TY - JOUR
T1 - Biomarkers of Immune Activation and Incident Kidney Failure With Replacement Therapy
T2 - Findings From the African American Study of Kidney Disease and Hypertension
AU - Chen, Teresa K.
AU - Estrella, Michelle M.
AU - Appel, Lawrence J.
AU - Coresh, Josef
AU - Luo, Shengyuan
AU - Reiser, Jochen
AU - Obeid, Wassim
AU - Parikh, Chirag R.
AU - Grams, Morgan E.
N1 - Publisher Copyright:
© 2021 National Kidney Foundation, Inc.
PY - 2021/7
Y1 - 2021/7
N2 - Rationale & Objective: Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear. Study Design: Prospective cohort. Setting & Participants: African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement. Predictors: Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Outcomes: Incident KFRT, all-cause mortality. Analytical Approach: Cox proportional hazards models. Results: Among 500 participants with available samples, mean glomerular filtration rate was 44.7 mL/min/1.73 m2, and median urinary protein-creatinine ratio was 0.09 g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P ≤ 0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P > 0.05 for interaction). Limitations: Limited generalizability to other ethnic groups or causes of CKD. Conclusions: Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.
AB - Rationale & Objective: Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear. Study Design: Prospective cohort. Setting & Participants: African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement. Predictors: Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). Outcomes: Incident KFRT, all-cause mortality. Analytical Approach: Cox proportional hazards models. Results: Among 500 participants with available samples, mean glomerular filtration rate was 44.7 mL/min/1.73 m2, and median urinary protein-creatinine ratio was 0.09 g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P ≤ 0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P > 0.05 for interaction). Limitations: Limited generalizability to other ethnic groups or causes of CKD. Conclusions: Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.
KW - APOL1 risk variant
KW - African American
KW - CKD progression
KW - IFN-γ
KW - TNF-α
KW - apolipoprotein L1 gene (APOL1)
KW - biomarkers
KW - chronic kidney disease (CKD)
KW - death
KW - end-stage kidney disease (ESKD)
KW - immune activation
KW - kidney failure
KW - mortality
KW - risk stratification
KW - sTNFR1
KW - sTNFR2
KW - soluble urokinase-type plasminogen activator receptor
KW - suPAR
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U2 - 10.1053/j.ajkd.2020.11.014
DO - 10.1053/j.ajkd.2020.11.014
M3 - Article
C2 - 33388403
AN - SCOPUS:85103307256
SN - 0272-6386
VL - 78
SP - 75-84.e1
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
IS - 1
ER -