Effects of Ramipril on Biomarkers of Endothelial Dysfunction and 1 Inflammation in Hypertensive Children on Maintenance Hemodialysis: The 2 SEARCH Randomized Placebo-Controlled Trial

Abstract

Background: Hypertension, endothelial dysfunction, and inflammation are associated with 34 increased cardiovascular mortality in end-stage kidney disease (ESKD). We evaluated the effects 35 of angiotensin-converting enzyme (ACE) inhibition on biomarkers of endothelial dysfunction and 36 inflammation in hypertensive children with ESKD on maintenance hemodialysis (MHD). 37 Methods: In a randomized, double-blind, placebo-controlled trial, 135 (72 males/63 females) 38 children and adolescents (age 7-15 years) were randomly assigned to treatment with either 2.5 mg 39 once daily ramipril (n=68) or placebo (n=67) for 16 weeks. Primary outcome were the serum 40 concentrations of asymmetric dimethylarginine (ADMA), a marker of endothelial dysfunction. and 41 high-sensitivity C-reactive protein (hs-CRP), a marker of inflammation. Changes in interleukin-6 42 (IL-6), tumor necrosis factor-alpha (TNF- α), systolic (S) and diastolic (D) blood pressure (BP) 43 were secondary outcomes. Change in potassium levels and incidence of hyperkalemia were among 44 the safety parameters. 45 Results: Ramipril but not placebo significantly reduced serum levels of ADMA (-79.6%; 46 p<0.001), hs-CRP (-46.5%; p<0.001), IL-6 (-27.1%; p<0.001) and TNF-α (-51.7%; p<0.001). SBP 47 and DBP were significantly lowered in both groups with a greater reduction in children receiving 48 ramipril (median between-group differences -12.0 [95% CI -18.0 to -9.5] and -9.0 [95% CI -12.0 49 to -4.5]; p<0.001, respectively). Changes in ADMA, hs-CRP, IL-6 or TNF-α in the ramipril group 50 did not significantly correlate with BP reductions. No severe cases of hyperkalemia or other serious 51 treatment-associated adverse events were observed.