The Role of Inflammation in Kidney Disease Progression

Introduction

Despite recent advancements in the treatment of chronic kidney disease (CKD), patients continue to experience high rates of morbidity and mortality. While pressure-related injury is a well-known factor in CKD progression, new data suggests that a combination of chronic inflammation, oxidative stress, hypoxia, cellular aging, and mitochondrial dysfunction significantly contributes to the disease's onset, progression, and pathology.

Various elements, such as oxidative stress and the proinflammatory transformation of kidney cells, drive chronic inflammation in CKD. The regulation of inflammatory responses by nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and nuclear factor erythroid 2–related factor 2 (Nrf2) plays a crucial role in how glomerular and tubular cells react to kidney injury. Chronic inflammation is a key factor in the decline of the glomerular filtration rate in CKD.

Although the role of chronic inflammation in diabetic kidney disease is well-documented, significant evidence now shows that unresolved inflammation leads to fibrosis and end-stage kidney disease in other conditions such as Alport syndrome, autosomal dominant polycystic kidney disease, immunoglobulin A (IgA) nephropathy, and focal segmental glomerulosclerosis. This review aims to elucidate the mechanisms of chronic inflammation in the pathophysiology and progression of various kidney diseases, emphasizing Nrf2.

What Is CKD?

Pressure-mediated injury is a well-established cause of structural damage in chronic kidney disease (CKD). Therapies that reduce intraglomerular pressure, such as angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), are commonly used in CKD treatment. These therapies consistently impact blood pressure and proteinuria-related pathogenic mechanisms.

However, their effects on clinically significant outcomes, such as slowing kidney function decline and reducing the incidence of end-stage kidney disease (ESKD), are relatively modest. To effectively mitigate CKD progression, nephrologists must target pathogenetic mechanisms beyond altered glomerular hemodynamics.

Chronic inflammation and mitochondrial dysfunction are increasingly recognized as contributors to kidney fibrosis and ESKD. Regardless of CKD's cause, chronic inflammation often serves as both a cause and consequence of glomerular and tubulointerstitial pathology.

Proteinuria is a well-known predictor of CKD progression and is associated with low-grade inflammation linked to endothelial dysfunction in patients with asymptomatic proteinuria. Proteinuria exacerbates CKD pathology by inducing adverse changes in glomerular function, such as reduced glomerular barrier selectivity and glomerular hypertrophy, as well as direct damage to tubular epithelial cells. It also promotes chronic inflammation.

A comprehensive pathway map analysis of gene sets associated with estimated glomerular filtration rate (eGFR) in 157 European patients with nine different types of CKD identified inflammation and metabolism as the two main pathways driving CKD progression. Steady-state mRNA expression profiles across various CKD etiologies showed upregulation of proinflammatory genes, including human leukocyte antigen isoforms, toll-like receptors 1 and 3, and NF-κB1.

This analysis revealed gene and protein interactions, outlining known and novel mechanisms driving biological impairment across several kidney diseases, including thin basement membrane disease, focal segmental glomerulosclerosis (FSGS), membranous nephropathy, minimal change disease, diabetic nephropathy, hypertensive nephropathy, immunoglobulin A nephropathy (IgAN), and lupus nephritis.

Importantly, the nuclear factor erythroid 2-related factor 2 (Nrf2) anti-inflammatory pathway, discussed in detail later in this review, emerged as a central hub linking inflammatory and metabolic pathways activated across multiple CKD etiologies, suggesting a common mechanism for regulating inflammation and metabolism. This comprehensive review aims to explore the role of inflammation and Nrf2 expression in the progression of CKD across different etiologies.

What Is the Role of Inflammation in Kidney Disease Progression?

The following are the roles of inflammation in kidney disease progression:

• Chronic Inflammation and Oxidative Stress - Persistent low-grade inflammation and oxidative stress, characterized by elevated reactive oxygen species (ROS), are closely intertwined and are standard features of the uremic phenotype that contribute to premature aging and kidney fibrosis. Inflammation and oxidative stress create a positive feedback loop, enhancing each other. Oxidative stress triggers inflammation by activating the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), leading to the production of cytokines such as interleukin (IL)-1α, IL-1β, tumor necrosis factor (TNF), and IL-6, which are associated with the progressive decline in estimated glomerular filtration rate (eGFR).

• Kidney Cells in Inflammation - CKD progression primarily occurs through kidney fibrosis, where activated myofibroblasts are the main cells responsible for collagen production. Fibrillar collagens I and III significantly contribute to fibrosis-induced cellular loss in CKD. Various strategies have been explored to reduce experimental fibrosis, including targeting transcription factors, signaling and developmental pathways, and epigenetic modulators like microRNAs. Recently, anti-inflammatory approaches have garnered attention. As mentioned earlier, chronic inflammation is closely associated with both the initiation and progression of CKD.

• Elevated Levels of Cytokines - Elevated levels of inflammatory cytokines and the accumulation of extracellular matrix (ECM) lead to tubulointerstitial fibrosis and mesangial expansion, which cause a decline in glomerular filtration rate (GFR).

• Proinflammatory Mediators in CKD - Glomerular damage occurs when harmful proinflammatory stimuli in glomerular cells are not eliminated or due to genetic mutations that create a proinflammatory state. Contributing factors to a proinflammatory response in tubular cells include cytokine release, leakage of albumin and complement proteins, hypoxia from endothelial dysfunction, and direct injury from immunological, infectious, toxic, metabolic, or ischemic insults.

• Anti-inflammatory Role of Nrf2 in CKD - Nrf2 is a vital cellular factor that evolved to protect against oxidative stress when early organisms started to explore environments with oxygen hundreds of millions of years ago. Nrf2 helps protect kidney cells and other tissues by activating various genes that reduce the production of proinflammatory cytokines. Some of the critical molecules increased by Nrf2 include catalase, superoxide dismutase, glutathione peroxidase, heme oxygenase-1, NAD(P)H quinone oxidoreductase, and glutamate-cysteine ligase. To keep Nrf2 levels low inside cells, there must be a balance between protein creation and breakdown.

Conclusion

There is growing evidence that inflammation and metabolism are critical factors in the progression of chronic kidney disease (CKD). Studies show that most CKD-related body changes are linked to inflammation or metabolism issues. In CKD, specific genes that cause inflammation are consistently more active.

The Nrf2 pathway is important because it connects inflammation and metabolism in CKD. When Nrf2 is not working well, it leads to problems like inflammation, cell damage, and lack of oxygen in tissues, all of which worsen kidney disease. Activating Nrf2 could help slow down or even stop CKD from getting worse. Boosting Nrf2 and its effects might help improve kidney function in people with CKD.