title: Tissue transcriptome-driven identification of epidermal growth factor as a chronic kidney disease biomarker.
abstract: Chronic kidney disease (CKD) affects 8 to 16% people worldwide, with an increasing incidence and prevalence of end-stage kidney disease (ESKD). The effective management of CKD is confounded by the inability to identify patients at high risk of progression while in early stages of CKD. To address this challenge, a renal biopsy transcriptome-driven approach was applied to develop noninvasive prognostic biomarkers for CKD progression. Expression of intrarenal transcripts was correlated with the baseline estimated glomerular filtration rate (eGFR) in 261 patients. Proteins encoded by eGFR-associated transcripts were tested in urine for association with renal tissue injury and baseline eGFR. The ability to predict CKD progression, defined as the composite of ESKD or 40% reduction of baseline eGFR, was then determined in three independent CKD cohorts. A panel of intrarenal transcripts, including epidermal growth factor (EGF), a tubule-specific protein critical for cell differentiation and regeneration, predicted eGFR. The amount of EGF protein in urine (uEGF) showed significant correlation (P < 0.001) with intrarenal EGF mRNA, interstitial fibrosis/tubular atrophy, eGFR, and rate of eGFR loss. Prediction of the composite renal end point by age, gender, eGFR, and albuminuria was significantly (P < 0.001) improved by addition of uEGF, with an increase of the C-statistic from 0.75 to 0.87. Outcome predictions were replicated in two independent CKD cohorts. Our approach identified uEGF as an independent risk predictor of CKD progression. Addition of uEGF to standard clinical parameters improved the prediction of disease events in diverse CKD populations with a wide spectrum of causes and stages.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Ju
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Viji
authors.initials: V
authors.lastname: Nair
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Shahaan
authors.initials: S
authors.lastname: Smith
authors.affiliation: Renal Division, Department of Internal Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing 100034, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.affiliation: Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.|Department of Statistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kerby
authors.initials: K
authors.lastname: Shedden
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Peter X K
authors.initials: PXK
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.|Arbor Research Collaborative for Health, Ann Arbor, MI 48104, USA.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Mariani
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Felix H
authors.initials: FH
authors.lastname: Eichinger
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Celine C
authors.initials: CC
authors.lastname: Berthier
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Randolph
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jennifer Yi-Chun
authors.initials: JY
authors.lastname: Lai
authors.affiliation: Department of Biostatistics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hawkins
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Bitzer
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Sampson
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Martina
authors.initials: M
authors.lastname: Thier
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Solier
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Gonzalo C
authors.initials: GC
authors.lastname: Duran-Pacheco
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Guillemette
authors.initials: G
authors.lastname: Duchateau-Nguyen
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Essioux
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Schott
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Ivan
authors.initials: I
authors.lastname: Formentini
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Magnone
authors.affiliation: Roche Pharmaceutical Research and Early Development-Roche Innovation Center, 4070 Basel, Switzerland.
authors.forename: Maria
authors.initials: M
authors.lastname: Bobadilla
authors.affiliation: Division of Nephrology, Institute of Physiology, University of Zurich, CH-8006 Zürich, Switzerland.
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Cohen
authors.affiliation: Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Serena M
authors.initials: SM
authors.lastname: Bagnasco
authors.affiliation: Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Barisoni
authors.affiliation: Renal Division, Department of Internal Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing 100034, China.
authors.forename: Jicheng
authors.initials: J
authors.lastname: Lv
authors.affiliation: Renal Division, Department of Internal Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing 100034, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Renal Division, Department of Internal Medicine, Peking University First Hospital, Peking University Institute of Nephrology, Beijing 100034, China.
authors.forename: Hai-Yan
authors.initials: HY
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.|Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
authors.affiliation: Temple Clinical Research Institute, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Crystal A
authors.initials: CA
authors.lastname: Gadegbeku
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.|Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000652:urine; D001706:Biopsy; D002454:Cell Differentiation; D015331:Cohort Studies; D018450:Disease Progression; D004815:Epidermal Growth Factor / Q000652:urine*; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D011506:Proteins / Q000737:chemistry; D012038:Regeneration; D051436:Renal Insufficiency, Chronic / Q000175:diagnosis* / Q000652:urine; D059467:Transcriptome
chemical_list: D015415:Biomarkers; D011506:Proteins; D004815:Epidermal Growth Factor