Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies.
Interstitial fibrosis (IF), tubular atrophy (TA) and interstitial inflammation (II) are known determinants of progression of renal disease. Standardized quantification of these features could add value to current classification of glomerulopathies.



We studied 315 participants in the Nephrotic Syndrome Study Network (NEPTUNE) study, including biopsy-proven minimal change disease (MCD = 98), focal segmental glomerulosclerosis (FSGS = 121), membranous nephropathy (MN = 59) and IgA nephropathy (IgAN = 37). Cortical IF, TA and II were quantified (%) on digitized whole-slide biopsy images, by five pathologists with high inter-reader agreement (intra-class correlation coefficient >0.8). Tubulointerstitial messenger RNA expression was measured in a subset of patients. Multivariable Cox proportional hazards models were fit to assess association of IF with the composite of 40% decline in estimated glomerular filtration rate (eGFR) and end-stage renal disease (ESRD) and separately as well, and with complete remission (CR) of proteinuria.



IF was highly correlated with TA (P < 0.001) and II (P < 0.001). Median IF varied by diagnosis: FSGS 17, IgAN 21, MN 7, MCD 1 (P < 0.001). IF was strongly correlated with baseline eGFR (P < 0.001) and proteinuria (P = 0.002). After adjusting for clinical pathologic diagnosis, age, race, global glomerulosclerosis, baseline proteinuria, eGFR and medications, each 10% increase in IF was associated with a hazard ratio of 1.29 (P < 0.03) for ESRD/40% eGFR decline, but was not significantly associated with CR. A total of 981 genes were significantly correlated with IF (|r| > 0.4, false discovery rate (FDR) < 0.01), including upstream regulators such as tumor necrosis factor, interferon gamma (IFN-gamma), and transforming growth factor beta 1 (TGF-B1), and signaling pathways for antigen presentation and hepatic fibrosis.



The degree of IF is associated with risk of eGFR decline across different types of proteinuric glomerulopathy, correlates with inflammatory and fibrotic gene expression, and may have predictive value in assessing risk of progression.
University of Michigan, Ann-Arbor, MI, USA.
Laura H
LH
Mariani
University of Michigan, Ann-Arbor, MI, USA.
Sebastian
S
Martini
University of Miami, Miami, FL, USA.
Laura
L
Barisoni
Columbia University, New York, NY, USA.
Pietro A
PA
Canetta
University of Michigan, Ann-Arbor, MI, USA.
Jonathan P
JP
Troost
University of Michigan, Ann-Arbor, MI, USA.
Jeffrey B
JB
Hodgin
University of Pennsylvania, Philadelphia, PA, USA.
Matthew
M
Palmer
Johns Hopkins University, Baltimore, MD, USA.
Avi Z
AZ
Rosenberg
Children's Hospital, Los Angeles, CA, USA.
Kevin V
KV
Lemley
Johns Hopkins University, Baltimore, MD, USA.
Hui-Ping
HP
Chien
Arbor Research Collaborative for Health, Ann Arbor, MI, USA.
Jarcy
J
Zee
Arbor Research Collaborative for Health, Ann Arbor, MI, USA.
Abigail
A
Smith
Columbia University, New York, NY, USA.
Gerald B
GB
Appel
New York University, New York, NY, USA.
Howard
H
Trachtman
National Institutes of Health, Bethesda, MD, USA.
Stephen M
SM
Hewitt
University of Michigan, Ann-Arbor, MI, USA.
Matthias
M
Kretzler
Johns Hopkins University, Baltimore, MD, USA.
Serena M
SM
Bagnasco
D000328:Adult; D001706:Biopsy; D003952:Diagnostic Imaging / Q000379:methods*; D018450:Disease Progression; D005260:Female; D005355:Fibrosis / Q000000981:diagnostic imaging / Q000473:pathology*; D005919:Glomerular Filtration Rate; D005921:Glomerulonephritis / Q000175:diagnosis* / Q000601:surgery; D006801:Humans; D008297:Male; D009395:Nephritis, Interstitial / Q000000981:diagnostic imaging / Q000473:pathology*; D010338:Pathology, Clinical / Q000379:methods*; D011379:Prognosis; D011507:Proteinuria / Q000175:diagnosis* / Q000601:surgery; D015996:Survival Rate; D055815:Young Adult
gene expression; interstitial fibrosis; kidney biopsy; proteinuria