MONOCYTE/MACROPHAGES AND C4d IN RENAL ALLOGRAFTS Alex Magil, MD
MONOCYTE/MACROPHAGES AND C4d IN RENAL ALLOGRAFTS
Alex Magil, MD
BACKGROUND
ACUTE HUMORAL REJECTION (AHR)
• C´ split factor C4d generated by Ag-Ab reaction• C4d binds covalently to PTC endothelium & BM• PTC C4d is a putative marker for AHR• Associated with poor outcome
BACKGROUND Cont’d
MONOCYTE/MACROPHAGE (MO)
• Component of the inflammatory infiltrate in acute rejection• Prominent numbers associated with poor outcome• C´ split factor C5a is chemotactic for MO• Uncertain whether MO has a role in AHR
Hypothesis
There is a significant association between PTC C4d deposition and MO infiltration in acute allograft rejection
Study Design
• Compare glomerular & interstitial MO & PMN infiltration in C4d + and C4d – biopsies
• All biopsies showing strong diffuse PTC C4d staining done between Jan. 1, 1999 and June 30, 2002 – C4d+ Group
• All biopsies showing ACR negative for C4d done between Jan. 1, 1999 and Dec. 31, 1999 – C4d- Group
• For each biopsy - mean no. MO/glomerulus
- mean no. PMN/glomerulus
- mean no. CI MO/hpf
- mean no. PTC PMN/hpf
• All biopsies graded according to Banff 97 criteria
Peritubular Capillary C4d
Acute Cellular Rejection
Suspicious for AHR (C4d +)
Suspicious for AHR (C4d +)
Glomerulitis
Glomerular CD 68+ Cells
Interstitial CD 68+ Cells
0
10
20
30
40
50
60
70
80
90
1st Qtr 2nd Qtr 3rd Qtr 4th Qtr
EastWestNorth
Pathological Criteria for AHR
• C4d deposition in peritubular capillaries (PTC)• At least one of the following:
≥2.0 PTC neutrophils per hpf
arterial fibrinoid necrosis
acute tubular injury• Circulating donor-specific antibodies
Mauiyeddi et al: JASN 13:234-241, 2002
Results – Banff 97 Grade
Suspicious 1A 1B 2A 3
C4d+ 16 5 0 2 0
C4d- 0 13 4 10 1
Patient Characteristics
C4d+ C4d- P
No. of Patients 15 24
Male:Female 5:10 19:5 0.0116
% with 2nd or 3rd TX 40 8 0.0483
% with PRA > 20% 62 12 0.0038
General Histological Results
C4d+ C4d- P
No. of Biopsies 23 28
% with Glomerulitis 57 11 0.0014
% with ≥ 1.0 PMN/GLOM 22 7 0.1193
% with ≥ 2.0 PTC PMN/hpf 9 0 NS
% with Neutrophilic Tubulitis
35 11 0.0823
Glomerular and Interstitial Monocytes
0
2
4
6
8
10
12
14
MO/GLOM CI MO/hpf
C4d+
C4d-
P < 0.0001 P = 0.0030
3.40.2
12.9
6.5
Glomerular and PTC Neutrophils
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
PMN/GLOM PTC PMN/hpf
C4d+
C4d-
P = 0.0003 P = 0.0035
0.8
0.3
0.9
0.4
Glomerular MO and Outcome
0
10
20
30
40
50
60
EVENT
NO EVENT
P=0.0027
13
21
8
57
MO/GLOM≥0.5 MO/GLOM<0.5
Association of Glomerular MO and C4d with Outcome
0
10
20
30
40
50
60
C4d- C4d- C4d+ C4d+
EVENT
NO EVENT
MO<0.5 MO≥0.5 MO<0.5 MO≥0.5
P=0.0109
8
51
8 9 0 6 5
12
Conclusions
• There is a strong association of glomerular and interstitial MO infiltration with PTC C4d
• The sensitivity (91%) and specificity (93%) of glomerular MO infiltration (mean MO/GLOM ≥ 1.0) for the C4d group suggest that glomerular MO be added to the current criteria for AHR
Acknowledgments
Kathryn Tinckam
Ognjenka Djurdjev
David Landsberg
Paul Keown