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 - Funding Information:
Teresa K. Chen, MD, MHS, Michelle M. Estrella, MD, MHS, Lawrence J. Appel, MD, MPH, Josef Coresh, MD, PhD, Shengyuan Luo, MBBS, MHS, Jochen Reiser, MD, PhD, Wassim Obeid, PhD, Chirag R. Parikh, MD, PhD, Morgan E. Grams, MD, PhD. Designed the study: TKC, MME, LJA, MEG; carried out biomarker measurements: WO, CRP; analyzed data: TKC; interpreted data: all authors; provided supervision: MEG. Each author contributed important intellectual content during manuscript drafting or revision and agrees to be personally accountable for the individual's own contributions and to ensure that questions pertaining to the accuracy or integrity of any portion of the work, even one in which the author was not directly involved, are appropriately investigated and resolved, including with documentation in the literature if appropriate. TKC is supported by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases (NIH/NIDDK) award K08DK117068 and a George M. O'Brien Center for Kidney Research Pilot and Feasibility grant from Yale University under NIH/NIDDK grant P30DK079310. Biomarkers were measured by the Translational Research Core of the George M. O'Brien Kidney Center at Yale University. MEG and SL are supported by NIH/NIDDK grant R01DK108803. CRP is supported by NIH/NIDDK grant U01DK106962. The funders did not have a role in study design, data collection, analysis, reporting, or the decision to submit for publication. CRP is a member of the advisory board of and holds equity in Renalytix AI; and serves on the Data Safety and Monitoring Board of Genfit. JR is a cofounder and shareholder of Trisaq. All other authors declare they have no relevant financial interests. The authors thank participants of African American Study of Kidney Disease and Hypertension (AASK). AASK was conducted by the AASK Investigators and supported by NIDDK. Samples from the AASK trial reported here were supplied by the NIDDK Central Repositories through NIH/NIDDK grant X01DK118497. The AASK trial and cohort were supported by institutional grants from NIH and NIDDK grants M01 RR-00080, M01 RR-00071, M0100032, P20-RR11145, M01 RR00827, M01 RR00052, 2P20 RR11104, RR029887, DK 2818-02, DK057867, and DK048689; and King Pharmaceuticals, Pfizer, AstraZeneca, GlaxoSmithKline, Forest Laboratories, Pharmacia, and Upjohn. This paper was not prepared in collaboration with Investigators of the AASK study and does not necessarily reflect the opinions or views of the AASK study, the NIDDK Central Repositories, the NIH, or the NIDDK. Received June 26, 2020. Evaluated by 2 external peer reviewers and a statistician, with direct editorial input from an International Editor, who served as Acting Editor-in-Chief. Accepted in revised form November 3, 2020. The involvement of an Acting Editor-in-Chief was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.
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 -