2.2.10. Inflammation

Inflammation and fibrosis contribute to the progression of CKD via many pathways in glomeruli, tubules, and interstitium. In the final common pathway to end-stage renal disease, nephron loss causes hyperperfusion and high glomerular capillary hydrostatic pressure in remaining nephrons. This results in injury to the major cell types within glomeruli: endothelial cells, podocytes, and mesangial cells [86]. Injured endothelial cells detach from the basement membrane, express more leukocyte adhesion molecules, and secrete more proinflammatory cytokines. Injured podocytes also detach from the basement membrane, allowing proteinuria, associated with increased angiotensin II, aldosterone, and TGF-β. Injured mesangial cells proliferate and synthesize extracellular matrix constituents, MCP-1, CGTF, and TGF-β. Monocytes recruited to injured glomeruli become macrophages, and glomerular inflammation leads to glomerulosclerosis [87].

Interstitial inflammation and fibrosis also contribute to the progression of CKD. Lymphocytes and macrophages infiltrate the renal interstitium. Lymphocytes are recruited into the interstitium early. Monocytes are recruited into the interstitium, where they become macrophages. Macrophage infiltration after nephron loss is chiefly in tubulointerstitial regions. The CC chemokine receptor type 1 is important in interstitial but not glomerular recruitment of leukocytes. Dendritic cells appear in the interstitium, with peak concentration at one week after nephron loss. Mast cells are identifiable in areas of tubulointerstitial inflammation and fibrosis [88]. Myofibroblasts secrete the components of extracellular matrix, leading to fibrosis. The predominant source of these myofibroblasts is from pericytes around blood vessels and resident fibroblasts, with a minor contribution from de-differentiated proximal tubule cells [89].

In the progression of chronic kidney disease, the cell type probably most often central to the various processes involved is the macrophage [90]. The mononuclear cell chemokine, CCL2, mediates migration of monocytes to the injured kidney. CCL2 blockade attenuates glomerular and interstitial infiltration of pro-inflammatory macrophages, but other chemokines such as CX3CL1, CXCL16, and macrophage migration inhibitory factor (MIF), also contribute to macrophage recruitment in kidney disease [85]. Opposing this recruitment, the mononuclear cell chemokine C-C motif chemokine 5 (CCL5) constrains CCL2 expression, macrophage infiltration, and kidney damage and fibrosis in hypertension via blood pressure-independent mechanisms. This balance illustrates the complex network of overlapping chemokines working to maintain renal health [85].

Macrophages polarized to the M1 phenotype play a pathogenic role in inflammatory renal injury, and macrophages polarized to the M2 phenotype play a pathogenic role in the follow-on renal fibrosis. Recruited macrophages produce a range of cytokines, including TNF-α and interferon-γ (IFN-γ), which increase M1 polarization and the progression of CKD. Damage-associated molecular patterns (DAMPs) from renal parenchyma such as high-mobility group protein B1 (HMGB1) and C-reactive protein (CRP) also augment the renal accumulation of pro-inflammatory macrophages. Additionally, DAMPS released from damaged renal tubular epithelial cells (RTEC) have been shown to increase the expression of pattern recognition receptors (PRR) on healthy RTEC. This leads to the expression of pro-inflammatory cytokines, which leads to further recruitment of inflammatory monocytes and macrophages [91]. There is experimental evidence that macrophage polarization to a pro-inflammatory phenotype, associated in turn with increased pro-inflammatory cytokines and renal inflammation, is promoted by a high salt intake, suggesting that this is one of the mechanisms by which a low-salt diet ameliorates the progression of CKD [92].

Macrophage phenotype is partly determined by prostaglandins in the microenvironment. Arachidonic acid metabolism into prostaglandins plays a role in renal inflammation and fibrosis. The lipoxygenase family of enzymes convert polyunsaturated fatty acids into bioactive lipid eicosanoids such as hydroxyeicosatetraenoic acids, hydroxyeicosaoctadecaenoic acids, leukotrienes, lipoxins, and resolvins [93]. The enzyme 15-lipoxygenase worsens inflammation and fibrosis in a rodent model of chronic kidney disease. Silencing 15-lipoxygenase promotes an increase in M2c-like wound-healing macrophages in the kidney and alters kidney metabolism, protecting against anaerobic glycolysis after injury [93].

The presence of free fatty acids may drive some of the inflammation causing the progression of chronic kidney disease. Renal tubular injury from free fatty acids may be partly mediated by increased expression of the CD36 scavenger receptor due to increased expression of the peroxisome proliferator-activated receptor (PPAR)-γ nuclear transcription factor [94]. Renal tubular injury and inflammation due to increased circulating free fatty acids could partly explain the accelerated progression of CKD in patients with insulin resistance (type 2 diabetes mellitus) and obesity. The decelerated progression of CKD by sodium-glucose co-transporter 2 (SGLT2) channel inhibitors may be partly from attenuated CD36 expression from downregulated PPAR-γ [94]. IL-33 may be an important driver of progressive CKD [95]. IL-33 is a member of the IL-1 cytokine family and exerts pro-inflammatory and pro-fibrotic effects via the suppression of tumorigenicity 2 (ST2) receptor, which, in turn, activates other inflammatory pathways. Recent studies have shown that a sustained activation of the IL-33/ST2 pathway promotes the development of renal fibrosis [95]. This pathway is a potential target for therapeutic intervention.

Excess amino acids from the heavy nutritional load of a high-protein diet are thought to increase renal inflammation and fibrosis primarily indirectly by increasing glomerular hyperfiltration, but also partly by increasing proinflammatory gene expression. Later in the course of chronic kidney disease, excess amino acids promote fibrosis by increasing TGF-β. Whatever the mechanisms, a low-protein diet slows the progression of chronic kidney disease [96].
