interleukin-1 trap to treat vascular dysfunction in chronic kidney disease (ckd)

Conditions: Renal Insufficiency, Chronic

Summary: risk of cardiovascular diseases (cvd) is significantly elevated in patients with chronic kidney disease (ckd); however, this increased risk is only partially explained by traditional cardiovascular risk factors. patients with ckd exhibit chronic inflammation, a key mechanism contributing to vascular dysfunction (i.e., large elastic artery stiffening and endothelial dysfunction). inhibiting inflammation improves vascular dysfunction in other populations characterized by chronic inflammation. however, it is currently unknown if reducing inflammation with an interleukin-1 (il-1) blocker enhances vascular function in ckd patients. aim 1 will assess the efficacy of il-1 blocking with rilonacept for treating vascular dysfunction in patients with stage iii or iv ckd (estimated glomerular filtration rate 15-60 ml/min/1.73 m2). aim 2 will determine if blocking il-1 with rilonacept also reduces inflammation and oxidative stress. these studies could shift clinical practice guidelines by establishing a novel therapy for reducing cvd risk in ckd patients not requiring chronic hemodialysis.


Eligibility criteria:
inclusion criteria: * age 18-80 years * ckd stage iii or iv (egfr with the 4-variable modified diet renal disease (mdrd) prediction equation: 15-60 ml/min/1.73m2; stable renal function in the past 3 months) * an elevated high sensitivity c-reactive protein (hs-crp) of \> 2.0 mg/l and \<30 mg/l on at least 2 consecutive weekly determinations * urine protein excretion \< 5.0 g/24h estimated by a spot urine protein/creatinine ratio * ability to provide informed consent exclusion criteria: * patients with advanced ckd requiring chronic dialysis * active infection (chronic or acute (within 3 months) or antibiotic therapy (w/in 1 mo); history of recurrent infection * significant co-morbid conditions that lead the investigator to conclude that life expectancy is less than 1 year * expected to undergo living related transplant in next 6 months * history of severe congestive heart failure (i.e., ef \< 35%) * hospitalization in the past month * severe arthritis, lupus, inflammatory bowel disease, asthma or other disease(s) or medical condition(s) that, in the opinion of the investigator, could interfere with hscrp or immune function * immunosuppressant agents such as cyclosporine, tacrolimus, azathioprine, etanercept, infliximab, adalimumab, anakinra or long-term oral glucocorticoids taken in past 12 months * known malignancy * hiv, active, chronic hepatitis b as evidenced by hbsag positive and hbsab negative, or hepatitis c positive * woman who are pregnant, nursing or planning to become pregnant * body mass index (bmi) \>40 kg/m2 * warfarin use (or other cytochrome p (cyp)450 substrates with a narrow therapeutic index) \[ok if do not participate in endothelial cell collection\] * taking medication(s) that interact with agents administered during experimental sessions (e.g., sildenafil interacts with nitroglycerin) * currently receiving or planning to receive live or inactivated vaccines * alcohol dependence or abuse * subjects at risk for tuberculosis (tb). specifically, subjects with: * current clinical, radiographic or laboratory evidence of active tb at screening or latent tb that has not been previously treated * a history of active tb within the last 3 years even if it was treated. * a history of active tb greater than 3 years ago unless there is documentation that the prior anti-tb treatment was appropriate in duration and type. * therapy for latent tb which has not been completed as per local guidelines.

Keywords: interleukin-1 endothelium, vascular vascular stiffness oxidative stress inflammation endothelial cells