Case no. 7.
Eva Honsova
Institute for Clinical and Experimental Medicine
Pathology Department
Prague, Czech Republic
eva.honsova@ikem.cz
Clinical history
• A 55 y/o woman was admitted to our transplant centre
to be considered for the second renal transplant
• She had agenesis of the left kidney and several stenotic
segments in the right ureter: repeated pyelonephritides
• Partial resection of the right kidney: when she was 15
year old
• Haemodialysis started when she was 35 y/o.
• A year later she received a cadaveric kidney and that
graft functioned for 18 years.
Clinical history
• Graftectomia.
• After one year on dialysis she received the 2nd
cadaveric kidney transplant (AB0 compatible)
• The donor: 61y/o woman who died of cerebral edema
due to pulmonary embolism.
• No induction therapy (0% PRA) and the recipient
received standard triple IS protocol therapy
(prednisone, tacrolimus, MMF).
• Delayed graft function, and a renal biopsy was
performed on POD6.
Biopsy sample: 6th day
C4d staining negative (IF)
Dg.: Acute T cell rejection,
grade IIA, acute tubular injury
Clinical course
• Treatment: solumedrol.
• Her renal function slowly improved and the S-Cr
stabilized on 170μmol/l (1.9mg/dl).
• She developed pollen allergy with asthmatic
problems
• High level of Tacrolimus was identified (tac 17.2
ng/ml), 8ng/ml
• She felt well and came to the our centre 3 months
later for a graft biopsy according to the protocol
• (S-Cr was between 130-160μmol/l)
2nd biopsy sample (under protocol, 3 months)
C4d staining negative (IF)
Dg.: Acute T-cell-mediated rejection, grade IIB, interstitial inflammation as a part of
rejection, glomerulitis
No TMA, mild arteriolar lesions
Clinical course
• She was treated with thymoglobulin and S-Cr improved
and descended on the level of 110μmol/l.
• She remained well but her renal dysfunction slowly
progressed
• A new graft biopsy for graft dysfunction (S-Cr 160200μmol/l) was performed 2 years later.
3rd biopsy sample (for dysfunction, 2 years post transplant)
C4d staining negative (IF and IH)
Dg.: Morphological features of C4d negative humoral rejection
Repeated cross match and Luminex were negative.
Clinical course
• Progressive anemia with
reticulocytopenia
• Infection by parvovirus B19
was diagnosed (consistent
sternal bone marrow smear,
virus DNA and IgM antibodies
in serum).
• Therapy: ivIgs, IS continued
• 2 years later: a liver mass
(4cm) which was considered
FNH. Normal architecture of
the liver tissue.
4th biopsy sample (for dysfunction, 5 years postTx,
S-Cr 300μmol/l; 3.39mg/dl; PU 4g/day)
C4d staining negative (IF and IH)
4th biopsy sample (for dysfunction, 5 years postTx,
S-Cr 300μmol/l; 3.39mg/dl; PU 4g/day)
Ptc,
BM multilayering
Repeated cross match and luminex were negative
Summary
•
1.
2.
3.
4.
4 graft biopsies (all C4d negative):
V1, acute tubular injury
V2, interstitial inflammation, glomerulitis
Transplant glomerulopathy
Transplant glomerulopathy, multilayering of ptc-BM, IF/TA
• Clinical course: delayed function, slowly progressive dysfunction
with proteinuria
• Pretransplant cross match negative, 0% PRA
• Last 2 biopsies with negative cross match, negative detection of
anti HLA antibodies (luminex), negative MICA.
Acute/active antibody-mediated rejection
Triad of tx glomerulopathy,
C4d+, anti-DSA: dg. criteria
of chronic active or
persistent AMR.
Both could be present at
variable time points.
Abs and C4d are not stable,
can increase and vanish.
At any given time, these
factors may or may not be
demonstrable, even if AMR
is present.
AHR has occurred with all IS regiments. The pathology of AHR has a wide spectrum of
findings. However, none of these features is specific.
Transplant glomerulopathy (cg)
The problem is that when morphological features (as tx glomerulopathy)
once set-in, there is not any further known treatment option to reverse CR.
Only early dg. of AMR can be beneficial.
Acute vascular rejection (v1, v2) and DSA
Analysis of 2079 recipients
with 302 biopsy proven
rejections.
They tested all the patients
for DSA in the stored sera.
71% of cases with vascular
rejection (v1, v2) were
associated with DSA.
Lancet; 2013(381):313-319.
More importantly, 45% v1
or v2 with DSA were C4d
negative and classified as
T-cell mediated rejection
Luminex
HLA antigens
patients
1. Donor (1989)
HLA
incompability
2.Donor (2008)
HLA
incompability
A3, A24
A2
A2
A31, A33
A31, A33
B13, B61
B13, B51
B51
B7, B40 (B60,61)
B7, B60
DR7, DR11
DR7
no
DR4,DR7
DR4
anti MICA
anti HLA
HLA class I
HLA class II
1. Biopsy (IIA, v1)
+ (B60)
0
0
2. Biopsy (IIB, v2)
n/d no serum
n/d
n/d
3. Biopsy cg
0
0
0
4. Biopsy cg, IF/TA
0
0
0
N. Angaswamy et al. / Human Immunology xxx (2013) xxx–xxx
• We do not know whether only low
level of anti DSA (HLA class I) were
the antibodies which really cause
graft injury in this case.
• Recent evidence has demonstrated
an important role of Th17
response against self-Ags as a
mechanism leading to CR
• Perclan, collagen IV and VI, agrin
• The key point is inflammation
• Exposure of cryptic self Ags or their
determinants can lead to
activation of both: cell- and Absmediated immune responses.
• ??? Continuous detection of Abs
Conclusion
• AMR may occur in the absence of peritubular capillary C4d
staining and may be difficult to identify.
• Correlation with DSA is helpful.
• However, both C4d staining and DSAb titers are not stable and
can increase and vanish.
• Therefore at any given time these factors may and may not be
demonstrable, even if AMR is or has been present.
• All v1 and v2 lesions may be indicative for AMR and CMR
• In this case, different management focused on the treatment of
AMR early after Tx would have been beneficial.
Pathology - A gate to the future
Future pre-congress meeting of ESP
Nephropathology Working Group???