Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies

Laura H. Mariani, Sebastian Martini, Laura Barisoni-Thomas, Pietro A. Canetta, Jonathan P. Troost, Jeffrey B. Hodgin, Matthew Palmer, Avi Z. Rosenberg, Kevin V. Lemley, Hui Ping Chien, Jarcy Zee, Abigail Smith, Gerald B. Appel, Howard Trachtman, Stephen M. Hewitt, Matthias Kretzler, Serena M. Bagnasco

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)310-318
Number of pages9
JournalNephrology Dialysis Transplantation
Volume33
Issue number2
DOIs
StatePublished - Feb 1 2018

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Fibrosis
Kidney
Biopsy
Atrophy
Glomerular Filtration Rate
Inflammation
Lipoid Nephrosis
Focal Segmental Glomerulosclerosis
Membranous Glomerulonephritis
Antigen Presentation
Nephrotic Syndrome
Proteinuria
Proportional Hazards Models
Transforming Growth Factor beta
Immunoglobulin A
Interferon-gamma
Chronic Kidney Failure
Disease Progression
Tumor Necrosis Factor-alpha
Gene Expression

Keywords

  • gene expression
  • interstitial fibrosis
  • kidney biopsy
  • proteinuria

ASJC Scopus subject areas

  • Nephrology
  • Transplantation

Cite this

Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies. / Mariani, Laura H.; Martini, Sebastian; Barisoni-Thomas, Laura; Canetta, Pietro A.; Troost, Jonathan P.; Hodgin, Jeffrey B.; Palmer, Matthew; Rosenberg, Avi Z.; Lemley, Kevin V.; Chien, Hui Ping; Zee, Jarcy; Smith, Abigail; Appel, Gerald B.; Trachtman, Howard; Hewitt, Stephen M.; Kretzler, Matthias; Bagnasco, Serena M.

In: Nephrology Dialysis Transplantation, Vol. 33, No. 2, 01.02.2018, p. 310-318.

Research output: Contribution to journalArticle

Mariani, LH, Martini, S, Barisoni-Thomas, L, Canetta, PA, Troost, JP, Hodgin, JB, Palmer, M, Rosenberg, AZ, Lemley, KV, Chien, HP, Zee, J, Smith, A, Appel, GB, Trachtman, H, Hewitt, SM, Kretzler, M & Bagnasco, SM 2018, 'Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies', Nephrology Dialysis Transplantation, vol. 33, no. 2, pp. 310-318. https://doi.org/10.1093/ndt/gfw443
Mariani, Laura H. ; Martini, Sebastian ; Barisoni-Thomas, Laura ; Canetta, Pietro A. ; Troost, Jonathan P. ; Hodgin, Jeffrey B. ; Palmer, Matthew ; Rosenberg, Avi Z. ; Lemley, Kevin V. ; Chien, Hui Ping ; Zee, Jarcy ; Smith, Abigail ; Appel, Gerald B. ; Trachtman, Howard ; Hewitt, Stephen M. ; Kretzler, Matthias ; Bagnasco, Serena M. / Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies. In: Nephrology Dialysis Transplantation. 2018 ; Vol. 33, No. 2. pp. 310-318.
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abstract = "Background 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. Methods 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. Results 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. Conclusions 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.",
keywords = "gene expression, interstitial fibrosis, kidney biopsy, proteinuria",
author = "Mariani, {Laura H.} and Sebastian Martini and Laura Barisoni-Thomas and Canetta, {Pietro A.} and Troost, {Jonathan P.} and Hodgin, {Jeffrey B.} and Matthew Palmer and Rosenberg, {Avi Z.} and Lemley, {Kevin V.} and Chien, {Hui Ping} and Jarcy Zee and Abigail Smith and Appel, {Gerald B.} and Howard Trachtman and Hewitt, {Stephen M.} and Matthias Kretzler and Bagnasco, {Serena M.}",
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T1 - Interstitial fibrosis scored on whole-slide digital imaging of kidney biopsies is a predictor of outcome in proteinuric glomerulopathies

AU - Mariani, Laura H.

AU - Martini, Sebastian

AU - Barisoni-Thomas, Laura

AU - Canetta, Pietro A.

AU - Troost, Jonathan P.

AU - Hodgin, Jeffrey B.

AU - Palmer, Matthew

AU - Rosenberg, Avi Z.

AU - Lemley, Kevin V.

AU - Chien, Hui Ping

AU - Zee, Jarcy

AU - Smith, Abigail

AU - Appel, Gerald B.

AU - Trachtman, Howard

AU - Hewitt, Stephen M.

AU - Kretzler, Matthias

AU - Bagnasco, Serena M.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Background 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. Methods 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. Results 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. Conclusions 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.

AB - Background 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. Methods 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. Results 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. Conclusions 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.

KW - gene expression

KW - interstitial fibrosis

KW - kidney biopsy

KW - proteinuria

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