In Press, 1995, Transplantation Proceedings copyright by Appleton and Lange.
Allograft Vascular Disease: Comparison of Heart and Other Grafted Organs
Stanley J. Radio„, Shelley Wood¶, Janet E. Wilson¶, Hong Lin¶, Gayle L.
Winters§, and Bruce M. McManus¶
„Department of Pathology and Microbiology, University of Nebraska
Medical Center, Omaha, NE;
¶Department of Pathology and Laboratory Medicine, St. Paul's
Hospital-University of British Columbia, Vancouver, BC;
§Department of Pathology, Brigham and Women's Hospital, Boston, MA
Allograft Vascular Disease: Comparison of Heart and Other Grafted
Correspondence: Bruce M. McManus, MD, PhD
Professor and Head, Department of Pathology and Laboratory Medicine
St. Paul's Hospital - University of British Columbia
Vancouver, BC V6Z 1Y6
Despite a growing understanding of the immunobiology and allo-immunity of
transplant rejection, long-term survival of solid allograft recipients has not
significantly increased. Improved general patient care, scrupulous perioperative
techniques, and more effective immunosuppression have not resulted in better
long-term prognosis. The leading cause of transplant failure is termed
"chronic rejection" and is most universally defined as the progressive
functional deterioration associated with vascular obliteration and other
structural changes including organ fibrosis.
Recent and ongoing studies have documented a number of similarities in the
nature of transplant vasculopathy in cardiac, lung, hepatic, renal and pancreas
allografts. Thus, while the pathogenetic mechanisms of initiation and
progression have not been established, it is clear that the pathology of
allo-vasculopathy is similar in different allografts, modulated by the nature
and intensity of immunosuppression regimens, perioperative ischemia and other
organ-specific factors. The structural parallels of vasculopathy between
different types of organs no doubt belie a concordance in pathogenesis .
We have established the pathological nature of vascular lesions in muscular
arteries and smaller vessels of cardiac allografts in a series of studies over
the last 8 years [2-15].
The following pathological features of allograft arteries are consistently
- Microscopic intimal disease virtually from the time of allograft implant.
- Diffuseness and equivalency in proximal and distal vessel segments.
- Prominence of intra-cellular and extra-cellular lipids.
- Striking accumulation of glycosaminoglycans.
- Involvement of both intima and media in the lipid- and glycosaminoglycan-rich
- Lipid-rich areas generally coincident with glycosaminoglycan-rich areas.
- Inclusion of both macrophages and T cells in superficial
"band-like" infiltrates and in deeper intimal and medial
In related pathobiological studies, we have demonstrated that cytomegalovirus
does not appear to directly infect arteriopathic vessel walls in a preferential
fashion, and, in particular, does not selectively infect vascular smooth
muscle cells [7,
12]. Meanwhile, inflammatory cells do interact directly with intimal
and medial smooth muscle cells, as well as with endothelial cells, and in this
manner may alter the gene expression of vascular wall cells. Invasion of
inflammatory cells into the outer media from the adventitia (outside-to-inside
progression) may be important in terms of alterations in vasomotor as well as
structural integrity of the media.
Recently, we have documented the magnitude of lipid overload in allograft
coronary arteries [8,
10] (Figure), and have extended these observations to include demonstration
of particular apolipoproteins [(a), B, and E] in these vessels [13,
14]. Glycosaminoglycan excess in arteriopathic intima corresponds to
significant deposits of proteoglycans including biglycan and versican ,
while the amount of intimal decorin is much lower than in established native
atherosclerotic disease. The co-localization of the apolipoproteins and
particular proteoglycans (versican and biglycan) has also been established in
these recent studies [13,
14]. Lipoprotein trapping appears tenable as one mechanism of lipid overload
perhaps spurred by excessive proteoglycan synthesis, and is, in turn, driven
allogeneically. In the latter regard, other mechanisms beyond lipoprotein
trapping that may be involved in arteriopathy include enhanced lipid uptake
through altered endothelial surfaces, enhanced lipid synthesis, diminished
ability to export lipoproteins from foam cells 
and accelerated cell death [15,
A pathological feature that has not received sufficient definition is the
"looseness" and "degenerative" appearance in the superficial
intima of transplant arteries. The "loose" zone generally corresponds
geographically to inflammatory infiltrates; however, the meaning of this
phenomenon has not been established. We initially saw many foam cells in this
intimal region and histochemical and ultrastructural studies indicated that at
least part of the "looseness" was due to excessive lipids. Cytotoxic
processes in tissue injury are being defined [19-21].
The issue of cytotoxicity in arteriopathy has also received recent attention ,
and an apoptotic, injurious pathway mediated by Fas appear to be important in
intimal looseness .
Chronic rejection of the lung is characterized primarily by bronchiolitis
obliterans, the major cause of organ failure, morbidity and poor survival rates
in short- and long-term lung allografts. Rejection is presaged by peribronchial
and perivascular mononuclear cell infiltrates which extend to interstitium and
alveolar spaces. Graft arteriopathy often, but not always, accompanies
bronchiolitis in lung allografts [23,
24]. The vascular changes in lung allografts may be patchy and involve large
elastic arteries, small muscular arteries or veins [23-25].
"Fibro-intimal" thickening, comparable to the accelerated vasculopathy
seen in other transplant organs, is described .The
vasculopathy may be present histologically in biopsy or explant specimens before
clinical changes in pulmonary artery pressures are apparent .
Microscopically, the arteriopathy in lung allografts consists of a concentric
intimal proliferation of cells that resemble myofibroblasts and smooth muscle
cells in a glycosaminoglycan-rich matrix (Figure). In patients with severe
chronic rejection, activated lymphoid cells and granulocytes become increasingly
conspicuous. The early lesions are predominantly intimal, whereas, in more
severe lesions, focal disruption and fragmentation of the internal elastic
lamina may be present along with associated medial damage and atrophy.
Combined heart-lung transplantation has become increasingly prevalent over the
past decade with successive improvements in cyclosporine immunosuppressive
therapies that promote healing of tracheal anastomoses. The post-transplant
phenomena seen in combined heart-lung transplant recipients share many
characteristics of the single organ transplants but include certain notable
features. Of particular interest, coronary artery disease associated with
heart-lung transplantation may develop more swiftly than in heart allografts
Seemingly contrary, the preferential pattern of rejection in combined heart-lung
allografts favors a reduction in acute cardiac rejection as compared with
singular heart implants .
"Foam cell" arteriopathy, described in cardiac allograft patients, is
also seen in orthotopic liver allograft recipients (Figure). Chronic rejection
in hepatic allografts is defined as loss of the original bile ducts in addition
to progressive luminal narrowing of blood vessels due to prominent proliferation
of smooth muscle cells and accumulation of lipid, foam cells and T lymphocytes .
Changes associated with chronic liver allograft rejection include the
disappearance of the bile ducts, thickening of hepatic arterioles and arteritis
(obliterative) with the majority of vascular changes occurring in the hilum .
The term "endothelialitis" is often used and pertains to the small
vessels. Chronic rejection normally presents clinically after the first year
post-transplantation and results in progressive graft failure. Most patients
affected do not respond to immunosuppression and require retransplantation .
In one study of 440 hepatic allograft patients, clinical and histological
features of chronic rejection were seen in 19% of allografts overall and in 41%
of explanted grafts surviving more than 30 days .
The most common finding at the time of explant in patients with chronic liver
rejection is moderate (50-75%) to severe (76-90%) cross-sectional narrowing
involving the primary and secondary hepatic artery branches. Marked loss of
original portal bile ducts is the primary finding in needle biopsies since the
vascular changes are largely limited to arteries of 25µm in diameter or larger.
KIDNEY AND PANCREAS
Several histopathologic changes concordant with those of chronic hepatic
allograft rejection are seen in the vascular pathology of kidney allografts
(Figure). In 1993, Mihatch et al. 
defined the morphological criteria of renal allograft rejection using three
parameters: vascular, glomerular, and tubulo-interstitial changes. They
emphasized the importance of sclerosing vascular and/or glomerular alterations
in the diagnosis of chronic rejection. The significance of these changes, most
notably the accumulation vascular lipids, have been recognized for over four
As with the heart and liver, common microscopic features of allogeneic injury in
the kidney include perivascular inflammation, focal injury of the internal
elastic lamina, thinning of the vascular media, apparent smooth muscle cell loss
or phenotypic alteration in the media, and characteristic smooth muscle cells,
foam cells, and matrix constituting concentric, generalized intimal thickening.
Although a large body of knowledge exists detailing the morphology of
allograft arteriopathy for heart, lung, kidney and liver transplants, much less
is known about graft function and rejection in pancreas allografts, and
particularly in concurrent pancreas-kidney transplants. One study records the
histological portfolio of 160 patients who underwent 169 whole organ
vascularized pancreas implants. Thirty-three failed allografts were examined in
this series (15 solitary pancreas, 12 combined pancreas-kidney, 6 pancreas after
kidney) and proved to have histopathologic features very similar to those
present in heart and liver transplant arteriopathy .
Vascular changes in pancreas allografts explanted after only two months include
intimal smooth muscle cell proliferation, lipid and prominent glycosaminoglycan
deposits, numerous superficial and deep foam cells. All of these vessel wall
components contributed to significant luminal narrowing. A superficial
inflammatory infiltrate of variable intensity was present in each artery studied
and was determined immunohistochemically to be composed of T-cells (UCHL-1+) and
monocyte- macrophages (MAC 387+) with occasional B-cells (L26+). Superimposed
acute or organized thrombi were present in 50% of grafts failing after 3 months.
In contrast to most other allografts, vascular changes can be detected in
cytoscopically directed core needle pancreas biopsies. In recent observations,
smooth muscle cell proliferation, fibrosis, foam cell change and
glycosaminoglycan deposition were present in 8 of 15 core needle biopsies from
patients with chronic pancreatic rejection. Acinar cell loss and parenchymal
fibrosis were uniformly present in these biopsies. The prognostic significance
of the vascular changes in pancreas grafts requires further study.
A striking resemblance exists between the vasculopathy in several different
allografts. The arteriopathy of epicardial coronary arteries is diffuse,
involving proximal, distal and small branch segments in a generally concentric
pattern of intimal thickening. Smooth muscle cells in a lipid- and
glycosaminoglycan-rich matrix are the predominant components of this expanded
intima. Varying amounts of collagen are present, more being present late
post-transplant. A superficial, and to a lesser degree, deep, band-like
infiltrate of T cells and macrophages is uniformly present although it is
somewhat more prominent in early lesions as compared to more severely narrowed
arteries from longer-term, susceptible grafts. The media is likewise altered by
areas of lipid and glycosaminoglycan deposition associated with smooth muscle
cell loss and phenotypic modulation. The media is altered in an
outside-to-inside direction, with percolation of adventitial leukocytes into the
Virtually all of the coronary features are seen in the medium to large
arteries of liver, pancreas, and kidney allografts. Chronic rejection in lung
allografts is manifest by obliterative bronchiolitis, and vascular changes,
although architecturally similar, are somewhat less common and result in less
severe luminal narrowing. The role of allograft vasculopathy in chronic lung
rejection is thus less certain. A finding perhaps unique to epicardial coronary
arteries of heart allografts is the presence of eccentric lesions more typical
of native atherosclerosis. Many of the latter grafts probably have preexistent,
undetected donor disease.
Sequential evaluation of vascular changes is limited in human biopsy material
by their general absence in endomyocardial or core liver needle specimens.
Fortunately, vascular changes can be detected in some renal and pancreas core
needle biopsies and these findings may provide an avenue for monitoring the
effectiveness of immunosuppressive therapy, antiviral or lipid altering
therapies, or modifications of smooth muscle cell proliferation and
glycosaminoglycan deposition yet to be developed.
The authors would like to express most sincere thanks to the Heart and
Stroke Foundation of British Columbia and Yukon and the Canadian Heart and
Stroke Foundation for their support of these studies. In addition, the authors
would like to thank Stuart Greene for excellent photographic assistance.
Return to Banff
Last Modified: April 03, 1996 2:05:28 PM