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 Organs

 


Correspondence:	Bruce M. McManus, MD, PhD
			Professor and Head, Department of Pathology and Laboratory Medicine
			St. Paul's Hospital - University of British Columbia
			1081 Burrard 
			Vancouver, BC   V6Z 1Y6

 


 

INTRODUCTION

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 [1].

 

HEART

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 found:
  1. Microscopic intimal disease virtually from the time of allograft implant.
  2. Diffuseness and equivalency in proximal and distal vessel segments.
  3. Prominence of intra-cellular and extra-cellular lipids.
  4. Striking accumulation of glycosaminoglycans.
  5. Involvement of both intima and media in the lipid- and glycosaminoglycan-rich process.
  6. Lipid-rich areas generally coincident with glycosaminoglycan-rich areas.
  7. Inclusion of both macrophages and T cells in superficial "band-like" infiltrates and in deeper intimal and medial infiltrates.

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 [12], 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 [16], 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 [17] and accelerated cell death [15, 18].

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 [18], and an apoptotic, injurious pathway mediated by Fas appear to be important in intimal looseness [22].

 

LUNG

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 [26].The vasculopathy may be present histologically in biopsy or explant specimens before clinical changes in pulmonary artery pressures are apparent [23]. 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.

 

HEART-LUNG

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 alone [27]. 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 [28].

 

LIVER

"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 [29]. 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 [1]. 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 [30]. 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 [31]. 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. [32] 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 decades [33]. 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 [34]. 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.

 

SUMMARY

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 outer media.

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.

 

ACKNOWLEDGEMENTS

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.

 


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Last Modified: April 03, 1996 2:05:28 PM