Chronic Kidney Disease as a Systemic Inflammatory Syndrome: Update on Mechanisms Involved and Potential Treatment

Abstract

Chronic kidney disease (CKD) is characterized by manifestations and symptoms involving systemic organs and apparatus, associated with elevated cardiovascular morbidity and mortality, bone disease, and other tissue involvement. Arterial hypertension (AH), diabetes mellitus (DM), and dyslipidemia, with glomerular or congenital diseases, are the traditional risk factors recognized as the main causes of progressive kidney dysfunction evolving into uremia. Acute kidney injury (AKI) has recently been considered an additional risk factor for the worsening of CKD or the development of CKD de novo. Evidence underlies the role of systemic inflammation as a linking factor between AKI and CKD, recognizing the role of inflammation in AKI evolution to CKD. Moreover, abnormal increases in oxidative stress (OS) and inflammatory status in CKD seem to exert an important pathogenetic role, with significant involvement in the clinical management of this condition. With our revision, we want to focus on and update the inflammatory mechanisms responsible for the pathologic conditions associated with CKD, with particular attention on the development of AKI and AKI-CKD de novo, the alteration of calcium-phosphorus metabolism with bone disease and CKD-MBD syndrome, the status of malnutrition and malnutrition-inflammation complex syndrome (MICS) and protein-energy wasting (PEW), uremic sarcopenia, the status of OS, and the different inflammatory pathways, highlighting a new approach to CKD. The depth comprehension of the mechanisms underlying the development of inflammation in CKD may present new possible therapeutic approaches in CKD and hopefully improve the management of correlated morbidities and provide a reduction in associated mortality.

Keywords: acute kidney injury; chronic kidney disease; cytokine; fibroblast growth factor 23; inflammation; interleukin-6; malnutrition; mineral bone disease; oxidative stress; sarcopenia.

Figure 1

Chronic kidney disease as a systemic inflammatory syndrome. We describe the principal pathologic conditions connected to CKD and the related inflammatory mechanisms. a1-AG alpha1-acid glycoprotein; Adc: central adiposity; AKI: acute kidney injury; AKI-a/p-rec AKI apparent/partial recovery; CKD-MBD: chronic kidney disease-mineral bone disorder; CRP: C-reactive protein; Cyt: cytokines; DAMPs: damage-associated molecular patterns; dysf Adt: dysfunctional adipose tissue; E-Sel: E-selectin; FGF23: fibroblast growth factor 23; Fibr: fibrinogen; HD: hemodialysis; ICAM-1: intracellular adhesion molecule-1; IL: interleukin; Ins-res: insulin resistance; L-act: leukocyte activation; M: macrophages; MICS: malnutrition–inflammation complex syndrome; NGAL: neutrophil gelatinase-associated lipocalin; Nrf2-Keap1: Nrf2 nuclear factor erythroid 2 (NF-E2)-related factor 2 (Nrf2)–Keap1 (Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated protein) 1; OS: oxidative stress; PAMPs: pathogen-associated molecular patterns; perit-cap: peritubular capillaries; PEW: protein-energy wasting; PINI: prognostic inflammatory and nutritional index; Pres/Proc: presepsin/procalcitonin; P-sel: P-selectin; PTH: parathormone; PTH meth: PTH methionine-sulfone residues; RAS: TC: tubular cells; TGF: transforming growth factor; TNF: tumor necrosis factor; transc act: transcription activation; Treg: T-cell subsets regulatory T cells; VCAM-1: vascular cell adhesion molecule-1; ↑: increase; ↓: reduction.

Figure 2

Acute to chronic kidney disease progression. Principal inflammatory mechanisms involved in acute to chronic kidney disease progression. AKI: acute kidney injury; AKI-a/p-rec AKI apparent/partial recovery; CKD: chronic kidney disease; DAMPs: damage-associated molecular patterns; HIFs: hypoxia-inducible factors; ICAM-1: intracellular adhesion molecule-1; IL: interleukin; O2: oxygen; OS: oxidative stress; NO: nitric oxide; PAMPs: pathogen-associated molecular patterns; VCAM-1: vascular cell adhesion molecule-1; ROS: reactive oxygen species; TGF-β: transforming growth factor-β; TNF-α: tumor necrosis factor-α Treg: T-cell subsets regulatory T cells; TC: tubular cell; VEGF: vascular endothelial growth factor; ↑: increase; ↓: reduction.