TY - JOUR
T1 - IL-1 inhibition and function of the HDL-containing fraction of plasma in patients with stages 3 to 5 CKD
AU - Hung, Adriana M.
AU - Tsuchida, Yohei
AU - Nowak, Kristen L.
AU - Sarkar, Sudipa
AU - Chonchol, Michel
AU - Whitfield, Victoria
AU - Salas, Natjalie
AU - Dikalova, Anna
AU - Yancey, Patricia G.
AU - Huang, Jiansheng
AU - Linton, MacRae F.
AU - Ikizler, T. Alp
AU - Kon, Valentina
N1 - Funding Information:
Study A: This work and Dr. Hung were supported by a Department ofVeteransAffairsClinicalScienceResearch&Development(CSR&D) Service Office merit review award “Dysmetabolism of CKD and Vascular Health” (CX000982 to Dr. Hung). The parent studies were supported by career development award “Inflammation in CKD and CVD—the Role of Genetics and IL-1ra” (CDA-CSR&D 2-031-09S to Dr. Hung) and by an American Heart Association postdoctoral fellowship award (12POST11920023 to Dr. Nowak). Study B: This work was supported in part by grant R21 DK077373 from the National Institute of Diabetes, Digestive and Kidney Diseases (to Dr. Hung and Dr. Ikizler). Additional support was provided by the National Center for Advancing Translational Sciences (grants UL1 TR000445 and UL1 RR025780) and the National Heart, Lung and Blood Institute (grant P01HL116263 to Dr. Kon, Dr. Ikizler, and Dr. Linton). Dr. Ikizler was supported in part by the CSR&D merit grant 1I01CX000414.
Funding Information:
Dr. Chonchol reports grants from American Heart Association, during the conduct of the study; grants and personal fees from Corvidia, personal fees from Amgen, grants and personal fees from Genzyme, grants from Otsuka, outside the submitted work. Dr. Ikizler reports grants and nonfinancial support from Sobi Pharmaceuticals, outside the submitted work. Dr. Linton reports grants from Regeneron, grants from Sanofi, grants from Regenxbio, grants from National Institutes of Health, other from Amgen, grants from Merck, outside the submitted work. In addition, Dr. Linton has a patent, Dicarbonyl Scavengers, for the prevention of atherosclerosis pending. Dr. Nowak reports grants from American Heart Association, grants and nonfinancial support from Regeneron Pharmaceuticals, during the conduct of the study. Dr. Hung reports grants from the Department of Veterans Affairs and National Institute of Diabetes and Digestive and Kidney Diseases, and nonfinancial support from Regeneron. Dr. Dikalova, Dr. Huang, Dr. Kon, Dr. Salas, Dr. Sarkar, Dr. Tsuchida, Dr. Whitfield, and Dr. Yancey have nothing to disclose.
Publisher Copyright:
© 2019, American Society of Nephrology. All rights reserved.
PY - 2019/5/7
Y1 - 2019/5/7
N2 - Background and objectives Systemic inflammation modulates cardiovascular disease risk and functionality of HDL in the setting ofCKD.Whether interventions thatmodify systemic inflammation can improveHDL function in CKD is unknown. Design, setting, participants, & measurements We conducted a post hoc analysis of two randomized, clinical trials, IL-1 trap in participants withGFR15-59 ml/min per 1.73m2 (study A) and IL-1 receptor antagonist in participants on maintenance hemodialysis (study B), to evaluate if IL-1 blockade had improved the anti-inflammatory activity (IL-6, TNF-α, and Nod-like receptor protein 3), antioxidant function (superoxide production), and net cholesterol efflux capacity of HDL. HDL function was measured using LPS-stimulated THP-1 macrophages or peritoneal macrophages of apoE-deficient mice exposed to the apoB-depleted, HDL-containing fraction obtained from the plasma of the study participants, collected before and after the interventions to block IL-1 effects. Analysis of covariance was used for between group comparisons. Results The mean age of the participants was 60±13 years, 72% (n=33) were men, and 39% (n=18) were black. There were 32 CKD (16 IL-1 trap and 16 placebo) and 14 maintenance hemodialysis (7 IL-1 receptor antagonist and 7 placebo) participants. Compared with placebo, IL-1 inhibition, in study A and B reduced cellular expression of TNF-α by 15%(P=0.05) and64%(P=0.02), IL-6 by 38%(P=0.004) and56%(P=0.08), andNod-like receptor protein 3 by 16% (P=0.01) and 25% (P=0.02), respectively. The intervention blunted superoxide production in the treated arm compared with placebo, with the values being higher by 17% in the placebo arm in study A (P<0.001) and 12% in the placebo arm in study B (P=0.004). Net cholesterol efflux capacity was not affected by either intervention. Conclusions IL-1 blockade improves the anti-inflammatory and antioxidative properties of the HDL-containing fraction of plasma in patients with stages 3-5 CKD, including those on maintenance hemodialysis.
AB - Background and objectives Systemic inflammation modulates cardiovascular disease risk and functionality of HDL in the setting ofCKD.Whether interventions thatmodify systemic inflammation can improveHDL function in CKD is unknown. Design, setting, participants, & measurements We conducted a post hoc analysis of two randomized, clinical trials, IL-1 trap in participants withGFR15-59 ml/min per 1.73m2 (study A) and IL-1 receptor antagonist in participants on maintenance hemodialysis (study B), to evaluate if IL-1 blockade had improved the anti-inflammatory activity (IL-6, TNF-α, and Nod-like receptor protein 3), antioxidant function (superoxide production), and net cholesterol efflux capacity of HDL. HDL function was measured using LPS-stimulated THP-1 macrophages or peritoneal macrophages of apoE-deficient mice exposed to the apoB-depleted, HDL-containing fraction obtained from the plasma of the study participants, collected before and after the interventions to block IL-1 effects. Analysis of covariance was used for between group comparisons. Results The mean age of the participants was 60±13 years, 72% (n=33) were men, and 39% (n=18) were black. There were 32 CKD (16 IL-1 trap and 16 placebo) and 14 maintenance hemodialysis (7 IL-1 receptor antagonist and 7 placebo) participants. Compared with placebo, IL-1 inhibition, in study A and B reduced cellular expression of TNF-α by 15%(P=0.05) and64%(P=0.02), IL-6 by 38%(P=0.004) and56%(P=0.08), andNod-like receptor protein 3 by 16% (P=0.01) and 25% (P=0.02), respectively. The intervention blunted superoxide production in the treated arm compared with placebo, with the values being higher by 17% in the placebo arm in study A (P<0.001) and 12% in the placebo arm in study B (P=0.004). Net cholesterol efflux capacity was not affected by either intervention. Conclusions IL-1 blockade improves the anti-inflammatory and antioxidative properties of the HDL-containing fraction of plasma in patients with stages 3-5 CKD, including those on maintenance hemodialysis.
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U2 - 10.2215/CJN.04360418
DO - 10.2215/CJN.04360418
M3 - Article
C2 - 31015261
AN - SCOPUS:85065806757
VL - 14
SP - 702
EP - 711
JO - Clinical journal of the American Society of Nephrology : CJASN
JF - Clinical journal of the American Society of Nephrology : CJASN
SN - 1555-9041
IS - 5
ER -