impact on renal function and reduced kidney O₂ levels in rats that had undergone hemi-nephrectomy, although the effects were not always consistent.

An expanding understanding of molecular mechanisms of chronic kidney disease has unveiled new therapeutic options. However, an incomplete comprehension of the pathophysiology impedes the quest for treatment targets for inflammation in the kidney (8). Two drugs, sirukumab and siltuximab, that directly target IL-6 ligands and block classical signaling and trans-signaling can be distinguished based on the inflammatory mechanism of CKD development. Moreover, antibodies such as tocilizumab and sarilumab block all three forms of IL-6 signaling (8, 158). Hsu et al. described another antibody, finding that anti-IL-20 (7E) therapy reduced glomerular area and blood glucose levels in mice with diabetic nephropathy, alongside improvements in kidney function (8, 161). The non-inflammatory mechanisms of CKD are linked to initially marked increases in glomerular permeability, which subsequently cause proteinuria or proliferation. It is well understood that podocyte depletion leads to proteinuria. When more than 40% of podocytes are damaged, it results in numerous dangerous side effects, including mesangial growth, adhesions, focal segmental glomerulosclerosis, or global sclerosis (211). Given that nephrotic non-inflammatory glomerulonephritis is a hallmark of many glomerular disorders, treatment approaches aimed at modifying podocyte activity are likely to be beneficial (8).

A complex network of cytokines/chemokines, growth factors, adhesion molecules, and signaling pathways is involved in kidney fibrosis (8, 212). Studies by Moon et al. demonstrate the potential to modulate TGF-β signaling in progressive fibrosis in the kidney. Their findings suggest that kidney damage from unilateral ureteral blockage can be significantly reduced by molecularly targeting the transforming growth factor-beta1 signaling pathway. An effective treatment option to prevent or mitigate the progression of renal fibrosis is IN-1130, an ALK5 inhibitor (8, 213).

In a diabetic nephropathy (DN) model, rats treated with coenzyme Q10 (CoQ10) or similar drugs, such as mitoquinone mesylate (MitoQ), exhibited improvements in renal function and tubular damage. Another mitochondria-targeting drug, dithiol a-lipoic acid, demonstrated renoprotective benefits in an animal model of hypertension and renal illness. Additionally, in mice with experimental tubulointerstitial nephritis, renoprotection was observed in conjunction with a reduction in the expression of inflammatory molecules when allopurinol or the blockade of genes linked to the NLRP3 inflammasome response (apoptosis-associated speck-like protein containing C-terminal caspase recruitment domain [CARD] (ASC) and caspase 1) was administered (126).

Inaxaplin (VX-147) was recently, shown to be a small-molecule blocker of APOL1 channel function (242). This APOL1 channel inhibitor prevents cell swelling and preserves cell viability and thus blocks cytotoxicity caused by G1 and G2 variants (243). A recent study by Egbuna et al. among participants with focal segmental glomerulosclerosis showed a significant reduction in proteinuria (244). Pharmacological strategies for slowing down the progression of kidney disease involve the use of drugs such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and sodium-glucose transporter-2 inhibitors (SGLT-2i) to reduce proteinuria and retard the progression of kidney disease. Thus, the APOL1 pore function inhibitor can potentially complement the effects of these drugs in the treatment of kidney disease patients, especially among Africans with a high burden of kidney disease and where the frequency of APOL1 high-risk alleles is high.

Iron supplements and erythropoiesis-stimulating agents (ESAs) are the two main therapies currently available for renal anemia. For example, there are concerns about the use of exogenous ESAs, which can lead to more death and heart problems in patients who do not respond well or who have cancer. This means that a new treatment method for renal anemia is needed. For the treatment of renal anemia, prolyl hydroxylase (PHD) inhibitors offer a novel therapeutic option. PHD inhibitors boost the transcription of EPO mRNA in REPCs by blocking the proteasomal degradation of HIFα, which activates the HIF pathway (230). Two of the most used ESAs for treating anemia in CKD patients are recombinant human erythropoietin and darbepoetin alfa. Except for longer half-life of darbepoetin alfa, which permits less frequent dosage, they are substantially comparable in terms of efficacy and adverse effect profile (245).

The half-life of human erythropoietin is approximately 6–10 h. It is a 30,400-Dalton glycosylated protein with a backbone consisting of 165 amino acid residues. The amino acid sequence of natural hormone is identical to that of recombinant human erythropoietin (rHuEPO) products. Darbepoetin alfa (Aranesp., Amgen), epoetin beta (Neo-Recormon, Roche), epogen (Amgen; Procrit, Centocor Ortho Biotech Products; Eprex, Janssen), and continuous erythropoietin receptor activators (Mircera, Roche) are some of the recombinant erythropoietin products that are on the market (233, 246, 247). There are specific negative effects associated with epoetin. Some of these negative effects are similar to both IV and SC; however, they vary in frequency and degree. Both routes share the following common outcomes: pain at the injection site, hypertension development, arteriovenous fistulae thrombosis, hyperkalemia, iron store depletion, flu-like symptoms, prolonged dialysis, and, infrequently, pure red cell aplasia (PRCA) and seizures. There is also an increased risk of thrombotic, cardiovascular, and cerebrovascular events overall (248).

To trigger the transcription of HIF-responsive element genes, the HIF-α and HIF-β subunits travel together in a heterodimer to the cell nucleus. Oxygen causes the prolyl hydroxylase (PH) enzyme to become active, which leads to the hydroxylation of two proline residues on HIF-α, making it susceptible to degradation. HIF-α survives degradation in the absence of oxygen and can dimerize with the always-available HIF-β. For this PH, 2-oxoglutarate is a necessary cofactor. It has been demonstrated that small-molecule oral 2-oxoglutarate analogs inactivate HIF-PH in the presence of oxygen, serving as HIF stabilizers. These substances are referred to as HIF-PH inhibitors (HIF-PHIs) based on their mode of action (239, 249, 250). By imitating hypoxia through HIF prolyl hydroxylase domain enzyme (HIF-PHD) inhibition, HIF stabilizer increases endogenous erythropoietin (EPO). HIF stabilizers have been demonstrated in phase 2 and phase 3 clinical trials to be equally effective as ESA in treating renal anemia (251). Numerous HIF stabilizers have been studied in a number of clinical trials, including enarodustat, molidustat, desidustat, vadadustat, roxadustat, and daprodustat (252).

One clinically proven mechanism of action for the therapy of autosomal dominant polycystic kidney disease is vasopressin V2 receptor inhibition (253). Tolvaptan, which is a V2-receptor antagonist, has been demonstrated in experimental studies and a large randomized controlled trial involving 1,445 patients with autosomal dominant PKD to limit the progression of the disease. There was also a considerable drop in the size of the kidneys from 5.5 to 2.8% as well as the reciprocal slope of the serum creatinine level from −3.81 to −2.61 mg per mL-1/year (240, 254).

Recent research has focused on the therapeutic effects of glucose-lowering therapy in kidney injury using sodium-glucose cotransporter-2 (SGLT2) inhibitors. Research on diabetic rats administered with streptozotocin (STZ) demonstrated that phlorizin and empagliflozin, which block SGLT2, reduce glomerular hyperfiltration and hypertrophy, oxidative stress, inflammation, and fibrosis. Empagliflozin therapy reduced albuminuria and mesangial matrix growth in hypertensive BTBR ob/ob mice. The benefits of SGLT2 inhibitors occur through various mechanisms (255).

Autophagy is the cellular process of breaking down and recycling cytosol components, which are used as building blocks for the regeneration of tissue (256). This process involves lysosomes. Defectiveness or absence of autophagy leads to kidney damage. Recent studies have demonstrated that SGLT2 inhibitors trigger autophagy via the mammalian target of rapamycin (mTOR), 5′adenosine monophosphate-activated protein kinase (AMPK), sirtuin 1 (SIRT1), and hypoxia-inducible factor (HIF) signaling pathways (257–259).

The mTOR protein complex 1 (mTORC1) is a protein complex that acts as a serine–threonine kinase and plays a crucial role in integrating signals related to nutrients such as glucose and amino acids. In a state of calorie excess, mTORC1 promotes anabolism (the synthesis of complex molecules) and inhibits autophagy (260). The role of proximal tubular mTORC1 in DKD is considered significant (261). SGLT2 inhibitors decrease mTORC1 function in proximal tubule cells, preventing tubulointerstitial fibrosis (261). AMPK, in contrast to mTOR, functions as a detector of insufficient cellular energy (low ATP to 5′adenosine monophosphate ratio). It promotes the breakdown of molecules and triggers autophagy by suppressing mTORC1 when the body is in a low-calorie state (262). AMPK activates the catabolic process, which, in turn, provides ATP to cells that need sufficient energy. Canagliflozin stimulates AMPK-mediated autophagic stimulation, presumably via increasing calorie loss, without relying on insulin or glucagon signaling (263). Various studies have shown that SGLT2 inhibitors promote autophagy by using mTOR-AMPK-mediated pathways, which, in turn, help protect the kidneys against various types of renal damage (264–266).

SIRT1 relies on nicotinamide adenine dinucleotide to deacetylate and serve as a nutrient deficiency sensor (267). It removes acetyl groups from tumor protein 53, which augments the autophagy signaling pathway (268). In glucose deficiency states, SIRT1 and AMPK activate each other to increase autophagy and biosynthesis through mitochondria (269). SIRT1 can inactivate mTORC1 in the absence of AMPK (270). Activation of SIRT1 reduces kidney injury (271). Animal studies have shown that SGLT2 inhibitors increase the expression of SIRT1 (272, 273).

The transcription factors that react to low oxygen levels in cells are from the HIF family. HIF-1α and HIF-2α are isoforms that are activated by low oxygen levels and start processes that improve oxygen delivery and reduce oxygen usage (274). Activation of HIF-1 upregulates inflammation, fibrosis, angiogenesis, and mitochondrial clearance through autophagy, whereas activation of HIF-2 reduces inflammation and fibrosis and increases erythropoietin synthesis clearance of the peroxisome by autophagy (274). The inhibition of SGLT2 decreases the expression of HIF-1α in human proximal tubules under hypoxic conditions, leading to a reduction in tubular damage and interstitial fibrosis (274, 275). Furthermore, SGLT2 inhibitors can enhance HIF-2α activity via a mechanism that relies on SIRT1 (276). Therefore, SGLT2 inhibitors could offer kidney protection by re-establishing the equilibrium of HIF-1α and HIF-2α activities in renal cells.

SGLT inhibitors may protect kidneys by remodeling F-actin and α-actinin-4 filaments, reducing β1-integrin loss on podocyte surfaces, blocking macrophage infiltration, activating M1-M2 polarization, and preventing profibrotic M2 macrophages. They also maintain cellular redox homeostasis and reduce oxidative stress by activating Kelch-L. (276–279).

SGLT2 inhibitors have revolutionized CKD management. Regardless of their impact on glucose regulation, these medications prevent the deterioration of kidney function by lowering glomerular hypertension, which is mediated by tubuloglomerular feedback (280). Research has shown that SGLT2 inhibitors benefit patients with and without type 2 diabetes mellitus (T2DM) by reducing proteinuria and slowing the progression of CKD (239, 281). In a 12-week study, researchers randomly assigned 52 T2DM patients 1:1 to either dapagliflozin or a placebo; during this period, dapagliflozin significantly raised transferrin levels and reduced hepcidin and ferritin levels. The rise in the hemoglobin levels versus placebo was 0.5 g/dL (p = 0.02) (239, 282).

In a systematic review and meta-analysis, Mavrakanas et al. found that SGLT2 inhibitors were associated with a decreased incidence of CKD progression among patients with preexisting CKD (RR: 0.77; 95% CI: 0.68–0.88), compared with placebo. SGLT2 inhibitors were also linked to a lower risk of AKI (RR: 0.82; 95% CI: 0.72–0.93) and stopping treatment in CKD patients than a placebo. For patients with CKD, SGLT2 inhibitors provide significant protection against cardiovascular and renal outcomes. These findings provide compelling evidence in support of its use in patients with CKD and its continued use as renal function diminishes (283). Examples of SGLT2 inhibitors, or gliflozins, are canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin. A study called DAPA-CKD (dapagliflozin in patients with CKD) and EMPA-KIDNEY (empagliflozin in patients with CKD) found that dapagliflozin and empagliflozin help patients with and without T2D by protecting the kidneys (284, 285) (Figure 1).