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Pediatric Pathology
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Case 4 -
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Antibody Mediated (Humoral) Rejection (AMR)
Aliya N. Husain
University of Chicago Hospitals
Chicago, IL
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Clinical History
The patient is a 3-year-old male born with complex heart anomalies, status post Norwood and Fontan repairs admitted to the University of Chicago Hospitals for heart transplantation. Post-operatively the patient was supported with ECMO due to poor cardiac function. The first endomyocardial biopsy was performed at 7 days post- transplant images from which are submitted for your review. The immunohistochemical stain for C4d is submitted for scanning as virtual slide. In addition, digital images are submitted as follows:
Case 4 - Figure 4
Endomyocardial biopsy on day 7 post- transplant, IHC stain for C4d
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Case 4 - Figure 5
H&E stained section of left anterior descending coronary artery at autopsy shows recent thrombus
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Case 4 - Figure 6
EVG stain of coronary artery at autopsy shows focal internal elastica disruption and intimal fibrosis (chronic rejection).
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Introduction:
History: The patient is a 3-year-old male born with complex heart anomalies, status
post Norwood and Fontan repairs admitted to the University of Chicago Hospitals for heart
transplantation. Post-operatively the patient was supported with ECMO due to poor cardiac function. The
first endomyocardial biopsy was performed at 7 days post- transplant images from which are submitted for
your review. The immunohistochemical stain for C4d is submitted for scanning as virtual slide. In
addition, digital images are submitted.
Pathological/Microscopic Findings and any Immunohistochemical or Other Studies:
On light microscopy,
there is no cellular infiltrate. IHC for C4d shows diffuse strong enothelial staining.
Differential Diagnoses:
Acute cellular rejection
Final Diagnosis:
Antibody mediated (humoral) rejection (AMR)
Case Discussion:
Follow-up: His pre-transplant PRA (panel reactive antibody), which is a measure of
% cross reactivity against random donor pool, was 93% which is considered highly sensitized. In addition
to standard immunosuppression, he received plasmapheresis and IVIG prior to as well as after
transplantation. His routine surveillance biopsies were negative for cellular rejection but were
consistently positive for C4d which showed strong endothelial staining. Over the following months, the
patient continued to deteriorate. After an episode of cardiac arrest, he was stabilized but was no
longer considered a candidate for ECMO or emergent re-transplantation. The patient experienced a second
cardiac arrest and expired following the family's decision to stop resuscitative efforts. A limited
heart autopsy (67 days post-transplant) revealed massive epicardial fibrosis extending to the medial
pleural surfaces bilaterally. The heart was enlarged (411 gm) and the ventricular walls were moderately
thickened. There was severe intimal hyperplasia of coronary arteries with a recent left anterior
descending (LAD) artery thrombus, and for the first time, moderate acute cellular rejection. Autopsy
diagnosis: Chronic rejection of heart (accelerated graft vascular sclerosis). Discussion: The
importance of antibody mediated rejection (AMR) in cardiac transplantation is becoming clearer although
there is still some controversy in the literature. AMR is well accepted in the renal transplant
literature and is now thought to occur in 10-20% of cardiac transplants. AMR has been associated with
poor graft survival, graft vasculopathy and hemodynamic compromise in the absence of cellular
infiltrates. AMR is mediated by allospecific, or donor antibodies, complement, and other inflammatory
mediators that stimulate the immune system. The histologic and immunopathologic features for diagnosing
humoral rejection in heart biopsies have recently been proposed but are still not uniformly accepted: -
Clinical acute graft dysfunction - Histologic evidence of capillary damage - Capillary endothelial
swelling/congestion, macrophages, neutrophils, interstitial edema - Immunopathologic evidence: Ig (G, M,
A), C4d/C3d, C1q by IF, CD68 positive macrophages, or C4d 2-3+ staining by IHC - Serologic evidence of
Anti HLA Class I and II antibodies AMR is associated with graft coronary artery vasculopathy which may be
due to repeated injury and activation of the endothelium. There is diffuse concentric proliferative
arteriosclerosis involving most branches of the coronary tree which is not amenable to traditional
PTCA/stenting or surgical revascularization. Poor prognosis necessitates broad aggressive approach to
treatment. Clinical picture often dictates empiric treatment which needs to be started early. Data from
the ISHLT registry show that, irrespective of whether transplantation was for ischemic or non ischemic
etiology in adults, 35-40% of patients will have significant graft vasculopathy by 5 years. Pediatric
patients also have a steady increase in the presence of graft vasculopathy although at a lesser rate.
<1year age group is the best with about 10% of them developing graft vasculopathy at 5 years while
1-10 year olds have an incidence of 15% and 11-17 year olds 20%. In conclusion, AMR is increasingly
recognized as a clinical entity, and can be diagnosed with IF or immunohistochemical staining for C4d.
In many centers, treatment is still initiated based on clinical suspicion rather than histologic
diagnosis. Treatment regimens using rituximab mark an advance in the treatment options. But despite
early diagnosis and utilization of all the current known treatment options, AMR can be fatal. Chronic
rejection continues to be a major problem in long-term survivors.
References:
- Miller DV, Roden AC, Gamez JD, Tazelaar HD. Detection of C4d deposition in cardiac allografts: a comparative study of immunofluorescence and immunoperoxidase methods. Arch Pathol Lab Med. 2010 Nov;134(11):1679-84. PubMed PMID: 21043822.
- Tan CD, Rodriguez ER. Diagnosis of antibody-mediated rejection in cardiac transplantation: a call for standardization. Curr Opin Organ Transplant. 2010 Sep 24. [Epub ahead of print] PubMed PMID: 20881496.
- Revelo MP, Stehlik J, Miller D, Snow GL, Everitt MD, Budge D, Bader FM, Alharethi RA, Gilbert EM, Reid BB, Selzman CH, Hammond ME, Kfoury AG. Antibody testing for cardiac antibody-mediated rejection: Which panel correlates best with cardiovascular death? J Heart Lung Transplant. 2010 Sep 18. [Epub ahead of print] PubMed PMID: 20855221.
- Fedrigo M, Gambino A, Tona F, Torregrossa G, Poli F, Benazzi E, Frigo A, Feltrin G, Toscano G, Caforio AP, Iliceto S, Valente M, Thiene G, Gerosa G, Angelini A. Can C4d immunostaining on endomyocardial biopsies be considered a prognostic biomarker in heart transplant recipients? Transplantation. 2010 Oct 15;90(7):791-8. PubMed PMID: 20811321.
- Colvin RB. Dimensions of antibody-mediated rejection. Am J Transplant. 2010 Jul;10(7):1509-10. PubMed PMID: 20642676. 6: Kucirka LM, Maleszewski JJ, Segev DL, Halushka MK. Survey of North American pathologist practices regarding antibody-mediated rejection in cardiac transplant biopsies. Cardiovasc Pathol. 2010 Apr 23. [Epub ahead of print] PubMed PMID: 20418115.
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