IL-1 Inhibition and Function of the HDL-Containing Fraction of Plasma in Patients with Stages 3 to 5 CKD

Adriana M. Hung, Yohei Tsuchida, Kristen L. Nowak, Sudipa Sarkar, Michel Chonchol, Victoria Whitfield, Natjalie Salas, Anna Dikalova, Patricia G. Yancey, Jiansheng Huang, MacRae F. Linton, T. Alp Ikizler, Valentina Kon

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND OBJECTIVES: Systemic inflammation modulates cardiovascular disease risk and functionality of HDL in the setting of CKD. Whether interventions that modify systemic inflammation can improve HDL 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 with GFR 15-59 ml/min per 1.73 m2 (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) and 64% (P=0.02), IL-6 by 38% (P=0.004) and 56% (P=0.08), and Nod-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.

Original languageEnglish (US)
Pages (from-to)702-711
Number of pages10
JournalClinical journal of the American Society of Nephrology : CJASN
Volume14
Issue number5
DOIs
StatePublished - May 7 2019
Externally publishedYes

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Interleukin-1
Placebos
Renal Dialysis
Interleukin-1 Receptors
Maintenance
Superoxides
Interleukin-6
Anti-Inflammatory Agents
Interleukin-16
Cholesterol
Inflammation
Apolipoproteins B
Peritoneal Macrophages
Apolipoproteins E
Proteins
Cardiovascular Diseases
Randomized Controlled Trials
Antioxidants
Macrophages

Keywords

  • Anti-Inflammatory Agents
  • Cardiovascular Diseases
  • Cholesterol
  • Chronic inflammation
  • CKD
  • dialysis
  • HDL
  • IL-1 inhibition
  • IL1RN protein, human
  • IL6 protein, human
  • Inflammation
  • Interleukin 1 Receptor Antagonist Protein
  • Lipoproteins, HDL
  • macrophages
  • Macrophages, Peritoneal
  • NLR Proteins
  • Oxidants
  • oxidative stress
  • Receptors, Interleukin-1
  • Renal Insufficiency, Chronic
  • Superoxides
  • Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Epidemiology
  • Critical Care and Intensive Care Medicine
  • Nephrology
  • Transplantation

Cite this

IL-1 Inhibition and Function of the HDL-Containing Fraction of Plasma in Patients with Stages 3 to 5 CKD. / Hung, Adriana M.; Tsuchida, Yohei; Nowak, Kristen L.; Sarkar, Sudipa; Chonchol, Michel; Whitfield, Victoria; Salas, Natjalie; Dikalova, Anna; Yancey, Patricia G.; Huang, Jiansheng; Linton, MacRae F.; Ikizler, T. Alp; Kon, Valentina.

In: Clinical journal of the American Society of Nephrology : CJASN, Vol. 14, No. 5, 07.05.2019, p. 702-711.

Research output: Contribution to journalArticle

Hung, AM, Tsuchida, Y, Nowak, KL, Sarkar, S, Chonchol, M, Whitfield, V, Salas, N, Dikalova, A, Yancey, PG, Huang, J, Linton, MF, Ikizler, TA & Kon, V 2019, 'IL-1 Inhibition and Function of the HDL-Containing Fraction of Plasma in Patients with Stages 3 to 5 CKD', Clinical journal of the American Society of Nephrology : CJASN, vol. 14, no. 5, pp. 702-711. https://doi.org/10.2215/CJN.04360418
Hung, Adriana M. ; Tsuchida, Yohei ; Nowak, Kristen L. ; Sarkar, Sudipa ; Chonchol, Michel ; Whitfield, Victoria ; Salas, Natjalie ; Dikalova, Anna ; Yancey, Patricia G. ; Huang, Jiansheng ; Linton, MacRae F. ; Ikizler, T. Alp ; Kon, Valentina. / IL-1 Inhibition and Function of the HDL-Containing Fraction of Plasma in Patients with Stages 3 to 5 CKD. In: Clinical journal of the American Society of Nephrology : CJASN. 2019 ; Vol. 14, No. 5. pp. 702-711.
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abstract = "BACKGROUND AND OBJECTIVES: Systemic inflammation modulates cardiovascular disease risk and functionality of HDL in the setting of CKD. Whether interventions that modify systemic inflammation can improve HDL 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 with GFR 15-59 ml/min per 1.73 m2 (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) and 64{\%} (P=0.02), IL-6 by 38{\%} (P=0.004) and 56{\%} (P=0.08), and Nod-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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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

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 of CKD. Whether interventions that modify systemic inflammation can improve HDL 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 with GFR 15-59 ml/min per 1.73 m2 (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) and 64% (P=0.02), IL-6 by 38% (P=0.004) and 56% (P=0.08), and Nod-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 of CKD. Whether interventions that modify systemic inflammation can improve HDL 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 with GFR 15-59 ml/min per 1.73 m2 (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) and 64% (P=0.02), IL-6 by 38% (P=0.004) and 56% (P=0.08), and Nod-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.

KW - Anti-Inflammatory Agents

KW - Cardiovascular Diseases

KW - Cholesterol

KW - Chronic inflammation

KW - CKD

KW - dialysis

KW - HDL

KW - IL-1 inhibition

KW - IL1RN protein, human

KW - IL6 protein, human

KW - Inflammation

KW - Interleukin 1 Receptor Antagonist Protein

KW - Lipoproteins, HDL

KW - macrophages

KW - Macrophages, Peritoneal

KW - NLR Proteins

KW - Oxidants

KW - oxidative stress

KW - Receptors, Interleukin-1

KW - Renal Insufficiency, Chronic

KW - Superoxides

KW - Tumor Necrosis Factor-alpha

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U2 - 10.2215/CJN.04360418

DO - 10.2215/CJN.04360418

M3 - Article

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JO - Clinical journal of the American Society of Nephrology : CJASN

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