Innate Immunity and CKD: Is There a Significant Association?
Abstract
:1. Contributing Factors to CKD-Related Immune System Activation
- Gut dysbiosis: Alterations in gut bacterial composition due to restricted diet, chronic use of medications including potassium and phosphorus chelators, proton pump inhibitors, and recurrent bowel wall edema secondary to volume overload all contribute to metabolite changes that escalate inflammation, exacerbate oxidative stress, and promote renal fibrosis [1,2];
- Lipid metabolism: The dysregulation of lipid metabolism has been observed in both animal models and CKD patients [3]. CKD is associated with a reduction in free fatty acid oxidation, increased lipid synthesis, and enhanced lipid gut uptake. Increased triglyceride synthesis augments the production of reactive oxygen species, thereby activating apoptotic and pro-fibrinogenic pathways [4];
- Hypertension: Persistent high blood pressure is both a cause and a consequence of CKD. Adaptive and innate immunity have been both shown to participate in the pathogenesis of hypertension and ensuing kidney damage [5];
- Waste product accumulation: The accumulation of waste products, including sodium, acids, phosphorus, urea, and medium-size molecules, alters the extracellular milieu, triggering immune activation [7];
- Sympathetic overactivation: Elevated sympathetic activity may initiate and modulate inflammation in CKD through multiple pathways, including interferon γ, IL-6, and IL-10 [8];
- Hemodialysis-related factors: Chronic hemodialysis exposes patients to substantial loads of dialysate water, with significant inter-dialytic variation in degrees of chemical purification microbiological quality and endotoxin levels, as well as in the biocompatibility of dialyzer membranes, potentially inducing an inflammatory state [9];
- Inadequate medium-sized molecule removal: Conventional dialysis treatment is not sufficiently effective in the adequate removal of medium-sized molecules, the accumulation of which may trigger immune activation [10];
- Immunomodulatory drug therapy: Medications targeting innate immunity cascade checkpoints, including NFκB and NLRP3 inflammasome, among others, as well as microbiota manipulation trials, which might give rise to a new era that is effective in diminishing chronic inflammation in CKD patients, with an effect on slowing the GFR decline curve.
2. CKD-Induced Activation of Innate Immunity
- Phagocytosis of the recognized PAMPs or DAPMs;
- Local inflammatory signaling;
- Activation of the adaptive immune system through the maturation of antigen-presenting cells.
3. TLR Signaling Pathway
4. NLRP3 Pathway
5. The NF-κB Role
Can the Local Renal Inflammatory Process Be Contained for Improved Patient Outcomes?
- Statins: Statins have a well-established role in reducing inflammation in patients with CKD and its associated CVD [3,5,43]. Treatment with atorvastatin has been shown to reduce inflammatory markers in CKD patients, independent of its cholesterol-lowering effects, suggesting its anti-inflammatory/antioxidant properties [44]. Combining other lipid-lowering drugs, such as bempedoic acid and ezetimibe, may offer additional therapeutic benefits;
- Sodium Glucose Cotransporter 2 (SGLT2) Inhibitors: SGLT2 inhibitors are known for their nephroprotective and cardiovascular benefits in patients with CKD [3,14,45]. Emerging evidence suggests they may also harbor an anti-inflammatory role, with indications of their capacity to inhibit the NLRP3 inflammasome and reduce inflammatory markers [46];
- Finerenone and Glucagon-like Peptide (GLP) 1 Agonists: Finerenone, a mineralocorticoid receptor antagonist, has demonstrated nephroprotective effects and reduced cardiovascular events in the FIDELIO DKD trial. Both finerenone and GLP-1 agonists have been shown to exert anti-inflammatory effects [14,47,48,49];
- Anti-IL-1R: The CANTOS trial investigated the use of canakinumab in inhibiting inflammation mediated by NLRP3-IL1-IL6 pathways. It showed a reduction in cardiovascular event rates and slowed disease progression in both CKD and non-CKD patients. The drug effect was directly related to the magnitude of downstream reduction in IL-6 and CRP levels [5,14,45,50]. However, its positive impact on renal function preservation was modest [3,14,42,48,49];
- IL-6 Inhibition: Inhibition of IL-6, a downstream effect of IL-1β, has been proposed to block the inflammatory response [3,14]. Tocilizumab is an IL6R inhibitor that was shown to reduce troponin and CRP in the setting of NON-ST elevation myocardial infarction. Zilitivekimab, a fully humanized anti-IL6 monoclonal antibody developed specifically for the prevention of atherosclerotic damage in CKD patients, was shown in the RESCURE trial [51] to reduce CRP levels in these patients. The currently ongoing ZEUS study (Ziltivekimab the drug impact on cardiovascular outcome study) aims to explore the drug’s effect on both cardiovascular events and kidney function [52];
- Colchicine and Low-Dose Methotrexate: These non-specific anti-inflammatory agents have broad effects related to microtubule polymerization, reducing leukocyte chemotaxis, cytokine secretion, and inhibiting NLRP3 pathways [14,43]. Colchicine has been shown to reduce cardiovascular events in the COLCOT [53] and LoDoCo2 trials [54], though gastrointestinal side effects were reported. In a meta-analysis [55], colchicine treatment was associated with a lower risk of major cardiovascular events, though a mild trend was noted towards higher non-cardiovascular mortality for unknown causes. Unlike the beneficial effect of colchicine, low-dose methotrexate did not show a cardiovascular benefit in a NIH-funded trial [56];
- NRF2 Agonists: Nrf2 is an anti-oxidative and anti-inflammatory transcription factor that is reduced in CKD and considered a potential therapeutic target [3,14]. Several Nrf2 agonists have been developed and studied. Older studies demonstrated the possible benefit of these agents; for example, butylhydroquinone significantly improved the phosphate-induced calcification of vascular smooth muscle cells via the activation of KEAP1/NRF2/P62 signaling and repressing ROS production [57]. Dimethyl fumarate also had similar vascular outcomes in vitro and in vivo [58]. Another Nrf2 agonist, hydrogen sulfide, showed similar in vitro results [59]. Bardoxolone methyl was studied in patients with CKD and diabetes mellitus type 2 [60,61], showing conflicting results and necessitating premature trial cessation. Additional Nfr2 agonists are under evaluation [14];
- Senolytics: Cellular senescence is associated with inflammation and tissue damage. Senolytics, which induce the death of senescent cells, hold potential anti-inflammatory properties [14]. This hypothesis has been studied through various kidney injury experimental models, including ischemia-reperfusion injury, diabetic nephropathy, and mouse kidney transplantation models, indicating improved cell repair and reduced proteinuria and fibrosis. In the phase one trial examining the effect of the tyrosine kinase inhibitor dasatinib, combined with the plant flavanol quercetin in diabetic nephropathy, results showed reduced cell senesce and diminished levels of the pro-inflammatory cytokines IL-1a and IL-6. Moreover, ABT-63, a potent B cell lymphoma (Bcl)2/w/Xl inhibitor, effectively depleted senescent cells when administered orally to mice and awaits further studies [62]. Another ongoing Mayo Clinic study, currently in process, examines the effect of fisetin, a dietary supplement with a presumably antioxidant effect [63], on the reduction in inflammatory markers, mesenchymal cell changes, and the GFR decline rate in patients with CKD and DM2. The use of senolytics for diverse medical indications is under investigation, showing potential as promising future therapies [64]. Figure 2 summarizes the above-mentioned therapeutic approaches.
6. Future Developments
7. Targeting Fibrosis
8. Summary
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Plonsky-Toder, M.; Magen, D.; Pollack, S. Innate Immunity and CKD: Is There a Significant Association? Cells 2023, 12, 2714. https://doi.org/10.3390/cells12232714
Plonsky-Toder M, Magen D, Pollack S. Innate Immunity and CKD: Is There a Significant Association? Cells. 2023; 12(23):2714. https://doi.org/10.3390/cells12232714
Chicago/Turabian StylePlonsky-Toder, Moran, Daniella Magen, and Shirley Pollack. 2023. "Innate Immunity and CKD: Is There a Significant Association?" Cells 12, no. 23: 2714. https://doi.org/10.3390/cells12232714
APA StylePlonsky-Toder, M., Magen, D., & Pollack, S. (2023). Innate Immunity and CKD: Is There a Significant Association? Cells, 12(23), 2714. https://doi.org/10.3390/cells12232714