Inflammation in Chronic Kidney Disease

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1		Saurav Kadatane	--	2604	2023-06-14 18:23:10	\|
2	format	Jason Zhu	Meta information modification	2604	2023-06-15 05:03:25	\|

This entry is adapted from the peer-reviewed paper 10.3390/cells12121581

Chronic kidney disease (CKD) affects many adults worldwide. Persistent low-grade inflammation is a substantial factor in its development and progression and has correlated with increased mortality and cardiovascular problems. This low-grade inflammation is a product of dysregulation of the normal balance between pro- and anti-inflammatory markers. Various factors such as increased innate immune system activation, reactive oxygen species production, periodontal disease, dysregulation of anti-inflammatory systems and intestinal dysbiosis result in the dysregulation of this balance.

chronic kidney disease inflammation immune

1. Introduction

Chronic kidney disease (CKD), an abnormal structure or function present for over three months, affects around 14% of US adults ^[1]^[2]. There is often an increased inflammatory state in patients with CKD. Low-grade systemic inflammation also is a substantial contributor to the development of CKD. However, the exact timeline between the initiation of inflammation and CKD is unclear. Low-grade systemic inflammation is a constant presence of inflammatory markers. Many conditions are associated with low-grade inflammation, such as metabolic syndrome, non-alcoholic fatty liver disease, cardiovascular disease and diabetes ^[3]. The inflammatory cascade is characterized by an inciting stimulus of tissue injury or foreign entity increasing the generation of proinflammatory cytokines (e.g., TNF-alpha and IL-1), resulting in increased blood flow, upregulation of chemical mediators and leukocyte infiltration ^[4]. The discontinuation of this cascade is mediated by anti-inflammatory molecules. However, low-grade inflammation can persist when there is a failure of discontinuation or persistence of proinflammatory markers. The persistence of an inflammatory state may be caused by poor diet and nutrition. Poor gut microbiota, maternal health during pregnancy, childhood infections and stress have all been linked with an inflammatory response ^[5]. CKD creates a setting for many causes of an increased inflammatory state, such as uremia, oxidative stress, infections, dyslipidemia, malnutrition, volume overload, dialysis, periodontal disease and reduced clearance of inflammatory factors ^[6].

2. Renal Physiology and Inflammation

2.1. Protective Measures against Inflammation in Kidneys

The kidneys play a large role in maintaining homeostasis of the immune system. The kidneys are responsible for clearing cytokines and bacterial antigens from circulation. Removal of proinflammatory cytokines and pathogen-associated molecular patterns (PAMPs) can reduce inflammation and activation of immune cells ^[7]. In addition to clearance, the kidneys play an important role in peripheral tolerance through resident dendritic cells (DCs) and macrophages (Mac) of the M2 subtype. DCs and Mac have been shown to inhabit the kidneys’ glomerular compartment, cortical and peritubular interstitium ^[8]. As the nephron filtrate is reabsorbed, DCs that survey the contents at the distal convoluted tubule encounter soon-to-be-excreted low molecular weight antigens at much higher concentrations than systemic circulation. Presentation of these innocuous antigens without inflammatory signals to T cells can potentially root out any autoreactive T cells, meaning that the kidneys assist in sustaining peripheral tolerance to harmless antigens, such as endogenous and food metabolites ^[2]^[9]. Besides peripheral tolerance, Mac heterogeneity has large implications for cytokine signaling within kidney health. M1 Mac has proinflammatory signaling and the M2 subtype has anti-inflammatory effects through the production of cytokines IL-10 and TGF-β. M2 Mac has been shown to protect against acute kidney injury (AKI), glomerulosclerosis, tubular atrophy, interstitial expansion and renal fibrosis in mice ^[10]^[11]^[12]. While the M1/M2 Mac ratio is tightly regulated, obesity and chronic inflammation states such as CKD lead to a higher expression of the M1 phenotype and a higher M1:M2 ratio ^[13]^[14]. Autophagy is also reno-protective against inflammation, as it prevents the accumulation of mitochondria, lysosomes and Damage-Associated Molecular Patterns (DAMPS) and suppresses inflammasome activation ^[15].

2.2. Why the Kidney Is Vulnerable to Inflammation

While the kidney has some protective effects against systemic inflammation, the kidney, as displayed in CKD and many other renal pathologies, is highly susceptible to damage from proinflammatory cytokines and oxidative stress. The kidney has a unique pairing of traits, making it particularly vulnerable to inflammation. The kidneys receive 25 percent of the entire blood volume without having anti-inflammatory defenses found in other highly vascularized organs, such as antioxidants or detoxifying agents of hepatic tissue. Damage from the physiologic hypoxic environment present within the medulla is prevented by regulatory hormones and vasoactive molecules, which are disrupted during inflammation. Furthermore, intrarenal changes in microvasculature triggered by chronic inflammation result in renal damage ^[2]. Furthermore, the renal tubules are home to many inflammatory cytokines, chemokines and mediators of fibrosis, which are key in responding to renal insults and injury. These markers are highly regulated; however, dysregulation contributes to maladaptive response and repair and progression to CKD. Dysregulation can occur due to exposure to repeat insults, such as diabetes, incomplete recovery from AKI and uncontrolled inflammatory responses ^[16]. In addition, the proximal tubules have high energy demands, making them prone to ischemia during inflammation and other times of energy supply-demand mismatch ^[17]. Oxidative damage is also increased in CKD, secondary to increased reactive oxygen species (ROS) and decreased nitric oxide due to increased homocysteine. Furthermore, antioxidant systems such as the glutathione redox cycle are at capacity, with an increased oxidized to reduced glutathione ratio, resulting in decreased ability to combat oxidation in CKD patients ^[6]. In patients with CKD, inflammatory markers IL-1—which is elevated in dialysis patients—fibrinogen and TNF-α are independent predictors of CKD progression ^[16]^[18]. Inflammatory activation in CKD also appears to be influenced by genetic and epigenetic conditions ^[3].

2.3. Endothelial Injury

The microvasculature of the kidney operates in an extreme environment with vastly changing levels of oxygenation and osmolality. Therefore, it is tightly regulated by vasoactive molecules, such as prostaglandins, endothelins, kinins, medullipin, nitric oxide and others, in order to keep the corticomedullary osmotic gradient intact, and any alteration to this delicate balance renders the kidneys vulnerable to dysfunction and damage ^[2]. One factor to consider in this microvasculature damage is renal vasculature resistance (RVR) increases. Any inflammatory damage to any portion of the renal microvasculature can increase RVR, causing ischemic kidney damage ^[19]^[20]. Any damage to pericytes, such as AKI-induced sepsis or ischemia-reperfusion, causes the pericytes to detach from peritubular capillaries and differentiate into myofibroblasts ^[21]^[22]. This has two pathologic effects on the kidney: fibrosis from the newly formed myofibroblasts and the leaky endothelium cascades inflammatory and oxidative damage in the nearby tissue ^[23]. In CKD patients, elevated levels of inflammatory signals (TNF-α, IL-6, IL-8) and elevated levels of vascular cell adhesion molecule, E-selectin and intracellular adhesion molecule (ICAM) were associated with higher incidences of salt and water retention and disturbances in macro-microcirculation ^[24].

2.4. Role of Different Inflammatory Markers in the Kidney

The renal system has many exposures to inflammatory markers during times of infection. In pyelonephritis, proinflammatory cytokines, such as Tumor Necrosis Factor-α (TNF-α), Monocyte Chemoattractant Protein-1 (MCP-1), Interleukin-6 (IL-6), IL-8 and IL-23, play an important role in mounting the immune response ^[25]^[26]. The initial response to injury or infection is similar in the kidneys to the rest of the body. During infection, IL-1 activates adhesion molecule expression in endothelium and induces another chemokine expression to recruit white blood cells (WBCs). TNF-α also activates endothelial inflammatory responses and causes capillary leakage for incoming immune cells. Incoming immune cells (monocytes and macrophages) are attracted by MCP-1. Elevated IL-6 levels confer a fever and acute phase protein response during this time. Neutrophils are chemoattracted by IL-8, and IL-23 upregulates the proliferation of Th17 cells, which incites more proinflammatory responses ^[27].

While these proinflammatory cytokines have a role in protection, they can also have damaging effects on the kidney. For example, children with acute pyelonephritis, IL-1β and IL-6 were associated with higher incidences of renal scarring ^[28]. In low-grade chronic inflammatory conditions such as CKD, the persistent release of these cytokines can cause arteriole fibrosis and exacerbate renal injury. Furthermore, TGF-β and IL-1β are secreted by macrophages during low-grade inflammation, resulting in renal fibrosis ^[28]. T cells have also recently been implicated in inducing renal fibrinogenesis through the IL-23/IL-17 axis ^[29].

3. Inflammation and CKD

3.1. Pathophysiology of Inflammasomes

Inflammasomes are protein complexes of the innate immune system responsible for sensing pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs) and activating downstream signals via the activation of protease caspase 1. Activation of caspase-1 leads to proteolytic activation of Interleukin-1β and IL-18 and pyroptosis, an inflammatory cell death process. PAMPs constitute bacterial, viral or fungal markers such as flagellin, HepC protein or Beta-glucan. DAMPs are endogenous signals released during tissue injury, including ion efflux, mitochondrial dysfunction and reactive oxygen species ^[30]. Toll-like receptors (TLRs), C-type lectin receptors (CLRs), intracellular Nod-like receptors (NLRs) and retinoic acid-inducible gene (RIGs) receptors constitute different families of pattern recognition receptors (PRRs), which are responsible for sensing PAMPs and DAMPs ^[31]. Intracellular molecular patterns are recognized by NLRs and RIGs; extracellular PAMPs and DAMPs are recognized by CLRs and TLRs ^[32]. PRRs can recruit inflammasome complexes. There are 5 traditional PRRs known to assemble into inflammasomes. Nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein (NLR) receptors such as NLRP1, NLRP4 and NLRC4 and the remaining two pyrin and absent in melanoma 2 (AIM2) are well characterized. However, there are less well-characterized receptors such as NLRP6, NLRP7, NLRP12 and RIG-1. All these inflammasomes activate caspase 1 (canonical pathway) or caspase 11 (non-canonical pathway). The NLRP3 inflammasome has been implicated in the pathophysiology of many renal diseases ^[33]. Its assembly depends on NEK7, a serine and threonine kinase, for proper NLRP3 oligomerization. The NLRP3 mechanism of activation is still unclear. However, there are several proposed triggers. NLRP3 is triggered by many pathogens, particulate matter, mitochondrial DNA or potassium efflux. As NLRP3 inflammasome lacks CARD (caspase recruiting domain), an adaptor molecule of ASC (apoptosis-associated speck-like protein containing CARD) is needed to activate caspase. Activating caspase results in the proteolytic activation of proinflammatory cytokines such as IL-1β and IL-18 and pyroptosis, an inflammatory cell death process. There are many internal regulators of inflammatory assembly, particularly at the interaction of ASC with caspase through CARD-only proteins (COPs) and PYD-only proteins (POPs), thereby preventing caspase activation. Protein phosphorylation and ubiquitylation also inhibit the activity of ASC and inflammasomes ^[31].

3.2. Inflammasomes in CKD

Some evidence points to the IL-1β/IL-18 axis’ role in the progression of CKD. Specifically, levels of IL-18 might be associated with monocyte chemoattractant protein-1 (MCP-1), which is independently related to the estimated glomerular filtration rate (eGFR). Furthermore, IL-18 is associated with vascular inflammation and calcification in CKD ^[2]. One study reported a reduction in tubular injury, inflammation and fibrosis after UUO (unilateral urethral obstruction), associated with a reduction in caspase-1 activation and maturation of IL-1β and IL-18 in NLRP3−/− mice ^[34]. In diabetic nephropathy, NLRP3 inflammasome activation has been reported and NLRP3 or caspase-1 deficiency improved albuminuria and the fractional mesangial area in diabetic mice ^[35]. Another study used the same UUO model to analyze early renal edema and vascular permeability and found that NLRP3-deficient (−/−) mice led to increased vascular leakage and interstitial edema. They displayed no effect on inflammation and fibrosis ^[36]. Despite these findings, the relationship between the inflammasome and CKD remains under debate. In addition to inflammasomes, regulating inflammatory markers is a key process mediating the progression of CKD. Nuclear factor kappa beta and nuclear factor erythroid 2 like 2 (Nrf2) are transcription factors that play a role in inflammatory marker regulation. Nrf2, in particular, has an anti-inflammatory role. Numerous antioxidant enzymes are produced, such as glutathione peroxidase, superoxide dismutase, catalase and heme oxygenase −1. In CKD, Nrf2 expression is downregulated.

Furthermore, patients on hemodialysis also have decreased expression of Nrf2. Downstream effects of this decreased expression are increased renal fibrosis, tubular damage, and worsening of CKD. Furthermore, increased mitophagy and mitochondrial biogenesis and regulation of glucose and lipid metabolism are also controlled by Nrf2 in macrophages during infections, helping restore normal cellular metabolism from the glycolysis and lipid synthesis-dominant metabolism during inflammation. Due to decreased Nrf2, defective mitophagy and ROS overproduction, CKD disrupts this process ^[37].

3.3. Role of Leptin in the Development of CKD

Leptin is an anorexigenic molecule in adipose tissue that controls appetite and body mass. However, leptin also has many other effects and regulates functions such as immune and endocrine response, sexual maturation, bone mass, hematopoiesis and blood pressure. It has been involved in the development of CVD and HTN ^[38]. Leptin levels are often elevated in CKD due to a reduction of normal physiologic clearance performed by megalin-mediated metabolic degradation in the proximal tubules, resulting in a proinflammatory uremic state. Leptin clearance is only effective for hemodialysis patients with high-flux membranes. In addition to poor clearance, hyperinsulinemia and low-grade inflammation have also been implicated in increased leptin levels in CKD ^[39]. The increased levels of leptin in turn increase the progression of CKD via increased glomerulosclerosis.

Leptin receptors (which stimulate Janus kinase/signal transducers) are mainly present in the inner medulla and vasculature of the cortico-medullary regions ^[40]. Leptin promotes endothelial cell proliferation by upregulating TGF-B1 levels. TGF-B1 levels induce profibrotic changes and decreased breakdown of the extracellular matrix. More specifically, leptin was not found to increase TGF-1 in the mesangial cells but increased TGF-2 receptor expression in the mesangium ^[41]. Leptin also increases collagen type 1 generation and glucose uptake ^[42].

Interestingly, leptin and TGF-1 addition enhance mesangial collagen type 1 generation, suggesting leptin-induced TGF-2 receptor upregulation enhances the interaction with increased TGF-1 levels. This in turn results in glomerulosclerosis and the progression of CKD. Furthermore, increased leptin-mediated sympathetic nervous system activation may promote arteriosclerosis and CKD progression in the kidneys via hypertension ^[41]. Increased matrix proliferation, neovascularization via vascular endothelial growth factor, promotion of vascular calcifications through vascular smooth muscle cell differentiation to osteoblast cells and prothrombotic effects of leptin all contribute to increased hypertension ^[40]. Furthermore, leptin was shown to be associated with elevated CRP levels and insulin resistance, which are both linked to CKD. The leptin receptor imitates the gp120 family of cytokine receptors (including the IL-6 receptor), increasing serum CRP levels ^[43]. Leptin’s proinflammatory effects also increase cytokines such as TNF-alpha, IL-1, IL-2, IL-2 and MCP-1, leading to accelerated atherosclerosis, insulin resistance and endothelial dysfunction ^[40]. While leptin may promote inflammatory cytokines and CD4+ T cell proliferation, it is associated with interference of innate immunity by inhibiting neutrophil chemotaxis and reducing oxidative burst, resulting in an increased risk of infections in the CKD patient ^[40].

3.4. Metabolic Syndrome and CKD

Metabolic syndrome (MetS) involves insulin resistance, central obesity, hyperglycemia, hyperuricemia, hyperlipidemia and hypertension, and is a risk factor for cardiovascular disease and pathologies such as myocardial infarction, stroke and thrombosis. The estimated worldwide prevalence of MetS is 20–25%, and it is well known that MetS harms the renal system. Several factors influence the pathophysiology of MetS on kidney function, such as obesity, insulin resistance, endothelial dysfunction, obesity, hypertension and inflammation ^[44].

3.4.1. Insulin Resistance

The cause of insulin resistance is multifactorial. Post-Phosphatidylinositol 2-kinase receptor pathway disruption has been attributed to insulin resistance. Furthermore, poor glucose clearance in CKD, complications of dialysis, obesity, increased leptin: adiponectin ratio, vitamin difference and chronic inflammation all lead to insulin resistance. Insulin resistance mainly progresses to CKD through fibrosis ^[45]. First, insulin resistance promotes sodium retention, subsequent RAAS activation and lipid accumulation in the tubules. Furthermore, insulin-mediated TGF-1 activation activates mesangial proliferation, fibrosis and progression to CKD. Similarly, insulin resistance causes sterol regulatory element binding protein-1 (SREBP-1) to promote lipid droplet accumulation in renal tubular cells, resulting in further interstitial fibrosis and tubular atrophy. Lastly, the connective tissue growth factor (CTFG) also promotes fibrosis after activation by insulin-like growth factor-1 ^[46].

3.4.2. Obesity

Obesity has been shown to lead to RAAS activation, elevated aldosterone levels and sodium retention. RAAS activation also results in elevated GFR and renal plasma flow with subsequent glomerular hyperfiltration, glomerulomegaly and segmental sclerosis. Obesity is also associated with elevated leptin levels, contributing to renal damage ^[46].

3.4.3. Hypertension

Hypertension in MetS is directly related to RAAS activation. Activation of this system is caused by several factors, such as secretion of angiotensinogen by visceral adipocytes, renal parenchymal cell compression by fat buildup around the kidneys with subsequently altered pressure natriuresis and increased sympathetic nerve activity by substances such as leptin. Hypertension directly injures the kidney due to ischemia, which damages the kidney and elevates angiotensin II levels ^[46].

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