title: Unique Transcriptional Programs Identify Subtypes of AKI.
abstract: Two metrics, a rise in serum creatinine concentration and a decrease in urine output, are considered tantamount to the injury of the kidney tubule and the epithelial cells thereof (AKI). Yet neither criterion emphasizes the etiology or the pathogenetic heterogeneity of acute decreases in kidney excretory function. In fact, whether decreased excretory function due to contraction of the extracellular fluid volume (vAKI) or due to intrinsic kidney injury (iAKI) actually share pathogenesis and should be aggregated in the same diagnostic group remains an open question. To examine this possibility, we created mouse models of iAKI and vAKI that induced a similar increase in serum creatinine concentration. Using laser microdissection to isolate specific domains of the kidney, followed by RNA sequencing, we found that thousands of genes responded specifically to iAKI or to vAKI, but very few responded to both stimuli. In fact, the activated gene sets comprised different, functionally unrelated signal transduction pathways and were expressed in different regions of the kidney. Moreover, we identified distinctive gene expression patterns in human urine as potential biomarkers of either iAKI or vAKI, but not both. Hence, iAKI and vAKI are biologically unrelated, suggesting that molecular analysis should clarify our current definitions of acute changes in kidney excretory function.
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Katherine
authors.initials: K
authors.lastname: Xu
authors.affiliation: Pathology.
authors.forename: Paul
authors.initials: P
authors.lastname: Rosenstiel
authors.affiliation: Department of Medicine, Division of Nephrology, University of Washington, Seattle, Washington.
authors.forename: Neal
authors.initials: N
authors.lastname: Paragas
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Hinze
authors.affiliation: Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Gao
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Tian
authors.initials: T
authors.lastname: Huai Shen
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Max
authors.initials: M
authors.lastname: Werth
authors.affiliation: Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
authors.forename: Catherine
authors.initials: C
authors.lastname: Forster
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Rong
authors.initials: R
authors.lastname: Deng
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Efrat
authors.initials: E
authors.lastname: Bruck
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Roger W
authors.initials: RW
authors.lastname: Boles
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Tornato
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Tejashree
authors.initials: T
authors.lastname: Gopal
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Madison
authors.initials: M
authors.lastname: Jones
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Justin
authors.initials: J
authors.lastname: Konig
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Jacob
authors.initials: J
authors.lastname: Stauber
authors.affiliation: Pathology.
authors.forename: Vivette
authors.initials: V
authors.lastname: D'Agati
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, New York.
authors.forename: Hediye
authors.initials: H
authors.lastname: Erdjument-Bromage
authors.affiliation: Department of Medicine, State University of New York Downstate Medical Center, Brooklyn, New York.
authors.forename: Subodh
authors.initials: S
authors.lastname: Saggi
authors.affiliation: Anesthesiology, and.
authors.forename: Gebhard
authors.initials: G
authors.lastname: Wagener
authors.affiliation: Max Delbrück Center for Molecular Medicine, Berlin, Germany.
authors.forename: Kai M
authors.initials: KM
authors.lastname: Schmidt-Ott
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Tatonetti
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Paul
authors.initials: P
authors.lastname: Tempst
authors.affiliation: Departments of *Medicine, Division of Nephrology.
authors.forename: Juan A
authors.initials: JA
authors.lastname: Oliver
authors.affiliation: Systems Biology, Columbia University Medical Center, New York, New York; p.guarnieri@hotmail.com jmb4@columbia.edu.
authors.forename: Paolo
authors.initials: P
authors.lastname: Guarnieri
authors.affiliation: Departments of *Medicine, Division of Nephrology, p.guarnieri@hotmail.com jmb4@columbia.edu.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Barasch
mesh_terms: D058186:Acute Kidney Injury / Q000145:classification* / Q000235:genetics*; D000818:Animals; D005260:Female; D015870:Gene Expression; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D059467:Transcriptome
keywords: acute kidney injury; biomarkers; renal ischemia; transcriptional profiling; volume depletion