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Molecular associations of IFTA . Michael Mengel Alberta Transplant Applied Genomics Centre University of Alberta, Edmonton Canada. Interstitial fibrosis and tubular atrophy (IFTA) in renal allografts. IFTA with inflammation. Issues with doing analysis for the causes / associates of IFTA.

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molecular associations of ifta

Molecular associations of IFTA

Michael Mengel

Alberta Transplant Applied Genomics Centre

University of Alberta, Edmonton Canada

issues with doing analysis for the causes associates of ifta
Issues with doing analysis for the causes / associates of IFTA
  • Most studies group comparisons “sick vs. well”, i.e. biopsies with moderate to severe IFTA are compared to normal biopsies without IFTA: starting with the extreme phenotypes
  • Cave! The first group generally has a lot of other pathologies while the others are really normal, thus it’s difficult to see whether the findings are related to IFTA or to a co-existing finding, e.g. interstitial inflammation or time post transplant
slide5

Example 1 of a “sick vs. well” studyTitle: “Molecular pathways involved in loss of kidney graft function with tubular atrophy and interstitial fibrosis.”

Mol Med. 2008 May-Jun;14(5-6):276-85.

scoring inflammation in renal allograft biopsies

100% Cortex

nodular

perivascular

absolute scoring

40% i-IFTA

10% i-Banff

5%

5%

3%

3%

subcapsular

25% = Banff i-score 1

“67% i-IFTA”

relative scoring

according to current Banff rules

40% non-scarred

compartment

60% IFTA compartment

Scoring inflammation in renal allograft biopsies
material and methods
Material and Methods
  • 129 biopsies for cause classified according to Banff ‘97
  • Semi-quantitative assessment as absolute percentages of:
    • i-Banff = inflammation in non scarred cortex
    • i-IFTA = inflammation in IFTA
    • nodular
    • perivascular
    • IFTA
  • Correlation of extent of histological lesions with gene expression data from microarrays and allograft survival
infiltrates in biopsies for cause are time dependent

3

months

27

months

8

months

79

months

246

months

Infiltrates in biopsies for cause are time dependent

129 biopsies ordered by time post TX

Mengel et al. Am J Transplant. 2009 Jan;9(1):169-78.

inflammation in fibrosis atrophy is associated with worse allograft survival

A

B

i <25%

+

i-Banff

i-IFTA

p<0.05

Inclusion criteria: IFTA >5%, i-Banff <25%

graft survival n

≥50% of fibrosis/atrophy show infiltrates 69.6% 46

<50% of fibrosis/atrophyshow infiltrates 93.5% 31

censored 77

biopsies with graft survival n

i-Banff >25%, i-IFTA <25% 69.2% 13

i-IFTA >25%, i-Banff <25% 60.0% 20

both <25% 88.7% 71

censored 104

+

Inflammation in fibrosis/atrophy is associated with worse allograft survival

uninflamed IFTA

inflamed IFTA

p=0.02

table 1 correlations between infiltrate types and pathogenesis based transcript sets pbts
Table 1: Correlations between Infiltrate types and Pathogenesis Based Transcript sets (PBTs)

# given is the highest r-value revealed for one PBT of each particular biological process

*Spearman correlation, p<0.001

correlations between individual genes and histological lesions
Correlations* between individual genes and histological lesions

484 probesets

249 probesets

202 probesets

172 probesets

34 probesets

Injury

Injury

Mac

B-cell

Mac

γ-IFN

γ-IFN

*r>0.4, p<0.001: no correlations between any genes and perivascular infiltrates at this cut-off

B-cell

B-cell

T-cell

T-cell

Injury

T-cell

Injury

figure 3 overlap in gene expression between infiltrate types

132

84 not annotated

26 B cell associated

15 Injury and Repair induced

3 cytotoxic T cell associated

3 Kidney parenchymal

1 Endothelial activation

IFTA

i-IFTA

40

70

Figure 3: Overlap in gene expression between infiltrate types

240

116 cytotoxic T cell associated

54 not annotated

39 γ-interferon dependent

14 Injury and Repair induced

17 macrophage associated

i-Banff

t-score

244

9

confirmation by immunohistochemistry
Confirmation by immunohistochemistry

p 0.006

i-Banff

i-IFTA

p 0.02

p 0.006

p 0.0004

p 0.05

mast cell associate transcript set macat
Mast cell associate transcript set (MACAT)

4 mast cell associated transcripts

  • CPA3 (Carboxypeptidase 3)
  • TPSB2 (Tryptase beta 2)
  • TPSAB1 ( Tryptase alpha-beta 1)
  • FCER1A (Fc fragment of IgE, high affinity I, receptor)
mast cell associated transcripts are a molecular correlate of ifta

p<0.0001

i-Banff

<25%, n=109

i-Banff

>25%, n=20

Mast cell associated transcripts are a molecular correlate of IFTA

Mast cell transcripts correlate with

time post TX: r=0.55, p <0.01

i-IFTA: r=0.63, p <0.01

IFTA: r=0.61, p <0.01

delta GFR: r= -0.35, p <0.0001

slide18

+

In biopsies with IFTA increased expression of Mast cell associated transcript is associated with worse allograft survival

low mast cell scores

p=0.01

high mast cell scores

Inclusion criteria: at least IFTA grade I

graft survival n

high* MACAT score 71.2% 29

low* MACATscore 96.6% 59

censored 88

*low = lowest tertile of MACAT score of the included 88 biopsies

*high = intermediate and highest tertile of MACAT score of the included 88 biopsies

summary ifta and infiltrates
Summary IFTA and infiltrates
  • There are two inflammatory compartments in renal allografts:
    • i-Banff (non-scarred):
      • time-independent, T-cell, γ-interferon, macrophage associated, prognostic relevant
    • i-IFTA (scarred):
      • time-dependent, T-cell, γ-interferon, macrophage + B-cell, mast cell associated, prognostic relevant
relationship between ifta and function in renal allografts biopsies for cause
Relationship between IFTA and function in renal allografts (biopsies for cause)

Kasiske et al. Kidney Int. 1991;40:514-524

slide22

Molecular correlates of eGFR at the time of biopsy

GFR transcript set

45

n = 144

40

35

n = 224

30

Annotation of probesets

(% of total of correlating probesets)

25

20

15

10

5

0

Negative Correlation

Positive Correlation

IMATs (Mactrophage activation)

IGTs (Plasma cell infiltration)

CISTs (severe injury)

GSTs (severe injury)

BATs (B cell infiltration)

GRIT1 (Ifng effects)

GRIT2 (Ifng effects)

KT1 (Parenchymal transcripts)

IRITD5 (Injury)

IRITD3 (Injury)

IRITD1 (Injury)

CMATs (Macrophage infiltration)

CATs (T cell infiltration)

Bunnang and Einecke et al. J Am Soc Nephrol. 2009 (5):1149-60

significant overlap between injury repair and ifta associated transcripts
Significant overlap between injury / repair / and IFTA associated transcripts

Am J Transplant. 2007 Nov;7(11):2483-95.

molecular changes in protocol biopsies background and hypothesis

Molecular changes in protocol biopsiesBackground and Hypothesis

early protocol biopsy

subclinical pathology =

harbinger of more severe, clinical overt, irreversible pathology

therapeutic intervention

 prevention of irreversible chronic allograft damage

assessment of the

subclinical molecular phenotype

of an allograft to further corroborate this hypothesis

no molecular evidence for emt in the onset of ifta in early protocol biopsies
No molecular evidence for EMT in the onset of IFTA in early protocol biopsies

J Am Soc Nephrol. 2008 Aug;19(8):1571-83.

slide27
Molecular associates of subclinical IFTA at 12-months in clinically uncomplicated living donor kidney transplants

Transplantation. 2007 Jun 15;83(11):1466-76

slide28
PBT-annotation of top 100 transcripts correlating* in 6-week protocol biopsies with future onset of IFTA in 6-month protocol biopsies

*Spearman correlation, p<0.001

pbt annotation of top 100 transcripts correlating with future end points in pb
PBT-annotation of top 100 transcripts correlating* with future end points in PB

*Spearman correlation, p<0.001

conclusions molecules and ifta
Conclusions: Molecules and IFTA
  • IFTA by histology is associated with inflammation and injury / repair molecules = sign of active/progressive IFTA or attempt to recovery?
  • Conclusion about cause for IFTA is yet not possible
  • Some molecular correlates (e.g. mast cells) might be used as a measurement for IFTA
  • More detailed resolution of the overall molecular disturbance might provide potential therapeutic targets for a non-cause specific anti IFTA treatment
outlook
Outlook
  • Test reproducibility for IF, TA, i-Banff, i-IFTA, and total i-score:
    • if feasible, reporting of the different inflammatory and morphological compartments might allow to design new clinical trials
    • i-Banff and i-IFTA might be amenable to different therapies
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