Failed Grafts

Although excellent rates of 1-year patient and graft survival have been achieved in recent years for all types of technically successful pancreas transplants (SPK, PTA, PAK) a significant number of grafts are still lost in the early post-implantation period, due to a variety of surgical complications. Graft losses due to leaks, bleeding, thrombosis, infections and early pancreatitis are grouped together under the category of technical failure. Currently the number of surgical complications is disproportionately high in comparison to the number of graft loses due to acute rejection. Thrombosis continues to be the leading cause of non-immunological graft loss (5.8-16.4 %) with higher rates seen in PAK and PTA cases with enteric drainage.

The pancreas has intrinsically a low blood flow compared to other solid organs. Perioperative inflammation and edema, as well as microvascular and endothelial damage relating to donor factors and organ preservation, all contribute to further compromise blood flow in the early post-transplant period leading to thrombosis. Correspondingly longer cold ischemia times have been associated with increased incidence of graft thrombosis.

Acute rejection is suspected to play a role in some patients with early graft thrombosis. HLA mismatches appear not to impact on the incidence of graft loss due to technical failures, however, HLA mismatch does have an overall negative impact on graft survival.

 

Graft pancreatectomies: Guidelines for gross and histological evaluation

Graft pancreatectomies usually consist of the whole pancreas and attached portion of duodenum. The latter is present in continuity either with a loop of recipient's small intestine or a patch of urinary bladder wall.

Systematic histological evaluation of failed grafts is necessary for accurate classification of the cause of graft loss. Minimun histological sampling should include cross sections of all large vessels and several sections from the parenchyma to include an adequate number of medium sized and small vessels. The number of histological sections depends on each case; the most important structures should be sampled routinely.

 

Gross evaluation:

- Large arteries and veins: evaluate for thrombosis (recent and organized), endotheliitis, arteriris, transplant vasculopathy)

- Random samples from parenchyma (viable and necrotic, usually 3-5 sections): evaluate for evidence of ischemia/pancreatitis, acute rejection, chronic rejection, presence of infectious organisms, etc.).

- Area of anastomosis: evaluate for dehiscences (leaks)

- Samples from any other lesions: masses (i.e. PTLD), cysts, abscesses, lymph nodes, etc.)

 

Ancillary studies:

- Immunoperoxidase stains for insulin and glucagon should be perfomed to evaluate for selective destruction of beta cells (recurrence of autoimmune destruction). These cases show near normal parenchyna with no significant evidence of fibrosis/acinar loss (chronic rejection).

 

- Frozen tissue for immunfluorescence stains for immunoglobulins and complement in cases suspected to represent hyperacute rejection.

 

- Electron microscopy: May be helpful in recurrence of diabetes type 1.

 

 

 

Histological evaluation:

Based on the histological findings pancreatectomies can be broadly classified as follows.

 

1) PURE VASCULAR THROMBOSIS IN AN OTHERWISE NORMAL PANCREAS

In these grafts the only pathological changes consist of recent vascular thrombosis and bland ischemic parenchymal necrosis. There is no underlying vascular pathology or any other specific histological change. (In early graft loss the most important histological determination relates to blood vessels.)

The majority of these grafts (78%) are lost in less than 48 hours after transplantation and we have never seen this pattern in grafts lost after the first 2 weeks post-transplantation.

 

In the case of early thrombosis, the lack of obvious histological changes associated with the thrombosis does not rule out ultrastructural or subtle functional damage in these organs, since older donor age and longer cold ischemia times are associated with increased risk for early thrombosis.

 

2) HYPERACUTE ALLOGRAFT REJECTION

Hyperacute rejection in the pancreas is indistinguishable from hyperacute rejection affecting other organs, and it is characterized by necrosis of arteries and veins with secondary massive and immediate thrombosis and parenchymal necrosis. We have rarely seen rapid graft loss (within 1-12 hours post-transplantation) with extensive fibrinoid necrosis of arteries and veins with associated massive vascular thrombosis and parenchymal necrosis. Immunohistochemical studies in these cases were positive for IgG and C3 in the wall of blood vessels.

 

3) ACUTE ALLOGRAFT REJECTION

Graft loss secondary to acute allograft rejection (other than hyperacute rejection) can be seen from the first week to few months post-transplantation (in our experience at a mean of 5.1 weeks). These cases show endotheliitis and various degrees of necrotizing arteritis (acute rejection Grades IV-V). Graft losses in the first months may result from a combination of infection and rejection.

 

4)ACUTE AND CHRONIC REJECTION

Patients with with persistent (biopsy proven) acute allograft rejection can show early interstitial fibrosis and acinar loss consistent with chronic rejection, starting in the second month post-transplantation. In our experience graft pancreatectomies with combined features of acute and chronic rejection were resected at times ranging from 6 weeks to 20 months (mean 6.6 months).

5) PANCREATITIS AND PERIPANCREATITIS

Necrotizing infectious duodeno-pancreatitis with or without abscess formation can present at variable times post-transplantation but occur often early on (mean 3.6 months); a vaiety of organisms can be cultured from these grafts, most commontly enterobacteria (Enterobacter cloacae, Proteus mirabilis) and Methicillin resistant Staphylococcus aureus (MRSA)). Fungal infections (Often Candida) and mixed infection are not uncommon.

 

6) CHRONIC REJECTION

These pancreatectomies show extensive interstitial fibrosis/ acinar atrophy and transplant (obliterative) arteriopathy. This pattern can be seen after few months post-transplantation but is more commonly seen after the second year post-transplantation (mean 28.6 months , range 4 to 81 months). Many of these grafts do not show any significant concurrent acute rejection.

Chronic rejection is the most important cause of graft loss after the first 6 months post-transplantation.

 

7) POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER

In our center allograft pancreatectomies for PTLD were performed in 4 patients in the second month post-transplantation and in one patient in month 12 (mean 5 months). The histological findings are described in the EBV section.

 

INCIDENCE OF VASCULAR THROMBOSIS

Recent thrombosis is seen to some degree in all cases of early graft loss due to acute allograft rejection with vascular involvement (superimposed on endotheliitis or arteritis) .

All cases with chronic rejection show scattered vessels with thrombosis (acute and chronic; this typically involves medium size to small arteries and veins.

Acute vascular thrombosis in one or more large vessels can lead to graft pancreatectomy in otherwise well functioning allografts. In these cases the thrombosis always occurs in abnormal blood vessels, either showing transplant arteriopathy or lesions consistent with healing vasculitis/endotheliitis. The presence of transplant arteriopathy (one of the histological features of chronic rejection) is strongly associated with recent and organized thrombosis. Correspondingly old (organized) thrombosis is seen almost invariably in pancreatectomies with chronic rejection. As expected, progressive graft fibrosis (correlating with increasing grades of chronic rejection) and the presence of transplant arteriopathy are directly related to the time elapsed after transplantation.

 

Thrombosis is insignificant in the pancreatectomies performed for infectious processes.

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