Inflammation and Premature Ageing in Chronic Kidney Disease

Abstract

Persistent low-grade inflammation and premature ageing are hallmarks of the uremic phenotype and contribute to impaired health status, reduced quality of life, and premature mortality in chronic kidney disease (CKD). Because there is a huge global burden of disease due to CKD, treatment strategies targeting inflammation and premature ageing in CKD are of particular interest. Several distinct features of the uremic phenotype may represent potential treatment options to attenuate the risk of progression and poor outcome in CKD. The nuclear factor erythroid 2-related factor 2 (NRF2)-kelch-like erythroid cell-derived protein with CNC homology [ECH]-associated protein 1 (KEAP1) signaling pathway, the endocrine phosphate-fibroblast growth factor-23-klotho axis, increased cellular senescence, and impaired mitochondrial biogenesis are currently the most promising candidates, and different pharmaceutical compounds are already under evaluation. If studies in humans show beneficial effects, carefully phenotyped patients with CKD can benefit from them.

Keywords: ageing; chronic kidney disease; end-stage kidney disease; inflammation; premature ageing; senescence; uremic toxins.

Figure 1

The phosphate-fibroblast growth factor-23 (FGF-23)–klotho endocrine axis. Main effectors of phosphate homeostasis with potential effects on ageing components (simplified overview). Phosphate (P_i) is taken up by the intestine and accumulates in the circulation of patients with advanced chronic kidney disease (CKD). In the circulation, fetuin A (blue circles)-bound calcium P_i in calciprotein particles (CPP) prevents precipitation of calcium P_i in the circulation. Increased P_i is further regulated by parathyroid hormone (PTH) secreted from the four parathyroid glands (orange circles) at the back of thyroid gland by increasing intestinal P_i resorption but also inducing phosphaturia. The 1,25(OH)₂ vitamin D₃ metabolite is activated in the kidneys and increases intestinal P_i resorption. Furthermore, bone-secreted fibroblast growth factor-23 (FGF-23) also exerts phosphaturic effects through its mandatory co-receptor klotho in the kidneys.

Figure 2

The phosphate-FGF-23–klotho endocrine axis and premature ageing in CKD. Association of the different effectors of the phosphate homeostasis with ageing components (light blue arrows: inducers; red arrows: inhibitors). In advanced CKD, calciprotein particles (CPP) can induce early vascular ageing (EVA) and inflammation. However, contradictory findings also suggest a beneficial role of CPP on EVA. Circulating phosphate (P_i) promotes EVA, cellular senescence, and oxidative stress by different mechanisms. Vitamin D inhibits inflammation and oxidative stress directly or indirectly. The anti-ageing-associated klotho counteracts EVA, cellular senescence, inflammation, and oxidative stress. Data for fibroblast growth factor-23 (FGF-23) are limited and further studies need to investigate whether FGF-23 directly induces different ageing components or whether the clinical associations to ageing are mediated by other factors, such as P_i.

Figure 3

Mechanisms by which uremic toxins and advanced glycation end products (AGE) induce pro-ageing effects. Both uremic toxins and AGE have adverse effects on mitochondrial function including formation of reactive oxygen species (ROS) but also structural disturbances. They impair anti-ageing defenses of the organism, and induce inflammation, as well as cellular senescence. All effects result in an adverse, pro-ageing milieu caused by uremic toxins and AGE. Light blue arrows: inducers; red arrows: inhibitors. ATF4: activating transcription factor 4, ROS: reactive oxygen species, SA-β-gal: senescence-associated beta-galactosidase.