C4d staining and morphology in
protocol biopsies
Michael Mengel*
For the ESPRIT-Group
European Study Group For Protocol Biopsies In Renal
Transplantation
*Disclosure: M.M. received travel grants form Wyeth and Roche
Multicentric Study• 3 European TX-Centers• Protocol- und Indication Bx• Classification according up-dated Banff • unstained paraffin slides from all centers• C4d positive > 25% of PTC stained
– 25-50% focal positive– >50% diffuse positive
• C4d negative < 25% of PTC stained• correlation with morphological and clinical
parameters
Incidence of C4dTX-center
type of biopsy Bxn Bx C4d (%)
>50%PTCC4d (%)
25-50%PTCC4d (%)negative
center 1indication Bx
48 5 (10.4) 7 (14.6) 36 (75.0)
center 2indication Bx
99 15 (15.2) 8 (8.1) 76 (76.7)
center 3indication Bx
230 26 (11.3) 17 (7.4) 187 (81.3)
total indication Bx 377 46 (12.2) 32 (8.5) 299 (79.3)
center 1protocol Bx
128 1 (0.8) 2 (1.6) 125 (97.6)
center 2protocol Bx
94 6 (6.4) 4 (4.3) 84 (89.3)
center 3protocol Bx
329 4 (1.2) 7 (2.1) 318 (96.7)
total protocol Bx 551 11 (2.0) 13 (2.4) 527 (95.6)
total 928 57 (6.1) 45 (4.8) 826 (89.1)
Inzidence of C4d
10,414,6
75,0
0,8 1,6
97,6
15,2
8,1
76,7
6,4 4,3
89,3
11,37,4
81,3
1,2 2,1
96,7
0,0
10,0
20,0
30,0
40,0
50,0
60,0
70,0
80,0
90,0
100,0
C4d diffusepositive
Indication
C4d focalpositive
Indication
C4dnegative
Indication
C4d diffusepositiveProtocol
C4d focalpositiveProtocol
C4dnegativeProtocol
C4d stain
% o
f ca
ses
center 1
center 2
center 3
Indication biopsies: C4d clinico-pathological correlationclinic C4d (%)
>50%PTCC4d (%)25-50%
C4d (%)<25%
univariatep value
multivariatep value
Sex(%females) 24 (52.2) 12 (37.5) 106 (35.5) ns ns
recipient age >60 years 6 (13.0) 4 (12.5) 46 (15.4) ns ns
Bx < 3 months after TX 34 (73.9) 17 (53.1) 202 (67.6) ns ns
prior cellular rejection to Bx 6 (13.0) 8 (25.0) 51 (17.1) ns ns
no induction therapy 3 (23.1) 5 (33.3) 49 (40.8) ns ns
induction therapy with anti-IL2 6 (46.2) 6 (40.0) 56 (46.7) ns ns
induction therapy with ATG/OKT 4 (30.8) 4 (26.7) 15 (12.5) ns ns
prior TX 11 (32.4) 7 (23.3) 37 (14.5) 0.02 ns
PRA >30% 12 (26.1) 5 (15.6) 22 (7.4) <0.0001 0.02
morphologyno cellular rejection 8 (24.2) 11 (36.7) 107 (43.1) ns ns
borderline 7 (21.2) 4 (13.3) 44 (17.7) ns ns
cellular tubular interstitial rejection (Banff IA+IB)
7 (21.2) 9 (30.0) 54 (21.8) ns ns
cellular vascular rejection(Banff IIA+IIB)
10 (30.3) 6 (20.0) 40 (16.1) ns ns
vascular rejection(Banff III)
1 (3.0) 0 3 (1.2) ns ns
ptc inflammation 42 (91.3) 20 (62.5) 123 (41.3) <0.0001 <0.0001
glomerular inflammation 24 (53.3) 7 (22.6) 50 (16.8) <0.0001 ns
acute tubular damage 42 (91.3) 25 (78.1) 158 (53.0) <0.0001 ns
glomerular thrombosis 1 (2.2) 1 (3.1) 6 (2.6) ns ns
arteriolar necrosis 1 (2.2) 0 5 (1.7) ns ns
protocol biopsies: C4d clinico-pathological correlation
clinic C4d (%)>50%PTC
C4d (%)25-50%
C4d (%)<25%
univariatep value
multivariatep value
Sex(%females) 3 (37.5) 1 (10.0) 190 (40.3) ns ns
recipient age >60 years 6 (13.0) 4 (12.5) 46 (15.4) ns ns
Bx < 3 months after TX 3 (27.3) 4 (30.8) 219 (41.6) ns ns
prior cellular rejection to Bx 2 (25.0) 2 (20.0) 98 (20.2) ns ns
no induction therapy 3 (60.0) 2 (22.2) 96 (22.0) ns ns
induction therapy with anti-IL2 2 (40.0) 7 (77.8) 281 (64.3) ns ns
induction therapy with ATG/OKT 0 0 60 (13.7) ns ns
prior TX 4 (80.6) 1 (11.1) 53 (12.4) <0.0001 ns
PRA >30% 1 (12.5) 1 (10.0) 26 (5.5) ns ns
morphologyno cellular rejection 6 (60.0) 7 (63.6) 286 (71.7) ns ns
borderline 3 (30.0) 3 (27.3) 89 (22.3) ns ns
cellular tubular interstitial rejection (Banff IA+IB)
1 (10.0) 1 (9.1) 23 (5.8) ns ns
cellular vascular rejection(Banff IIA+IIB)
0 0 1 (0.3) ns ns
vascular rejection(Banff III)
0 0 0 - ns
ptc inflammation 6 (85.7) 3 (37.5) 12 (3.3) <0.0001 <0.0001
glomerular inflammation 2 (28.6) 2 (25.0) 10 (2.8) <0.0001 ns
acute tubular damage 4 (57.1) 3 (37.5) 157 (43.5) ns ns
glomerular thrombosis 0 0 0 - ns
arteriolar necrosis 0 0 0 - ns
30 60 90 120 150
Time of survival in months
0,0
0,2
0,4
0,6
0,8
1,0
Gra
ft S
urv
ival
C4dC4d negative
C4d positive
C4d negative-censored
C4d positive-censored
Kaplan Meier Analysis
24 C4d+ protocol Bx
matched with
72 C4d- protocol Bx
for: Age, Sex, time point of Bx, Banff grade
F.R., male, born 1944Renal-Transplantation 31.08.01
Analgesic nephropathy, stone kidneys
Hemodialysis 11/1988
1. Transplantation 5/1990
Transplant failure 1/1999 with CAN
2. Transplantation 8/2001
Relapsing peptic ulcers (bleeding), Hypertension (4
antihypertensive drugs), Hyperlipoproteinemia, Coronary heart
disease
K 1
K 1-C4d+
K 2
K 2-C4d+
Indication
K 3
F.R., male, born 1944Renal-Transplantation 31.08.01
0,5
0
20
40
60
80
100
120
140
160
180
200
220
240
260
280
300
Biopsies
Predni
CSA
MMF
RR Med
Pravastatin
ASS
U- Protein(g/L)
S-Creatinine(µmol/L)
1,3
0,9
0,08 0,20,4 0,3
(4)
Summary • Incidence for C4d in protocol bx significantly lower
• Incidence varies between centers
• Incidence is higher with presensitized patients
• focal C4d stain correlates with AHR morphology
• C4d in protocol bx less often with cellular rejection
• cases of “subclinical” humoral rejection
prognostic relevance:
No acute graft losses
Harbinger of chronic humoral rejection??
Hannover-GermanyHermann HallerAnke SchwarzWilfried GwinnerMichael Mengel
ESPRIT-Group
European Study Group For Protocol Biopsies In Renal Transplantation
Antwerp-BelgiumMarc De Broe
Jean-Louis Bosmans
Johannes Bogers
Barcelona-SpainDaniel Seron
Francesco Moreso
Marta Carrera
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