Colchicine Influence on Chronic Inflammation in Hemodialysis Patients

Adult end-stage kidney disease (ESKD) patients undergoing maintenance hemodialysis (MHD) experience high mortality and morbidity with diminished quality of life . Death and hospitalization rates in MHD patients correlate strongly with indicators of chronic inflammation .

Chronic, low-grade inflammation is regarded as a common comorbid condition in CKD, and particularly in chronic dialysis patients.Several circulating markers are commonly assessed as indicators of systemic inflammation. IL-1 is a pro-inflammatory mediator of both acute and chronic inflammation, and induces synthesis and expression of hundreds of secondary inflammatory mediators .IL-1β is the main form of circulating IL-1 and is initially synthesized as a precursor (pro-IL-1β) that becomes activated in the setting of a macromolecular structure known as the inflammasome , which is activated in CKD and perpetuates the inflammatory response .IL-6 is a pro-inflammatory cytokine that promotes inflammatory events through activation and proliferation of lymphocytes, differentiation of B cells, leukocyte recruitment, and induction of the acute-phase protein response in the liver .IL-6 can be induced by IL-1 and by TNF-α, the latter of which is a soluble receptor primarily produced by monocytes and macrophages and elevated in states of chronic inflammation .CRP is an acute phase reactant, downstream from IL-6, and is a more specific marker of plaque vulnerability and risk of cardiovascular events, with data suggesting it may play a direct role in atherogenesis rather than simply acting as a marker, as previously believed .

Increased inflammatory markers in chronic dialysis patients are associated with adverse clinical outcomes including all-cause mortality, cardiovascular events ,protein energy wasting and diminished motor function, cognitive impairment ,as well as other adverse consequences including CKD-mineral and bone disorder (CKD-MBD) ,anemia ,and insulin resistance .

Despite the strong evidence that the prevalence of chronic inflammation is high and it independently predicts numerous adverse clinical outcomes in chronic dialysis patients, the evidence for a role of inflammation in affecting outcomes is limited by the fact that most of the available evidence is epidemiological in nature, with some additional support provided by mechanistic animal studies .Strategies shown to reduce systemic inflammatory markers in chronic kidney disease and/or chronic dialysis patients include pharmacological and non-pharmacological approaches. Pharmacological strategies that have been evaluated are specific anti-cytokine therapies (anakinra, as well as IL-6 monoclonal antibody etc.), as well as non-specific agents with anti-inflammatory properties, including statins, angiotensin converting enzyme inhibitors and angiotensin receptor blockers, cholecalciferol (vit D), sevelamer, peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists, and growth hormone .However, the data that reducing systemic inflammation improves clinical outcomes are currently lacking; this area represents an important future research direction.

Colchicine is an ancient medication that is currently approved for the treatment of gout and FMF .However, colchicine has a wide range of anti-inflammatory activities, and studies indicate that it may be beneficial in a variety of other conditions .In this respect, attention should be paid to the recently published article that shows that colchicine at a dose of 0.5 mg daily led to a reduction of inflammation expressed by serum CRP levels and a significantly lower risk of ischemic cardiovascular events than placebo among patients with a recent myocardial infarction .Interestingly, although acute preprocedural administration of colchicine did not lower the risk of percutaneous coronary intervention (PCI)-related myocardial injury, it successfully attenuated the increase in interleukin-6 and high-sensitivity C-reactive protein concentrations after PCI when compared with placebo .Recently reported that short-term administration of low-dose colchicine significantly alleviated endothelial inflammation with reduction of serum CRP concentration in coronary artery disease patients .It was found that short-term colchicine therapy dramatically reduced the expression levels of IL-1β, IL-6 and IL-18 by blockade of nucleotide-binding oligomerization domain-like receptors, pyrin domain-containing 3 (NLRP3) inflammasome activation in acute coronary syndrome patients .