TY - JOUR
T1 - Circulating Plasma Biomarkers in Biopsy-Confirmed Kidney Disease
AU - Schmidt, Insa M.
AU - Mothi, Suraj Sarvode
AU - Wilson, Parker C.
AU - Palsson, Ragnar
AU - Srivastava, Anand
AU - Onul, Ingrid F.
AU - Kibbelaar, Zoe A.
AU - Zhuo, Min
AU - Amodu, Afolarin
AU - Stillman, Isaac E.
AU - Rennke, Helmut G.
AU - Humphreys, Benjamin D.
AU - Waikar, Sushrut S.
N1 - Funding Information:
This study was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant R01DK093574 (to S.S. Wai-kar). This work was conducted with support from Harvard Catalyst, the Harvard Clinical and Translational Science Center (National Institutes of Health, National Center for Advancing Translational Sciences award UL1TR001102), and financial contributions from Harvard University and its affiliated academic health care centers.
Funding Information:
B.D. Humphreys reports consultancy agreements with Chinook Therapeutics, Janssen, and Pfizer; ownership interest in Chinook Therapeutics; receiving research funding from Chinook Therapeutics and Janssen; receiving honoraria from the American Society of Nephrology; patents and inventions with Evotec, AG; serving on editorial boards for American Journal of Physiology Renal Physiology, JCI Insight, Kidney International, and Seminars in Nephrology; serving as Vice President of the American Society of Clinical Investigation (ASCI) and as an associate editor for JASN; and serving as a scientific advisor or member of Chinook Therapeutics SAB, the National Institute of Diabetes and Digestive and Kidney Diseases Board of Scientific Advisors, and RegMed XB Regenerative Medicine Crossing Borders SAB. H.G. Rennke reports consultancy agreements with Ionis Pharmaceuticals Inc. and receiving honoraria from Wol-ters Kluwer for book royalties for Renal Pathophysiology: The Essentials, 5th Ed. I.M. Schmidt is supported by the American Philosophical Society Daland Fellowship in Clinical Investigation. A. Srivastava reports consultancy agreements with CVS Caremark and Tate & Latham (medicolegal consulting); receiving honoraria from AstraZeneca, Bayer, and Horizon Therapeutics PLC; and speakers bureau for AstraZeneca. A. Srivastava is also supported by National Institutes of Health grant K23DK120811, National Institute of Diabetes and Digestive and Kidney Diseases Kidney Precision Medicine Project Opportunity Pool grant U2CDK114886, and core resources from George M. O’Brien Kidney Research Center at Northwestern University (Northwestern University-GoKIDNEY) grant P30DK114857. I.E. Stillman reports serving as a board member of the Organization for Renal Care in Haiti, Torch Inc. (no compensation), and legal consulting. S.S. Waikar reports consultancy agreements with Allena, BioMarin, CVS, GSK, JNJ, Mallinckrodt, Mass Medical International, Metro Biotechnology, Oxidien, Pfizer, Regeneron, Roth Capital Partners, Sironax, Stra-taca/3ive, Venbio, and Wolters Kluewer; receiving research funding from Vertex; serving as a scientific advisor or member of Kantum (scientific advisory board); receiving personal fees from Barron and Budd (versus Fresenius), Bunch and James, Cerus, CVS, GE Health Care, GSK, the Harvard Clinical Research Institute (also known as Baim), JNJ, Kantum Pharma, Mallinckrodt, Mass Medical International, Pfizer, the Public Health Advocacy Institute, Roth Capital Partners, Strataca, Takeda, Venbio, and Wolters Kluewer; receiving grants and personal fees from Allena Pharmaceuticals; and serving as an expert witness for litigation related to GE product Omniscan, an expert witness for litigation related to the Fresenius product Granuflo, an expert witness for litigation involving cisplatin toxicity, an expert witness for litigation related to the Gilead product Tenofovir, and an expert witness for litigation related to DaVita laboratory testing. S.S. Waikar is also supported by National Institutes of Health grants UH3DK114915, U01DK085660, U01DK104308, R01DK103784, and R21DK119751. P.C. Wilson reports receiving research funding from NovoNordisk. M. Zhuo is supported by National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases T32 award DK007199. All remaining authors have nothing to disclose.
Publisher Copyright:
© 2022 by the American Society of Nephrology.
PY - 2022/1
Y1 - 2022/1
N2 - Background and objectives Biomarkers for noninvasive assessment of histopathology and prognosis are needed in patients with kidney disease. Design, setting, participants, & measurements Using a proteomics assay, we measured a multimarker panel of 225 circulating plasma proteins in a prospective cohort study of 549 individuals with biopsy-confirmed kidney diseases and semiquantitative assessment of histopathology. We tested the associations of each biomarker with histopathologic lesions and the risks of kidney disease progression (defined as $40% decline in eGFR or initiation of KRT) and death. Results After multivariable adjustment and correction for multiple testing, 46 different proteins were associated with histopathologic lesions. The top-performing markers positively associated with acute tubular injury and interstitial fibrosis/tubular atrophy were kidney injury molecule-1 (KIM-1) and V-set and Ig domain-containing protein 2 (VSIG2), respectively. Thirty proteins were significantly associated with kidney disease progression, and 35 were significantly associated with death. The top-performing markers for kidney disease progression were placental growth factor (hazard ratio per doubling, 5.4; 95% confidence interval, 3.4 to 8.7) and BMP and activin membrane-bound inhibitor (hazard ratio, 3.0; 95% confidence interval, 2.1 to 4.2); the top-performing markers for death were TNF-related apoptosis-inducing ligand receptor-2 (hazard ratio, 2.9; 95% confidence interval, 2.0 to 4.0) and CUB domain-containing protein-1 (hazard ratio, 2.4; 95% confidence interval, 1.8 to 3.3). Conclusion We identified several plasma protein biomarkers associated with kidney disease histopathology and adverse clinical outcomes in individuals with a diverse set of kidney diseases.
AB - Background and objectives Biomarkers for noninvasive assessment of histopathology and prognosis are needed in patients with kidney disease. Design, setting, participants, & measurements Using a proteomics assay, we measured a multimarker panel of 225 circulating plasma proteins in a prospective cohort study of 549 individuals with biopsy-confirmed kidney diseases and semiquantitative assessment of histopathology. We tested the associations of each biomarker with histopathologic lesions and the risks of kidney disease progression (defined as $40% decline in eGFR or initiation of KRT) and death. Results After multivariable adjustment and correction for multiple testing, 46 different proteins were associated with histopathologic lesions. The top-performing markers positively associated with acute tubular injury and interstitial fibrosis/tubular atrophy were kidney injury molecule-1 (KIM-1) and V-set and Ig domain-containing protein 2 (VSIG2), respectively. Thirty proteins were significantly associated with kidney disease progression, and 35 were significantly associated with death. The top-performing markers for kidney disease progression were placental growth factor (hazard ratio per doubling, 5.4; 95% confidence interval, 3.4 to 8.7) and BMP and activin membrane-bound inhibitor (hazard ratio, 3.0; 95% confidence interval, 2.1 to 4.2); the top-performing markers for death were TNF-related apoptosis-inducing ligand receptor-2 (hazard ratio, 2.9; 95% confidence interval, 2.0 to 4.0) and CUB domain-containing protein-1 (hazard ratio, 2.4; 95% confidence interval, 1.8 to 3.3). Conclusion We identified several plasma protein biomarkers associated with kidney disease histopathology and adverse clinical outcomes in individuals with a diverse set of kidney diseases.
UR - http://www.scopus.com/inward/record.url?scp=85123377744&partnerID=8YFLogxK
U2 - 10.2215/CJN.09380721
DO - 10.2215/CJN.09380721
M3 - Article
C2 - 34759008
AN - SCOPUS:85123377744
SN - 1555-9041
VL - 17
SP - 27
EP - 37
JO - Clinical Journal of the American Society of Nephrology
JF - Clinical Journal of the American Society of Nephrology
IS - 1
ER -