Vascularized pancreatic transplantation

 

DAVID J. CONTI AND A. BENEDICT COSIMI

 

 

INTRODUCTION

Footnote 3 At least 100000 new cases of insulin-dependent (type I) diabetes mellitus appear worldwide each year. The discovery of insulin in 1921 provided the means to control the previously fatal complications of diabetic ketoacidosis. However this is only changed the natural history of the disease, since the extended survival which was suddenly provided by insulin treatment also allowed time for the degenerative secondary complications to develop.

 

Asymptomatic microangiopathic lesions develop in nearly all type I diabetics after 10 to 15 years of insulin-controlled hyperglycaemia. In nearly one-half of these patients, this progressive thickening of capillary basement membranes, together with accelerated atherosclerosis, results in clinically significant complications, typically first affecting the eyes, and then the peripheral nerves and vessels, the kidneys, and ultimately the heart and brain. Cardiovascular mortality in these patients is four times as great as that of the general population, cerebral vascular accidents are three times as frequent, and the prevalence of amputation is 20 times as high. Diabetes is the single most common cause of end-stage renal disease in the United States: approximately 30 per cent of patients who currently receive kidney transplants have diabetes. Despite successful renal transplantation, may of these recipients continue to suffer from the effects of other progressive complications of diabetes (Fig. 1) 723. This dismal prognosis may not be inevitable, however, since experimental studies indicate that scrupulously tight control of glucose homeostasis may prevent or minimize the development of diabetic complications.

 

Currently, there are two possible approaches to achieving ‘near-normoglycaemia’: intensive regimens of exogenous insulin administration regulated by frequent glucose monitoring, and pancreas transplantation. The use of multiple daily insulin injections or insulin infusion pumps clearly maintains lower blood glucose levels than those which can be attained with standard insulin regimens. However, normoglycaemia is seldom achieved and a number of technical problems continue to limit the widespread application of these approaches. Obtaining frequent blood samples for monitoring of glucose by finger-pricks is a burden for many patients; subcutaneous abscesses may develop around the infusion devices; finally, not only does intermittent hyperglycaemia persist, but more importantly, there is a significant incidence of hypoglycaemic reactions, including occasional seizures and even sudden death. As a result, only the most motivated and compliant patients are able to follow these regimens. The attractiveness of pancreas transplantation arises form the expectation that a successful allograft will ensure complete euglycaemia, even without frequent blood glucose monitoring. The limitations are that, at least at present, this euglycaemia can be achieved only after a major surgical procedure, the life-long administration of immunosuppressive drugs, and reliance upon a limited supply of donor organs.

 

To avoid the surgical problems associated with the revascularization of the pancreas and the management of its exocrine secretions, transplantation of purified islet-cell preparations has been vigorously investigated. There is little doubt that, if islet-cell transplantation were to become a clinical reality, it would be the treatment of choice for insulin-dependent diabetes mellitus. The procedure itself would be minor, perhaps involving only a percutaneous intravenous injection, yet adequate islet-cell function would remove the need for exogenous insulin therapy. Recently, improved techniques for the isolation of islet cells, using continuous collagenase perfusion and more precisely defined density gradients for purification of the islet preparation have been developed. This has led to the first successful islet transplants with a handful of patients remaining normoglycaemic for over 6 months.

 

Until recently, trials using vascularized whole or segmental pancreas transplants were also largely unsuccessful (Table 1) 248. However, refinements in the surgical procedure, together with advances in the immunosuppressive management of allograft recipients, now make it possible to achieve much more acceptable patient and allograft survival rates. In our experience, combined pancreatic and renal transplantation can now be accomplished with only a modest increase in risk over that associated with renal transplantation alone in diabetic recipients.

 

HISTORY

Pancreas transplantation was initially described in a large animal model in 1929. During the next four decades various investigators perfected the technical details of pancreaticoduodenal transplantation in dogs. This experimental background provided the setting for the first clinical pancreatic allograft performed by Kelly and Lillehei in December 1966, at the University of Minnesota. In that recipient, the pancreatic duct was managed by ligation. Over the next 7 years Lillehei and his associates performed another 13 pancreas allografts in diabetics, preserving exocrine function by anastomosing the donor ampulla of Vater or duodenal segment to a recipient jejunal Roux-en-Y loop. Only one of these pancreas allografts was still functional 1 year after surgery. Unacceptable mortality rates were encountered, predominantly because of septic complications. Since then, progress in pancreas transplantation has continued to lag well behind that of other solid organs, largely because of the unresolved technical difficulties related to management of the exocrine secretions. Of the 64 pancreaticoduodenal transplants performed between 1966 and 1977, only two grafts functioned for more than 1 year. Failures were the result of high infection rates, thrombosis, duodenal and/or pancreatic necrosis due to inadequate preservation, duodenal ulceration, and pancreatic or duodenal fistulae. As a consequence of these poor results, interest shifted from whole organ to segmental pancreas transplants, with multiple approaches to the management of the pancreatic duct, including ductal ligation, ductal obliteration by various polymers, free drainage of the exocrine secretions into the peritoneal cavity, or pancreatic duct-to-ureter anastomosis. None of these techniques proved completely satisfactory. Complications, including pancreatitis, pancreatic abscesses, fistulae, intractable pancreatic ascites, and diffuse pancreatic fibrosis, continued to limit their widespread application.

 

As a result, many groups, including our own, have refocused attention on whole organ transplantation (Fig. 2) 724 using newer, more reliable approaches to exocrine drainage into the recipient's bladder. These whole organ techniques provide a number of advantages: a larger islet-cell mass is transplanted; the technical aspects of the vascular anastomoses are simplified as larger calibre vessels are used; venous drainage is enhanced, assuring greater blood flow through the allograft; and the use of a patch or short segment of donor duodenum for urinary exocrine drainage has proved to be relatively free of complications. The technique originally described suggested that urinary diversion of the pancreatic exocrine secretions could be best accomplished by using only a tiny patch of donor duodenum surrounding the ampulla of Vater. Because of the technical difficulty which may be encountered when dissecting the duodenum from the head of the pancreas, most groups have adopted the modification of retaining a 10- to 12-cm long segment of donor duodenum which can be anastomosed to the recipient bladder. These techniques allow free drainage of the pancreatic duct without the need for entering the recipient bowel, with the attendant potential for contamination. As described below, this approach also provides a means for serial monitoring of allograft exocrine function by simply measuring urinary pH and amylase concentrations.

 

DONOR AND PATIENT SELECTION

It is possible to remove the tail of the pancreas from a living donor and transplant it as a segmental graft. Because of the not insignificant risk to the donor, however, the great majority of pancreas grafts procured for transplantation have been from cadavers. As for any organ to be transplanted, active infection or malignancy in the donor, with the exception of non-disseminating intracerebral tumours, constitute generalized contraindications to pancreas procurement. In addition, since both hepatitis B and the acquired immune deficiency syndrome can be conveyed with the allograft, all donors must be shown to be hepatitis B surface antigen and HIV antibody-negative. Certain other conditions make the donor specifically unsuitable for pancreas donation. Diabetes (type I or II), a history of chronic pancreatitis, or traumatic pancreatic injury, are all contraindications to pancreatic retrieval. Suitable donors should be haemodynamically stable with adequate urine output, indicating sustained organ perfusion. Serum amylase, creatinine, and blood urea nitrogen levels should be near normal. A modest elevation in blood glucose does not necessarily preclude pancreatic donation: hyperglycaemia is not infrequently observed in cadaveric donors, and presumably results from the large volumes of intravenous solutions administered during resuscitative efforts and from the metabolic derangements induced by cerebral oedema and infarction. The administration of non-glucose containing intravenous solutions usually produces a normal blood sugar level over a period of 8 to 12 h. If adequate islet function is still in doubt, determination of glycosylated haemoglobin levels will confirm prior euglycaemia in the potential donor.

 

During the initial phases of pancreas transplantation, there was only one absolute requirement for histocompatibility, namely a negative T-cell crossmatch (absence of antibodies in recipient serum to donor HLA class I antigens). Retrospective analysis now suggests that graft survival rates may be improved if recipients are well matched with their donors at the HLA-DR loci. Worldwide results indicate a 71 per cent 1-year survival rate in recipients sharing two DR antigens, versus only 48 per cent allograft survival for those sharing one or no DR antigens with the donor. As new techniques for pancreas preservation are developed which allow sufficient time for more distant transport of the allograft, prospective matching of donor and recipient HLA-DR antigens will probably be more widely employed.

 

Currently, the typical candidate for pancreas transplantation has type I juvenile onset diabetes and significant renal dysfunction. The rationale for transplantation in such patients is that they are already candidates for renal transplantation and chronic immunosuppression. The additional surgical morbidity of the pancreas transplant only minimally increases the risks associated with renal transplantation. Contraindications include the presence of other advanced complications of diabetes, particularly coronary artery disease, blindness, or severe peripheral vascular disease. In our unit, we initially selected patients who were already dialysis dependent for simultaneous kidney and pancreas transplantation (Table 2) 249. Although excellent survival can be achieved in this group of patients, the postoperative morbidity is greatly increased in those recipients with advanced diabetic complications prior to transplantation. In addition, there is little or no likelihood of reversal of these advanced complications despite persistent post-transplant euglycaemia. Currently, therefore, we favour combined kidney and pancreas transplantation for uraemic diabetic individuals who have not yet commenced dialysis. In some centres, the indication for pancreas transplantation has been extended even further to include patients with biopsy demonstrable diabetic nephropathy, but with good kidney function. Such patients would receive only a pancreas transplant. These patients should benefit most from a successful transplant, since their microangiopathic complications will be less advanced. However, because of the increased difficulties in diagnosing rejection in recipients of pancreas transplants alone (see below) and the lack of uraemia with its associated immunosuppression, current graft survival rates have proved less satisfactory than in kidney and pancreas graft recipients.

 

SURGICAL TECHNIQUES

Donor procedure

The composite pancreaticoduodenal allograft is isolated and perfused in the cadaver donor, nearly always in combination with kidney, liver, and heart procurement. The abdominal organs are initially exposed through a midline incision made from the suprasternal notch to the pubis (Fig. 3) 725. Preparation of the pancreas allograft for removal is the most time consuming procedure, since extreme care must be taken to avoid operative trauma, which is probably the major factor leading to vasospasm and thrombosis of the pancreas after reimplantation. The spleen and tail of the pancreas are initially deflected medially by incising the peritoneum along the superior and inferior borders of the pancreas, to the level of the coeliac artery and superior meseneteric vessels, respectively. The inferior mesenteric vein can be cannulated for subsequent portal perfusion or ligated and divided along the inferior border of the pancreas. During this portion of the dissection excessive handling of the pancreas is avoided by using the spleen as a handle to manipulate the organ (Fig. 4) 726. The arterial and portal vessels, shared by the liver and pancreas (Fig. 5) 727 are divided at levels which will allow subsequent successful revascularization of both allografts. The gastroduodenal artery is usually ligated and divided at its origin from the common hepatic artery. If the liver team is satisfied with the calibre of the common hepatic artery, it is divided at its origin from the coeliac axis (Fig. 6) 728. If the hepatic artery is of inadequate size for hepatic revascularization, the splenic artery may be divided at its origin and the coeliac axis retained with the liver. The portal vein is typically divided at the level of the coronary vein. The superior mesenteric vein is divided as it crosses over the duodenum at the lower edge of the pancreas (Fig. 3) 725. The distal superior mesenteric artery is also ligated at this level. Just prior to division of the vessels, the distal aorta is cannulated and the supracoeliac aorta is cross clamped as hypothermic perfusion via the aorta and portal vein is initiated. The liver and kidneys should be removed prior to division of the duodenum to avoid contamination by enteric flora. The duodenum is then divided with a stapling device just distal to the pylorus and approximately 5 cm distal to the ampullary region. The composite allograft is immediately placed into an iced solution (Fig. 2) 724. The lateral wall of the duodenum is opened and the short duodenal segment irrigated with antibiotic and antifungal solutions. The arterial supply to the graft is further flushed with silica-gel filtered plasma or University of Wisconsin preservation solution and then the pancreas is placed in a sterile plastic bag for storage on ice until transplantation. This approach provides for a maximum safe ischaemic period of approximately 15 h.

 

For segmental pancreas transplantation, the tail and body of the pancreas are procured from a living, related donor by dividing the organ and the splenic vessels in a plane overlying the superior mesenteric vessels.

 

Recipient procedure

For simultaneous kidney and pancreas transplantation, the renal allograft is first placed usually into the left iliac fossa. Reconstruction of the urinary tract can be accomplished via a ureteropyelostomy or ureteroneocystostomy. The right iliac fossa is the preferred location for the composite pancreaticoduodenal allograft. If the donor coeliac axis was removed with the liver, the remaining splenic artery is usually anastomosed end-to-side to the superior mesenteric artery while the pancreatic allograft is still in the cold preservation solution. If the coeliac axis has been retained with the pancreas, the allograft is revascularized by anastomosing the donor portal vein and the aortic patch, which encompasses the origins of the coeliac and superior mesenteric arteries, to the recipient iliac vessels in an end-to-side fashion (Fig. 7) 729. The vascular clamps are removed and perfusion is re-established with the donor spleen still attached. Currently, the preferred management of the exocrine secretions is by anastomosis of the donor duodenum to the dome of the recipient bladder. This is performed in a standard two-layer technique. Absorbable sutures are used for both layers of the bladder anastomosis to prevent subsequent stone formation on sutures which can erode into the bladder lumen. Exocrine secretions can alternatively be drained into a Roux-en-Y loop of recipient jejunum.

 

The spleen is removed after the duodenocystostomy has been completed and the vascular anastomoses have been inspected for patency and haemostasis. The rationale for temporarily leaving the spleen in place is that this provides the equivalent of a large arteriovenous shunt at the tail of the pancreas. This should encourage increased blood flow through the allograft during the early rewarming period, when the most intense vasospasm would be anticipated. Evidence supporting the validity of this hypothesis is provided by sequential measurements of arterial blood flow to the allograft, which reveal a 30 to 40 per cent decrease in flow after splenectomy is performed.

 

For segmental pancreas transplantation, revascularization is by simple end-to-side anastomosis of the donor splenic vessels to the recipient's iliac artery and vein. The pancreatic duct is managed either by occlusion with a synthetic polymer or by anastomosis of the duct into the bladder or a Roux-en-Y jejunal loop.

 

POST-TRANSPLANT MANAGEMENT

Although experimental studies of islet-cell transplantation suggest that endocrine pancreatic tissue is particularly immunogenic and so more likely to suffer rejection than other allografts, experience with vascularized segmental and whole pancreas transplantation do not confirm this concern, presumably because of the different nature of the grafts. Immunosuppression for pancreatic allograft recipients is, therefore, provided by protocols similar to those used in renal, hepatic, or cardiac transplantation. In our programme, initial immunosuppression includes a combination of cyclosporin administered orally (12 mg/kg.day, tapered to maintain plasma levels of 50–100 &mgr;g/l), prednisone (tapered over 5 days from 200 to 20 mg/day), and azathioprine (100 mg/day). Acute rejection episodes are initially treated with intravenous solumedrol. Patients whose rejection proves unresponsive to steroids are treated with OKT3 monoclonal antibody.

 

Because thrombotic complications historically accounted for up to 25 per cent of pancreatic allograft failures, many centres also recommend anticoagulation as part of the early postoperative regimen. We favour a protocol combining low molecular weight dextran (20 ml/h) and subcutaneous heparin (3000 U/8), beginning intraoperatively and continuing for 5 days postoperatively. Aspirin (325 mg/day) is initiated on day 1 and continued for 4 months unless haematuria necessitates earlier withdrawal. This approach, in conjunction with meticulous procurement techniques and temporary splenic retention following revascularization in the recipient, has resulted in only one instance of pancreatic vessel thrombosis in 36 consecutive recipients.

 

A cystogram is performed 5 to 7 days after transplantation to evaluate the duodenocystostomy. The Foley catheter is removed at this time, provided that the cystogram shows that the anastomosis is patent and without evidence of leakage. Renal and pancreatic function are serially monitored by serum creatinine and glucose levels. Unfortunately, the only completely valid clinical parameter indicative of pancreas rejection continues to be an elevation in the blood glucose level. Hyperglycaemia, however, is generally not manifested until rejection is well established, and at this late stage, the rejection process is often unresponsive to increased immunosuppressive therapy. This phenomenon results from the pathophysiology of pancreas destruction by rejection in which the early effector mechanisms primarily involve only the acinar tissue, with sparing of the islet-cells until quite extensive allograft damage has already occurred. Even at this late stage, hyperglycaemia is often not evident because of the large residual functional capacity of the islet cells: this clinical warning may not become evident until 80 to 90 per cent of the islet cell mass has been destroyed. Unfortunately, despite the much greater sensitivity of the acinar tissue to rejection, an elevated serum amylase level is also an unreliable diagnostic measure. Hyperamylasaemia in these patients may also result from perioperative trauma to the allograft, postoperative wound collections, and infection. Since rejection of renal allografts is usually detected at an early stage, serial monitoring of renal allograft function in recipients of kidney and pancreas transplants retrieved from the same donor, provides a reliable means of diagnosing rejection and initiates early treatment for a process presumably occurring simultaneously in both organs (Fig. 8) 730. Furthermore, if the diagnosis is in doubt, percutaneous biopsies of the renal allograft can usually be obtained without difficulty. In our experience, renal allograft dysfunction secondary to rejection has always preceded any evidence of islet cell dysfunction.

 

One aspect of patient management unique to individuals who have received pancreatic allografts with urinary drainage of the exocrine secretions is that some indication of pancreatic allograft function can be obtained from measurements of urine pH (generally 7.5) and amylase levels (generally 30000 units/24 h). A fall in urinary pH and amylase concentration often occurs during rejection crises (Fig. 8) 730. However a disadvantage of urinary exocrine drainage is that these patients typically exhibit some degree of metabolic acidosis because of the bicarbonate loss. During periods of decreased renal function this can become severe and may require intensive oral or intravenous bicarbonate supplementation. Nevertheless, higher pancreas allograft survival rates are currently being observed in recipients of simultaneous kidney and pancreas transplants with bladder exocrine drainage than in recipients who receive a pancreas allograft after a previous kidney transplant, or in non-uraemic recipients of pancreas transplants alone (see below). This improvement in allograft survival is though to be due to the detection of rejection at an earlier, more treatable, stage.

 

RESULTS

As discussed above, early clinical results of vascularized pancreas transplantation were clearly unsatisfactory and the procedure properly remained experimental until the mid 1980s. Recent results, however, are more encouraging. Over 1200 pancreas transplants were reported worldwide between 1986 and 1989; 87 per cent of the recipients were alive at 1 year and 56 per cent of these patients were insulin independent. This improved success rate has been achieved even in recipients with advanced diabetic complications. Since the 1-year patient mortality rate following renal transplantation alone in this group of recipients is approximately 10 per cent, diabetic patients can now be honestly advised that the addition of pancreas transplantation does not significantly decrease their chances of survival. In some centres, the early survival rate for the pancreatic allograft itself is also approaching that for cadaver donor renal allografts, that is, approximately 80 per cent. Of our first 36 consecutive combined pancreas and kidney transplant recipients, 29 patients (80.6 per cent) remain independent of dialysis, 27 of whom (75 per cent) remain insulin free, at a mean follow-up of 28.4 months (Table 3) 250.

 

METABOLIC EFFECTS

Factors that might delay a return to normal glucose metabolism during the immediate post-transplant period include: systemic rather than portal venous delivery of insulin from the allograft; denervation of the pancreas; intravenous infusions of large volumes of glucose-containing solutions during the perioperative period; immunosuppressive protocols using diabetogenic agents including steroids and cyclosporin; and ischaemic injury to the donor islet cell mass incurred either before death or during procurement and preservation. Despite these possibly adverse influences, the immediate clinical effects following successful pancreas transplantation are dramatic. Within the first 24 h, the allograft provides a self-regulating source of insulin: none of the recipients in our series required any intra- or postoperative exogenous insulin. Fasting blood glucose levels are typically mildly subnormal (60–90 ml/dl) because of the systemic venous drainage of the pancreas allograft. Interestingly, symptomatic hypoglycaemia has not been reported by these recipients. Glycosylated haemoglobin levels return to normal within 2 months after transplantation (Fig. 9) 731, and the majority of recipients have normal responses to oral and intravenous glucose tolerance tests. Serum C-peptide and serum insulin levels are increased, both because of the systemic delivery of insulin and the decreased insulin sensitivity induced by steroid therapy.

 

Subjectively, the allograft recipients have been enthusiastic over their sense of well-being and freedom from years of insulin dependence and dietary restrictions. However, the precise impact of pancreas transplantation on the secondary complications of diabetes remains to be defined. While studies in laboratory animals have provided good evidence to suggest that pancreas transplantation can prevent and even reverse the early degenerative complications of diabetes, fewer data are available from humans. Most patients selected for pancreas transplantation to date have suffered from near end-stage diabetes, and advanced microangiopathic lesions are unlikely to regress substantially following correction of glucose metabolism. Nevertheless, some encouraging clinical evidence is beginning to accumulate, especially with regard to diabetic nephropathy. For example, pancreas transplantation prevents the simultaneously placed renal allograft from developing the histological lesions of diabetes which are typically seen after 1 to 3 years in diabetic patients receiving renal allografts only. Furthermore, in instances in which kidneys of a diabetic cadaveric donor have been transplanted into non-diabetic recipients, the microscopic lesions of mild nephropathy have been observed to reverse. Reversal of mild functional and morphological lesions in the kidneys of diabetic recipients without end-stage nephropathy has also been observed following pancreas transplantation. These observations indicate not only that diabetic glomerular lesions may be preventable, but also that early diabetic nephropathy may even be reversed if normal glucose homeostasis is provided. The progression of diabetic polyneuropathy has also been observed to cease once euglycaemia has been achieved by successful pancreas transplantation. Evaluation of this evidence is difficult, however, since correction of uraemia alone by a renal allograft often produces improvement in diabetic polyneuropathy. A number of investigators have reported stabilization or improvement in diabetic retinopathy in recipients of pancreas allografts, while others have failed to observe a consistently beneficial effect on established retinopathy.

 

CONCLUSIONS

Progressive improvement in the success rates of pancreas transplantation has prompted a rapidly expanding application of this procedure. More than 2000 cases have now been reported to the International Human Pancreas Transplant Registry, with the number performed during the past several years exceeding the worldwide total for the previous 20 years. Survival rates following combined pancreas and kidney transplantation are now approaching those achieved for renal allografts alone. As with most innovative therapeutic approaches, pancreas transplantation has been initially evaluated only in patients with already advanced complications, such as uraemic diabetics who are already candidates for renal transplantation and immunosuppressive therapy. Our experience, and that of others using this approach, has emphasized that most of the postoperative morbidity and failure of rehabilitation is directly related to the severity of the patient's pretransplant complications. With the establishment of the reasonable safety of this procedure, even in these patients with more severe disease, pancreas transplantation is now being offered to diabetics with less severe secondary complications.

 

Because only approximately half of the patient population with juvenile onset diabetes eventually develops clinically significant angiopathic complications, specific criteria are required to enable selection of appropriate candidates for pancreas transplantation. Unfortunately, it is impossible to identify at the time of onset of diabetes patients who will be most susceptible to the deleterious effects of deranged glucose metabolism. The most reliable early predictor of further complications continues to be renal dysfunction. Thus, we are currently recommending that combined kidney and pancreas transplantation be performed in patients with impaired renal function which has not progressed to dialysis dependence. We anticipate that the restoration of normal glucose metabolism at this earlier stage of the disease might be more effective in delaying or preventing the progression of microangiopathic complications. Obviously, if this expectation is realized and reliable means of diagnosing early rejection in the pancreas are developed, the logical approach would be to evaluate pancreas transplantation alone in patients with minimal albuminuria but normal renal function. In these patients, the expectation would be that euglycaemia might prevent the otherwise consistently predictable progressive renal failure and later need for kidney transplantation.

 

In summary, we and others have shown that vascularized pancreas transplantation can be preformed successfully, that such transplantation provides normal glucose metabolism, and that this can be accomplished with only a modest increase in risk over that of renal transplantation alone. In order to achieve the full therapeutic benefit of pancreas transplantation we still need to determine when in the course of the diabetic illness the procedure will be optimally effective in delaying or preventing secondary complications. Currently used procedures will almost surely become outmoded as islet transplantation is perfected or molecular approaches to regulation of insulin gene expression are defined. Meanwhile, it seems reasonable to continue exploration of the benefits of vascularized pancreatic transplantation in a gradually expanding population of insulin-dependent diabetics.

 

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