Search

Pancreas graft survival is influenced by various donor and recipient factors. Factors that have posed serious problems to pancreas transplantation have included the limited cold ischemia time, early graft thrombosis, and rejection. A limited cold ischemia time not only causes problems in terms of logistics but also implies limitations with regard to HLA matching and organ exchange. Between August 1988 and August 1989 we performed a prospective, nonrandomized European multicenter study to evaluate the effect of University of Wisconsin (UW) solution on pancreas graft survival. In addition, donor and recipient factors were collected and their influence on graft survival analyzed. Overall pancreas graft survival at 1 and 4 years was 67% and 59%, respectively (n = 62). When only simultaneous pancreas and kidney transplants were included, the graft survival was 70% and 63% at 1 and 4 years, respectively. The incidence of pancreas graft thrombosis was 8%. Cold ischemia time was not found to significantly influence pancreas graft survival even when it exceeded 12 h. Factors that did were HLA-DR matching, simultaneous pancreas and kidney transplantation versus pancreas transplantation alone, and ABO blood group matching. We feel that the use of UW solution for pancreas preservation has contributed to improved pancreas graft survival and has reduced early graft thrombosis despite much longer cold ischemia times of over 12 h. Given this and the significant effect of HLA and blood group matching, we conclude that more attention should be paid to preoperative matching and organ exchange in order to further improve pancreas graft survival.

The quality of life after a successful combined kidney-pancreas transplantation was studied in 17 diabetic patients with end-stage renal disease (ESRD) and in 11 patients who experienced a failure of one or both grafts. The control group comprised 23 patients who received a kidney transplantation only. The aspects of quality of life chosen for study were: physical, psychological and social wellbeing, daily activities, level of functioning and global quality of life evaluation. Additionally, future expectations, the perceived burden of treatment, and main reason for undergoing organ replacement therapy were evaluated. In only one aspect of quality of life did patients with a successful combined transplantation score significantly better than patients with a kidney transplantation, i.e., mobility in daily functioning and activities (p = 0.03). Patients with a failure of one or both grafts reported significantly more fatigue (p = 0.02), less energy (p = 0.04), and more social isolation (p = 0.05) than patients who had well-functioning grafts. The mean duration of hospitalization following combined transplantation is twice that for kidney transplantation only 10 vs 5 weeks. Although the combined transplantation group found the first 3 months after transplantation more burdensome (p = 0.04) and more often wondered whether it had been worth all the trouble (p = 0.05), they indicated the same willingness as the group with a kidney transplant only to undergo another transplantation under similar circumstances. Although the recipients of a kidney transplant had not been offered the choice of a combined transplantation, their reasons for transplantation did not, in essence, differ from those of recipients of a combined transplantation. In both groups the main motivation to opt for organ replacement therapy was the burden of dialysis, to stop the progressive deterioration of their health, and to experience a better quality of life.

Pancreatic graft procurement, preservation, and transplantation surgery may result in damage to and loss of the integrity of endocrine cells and consequently in leakage of cell products into the insular vascular capillaries. Thus, the amount of alpha-, beta-, and pancreatic polypeptide (PP) cell products released into the vascular space of the recipient immediately after graft reperfusion may reflect islet cell injury. To test this hypothesis, we assessed glucagon, PP, C-peptide, and insulin levels in a prospective study of 22 consecutive renal-pancreatic transplantations. Transplantation-related parameters were used to account for differences in hormone release. Five grafts were preserved using Euro-Collins preservation fluid and 17 grafts were preserved using University of Wisconsin solution (UW). The first sign of a reinstalled physiological axis was the decrease of the blood glucose concentration after a median duration of 40 min (range 5-90 min) and the association of the recipient's ambient blood glucose levels with insulin release between 25 and 180 min after reperfusion. The delay period before a fall in blood glucose was observed correlated with cold ischemia time (rs = 0.73, P < 0.001, n = 21). An immediate and marked increase in plasma levels of glucagon (from 180 +/- 18 to 585 +/- 99 ng/L, mean +/- SEM), PP (from 57 +/- 8 to 122 +/- 13 pmol/L), C-peptide (from < 0.06 +/- 0.02 to 5.43 +/- 0.63 nmol/L), and insulin (from 0.15 +/- 0.21 to 2.05 +/- 0.26 nmol/L) was observed. C-peptide release correlated with glucagon (r = 0.76, P < 0.001) and PP (r = 0.60, P < 0.01). The hormone release was compared with computed tomography scans that were performed in the immediate postoperative period in 15 UW-preserved allografts. The diameter of the pancreatic head was increased and ranged from 4.5 to 7.7 cm (mean 6.2 cm). Peroperative C-peptide release significantly correlated with morphological graft changes reflected by the pancreatic head diameter (r = 0.58, P = 0.02). In a stepwise multiple regression analysis, cold ischemia time was a significant factor for the release of PP (r2 = 0.18, P = 0.049) and C-peptide (r2 = 0.35, P = 0.004). We suggest that peroperative hormone release reflects endocrine tissue damage. Furthermore, cold ischemia time may jeopardize the pancreatic allograft after relatively short preservation times, even when UW is used.

Vascular thrombosis following pancreas transplantation is one of the main causes of early graft loss. Successful thrombectomy after pancreatic graft thrombosis has not been reported yet. A patient with arterial graft thrombosis in whom the graft survived after thrombectomy is described. Different varieties of pancreatic graft thrombosis are discussed.

In a prospective study, 17 early baseline computed tomography (CT) scans were obtained 2 or 3 days after simultaneous kidney-pancreas transplantation. Morphological changes and their relevance to the early detection of graft rejection and complications were evaluated. The pancreatic grafts were enlarged and showed signs of mild pancreatitis. Serial scans obtained during the first renal graft rejection episode were compared with the baseline CT scans (n = 7). They showed a significant increase in pancreatic graft size in the case of biopsy-proven severe renal graft rejection (P = 0.008). Normally functioning pancreatic allografts showed a 15%-40% decrease in size 1-6 months after transplantation. We conclude that the morphological changes observed early after transplantation are compatible with mild pancreatitis, which may contribute to the development of pancreatic graft thrombosis. There is an increase in the number of morphological changes during severe rejection, yet enlarged pancreatic grafts appear to recover from transplantation-related damage and regain their normal size without signs of atrophy.

We analyzed the overall results of 24 simultaneous pancreas and kidney transplantations (SPK), performed in our hospital between April 1986 and June 1990. All patients had type I diabetes mellitus and end-stage renal failure. We used bladder drainage of the pancreatic exocrine secretions through a duodenocystostomy. The blood vessels of both grafts were anastomosed to the iliac vessels. The immunosuppressive management was triple-therapy with cyclosporin, azathioprine and prednisone. All organs were transplanted without matching donors and recipients for HLA. At the time of transplantation, mean recipient age was 37 yr; the average duration of diabetes was 22 yr. After disappointing results in the first 4 patients, the pancreas was placed intraperitoneally instead of extraperitoneally and the antibiotic drug regimen was altered. In the second group (n = 20), patient survival was 100%; 1-yr pancreas and kidney graft survival were 65 and 62%, respectively. Duration of hospitalization and pancreas and kidney graft loss were positively correlated with the number of rejection episodes. After 1 yr of follow-up, the mean creatinine clearance was 62 ml/min and the mean HbA1c was 5.5%. Blood glucose levels and oral glucose tolerance tests were also normal. We conclude that patient and graft survival after SPK are satisfactory, although rejection-related morbidity is still a major problem.

The role of hydroxyethyl starch (HES), the colloid component of the UW solution, was tested in canine pancreas preservation. Segmental pancreatic autografts were preserved for 48 hr cold storage with UW solution with HES (group 1) or UW solution without HES (group 2). After preservation, the pancreas was transplanted, and survival, serum glucose, serum amylase, intravenous glucose tolerance tests, tissue water content, and histology were compared between groups. In group 1 (with HES), 9/10 dogs were long-term survivors with one dog dying due to causes unrelated to preservation failure. In group 2 (without HES), 3/6 dogs died due to graft loss within one week posttransplant (P = 0.01). No graft failure occurred in group 1 (0/9) versus graft loss in 4/6 dogs in group 2 (P = 0.04). All animals in group 1 (with HES) showed normal serum glucose and amylase concentrations postoperatively, normal tissue water values after preservation, k values comparable to those observed after segmental autotransplantation without preservation, and relatively good histology. In group 2 (without HES), in 4/6 dogs graft failure occurred that led to the death (3 dogs) of the animals or to a diabetic state (1 dog). After 48-hr cold storage without HES, a significant increase in tissue water content, glucose and amylase levels was seen. After transplantation, hyperglycemia, hyperamylasemia, and clinical diabetes were observed in 4/6 dogs. Autopsy and histological evaluation showed evidence of thrombosis and ischemic insult. Two of 6 dogs in group 2 remained normoglycemic during follow-up with borderline k values. The results suggested that for consistently successful 48-hr preservation of the pancreas, HES is an important component of the UW solution. Although a colloid may not be essential for short-term preservation of kidney and liver, it appears to be an important factor in successful pancreas preservation.

This study in dogs addresses itself to the endocrine function of the duct-obliterated left pancreatic lobe (body and tail), which is the portion of the pancreas used for segmental transplantation. The endocrine function was determined with intravenous (i.v.) glucose tolerance tests and expressed in K-values and insulin-response curves. Duct obliteration of the nontransplanted left lobe was associated with normal K-values in the presence of the unmodified right lobe, but with reduced K-values in its absence. Removal of the left lobe while leaving the right lobe untouched was not associated with reduced K-values, but duct obliteration of the whole pancreas was. When the duct-obliterated left lobe was transplanted onto the iliac vessels (segmental autografts), K-values were reduced when compared with the unmodified situation, but were significantly higher than with nontransplanted, duct-obliterated left lobes. Insulin-response curves of nontransplanted, duct-obliterated segments differed both qualitatively and quantitatively from the unmodified situation, but insulin-response curves of duct-obliterated segmental autografts showed only qualitative differences with the unmodified situation. It is concluded that duct obliteration rather than the absence of the right lobe is the predominant cause of reduced glucose tolerance with duct-obliterated left pancreatic lobes. It is suggested that duct obliteration affects the endocrine pancreas both in a qualitative and quantitative fashion. The qualitative effect is similarly demonstrable with segmental autografts and nontransplanted segments, but the quantitative effect is largely dissolved with autografting by virtue of caval as opposed to portal venous drainage.

In this study, we have quantitatively assessed the changes in insulin-secreting capacity after duct-obliterated segmental pancreatic autotransplantation in dogs. To this end, we have used a technique for the sampling of the complete and undiluted pancreatic venous blood with simultaneous flow measurement, by which means the actual insulin-secreting capacity was determined in a direct fashion. Histologic changes were analyzed in addition in order to address the underlying mechanisms of the changes in insulin-secreting capacity. Intraoperative glucose-stimulated insulin secretion of the left pancreatic lobe was measured before (group I, n = 8), at 6 weeks (group II, n = 5), and at 18-24 months (group III, n = 7) after duct-obliterated segmental pancreatic autotransplantation. At all 3 intervals, histologic analysis was performed. Since the experiments in groups I-III were performed under general anesthesia, a 4th group of dogs (group IV, n = 6) was studied in addition in order to determine the effect of general anesthesia on glucose metabolism. K-values appeared to be reduced to 1/5 and peripheral insulin response (AUC) to about 1/3 of the values obtained from fasting conscious dogs. Although all animals in groups I-III had normal fasting glucose levels and normal K-values at each test interval, a 75% reduction of insulin secretion after duct-obliterated transplantation was observed. Insulin secretion not only showed marked quantitative changes but significant qualitative alterations in glucose-stimulated insulin response were found. Disturbance of functional islet architecture appears to be the main causative factor in the decrease in insulin secretion. If applicable to man, our results indicate that especially the duct-obliterated graft, with its borderline endocrine capacity, is prone to loss of sufficient graft function by the damage induced by eventual rejection crises.

Our aim was to isolate and determine the contribution of partial pancreatectomy, systemic delivery of pancreatic hormones, and duct obliteration to glucose regulation after segmental pancreas transplantation in dogs. Fasting, postprandial, and intravenous glucose-stimulated glucose, insulin, glucagon, pancreatic polypeptide (PP), and cholecystokinin (CCK) and intravenous bombesin-stimulated PP levels were studied in beagles at three successive intervals in a crossover design. The first was 6 wk after partial (approximately 70%) pancreatectomy with intact regular enteric exocrine drainage from the duodenal pancreatic remnant, the next was 2 wk after venous transposition with systemic delivery of pancreatic hormones, and the third was 6 wk after in situ duct obliteration of the remnant. With partial pancreatectomy, K values were modestly diminished (30%), and a concomitant reduction of second-phase intravenous glucose-stimulated insulin release was observed. Other parameters were not significantly affected. Venous transposition doubled peripheral plasma levels of insulin under all conditions. Fasting glucose, PP, and CCK levels decreased slightly. Other parameters were not affected. Duct obliteration of the systemic draining pancreatic remnants seriously impaired glucose sensitivity, resulting in a 50% reduction of K values and fasting and sustained postprandial hyperglycemia (approximately 8 mM) and a 70-50% reduction (acute and overall responses, respectively) of intravenous glucose-stimulated insulin. Fasting hormone and postprandial insulin, glucagon, and CCK levels were not affected. The postprandial PP response was severely reduced, and bombesin-stimulated PP release was abolished by duct obliteration. We conclude that histological changes associated with duct obliteration are the major determinants of glucose regulation in segmental pancreas transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Pancreatic duct obliteration is a procedure to abolish exocrine secretion in order to prevent complications such as leakage, abscess and fistula occurring formation after diversion techniques like pancreatico-enterostomy. Pancreatic duct obliteration is applicable after all sorts of partial pancreatic resections, pancreas transplantation included. Although the method is safe, experiments have shown that not only complete exocrine atrophy is induced, but that also the endocrine architecture is destroyed. In dogs, the destruction of islet architecture leads to about 70% reduction of the insulin secreting capacity. It is not known whether such a severe reduction of endocrine function also occurs after pancreatic duct obliteration in man. This would discard duct obliteration as a procedure suitable for pancreas transplantation, since optimal endocrine pancreas function is the aim of pancreas transplantation in patients suffering from type-I diabetes mellitus.

This case report describes the first clinical pancreas transplant performed in The Netherlands. A duct-obliterated segmental graft from a cadaver donor was transplanted to a male recipient who was insulin-dependent after total pancreatectomy eight years earlier. The recipient was off insulin for four postoperative months; during this period a rejection crisis was successfully treated. The graft was removed eight months after transplantation. Histologic examination indicated both fibrosis and rejection to have presumably contributed to graft failure. The patient is well but again insulin-dependent.

This study addresses itself to the eventual interference of cyclosporine (CsA) with the function of pancreatic beta cells in vivo. We have used dogs that had at least six weeks previously been subjected to segmental pancreatic autotransplantation. This model has been well established to be associated with stable normoglycemia but with incomplete endocrine reserve capacity, which renders it suitable for detecting eventual toxic drug effects. CsA was administered for 6 weeks in an oral dose of either 30 mg/kg/day (first series of 4 dogs) or 40 mg/kg/day (second series of 7 dogs). CsA trough levels in blood were determined at least weekly, and the mean of the levels in each dog ranged from 218 to 1274 ng/ml, with one exception (2191 ng/ml). The endocrine function was tested not only before and after 6 weeks of CsA administration, but also at 4 weeks after cessation of CsA administration. The postprandial insulin output was reversibly reduced in the first series (P less than 0.05) and the i.v. glucose-stimulated insulin output was reversibly reduced in the second series (P less than 0.001). Other parameters, like postprandial peak and mean blood glucose levels and K-values, showed reversible changes that, although not always statistically significant, were compatible with a reversible suppressive effect by CsA in all instances. Finally, we found that the severity of suppression as expressed in individual reduction of i.v. glucose-stimulated insulin output correlated with the individual mean CsA trough level (r = 0.71, P less than 0.015). It is concluded that CsA exerts a detrimental effect on the function of canine beta cells in vivo, which effect is reversible and dependent upon the CsA blood level.

In segmental-pancreas transplantation the body and tail of the pancreas are used. In an experimental study in dogs, the effects of sequentially conducted removal of the right pancreatic lobe (pancreatic head), duct obliteration, celiac denervation, and autotransplantation were studied according to a crossover design. Two groups of dogs were studied. In both groups the right lobe of the pancreas was removed at primary operation, and the duct of the transected left lobe (body and tail) was injected with fibrin sealant. The left lobe was completely freed from surrounding tissue (celiac denervation) in group 1 (n = 9), and the innervation of the left lobe was left intact in group 2 (n = 8). At 12 wk, two dogs in group 1 and four dogs in group 2 underwent successful autotransplantation of the left lobe. Pancreatic hormone secretion was stimulated by intravenous glucose injection and test-meal administration before primary operation and at 11 and 18 wk thereafter. The combination of removal of the right lobe and duct obliteration led to a decrease in glucose tolerance at both stimulation tests and a decrease in peripheral insulin release after intravenous glucose injection. At test-meal administration, no change in insulin and glucagon levels was demonstrated. If celiac denervation was added, similar results were obtained based on the understanding that the peripheral insulin release after the test meal was significantly elevated. Meal-stimulated pancreatic polypeptide response was abolished in both groups. Removal of the right lobe leads to parasympathic denervation of the left lobe, and celiac denervation mainly interferes with alpha-adrenergic innervation.(ABSTRACT TRUNCATED AT 250 WORDS)