title: RNA Sequencing Identifies Novel Translational Biomarkers of Kidney Fibrosis.
abstract: CKD is the gradual, asymptomatic loss of kidney function, but current tests only identify CKD when significant loss has already happened. Several potential biomarkers of CKD have been reported, but none have been approved for preclinical or clinical use. Using RNA sequencing in a mouse model of folic acid-induced nephropathy, we identified ten genes that track kidney fibrosis development, the common pathologic finding in patients with CKD. The gene expression of all ten candidates was confirmed to be significantly higher (approximately ten- to 150-fold) in three well established, mechanistically distinct mouse models of kidney fibrosis than in models of nonfibrotic AKI. Protein expression of these genes was also high in the folic acid model and in patients with biopsy-proven kidney fibrosis. mRNA expression of the ten genes increased with increasing severity of kidney fibrosis, decreased in response to therapeutic intervention, and increased only modestly (approximately two- to five-fold) with liver fibrosis in mice and humans, demonstrating specificity for kidney fibrosis. Using targeted selected reaction monitoring mass spectrometry, we detected three of the ten candidates in human urine: cadherin 11 (CDH11), macrophage mannose receptor C1 (MRC1), and phospholipid transfer protein (PLTP). Furthermore, urinary levels of each of these three proteins distinguished patients with CKD (n=53) from healthy individuals (n=53; P<0.05). In summary, we report the identification of urinary CDH11, MRC1, and PLTP as novel noninvasive biomarkers of CKD.
authors.affiliation: Renal Division, Department of Medicine and.
authors.forename: Florin L
authors.initials: FL
authors.lastname: Craciun
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Vanesa
authors.initials: V
authors.lastname: Bijol
authors.affiliation: Renal Division, Department of Medicine and.
authors.forename: Amrendra K
authors.initials: AK
authors.lastname: Ajay
authors.affiliation: Renal Division, Department of Medicine and.
authors.forename: Poornima
authors.initials: P
authors.lastname: Rao
authors.affiliation: Renal Division, Department of Medicine and.
authors.forename: Ramya K
authors.initials: RK
authors.lastname: Kumar
authors.affiliation: Department of Biostatistics and.
authors.forename: John
authors.initials: J
authors.lastname: Hutchinson
authors.affiliation: Department of Biostatistics and.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hofmann
authors.affiliation: Department of Pathology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan;
authors.forename: Nikita
authors.initials: N
authors.lastname: Joshi
authors.affiliation: Department of Pathology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan;
authors.forename: James P
authors.initials: JP
authors.lastname: Luyendyk
authors.affiliation: Institute for Systems Biology, Seattle, Washington;
authors.forename: Ulrike
authors.initials: U
authors.lastname: Kusebauch
authors.affiliation: Institute for Systems Biology, Seattle, Washington;
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Moss
authors.affiliation: Renal Division, Department of Medicine and.
authors.forename: Anand
authors.initials: A
authors.lastname: Srivastava
authors.affiliation: Kidney Research Institute, University of Washington, Seattle, Washington; and.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Himmelfarb
authors.affiliation: Renal Division, Department of Medicine and.
authors.forename: Sushrut S
authors.initials: SS
authors.lastname: Waikar
authors.affiliation: Institute for Systems Biology, Seattle, Washington;
authors.forename: Robert L
authors.initials: RL
authors.lastname: Moritz
authors.affiliation: Renal Division, Department of Medicine and Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts; Harvard Program in Therapeutic Sciences, Harvard Medical School, Boston, Massachusetts vvaidya@bwh.harvard.edu.
authors.forename: Vishal S
authors.initials: VS
authors.lastname: Vaidya
mesh_terms: D000818:Animals; D005355:Fibrosis / Q000235:genetics; D005819:Genetic Markers; D006801:Humans; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000235:genetics*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D014176:Protein Biosynthesis; D017423:Sequence Analysis, RNA
chemical_list: D005819:Genetic Markers
keywords: CKD; fibrosis; transcriptional profiling