Abstract
The accumulation of uremic toxins (UTs) is a prototypical manifestation of uremic milieu that follows renal function decline (chronic kidney disease, CKD). Frailty as a potential outcome-relevant indicator is also prevalent in CKD. The intertwined relationship between uremic toxins, including small/large solutes (phosphate, asymmetric dimethylarginine) and protein-bound ones like indoxyl sulfate (IS) and p-cresyl sulfate (pCS), and frailty pathogenesis has been documented recently. Uremic toxins were shown in vitro and in vivo to induce noxious effects on many organ systems and likely influenced frailty development through their effects on multiple preceding events and companions of frailty, such as sarcopenia/muscle wasting, cognitive impairment/cognitive frailty, osteoporosis/osteodystrophy, vascular calcification, and cardiopulmonary deconditioning. These organ-specific effects may be mediated through different molecular mechanisms or signal pathways such as peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α), mitogen-activated protein kinase (MAPK) signaling, aryl hydrocarbon receptor (AhR)/nuclear factor-κB (NF-κB), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), Runt-related transcription factor 2 (RUNX2), bone morphogenic protein 2 (BMP2), osterix, Notch signaling, autophagy effectors, microRNAs, and reactive oxygen species induction. Anecdotal clinical studies also suggest that frailty may further accelerate renal function decline, thereby augmenting the accumulation of UTs in affected individuals. Judging from these threads of evidence, management strategies aiming for uremic toxin reduction may be a promising approach for frailty amelioration in patients with CKD. Uremic toxin lowering strategies may bear the potential of improving patients’ outcomes and restoring their quality of life, through frailty attenuation. Pathogenic molecule-targeted therapeutics potentially disconnect the association between uremic toxins and frailty, additionally serving as an outcome-modifying approach in the future.
Highlights
Nephrology Division, Department of Internal Medicine, National Taiwan University Hospital BeiHu Branch, Graduate Institute of Toxicology, National Taiwan University College of Medicine, Taipei 100233, Taiwan
uremic toxins (UTs) play an under-recognized role in affecting mitochondrial health, and existing literature frequently addresses the adverse influences exerted by protein-bound ones, such as indoxyl sulfate (IS) and p-cresyl sulfate (pCS), such as changes in the extent of autophagy [32]
In vitro studies found that IS-treated astrocytes and glial cells had downregulation of nuclear factor erythroid-derived 2-like 2 (Nrf2), heme oxygenase-1 (HO-1), and nicotinamide adenine dinucleotide phosphate (NADPH) dehydrogenase quinone 1 (NQO1), but upregulation of aryl hydrocarbon receptor (AhR) and nuclear factor-κB (NF-κB) [62]
Summary
The underlying machineries responsible for incident frailty can be complex. Several factors have been implicated during the process of unsuccessful aging, such as anemia resulting from ineffective erythropoiesis [8], architectural bony deterioration [9], vitamin. Among these factors, many occur in patients with CKD as well. Many occur in patients with CKD as well This phenomenon underlies the possibility that shared pathophysiology exists between CKD and frailty, a physical presentation of biological ageing
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