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Rejection Associated Glomerular Lesions Part 2 M.J. Mihatsch, H. Hopfer, F. Gudat, V. Nickeleit
Material Collected over 40 years: 1968-2007
Kidney transplant biopsies (and other material): n= 7700* Biopsies ≥ 5 glomeruli and 1 artery n= 6980
Zero hour biopsies n=690Protocol biopsies or by local practice n= 750Indication biopsies n=4800Nephrectomies n= 470Autopsies n= 270
* Studied by LM, and whenever possible by IF (IHC) n=3800 and/or EM
Biopsies and Methods
• Introduction
• Prevalence of glomerular lesions
• Time to event
• Correlation with other morphological findings
• Glomerular lesions and C4d and/or HLA DR
• Glomerular Lesions and DSA
• Evolution and Regression
Rejection Associated Glomerular Lesions
Results
Overall Prevalence of Rejection-Related Glomerular Lesions (n=4800)
Prevalence
Tx-TMA n=143 3.0%
Tx-Gitis n=436 9.1%
Tx-Pathy n=325 6.8%
Total n=745 15.5%
Prevalence
Glomerular Lesions Per Decade
Decade Cases Tx-TMA Tx-Gitis Tx-Pathy
1968 - 1987 n=1183 5.5% 11.7% 9.8%
1988 - 1997 n=1487 3.2% 9.8% 4.6%
1998 - 2007 n=1509 1.3% 7.0% 3.6%
Chi-square test; for all lesions P<0.0001, % of raw, without biopsies > 8 years
Summary Prevalence
1. Rejection related glomerular lesions (Tx-TMA, Tx-Gitis, Tx-Pathy) decreased by about 50% over the last 40 years.
2. The overall prevalence is today about
10% of biopsies.
Prevalence
• Introduction
• Prevalence of glomerular lesions
• Time to event
• Correlation with other morphological findings
• Glomerular lesions and C4d and/or HLA DR
• Glomerular Lesions and DSA
• Evolution and Regression
Rejection Associated Glomerular Lesions
Results
Time to Event
Tx-glomerular Lesions and Time to Event
0 54321
transplantation to biopsy intervall (years)
100
80
60
40
20
0
Tx-Gitis
Tx-Pathy
Tx-TMA
Time to Event : Tx-Bx- Interval (Days)
Median-test: Lesion vs Control: P<0.0001
Time to Event
Cases 25 Quartile 50 Quartile 75 Quartile
Tx-TMA n= 136 15 32 56
Tx-Gitis n=417 25 84 965
Tx-Pathy n=316 410 1360 2810
Control Group n>4000 50 250 1175
Summary Time To Event
Rejection related glomerular lesions are preferentially found in the following time intervals after Tx:
• Tx-TMA within 30 days• Tx-Gitis within 90 days• Tx-Pathy after 3 to 4 years
But they may be found any time after Tx in individual cases.
Time to Event
Results
• Introduction
• Prevalence of glomerular lesions
• Time to event
• Correlation with other morphological findings
• Glomerular lesions and C4d and/or HLA DR
• Glomerular Lesions and DSA
• Evolution and Regression
Rejection Associated Glomerular Lesions
Tx-TMA Tx-Gitis Tx-Pathy No. of cases (n) 110 200 170 Tx-Bx Interval (days) 15-55 25-965 410-2810
Int.cellular Re. Borderline 71 vs 55% Grade I A/B 50 vs 23% Vascular Re.
With TMA 14 vs 2% Necrotizing vasculitis 29 vs 1% 8 vs 1% Endovasculitis: inf -prolif. 58 vs 12% 24 vs 14% Endovasulitis:sclerosing 40 vs 11% Glomerular Re TX-TMA 14 vs 2% Tx-Gitis 38 vs 8 % 40 vs 7% Tx-Pathy 14 vs 5 %
Correlation of Tx-Glomerular Lesions with other Morphological Findings (1)
Correlations
Tx-TMA Tx-Gitis Tx-Pathy No. of cases (n) 110 200 170 Tx-Bx Interval (days) 15-55 25-965 410-2810
Unspecific lesions Infarct 38 vs 3% 10 vs 4% Striped fibrosis 71 vs 57% Arteriolar hyalinosis 55 vs 32 % CIN-Arteriolopathy 47 vs 30 % FSGS 32 vs 10 %
Spearman rank correlation: only positive rho -values p<0.0001 and Chi-square test: p<0.0001. Prevalence in the test group vs control group Control group: >4000 cases, without the lesion in question
Correlation of Tx-Glomerular Lesions with other Morphological Findings (2)
Correlations
Summary Morphological Correlations
Correlations
Tx-TMA
Tx-Pathy
Tx-Gitis
Glomeruli
Re with TMA
Necrot. Vasculitis
Endo: inf.-prolif.
Endo.sclerosing
ArteriesTub.Int.-Space
Borderline
ICR:Grade1/2
Results
• Introduction
• Prevalence of glomerular lesions
• Time to event
• Correlation with other morphological findings
• Glomerular lesions and C4d and/or HLA DR
• Glomerular Lesions and DSA
• Evolution and Regression
Rejection Associated Glomerular Lesions
C4d/HLA-DR
Focal HLA-DR expression in ICR: Grade IA/B
C4d/HLA-DR
C4d in PTC Normal
C4d and HLA-DRn=1263
C4d positive only 9.4%HLA DR positive only 21.5%C4d and HLA DR positive 9.3%
C4d and HLA DR negative 59.8%
C4d/HLA-DR
HLA-DR positiveC4d negative
C4d positiveHLA DR negative
Statistics.
Cases (n=) 271 119Tx-Bx interval (med.) (days) 98 87 p=nsInt.Cellular ReBorderline 32% 65% p<0.0001Grade 1-2 63% 10% p<0.0001Vascular ReTMA 1% 3% p=nsNecrotizing vascultis 1% 0% p=nsEndovasculitis:inf-proliferative 20% 30% p=0.0091Endovasculitis: sclerosing 7% 16% p=nsGlomerular ReTx-TMA 1% 3% p=nsTx-glomerulitis 10% 19% p=0.0100Tx-glomerulopathy 2% 11% p=0.0002Chi square or Median test
C4d or HLA-DR Positive in Correlation with other Morphological Features
C4d/HLA-DR
Tx-TMA
Tx-Pathy
Tx-Gitis
Glomeruli
Re with TMA
Necrot. Vasculitis
Endo: inf.-prolif.
Endo.sclerosing
ArteriesTub.Int.-Space
Borderline
Grade I A/B
Summary Morphological Correlations including C4d and HLA DR
HLA-DR in tubules
C4d in PTC
C4d/HLA-DR
ICR: None
Results
• Introduction
• Prevalence of glomerular lesions
• Time to event
• Correlation with other morphological findings
• Glomerular lesions and C4d and/or HLA DR
• Glomerular Lesions and DSA
• Evolution and Regression
Rejection Associated Glomerular Lesions
Material: Biopsies and Patients from Basel1999-2007
Indication biopsies: n= 930 in 380 patients
DSA
Tx-Bx Interval: <30 days: 31%<90 days: 21%<180 days: 16%<360 days: 11%>360 days: 21%
• Anti-HLA-AB determined pre-transplant by Luminex single-antigen flow-beads in 585 patients (all virtual crossmatch negative) • Patients with Anti-HLA-AB determinations and C4d in 730 biopsies of 305 patients
DSA and C4d in PTC in Biopsies (n=737)
DSA* and C4d negative: 70%DSA positive and C4d negative: 15%DSA negative and C4d positive: 7% DSA positive and C4d positive: 8%
DSA
* Presence of donor specific HLA-AB
Correlation between DSA and C4d: • only in biopsies <180 days
No correlation at all for the following variables:• ICR: Borderline and Grade I A/B
Too few cases for the evaluation of the following variables:
• Tx-TMA• Tx-Pathy• VR: TMA/necrotizing vasculitis• VR: Sclerosing endovasculitis
DSA
Results Overview
Biopsies <30 days n=235
Biopsies 31 -180 days
n=285 DSA positive (n) 51 64 Tx-Gitis positive * 26 vs 8%
p = 0.0008 7 vs 5 % p = ns
Endovasculitis: inf-proliferative *
38 vs 16% p = 0.0006
17 vs 13 % P = ns
C4d in PTC * 45 vs 9% p <0.0001
27 vs 7% p < 0.0001
* in % of biopsies of DSA positive vs negative patients Chi square test
Association between DSA and Morphology
DSA
DSA and C4d Status in all biopsies (n= 737)
Chi -square test
c4d-dsa c4d-DSA C4d-dsa C4d-DSA Biopsies (%) 70 15 7 8 Tx-Gitis (positive in %)
5 10 25 30 p<0.0001
Tx-Path
1 2 6 7 p=0.008
Endovasculitis: Inf-proliferative
11 20 36 40 p<0.0001
Endovasculitis: sclerosing
6 11 15 18 p=0.0109
Association between DSA and C4d Status and Morphology
In % of biopsies of the different status groups
DSA
DSA and C4d Status in biopsies <180 days (n= 520)
Chi -square test
c4d-dsa c4d-DSA C4d-dsa C4d-DSA Biopsies (%) 72 14 6 8 Tx-Gitis (positive in %)
5 8 27 30 p<0.0001
Endovasculitis: Inf-proliferative
13 17 39 43 p<0.0001
Association between DSA and C4d Status and Morphology
In % of biopsies of the different status groups
DSA
Tx-TMA
Tx-Pathy
Tx-Gitis
Glomeruli
Re with TMA
Necrot. Vasculitis
Endo: inf.-prolif.
Endo.sclerosing
Arteries
C4d in PTC
Time to Event
Tx 25th to 75th
15 – 30 – 60 d
30 – 60 - 90 d
> 365 d
Summary Morphological Correlations including C4d and HLA DR
DSA
DSA (pre-transplant)
Results
• Introduction
• Prevalence of glomerular lesions
• Time to event
• Correlation with other morphological findings
• Glomerular lesions and C4d and/or HLA DR
• Glomerular Lesions and DSA
• Evolution and Regression
Rejection Associated Glomerular Lesions
Summary The Dynamics of C4d and Tx-Glomerular Lesions
• Morphological lesions may come and go
• C4d may come and go
• C4d preceeds Tx glomerular lesions (the contrary may also be found)
• Morphological lesions may persist after removal of C4d or vice versa
• Glomerular lesions without C4d ever! are very rare
Evolution
Take home message
• Tx-glomerular lesion are rare today (about 10% of biopsies)
• The prevalence decreased over the last 4 decades (by about 50%)
• Tx-glomerular lesions are typically associated with VR
• Tx-glomerular lesions are typically associated with C4d
• C4d negative cases ever are very rare
• Discrepancies between Tx-glomerular lesions and C4d may be explained by different “tempi” of evolution and regression (as well as other causes)
Evolution
ICRGrade I A/B
+ HLA-DR-C4d-DSA
= T-cell mediated rejection
DSA
Interstitial Cellular Rejection
Target cell:Tubular cell
DSA
Vascular and Glomerular Rejection
VR:TMA
Endovasculitis
Tx-TMATx-GitisTx-Path
+ C4d and DSA Humoral Rejection
Target cell:Endothelium
Plus cellularrejection
PD Dr. S.Schaub PD Dr.M.Dickenmann
Transplantation Immunology and Nephrology, University Hospital Basel
