9b Pancreatic transplantation: indications and results

9b Pancreatic transplantation: indications and results X. MARTIN J. M. DUBERNARD N. LEFRANCOIS

Insulin-dependent diabetes mellitus is a major health problem in all developed countries because of its frequency and the high incidence of vascular complications. For example, in France, a survey in 1985 estimated that the prevalence of type I diabetes was between 150 000 and 250 000; the incidence of new cases of insulin-dependent diabetes was approximately 50 per million per year. The majority of cases occurred during childhood (Laporte and Tajima, 1985). Complications of diabetes fall into three categories: infectious, metabolic and degenerative. Degenerative complications may be macro- or microangiopathic. Macroangiopathic complications are not specific to diabetes and result in disease of the coronary, lower limb and cerebral vasculature. Microangiopathy in the diabetic most commonly results in retinopathy and nephropathy. Twenty years after the onset of Type I diabetes nearly 100% of patients suffer from retinopathy and 30% from nephropathy (Andersen et al, 1983; Krolewski et al, 1987). Advances in the treatment of diabetes and its degenerative complications have resulted in an increase in the number of diabetic patients requiring and being treated for chronic renal insufficiency. In France, at present, there are approximately 60 new patients with end-stage renal failure per million population per year. Nearly 10% of new patients requiring dialysis are diabetics. Considerably higher figures are found in other countries, such as 19% in Sweden and 34% in Finland (Brunner et al, 1988; Cordonnier et al, 1988). As a consequence of the improved treatment of diabetes and the increased life expectancy of diabetics, diabetic nephropathy is the only cause of end-stage renal failure that is increasing (Brunner et al, 1988). The management of patients with end-stage diabetic renal failure has changed considerably over the past three decades. In the 197Os, physicians were reluctant to offer haemodialysis to these patients since the mortality rate was high. However, there have been major improvementsin the management of patients with chronic renal failure owing to improved techniques of haemodialysis and peritoneal dialysis; furthermore, the results of renal transplantation in diabetics have been encouraging (Najarian et al, 1977). The first pancreatic transplants, performed in 1966 in the USA by Kelly BailliPre’s

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and Lillehei were successful, but only in the short term. Nevertheless, they did show that such a technique could result in insulin independence (Kelly et al, 1967). The increasing number of patients receiving pancreatic transplants was due to two major factors: the development of new transplantation techniques, developed by Dubernard et al (1978), and the introduction of cyclosporin. This later allowed the dose of glucocorticoids to be reduced. Currently, more than 3000 pancreatic transplants have been performed (Sutherland et al, 1989). Currently, pancreatic transplantation appears to be the only treatment able to combat diabetes, removing the need for insulin therapy and restoring normal glucose metabolism as shown by a return to normal levels of glycosylated haemoglobin. Furthermore, pancreatic transplantation improves the quality of life of the formerly diabetic patient by removing the consequences of unpredictable variations in blood glucose concentration, allowing a normal diet and removal of other constraints upon the patient’s activities. The main aim of pancreatic transplantation, however, is to slow down, stabilize or even reverse the degenerative complications of diabetes. Evidence for such a beneficial effect of pancreatic transplantation on the consequences of diabetes are becoming clearer (Sutherland, 1989). However, such an effect has been difficult to demonstrate since, in the early series, pancreatic transplantation was reserved for the diabetic patient with end-stage nephropathy, which was often associated with end-stage macroand microangiopathic degenerative complications. However, the increasing use of isolated pancreatic transplantation in non-uraemic patients has demonstrated the beneficial effect of this surgery for some of the diabetic complications (Sutherland et al, 1988). The outcome of pancreatic transplantation has gradually improved since 1985, but results are less good than those for other organs. This is, in part, due to the fact that many recipients have micro- and macroangiopathy which are themselves associated with a high degree of morbidity and mortality. Surgical problems relate to the dual functions of the pancreas (endocrine and exocrine), although it is only the endocrine functions that are required. Furthermore, in contrast to other organ transplantation, there are no early and reliable markers of rejection and many grafts are lost because of late diagnosis of rejection. INDICATIONS

FOR PANCREATIC

TRANSPLANTATION

Pancreatic transplantation can be performed either alone or with a kidney. Approximately 80% of pancreatic transplants are performed in conjunction with a simultaneous kidney transplant. The remaining 20% are isolated pancreatic transplants in non-uraemic diabetics or diabetics with a wellfunctioning renal graft (Sutherland et al, 1991). Simultaneous kidney and pancreatic transplantation

The indications for a simultaneous patients with type I diabetes are:

pancreas and kidney

transplant

in

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2.

3. 4.

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In diabetic patients awaiting a renal graft (an operation requiring immunosuppressive therapy), simultaneous pancreatic transplantation seems logical as the diabetes itself can be treated and recurrence of diabetic nephropathy in the renal graft can be prevented. Pancreatic transplantation itself does not appear to add any surgical risk to a renal transplant (Traeger et al, 1989). In our experience no patient has died as a result of technical problems related to pancreatic transplantation (i.e. pancreatitis or pancreatic infection). The survival of patients undergoing a double graft is not significantly different from that of the non-diabetic patient receiving only a kidney graft (Lefrancois et al, 1989). Rejection in the renal allograft may be an early marker for associated pancreatic rejection (Lefrancois et al, 1989). Patient survival rate is higher when the pancreas is transplanted with the kidney (Sutherland et al, 1989).

The best time to perform a pancreatic transplantation in a patient with progressive diabetic nephropathy remains controversial. At present, a double transplant is performed when the patient has end-stage renal failure, controlled by either haemodialysis or peritoneal dialysis. The International Registry of Pancreas Transplants held by Sutherland in Minneapolis reports that the best results in terms of pancreas survival are achieved when the operation is performed with the patient in end-stage renal failure. However, the survival rate is better if the operation is carried out at an earlier stage (Sutherland et al, 1989). Chronic renal insufficiency, dialysis and multiple blood transfusions have been implicated as the cause of the improved pancreas survival, but these factors have had less effect since the introduction of cyclosporin (Cecka and Cicciarelli, 1985). As indicated above, it is with this form of transplantation that the beneficial effect of a transplant on the degenerative complications of diabetes is most difficult to evaluate since in many patients these complications are already well established. Our experience of such patients, the average age was 39 years and diabetes had been present for a mean of 25 years. The majority (88%) were undergoing dialysis. Twenty-eight per cent of grafted patients were already blind, 74% had neuropathy of the lower limbs and 20% had coronary artery disease. The present tendency, therefore, is to offer transplantation before the patient is end-stage and requiring haemodialysis, thus sparing the patient the consequences of end-stage chronic renal insufficiency (Stratta et al, 1993). In summary, the combined kidney and pancreas transplant should be considered as the treatment of choice for patients with type I diabetes and established nephropathy. Isolated pancreas transplantation

This operation is indicated in a patient, in a non-uraemic patient who has had a previous renal transplant.

patient or in a

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renal transplantation

The advantage of this approach is that the pancreatic transplantation is performed when the patient is in better health, when renal function is normal or stabilized, and immunosuppressive therapy has already been given. However, most reports of this approach suggest that results are less satisfactory in terms of graft survival than those obtained with simultaneous pancreas and kidney transplants (Sutherland et al, 1989). Isolated pancreatic transplantation

Few teams carrying out pancreatic transplants undertake isolated pancreatic transplantation in non-uraemic patients since the outcome remains far from satisfactory. Ideally, such a procedure could be performed in all diabetics before the onset of degenerative complications. However, it is not possible to predict which patients are likely to develop these problems. Although pancreatic transplantation may result in a freedom from insulin which cannot be achieved with any other form of therapy, this is at the expense of long-term immunosuppressive treatment and hyperinsulinism. Thus, apart from rare cases of very labile diabetes, the aim of achieving a state of insulin independence is not sufficient in itself to justify the consequences of chronic immunosuppression unless the favourable effects on the degenerative complications of diabetes can be clearly identified (Sutherland, 1990). Indications at present are for the procedure to be performed inpatients with at least one degenerative complication in whom further progression would have greater consequences than those of long-term immunosuppression. Sutherland, an advocate of this form of transplantation, has clearly demonstrated the beneficial effect of pancreatic transplantation for some degenerative complications (Sutherland et al, 1988). Although the functional results are still unsatisfactory, patient survival is excellent (Sutherland et al, 1989).

SELECTION

AND EVALUATION

OF RECIPIENTS

Assessment of potential recipients of pancreatic transplants involves the general assessment common to all transplant candidates (such as exclusion of those with intercurrent infection or malignancy) and those tests specific to diabetic patients (Table 1). It is important to confirm the presence of type I diabetes and to assess the extent of complications such as macroangiopathy and of degenerative complications that may contraindicate transplantation. It is important to confirm the presence of type I diabetes. Type II diabetes is not an indication for transplantation, although its progression is often similar to that of type I. Long-standing obesity, onset of diabetes in adulthood and good control of the diabetes are all features suggestive of type II disease. C-peptide determination in a glucose tolerance test followed by a glucagon test will allow confirmation of type I diabetes by showing reduced levels of C-peptide which are not increased on stimulation. Examination for microangiopathy in our centre includes angiography of

PANCREATIC TRANSPLANTATION-INDICATIONS Table 1. Pretransplantation Standard

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evaluation protocol.

check-up

Blood urea, creatinine, electrolytes and liver function tests Blood lipids Full blood count, coagulation tests Creatinine clearance, protein excretion Chest radiology, abdominal ultrasonography Consultations: nephrology, diabetology, anaesthesia and surgery, gynaecology and dental Immunology

and viral

check-up

ABO typing HLA typing Anti-HLA antibodies Viral serologies: hepatitis B and C, Epstein-Barr immunodeficiency virus, cytomegalovirus Diabetes

virus, herpes simplex virus, human

check-up

Glycosylated haemoglobin Glucose tolerance test, C-peptide and insulin (basal and after stimulation) Anti-islet and anti-insulin antibodies of complications of diabetes Cardiovascular: ECG, cardiac echography, myocardial effort scintigraphy, coronary angiography if scintigraphy positive; Doppler ultrasonography of lower limbs and carotids; iliac lower-limb angiography; autonomic neuropathy studies Ocular: background staining, visual acuity, fluorescein angiography Neurological and gastrointestinal: nerve conduction studies of all limbs; upper gastrointestinal endoscopy Genitourinary and renal: intravenous urography with post-micturition radiography completed by cystomanometry if necessary; evaluation of sexual function Check-up

Respiratory (if necessary): respiratory function tests and arterial blood gases 5.

Psychological

examination

Counselling of patients Ensuring reliability of taking immunosuppressant drugs

the aorta, iliac and lower-limb arteries. This shows the state of iliac vessels involved in transplantation and identifies the need for dilatation or endarterectomy before surgery. It is also important to examine in detail the peripheral vascularization of the lower limbs because of the high frequency of distal atheromatous lesions. Doppler examination of the lower limbs will allow assessment of the functional consequences of any vascular abnormality. When the distal lesions are pronounced and inaccessible to surgery, the risk of a vascular steel by the graft must be considered and may even contraindicate transplantation. When the lesions are asymmetrical, it is preferable that the kidney is put on the side with the fewest lesions. Cardiac examination must be thorough since this is the major cause of death in diabetics (Braun et al, 1983). In our experience, cardiovascular complications are the main cause of death in patients receiving simultaneous double transplantation. The results are similar to those reported in the

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literature for kidney transplantation alone (Rohrer et al, 1986). Cardiac echosonography can detect latent cardiac insufficiency and show the state of the myocardium by determining the systolic ejection fraction. Thallium scintigraphy with the persantin test will show any ischaemic myocardial areas that may not be evident from the ECG. When the myocardial scintigraphy scan is positive, or when there are other risk factors such as older age or a previous limb amputation because of diabetic arteriopathy, coronary angiography should be undertaken. High-risk patients can be identified before surgery and correctable coronary artery lesions identified and treated. Patients with a diffusely ischaemic myocardium should undergo full cardiac catheterization since overt cardiac insufficiency is a contraindication to transplantation. Significant coronary artery disease that cannot be readily corrected is in some centres a contraindication to double transplantation (Velosa et al, 1990). However, other groups have suggested that those with coronary artery disease (stenosis >70% in one or more arteries) have a better survival rate after transplantation than those who are not transplanted (l- and 5-year survival rates of 100% and 40% compared with 65% and 6% in the non-transplanted group) (Cheung et al, 1993). Finally, cystography followed, if necessary, by vesical cystomanometry will show the extent, if any, of vesical neuropathy, which may be important if bladder implantation techniques are used. The extent of any degenerative complications (ocular, peripheral or autonomic neuropathies) will be useful as a base-line for further evaluation following transplantation. The indications for pancreatic transplantation are summarized in Table 2. Table 2. Indications for pancreatic transplantation. Type I diabetes Absence of contraindications for the transplantation in general Age < 60 years Stable cardiac condition Absence of cardiac insufficiency Absence of recent myocardial infarction Stabilized blood pressure Stabilized ocular condition (absence of recent haemorrhage) Satisfactory cutaneous condition (absence of progressive gangrenous lesion) Vascular condition permitting organ implantation Ambulant patient

OPERATIVE

TECHNIQUE

Evolution of techniques When pancreatic transplants were first performed, corticosteroids formed the basis of immunosuppressive treatment. In 1966 Kelly and Lillehei used the technique of total duodenopancreatic transplantation with drainage to the digestive tract, but the high incidence of fatal complications, such as the development of fistulas, led to early abandonment of this technique (Kelly et

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al, 1967). Pancreatic transplantation was abandoned for many years since it was technically difficult to drain the exocrine secretions without the development of fistulas and peritonitis. In the 1970s Dubernard demonstrated in animal models that intraductal administration of neoprene resulted in atrophy of the endocrine gland without modifying the function of the islets of Langerhans (Dubernard et al, 1978). Dogs that had been transplanted with pancreas injected with neoprene survived without diabetes for over 10 years. The reduction in the pancreatic secretions obtained in this experimental model of intraductal injection was successfully achieved in humans in 1976. Neoprene was used as it can solidify by flocculation when it comes into contact with alkaline fluid. In practice, this occurs in the pancreatic acini. Other substances have been tested in the laboratory, including latex and Ethibloc@, with results similar to those obtained with neoprene. Some B-emitting radioactive substances have been given by intraductal injection, and results have shown a transient reduction of exocrine secretion without any modification of endocrine function. The lack of need to drain secretions and the absence of general complications such as peritonitis resulted in this method of pancreas transplantation being used up to the 1970s. In the following decade, the introduction of cyclosporin allowed the dose of corticosteroids to be reduced considerably. This resulted in a return to the techniques of pancreatic transplantation with drainage into the gastrointestinal tract. Some groups have used a segmental graft, which was easier to procure, and drained the duct into the gut using a Roux-en-Y loop. Others have used a total graft with interposition of the duodenum serving as a patch for restoration of gut continuity (Groth et al, 1976, 1982). More recently, Sollinger et al (1984) described the technique of vesical drainage of the digestive secretions. In addition to its use in allowing drainage of pancreatic secretions, this technique also enables monitoring of graft function by measuring, for example, urinary amylase concentration. This technique of total pancreatic transplantation with vesical drainage has come to be used extensively in both North America and Europe. By using a segmental graft, it is also possible to allow drainage into the bladder by creating a mucomucosal anastomosis between the pancreatic duct and vesical mucosa. At the same time as the development of these techniques of pancreas transplantation where venous drainage was systemic, other authors were developing techniques of portal venous drainage of pancreatic blood. This is more physiological with respect to insulin metabolism. For each of the pancreas transplant techniques, there are advantages and disadvantages. It is difficult to compare all these techniques since their development has extended over many years. The data from the International Pancreas Transplant Registry clearly indicate that the only reliable method of comparing different techniques is in the context of prospective trials. The findings of these studies suggest improved metabolic control with total grafts but more complications and associated morbidity with vesical or intestinal bypass techniques. Most of the major European centres have not confirmed the excellent results of groups in North America.

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In conclusion, there is, as yet, no ideal technique. It is still too early to abandon research in pancreatic transplantation. Transplantation of Langerhans cells is still beset with a number of problems, including rejection, the large number of donors required to perform islet transplantation and uncertainty about the number of islet cells to be transplanted. Solutions are unlikely to be available in the next few years. Donor procurement Donor selection involves the same basic criteria as those for other organs. For pancreatic transplants the best organs come from those who are aged < 50 years, since above that age the number of islets decreases significantly with time. It is important to exclude pancreatic disease (including chronic pancreatitis and alcoholism). The pancreas should not be taken from those with significant post-traumatic haematomas or haemodynamic instability as it is very sensitive to ischaemia. The most commonly used approach is to perform a midline mentopubic incision for multiple organ harvesting. Depending on the haemodynamic state of the donor, a rapid en bloc procurement with dissection of the already perfused organ on the back-table is possible but requires much preparation. When the haemodynamic status of the donor is satisfactory, a beating heart procurement can be performed. This technique takes longer but allows for a more systematic ligaturing of all the small vessels sectioned at the time of dissection. En bloc procurement hepatopancreatic

technique preparation: block

extraction of the

After incision and mobilization of the colon, a small ligature is placed on the inferior vena cava. The lower part of the roof of the mesentery is cut and the suprarenal aorta is dissected, under which a ligature is placed and the aorta and vena cava are cannulated. The coeliac axis is also dissected and a ligature placed around it. After clamping the abdominal aorta, the aorta is perfused with University of Wisconsin (VW) solution. About 3 litres are usually required for perfusion of liver, pancreas and kidneys. To save on cost, a clamp may be placed at the level of the superior mesenteric artery, sufficiently far from its origin so as not to obstruct a possible right hepatic artery or the lower branches supplying the pancreas. Supplementary cooling with ice-cold serum poured into the abdominal cavity is always undertaken. The liver is then removed by sectioning the triangular ligaments and the ligaments of the suprahepatic inferior vena cava. Dissection then continues towards the aorta following the coeliac trunk. Once the aorta has been reached, ligation of the semilunar ganglions reveals the origin of the superior mesenteric artery. A large patch of the aorta with the superior mesenteric artery and coeliac trunk can be removed. Dissection of the rest of the pancreas is facilitated by sectioning the first segment of the duodenum and duodenojejunal angle using GIA pincers. Dissection is continued as far as the tail of the pancreas, which is removed with the spleen.

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During the dissection the stomach is pulled upwards and the lesser sac is opened. The final step is to cut the mesentery and the superior mesenteric vessels (artery and vein) where they emerge from the pancreas. The duodenopancreaticohepatic bloc can then be removed from the abdominal cavity and placed in a bowl with UW fluid and crushed ice. Dissection can be continued with the organs protected against warm ischaemia. In the case of a total duodenopancreatic transplantation, the portal vein and hepatic pedicle are dissected. It is preferable to dissect the portal vein over its entire length so as to allow an adequate distribution for the two transplantation teams. During the dissection, the hepatic artery is identified. If the liver transplant is done using end-to-end anastomosis of the hepatic artery, this artery can be sectioned level with the gastroduodenal artery. In this case, the pancreas transplant will be vascularized on the one hand by its coeliac pedicle, by taking the splenic artery and the common hepatic artery, and on the other hand by the superior mesenteric pedicle including the inferior pancreaticoduodenal artery. When the liver is taken with the coeliac trunk, the splenic artery, gastroduodenal artery are cut at their origin. In this case the pancreas transplant will include the splenic pedicle and the superior mesenteric pedicle. The presence of two out of the three arterial pedicles of the gland seems sufficient to provide an adequate vascularization. Arterioplasty can be performed so as to revascularize only one pedicle. In this case an iliac bifurcation is removed and the splenic artery anastomosed end-to-end to the ostium of the hypogastric artery; the superior mesenteric artery is anastomosed to the ostium of the external iliac artery. The terminal branch of the iliac artery can be cut obliquely and can serve as an anastomosis on the recipient vessel. An alternative is to perform an end-toside anastomosis of the splenic artery with the superior mesenteric artery, if the latter has been taken with a sufficient aortic patch. To perform this arterioplasty, it is necessary to resect the sympathetic elements in this region which separate the two arterial pedicles. The duodenal area should be refashioned so as to leave a portion of the second part of the duodenum. The duodenal stumps can be sutured with mechanical TA pincers. The stump may be buried using non-resorbable thread. It is important to check for the absence of vascular leaks by reperfusion with UW solution. In the case of segmental grafts, the procurement is easier. The isthmus of the pancreas is sectioned at the base of the portal vein and a segment taken at the level of splenic vein implantation to serve as a lengthening patch if necessary. The splenic artery may be sectioned at the base of the coeliac trunk, in which case it can be lengthened using a segment of iliac artery taken from the same donor. If there is a coeliac trunk present, it can be used to lengthen part of the splenic vein and thus facilitate reimplantation in the recipient. It is important not to dissect the splenic artery too far from its origin so as to avoid damaging the small pancreatic branches that vascularize the tail of the pancreas. To ensure that the segmental graft is adequately vascularized, the graft should be perfused to confirm adequate venous flow. In all cases careful haemostasis should be performed at the level of the splenic vessels.

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Preparation of the pancreas is carried out in cold UW solution. For a duodenopancreatic graft it is our custom to open the duodenum and wash it with a solution of Betadine (povidone-iodine) before preservation. Technique of procurement

with a beating-heart donor

For a total duodenopancreatic graft, part of the splenorenal ligament should be cut to expose the gastrosplenic sac. The posterior cavity is then opened to show the pancreas and confirm the absence of oedema. The posterior cavity is opened as far as the spleen. After the splenocolic ligament has been sectioned it is possible to separate the pancreas. The tail of the pancreas is removed using the spleen as a handle. The dissection is performed from left to right as far as the superior mesenteric vein. The inferior mesenteric vein must be tied. At the superior edge of the pancreas, when the tail of the pancreas is pedicled, the splenic artery can be felt pulsating and can serve as a guide to direct the dissection towards the coeliac trunk. The coronary vein and artery can be tied at this point. The gastroduodenal artery is clearly visible to the right and can be followed as far as the hepatic artery. This can then be identified and dissected as far as the coeliac trunk. The hepatic branch is dissected and the portal vein ligated. The duodenum can then be cut with GIA pincers at the level of the gastroduodenal artery. The duodenal-jejunal angle is identified and sectioned with GIA pincers. The superior mesenteric vein and branches of the superior mesenteric artery are tied where they emerge from the pancreas. The dissection is completed by sectioning the semilunar ganglions level with the aorta. The coeliac trunk and superior mesenteric artery are identified during this procedure. Once the dissection is finished, intra-aortic perfusion with UW solution can be started. Organ procurement is then carried out by first removing the liver, the pancreas and then the kidneys. An aortic patch is taken with the coeliac trunk and the superior mesenteric artery. For a segmental graft the procurement is much easier. It needs only the time to dissect the tail of the pancreas and identify the splenic artery, the superior mesenteric artery and the portal vein. Liver and pancreas procurement

in the same donor

In most cases procurement of the liver is performed at the same time as that of the pancreas. The only contraindication for total pancreas procurement is the presence of a right hepatic artery originating from the superior mesenteric artery. However, in such cases it is always possible to take a segmental graft. Procurement

in the living donor

This is only rarely performed and is justified following renal transplantation from the same donor. The technique is similar to that performed on the cadaver but the spleen is left in place, its vascularization being assured by the

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short splenic vessels. The splenic artery is cut at its origin and the splenic vein sectioned at its end. Pancreas procurement

and sharing for two recipients

This technique is also exceptional, and is justified only when there are several hyperimmunized recipients for the same donor. A total duodenopancreatic graft is taken first. On the back-table it is then split into a segmental graft, pedicled on the splenic artery and the splenic vein. The head of the pancreas is pedicled on to the coeliac trunk, if it has been preserved, and the superior mesenteric artery. The trunk of the portal vein, which receives the veins of the pancreatic arcades, provides venous drainage. Surgery in the recipient Surgical peculiarities

in diabetics

In patients with long-standing insulin-dependent diabetes, the iliac vessels are often the site of significant atheroma. Advances in the medical management of diabetes and in the prevention of hypercholesterolaemia have resulted in a considerable decrease in the significance of these macroangiopathic complications. None the less, they remain a problem. If calcified arteries and large ulcerative atheromatous plaques are present, the vessel is often very fragile and the intima detaches easily. These vessels should therefore be handled with great care. Handling and clamping can lead readily to detachment and dissection of the intima with consequent ischaemia. The autonomic neuropathy affecting the gastrointestinal tract often makes it difficult to re-establish normal intestinal function. Recovery is generally more rapid when surgery is performed by a retroperitoneal rather than an intraperitoneal route. Autonomic neuropathy may also result in orthostatic hypotension after surgery and give rise to decreased blood flow in the graft and increase the risk of arterial thrombosis. It is, therefore, important to ensure mobilization of the patient early but slowly and, if need be, to maintain a high intravascular pressure with colloid infusion. Segmental pancreatic transplantation

Neoprene is injected before revascularization of the graft. A small catheter is inserted in to the duct of Wirsung at a distance of about 5 cm. A pouch is formed with non-resorbable thread around the canal and tightened on the catheter to prevent any leakage of neoprene during the injection. At the same time, two Kocher pincers without claws are placed on the section slightly above the graft. Between 2 and 5 ml neoprene is injected. Injection should be administered without undue pressure; the surface of the pancreas turning white indicates good injection of the entire gland.

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The approach for segmental pancreatic transplantation with injection of neoprene may be retroperitoneal and should be made with an iliac incision, but a subumbilical median incision is also possible. The recipient site is generally the external iliac axis. The orientation and arrangement of the vessels of the segmental vessel usually mean that the vascular arrangement is easier when the transplantation is on the right side. Before clamping the vessels, the site of the anastomosis is selected by placing the graft in the operative field. Grafts may be placed in the external iliac fossa with the splenic extremity pointing to the inferior pole of the right kidney, in which case the graft is placed with the posterior face to the front. The segmental graft can also be positioned laterovesically, in which case a small logette must be made by detaching the anterior part of the bladder. The caudal extremity of the pancreas is positioned in the subperitoneal region in front of the bladder. The pancreas is positioned with the anterior face to the front. Whatever the position of the graft, the vascular anastomoses are somewhat displaced. In general, the venous anastomosis is situated lower down on the iliac axis than the arterial anastomosis. The venous anastomosis is performed after having made two semicontinuous stitches with nonresorbable thread. The arterial anastomosis is slightly displaced upwards and is also fashioned by a continuous stitch with 5/O thread. When the recipient vessels are very atheromatous and it is dangerous to clamp them, it is possible to place two Fogarty probes by an endoluminal routine to achieve haemostasis while the arterial anastomosis is being performed. When the vessels are clamped and haemostasis of the graft is achieved, the graft is positioned to obtain the best arrangement of the vessels. To promote reabsorption of the pancreatic juice, which may leak from the sectioning of the graft, a peritoneal opening can be made. The greater omentum is drawn through the opening and positioned around the graft. The peritoneal breach is closed sufficiently tightly to prevent herniation of the intestine. It is also possible to perform transplantation of pancreatic segments with vesical or digestive drainage. For segmental transplantation with vesical drainage, the pancreatic duct is anastomosed directly with the vesical mucosa. Supports are then passed round between the detrusor and the pancreatic parenchyma. For segmental transplantation with drainage, a Roux loop is positioned on the pancreatic section slice. A catheter is placed in the duct of Wirsung to permit drainage of pancreatic secretions and prevent scarring of the iliac-pancreatic anastomosis. This also allows measurement of the pancreatic liquid and determination of its amylase concentration. Total pancreas transplantation

When the transplantation is performed with drainage into the bladder, the pancreatic graft is positioned with the duodenal region towards the bottom. It is preferable to place it in the right side to obtain an optimal arrangement of the vessels. In this case, the vein is slightly displaced downwards in

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relation to the arterial anastomosis. When the graft is positioned retroperitoneally, it is important to detach the peritoneal sac sufficiently far up so that the graft is not compressed in this site. When the graft is positioned intraperitoneally, its upper extremity can be positioned behind the caecum, which needs to be detached to give access to the iliac vessels. Duodenovesical anastomosis can be performed after opening the detrusor at the dome of the bladder, either with two strands of non-resorbable thread using a continuous stitch or, if necessary, by suturing with EEA pincers. In this case, the anterior portion of the bladder should be opened beforehand to position the lower part of the stapler. This endovesical approach will then enable the surgeon to make a continuous stitch from the inside of the bladder, thus ensuring haemostasis of the mechanical anastomosis and the new cystostomy for the kidney transplant. For a duodenopancreatic transplantation with gut drainage, the pancreas is positioned with the duodenal part towards the top. The side-to-side anastomosis between the ileum and duodenum allows drainage of exocrine secretions. A catheter can be placed in the duct of Wirsung, which will emerge from the jejunum by a trajet d’enfouissement. Closure of the incision is generally performed with non-resorbable thread, as resorbable thread may not last sufficiently long for patients treated with glucocorticoids . For a second pancreatic transplant, the second pancreatic graft may be positioned above the first. It is also possible to resect the rejected graft and place a second on the external iliac vessels on the site of the first graft. SURVEILLANCE

OF THE PANCREAS

GRAFT

RECIPIENT

Perioperative surveillance Choice of anaesthesia

General anaesthesia appears to be the anaesthetic of choice for such a procedure. Myocardial depressant drugs are to be avoided. Isoflurane induces only slight myocardial depression. Alfentanil has a shorter half-life than fentanyl and a more rapid elimination and is, therefore, more suitable. SulfentaniP can also be administered in patients with renal insufficiency without the need for reduction of dose. Atracurium appears to be the ideal muscle relaxant. Surveillance of the diabetes

The aim is to maintain a blood glucose level between 6 and 8 mmol/l before, during and after operation. Continuous insulin infusion and measurement of the blood sugar level every 30min usually allows normoglycaemia to be maintained. Utilization of an artificial pancreas is costly and needs specially trained staff. In practice, normoglycaemia is difficult to maintain since the tendency to hyperglycaemia is increased by insulin resistance related to

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therapy given before operation, to surgical stress and to renal

of the patient

In diabetic patients, it is particularly important to avoid nerve compression. The use of a Swan-Ganz catheter is very helpful in optimizing volume replacement. Perioperative

complications

In our experience there are few complications despite the diabetic background. Haemodynamic instability is found in 52% of patients with prolonged arterial hypotension (> 20 min) in 10% of patients (Mercatello et al, 1989); hypotension is associated with poor perfusion of the graft. Postoperative monitoring Immunosuppressive

treatment

At present, the immunosuppressive protocols most widely used in pancreatic transplantation are derived from experience gained in renal transplantation. However, the effect of immunosuppression on pancreatic transplantation is difficult to analyse when graft survival is considered. It remains difficult and sometimes impossible to diagnose early an episode of graft rejection, and there is still uncertainty as to the proportion of grafts that are lost from immunological causes. At Lyons, we used an initial quadruple immunosuppressive regimen with cyclosporin, azathioprine, corticosteroids and polyclonal antilymphocyte globulin (Dubernard et al, 1980b). Monoclonal serum is used only for the treatment of rejection. The aim is to maintain a minimum administration of glucocorticoids, thus avoiding their negative effect on pancreatic function. Nephrotoxicity is a well-known side-effect of cyclosporin therapy, but there are conflicting data in the literature regarding its toxic effect on the pancreas. Diabetics seem to require higher doses of cyclosporin than non-diabetic recipients of kidney and pancreatic transplants, and this may be related to neuropathy affecting the gastrointestinal tract (Cantarovich et al, 1992a). Other treatments Anticoagulation therapy. This is justified because it reduces the risk of pancreatic venous thrombosis, an early complication of pancreatic transplantation, although there has been no controlled study to confirm its benefit. In our centre we use low-dose heparin (100 units/kg daily). This is followed in the second postoperative week by platelet inhibitors (Nader et al, 1993). Antibiotic therapy. Because of the increased risk of infection, use antibiotic therapy involving p-lactams and quinolones.

most teams

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Other treatment. Antacids or Hz-blockers are generally used. Cardiovascular medication (for hypertension or angina) often needs to be continued after transplantation. Post-graft period

This period is indicated by resumption of diuresis following transplantation of the kidney. The rate of acute tubular necrosis is low in our series (8%) and is related to the short ischaemia time. The unstable cardiovascular status of most patients requires strict monitoring of weight and fluid balance. Food should be started as early as possible, but this is often difficult so enteral or parenteral nutrition may be required. Pyrexia is not uncommon and antibiotics should be used if there is a suspicion of infection. PANCREATIC

REJECTION

Pancreatic rejection is difficult to diagnose because early markers of endocrine pancreatic rejection do not exist. Furthermore, biopsy of the pancreas is not easy to perform, causes morbidity, and results are difficult to interpret. The incidence of technical failure in pancreatic transplantation, such as thrombosis or inflammation, is relatively high (11% in a recent report from the International Registry). Rejection, however, remains the most frequent cause of pancreas loss (Dubernard et al, 1980b). However, in the case of simultaneous kidney and pancreatic transplantation from the same donor, Dubernard et al (1980b) reported that features of kidney rejection occur earlier than those of pancreatic rejection; the kidney is therefore an excellent marker of rejection, and antirejection therapy given for kidney rejection may mask or prevent concomitant pancreatic rejection. Some centres try to make an earlier diagnosis of pancreas rejection based on analysis of exocrine secretion (vesical or percutaneous), when decreased activity is thought to be an early sign of rejection of the exocrine portion of the pancreas. This allows early treatment, thereby avoiding rejection of the islets of Langerhans (Gil-Vemet et al, 1986; Sollinger et al, 1990). The clinical and biological manifestations of pancreatic rejection are non-specific and there are many causes for dysfunction of graft. These include thrombosis, pancreatitis, infection, fibrosis and ischaemia. Rejection of the pancreas is evidenced mainly by deterioration of endocrine function (hyperglycaemia) or exocrine function (increased amylase concentration in the urine if vesical drainage has been performed). Local or general inflammatory signs that may be observed in kidney rejection are unusual. Amylasaemia

In most cases of rejection, the level of serum amylase is not significantly increased. However, some have reported a slight increase in serum amylase concentration before the onset of rejection (Tyden et al, 1984).

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Concentration of amylase in the pancreatic juice (drained in the bladder or externally through a catheter)

Pancreatic rejection is accompanied by a fall in the urinary amylase level. This decrease in the amount of amylase in the pancreatic juice is at present considered to be the best test for pancreatic rejection. However, specificity may be low and interpretation difficult on account of variations in the flow of urine. Modification

of blood sugar levels

A change in the level of blood sugar is the most specific marker of pancreatic rejection, but occurs later. During rejection, the earliest modifications in blood sugar levels are observed after meals. These changes occur about 5 days before fasting hyperglycaemia develops (Groth et al, 1980). The second and larger rise in blood sugar concentration on fasting is often a sign of irreversible rejection. Levels of C-peptide

During rejection the rate of C-peptide secretion decreases, whereas it is normal or even increased when there is insulin resistance with hyperglycaemia due, for example, to parenteral nutrition, pyrexia or glucocorticoid therapy. Pulsed Doppler

ultrasonography

of the pancreas

This technique has recently been introduced and early results are encouraging. It allows for determination of resistance indices of the intraparenchymal vessels and examination of the homogeneity and echogenicity of the parenchyma. It may be particularly useful in the diagnosis of acute rejection associated with an increase in intrapancreatic resistance (Kubota et al, 1990). Scintigraphy

and angiography

These investigations are not particularly helpful in the diagnosis of rejection, but do exclude technical vascular problems. Magnetic resonance imaging and computed tomography

As yet, it is too early to know the place of these techniques in the diagnosis of graft rejection. However, the results of MRI scanning appear promising. Pancreatic biopsy

This is the only examination that allows confirmation of the diagnosis of rejection, but open surgical biopsy is difficult to perform and carries a risk of

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haematoma and fistula formation. Where the pancreas drains into the bladder, a cystoscopic route may be used. Signs of acute rejection include infiltration by mononuclear cells into the pancreatic parenchyma associated with acute or chronic vasculitis (Sibley, 1989). COMPLICATIONS Complications

OF PANCREATIC

TRANSPLANTATION

related to the graft

These are essentially related to the exocrine pancreas and depend on the surgical technique used. Thrombosis of the pancreas

Thrombosis, more often venous than arterial, is a frequent complication after transplantation occurring in 12% of cases (Sutherland et al, 1989). This complication occurs as a consequence of the haemodynamic situation of the graft. The incidence of thrombosis is similar whether the graft is segmental or total, and is more common if hypovolaemia or atheroma is present. Thrombosis is seen early in the first week after transplantation and is often indicated by a sudden increase in blood sugar levels. The occurrence of pain around the graft is unreliable. The diagnosis made by Doppler ultrasonography of the graft, which shows absent circulation in the vessels of the graft, can be confirmed by angiography. The thrombosed pancreas becomes necrotic and removal of the affected graft is often necessary. Thrombectomy, immediately after the diagnosis of pancreatic thrombosis has been made, may be beneficial (Fernandez-Cruz et al, 1993). Most groups undertaking pancreatic transplantation use anticoagulation but no controlled studies have confirmed the benefits of such an approach. The decrease in the overall incidence of thrombosis over the past few years is related to improved procurement, to reduction in the handling of the pancreas during the surgical harvesting, to low-pressure lavage with small volumes, and to better care of the recipient. Pancreatic fitulas

The fistulas observed in pancreatic transplantation can either be pure, as in the case of segmental grafts injected with neoprene, or result from drainage into hollow organs. The pure pancreatic fistulas observed after transplantation of segmental grafts injected with neoprene present a picture of parietal suppuration. The fistulas often drain at the site of the incision. In the case of a retroperitoneal graft, the pancreatic juice is drained directly externally. If the graft is placed within the peritoneal cavity the collections are often limited and loculated. It is important to drain the collections either by reopening the incision or, if necessary, by percutaneous drainage. The discharge from these fistulas may be clear and sterile, composed mainly of pancreatic juice, sometimes in very large quantities (up to 3OOml). This is

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the true pancreatic fistula (Dubernard et al, 1980b, 1985). Such fistulas may be considerably lessened by the use of a somatostatin analogue (such as octreotide). This is accompanied by a problem of absorption of drugs, especially cyclosporin, and an associated decrease in pancreatic blood flow. If there is pancreatitis as well, the decreased blood flow may result in thrombosis. Thus, the use of somatostatin analogues should be considered very carefully. If the pancreatic fistula is of small volume, there may be local infection; the fistula often dries up after a few weeks. Duodenal-vesical fistulas seen after total pancreatic transplantation with vesical drainage are easily recognized by an abundant discharge of liquid containing pancreatic juice and urine. The discharge may be via the drains or through the incision if the transplant was performed retroperitoneally. When a transplant is carried out retroperitoneally, the discharge may not be clinically apparent. The patient may become septic with an increase in serum creatinine concentration; the presence of peritoneal liquid is detected by ultrasonography. Cystoscopy allows the diagnosis to be confirmed. In some cases the fistula appears to be minimal, and simple drainage with a Foley catheter will ensure spontaneous resolution. In most cases, however, the discharge is large and treatment is surgical. On re-exploration, the site of the fistula can be seen and a further suture will resolve the situation. The greater omentum can be positioned over the suture to help reabsorb some of the secretions. A Foley catheter is left in place for about 10-12 days. Duodenal-vesical fistulas develop particularly if there is sepsis, and it is important that surgery is accompanied by appropriate antibiotic therapy. It is important to look for the presence of fungus. Duodenal-vesical fistulas can sometimes constitute a late complication of transplantation and may present more than 1 month after transplantation owing to urinary retention; the clinical picture is that of graft pancreatitis. Unless vesical drainage is established rapidly, a cutaneous fistula may develop. In most cases late fistulas can be treated effectively by leaving a Foley catheter in place for several weeks. Recurrent episodes of pancreatitis or reflux and development of a fistula can be treated, if necessary, by injection of neoprene into the pancreatic gland. Duodenal-ilial fistulas areseen in the cases of pancreatic transplantation with gastrointestinal tract drainage. This presents a picture of severe shock and requires rapid surgical intervention. Vascular complications

Vascular complications affect the iliac or femoral vessels. They generally follow embolus of an atheromatous plaque or dissection of the iliac artery associated with clamping. Such complications are treated by the usual techniques of vascular surgery. It is important not to overlook the possibility of septic fistulas. Mycotic aneurysms may be seen at the level of vascular anastomoses. They are found in patients with severe septic complications and are often associated with severe haemorrhage. Fortunately, this occurs rarely. In some cases this can be treated conservatively. Mycotic aneurysms can also be associated with peripheral embolism to the lower limb. In these

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cases it is important to remove the aneurysm surgically and to revascularize the limb using an external bypass. Postoperative haemorrhage

This is rare and requires surgical intervention. If transplantation has been performed with vesical drainage, the haemorrhage may be due to leakage from the duodenal vesical anastomosis. This may occur after automatic suturing because of the differences in thickness between the detrusor muscle and the duodenum. Haemorrhage can be prevented by performing a haemostatic running suture by the endovesical route at the level of the staple line. Later, haematuria may be present. This is often due to ulcerative lesions at the site of the gut and vesical mucomucous anastomoses. Late haematuria (several months after transplantation) can be due to chemical cystitis or ulcerative lesions of the duodenum associated with cytomegalovirus infection (Schleibners et al, 1992). Pancreatitis

A pancreatic reaction with hyperamylasaemia occurs early and frequently after transplantation. The degree of hyperamylasaemia depends on a number of factors including the duration of ischaemia, handling of the pancreas during surgery a6d the surgical techniques employed (Lundgren et al, 1984). Severe pancreatitis with local signs may be responsible for graft loss because of thrombosis. Marked amylasaemia may be related to a intrahepatic reflux of amylase secondary to vesical stasis in the pancreas anastomosed to the bladder or in chronic rejection. Zntrapancreatic abscess

This is rare and is seen only in total pancreatic grafts with vesical or intestinal bypass; it is secondary to intrapancreatic reflux. Urinary infections

Urinary infection is particularly frequent and relapsing in the case of a total pancreas transplant with vesical drainage, and is made more likely by alkalinization of the urine. Prolonged treatment is required to avoid relapse. Metabolic disturbance

Hyperchloraemic acidosis secondary to pancreatic or duodenal bicarbonate urinary leakage may be observed in cases of total pancreatic transplantation with vesical drainage. The acidosis may be severe and require intravenous therapy.

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Non-specij’ic surgical complications Postoperative haemorrhage is rare and is more likely where there is atheroma of the recipient vessels. Intra-abdominal complications, (e.g. intestinal occlusion and perforation) can account for up to 20% of complications observed after transplantation with gut drainage (Groth, 1988). Complications

relating to diabetes

These are non-specific and are also seen following kidney transplantation in diabetic patients. The majority of these complications are cardiovascular (Rohrer et al, 1986). In most series, cardiovascular complications account for 50% of deaths. Apart from cardiac insufficiency and coronary artery disease, there are often haemodynamic problems with orthostatic hypotension, which may be severe. These usually resolve after several weeks. In our experience 20% of patients have a cardiovascular complication following transplantation; these include angina, myocardial infarction, heart failure, rhythm disorders and even cardiac arrest. Hypertension appears to be less common in double transplantation than in single-kidney transplantation in diabetics (64%) (Raja et al, 1993). Digestive disorders are also common. Intestinal problems may relate to diabetic neuropathy with a slow resumption of normal bowel movement. Vomiting is more common in those with gastrointestinal reflux present before surgery. Autonomic neuropathy affecting the bladder may account for some episodes of acute urinary retention which may require catheterization. Aggravation of peripheral arteriopathy may be observed after transplantation as a result of a vascular steel, especially homolateral to the transplanted kidney. Lower-limb neuropathy can hinder convalescence. Immunosuppressive

and renal complications

There is little specific to the pancreas transplant recipient other than an increased risk of urinary fistula where there is bladder drainage. PATIENT

AND GRAFT

SURVIVAL

Data for pancreatic transplantation performed throughout the world have been gathered in up to 100 groups in Europe. Between December 1966 and May 1991,3207 pancreatic transplantations were reported (Sutherland and Moudry Munns, 1990; Sutherland et al, 1991, 1992; Sutherland, 1992a,b). One-year patient and graft survival rates were 92% and 72% respectively. The l-year graft survival rate varies according to the surgical technique used: European figures suggest 62% for vesical drainage, 58% for duct injection and 39% for intestinal drainage. Figures for graft survival, according to the type of pancreatic transplantation, show that the survival rate is significantly higher for a simultaneous kidney and pancreas graft (63-73%)

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than for kidney followed by pancreatic graft (15-54%) or pancreatic graft alone (26-52%). The Registry data confirm that results improve over time. The best results are obtained in patients who have undergone dialysis and have received a simultaneous double transplant with a total pancreas grafted to the liver. The length of preservation time is not a factor in influencing graft survival. The beneficial effect of HLA matching is modest.

METABOLIC RESULTS AND THE EFFECTS ON DEGENERATIVE COMPLICATIONS Metabolic results Initial period Revascularization of the graft is accompanied by immediate secretion of pancreatic hormones, mainly insulin and glucagon (Piatti et al, 1985). However, discontinuation of insulin after operation is not always possible as hyperglycaemia may be found even in the presence of a satisfactory level of C-peptide, indicating functioning of the pancreatic graft. This hyperinsulinaemia is a consequence of severe insulin resistance. The interpretation, therefore, of early hyperglycaemia after transplantation is difficult as it may relate to malfunction of the graft owing to rejection or technical complications such as vascular thrombosis. In these conditions, the best way to confirm the endocrine function of the transplanted B cells is to measure C-peptide levels in blood. If the level is normal or high (> 5 mg/ml), then hyperglycaemia can be attributed to insulin resistance. Unfortunately, it is not always possible to perform Cpeptide determination rapidly. A good test of pancreatic functional reserve is to stop intravenous administration of glucose and insulin for 2-3 h (some hours after corticoid treatment). If the hyperglycaemia deteriorates, this is most likely due to abnormality of the pancreatic graft indicating the need for additional investigations by pulsed Doppler ultrasonography and arteriography. Depending on the surgical technique used, analysis of the exocrine functions of the pancreas (amylasaemia and amylasuria) may be of help. Regular CT or MRI scanning can monitor the texture of the graft and detect any peripancreatic collection. In the early days and weeks after transplantation, normalization of the blood sugar level, both fasting and post-prandial, indicates that insulin therapy can be stopped. However, although the blood sugar values may be normal during a glucose tolerance test, serum insulin levels are often higher than normal with delayed post-prandial peaks (Pozza et al, 1983). In 31 transplanted diabetics studied in Lyon 1 year after grafting, the blood sugar level returned to normal only 180min after oral glucose administration, suggesting glucose intolerance. In parallel, the secretion of insulin was often delayed but raised. Several hypotheses have been put forward to account for

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this disorder in insulin secretion following pancreatic transplantation: they include an insufficient mass of islets, denervation of the graft and secretion of insulin into the peripheral non-portal circulation (Pozza and Secchi, 1989). The initial monitoring is shown in Table 3. Table 3. Principles of transplanted pancreas monitoring. During initial hospitalization Clinical: daily Biological: Blood glucose: every 2 h from day 1 to day 3 C-peptide: every 4 h from day 4 to day 7 Blood insulin: twice daily from day 8 to day 15, once daily from day 16 to end of hospitalization Blood ions and amylase: once daily Amylasuria, glycosuria and usual biological and viral surveillance for transplanted patients: once daily Radiological: Abdominal and pulsed Doppler ultrasonography of the pancreas: once weekly Arteriography if pancreatic dysfunction At 3 months Usual clinical and biological check-up for transplanted patients +HbAlC At 6 months then every year Usual clinical and biological check-up for transplanted patients OGTf and IVGTI with glycaemia, C-peptide and insulin estimations each visit Ophthalmic: eye background and visual acuity EMG of lower and upper limbs Abdominal ultrasonography Hb A lC, Glycosylated haemoglobin; glucose tolerance test.

Long-term

OG’IT, oral glucose tolerance test; IVGIT,

i.v.

metabolic results

Between 4 months and 6 years after segmental pancreatic transplantation, the glucose tolerance test remains normal with euglycaemia at 180 min and insulin secretion following a more physiological profile with a higher peak at 30 min (Secchi et al, 1990). Similar improvements are observed during the glucose tolerance test immediately after transplantation. Normalization of glucose haemostasis is shown by normality of glycosylated haemoglobin in these patients. These results have been confirmed by several groups (Morel et al, 1992; Cantarovich et al, 1992b). Effect of pancreatic transplantation on diabetic complications The main aim of pancreatic transplantation is to alter the natural history of the degenerative complications of diabetes. Until recently, the effect of pancreatic transplantation on these complications was not fully understood; the initial studies were performed on patients with very late-stage and often irreversible complications.

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Diabetic nephropathy

Pancreatic transplantation prevents relapse of diabetic nephropathy in the grafted kidneys. However, no controlled randomized study has been carried out to compare the rate of relapse of diabetes in patients with or without a transplanted pancreas. However, two groups in Minneapolis and Stockholm have examined renal biopsies of diabetic patients receiving only a kidney graft. Biopsies were performed at various times after transplantation (Bohman et al, 1987; Bilous et al, 1989). The authors concluded that maintenance of the euglycaemia induced by the pancreatic transplant prevented the development of renal microangiopathy in the graft. Diabetic nephropathy

of ‘clean’ kidneys

It has been shown recently that the isolated pancreatic transplant in diabetics without renal insufficiency has a beneficial effect. Bilous et al (1987) in Minneapolis noted, in seven patients without renal failure who received a pancreatic transplant, an improvement in the indices of diabetic nephropathy (decreased glomerular and mesangial volumes) after transplantation. However, following the administration of cyclosporin there was a reduction in the mean (+s.d.) creatinine clearance from 90+21 to 60 + 14ml/min. Sutherland et al (1988) reported similar findings in 111 patients who received only a pancreas. Sutherland (1992b) showed that there was initial deterioration in renal function following pancreatic transplant, but an improvement in the histological lesions of diabetic nephropathy (Sutherland, 1992b). Diabetic retinopathy

Because most patients have very advanced retinal lesions at the time of transplantation, it is difficult to document the changes after double transplantation. Furthermore, any improvement in retinopathy could be a consequence in part of the correction of uraemia. However, two studies from Munich (Landgraf et al, 1989) and Minneapolis (Ramsay et al, 1988) have provided interesting information on the effect of the grafted pancreas. In a recent prospective study, the Munich group analysed 46 retinas with regard to the visual acuity, macular oedema and haemorrhage; there was no control group. In the most cases there was an improvement in all measures and stabilization. The University of Minnesota study compared the progression of retinopathy in a group of patients who had received only a pancreas or kidney graft with that in a group whose pancreas graft had failed at an early stage. During the first 3 years after transplantation, there was no difference between the two groups in the grade of retinopathy. However, after this period, patients with a non-functional pancreas continued to develop signs of deterioration whereas those with a well-functioning pancreas stabilized. These observations are in keeping with those reported in patients receiving intensive insulin therapy to maintain normoglycaemia; retinopathy worsened during the first year but in those with perfect sugar

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control it stabilized thereafter. In 21 patients transplanted in Lyon between September 1983 and April 1990 who underwent annual follow-up, visual acuity remained stable but 70% had a progressive proliferative retinopathy. However, use of photocoagulation following transplantation allowed stabilization of the proliferation in 60% of the eyes (Zech et al, 1992). Thus, these results show that in isolated pancreatic transplantation there is beneficial effect on the evolution of diabetic nephropathy only if the transplant is performed during the early stage of the condition. Diabetic neuropathy A recent study of 60 patients in Lyon showed that successful pancreatic transplantation is associated with arrest of diabetic neuropathy (Brunner et al, 1988). Clinical signs, nerve conduction studies and autonomic neuropathy tests before and after transplantation were compared in two groups of patients (61 diabetics with a functioning pancreatic graft and 48 with a non-functioning graft). Patients were studied 12, 24 and 42 months after transplantation. In the control group the neuropathy tended to worsen during the 12 months of follow-up. In the patients with a pancreatic graft, nerve conduction studies in the lower limb improved significantly; the index of autonomic neuropathy improved only slightly and non-significantly (Kennedy et al, 1990). The electrophysiological studies on transplanted patients in Lyon (Vial et al, 1992) confirmed the improvement in the speed of motor and sensory conduction, although the modifications in sensory amplitude were very slight. The results suggest that progression of diabetic polyneuropathy can be stopped and, indeed, improves slowly after successful pancreatic grafting. Quality of life after transplantation Pancreatic transplantation undeniably improves the quality of life of the previous diabetic; since the diabetes is cured, there is no longer any need to follow a diet and its constraints, and there is a positive effect on degenerative complications. However, it must be remembered that certain factors do limit the quality of life after transplantation: the constraints of treatment, the need for medical surveillance, the fear of graft rejection and a return to the need for insulin and dialysis, the change of body image induced by transplantation, the psychological and social problems related to the diabetes, and uncertainty about long-term outcome. One American group (Corry and Zehr, 1990) and three European groups (Nakache et al, 1989; Voruganti and Sells, 1989; Piechlmeier et al, 1992) analysed the quality of life after pancreatic transplantation by comparing these patients with diabetic patients who had undergone kidney grafting. The kidney-pancreas transplantation resulted in a better quality of life with improved psychosocial, domestic, professional and sexual adaptation leading to better family and social relationships. However, the psychological impact is less obvious and there remains a certain degree of fear owing to the possibility of

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rejection. There is little improvement in self-image, which reflects the profound impact of diabetes on the personality. Diabetic relapse after transplantation The Minnesota group described the clinical and histological relapse of diabetes in nine pancreatic transplant recipients. The pancreas came from living related donors (identical HLA, twins and non-twins) under moderate immunosuppression (Sibley and Sutherland, 1987, 1988). Relapse was marked by a resumption of insulin therapy 2.5-38 months after transplantation. Insulinitis is a characteristically early histological sign with infiltration of the islets of Langerhan’s by T lymphocytes and macrophages. There is increased expression of class I HLA antigens by islet cells and of class II antigens by endothelial cells. There is subsequent selective destruction of B cells and normalization of class I and II antigen expression (Foulis et al, 1987). The histological signs are similar to those reported by others in type I diabetics during the early stage of the disease. Different mechanisms have been postulated to explain B-cell destruction. CONCLUSION Pancreatic transplantation allows effective treatment of type II diabetes. At present, it is the only treatment leading to insulin independence. Pancreatic transplantation improves certain degenerative complications or stabilizes them when advanced. In a diabetic without renal failure, transplantation of the pancreas alone is still problematic and difficulties remain to be overcome, especially with respect to the early diagnosis of rejection. Results in this group are, at best, mediocre. At present, the best results are in those receiving simultaneous kidney and pancreatic transplantation. None of the surgical techniques is devoid of complications, but segmental pancreatic transplantation with injection of neoprene is simple, applicable to all patients, and does not require opening of the bladder or gastrointestinal tract. The development of this technique throughout the world will lead to refinement of surgical technique and a better understanding of the immunological processes involved. In time, pancreatic transplantation will be used at an early stage of diabetes to prevent progression and its complications. REFERENCES Andersen AR, Standahl Christiansen J, Andersen JK et al (1983) Diabetic nephropathy in type 1 (insulin-dependent) diabetes: an epidemiological study. Diabetologia 25: 496-501. Bilous RW, Mauer SM. Sutherland DER et al (1987) Glomerular structural function followine treatment of pancreas transplantation for‘IDDk Diabetes 36 (supplement): 43A. Bilous RW, Mauer SM, Sutherland DER et al (1989) The effects of pancreas transplantation on the glomerular structure of renal allografts in patients with insulin-dependent diabetes. New England Journal of Medicine 321: 80-85.

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Bohman SO, Wilczek H, Tyden G et al (1987) Recurrent diabetic nephropathy in renal allografts placed in diabetic patients and protective effect of simultaneous pancreatic transplantation. Transplantation Proceedings 19(l): 229CL2293. Braun WE, Phillips D, Viot D et al (1983) The course of coronary artery disease in diabetics with and without renal allografts. Transplantation Proceedings 15: 1114-1119. Brunner FP, Brynger H, Challah S et al (1988) Renal replacement therapy in patients with diabetic nephropathy, 1980-1985. Nephrology, Dialysis, Transplantation 3: 585-595. Cantarovich D, Dantal J, Hourmand M et al (1992a) Importance of cyclosporine dosage and blood levels in simultaneous pancreas and kidney transplant success. Transplantation Proceedings

24: 890-891.

Cantarovich D, Mura T, Paineau J et al (1992b) Long term glucose homeostasis and insulin secretion following segmental heterotopic pancreas transplantation. Transplantation Proceedings

24: 883-884.

Cecks JM & Cicciarelli J (1985) The transfusion effect. In Terasaki P (ed.) Clinical Kidney Transplants, pp 73-78. Los Angeles: UCLA Tissue Typing Laboratory. Cheung AMS, Matas AJ, Gruessner RGF et al (1993) Should uremic diabetic patients who want a pancreas transplant receive a simultaneous cadaver kidney pancreas transplant or a living related donor kidney first followed by cadaver pancreas transplant? Transplantation Proceedings 25: 1184-l 185. Cordonnier D, Halimi S, Benhamou PY & Zaoui Ph (1988) La nephropathie diabetique avant le stade de I’insuffisance renale. In Editions MSD Medicales, pp 9-37. Corry RJ & Zehr P (1990) Quality of life in diabetic recipients of kidney transplants is better with the addition of the pancreas. Clinical Transplantation 4: 238-241. Dubernard JM, Traeger J, Neyra P et al (1978) A new method of preparation of segmental pancreatic grafts for transplantation in trials in dogs and in man. Surgery 84: 63s 639. Dubernard JM, Traeger J, Martin X et al (1980a) Pancreatic transplantation in man: surgical technique and complications. Transplantation Proceedings 12: 4043. Dubernard JM, Traeger J, Touraine JL et al (1980b) Rejection of human pancreatic allografts. Transplantation Proceedings 12: 103-106. Dubernard JM, Traeger J, Piatti P & Gelet A (1985) Report of 54 human segmental pancreatic allografts prepared by duct obstruction with neoprene. Transplantation Proceedings 17: 312-314. Fernandez-Cruz L, Gilavert R, Sabater L et al (1993) Pancreas graft thrombosis: prompt diagnosis and immediate thrombectomy or retransplantation. Clinical Transplantation 7: 230-234. Foulis AK, Farquharson MA & Hardman R (1987) Aberrant expression of class II major histocompatibility complex molecules by B cells and hyperexpression of class I major histocompatibility complex molecules by insulin containing islets in type I (insulindependent) diabetes mellitus. Diabetologia 30: 333-343. Gil-Vernet JM, Fernandez-Cruz L, Andreu J et al (1986) Urinary tract diversion in clinical transplantation. Transplantation Proceedings 18: 1132-1133. Groth CG (1988) Surgical complications following pancreatic transplantation. In Groth CG (ed.) Pancreatic Transplantation, pp 219-238. Philadelphia: WB Saunders. Groth CG, Lundgren G, Arner P et al (1976) Resection of isolated pancreatic allograft in patients with diabetes. Surgery, Gynecology and Obstetrics 143: 133-140. Groth CG, Lundgren G, Gunnarson R & Arner P (1980) Segmental pancreatic transplantation with duct ligation or drainage to a jejunal Roux-en-Y loop in non-uremic diabetic patients. Diabetes

29: %9.

Groth CG, Collste H, Lundgren G et al (1982) Successful outcome of segmental human pancreatic transplantation with enteric exocrine diversion after modifications in technique. Lancet i: 522-524. Kelly WD, Lillehei RC, Merkel FK et al (1967) Allotransplantation of the pancreas and the duodenum along with the kidney in diabetic nephropathy. Surgery 61: 827-837. Kennedy WR, Navarro X, Goetz FC et al (1990) Effects of pancreatic transplantation on diabetic neuropathy. New England Journal of Medicine 322: 1021-1037. Krolewski AS, Warram JH, Rand LI & Kahn CR (1987) Epidemiologic approach to the etiology of type 1 diabetes mellitus and its complications. New England Journal of Medicine 317: 1390-1398.

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