Tissue transglutaminase: a mediator and predictor of chronic allograft nephropathy?

Timothy S. Johnson, Hamdy Abo-Zenah, James N. Skill, Samantha Bex, Graham Wild, Colin B. Brown, Martin Griffin, A. Meguid El Nahas

Research output: Contribution to journalArticle

Abstract

Background. The precise mechanisms underlying the development of chronic allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain. The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been implicated in renal fibrosis.
Methods. We investigated the involvement of tTg and its crosslink product, [epsilon]-([gamma]-glutamyl) lysine, in 23 human kidney allografts during the early posttransplantation period and related these to changes of CAN that developed in 8 of them. Sequential biopsies were investigated using immunohistochemical, immunofluorescence, and in situ enzyme activity techniques.
Results. From implantation, tTg (+266%) and [epsilon]-([gamma]-glutamyl) lysine crosslink (+256.3%) staining increased significantly (P <0.001) in a first renal biopsy performed within 3 months from transplantation. This was paralleled by elevated tTg in situ activity. The eight patients who developed CAN had further increases in immunostainable tTg (+197.2%, P <0.001) and [epsilon]-([gamma]-glutamyl) lysine bonds (+465%, P <0.01) that correlated with interstitial fibrosis (r=0.843, P =0.009 and r=0.622, P =0.05, respectively). The staining for both was predominantly located within the mesangium and the renal interstitium. Both implantation and first biopsies showed tTg and [epsilon]-([gamma]-glutamyl) lysine crosslinking levels in patients who developed CAN to be twice the levels of those with stable renal function. Cox regression analysis suggested the intensity of the early tTg staining was a better predictor of inferior allograft survival that other histologic markers (hazard ratio=4.48, P =0.04).
Conclusions. tTg and [epsilon]-([gamma]-glutamyl) lysine crosslink correlated with the initiation and progression of scarring on sequential biopsies from renal-allograft recipients who experienced CAN. Elevated tTg may offer an early predictor of the development of CAN, whereas tTg manipulation may be an attractive therapeutic target
Original languageEnglish
Pages (from-to)1667-1675
Number of pages9
JournalTransplantation
Volume77
Issue number11
DOIs
Publication statusPublished - 15 Jun 2004

Fingerprint

Allografts
Kidney
Biopsy
Fibrosis
Staining and Labeling
transglutaminase 2
Enzymes
Cicatrix
Fluorescent Antibody Technique
Transplantation
Regression Analysis
epsilon-(gamma-glutamyl)-lysine

Keywords

  • homologous transplantation
  • chronic disease
  • dipeptides
  • extracellular fluid
  • transglutaminases
  • GTP-binding proteins
  • tissue distribution
  • immunologic techniques
  • kidney
  • kidney diseases
  • Kidney Transplantation
  • staining and labeling
  • treatment outcome
  • postoperative period
  • prognosis
  • solubility

Cite this

Johnson, T. S., Abo-Zenah, H., Skill, J. N., Bex, S., Wild, G., Brown, C. B., ... El Nahas, A. M. (2004). Tissue transglutaminase: a mediator and predictor of chronic allograft nephropathy? Transplantation, 77(11), 1667-1675. https://doi.org/10.1097/01.TP.0000131171.67671.3C
Johnson, Timothy S. ; Abo-Zenah, Hamdy ; Skill, James N. ; Bex, Samantha ; Wild, Graham ; Brown, Colin B. ; Griffin, Martin ; El Nahas, A. Meguid. / Tissue transglutaminase : a mediator and predictor of chronic allograft nephropathy?. In: Transplantation. 2004 ; Vol. 77, No. 11. pp. 1667-1675.
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title = "Tissue transglutaminase: a mediator and predictor of chronic allograft nephropathy?",
abstract = "Background. The precise mechanisms underlying the development of chronic allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain. The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been implicated in renal fibrosis.Methods. We investigated the involvement of tTg and its crosslink product, [epsilon]-([gamma]-glutamyl) lysine, in 23 human kidney allografts during the early posttransplantation period and related these to changes of CAN that developed in 8 of them. Sequential biopsies were investigated using immunohistochemical, immunofluorescence, and in situ enzyme activity techniques.Results. From implantation, tTg (+266{\%}) and [epsilon]-([gamma]-glutamyl) lysine crosslink (+256.3{\%}) staining increased significantly (P <0.001) in a first renal biopsy performed within 3 months from transplantation. This was paralleled by elevated tTg in situ activity. The eight patients who developed CAN had further increases in immunostainable tTg (+197.2{\%}, P <0.001) and [epsilon]-([gamma]-glutamyl) lysine bonds (+465{\%}, P <0.01) that correlated with interstitial fibrosis (r=0.843, P =0.009 and r=0.622, P =0.05, respectively). The staining for both was predominantly located within the mesangium and the renal interstitium. Both implantation and first biopsies showed tTg and [epsilon]-([gamma]-glutamyl) lysine crosslinking levels in patients who developed CAN to be twice the levels of those with stable renal function. Cox regression analysis suggested the intensity of the early tTg staining was a better predictor of inferior allograft survival that other histologic markers (hazard ratio=4.48, P =0.04).Conclusions. tTg and [epsilon]-([gamma]-glutamyl) lysine crosslink correlated with the initiation and progression of scarring on sequential biopsies from renal-allograft recipients who experienced CAN. Elevated tTg may offer an early predictor of the development of CAN, whereas tTg manipulation may be an attractive therapeutic target",
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Johnson, TS, Abo-Zenah, H, Skill, JN, Bex, S, Wild, G, Brown, CB, Griffin, M & El Nahas, AM 2004, 'Tissue transglutaminase: a mediator and predictor of chronic allograft nephropathy?', Transplantation, vol. 77, no. 11, pp. 1667-1675. https://doi.org/10.1097/01.TP.0000131171.67671.3C

Tissue transglutaminase : a mediator and predictor of chronic allograft nephropathy? / Johnson, Timothy S.; Abo-Zenah, Hamdy; Skill, James N.; Bex, Samantha; Wild, Graham; Brown, Colin B.; Griffin, Martin; El Nahas, A. Meguid.

In: Transplantation, Vol. 77, No. 11, 15.06.2004, p. 1667-1675.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tissue transglutaminase

T2 - a mediator and predictor of chronic allograft nephropathy?

AU - Johnson, Timothy S.

AU - Abo-Zenah, Hamdy

AU - Skill, James N.

AU - Bex, Samantha

AU - Wild, Graham

AU - Brown, Colin B.

AU - Griffin, Martin

AU - El Nahas, A. Meguid

N1 - MEDLINE® is the source for the MeSH terms of this document.

PY - 2004/6/15

Y1 - 2004/6/15

N2 - Background. The precise mechanisms underlying the development of chronic allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain. The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been implicated in renal fibrosis.Methods. We investigated the involvement of tTg and its crosslink product, [epsilon]-([gamma]-glutamyl) lysine, in 23 human kidney allografts during the early posttransplantation period and related these to changes of CAN that developed in 8 of them. Sequential biopsies were investigated using immunohistochemical, immunofluorescence, and in situ enzyme activity techniques.Results. From implantation, tTg (+266%) and [epsilon]-([gamma]-glutamyl) lysine crosslink (+256.3%) staining increased significantly (P <0.001) in a first renal biopsy performed within 3 months from transplantation. This was paralleled by elevated tTg in situ activity. The eight patients who developed CAN had further increases in immunostainable tTg (+197.2%, P <0.001) and [epsilon]-([gamma]-glutamyl) lysine bonds (+465%, P <0.01) that correlated with interstitial fibrosis (r=0.843, P =0.009 and r=0.622, P =0.05, respectively). The staining for both was predominantly located within the mesangium and the renal interstitium. Both implantation and first biopsies showed tTg and [epsilon]-([gamma]-glutamyl) lysine crosslinking levels in patients who developed CAN to be twice the levels of those with stable renal function. Cox regression analysis suggested the intensity of the early tTg staining was a better predictor of inferior allograft survival that other histologic markers (hazard ratio=4.48, P =0.04).Conclusions. tTg and [epsilon]-([gamma]-glutamyl) lysine crosslink correlated with the initiation and progression of scarring on sequential biopsies from renal-allograft recipients who experienced CAN. Elevated tTg may offer an early predictor of the development of CAN, whereas tTg manipulation may be an attractive therapeutic target

AB - Background. The precise mechanisms underlying the development of chronic allograft nephropathy (CAN) and the associated renal fibrosis remain uncertain. The protein-crosslinking enzyme, tissue transglutaminase (tTg), has recently been implicated in renal fibrosis.Methods. We investigated the involvement of tTg and its crosslink product, [epsilon]-([gamma]-glutamyl) lysine, in 23 human kidney allografts during the early posttransplantation period and related these to changes of CAN that developed in 8 of them. Sequential biopsies were investigated using immunohistochemical, immunofluorescence, and in situ enzyme activity techniques.Results. From implantation, tTg (+266%) and [epsilon]-([gamma]-glutamyl) lysine crosslink (+256.3%) staining increased significantly (P <0.001) in a first renal biopsy performed within 3 months from transplantation. This was paralleled by elevated tTg in situ activity. The eight patients who developed CAN had further increases in immunostainable tTg (+197.2%, P <0.001) and [epsilon]-([gamma]-glutamyl) lysine bonds (+465%, P <0.01) that correlated with interstitial fibrosis (r=0.843, P =0.009 and r=0.622, P =0.05, respectively). The staining for both was predominantly located within the mesangium and the renal interstitium. Both implantation and first biopsies showed tTg and [epsilon]-([gamma]-glutamyl) lysine crosslinking levels in patients who developed CAN to be twice the levels of those with stable renal function. Cox regression analysis suggested the intensity of the early tTg staining was a better predictor of inferior allograft survival that other histologic markers (hazard ratio=4.48, P =0.04).Conclusions. tTg and [epsilon]-([gamma]-glutamyl) lysine crosslink correlated with the initiation and progression of scarring on sequential biopsies from renal-allograft recipients who experienced CAN. Elevated tTg may offer an early predictor of the development of CAN, whereas tTg manipulation may be an attractive therapeutic target

KW - homologous transplantation

KW - chronic disease

KW - dipeptides

KW - extracellular fluid

KW - transglutaminases

KW - GTP-binding proteins

KW - tissue distribution

KW - immunologic techniques

KW - kidney

KW - kidney diseases

KW - Kidney Transplantation

KW - staining and labeling

KW - treatment outcome

KW - postoperative period

KW - prognosis

KW - solubility

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UR - http://journals.lww.com/transplantjournal/pages/articleviewer.aspx?year=2004&issue=06150&article=00009&type=abstract

U2 - 10.1097/01.TP.0000131171.67671.3C

DO - 10.1097/01.TP.0000131171.67671.3C

M3 - Article

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SP - 1667

EP - 1675

JO - Transplantation

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SN - 0041-1337

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Johnson TS, Abo-Zenah H, Skill JN, Bex S, Wild G, Brown CB et al. Tissue transglutaminase: a mediator and predictor of chronic allograft nephropathy? Transplantation. 2004 Jun 15;77(11):1667-1675. https://doi.org/10.1097/01.TP.0000131171.67671.3C