TY - JOUR
T1 - Associations of Plasma Biomarkers of Inflammation, Fibrosis, and Kidney Tubular Injury With Progression of Diabetic Kidney Disease
T2 - A Cohort Study
AU - Gutiérrez, Orlando M.
AU - Shlipak, Michael G.
AU - Katz, Ronit
AU - Waikar, Sushrut S.
AU - Greenberg, Jason H.
AU - Schrauben, Sarah J.
AU - Coca, Steven
AU - Parikh, Chirag R.
AU - Vasan, Ramachandran S.
AU - Feldman, Harold I.
AU - Kimmel, Paul L.
AU - Cushman, Mary
AU - Bonventre, Joseph V.
AU - Sarnak, Mark J.
AU - Ix, Joachim H.
N1 - Funding Information:
Orlando M. Gutiérrez, MD, MMSc, Michael G. Shlipak, MD, MPH, Ronit Katz, DPhil, Sushrut S. Waikar, MD, MPH, Jason H. Greenberg, MD, MHS, Sarah J. Schrauben, MD, MSCE, Steven Coca, DO, MS, Chirag R. Parikh, MBBS, PhD, Ramachandran S. Vasan, MD, Harold I. Feldman, MD, MSCE, Paul L. Kimmel, MD, Mary Cushman, MD, MSc, Joseph V. Bonventre, MD, PhD, Mark J. Sarnak, MD, MS, and Joachim H. Ix, MD, MAS. Research idea and study design: OMG, MGS, MJS, JHI; data acquisition: OMG, MGS, MJS, JHI; data analysis/interpretation: OMG, MGS, MJS, JHI, SSW, JHG, SJS, SC, CRP, RSV, HIF, PLK, MC, JVB; statistical analysis: RK. 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. This research project is supported by cooperative agreement U01 NS041588 cofunded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health (NIH), Department of Health and Human Services. This work was also supported by award U01DK102730 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr Gutierrez was supported by award K24DK116180. Dr Schrauben was supported by award K23DK118198-01A1. Drs Schrauben and Feldman also receive support from the Chronic Kidney Disease Biomarker Consortium (U01-DK103225). Dr Gutierrez discloses that he has received honoraria and grant support from Akebia and Amgen; honoraria from AstraZeneca, Reata, and Ardelyx; and grant support from GSK; and serves on a data monitoring committee for QED. Dr Shlipak discloses that he has received consulting income from Cricket Health and Intercept Pharmaceuticals. Dr Ix discloses that he is principal investigator of an investigator-initiated research grant supported by Baxter International, serves as a member of a data safety monitoring board for Sanifit Therapeutics, is a member of the scientific advisory board for Alpha Young, and has served on advisory boards for AstraZeneca and Ardelyx. Dr Coca is a member of the scientific advisory board of Renalytix AI and owns equity in the same and has received consulting fees from Renalytix AI, CHF Solutions, Relypsa (now Vifor), Bayer, Boehringer Ingelheim, ProKidney, and Takeda Pharmaceuticals in the past 3 years. Dr Parikh is a member of the advisory board of and owns equity in Renalytix AI. He also serves as a consultant for Genfit and Novartis. Dr Bonventre is coinventor on KIM-1 patents assigned to MassGeneralBrigham. He also has equity and is a consultant for Renalytix. The authors thank the other investigators, the staff, and the participants of REGARDS for their valuable contributions. A full list of participating REGARDS investigators and institutions can be found at http://www.regardsstudy.org. The content is solely the responsibility of the authors and the opinions expressed in this article do not necessarily reflect those of NINDS, NIA, NIDDK, NIH, the US Department of Health and Human Services, or the US government. The data reported here have been supplied by the US Renal Data System (USRDS). The interpretation and reporting of these data are the responsibility of the authors and in no way should be seen as an official policy or interpretation of the US government. Received March 30, 2021. Evaluated by 3 external peer reviewers, with editorial input from a Statistics/Methods Editor and an Acting Editor-in-Chief (Editorial Board Member Paul J. Phelan, MB BCh, MD). Accepted in revised form September 7, 2021. The involvement of an Acting Editor-in-Chief to handle the peer-review and decision-making processes was to comply with AJKD's procedures for potential conflicts of interest for editors, described in the Information for Authors & Journal Policies.
Funding Information:
This research project is supported by cooperative agreement U01 NS041588 cofunded by the National Institute of Neurological Disorders and Stroke (NINDS) and the National Institute on Aging (NIA), National Institutes of Health (NIH), Department of Health and Human Services . This work was also supported by award U01DK102730 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Dr Gutierrez was supported by award K24DK116180. Dr Schrauben was supported by award K23DK118198-01A1. Drs Schrauben and Feldman also receive support from the Chronic Kidney Disease Biomarker Consortium (U01-DK103225).
Publisher Copyright:
© 2021 National Kidney Foundation, Inc.
PY - 2022/6
Y1 - 2022/6
N2 - Rationale & Objective: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture nonglomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes. Study Design: Cohort study. Setting & Participants: 594 participants (mean age, 70 years; 53% women) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes and an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Exposures: Plasma biomarkers of inflammation/fibrosis (TNFR1 and TNFR2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit. Outcomes: Incident kidney failure with replacement therapy (KFRT). Analytical Approach: Cox proportional hazards regression and least absolute shrinkage and selection operator regression adjusted for established risk factors for kidney function decline, baseline eGFR, and urinary albumin-creatinine ratio (UACR). Results: A total of 98 KFRT events were observed over a mean of 6.2 ± 3.5 (standard deviation) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from −0.08 to −0.65) and UACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, UACR, and established risk factors, hazard ratios for incident KFRT per 2-fold higher biomarker concentrations were 1.52 (95% CI, 1.25-1.84) for plasma KIM-1, 1.54 (95% CI, 1.08-2.21) for TNFR1, 1.91 (95% CI, 1.16-3.14) for TNFR2, and 1.39 (95% CI, 1.05-1.84) for YKL-40. In least absolute shrinkage and selection operator regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT. Limitations: Single biomarker measurement, lack of follow-up eGFR assessments. Conclusions: Individual plasma markers of inflammation/fibrosis (TNFR1, TNFR2, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR <60 mL/min/1.73 m2 after adjustment for established risk factors.
AB - Rationale & Objective: Most circulating biomarkers of chronic kidney disease (CKD) progression focus on factors reflecting glomerular filtration. Few biomarkers capture nonglomerular pathways of kidney injury or damage, which may be particularly informative in populations at high risk for CKD progression such as individuals with diabetes. Study Design: Cohort study. Setting & Participants: 594 participants (mean age, 70 years; 53% women) of the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study who had diabetes and an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Exposures: Plasma biomarkers of inflammation/fibrosis (TNFR1 and TNFR2, suPAR, MCP-1, YKL-40) and tubular injury (KIM-1) measured at the baseline visit. Outcomes: Incident kidney failure with replacement therapy (KFRT). Analytical Approach: Cox proportional hazards regression and least absolute shrinkage and selection operator regression adjusted for established risk factors for kidney function decline, baseline eGFR, and urinary albumin-creatinine ratio (UACR). Results: A total of 98 KFRT events were observed over a mean of 6.2 ± 3.5 (standard deviation) years of follow-up. Plasma biomarkers were modestly associated with baseline eGFR (correlation coefficients ranging from −0.08 to −0.65) and UACR (0.14 to 0.56). In individual biomarker models adjusted for eGFR, UACR, and established risk factors, hazard ratios for incident KFRT per 2-fold higher biomarker concentrations were 1.52 (95% CI, 1.25-1.84) for plasma KIM-1, 1.54 (95% CI, 1.08-2.21) for TNFR1, 1.91 (95% CI, 1.16-3.14) for TNFR2, and 1.39 (95% CI, 1.05-1.84) for YKL-40. In least absolute shrinkage and selection operator regression models accounting for biomarkers in parallel, plasma KIM-1 and TNFR1 remained associated with incident KFRT. Limitations: Single biomarker measurement, lack of follow-up eGFR assessments. Conclusions: Individual plasma markers of inflammation/fibrosis (TNFR1, TNFR2, YKL-40) and tubular injury (KIM-1) were associated with risk of incident KFRT in adults with diabetes and an eGFR <60 mL/min/1.73 m2 after adjustment for established risk factors.
KW - CKD progression
KW - End-stage kidney disease (ESKD)
KW - TNFR2
KW - biomarkers
KW - chitinase 3–like 1 (YKL-40)
KW - chronic kidney disease (CKD)
KW - diabetes
KW - dialysis
KW - end-stage renal disease (ESRD)
KW - fibrosis
KW - inflammation
KW - kidney injury marker 1 (KIM-1)
KW - kidney tubule injury
KW - monocyte chemotactic protein 1 (MCP-1)
KW - prognosis
KW - renal failure
KW - soluble urokinase-type plasminogen activator receptor (suPAR)
KW - tumor necrosis factor receptor 1 (TNFR1)
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U2 - 10.1053/j.ajkd.2021.09.018
DO - 10.1053/j.ajkd.2021.09.018
M3 - Article
C2 - 34752914
AN - SCOPUS:85123882397
VL - 79
SP - 849-857.e1
JO - American Journal of Kidney Diseases
JF - American Journal of Kidney Diseases
SN - 0272-6386
IS - 6
ER -