Protein damage and inflammation in uraemia and dialysis patients

The presence of high molecular weight toxins in the uraemic blood had largely been ignored until the beginning of the era of proteomics. In the last decade, increasing interest focused on these solutes has yielded evidence to suggest that some of these proteinaceous uraemic compounds can play pathogenic roles in the inflammatory and vascular comorbidities and mortality in patients with end-stage renal disease (ESRD). The finding that the blood levels of a number of glycation and oxidation markers are simultaneously increased in patients with uraemia suggests that several uraemic and inflammatory pathways may conspire to sustain the protein damage. Although the molecular characteristics and biological roles of the solutes derived from this abnormal chemistry remain poorly understood, it is proposed that they are not only laboratory hallmarks, but that their accumulation might also be the key underlying event in the establishment of a vicious and self-propelled 'inflammatory loop'. The 'switch' is believed to be turned on by the scavenger receptor-dependent recognition of these protein damage products and activation of inflammatory and vascular reactions, which once activated generate further and even more marked protein injuries and inflammatory mediators, establishing a vicious loop together with the contribution of the uraemic intoxication and dialysis-related events. This paper provides the description of this inflammatory model, along with an overview of the literature on the proteinaceous solutes associated with inflammation and oxidative stress reactions, their biological roles, expected therapeutic tools--either pharmacological or dialytic--and investigation strategies based on the most recently introduced proteomic approaches.