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Popular Reports / nephrology

This report is written by MaltSci based on the latest literature and research findings

What are the mechanisms of chronic kidney disease? ​

Abstract ​

Chronic kidney disease (CKD) is a pressing global health issue affecting approximately 10% of the population, characterized by a progressive decline in kidney function leading to end-stage kidney disease (ESKD). The rising prevalence of CKD is closely linked to traditional risk factors such as obesity, hypertension, and diabetes mellitus, alongside metabolic abnormalities like insulin resistance and dyslipidemia. This review aims to elucidate the multifactorial mechanisms driving CKD, focusing on inflammation, oxidative stress, metabolic dysregulation, and the influence of genetic and environmental factors. Inflammation plays a critical role in CKD progression, driven by chronic low-grade inflammatory states and immune dysregulation. Oxidative stress contributes to cellular damage and renal dysfunction, creating a vicious cycle that exacerbates kidney injury. Metabolic dysregulation, including conditions like hyperuricemia and diabetes, further complicates CKD progression by inducing oxidative stress and promoting fibrosis. Genetic predispositions and environmental influences, including lifestyle choices, significantly affect individual susceptibility to CKD. Common comorbidities such as diabetes and hypertension are analyzed for their impact on CKD progression, emphasizing the need for integrated management strategies. Current therapeutic approaches, including pharmacological interventions and lifestyle modifications, are reviewed, alongside emerging therapies targeting specific pathways involved in CKD. The synthesis of recent research highlights the importance of understanding CKD mechanisms to develop effective therapeutic strategies aimed at improving patient outcomes and mitigating the global health burden of this debilitating disease.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Pathophysiological Mechanisms of CKD
    • 2.1 Inflammation and Immune Response
    • 2.2 Oxidative Stress and Cellular Damage
    • 2.3 Metabolic Dysregulation
  • 3 Genetic and Environmental Factors
    • 3.1 Genetic Predispositions
    • 3.2 Environmental Influences and Lifestyle Choices
  • 4 Comorbidities and Their Impact on CKD Progression
    • 4.1 Diabetes Mellitus
    • 4.2 Hypertension
    • 4.3 Cardiovascular Diseases
  • 5 Current Therapeutic Approaches and Future Directions
    • 5.1 Pharmacological Interventions
    • 5.2 Lifestyle Modifications
    • 5.3 Emerging Therapies
  • 6 Summary

1 Introduction ​

Chronic kidney disease (CKD) represents a significant and escalating global health crisis, affecting approximately 10% of the population worldwide[1]. This progressive condition is characterized by a gradual decline in kidney function, often leading to end-stage kidney disease (ESKD), which necessitates renal replacement therapies such as dialysis or transplantation[2]. The increasing prevalence of CKD is closely linked to traditional risk factors, including obesity, hypertension, and diabetes mellitus, alongside metabolic abnormalities like insulin resistance and dyslipidemia[2]. As kidney function deteriorates, patients face rising mortality rates and a host of comorbidities, particularly cardiovascular complications, which further complicate management and treatment outcomes[2].

Understanding the mechanisms underlying CKD is critical for developing effective therapeutic strategies aimed at slowing disease progression and improving patient outcomes. The pathophysiology of CKD is multifactorial, encompassing a variety of biological processes such as inflammation, oxidative stress, and metabolic dysregulation[3]. Recent research has highlighted the role of persistent low-grade inflammation and increased oxidative stress as pivotal factors in the progression of CKD[2][4]. Additionally, the interplay between genetic predispositions and environmental factors, including lifestyle choices, further complicates the disease's trajectory[2][5].

This review aims to provide a comprehensive overview of the current understanding of the mechanisms driving CKD. We will explore the following key areas: first, the pathophysiological mechanisms of CKD, including inflammation, oxidative stress, and metabolic dysregulation; second, the influence of genetic and environmental factors on disease progression; third, the impact of common comorbidities such as diabetes and hypertension; and finally, current therapeutic approaches and future directions for managing CKD.

In the section on pathophysiological mechanisms, we will delve into the roles of inflammation and immune responses, oxidative stress, and metabolic dysregulation in kidney damage[2][3]. Chronic inflammation, driven by various factors including oxidative stress, plays a crucial role in the decline of kidney function[6]. Additionally, we will discuss how oxidative stress contributes to cellular damage and the complex interplay between metabolic dysregulation and kidney health[4].

Next, we will examine the genetic and environmental factors that predispose individuals to CKD. Genetic predispositions, including polymorphisms in genes related to kidney function, as well as environmental influences such as diet and lifestyle choices, will be addressed[2][5]. Understanding these factors is essential for identifying at-risk populations and tailoring preventive strategies.

The impact of comorbidities on CKD progression will also be a focal point of this review. Diabetes mellitus and hypertension are two of the most prevalent comorbid conditions associated with CKD, and their roles in exacerbating kidney damage will be critically analyzed[2][5]. Furthermore, we will explore the emerging recognition of cardiovascular diseases as significant contributors to CKD morbidity and mortality[4].

Finally, we will discuss current therapeutic approaches, including pharmacological interventions and lifestyle modifications, while highlighting emerging therapies that target specific pathways involved in CKD progression[2][2]. By synthesizing recent research findings, this review will illuminate key pathways and molecular targets that hold promise for future therapeutic interventions, ultimately aiming to enhance the management and prevention of CKD.

In summary, this review seeks to provide a thorough understanding of the multifaceted mechanisms underlying CKD, emphasizing the need for innovative strategies to mitigate its impact on global health. A deeper comprehension of these mechanisms will pave the way for the development of effective therapies that can improve patient outcomes and reduce the burden of this devastating disease.

2 Pathophysiological Mechanisms of CKD ​

2.1 Inflammation and Immune Response ​

Chronic kidney disease (CKD) is characterized by a complex interplay of pathophysiological mechanisms, among which inflammation and immune response play crucial roles. Chronic inflammation is increasingly recognized as a significant contributor to CKD progression, affecting renal function and leading to adverse outcomes.

One of the primary mechanisms of CKD involves the dysregulation of the immune system. Patients with CKD exhibit a state of chronic low-grade inflammation, which is associated with an imbalance between pro-inflammatory and anti-inflammatory markers. This persistent inflammation is driven by various factors, including oxidative stress, activation of the innate immune system, and alterations in the microbiota [7]. Specifically, the activation of monocytes and neutrophils leads to endothelial damage, contributing to cardiovascular risks commonly observed in CKD patients [8].

Innate immune cells, such as macrophages and granulocytes, play a dual role in CKD. While they can induce acute kidney injury (AKI) through the release of pro-inflammatory mediators, they also participate in the repair processes following injury. However, in the context of CKD, these cells often contribute to disease progression by promoting fibrosis and nephron loss through sustained inflammatory responses [9]. The infiltration of immune cells into renal tissues, particularly during chronic inflammation, exacerbates renal injury and leads to further decline in kidney function [10].

Moreover, the mechanisms of inflammation in CKD are closely linked to cellular and molecular pathways involving various signaling cascades. For instance, the nuclear factor kappa B (NF-κB) pathway is pivotal in regulating pro-inflammatory gene expression, while the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway is involved in counteracting oxidative stress and inflammation [6]. Dysregulation of these pathways contributes to the persistent inflammatory state observed in CKD.

The formation of tertiary lymphoid structures (TLSs) in injured kidneys is another aspect of the immune response in CKD. These ectopic lymphoid aggregates develop in response to chronic inflammation and may facilitate maladaptive repair mechanisms, further driving the progression from AKI to CKD [10]. The presence of TLSs has been implicated in various kidney diseases, including diabetic kidney disease and lupus nephritis, underscoring their potential role in modulating immune responses and renal pathology [10].

In summary, the pathophysiology of CKD is significantly influenced by chronic inflammation and immune responses. The interplay between innate immune cells, signaling pathways, and the formation of TLSs highlights the multifaceted nature of immune involvement in CKD progression. Understanding these mechanisms is critical for developing targeted therapeutic strategies aimed at mitigating inflammation and improving outcomes for patients with CKD.

2.2 Oxidative Stress and Cellular Damage ​

Chronic kidney disease (CKD) is a multifactorial disorder characterized by progressive renal dysfunction, which ultimately leads to end-stage renal disease (ESRD). A significant aspect of CKD pathophysiology involves oxidative stress and its associated cellular damage. Oxidative stress is defined as an imbalance between the production of reactive oxygen species (ROS) and the body’s antioxidant defenses, leading to cellular injury.

The mechanisms through which oxidative stress contributes to CKD are multifaceted. Firstly, oxidative stress is implicated in the decline of renal function by causing damage to renal cells, particularly affecting nephrons, glomeruli, and the interstitial environment. The production of ROS can induce cellular damage by modifying DNA, proteins, and lipids, ultimately leading to cell death and dysfunction (Pellegrino et al., 2019; Tamay-Cach et al., 2016). This oxidative damage is often exacerbated by factors such as inflammation and mitochondrial dysfunction, creating a vicious cycle that further deteriorates renal health (Lv et al., 2018; Ho & Shirakawa, 2022).

In CKD, various mechanisms contribute to oxidative stress. For instance, the upregulation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) activity, coupled with the downregulation of antioxidant defenses mediated by nuclear factor erythroid 2-related factor 2 (Nrf2), results in increased ROS production. This imbalance not only leads to direct cellular injury but also triggers inflammatory pathways, further perpetuating kidney damage (Yuan et al., 2022; Verma et al., 2021).

Moreover, oxidative stress has been shown to activate the transforming growth factor beta (TGF-β) signaling pathway, which is crucial in promoting renal fibrosis. Fibrosis, a common final pathway in CKD, results from the excessive deposition of extracellular matrix components, leading to scarring and loss of functional kidney tissue (Patera et al., 2024; Ravarotto et al., 2022). The interplay between oxidative stress and fibrosis underscores the importance of targeting oxidative pathways in therapeutic strategies for CKD.

Environmental factors also play a role in the oxidative stress associated with CKD. Exposure to pollutants and toxins can enhance oxidative damage to renal tissues, which may be particularly detrimental during early life stages, leading to long-term susceptibility to kidney disease (Hsu et al., 2025).

In conclusion, oxidative stress is a central mechanism in the pathophysiology of CKD, contributing to cellular damage, inflammation, and fibrosis. The understanding of these mechanisms highlights the potential for antioxidant therapies as a strategy to mitigate kidney injury and progression of the disease (Verma et al., 2021; Assani et al., 2025).

2.3 Metabolic Dysregulation ​

Chronic kidney disease (CKD) is characterized by a progressive decline in renal function, and its pathophysiology is multifaceted, particularly involving metabolic dysregulation. The mechanisms contributing to CKD progression include oxidative stress, inflammation, dysregulation of autophagy, and alterations in metabolic pathways.

One significant aspect of metabolic dysregulation in CKD is the impact of various metabolic abnormalities such as hyperuricemia, dyslipidemia, obesity, and type 2 diabetes mellitus. These metabolic disorders exacerbate CKD progression through mechanisms including oxidative stress and chronic inflammation. For instance, oxidative stress is intensified by ectopic lipid deposition and lipid peroxidation, leading to mitochondrial dysfunction and the excessive production of reactive oxygen species (ROS) [11]. Furthermore, the activation of signaling pathways such as p38 MAPK, ERK, and JNK is linked to these metabolic changes, promoting cellular injury and fibrotic responses [11].

In addition, the retention of uremic toxins due to impaired renal clearance contributes to cardiovascular complications in CKD patients. The accumulation of these toxins exacerbates inflammation and endothelial dysfunction, which further complicates the metabolic state of CKD patients [12]. Moreover, dysregulation of lipid metabolism is another critical factor; lipid overload can lead to lipotoxicity, characterized by cellular and organ dysfunction [13]. This is particularly evident in diabetic and obesity-associated kidney diseases, where metabolic alterations disrupt renal cellular homeostasis and promote fibrosis [13].

Metabolic reprogramming also plays a crucial role in the pathogenesis of renal fibrosis, as it involves changes in energy metabolism, particularly fatty acid and glucose metabolism. These alterations are linked to the activation of myofibroblasts and the aberrant accumulation of extracellular matrix components, which are hallmarks of CKD [14]. The interplay between immune and metabolic pathways further complicates the disease, as immune dysregulation can exacerbate renal inflammation and fibrosis [15].

Moreover, the gut-kidney axis has been identified as a critical factor in CKD pathophysiology, with dysbiosis potentially influencing metabolic and inflammatory responses [3]. The relationship between metabolic dysregulation and kidney disease is thus complex, as metabolic disturbances not only contribute to kidney injury but also hinder the repair mechanisms, perpetuating a cycle of damage.

In summary, the mechanisms underlying metabolic dysregulation in CKD are multifactorial, involving oxidative stress, inflammatory responses, dysregulated lipid metabolism, and the interplay of various signaling pathways. These processes collectively contribute to the progression of CKD, highlighting the need for targeted therapeutic strategies that address these underlying metabolic abnormalities to improve patient outcomes.

3 Genetic and Environmental Factors ​

3.1 Genetic Predispositions ​

Chronic kidney disease (CKD) is a multifactorial condition characterized by a progressive decline in kidney function, with various genetic and environmental factors contributing to its development and progression. The mechanisms underlying CKD are complex and involve both genetic predispositions and environmental influences.

Genetic predispositions play a significant role in the susceptibility to CKD. Recent studies have highlighted the importance of genetic polymorphisms and epigenetic variations that influence individual susceptibility to chronic progressive kidney disease. Genome-wide association studies (GWAS) and gene-linkage studies have provided insights into the genetic factors associated with CKD, revealing a high degree of genetic and phenotypic heterogeneity among patients. For instance, rare inherited forms of CKD exhibit diverse phenotypes due to genetic phenomena such as pleiotropy, incomplete penetrance, and variable expressivity, which complicate the understanding of CKD mechanisms [16].

In addition to genetic factors, environmental influences are critical in the etiology of CKD. Various environmental exposures, including heat stress, chemical contaminants, and socioeconomic factors, have been linked to the onset and progression of CKD. For example, a case-control study in the Iranian population found that proximity to mines, mobile antennas, and exposure to chemicals significantly increased the risk of CKD [17]. Moreover, chronic kidney disease of unknown etiology (CKDu), particularly prevalent in tropical farming communities, has been associated with environmental factors, underscoring the need to understand how these external elements interact with genetic predispositions [18].

The interplay between genetic and environmental factors is crucial for understanding CKD mechanisms. Genetic factors may predispose individuals to CKD, but environmental conditions can exacerbate or mitigate these risks. For instance, developmental conditions that impact kidney development are often linked to poverty and structural factors that persist throughout life, suggesting that addressing these socioeconomic determinants could help reduce CKD risk in future generations [19].

Overall, the mechanisms of CKD are multifaceted, involving a complex interaction between genetic predispositions and environmental factors. A comprehensive understanding of these interactions is essential for developing targeted prevention and treatment strategies for CKD, which remains a significant global public health challenge.

3.2 Environmental Influences and Lifestyle Choices ​

Chronic kidney disease (CKD) is increasingly recognized as a multifactorial public health issue, influenced by both genetic and environmental factors. The mechanisms underlying CKD encompass a variety of biological processes, particularly emphasizing the role of environmental influences and lifestyle choices.

Environmental exposures are critical contributors to the development and progression of CKD. These exposures include heat stress, chemical contaminants such as heavy metals and herbicides, and various traditional medicines. For instance, chronic kidney disease of unknown etiology (CKDu), prevalent in tropical farming communities, has been associated with environmental factors like glyphosate and fluoride, which induce oxidative stress and renal inflammation. Research indicates that glyphosate exposure activates caspases and promotes lipid peroxidation, while heavy metals are linked to endoplasmic reticulum stress and inflammatory pathways through reactive oxygen species (ROS) [18].

Furthermore, the lifestyle choices of individuals, such as dietary habits and physical activity levels, can also significantly impact kidney health. For example, poor dietary choices can lead to obesity and metabolic syndrome, which are well-documented risk factors for CKD. The interplay between genetics and environmental factors, including lifestyle choices, creates a complex landscape that affects individual susceptibility to CKD. It is suggested that optimizing conditions that influence kidney development and function may help mitigate the risk of CKD in future generations [19].

Additionally, genetic predispositions can exacerbate the effects of environmental influences. Genetic polymorphisms related to kidney function may interact with environmental factors, leading to increased risk for CKD in susceptible populations [20]. For example, variations in genes associated with inflammation and fibrosis can modulate the kidney's response to environmental stressors, potentially accelerating the progression of kidney damage [16].

Overall, the mechanisms of CKD are multifaceted, integrating genetic predispositions with environmental and lifestyle factors. The need for further research into these interactions is paramount, as a deeper understanding could lead to novel therapeutic strategies aimed at preventing and managing CKD more effectively.

4 Comorbidities and Their Impact on CKD Progression ​

4.1 Diabetes Mellitus ​

Chronic kidney disease (CKD) is characterized by a progressive decline in glomerular filtration rate, leading to various adverse health consequences, including fluid retention, electrolyte imbalance, and increased cardiovascular risk. Diabetes mellitus is a significant contributor to the development of CKD, specifically diabetic kidney disease (DKD). The mechanisms underlying the progression of CKD in the context of diabetes are multifaceted and involve several key factors.

One primary mechanism is the dysregulation of epigenetic processes, which has emerged as a crucial player in the progression of DKD. Hyperglycemia-associated metabolic disturbances lead to oxidative stress and uncontrolled inflammation, which contribute to epigenetic alterations in renal cells, including mesangial cells, podocytes, tubular epithelial cells, and glomerular endothelial cells. These epigenetic changes can result in functional impairments of these cells, further exacerbating kidney damage and promoting the progression of CKD [21].

Another significant factor is mitochondrial dysfunction, which is increasingly recognized as a pathological mediator of DKD. Mitochondria play a vital role in ATP production, and the kidneys, being highly metabolic organs, are particularly reliant on mitochondrial function. In diabetes, changes in metabolic fuel sources disrupt ATP production, leading to renal hypoxia and subsequent kidney injury. Inherited genetic factors that affect mitochondrial function may also contribute to the risk of developing DKD [22].

Additionally, inflammation and fibrosis are critical components in the progression of CKD. The interplay between inflammatory cells and myofibroblasts leads to excessive extracellular matrix production and accumulation, resulting in renal fibrosis. Transforming growth factor β (TGF-β) has been identified as a pivotal mediator in this process. CKD itself can promote further fibrosis through the accumulation of toxins and hormonal changes, with proteinuria acting both as a manifestation of CKD and a driver of renal fibrosis [23].

Moreover, obesity, often comorbid with diabetes, has been shown to drive CKD progression through mechanisms that include hemodynamic changes, increased inflammation, oxidative stress, and activation of the renin-angiotensin-aldosterone system (RAAS). Obesity-related kidney disease typically presents with glomerulomegaly and localized glomerulosclerosis, where microproteinuria is a common early symptom [24].

In summary, the mechanisms of CKD progression, particularly in the context of diabetes mellitus, involve a complex interplay of epigenetic dysregulation, mitochondrial dysfunction, inflammation, and fibrosis, alongside the exacerbating effects of comorbidities such as obesity. Understanding these mechanisms is crucial for developing effective strategies to mitigate the progression of CKD and improve patient outcomes.

4.2 Hypertension ​

Chronic kidney disease (CKD) is frequently accompanied by hypertension, which is a significant factor in both the progression of CKD and the associated cardiovascular events. The mechanisms contributing to hypertension in CKD are multifaceted and involve several interconnected physiological pathways.

One of the primary mechanisms is the activation of the renin-angiotensin-aldosterone system (RAAS). This system plays a crucial role in regulating blood pressure and fluid balance. In CKD, there is often an upregulation of RAAS, which leads to increased blood pressure due to vasoconstriction and sodium retention [25]. Additionally, sodium retention is recognized as a significant contributor to elevated blood pressure in CKD, with both total body sodium and volume overload being implicated [26].

Volume overload, resulting from impaired renal function, leads to increased intravascular volume, which further elevates blood pressure. The interplay between volume status and neurohormonal modulation is essential, as it influences the efficacy of antihypertensive treatments. Recent studies suggest that intensive blood pressure control may require a reassessment of the balance between volume and neurohormonal control in CKD patients [26].

Moreover, sympathetic nervous system (SNS) hyperactivity is another critical factor. Sympathetic overactivity has been shown to contribute to the development of hypertension and the progression of renal failure, with increased sympathetic tone being associated with adverse cardiovascular outcomes in CKD patients [27]. The exact mechanisms that lead to heightened sympathetic activation in CKD remain unclear, but they are believed to include neurohormonal changes and altered baroreceptor sensitivity [27].

Oxidative stress and vascular remodeling also play significant roles in the pathogenesis of hypertension in CKD. These processes can lead to endothelial dysfunction, which impairs the vasodilatory capacity of blood vessels and contributes to increased vascular resistance and hypertension [25]. The structural changes in blood vessels, alongside increased endothelin production and decreased availability of vasodilators, further complicate the hypertensive state in CKD [28].

Finally, it is important to note that hypertension in CKD is often resistant to treatment, primarily due to the complex interplay of these mechanisms. Traditional treatment approaches may not adequately address the multifactorial nature of hypertension in CKD, necessitating a comprehensive understanding of the underlying pathophysiology to develop more effective management strategies [28].

In summary, the mechanisms of hypertension in chronic kidney disease are complex and include RAAS activation, volume overload, sympathetic nervous system hyperactivity, oxidative stress, and vascular remodeling. Understanding these mechanisms is crucial for developing targeted therapeutic interventions aimed at managing hypertension and slowing the progression of CKD.

4.3 Cardiovascular Diseases ​

Chronic kidney disease (CKD) is a multifaceted condition characterized by progressive loss of kidney function, which significantly elevates the risk of cardiovascular diseases (CVD). The interplay between CKD and CVD is intricate, involving various pathophysiological mechanisms that exacerbate both conditions.

One of the primary mechanisms underlying CKD involves mineral imbalance and the accumulation of uremic toxins. As kidney function declines, the ability to excrete waste products diminishes, leading to the retention of minerals such as calcium and phosphate, as well as uremic toxins. This accumulation not only exerts additional stress on the cardiovascular system but also contributes to the progression of CKD itself. Specifically, the retention of these substances can lead to inflammation, endothelial dysfunction, oxidative stress, and vascular calcification, which are pivotal in accelerating multi-organ damage, particularly in the cardiovascular system (Lu et al. 2025) [12].

Oxidative stress is another crucial factor linking CKD and CVD. In CKD patients, oxidative stress arises due to the impaired kidney function and contributes to endothelial dysfunction and inflammation. This vicious cycle of oxidative stress, inflammation, and endothelial dysfunction creates a feedback loop that exacerbates both CKD and CVD, resulting in high morbidity and mortality rates among affected individuals (Ravarotto et al. 2018) [4].

Increased arterial stiffness is a hallmark of CKD, which further complicates cardiovascular health. It is associated with adverse alterations in cardiac structure and function, predisposing patients to a higher risk of cardiovascular death. These changes can be observed even in the early stages of kidney disease, highlighting the importance of understanding the mechanisms behind increased arterial stiffness to develop novel therapeutic strategies aimed at mitigating cardiovascular risk in CKD patients (Chue et al. 2010) [29].

Moreover, CKD can lead to specific cardiac alterations known as uremic cardiomyopathy, characterized by structural changes such as hypertrophy and fibrosis of the myocardium. These alterations can result in impaired cardiac function, both diastolic and systolic, which further increases the risk of heart failure and other cardiovascular complications (Nguyen & Schulze 2023) [30].

In summary, the mechanisms of chronic kidney disease significantly overlap with those of cardiovascular diseases. The retention of uremic toxins, oxidative stress, inflammation, increased arterial stiffness, and structural cardiac changes are all interlinked processes that exacerbate both conditions. Understanding these mechanisms is essential for developing effective therapeutic interventions aimed at improving the prognosis and quality of life for patients suffering from CKD and its associated cardiovascular complications.

5 Current Therapeutic Approaches and Future Directions ​

5.1 Pharmacological Interventions ​

Chronic kidney disease (CKD) is characterized by a complex interplay of various pathogenic mechanisms that contribute to its development and progression. Key mechanisms include oxidative stress, inflammation, fibrosis, and dysregulation of metabolic pathways. Chronic hyperglycemia in diabetic kidney disease (DKD) triggers a cascade of molecular events such as the accumulation of advanced glycation end products (AGEs), activation of the polyol pathway, enhanced protein kinase C (PKC) signaling, and mitochondrial dysfunction, leading to glomerular hyperfiltration, podocyte injury, and subsequent fibrosis [31].

Furthermore, the role of the immune system and gut-kidney axis has been increasingly recognized in CKD pathogenesis. Neutrophil gelatinase-associated lipocalin and matrix metalloproteinases are also implicated in the disease's progression [3]. Fibrosis is considered the final common pathway of CKD, with myofibroblasts and inflammatory cells playing crucial roles in its development. The dynamic equilibrium between extracellular matrix synthesis and degradation becomes disturbed, leading to excessive fibrosis [23].

Current therapeutic approaches primarily focus on managing symptoms and delaying disease progression rather than addressing the underlying mechanisms. Pharmacological interventions include renin-angiotensin-aldosterone system inhibitors (RAASi), sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and mineralocorticoid receptor antagonists (MRAs). These agents have shown efficacy in slowing CKD progression and improving patient outcomes [31].

Despite these advancements, there remains a substantial residual risk of disease progression, highlighting the need for improved treatment strategies that target multiple pathogenic pathways. Investigational therapies such as endothelin receptor antagonists (ERAs), nuclear factor erythroid 2-related factor 2 (Nrf2) activators, and modulators of gut microbiota are under evaluation [32]. Moreover, the integration of Traditional Chinese Medicine formulations has demonstrated potential in lowering albuminuria in clinical studies [31].

Future directions in pharmacological interventions should prioritize biomarker-driven precision medicine approaches, allowing for individualized therapy selection. This entails the development of agents that concurrently target ferroptosis, inflammation, and other emerging mechanisms of CKD [31]. A multifaceted approach is crucial, as optimal management must address hyperglycemia, hypertension, inflammation, and fibrosis to effectively slow or halt disease progression [31].

In conclusion, while current therapies provide a foundation for managing CKD, a deeper understanding of the underlying mechanisms and the development of novel, multitargeted pharmacological interventions will be essential in improving outcomes for patients suffering from this complex disease.

5.2 Lifestyle Modifications ​

Chronic kidney disease (CKD) is characterized by a progressive loss of kidney function, which can lead to end-stage kidney disease (ESKD) and significantly impacts patient morbidity and mortality. The mechanisms underlying CKD are multifaceted, involving a complex interplay of metabolic, hemodynamic, inflammatory, oxidative, and fibrotic pathways.

One of the primary mechanisms of CKD progression is chronic inflammation, which contributes to the persistent low-grade inflammatory state observed in patients. This inflammation is often exacerbated by metabolic dysregulation, including insulin resistance and dyslipidemia, and is linked to conditions such as obesity and hypertension [2]. Oxidative stress also plays a critical role, leading to cellular damage and contributing to the progression of renal dysfunction [3].

In addition to these classical mechanisms, emerging processes such as ferroptosis (an iron-dependent form of cell death), impaired autophagy, gut microbiota dysbiosis, and epigenetic alterations have been identified as significant contributors to CKD pathogenesis [31]. The accumulation of advanced glycation end products (AGEs) due to chronic hyperglycemia further complicates the disease process, activating various signaling pathways that lead to glomerular hyperfiltration and podocyte injury [31].

Current therapeutic approaches for CKD primarily focus on managing symptoms and slowing disease progression rather than reversing the underlying pathological mechanisms. The cornerstone of pharmacological treatment includes renin-angiotensin-aldosterone system inhibitors (RAASi), sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and mineralocorticoid receptor antagonists (MRAs) [31]. These agents have shown efficacy in providing cardiorenal protection and reducing the risk of progression to ESKD [2].

Lifestyle modifications play a crucial role in the management of CKD. Evidence suggests that dietary changes, such as sodium restriction and controlled intake of phosphorus and potassium, are vital in preserving renal function [33]. Furthermore, regular physical activity and weight management are essential components of a comprehensive approach to mitigate CKD progression [34]. These lifestyle interventions, combined with pharmacological therapies, form a multimodal treatment strategy aimed at addressing the various aspects of CKD, including hyperglycemia, hypertension, inflammation, and fibrosis [31].

Looking forward, future research should focus on biomarker-driven precision medicine approaches that allow for individualized therapy selection and the development of agents targeting multiple pathogenic pathways simultaneously [31]. Investigational therapies, including endothelin receptor antagonists (ERAs) and nuclear factor erythroid 2-related factor 2 (Nrf2) activators, are under evaluation, with the potential to enhance current treatment paradigms [31].

In summary, the mechanisms of CKD are complex and involve multiple interrelated pathways. Current therapeutic approaches emphasize symptom management and the slowing of disease progression, while lifestyle modifications remain a fundamental aspect of comprehensive care. Future strategies will likely focus on personalized medicine and novel therapeutic targets to address the multifaceted nature of CKD.

5.3 Emerging Therapies ​

Chronic kidney disease (CKD) is a progressive condition characterized by a gradual loss of kidney function, often leading to end-stage kidney disease (ESKD). The mechanisms underlying CKD are multifaceted, involving a complex interplay of metabolic, hemodynamic, inflammatory, and fibrotic pathways. Key contributors to CKD progression include chronic hyperglycemia, hypertension, oxidative stress, and inflammation, all of which exacerbate renal injury and fibrosis.

Recent studies have identified several novel mechanisms that contribute to the pathogenesis of CKD. These include:

  1. Vascular Changes and Endothelial Dysfunction: Alterations in vascular health significantly impact kidney function. Endothelial dysfunction can lead to impaired renal perfusion and contribute to the progression of CKD [2].

  2. Loss of Podocytes and Renal Epithelial Cells: Podocyte injury is a critical factor in the development of glomerulosclerosis, a common feature in CKD. The loss of these specialized cells compromises the kidney's filtering ability [35].

  3. Matrix Deposition and Fibrosis: Excessive extracellular matrix deposition leads to renal fibrosis, which is a unifying feature of CKD. This process is driven by factors such as transforming growth factor-beta (TGF-β) and involves the activation of myofibroblasts [31].

  4. Chronic Inflammation: Persistent, low-grade inflammation is increasingly recognized as a crucial aspect of CKD. This inflammation can stem from various sources, including metabolic dysregulation and immune system activation [2].

  5. Metabolic Dysregulation: Factors such as insulin resistance, dyslipidemia, and hyperuricemia are linked to CKD progression. These metabolic derangements can exacerbate kidney injury and contribute to cardiovascular complications [2].

Emerging therapeutic approaches aim to address these underlying mechanisms to slow disease progression and improve patient outcomes. Current treatment strategies for CKD primarily focus on controlling blood pressure through the renin-angiotensin-aldosterone system (RAAS) inhibitors, which have shown efficacy in delaying progression but do not halt the disease [35].

Novel therapies under investigation include:

  1. SGLT2 Inhibitors: These agents have been shown to provide renal protection by reducing hyperglycemia and improving cardiovascular outcomes, thereby addressing multiple pathways involved in CKD [31].

  2. Mineralocorticoid Receptor Antagonists (MRAs): MRAs target pathways associated with inflammation and fibrosis, offering potential benefits in managing CKD [31].

  3. Apolipoprotein L1 (APOL1) Channel Function Inhibitors: These inhibitors are being explored for their role in addressing genetic risk factors for CKD, particularly in populations with high-risk alleles [2].

  4. Antifibrotic Agents: Targeting fibrosis through agents that inhibit TGF-β signaling and other pathways may offer a strategy to reverse or halt kidney damage [31].

  5. Gut Microbiota Modulators: Emerging evidence suggests that the gut-kidney axis plays a role in CKD, and modulating gut microbiota may provide therapeutic benefits [3].

The complexity of CKD necessitates a multimodal approach to treatment, integrating lifestyle modifications, pharmacologic interventions, and possibly novel therapies targeting specific pathways. Future research should focus on biomarker-driven precision medicine to enable individualized therapy selection and to develop agents that concurrently target multiple pathogenic processes [31]. As the understanding of CKD mechanisms deepens, it is anticipated that more effective, targeted therapies will emerge, enhancing the quality of life for patients and reducing the burden of this chronic condition.

6 Conclusion ​

Chronic kidney disease (CKD) is a complex and multifactorial condition that poses a significant global health challenge, with its mechanisms rooted in inflammation, oxidative stress, metabolic dysregulation, and genetic and environmental factors. The review has highlighted several critical findings: First, chronic inflammation and oxidative stress are pivotal in the progression of CKD, leading to renal injury and fibrosis. Second, metabolic dysregulation, including conditions such as diabetes and hypertension, exacerbates CKD and contributes to cardiovascular complications. Third, genetic predispositions and environmental influences interact intricately, affecting individual susceptibility to CKD. Despite advances in pharmacological therapies aimed at managing symptoms and slowing progression, there remains a substantial unmet need for targeted interventions that address the underlying mechanisms of CKD. Future research should focus on biomarker-driven precision medicine approaches, integrating lifestyle modifications and novel therapeutic strategies that simultaneously target multiple pathways involved in CKD progression. By enhancing our understanding of CKD mechanisms, we can pave the way for innovative treatments that improve patient outcomes and reduce the burden of this chronic disease.

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