Colchicine and Inflammation in Hemodialysis Patients

Overview

Chronic, low-grade inflammation is regarded as a common comorbid condition in chronic dialysis patients. Increased inflammatory markers in chronic dialysis patients are associated with adverse clinical outcomes . Considering the association of low-grade inflammation with high rate of morbidity and mortality we decided to evaluate the anti inflammatory effect of colchicine on inflammatory markers 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 . The only paper reported on the use of colchicine in dialysis patients is the report on the use of colchicine in peritoneal dialysis (PD) rats with encapsulating peritoneal sclerosis .There is no information in the literature on whether colchicine affects inflammation measures in dialysis patients. Given the high morbidity and mortality in MHD patients, targeting inflammation represents a potentially novel and attractive strategy if it can indeed be shown to improve their adverse outcomes. Considering the association of low-grade inflammation with high rate of morbidity and mortality in MHD population and anti-inflammatory potential of colchicine on the other hand, we decided to conduct the Colchicine Influence on Chronic Inflammation in Hemodialysis Patients (CICI-HP) study to evaluate the effects of colchicine on inflammatory markers as well as its safety profile in MHD patients. The study will be conducted as a 3-month, double-blind, parallel-group, placebo-controlled, single center study. The study population will include 50 ESKD patients receiving MHD treatment with different degrees of low-grade inflammation (defined as plasma CRP above 10 mg/L and below 100 mg/L). A total of 50 subjects will be randomized to treatment with either colchicine 0.5 mg three times a week (at the end of each hemodialysis session) or matching placebo. Both patients and investigators (including doctors, nurses and dietitians) will be blinded to group assignment. Randomization codes will conceal until end of trial . The randomization list and all study products will be provided by "Super Pharm Professional" laboratory Petah Tikva . After meeting all inclusion criteria all study participants will be seen at 4 visits over the 3 month period. All visits will take place in connection with a regular dialysis session. At all study visits predialysis blood samples will be collected in a fasting state from each study patient. The dietary energy and protein intake will be calculated and normalized for ideal body weight according to the European Best Practice Guidelines by skilled dietitian. Dietitian records based on self-completed food diaries with continuous 3-day dietary histories (including a dialysis day, a weekend day and a non-dialysis day) will be used to calculate the dietary intake. The same dietitian will perform all anthropometric measurements and calculation of daily calorie and protein intake per diaries records. During the dialysis session SNAQ questionnaires for appetite assessment will be filled out. At study entry, each participant will be instructed how to work with questionnaires. All participants will also fill out the EQ-5D questionnaires on their own, or will be assisted by an independent person if the patient himself unable to complete questionnaire. Handgrip strength (HGS) will be measured in all patients using the non-dominant hand. The patients will undergo BIA at approximately 30-minutes postdialysis. The study parameters will be: SNAQ (the simplified nutritional appetite questionnaire) for appetite assessment; daily energy and protein intake for dietary assessment; EQ-5D for health-related QoL assessment; biochemical nutritional markers (serum albumin, creatinine, transferrin, uric acid, lipid profile, IGF-1), appetite-regulating peptides (leptin, acyl-ghrelin, obestatin, NPY); inflammatory biochemical mediators (CRP, neutrophil-to-lymphocyte ratio, IL-6, and TNFα); handgrip strength as functional assessment of muscle mass; anthropometric parameters (body weight, BMI, skinfold thickness, mid arm circumference and mid arm circumference calculated); lean body mass, % fat mass, fat free mass, phase angle measured by BIA, malnutrition inflammation score, geriatric nutritional risk index (GNRI) and objective score of nutrition on dialysis (OSND) as quantitative assessment of nutritional status. All patients will undergo regular hemodialysis via their vascular access 4-5 h 3-4 times per week at a blood flow rate 250-300 mL/min. Bicarbonate dialysate (30 mEq/L) at a dialysis solution flow rate of 500 mL/min will be used in all cases. All patients will use the same high flux dialyser membrane (biocompatible) with surface area of 1.8-2.2m2 and patients won't use re-used dialyzer membrane. The efficiency of the dialysis will be assessed based on the delivered dose of dialysis (Kt/Vurea) using a single-pool urea kinetic model. Protein equivalent of nitrogen appearance (nPNA), an indirect indicator of protein intake, will be calculated from serum urea levels using three-point method. During the study period (from screening to the last follow up visit - about 3 months period) we will monitor all morbid events for all study patients. Specific causes of hospitalization (grouped as infectious causes, cardiac causes, vascular-access related causes, and other causes classified according to ICD-9 codes) will be recorded.

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