Abstract
Background: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. Methods: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. Results: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. Conclusions: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 115-126 |
| Number of pages | 12 |
| Journal | Journal of the American Society of Nephrology |
| Volume | 32 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2021 |
| Externally published | Yes |
ASJC Scopus subject areas
- Medicine(all)
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In: Journal of the American Society of Nephrology, Vol. 32, No. 1, 01.2021, p. 115-126.
Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Association of multiple plasma biomarker concentrations with progression of prevalent diabetic kidney disease
T2 - Findings from the Chronic Renal Insufficiency Cohort (CRIC) study
AU - CKD Biomarkers Consortium and the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators
AU - Schrauben, Sarah J.
AU - Shou, Haochang
AU - Zhang, Xiaoming
AU - Anderson, Amanda Hyre
AU - Bonventre, Joseph V.
AU - Chen, Jing
AU - Coca, Steven
AU - Furth, Susan L.
AU - Greenberg, Jason H.
AU - Gutierrez, Orlando M.
AU - Ix, Joachim H.
AU - Lash, James P.
AU - Parikh, Chirag R.
AU - Rebholz, Casey M.
AU - Sabbisetti, Venkata
AU - Sarnak, Mark J.
AU - Shlipak, Michael G.
AU - Waikar, Sushrut S.
AU - Kimmel, Paul L.
AU - Vasan, Ramachandran S.
AU - Feldman, Harold I.
AU - Schelling, Jeffrey R.
AU - Appel, Lawrence J.
AU - Go, Alan S.
AU - He, Jiang
AU - Nelson, Robert G.
AU - Rao, Panduranga S.
AU - Rahman, Mahboob
AU - Shah, Vallabh O.
AU - Townsend, Raymond R.
AU - Unruh, Mark L.
AU - Denburg, Michelle
AU - Warady, Bradley
AU - Coresh, Josef
AU - Grams, Morgan
AU - Abraham, Alison
AU - Rhee, Eugene
AU - Gutiérrez, Orlando M.
AU - Dubin, Ruth
AU - Hostetter, Tom
AU - Deo, Rajat
AU - Xie, Dawei
AU - Ballard, Shawn
AU - Whitehead, Krista
AU - Collins, Heather
AU - Ganz, Peter
N1 - Funding Information: S. Schrauben is supported by the NIDDK career development grant K23DK118198-01A1. S. Coca and C. Parikh are members and have salary support from the CKD Biomarker Consortium via NIDDK grant U01DK106962. S. Coca is also supported, in part, by National Heart, Lung, and Blood Institute grants R01DK115562, R01HL85757, and R01DK112258; and by National Institute for Occupational Safety and Health grant U01OH011326. J. Bonventre is supported by National Heart, Lung, and Blood Institute grants R37DK039773 and R01DKD072381; and by NIDDK contract U01DK085660. V. Sabbisetti and S. Waikar are supported by the NIDDK contract U01DK085660. J. Ix, M. Sarnak, O. Gutierrez, and M. Shlipak were supported by the NIDDK contract U01DK102730. J. Schelling is supported by NIDDK contract U01DK106965. J. Greenberg is supported by the NIH career development grant K08DK110536, and by the Charles H. Hood Foundation (Boston, MA). A. Anderson has received support from NIDDK grants U01DK103225 and U01DK060990, and R01DK104730 related to this project. C. Rebholz was supported by NIDDK mentored research scientist development award K01 DK107782, and a National Heart, Lung, and Blood Institute grant R21 HL143089. Funding for the CRIC Study was obtained under a cooperative agreement from the NIDDK under grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902, and U24DK060990. In addition, this work was supported, in part, by National Center for Advancing Translational Sciences (NCATS) grants UL1TR000003 (via the Perelman School ofMedicine at the University of Pennsylvania Clinical and Translational Science Award), UL1 TR-000424 (via Johns Hopkins University), M01 RR- 16500 (via University of Maryland General Clinical Research Center), UL1TR000439 (Case Western Reserve University/Cleveland Clinic CTSA), UL1TR000433 (via Michigan Institute for Clinical and Health Research), and UL1RR029879 (via University of Illinois at Chicago Clinical and Translational Science Awards); NIH grant P20 GM109036 (via Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases); National Center for Research Resources grant NCRR UCSF-CTSI UL1 RR-024131 (via Kaiser Permanente); and National Heart, Lung, and Blood Institute grant R01DK119199 (via Department of Internal Medicine, University of New Mexico School of Medicine Albuquerque, NM). Funding Information: A. Anderson consulted for Kyowa Hakko Kirin. J. Bonventre declares ownership interests (stock or stock options, excluding diversified mutual funds) with Goldfinch Bio (cofounder and equity holder) and Medibeacon; being a coinventor on KIM-1 patents assigned to Partners Healthcare and thus receives patent rights and royalty payments for intellectual property; and consultancy with Renalytix. J. Bonventre also holds equity in DX Now, Innoviva, Medibeacon, Rubius, Sensor‐Kinesis, Sentien, and Thrasos; has received consulting income from Aldeyra, Biomarin, Cadent, Esperion, Praxis, Sarepta, Seattle Genetics, and Sumitomo Dainippon; and has received grant funding from the National Institutes of Health (NIH)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). J. Bonventre’s interests were reviewed and are managed by Brigham and Women’s Hospital and Partners HealthCare in accordance with their conflict of interest policies. S. Coca declares providing consultancy for Bayer, CHF Solutions, Relypsa, RenalytixAI, and Takeda; receiving personal fees from Boehringer-Ingelheim, inRegan, and Quark; and being on the advisory committee of and having ownership interests (stock or stock options, excluding diversified mutual funds) in Renaly-tixAI. S. Coca also has the patent “Derivation and Validation of a Machine Learning Risk Score using Biomarker and Electronic Patient Data To Predict Rapid Progression of Diabetic Kidney Disease” licensed to RenalytixAI. H. Feldman reports being a scientific advisor or having membership of the steering committee of the CRIC Study; consultancy agreements with DLA Piper, LLP; InMed, Inc.; Kyowa Hakko Kirin Co., Ltd. (ongoing); and National Kidney Foundation; being editor-in-chief of the American Journal of Kidney Diseases (member of advisory board); receiving research funding from Regen-eron; and receiving honoraria from Rogosin Institute (as invited speaker). O. Gutierrez has received grant funding and consulting fees from Akebia and Amgen, grant funding from GlaxoSmithKline, and personal fees from QED. J. Ix is the principal investigator of an investigator-initiated research grant supported by Baxter International. P. Kimmel reports being an editor of Chronic Renal Disease, and being a scientific advisor to or a member of the board of directors of Washington Academy of Medicine. C. Parikh declares having a consulting arrangement with Genfit and Tricida, and having ownership interests (stock or stock options, excluding diversified mutual funds) in and consultancy with Renalytix. V. Sabbisetti declares KIM-1 patents assigned to Partners Healthcare (patent rights). M. Sarnak declares being on the steering committee for Akebia, being on the advisory board for Bayer, and being a consultant for Cardurian. M. Shlipak has served as a consultant for Cricket Health and Intercept Pharmaceuticals, and is a scientific advisor for TAI Diagnostics. S. Waikar reports receiving grants and personal fees from Allena Pharmaceuticals; and personal fees from Barron and Budd (versus Fresenius), Bunch and James, Cerus, CVS, GE Healthcare, GlaxoSmithKline, Harvard Clinical Research Institute (also known as Baim), Johnson & Johnson, Kantum Pharma, Mallinckrodt, Mass Medical International, Pfizer, Public Health Advocacy Institute, Roth Capital Partners, Strataca, Takeda, Venbio, and Wolters Kluewer; outside the submitted work. All remaining authors have nothing to disclose. Funding Information: S. Schrauben is supported by the NIDDK career development grant K23DK118198-01A1. S. Coca and C. Parikh are members and have salary support from the CKD Biomarker Consortium via NIDDK grant U01DK106962. S. Coca is also supported, in part, by National Heart, Lung, and Blood Institute grants R01DK115562, R01HL85757, and R01DK112258; and by National Institute for Occupational Safety and Health grant U01OH011326. J. Bonventre is supported by National Heart, Lung, and Blood Institute grants R37DK039773 and R01DKD072381; and by NIDDK contract U01DK085660. V. Sabbisetti and S. Waikar are supported by the NIDDK contract U01DK085660. J. Ix, M. Sarnak, O. Gutierrez, and M. Shli-pak were supported by the NIDDK contract U01DK102730. J. Schelling is supported by NIDDK contract U01DK106965. J. Greenberg is supported by the NIH career development grant K08DK110536, and by the Charles H. Hood Foundation (Boston, MA). A. Anderson has received support from NIDDK grants U01DK103225 and U01DK060990, and R01DK104730 related to this project. C. Rebholz was supported by NIDDK mentored research scientist development award K01 DK107782, and a National Heart, Lung, and Blood Institute grant R21 HL143089. Funding for the CRIC Study was obtained under a cooperative agreement from the NIDDK under grants U01DK060990, U01DK060984, U01DK061022, U01DK061021, U01DK061028, U01DK060980, U01DK060963, U01DK060902, and U24DK060990. In addition, this work was supported, in part, by National Center for Advancing Translational Sciences (NCATS) grants UL1TR000003 (via the Perelman School of Medicine at the University of Pennsylvania Clinical and Translational Science Award), UL1 TR-000424 (via Johns Hopkins University), M01 RR-16500 (via University of Maryland General Clinical Research Center), UL1TR000439 (Case Western Reserve University/Cleveland Clinic CTSA), UL1TR000433 (via Michigan Institute for Clinical and Health Research), and UL1RR029879 (via University of Illinois at Chicago Clinical and Translational Science Awards); NIH grant P20 GM109036 (via Tulane COBRE for Clinical and Translational Research in Cardiometabolic Diseases); National Center for Research Resources grant NCRR UCSF-CTSI UL1 RR-024131 (via Kaiser Per-manente); and National Heart, Lung, and Blood Institute grant R01DK119199 (via Department of Internal Medicine, University of New Mexico School of Medicine Albuquerque, NM). Publisher Copyright: Copyright © 2021 by the American Society of Nephrology.
PY - 2021/1
Y1 - 2021/1
N2 - Background: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. Methods: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. Results: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. Conclusions: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.
AB - Background: Although diabetic kidney disease is the leading cause of ESKD in the United States, identifying those patients who progress to ESKD is difficult. Efforts are under way to determine if plasma biomarkers can help identify these high-risk individuals. Methods: In our case-cohort study of 894 Chronic Renal Insufficiency Cohort Study participants with diabetes and an eGFR of <60 ml/min per 1.73 m2 at baseline, participants were randomly selected for the subcohort; cases were those patients who developed progressive diabetic kidney disease (ESKD or 40% eGFR decline). Using a multiplex system, we assayed plasma biomarkers related to tubular injury, inflammation, and fibrosis (KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40). Weighted Cox regression models related biomarkers to progression of diabetic kidney disease, and mixed-effects models estimated biomarker relationships with rate of eGFR change. Results: Median follow-up was 8.7 years. Higher concentrations of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were each associated with a greater risk of progression of diabetic kidney disease, even after adjustment for established clinical risk factors. After accounting for competing biomarkers, KIM-1, TNFR-2, and YKL-40 remained associated with progression of diabetic kidney disease; TNFR-2 had the highest risk (adjusted hazard ratio, 1.61; 95% CI, 1.15 to 2.26). KIM-1, TNFR-1, TNFR-2, and YKL-40 were associated with rate of eGFR decline. Conclusions: Higher plasma levels of KIM-1, TNFR-1, TNFR-2, MCP-1, suPAR, and YKL-40 were associated with increased risk of progression of diabetic kidney disease; TNFR-2 had the highest risk after accounting for the other biomarkers. These findings validate previous literature on TNFR-1, TNFR-2, and KIM-1 in patients with prevalent CKD and provide new insights into the influence of suPAR and YKL-40 as plasma biomarkers that require validation.
UR - http://www.scopus.com/inward/record.url?scp=85098515474&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098515474&partnerID=8YFLogxK
U2 - 10.1681/ASN.2020040487
DO - 10.1681/ASN.2020040487
M3 - Article
C2 - 33122288
AN - SCOPUS:85098515474
SN - 1046-6673
VL - 32
SP - 115
EP - 126
JO - Journal of the American Society of Nephrology
JF - Journal of the American Society of Nephrology
IS - 1
ER -