Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy

Diagnosis versus prediction

Mariano J. Scian, Daniel Maluf, Kellie J. Archer, Jihee L. Suh, David Massey, Ryan C. Fassnacht, Benjamin Whitehill, Amit Sharma, Anne King, Todd Gehr, Adrian Cotterell, Marc P. Posner, Valeria Mas

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Background. Loss of kidney graft function due to interstitial fibrosis (IF) and tubular atrophy (TA) is the most common cause of kidney allograft loss. Methods. One hundred one allograft tissues (26 samples with IF/TA, 17 normal allografts, and an independent biopsy group collected at 3 month [n=34] posttransplantation) underwent microarray analysis to identify early detection/diagnostic biomarkers of IF/TA. Profiling of 24 allograft biopsies collected at or after 9-month posttransplantation (range 9-18 months) was used for validation. Three-month posttransplantation biopsies were classified as IF/TA nonprogressors (group 1) or progressors (group 2) using graft function and histology at 9-month posttransplantation. Results. We identified 2223 differentially expressed probe sets between IF/TA and normal allograft biopsies using a Bonferroni correction. Genes up-regulated in IF/TA were primarily involved in pathways related to T-cell activation, natural killer cell-mediated cytotoxicity, and programmed cell death. A least absolute shrinkage and selection operator model was derived from the differentially expressed probe sets, resulting in a final model that included 10 probe sets and had 100% training set accuracy. The N-fold crossvalidated error was 2.4% (sensitivity 95.8% and specificity 100%). When 3-month biopsies were tested using the model, all the samples were classified as normal. However, evaluating gene expression of the 3-month biopsies and fitting a new penalized model, 100% sensitivity was observed in classifying the samples as group1 or 2. This model was evaluated in the sample set collected at or after 9-month posttransplantation. Conclusions. An IF/TA gene expression signature was identified, and it was useful for diagnosis but not prediction. However, gene expression profiles at 3 months might predict IF/TA progression.

Original languageEnglish (US)
Pages (from-to)657-665
Number of pages9
JournalTransplantation
Volume91
Issue number6
DOIs
StatePublished - Mar 27 2011
Externally publishedYes

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Atrophy
Fibrosis
Transplants
Kidney
Gene Expression
Allografts
Biopsy
Transcriptome
Microarray Analysis
Natural Killer Cells
Histology
Cell Death
Biomarkers
T-Lymphocytes
Sensitivity and Specificity
Genes

All Science Journal Classification (ASJC) codes

  • Transplantation

Cite this

Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy : Diagnosis versus prediction. / Scian, Mariano J.; Maluf, Daniel; Archer, Kellie J.; Suh, Jihee L.; Massey, David; Fassnacht, Ryan C.; Whitehill, Benjamin; Sharma, Amit; King, Anne; Gehr, Todd; Cotterell, Adrian; Posner, Marc P.; Mas, Valeria.

In: Transplantation, Vol. 91, No. 6, 27.03.2011, p. 657-665.

Research output: Contribution to journalArticle

Scian, MJ, Maluf, D, Archer, KJ, Suh, JL, Massey, D, Fassnacht, RC, Whitehill, B, Sharma, A, King, A, Gehr, T, Cotterell, A, Posner, MP & Mas, V 2011, 'Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy: Diagnosis versus prediction', Transplantation, vol. 91, no. 6, pp. 657-665. https://doi.org/10.1097/TP.0b013e3182094a5a
Scian, Mariano J. ; Maluf, Daniel ; Archer, Kellie J. ; Suh, Jihee L. ; Massey, David ; Fassnacht, Ryan C. ; Whitehill, Benjamin ; Sharma, Amit ; King, Anne ; Gehr, Todd ; Cotterell, Adrian ; Posner, Marc P. ; Mas, Valeria. / Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy : Diagnosis versus prediction. In: Transplantation. 2011 ; Vol. 91, No. 6. pp. 657-665.
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T1 - Gene expression changes are associated with loss of kidney graft function and interstitial fibrosis and tubular atrophy

T2 - Diagnosis versus prediction

AU - Scian, Mariano J.

AU - Maluf, Daniel

AU - Archer, Kellie J.

AU - Suh, Jihee L.

AU - Massey, David

AU - Fassnacht, Ryan C.

AU - Whitehill, Benjamin

AU - Sharma, Amit

AU - King, Anne

AU - Gehr, Todd

AU - Cotterell, Adrian

AU - Posner, Marc P.

AU - Mas, Valeria

PY - 2011/3/27

Y1 - 2011/3/27

N2 - Background. Loss of kidney graft function due to interstitial fibrosis (IF) and tubular atrophy (TA) is the most common cause of kidney allograft loss. Methods. One hundred one allograft tissues (26 samples with IF/TA, 17 normal allografts, and an independent biopsy group collected at 3 month [n=34] posttransplantation) underwent microarray analysis to identify early detection/diagnostic biomarkers of IF/TA. Profiling of 24 allograft biopsies collected at or after 9-month posttransplantation (range 9-18 months) was used for validation. Three-month posttransplantation biopsies were classified as IF/TA nonprogressors (group 1) or progressors (group 2) using graft function and histology at 9-month posttransplantation. Results. We identified 2223 differentially expressed probe sets between IF/TA and normal allograft biopsies using a Bonferroni correction. Genes up-regulated in IF/TA were primarily involved in pathways related to T-cell activation, natural killer cell-mediated cytotoxicity, and programmed cell death. A least absolute shrinkage and selection operator model was derived from the differentially expressed probe sets, resulting in a final model that included 10 probe sets and had 100% training set accuracy. The N-fold crossvalidated error was 2.4% (sensitivity 95.8% and specificity 100%). When 3-month biopsies were tested using the model, all the samples were classified as normal. However, evaluating gene expression of the 3-month biopsies and fitting a new penalized model, 100% sensitivity was observed in classifying the samples as group1 or 2. This model was evaluated in the sample set collected at or after 9-month posttransplantation. Conclusions. An IF/TA gene expression signature was identified, and it was useful for diagnosis but not prediction. However, gene expression profiles at 3 months might predict IF/TA progression.

AB - Background. Loss of kidney graft function due to interstitial fibrosis (IF) and tubular atrophy (TA) is the most common cause of kidney allograft loss. Methods. One hundred one allograft tissues (26 samples with IF/TA, 17 normal allografts, and an independent biopsy group collected at 3 month [n=34] posttransplantation) underwent microarray analysis to identify early detection/diagnostic biomarkers of IF/TA. Profiling of 24 allograft biopsies collected at or after 9-month posttransplantation (range 9-18 months) was used for validation. Three-month posttransplantation biopsies were classified as IF/TA nonprogressors (group 1) or progressors (group 2) using graft function and histology at 9-month posttransplantation. Results. We identified 2223 differentially expressed probe sets between IF/TA and normal allograft biopsies using a Bonferroni correction. Genes up-regulated in IF/TA were primarily involved in pathways related to T-cell activation, natural killer cell-mediated cytotoxicity, and programmed cell death. A least absolute shrinkage and selection operator model was derived from the differentially expressed probe sets, resulting in a final model that included 10 probe sets and had 100% training set accuracy. The N-fold crossvalidated error was 2.4% (sensitivity 95.8% and specificity 100%). When 3-month biopsies were tested using the model, all the samples were classified as normal. However, evaluating gene expression of the 3-month biopsies and fitting a new penalized model, 100% sensitivity was observed in classifying the samples as group1 or 2. This model was evaluated in the sample set collected at or after 9-month posttransplantation. Conclusions. An IF/TA gene expression signature was identified, and it was useful for diagnosis but not prediction. However, gene expression profiles at 3 months might predict IF/TA progression.

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