Clinical pancreatic transplantation using the prolamine duct occlusion technique—The Munich experience

W. Land, D. Abendroth, W.-D. IIIner, R. Landgraf, F. P. Lenhart, W. MOiler, S. Thurau, A. Kampik

9 Clinical Pancreatic Transplantation Using the Prolamine Duct Occlusion TechniqueThe Munich Experience

INTRODUCTION

The idea of handling the exocrine secretion in pancreatic transplantation by duct occlusion was first described in 1892 by Thiroloix,' who performed experimental studies in dogs. This author injected a sterile mixture of oil and soot into the pancreatic duct with the aim of preventing autodigestion. In 1979, nearly 100 years later, again French researchers (Dubernard et al.) reported on experimental trials of pancreas transplantation by using the duct occlusion technique. This time, however, the substance used for occlusion was neoprene.' Subsequently, this group used the duct occlusion technique in clinical pancreatic transplantation and thus, promoted the 'renaissance' of this kind of organ transplantation after the original Minnesota series.' The first pancreatic transplant at the University of Munich was performed in August 1979. Since then, 102 pancreatic transplants have been performed: combined pancreas and kidney transplantation (n=89), pancreas transplantation alone (n=8) and pancreas retransplantation (11=4), pancreas transplantation following kidney transplantation (11= 1). In all cases, duct obliteration with prolamine in a segmental pancreatic graft was used as the standard procedure. Patient selection criteria, surgical technique of recipients' operation, postoperative management, and immunosuppressive protocols were modified several times during the past 9 years. In this paper, our experience with organ procurement, indications for pancreas transplantation, surgical technique, postoperative management, current immunosuppressive protocol, recent results, metabolic studies, and in particular, the effect of successful transplantation on the secondary complications of diabetes will be described. Since our results of pancreas transplantation alone in non163

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uraemic patients are still extremely poor, we concentrate here on the clinical observations obtained in cyclosporin (Cs)-treated patients who have undergone combined (simultaneous) transplantation of the pancreas and kidney (11=93). From the very beginning, it was our intent to establish a multidisciplinary transplant group consisting of surgeons, diabetologists, intensive care physicians, ophthalmologists, nephrologists, urologists and neurologists. In our opinion, only such a group can guarantee the performance of all clinical and laboratory studies needed for proper evaluation of pancreas transplantation as a possible treatment of type I diabetes mellitus. This report summarizes, therefore, some of our experiences during the past 9 years, which have been already published in part elsewhere.'

RECIPIENT SELECTION

Pancreas transplantation has been performed in two groups of patients according to the indications described in Table 9-1. Table 9-1 Indication for Pancreatic Transplantation I. Type I diabetes mellitus associated with manifest late complications Without end-stage With end-stage renal disease renal disease

Transplantation of the pancreas in combination with the kidney (or following previous kidney transplantation) 2. Extreme unstable diabetes (brittle diabetes) Pancreas transplantation alone

These are uraemic type I diabetic recipients (in combination with a renal graft) and more recently, non-uraemic diabetics suffering from preproliferative or proliferative retinopathy with a high risk of blindness. The stage of the disease in our patients (clinical data) before pancreas transplantation is summarized in Table 9-2. All patients underwent detailed ophthalmologic, neurological and angiologic evaluation. In recent years cardiological evaluation has routinely included coronary angiography, even in patients without any symptoms of coronary artery disease (CAD). If there is evidence of CAD proved by arteriography, the patient will not be accepted for pancreas transplantation, but only for renal transplantation in case of end-stage renal failure. This decision is being made regardless of whether the detected CAD requires treatment (angioplasty, coronary bypass). Thus, CAD proved by arteriography is used as an indication of a potentially poor prognosis of pancreas transplantation-by reflecting a too-advanced stage of the underlying metabolic disorder.

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Table 9-2 Patient Characterist ics Before Transplantation Functioning 11=31 No of patients Age (years) Sex female male Duration of diabetes (years) Hypertension yes no Retinopathy grade II grade III Neuropathy mild moderate severe Dialysis (month)

34 33±1 22 12 21±1

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28 23±1

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14

18

20

31

15 16 3 19± 14

21 19

9 21±14

ORGAN PROCUREMENT As is true for all other kinds of organ transplantation, procurement of the pancreas (donor selection criteria, donor pancreatectomy, pancreas preservation, etc) is of utmost importance with regard to the outcome of implantation of the pancreas. In fact, from the surgical point of view, the donor operation appears to be more important than the recipient operation. As far as donor selection criteria are concerned, we only accept heart-beating donors with a stable circulation. The upper donor age has been 45 years, but recently we have also accepted elderly donors provided that first the HbA 1 values are normal (HbA 1 levels are now routinely measured in every pancreas donor) and second, that there is no intraoperative evidence of severe atheroma of the aorta (macroangiopathy). Serum amylase and glucose values should be within normal limits, but on the other hand, we have successfully used the pancreas from many donors showing a moderate rise in both laboratory values. It appears to be of interest that pancreatic transplants taken from donors with successful rescuscitation after a short cardiac arrest failed in all cases (venous thrombosis; never functioning). Thus, one must be very cautious using pancreatic organs from resuscitated donors or from donors suffering from shock over an unknown period of time. Immunologic selection is based only upon ABO blood group compatibility and a negative cross-match. In view of the short cold ischaemia time, HLA typing was only done retrospectively.

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Figure 9-1. Donor hepatectomy, pancreatectomy, nephrectomy: in situ perfusion of both the liver and pancreas as well as the kidneys (see text). The donor operation is started 'under the protection' of somatostatin, which is administered to the donor during the entire period oforgan removal (250 pg as a bolus, then 250 Jigh via infusion). The rationale behind this is to reduce exocrine function of the gland during the surgical procedure and thus to reduce potential oedema. Donor pancreatectomy is performed by leaving the spleen in place (providing for better handling of the pancreas), and mobilizing and dissecting free the pancreas, special care being taken with the coeliac axis and the portal vein, which are ultimately used for vessel anastomosis. Together with the pancreas, we harvest other organs, including kidneys, heart, or heart-lung. Recently, removal of both pancreas and liver is performed in every multiple organ donor available (Fig. 9-1). In these cases, the coeliac artery and the protal vein are left to the liver, the donor iliac artery and iliac vein are used for vessel reconstruction of the pancreatic allograft: the portal vein is extended by a segment of the iliac vein and the donor iliac artery is anastomosed to the splenic artery, thus providing sufficient length for anastomosis to the recipient external iliac artery and vein. In fact, simultaneous removal of the pancreas and the liver appears to be mandatory in view of the shortage of multiple organ donors. Pancreas preservation was done simultaneously with the kidneys by in situ flushing with

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Euro-Collins' solution via an intraaortic cannula. The pancreatic segment (corpus/tail+spleen) together with the coeliac axis plus an aortic patch and the portal vein are removed en bloc when the organ becomes pale and the venous effiuate is clear. This usually happens about 3-5 min after the start of in situ perfusion. By using this procedure, the exact amount of preservation fluid used for the pancreas is generally unknown. After removal of the pancreas, in situ flushing of the kidneys is continued for a short time by cross-clamping the aorta near the superior mesenteric artery. Ex vivo preparation of the pancreas (removal of the spleen, preparation of the vessels for anastomosis, and duct occlusion) is done just before the recipient operation in the operating room of the transplant centre (after transportation of the donor organs from peripheral hospitals). With two exceptions (8 and II h), cold storage of the pancreata harvested for transplantation was less than 6 h (including long-distance pancreas harvesting with helicopter transportation).

RECIPIENT OPERATION Ex Vivo Duct Occlusion With Prolamine

From the very beginning we have used prolamine (Ethibloc," Ethicon Compo Norderstedt, FRG) for duct obliteration exclusively. Prolamine becomes rapidly solidified in the duct system; it is broken down and reabsorbed within about 6 weeks in humans (according to a few histological investigations of specimens obtained during the first 3 months). Prolamine produces early necrosis and degeneration of the duct epithelium and late (up to 6 months) necrosis and atrophy of acinar cells. It causes complete fibrosis of the exocrine parenchyma at approximately 6 months after transplantation and is radio-opaque. The major rationale behind the use of prolamine for duct obliteration is that first the procedure of duct injection can be followed under X-ray control which guarantees a proper and adequate injection of prolamine into the duct system; second, in addition the reabsorption of prolamine may prevent the formation of excessive fibrosis because prolamine does not act as a permanent foreign body in the transplanted gland.

Some Aspects of the Recent Operative Technique in Recipients

The technique of prolamine-treated duct-occluded segmental pancreatic transplants was not essentially modified (except for positioning of the graft) up to now. Regarding positioning of the pancreatic graft some minor modifications have been made in the past years. Since autumn 1984 we have performed the recipient operation as follows: a right transrectal incision is made to enter the abdomen, regardless of whether a combined kidney-pancreas or a pancreas transplant alone is performed. After careful intraperitoneal positioning of the pancreatic graft, vascular anastomosis ofthe donor portal vein is performed end-

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I

~Figure 9-2. Recipient operation: simultaneous transplantation of both the pancreas and kidney to the recipient iliac vessels (details see text).

to-side to the recipient's external iliac vein, and anastomosis of the aortic patch is performed end-to-side to the external iliac artery (Fig. 9-2). Care is taken to place the graft laterally along the ascending colon and to cover the graft with a piece of omentum fixed to the lateral abdominal wall (and the graft itself). It is of utmost importance that the pancreatic graft should be positioned in this way and fixed to the lateral abdominal wall thus providing a non-twisted, non-kinked positioning of the long vessel pedicle to avoid thrombosis. Two tubes (inlet and outlet) are placed close to the graft, thereby allowing continuous intraperitoneal irrigation of the cavity. This is started intraoperatively after closure ofthe wound and is continued for about 2 days by using a commercially available peritoneal dialysis solution. The rationale behind the manoeuvre is to prevent the early heavy fibrinoid reaction of the peritoneum to the high residual exocrine secretions in the first 4 days. Although the duct is occluded and oversewn, exocrine pancreatic juice normally exudes through the parenchyma of the graft. This clinical sequela had required surgical intervention because of mechanical adhesion and ileus in two earlier patients. It has not been observed since shortterm irrigation was introduced as a routine procedure. The other local complications are due to the residual exocrine secretion and the nature of the pancreatic parenchyma: the tryptic activity in combination

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with the possibility of laceration. Consequences are bleedings, peripancreatic fluid collections, pseudo-cysts and fistulas. In order to correct these troublesome complications we tried to seal the surface without harming the organ and its function. Thus, based on the experience in general pancreatic surgery! we used fibrin tissue adhesive to 'seal' the organs surface. So far the high incidence of pancreatic fistulas appears to be reduced by this modification in our recent experience.

PERIOPERATIVE AND INTRAOPERATIVE MANAGEMENT

From the very beginning, postoperative management was considered of great importance. All patients were transferred to the intensive care unit immediately after surgery under the care of a well-trained and experienced staff, The perioperative management after pancreas or simultaneous pancreas and kidney transplantation includes the monitoring of vital functions as well as early detection of any graft failure or deterioration offunction due to technical and/or immunological problems. Table 9-3 Assessment of Late Complications in Diabetics Prior to Transplantation I. 2. 3. 4. 5. 6.

Thorough clinical/laboratory check-up Gastrointestinal examination (sonography, endoscopy) Urological examination (infection?, urinary bladder dysfunction, ureter reflux) Degree of diabetic nephropathy (proteinuria, creatinine-clearance) Degree and progression of retinopathy (functional and morphological parameters) Degree of peripheral and autonomic neuropathy (R-R intervals, gastroparesis, sensory and motor nerve conduction velocity) 7. Degree of macroangiopathy (Doppler sonography, arteriography of large vessels including coronary angiography)

Possible intraoperative complications are due to the preoperative condition of the diabetic recipient. Therefore, the selection of patients by clinical, laboratory and supporting technical examinations (sonography and angiography of the carotid, coronary and iliac arteries for example) is necessary before accepting a diabetic patient for pancreatic grafting (Table 9·3). However, intraoperative complications, which are mainly due to the associated uraemia and severe derangements of carbohydrate metabolism and hypertension in the patients, still occur. Patients with end-stage renal failure on chronic dialysis treatment should-if time allows-be optimally dialysed prior to transplantation in order to balance potassium and fluid. Chronic anaemia has to be partially corrected intraoperatively in order to avoid problems of cardiac and cerebral hypoxia, especially when intraoperative blood loss is significant. Uraemic platelet dysfunction can be one of the reasons for increased bleeding during and after the operation.

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Prior to grafting hypertension is present in almost all patients. Intraoperative blood pressure monitoring is very important since most patients are taking antihypertensive drugs and most of them have autonomic neuropathy with disturbance of vasomotor function. Hypotonic phases during transplantation can occur which might also be hazardous in the low flow pancreatic graft. Sometimes a sudden drop of blood presure can be monitored after declamping the transplanted organ. Immunological reasons or the perfusion fluid of the graft are discussed as the main causes of this fall in blood pressure. Pulmonary oedema and acute respiratory failures occur very rarely. The incidence of these problems is most common in the presence of insufficient preoperative dialysis, pleura effusion due to uraemia, or complications of a misplaced venous catheter. Kidney grafting today is a standardized operation with relatively small intraand postoperative risk. Most failures-beside surgical ones-are due to a mistake during organ harvesting. Kidney transplant function is monitored by measuring urinary output, urine osmolality, creatinine, creatinine clearance and urea levels in the serum. Fluid balance is maintained every day (Table 9-4).

Table 9-4 Monitoring of the Kidney Graft Urinary output (Ih-intervals for the 1st week) Urine osmolality Creatinine clearance Creatinine and urea levels (serum) Additional parameters: blood cell count electrolytes, liver function tests, CyA-level (daily) Perfusion studies (99 mTc) isotope excretory urography (IN G), Sonography, ditigal substraction angiography (DSA), duplex-doppler-sonography, NMR

Despite control of blood glucose and intensified insulin treatment in many of the diabetics prior to transplantation, derangement of glucose homeostatis is observed frequently pre- and intraoperatively. Intravenous insulin administration under strict blood glucose and potassium control is mandatory to avoid ketoaceidosis and hyperosmolality as well as hyperglycaemia. Since the uramemic diabetic has altered peripheral insulin sensitivity-often hypersensitivity-low dose intravenous insulin therapy is strongly recommended. In the declamping period of the grafted pancreas insulin can be 'washed out' of the graft which might lead to severe hypoglycaemia. Therefore during this surgical period blood glucose has to be measured very frequently. Due to the possibly reduced defence mechanisms in diabetics, the intraoperative initiation of immunosup-

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pression and the implantation of two organs, many groups recommend an antibiotic prophylaxis starting prior to the operation with aminoglycosids and cephalosporine derivates or with imipenem as a broad spectrum antibiotic mono therapy. Vascular thrombosis of the pancreatic vessels is one reason for early graft failure. Therefore intraoperative anti-coagulation regimes have been introduced. Since effective early heparinization can cause severe bleeding complications, intraoperative dextran infusions are now favoured by many centres to avoid venous thrombosis of the grafted pancreas (Table 9-5). Table 9-5 Postoperative Management Creatinine and urea levels Insulin requirement: blood sugar, C-peptide Anticoagulation: ASA, dextran, low-dose heparin Antibiotics: perioperative prophylaxis (5 days: imipenem as broad spectrum monotherapy) Immunosuppressive starting quadruple drug induction therapy protocol: (CyA, Aza, Steroids, ATG/OKT3 10 days) triple drug maintenance therapy

POSTOPERATIVE MANAGEMENT The essential points which have to be monitored carefully in the postoperative phase are listed in Table 9-5. Postoperative care depends on the course, the status of the recipient and on the surgical technique applied. The drainage of the exocrine juice of the grafted pancreas into the urinary bladders" the stomach! or the jejunum? means that other problems have to be dealt with than those that occur with the duct occlusion method. In addition, single pancreatic transplantation in nonuraemic diabetics has to be monitored in a different way than simultaneous kidney and pancreas transplantation in uraemic patients. As in almost all other centres our patients will stay in an intensive care unit for a few days, and then be transferred to a special transplantation ward. Besides monitoring the usual functions, like blood pressure, heart rate, body temperature, acid-base balance, pulmonary gas exchange, bowel function, function of the central nervous system, the diabetic with a pancreas graft with or without a kidney graft needs special attention given in the following areas. Patient Care

Almost all patients suffer from at least partial postoperative ileus due to the surgery and residual pancreatic excretions intraperitoneally. Consequently, we

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maintain the recipients on nasogastric suction and intravenous fluids until the postoperative ileus resolved (around the 6th to 10th days). While the patient is receiving intravenous high-concentration glucose solutions, insulin is administered to maintain plasma glucose levels below 150 mg/dI. The rationale for administering insulin immediately is based on the concept that freshly transplanted islets are 'protected', and thus allowed to recover from ischaemic damage. According to our postoperative regimen, a need for about I IV insulin/h or less is indicative of primary function of the pancreatic graft. Within the early postoperative phase, somatostatin is administered intravenously for 10 days to reduce exocrine residual function in the transplanted gland. In our experience, amylasaemia and lipasaemia can be decreased but not completely prevented by somatostatin administration. Isotope studies to monitor perfusion of the graft are done routinely; radiographic and sonographic studies as well as nuclear magnetic resonance studies are only done in response to clinical problems (suspected fluid collections, suspected venous thrombosis, etc.). Current evaluation of postoperative complications under this management reveals a significant reduction in the number of wound haemorrhagic complications. It is the main improvement achieved in the past years. There is also growing evidence that early infection problems and early deaths ofpatients have decreased. One more index of improving results due to the modifications of postoperative management has been the reduction in the duration of intensive care, which was formerly 16.9±2.8 days and is now 7.5± 1.9 days. Pancreatic Graft Monitoring and Management

Exocrine Function and Complications due to Residual Transient Exocrine Secretion The principles of pancreatic graft monitoring are summarized in Table 9-6. Table 9-6 Monitoring of the Pancreatic Graft Glucose blood levels (Zh-interval in the 1st 2 days) HbA 1 Amylase activity Perfusion study (99 mTc) Insulin requirement Angiography, DSA, Sonography, NMR

The exocrine function of the graft is judged by serum amylase and lipase, as well as the pancreatic enzyme excretion and fluid output ofthe graft, for in the case of duct-occluded intraperitoneally-placed pancreatic segments, continuous perito-

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neal lavage for 2 to 5 days allows analysis of exocrine activity. One disadvantage of the occlusion technique is the fact that there is no possibility of monitoring exocrine function over a prolonged period of time. Pancrcatico-cystostcmy? is probably the best and easiest way for long-term control of pancreatic graft function by the additional measurement of urinary pH and bicarbonate. Deterioration of graft function would lead to an increase of urinary pH and a dramatic fall of the concentration of pancreatic enzymes in the urine. Substitution of bicarbonate in case of greater loss might be necessary." If pancreatic function decreases, sonography, radioisotope techniques (e.g. indium-labelled platelets, DTPA perfusion) or angiography are not reliable measures for determining the cause of graft deterioration. Whether NMR techniques will enable us better to judge the causes of graft failure cannot be answered at the moment. Cell analysis of the pancreatic juice to detect the rejection crisis, as reported by Margreiter et aI.I2 is attractive but the experience is not sufficient for a definite statement of its diagnostic value. Blind biopsies of the duct occluded pancreatic graft have failed to be of any value for judging graft function even under experimental conditions and also have not been able to determine whether or not immunological processes are responsible for deteriorating graft function. The indication for open graft biopsies are rare. To reduce local complications in the early postoperative phase, suppression of the exocrine graft function by continuous infusion of somatostatin during transplantation for 10 to 14 days after transplantation has been proposed by us. However, the value of this treatment has not been proven to be very effective. On the other hand, the somatostatin analogue SMS 201-995 can suppress exocrine graft function strongly. When SMS is used the interaction with cyclosporin has to be monitored carefully,'? Local complications are due to wound healing disturbances as a consequence of both the diabetic state of the patient and the residual exocrine secretion of the graft. Therefore, pancreatic fistulas are relatively often encountered. These fistulas must be well drained, and we prefer irrigation techniques for this complication. The risk of infection in this situation is very high and antibiotic treatment is necessary. A very acute and life-threatening complication following infection at the operation site is the rupture of the vessel anastomosis associated with arrosion bleeding. We have seen massive bleeding in eight patients, so far. These local complications caused by residual secretion of pancreatic juice are summarized in Table 9-7.

Endocrine Function Frequent blood glucose determinations every 2-3 h and once to twice daily analysis of C-peptide levels are at the moment the suboptimal way for the detection of graft failure. Peripheral insulin sensitivity is decreased postoperatively by surgical stress, high doses of steroids and possible fever and infections. C-peptide levels are often difficult to interpret because of altered urinary Cpeptide clearance in kidneys which are not functioning optimally. During the phase of peripheral insulin resistance and parenteral nutrition (see below) we use

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Table 9-7 Duct Occlusion Technique with Prolamine (Ethibloc-) in Segmental Pancreatic Allografts Local complications caused by residual excretion (=pancreatic juice 'pouring out' through the necrotizing gland): Free excretion into the peritoneal cavity: Pseudo-cysts formation: Pancreatic fistula: Infected pancreatic fistula:

paralytic ileus abdominal pain (management by aspiration) discomfort (managable) arterial arrosion bleeding (life-threatening) (managable by urgent surgery)

intravenous insulin, in all patients, to achieve near normoglycaemia. The hourly intravenous insulin requirement has been proven to be a reasonable parameter for assessment of endocrine graft function. Altogether, methods of monitoring endocrine function are not satisfactory at the time being. Parenteral Nutrition

The patients are maintained on parenteral nutntion for about a week. Hyperalimentation between 3000-4000 kcal/day is recommended when the patients are in a severe catabolic state prior to transplantation. About 50 percent of the calories should be carbohydrates (e.g. xylit: glucose: fructose = I:2: I), the other half should contain lipids and amino acids. Autonomic neuropathy with gastroparesis and enteric dysfunction can lead to serious postoperative problems including paralytic ileus which forces a longer parenteral nutritional period. Parasympathomimetic drugs used to overcome paralysis also stimulate the exocrine part of the grafted pancreas which can cause local problems by hypersecretion of pancreatic juice. The oral nutrition should be started as soon as possible, depending on bowel function. Early mobilization of patients, laxatives or clysmas can help bowel function.'! Anticoagulation

Low-dose heparin is administered in combination with dextran 40. The first administration of dextran 40 occurs on the day of operation at a dose of 500 ml124 h. This dose is gradually tapered to 100 ml/24 h, which is then maintained from the 5th postoperative day to the end of the 3rd week postoperatively. Lowdose heparin (200-400 IV/h) is administered from the 2nd postoperative day and maintained for a period of 3 weeks. During postoperative weeks 3 to 6, lowdose heparinization is continued by subcutaneous injection. Up to the 6th postoperative month, all patients are put on a regimen with Marcumar", Thereafter, all patients take (100-250 mg) aspirin daily.

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Antibiotics

Perioperative antibiotic prophylaxis extends for 5 days postoperatively. In former times, we used prophylactic triple antibiotics; this has recently been modified to a protocol consisting of imipenem/cilastatin therapy to avoid potentially nephrotoxic drug combinations (e.g. arninoglycosides, cephalosporines). IMMUNOSUPPRESSIVE PROTOCOL Current Concepts

Our current concept of immunosuppression is based upon providing a high initial immunosuppressive index while using low non-nephrotoxic doses of cyclosporin (Cs). This is achieved by using a quadruple-drug induction regimen consisting of Cs, azathioprine, steroids, and antilymphocyte globulinlantithymocyte globulin (ALGIATG) or monoclonal antibodies (OKT3). The high initial immunosuppressive index was chosen for two reasons: to reduce or even avoid the high risk of early severe rejection crises of the kidney as well as the pancreas and to prevent even moderate rejection crises in the pancreas (assuming that even moderate rejection reactions may lead to graft loss due to secondary venous thrombosis with rejection-associated inflammatory graft oedema resulting in compression of the vein). Our current immunosuppressive protocol is also based upon maintaining multiple-drug maintenance treatment in view of the fact that we have observed a high incidence of chronic rejection of the kidney in patients treated 6 months after transplantation with Cs alone (first series of 3 I patients). The current triple-drug maintenance programme consists of low doses of Cs, azathioprine and steroids. We plan to withdraw steroid therapy 6 months after transplantation and to continue with double-drug maintenance treatment using Cs and azathioprine. Thus, the current immunosuppressive protocol for pancreatic transplantation is as described in the following sections in more detail. Basic Immunosuppressive Regimen for Induction Treatment

Cyclosporin , initially administered intravenously (24-hour infusion) at a starting dose of 1-2 mg/kg body weight (BW)/day (desired target for whole blood through levels (polyclonal antibody RIA) is 100-250 ng/ml). This is switched to oral administration by the 10th postoperative day (doses of6-12 mg/kg mvIday, adjusted to trough levels of 300-500 ng/ml). Azathioprine is given at a dose of 1-2 mg/kg BW/day (formerly discontinued at 3 weeks but now reduced to I mg/kg mV/day for maintenance). Prednisolone is rapidly tapered from 250 mg/day to 30 mg/day, and ATG (Fresenius, Homburg, FRG) ALG (Behring, Marburg, FRG) is administered from day I to day 10 at a dose of 4 mg/kg BW/day or 20 mg/kg BW/day, respectively. Recently we have used the monoclonal antibody OKT3 instead of polyc1onal preparations; OKT3 was given in a dose of 5 mg intravenously per day over a period of 10 days.

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Basic Immunosuppressive Regimen for Maintenance Treatment

Maintenance treatment is as follows: Cs is given orally at doses of 4-6 mg/kg BW/day (keeping trough levels at 200-300 ng/ml), azathioprine at a dose of 1 mg/kg BW/day, and prednisolone at a dose of 5-10 rug/day over a period of 6 months. Antirejection Treatment

Methylprednisolone is given by bolus intravenous injection at a dose of 250 mg (125 mg)/day for the first 3 days. More recently, we administer ALG or ATG in conjunction with steroids, 125 to 250 mg/day methylprednisolone from the 1st day of antirejection therapy for a period of 7 days. To avoid secondary venous thrombosis due to immunlogically induced inflammatory oedema, we combine this treatment with anticoagulation (low-dose heparin for a period of 7 days) routinely. RESULTS The Survival Rates

Simultaneous pancreas and kidney transplantation has been performed in 93 type I diabetic recipients up to December 1988. In autumn 1984, our major modifications were introduced: (1) restrictive recipient selection (normal coronary angiography results), (2) intraperitoneal positioning of the graft, (3) multiple-drug induction treatment, and (4) anticoagulation protocol using dextran 40 plus low-dose heparin. Since this time, a subgroup of 58 patients treated in this manner underwent combined pancreas and kidney transplantation. Patient and graft survival rates in the first subgroup (group I) are shown in Fig. 9-3: There is an 82 percent 3-year patient survival rate, and 33 percent and 25 percent kidney and pancreas graft 3-year survival rates respectively.

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As shown in Fig. 9-4 the actuarial survival rate has improved in subgroup II: the 4-year patient survival rate is 98 percent, the 4-year pancreas graft-survival rate 48 percent; the 4-year kidney graft survival rate 70 percent. Patient

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Table 9-8 Complications after Simultaneous Pancreas and Kidney Transplantation (n=93) Loss Total

49 (52 percent) Group I (n=32) Group II (n=58)

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Postoperative Complications

The postoperative complications are listed in Table 9-8. The causes of death (11=9) in the entire group included acute liver failure (11=2), anastomotic bleeding (11=2), septicaemia (11=3), intracerebral bleeding (11= I), and 'obscure' death (11= I) and acute massive haemorrhage from an erosion at the site of graft anastomosis (11= I). Causes of graft loss in the first subgroup (11=32) up to autumn 1984 included acute rejection (11 = 1), chronic rejection (11=7), venous thrombosis (11=3), and local infection (11=5). In the recent subgroup of 58 patients the causes were acute rejection (11= I) and venous thrombosis (11=4). In this recent subgroup of combined pancreatic and renal grafts, the only (rare) major surgical complications were pancreatic fistulas with secondary infection complications and peripancreatic fluid collections requiring aspiration.

LONG·TERM FOLLOW-UP OF SECONDARY COMPLICATIONS FOLLOWING TRANSPLANTATION Metabolic Control

Because our definition of successful pancreatic transplantation is no further requirement of exogenous insulin for a good glucose control, all our patients with functioning grafts are free of insulin therapy. From these 34 patients (all combined kidney and pancreatic transplant recipients) the survival of the pancreatic graft was as follows: Less than 6 months: five; 6-12 months: seven; 13-24 months: nine; 25-36 months: six; 37-48 months: four; 49-60 months: two; 61-72 months: one. The posttransplantation values for blood glucose, serum insulin, and Cpeptide as well as plasma glucagon, during an oral glucose-intravenous arginine test are depicted in Fig. 9-5 A. According to WHO criteria, from the 31 patients with functioning grafts for more than 3 months, 22 (71 percent) had normal and 9 (29 percent) had impaired glucose tolerance (Fig. 9-58). In those with normal glucose disposal insulin and C-peptide secretion was significantly higher during glucose and arginine provocation despite the fact that serum creatinine levels were lower in these patients. It is worthwhile to note that normal glucose tolerance is not achieved at the expense of hyperinsulinaemia despite the fact that a segment of a denervated pancreas is transplanted and hormonal drainage of the graft is not into the portal but into the systemic circulation. In view of the possible involvement of insulin in the pathogenesis of macroangiopathy, normoinsulinaemia might also be one of the important goals of pancreatic grafting. In both groups glucose-induced glucagon-suppression and arginineprovoced glucagon secretion are comparable. Glycosylated haemoglobin in both groups was within the normal limits: HbA. in the patients with normal glucose tolerance 6.8 ± 0.3 percent and in the group with glucose intolerance 7.6 ± 0.3 percent. There was no deterioration of graft function as judged by glucose

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Figure 9-5. Blood glucose, serum insulin, C-peptide, and plasma glucagon before and during an oral glucose-intravenous arginine test (A, left): Values of31 grafted patients with normal (left) and impaired glucose tolerance (right) . (e-e normal , 0-0 impaired) (B, right): blood glucose and serum insulin during oral glucose load and intravenous arginine stimulation (shaded area) at different periods posttransplant: 3 ± 2 months (0-0) and 27 ± 17 months (e-e) posttransplant. tolerance and insulin secretion when the values of 24 patients were compared 3 ± 2 and 27 ± 17 months after transplantation despite the fact that after duct occlusion, fibrosis and atrophy of the exocrine part of the graft has been demonstrated (Fig. 9-5B). Other important parameters associated with the development or progression of angiopathy were improved after combined transplantation. In all 31 patients hypertension was present before transplantation, which normalized after grafting in 14 (134 ± 4/86 ± 3 mmHg) and could be better controlled by antihypertensive treatment in 17 patients (165 ± 6/7 ± 5 mmHg). These values are means of multiple measurements on various occasions. Other vascular risk factors were measured after grafting: uric acid 6,7 ± 0.3 mg/dl, triglycerides 117 ± II mg/dl; total cholesterol 219 ± 8 and HDL-chlolesterol 66 ± 7 rng/dl, These data indicate strongly that the vascular risk profile decreases markedly after combined kidney and pancreatic grafting.

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Neuropathy

Twenty-eight patients were studied for a mean observation time of24 months for peripheral sensory and motor polyneuropathy. Prior to transplantation of a pancreas and a kidney 18 (64 percent) diabetics complained of neuropathic symptoms, such as pain, paraesthesia, numbness and cramps. At the examination all patients had clinical signs of neuropathy and had pathological electrophysiological test results. After transplantation paraesthesias and painful sensations improved or disappeared in 46 percent within 6 months, while 18 percent showed no changes of their symptoms of neuropathy. Changes of motor nerve conduction velocity expressed in percent of starting values were recorded. None of the patients had a decrease of more than 5 percent. Eight patients did not show any difference before and after transplantation. There was an increase of 5 to 20 percent of motor nerve conduction velocity in 12 patients, between 20 and 50 percent in six patients, and more than 50 percent increase in one patient. After renal graft loss with continuing pancreatic transplant function, there was a decrease of nerve conduction velocity within 6 months of7, 12, and 35 percent in three patients, no change in one patient and an increase of 6.percent in another patient. Two patients were retransplanted. The nerve conduction velocity increased from 40 to 43 m/s and from 53 to 65 m/s respectively. There was no correlation between serum creatinine levels and motor nerve conduction velocity. A carpal tunnel syndrome (CTS) was documented in nine patients after mean time posttransplant of 19 months (4-36 months). Unilateral CTS was present in three and bilateral in six patients. Spontaneous remission was observed in five, improvement after splinting in three, and after surgery in one of the grafted patients. Seven patients developed trophic ulcers despite improvement of neuropathy, peripheral microcirculation and glucose metabolism. Surgery was necessary in five of them. Subjective signs of autonomic neuropathy such as dyshydrosis, sexual impotency or gastrointestinal disturbances improved. However, thorough analysis of these symptoms was unable to confirm any amelioration. Only in three of 18 patients studied did beat-to-beat variations increase significantly., Retinopathy

All patients, who were blind or had a visual acuity less than 1150 were excluded from our prospective study. Also excluded were those patients with an observation period of less than 15 months. From the 25 patients studied prospectively for a mean observation time of 38 months (15-76 months) nine patients had lost one eye pretransplant. Therefore, 41 eyes were studied prospectively. Pretransplant, no fundus alterations were present in three, background retinopathy in six, preproliferative retinopathy in seven, proliferative retinopathy in 24 and tractions in one eye. In 33 eyes (80 percent) there was argon laser treatment before transplantation. The visual acuity improved in 13 eyes (32 percent), was unchanged in 19 eyes (46 percent), and deteriorated in nine eyes (22 percent) posttransplant. Change of visual acuity was defined as an increase or a decrease in more than two lines. Reasons for worsening were developing posterior subcapsular cataract, mild vitreous haemorrhages or an

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increase of the proliferative process with vitreous haemorrhage. There was a change of diabetic retinopathy using the criteria of proliferations and macular oedema. In eight eyes, these morphological retinal alterations improved, stabilized in 28 eyes and worsened in five eyes. The frequency and intensity of vitreous haemorrhages decreased in 19 eyes (46 percent), were the same in 18 eyes (44 percent) and increased in four eyes (10 percent) posttransplant.

Peripheral Microcirculation

Diabetic microangiopathy is a poorly defined term to describe many functional and degenerative changes in the arterioles, capillaries and venules of diabetics. Increased capillary permeability, thickening of basement membrane and disturbed autoregulation in capillary blood flow are considered to be main pathophysiological pattern of diabetic micro angiopathy. To evaluate the effect of pancreas transplantation on the diabetic microangiopathy of the skin we used three different non-invasive methods." 1. Transcutaneous oxygen measurement to provide information about the degree of disturbed hyperaemic blood supply to the skin. The skin is locally heated up to 44°C so that maximum intra- and subdermal vessel dilatation is achieved. A cuff-test (superasystolic stop of blood supply for 4 min) gives information about reactive hyperaemia reaction as a dynamic functional test. In the presence of microangiopathy the delay in re-establishment of the control P0 2 is characteristic. The tcPOrvalues are directly related to skin oxygen delivery. It had a higher diagnostic accuracy than methods like Doppler anklebrachial pressure ratio or pulse volume recording. 2. Telethermography for visualization of the whole extremity to get information about the thermoregulatory behaviour. 3. The laser speckle method. A new non-contact method utilizing the dynamic laser speckle effect to get information about blood flow in the nutritional compartment of the skin.

Twenty-one type I diabetics underwent combined segmental pancreatic and renal transplantation and were accepted for our study. Control groups were 10 patients (IDDM) who had undergone only kidney transplantation and 10 patients (non-diabetics) with renal insufficiency after kidney transplantation. The microcirculatory parameter over a follow-up time of25 months revealed a significant improvement up to normal range. The tcPOrvalues rose from 44±2 to 63±l mmHg (p
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normal after transplantation. Because of the very low number of patients in this study (only five patients) these findings are preliminary. It should be mentioned that although the best restitution was found in the patients with the least severe microangiopathy. Functional rather than structural changes are probably responsible for the better skin microvascular reactivity after pancreas transplantation. Recently similar vascular dysfunction have been found in diabetic children without secondary complications. This is compatible with the view that there is a reduction of skin circulation.

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Figure 9-6. TcP0 2 values and reoxygenation time in 21 patients following successful pancreas and kidney transplantation.

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CONSIDERATIONS AND CONCLUSIONS

In summary, 102 pancreas transplantations have been performed using the duct occlusion technique exclusively, at the University of Munich . According to the recent series of 58 simultaneous transplantations of the pancreas and kidney in uraemic type I diabetics this technique appears to be safe as judged by the 4year patient survival rate of 96 percent. In addition (and in contrast to an earlier observation by our group) the 4-year kidney graft survival rate of 70 percent demonstrates that the simultaneous transplantation of the pancreas does not essentially jeopardize the result of renal transplantation. Moreover, the 4-year pancreatic graft survival rate of nearly 50 percent indicates a satisfactory long-term result although quite admittedly, the Iyear pancreatic graft survival rate has not been reached 80 percent so far at our institution (as has been achieved in one unit using the bladder drainage technique)." As described earlier the duct occlusion technique using prolamine is still associated with a relatively high rate of local residual transient exocrine activity (leading to complications with increasing severity, such as free excretion into'the peritoneal cav ity/pseudocysts-formationJpancreatic fistula/infected pancreatic fistula). However, it has to be stressed that this residual exocrine secretion is transitory and stops generally within 3-6 months. There is some evidence suggesting that that kind of residual exocrine secretion is less when using neoprene instead of prolaminej.!? Another still serious postoperative problem remains the incidence of primary venous thrombosis of the transplant vein in spite of obviously effecient anticoagulation. We still observe this complication, which leads to graft loss, in 7 percent of all cases. In contrast to these still existing and disturbing problems in the postoperative phase, the beneficial effect of successful pancreas transplantation using prolamine-occluded pancreata on the glucose metabolism is more than satisfactory: 71 percent of all successfully transplanted type I diabetic recipients show complete normalization of glucose tolerance as revealed by extensive metabolic studies; only 29 percent of those patients show a slightly disturbed glucose tolerance, but with normal glycoslyated haemoglobin values . Moreover, this state of complete normalization and restoration of the glucose metabolism following successful pancreatic transplantation remains stable at least over a period of 6 years in our experience. Thus, we are not able to demonstrate a steadily deteriorating endocrine function of the pancreatic graft caused by duct occlusion induced graft fibrosis. Thus this often theoretically assumed disadvantage of the technique of duct occlusion has not been observed in our series of successfully transplanted patients so far. Obviously the most discussed issue of successful pancreas transplantation concerns its influence of the late secondary complications. According to our observations there is growing clinical evidence suggesting a beneficial effect of successful pancreas transplantation on secondary complications. As described above, diabetic polyneuropathy, retinopathy, as well as peripheral microcirculation have stabilized or even improved in a high percentage of successfully

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transplanted patients who had suffered from the metabolic disease severely before transplantation. However, one has to admit that our clinical observations could not be unanimously confirmed by other investigators. Thus, the Minnesota group failed to observe any beneficial effect of pancreas transplantation on diabetic retinopathy,'! but was able to confirm our observations regarding diabetic polyneuropathy." On the other hand, the Stockholm group failed to observe any beneficial effect of pancreas transplantation on polyneuropathy when comparing pancreas and kidney transplanted patients and only kidney transplanted patients." Certainly, one has to stress the fact that we are treating diabetic and uraemic patients when transplanting a pancreas and kidney simultaneously. Both the disturbed glucose metabolism and the uraemic state may have contributed-to a various extent-to the clinical picture of the late syndrome encountered at the time of transplantation. In case of simultaneous correction of both the metabolic disorder (by the pancreatic graft) and the uraemic state (by the renal graft) the subsequent improvement/stabilization of the symptoms concerned is extremely difficult to ascribe with 100 percent certainty to only one of the organs transplanted. In this respect, our clinical studies in simultaneously transplanted diabetic and uraemic patients suffer from the fact that similar prospective control studies in only kidney transplanted diabetic and uraemic patients were not carried out. There appears to be now general agreement that only prospective multicentre control trials are able to provide a final evaluation of a potentially curative effect of successful pancreas transplantation on the late secondary syndrome of type I diabetes mellitus-a prospective trial which could include the performance of simultaneous pancreas and kidney vs kidney transplantation in diabetic and uraemic diabetics. The conduction of such a prospective trial is currently being discussed by us on a national level (as discussed and planned also by others on an international level). Another important evaluation concerns the surgical technique of duct occlusion vs the techniques of enteric as well as bladder drainage. An attempt at such an evaluation of all three techniques is depicted in Table 9-9, where factors like physiology, recipient operation, short-zlong-term results, short-/long-term risks, are used as factors for assessment. With regard to physiological assessment, enteric drainage certainly is the most biological surgical approach and duct occlusion the most unphysiological technique. The bladder drainage technique fulfills the criteria of physiology only regarding the graft. As far as the recipient operation is concerned enteric drainage procedure is regarded as a more or less difficult operation, whereas duct occlusion and bladder drainage appear to be easy to perform. Currently, the best I-year graft survival rate obviously can be achieved by using the bladder drainage procedure which has to be judged superior in comparison to the two other techniques. On the other hand, at the present time long-term results are much the same regardless what technique has been used. This also seems to be true when looking at potential short-term harm caused by the techniques, which are comparable. However, when looking at the potential long-term harm the duct occlusion technique appears to be definitely superior. We have to be aware of the

Table 9-9 Evaluation of Surgical Techniques in Pancreatic Transplantation (Evaluation based on the experience of the Munich Group)

Physiology

Duct Occlusion

Enteric Drainage

Bladder Drainage

Evaluation/Scoring*

RJ

+ graft + recipient

+ graft

enteric drainage

j?J recipient

graft

Recipient operation

easy

not easy

easy

l-Year graft survival

good

good

excellent

Current long-term results Potential short-term harm

good + graft + recipient j?J graft RJ recipient

good + graft + recipient + graft + recipient

good + graft + recipient + graft + recipient

Potential long-term harm

•

In favour for

RJ No, none

+

Yes

bladder drainage duct occlusion bladder drainage

duct occlusion

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fact that the process of occlusion-induced fibrosis (associated with complete replacement of the exocrine system by fibrosis tissue) is a long-lasting event (about 3-6 months) but which finally ends up resembling a special kind of a real islet transplant. This existence of an islet cell transplant (ca 6 months following the transplantation of the whole gland) can be interpreted in terms of the existence of vascularized islets embedded in a matrix consisting of fibrous tissue. Quite obviously, such a transplant exerts no long-term harm to the recipients because a gland does not exist any more. In contrast, in the situation of enteric or bladder drainage of pancreatic juice we are dealing with the transplantation ofa whole active gland which exerts a permanent exocrine function. Long-term risks like acute/chronic pancreatitis are possible; in addition, drainage of the pancreatic juice may be associated with intractable infections of the urinary tract. Morever, discussion continues whether or not chronic drainage of pancreatic juice might lead to malignancy of the bladder wall. Using a 'personal' scoring system, chosen more or less arbitrarily (Table 9·9), there seems to be a 'pat' between the duct occlusion technique and the bladder drainage procedure, whereas enteric drainage appears to be inferior. Nevertheless, only the future will show us what technique proves definitely the best. In summary, clinical pancreas transplantation today is characterized by more uncertainties than certainties, more unsolved than solved problems. This will ensure that, in the field of transplant medicine, pancreas transplantation will remain particularly interesting in the next few years.

REFERENCES 1. Thiroloix J: Note sur la physiologic du pancreas. Arch Physiol Norm Pathol 4:716-720, 1892. 2. Dubemard JM, Traeger J, Neyra P, et al: Long-term effect of neoprene injection in the canine pancreatic duct. Transplant Proc 11:1498-1499, 1979. ' 3. Traeger J, Dubemard JM, Ruitton AM, Malik MC, Touraine JL: Clinical experience with 15 neoprene-injected pancreatic allotransplants. Transplant Proc 12:44-50, 1980. 4. Land W, Landgraf R, IIIner W-D, Abendroth D, Kampik A, et al: Clinical pancreas transplantation using the prolamine duct occlusion technique-the Munich experience. Transplant Proc 19:75:82, 1987. 5. Marczell A: Erfahrungen mit dem Fibrinkleber bei Operationen am Pankreas. Akt Chir 20:52-54, 1985. 6. Nghiem DO, Corry RJ: Technique of simultaneous renal pancreatico-duodenal transplantation with urinary drainage of pancreatic secretion. Am J Surg 153:405-406,1987. 7. Sollinger HW, Kalayoglu M, Hoffman RM, Belzer FO: Results of segmental and pancreatico splenic transplantation with pancreatico-cystostomy. Transplant Proc 17:360-362, 1985. 8. Caine RY: Paratopic segmental pancreas grafting: a technique with portal venous drainage. Lancet i:595-597, 1984.

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9. Tyden G, Wilzek M, Lundgren C, Ostermann J, Gunnarsson R, et al: Experience with 21 intraperitoneal segmental pancreatic transplantations with enteric or gastric exocrine diversion in man. Transplant Proc 17(1):331-335, 1985. 10. Burke GW, Sutherland DER, Najarian JS: Intra-abdominal fluid collections in pancreas transplant recipients. Bladder versus enteric drainage. Transplant Proc 20(1):887-888, 1988. II. Tom WW, Munda R, First MR, Alexander J\V: Physiologic consequences of pancreatic allograft exocrine drainage into the urinary tract. Transplant Proc 19(1):2339-2342, 1987. 12. Steiner E, Klima G, Niederwieser D, Konigstrainer A, Herold M, et al: Monitoring of the pancreatic allograft by analysis of exocrine secretion. Transplant Proc 19(1):2336-2338, 1987. 13. Landgraf R, Landgraf-Leurs MMC, Nusser J, Hillebrand G, IIIner W-D, et al: Effect of somatostatin analogue (SMS 201-995) on Cyclosporine levels. Transplantation 44(5):724-725, 1987. 14. Lenhart FP, Unertl K, Jensen U, Landgraf R, Land W: Postoperative management after simultaneous segmental pancreas and kidney transplantation. Transplant Proc 16(3):713-714, 1984. 15. Abendroth D, Sunder-Plassmann L, Land W, Landgraf R: Changes of diabetic microangiopathy after pancreas transplantation. Transplant Proc 19:3886-3887, 1987. 16. Sollinger HW: Panel Discussion on "Is there an optimal surgical technique for pancreatic transplantation? 1st Int Congr on Pancreatic and Islet Transplantation. StockholmfSW 1988. 17. Brekke IB, Flatmark A, Tyden G, Groth CG: Pancreatic duct occlusion versus duct drainage. Post transplant complications and survival rates. 1st Int Congr on Pancreatic and Islet Transplantation. StockholmfSW 1988. 18. Ramsay RC, Frederick MD, Goetz SC, Sutherland DER, Mauer SM, et al: Progression of diabetic retinopathy after pancreas transplantation for insulindependent diabetes mellitus. New Engl Med 28:208-214,1988. 19. Van der Vliet JA, Navarro X, Kennedy, WR, Goetz FC, Najarian JS, Sutherland DER: The effect of pancreas transplantation on diabetic polyneuropathy. Transplantation, 45(2):368-370, 1988. 20. Wilczek H, Solders G, Gunnarsson, R, Tyden G, Persson A: Effects of successful combined pancreatic and renal transplantation on advance diabetic neuropathy: A one-year follow-up study. Transplant Proc 19(1):2327-2328, 1987.