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Simultaneous pancreas-kidney (SPK) transplantation is considered a valid therapeutic option for patient with type I diabetes mellitus and end-stage diabetic nephropathy. This study was performed to determine whether the technique of pancreas venous drainage affects patient survival as well as graft survival and function. From October 1996 to April 1999 34 uremic patients with type I diabetes mellitus were randomly assigned to two groups: the first group (SV group = 17) received SPK transplantation with systemic venous drainage, and the second group (PV group = 17) received pancreas allograft with portal drainage. A Roux-en-Y loop was performed in all the patients. Patient follow-up included clinical course and metabolic studies. At 1 yr, patient survival rates were 88.2% in the SV group and 94.1% in the PV group while graft survival rate was 76.4% in both groups. Several surgical complications were attributed to the enteric drainage without any graft failure in both groups. One venous thrombosis occurred in each group. No significant differences have been evidenced in kidney and pancreas function. The preliminary results of this randomized trial did not evidence any significant differences between portal and systemic venous drainage of pancreas allograft.

This brief article is a summary of the presentations at a meeting organized in Lyon, France, to discuss strategies of reducing post-transplant diabetes mellitus and to suggest an ideal immunosuppressive therapy for pancreatic and islet allografts.

Type 1 diabetes mellitus is considered as an autoimmune disease against beta cells. Diabetes recurrence after pancreas transplantation is well known in HLA-identical twins while it is rarely reported in recipients of cadaveric pancreatic grafts. In the present case report, diabetes recurrence occurred in a recipient who underwent cadaveric combined pancreas kidney transplantation. Seven years after transplantation the patient exhibited progressive hyperglycemia needing insulin therapy while the renal graft was well functioning. The diagnosis of recurrent disease was obtained on the histological features such as selective loss of beta cells without clear signs of insulitis and on the presence of markers (GAD 65 and IA-2) for humoral autoimmunity. It is intriguing that, at the time of recurrence of type 1 diabetes, the patient had stopped steroids and azathioprine, while only cyclosporine was maintained as immunosuppressive treatment. Our case report underlines the relevance of studying the humoral autoimmune response directed to islet autoantigens in cadaveric pancreas allograft recipients. Furthermore, it suggests that an efficient immunosuppressive treatment after transplantation may be able to reduce the autoimmune response against the pancreatic allograft.

Background: Besides alloimmunity to transplanted pancreatic tissue, recurrent autoimmune beta cell destruction is an additional limitation to successful clinical pancreatic allografts in type 1 diabetic patients., Methods: We studied the prevalence of autoantibodies to glutamate decarboxylase (GAD) 65 and tyrosine phosphatase (IA-2) in 68 C-peptide-negative diabetic patients receiving pancreatic allografts. Sera from patients were obtained immediately before grafting. A second blood sample was analyzed at the time of graft failure in patients who returned to hyperglycemia and during the same follow-up period in those who experienced a functional pancreatic allograft. Patients were classified according to clinical outcome into chronic graft failure (group A, n=20), acute graft failure and/or arterial thrombosis (n=7), or functional pancreatic graft (group C, n=41). Sera from patients were screened for the presence of specific autoantibodies using an islet cell autoantibody assay, a combi-GAD and IA-2 test, and individual GAD and IA-2 assays., Results: Patients from group A had significantly higher combi-test values than patients from group C (13+/-16 vs. 4.5+/-12 units, P<0.02) and higher anti-GAD65 antibody (Ab) levels (0.19+/-0.3 vs. 0.04+/-0.13 units, P<0.01) immediately before grafting. After graft failure in group A, both anti-GAD65 and anti-IA-2 Ab levels increased from baseline, but only the increase in anti-IA-2 Ab levels reached statistical significance (0.28+/-0.12 vs. 15+/-34, P=0.03). When compared with group C, patients from group A had higher anti-GAD65 Abs (0.29+/-0.35 vs. 0.05+/-0.16, P<0.001) after graft failure. Interestingly, the number of double-Ab-positive patients rose from 5% to 35% in group A, whereas it remained at 5% in group C. In pancreatic transplants with bladder drainage, the presence of anti-GAD65 and/or anti-IA2 Abs was not associated with a reduction in urinary amylase levels. This suggests that a loss of endocrine function was not associated with exocrine failure in patients from group A., Conclusions: We can conclude from the present study that peripheral autoimmune markers are useful in diabetic patients receiving pancreatic allografts.

A randomized study of combined kidney-pancreas transplantation was performed on 30 insulin-dependent diabetic patients with end-stage renal disease to compare the consequences of pancreas transplantation with portal venous (PV) and systemic venous (SV) drainage. Fourteen patients (SV) group) received systemically drained and sixteen (PV group) portally drained pancreas allografts. Enteric drainage was performed in both groups. The routine follow-up included documentation of the clinical course and detailed endocrine studies. At 1 year after transplantation, the patient survival rate was 92% for the SV group and 96% for the PV group; the graft survival rate was 78% and 82%, respectively. Endocrine studies indicated no difference in fasting and stimulated glucose or in glycosylated hemoglobin between the two groups. In addition, no hyperinsulinemia and lipidic abnormalities were evidenced in either group Long-term studies are required to conclude whether PV and SV drainage in pancreas transplantation are equivalent in terms of patient and graft survival as well as metabolic consequences.

Pancreatic transplantation is the best method of replacing the endocrine function of the gland in Type 1 insulin-dependent diabetic patients. At the end of 1996, 9,000 pancreas transplants had been reported to the international Pancreas Transplant Registry. For 1994-1996, one-year pancreas survival rates were 81% for simultaneous pancreas and kidney transplantation (n = 1,516), 71% for pancreas after kidney (n = 141) and 64% for pancreas alone (n = 64). In patients with a functional graft, glycosylated haemoglobin, fasting blood sugar, and 24-h metabolic profiles are normal. The effect of pancreatic transplantation on secondary complications often appears after several years of normal pancreatic function. Successful transplantation is associated with an improvement in different aspects of the quality of life. The decision to perform pancreatic transplantation depends on the balance between the risks of transplantation, mainly surgical or related to immunosuppression, and those of diabetes development. The advantages and drawbacks of pancreatic transplantation and insulin therapy need to be honestly and carefully analysed for specific populations of diabetic patients as well as for each individual. At present, simultaneous pancreaticorenal transplantation is the best treatment for diabetic patients with chronic renal failure. Transplantation of the pancreas alone in non-uraemic patients may also be considered in carefully selected subjects.

To date there is no general consensus as to the best surgical technique for pancreas transplantation. Patients with a pancreas transplant functioning for 3 years or more were retrospectively investigated to compare three surgical techniques: segmental graft with duct obstruction (DO), whole graft with bladder drainage (BD), and whole graft with enteric drainage (ED). Several parameters were studied: patient and graft survival, rejection, long-term surgical and medical complications, and endocrine function. The best results in terms of graft survival and quality of metabolic control were obtained in the group that underwent whole graft transplantation with ED. At 3 years, overall pancreas graft survival was 65% for ED, 60% for BD, and 47% for DO. This surgical method has become the preferred technique in our unit.

We report 23 cases of lymphoproliferative diseases which occurred among 2,100 patients with kidney or combined kidney+pancreas transplant. Eleven patients developed a severe diffuse disease within the first 3 months post-transplantation; immunoblastic B cells of recipient origin infiltrated the bone-marrow, transplanted organs, liver, spleen, lymph nodes, lungs, and brain; immunoglobulin abnormalities with fever, leuko-thrombocytopenia and liver dysfunction constituted the symptoms; all patients received anti-lymphocyte globulins; 9 patients were also treated with cyclosporin. Three out of 6 tumors analysed were monoclonal. Epstein-Barr virus was present in 3 lesions analysed. Treatment consisted of cessation of immunosuppressive therapy. Nine patients died with lactic acidosis. Five patients had a less severe form. Seven patients had solid tumors involving the tonsils, lungs (2), lymph nodes (2), and bladder, 8 months after transplantation. All patients received cyclosporin; 4 also received anti-lymphocyte globulins and 3 OKT3. Tumor cells were immunoblasts expressing B cells markers at a late stage of B cell differentiation; 4 tumors were monoclonal. C myc was negative. Treatment consisted of cessation of immunosuppressive therapy, antiviral agents, and monoclonal antibodies (mAb): anti-CD21 and anti-CD24 mAb therapy was followed by cure of the lymphoma in 1 patient, by transient remission in a second one and by failure in the third patient. Two patients had a recurrence of the lymphoma and received chemotherapy; 2 patients died of the lymphoma, 1 died of unrelated cause; 4 are alive, 3 of them having a good graft function.

The aim of the study was to evaluate the virological parameters associated with the severity of cytomegalovirus (CMV) disease in renal and simultaneous renal and pancreatic transplantation. The association of the viral profile and the severity of the viral disease was analysed taking into account different confounding variables susceptible to linkage with the severity of the CMV infection and the viral parameters. All the patients transplanted between 1 January 1989 and 31 December 1990, a total of 242, were prospectively followed by viral cultures in blood and urine and by serological methods using the detection of CMV-specific IgM and the complement fixation (CF) test. The samples were taken systematically each week for the first month and then at day 90, 180 and every 6 months and also in cases of clinical manifestations related to viral disease. CMV infection was diagnosed virologically by the presence of viraemia, viruria, IgM, or a significant rise in CMV antibody titre in CF. CMV disease was classified as asymptomatic, mild (fever and/or leukopenia), moderate (fever, leukopenia and liver abnormalities), severe (CMV pneumopathy and/or gastrointestinal disease) or fatal. The incidence of CMV infection was 65% (157/242): 32% asymptomatic, 36% mild, 30% moderate and 2% severe. The presence of IgM was associated with the severity of CMV disease: 51.4% of moderate and severe CMV infections in the group with IgM versus only 16% in the group without IgM (P < 0.0001). The risk of having severe or moderate CMV disease was 3.28 times higher in patients with positive IgM. However the serological changes in CF were not significantly associated with the severity of the viral disease since 34.6% of the patients with CF changes had a severe form versus 20.8% in the group without CF modification. Viruria was significantly associated with moderate or severe infection: 43.6% of the patients with viruria had severe infection versus only 12.5% in the patients without viruria (P < 0.0002). The risk of having moderate or severe CMV disease was 3.48 times higher in the patients with viruria. Viraemia was also associated with more severe CMV infection: 48.6% of moderate or severe CMV infection in the group of patients with viraemia versus 19% in the group without viraemia (P < 0.0001). The risk of having severe or moderate CMV infection was 2.58 times higher in the patients with viraemia. Viraemia was not more associated with severe CMV infection than viruria. Using the maximum likelihood ratio method and the logistic regression model, CMV-specific IgM, viruria and viraemia were each shown to be associated with the severity of CMV disease and the addition of one parameter to the other(s), whatever the type (except the CF changes) and whatever the order of this addition, did not remove the link between the severity and IgM, viruria and viremia. The incidence of severe and moderate CMV disease increased with the number of positive viral parameters (PVP) from 2% of moderate and severe infections in the group with one PVP, to 28% in the group with two PVP, to 39% in the group with three PVP and 68% in the group with four PVP (trend, 35.95; P < 0.0001). Taking the absolute risk of the group of patients without IgM, viruria or viraemia as the basal level, the observed relative risk of severe CMV infection varied from 6.45 in the group with positive IgM without viruria or viraemia, to 10.74 in the group with positive IgM and viruria without viraemia and to 22.5 in the group with the three positive parameters IgM, viruria and viraemia. The different potential confounding factors (recipient and donor serology, renal or renal and pancreatic transplantation, DR compatibility, rejection before CMV infection) did not modify the link between the viral profile and the severity of CMV disease. This study suggests that the severity of CMV disease might be linked to the overspread of the virus as well as to the consequences of a CMV-specific humoral immune response.

The limitations of insulin therapy explain the growing interest expressed by diabetologists in pancreas and islet cell transplantations. Pancreatic graft is the most used method, and its technique is now well established; the exocrine secretion can be either dried up by pancreatic duct obstruction or drained, often into the bladder. However, this method demands permanent immunosuppression and for this reason it is used in 85 percent of the cases in diabetics requiring kidney transplantation. The mortality and morbidity due to transplantation have decreased considerably. The survival rate at 1 year is 81 percent for patients and 46 percent for grafts, with return to normal glycaemia levels in most cases. The effects of pancreas transplantation on diabetic microangiopathy are difficult to evaluate in these patients who often have very advanced complications, but the first data are encouraging. The indications for this transplantation are limited, and they should not be extented to early stage diabetes unless they are part of controlled studies. Islet cell transplantation has many potential advantages, including safety and the hope of grafts without permanent immunosuppression, but the results available in man are still very preliminary.

From October 1976 to December 1990 181 pancreatic transplants were performed in our centre on 171 Type 1 (insulin-dependent) diabetic patients. Oral glucose tolerance test evaluated 1 year after surgery in 31 subjects showed an impaired glucose tolerance at 120 min (blood glucose 9.5 +/- 0.6 mmol/l). Similar results were obtained in seven patients 3 years after transplantation (blood glucose at 120 min 8.3 +/- 1.08 mmol/l). 24h metabolic profiles performed at the same intervals showed near normal blood glucose levels and good insulin release. Preliminary data concerning a randomized, comparative study between whole pancreas with bladder diversion and segmental pancreas transplantation, showed better metabolic control in the patients who received the whole pancreas, probably due to the greater islet mass grafted.

To assess the long-term evolution of diabetic polyneuropathy after a combined kidney-pancreas transplant, an electrophysiological study was performed in 20 diabetic patients before transplant, and 1 (n = 18), 2 (n = 16), 3 (n = 10) and 4 years (n = 5) at a later date. Motor and sensory scores were calculated for conduction velocity and amplitude to determine the physiopathological process. During evolution the scores were not found to be decreasing. Motor and sensory velocity scores were significantly improved (p less than 0.05) 1 and 2 years after the graft, when score values tended to stabilize. Motor and sensory amplitude scores, which are more sensitive for axonal loss assessment were slightly but not significantly improved.

We studied the effect of successful kidney and pancreas transplantation on visual function and diabetic retinopathy in 18 patients with long-term Type 1 (insulin-dependent) diabetes mellitus (17 to 38 years) and with advanced proliferative retinopathy. The average age of the patients was 42 years. Prior to transplantation, 5 eyes were in end-stage ophthalmic complication due to neovascular glaucoma. An ophthalmological follow-up was performed between 1-6 years post-surgery. Analysis of the results showed that the diabetic retinopathy had stabilized after transplantation in 12 cases (66%) with a supplementary photocoagulation in the majority of cases. The proliferation continued in 4 patients (22%) leading to blindness in 2 patients and recurrence of vitreous haemorrhages despite the photocoagulation in the other 2 cases. An improvement was observed on fluorescein angiography in a patient with pre-papillar glial proliferation without photocoagulation. Ten patients were reported to have a cataract and were operated on in two cases before transplantation; in one patient, the cataract increased following transplantation. In conclusion, the kidney and pancreas transplantation was not effective in our patients in reversing the clinical and angiographic signs of diabetic retinopathy. Moreover, a worsening of the lesions was observed in some cases; this was probably due to the irreversible microangiopathic lesions due to advanced evolution of diabetes.

A total of 182 pancreatic transplantations were performed between 1976 and 1990. Survival of the grafts was 45% at 5 years. Major causes of graft loss have been rejection and venous thrombosis. Death occurred in 24 patients and was usually related to vascular complications. The techniques of duodenopancreatic transplantation with enteric drainage, bladder drainage and the technique of segmental duct obstructed grafts were compared. A higher rate of surgical complications was observed with enteric drainage, whereas it is unclear from the data whether segmental grafts or duodenopancreatic grafts drained into the bladder lead to different results.

The rationale behind pancreatic transplantation is to provide a self-regulated, endogenous source of insulin and other islet hormones, thus restoring normal metabolism with the ultimate goals of prevention, stabilization or reversal of secondary degenerative complications. We report clinical and metabolic data of 8 patients submitted to simultaneous kidney and pancreas transplantation in our institute, who had a pancreatic graft function for 4 (1 case) and 5 (7 cases) years. To assess the impact of transplanted pancreatic mass on long-term function, we also included 10 patients from a comparative study between segmental pancreas transplantation (group A, 5 pts) and whole pancreas with enteric diversion transplantation (group B, 5 pts), who had pancreatic function for 2 and 3 yr. All patients are alive. Seven of these patients are off insulin, while one patient lost pancreatic function during an operation performed to correct an arterial stenosis of the graft. HbAlc levels were normal during the entire follow-up period (5.2+/-0.14% at 4 yr; 5.1+/-0.6% at 5 yr). In 24-hour metabolic profiles we observed near normal blood glucose levels, with good insulin release at 4 yr and a mild hyperglycemia at 5 yr (BG at 9 p.m.: 8.8+/-1.3 mmol/l). OGTT performed in 5 patients, 4 yr after pancreas transplantation, showed an impaired glucose tolerance, while the same test performed at 5 yr, showed higher values (BG 120 minutes: 14.7+/-0.2 mmol/l). Group A and group B patients are all alive, with good renal and pancreatic function.(ABSTRACT TRUNCATED AT 250 WORDS)

We have investigated the metabolic effects of segmental (neoprene-injected) pancreas transplantation versus whole (enteric-diverted) pancreas transplantation. Seventeen uremic insulin-dependent diabetes mellitus (IDDM) patients received a simultaneous pancreaticorenal transplant: in a prospective, randomized study, 9 patients received a segmental neoprene-injected graft (group A) while 8 patients received a total pancreaticoduodenal graft, with enteric diversion (group B). The immunosuppressive therapy was based on ALG, CsA, azathioprine, and steroids. Three months after surgery, patients were submitted to the following metabolic investigation: i.v. and oral glucose tolerance tests, Hba1, i.v. arginine test, and a 24-hr metabolic profile. The OGTT, HbA1, and metabolic profile were repeated 12 and 24 months after transplantation. At 3 months after transplantation, the OGTT showed delayed insulin secretion and higher blood glucose levels in group A. Serum insulin levels after IVGTT or arginine were higher in group B than in group A. OGTT at 12 and 24 months were unchanged in group B, while in group A a higher incidence of impaired glucose tolerance (IGT) and diabetes mellitus response were observed. HbA1 and blood glucose levels during the 24-hr profile showed good metabolic control in both groups at 3, 12, and 24 months. We can conclude that both the segmental and total pancreas transplantation restore a good metabolic control in IDDM patients, though a higher incidence of IGT and DM responses were observed after OGTT in the patients receiving a segmental graft. These abnormalities do not seem to interfere with metabolic control in everyday life. These results seem to be the consequence of the different B cell masses transplanted with these two techniques.

A total of 140 pancreatic transplants have been performed in 132 insulin-dependent diabetic patients at Lyon (France). Most cases received a double pancreatic and renal transplant. The duct obstruction technique was utilized in 113 segmental transplants. A total pancreatic transplant was performed in 27 patients, with duct obstruction in 27, GI tract derivation in 14, urinary tract derivation in 11 and intraductal obstruction in 2 patients. Utilizing quadruple immunosuppression, the one year survival rate was 90% and the transplant survival was 60%.

Combined liver and pancreas harvesting in the same donor is nowadays a routine procedure in our institution. In terms of sharing of the vascular pedicule the priority is given in the majority of cases to the liver graft. Thus vascular reconstruction of the pancreatic graft is often required before transplantation. From February 1987 to June 1990 we transplanted 62 pancreases coming from a donor where also a liver graft had been harvested; 46 were segmental grafts prepared by duct injection with neoprene, 14 were pancreatico-duodenal grafts with bladder diversion of the exocrine secretion, and 2 were whole pancreas scheduled for bladder diversion and secondarily reconverted to duct injection (1 whole and 1 segmental graft) for poor duodenal blood supply. Among the 47 segmental grafts (46 + 1 reconverted from whole to segmental), in only 10 cases was the celiac axis with an aortic patch possible; conversely in 37 cases the splenic artery had been divided at its origin during the harvesting; bench surgery for vascular reconstruction was realized in 33 cases. Among the 14 pancreatico-duodenal grafts with bladder diversion and the whole pancreas with duct obstruction, in 5 cases the celiac axis and the superior mesenteric artery were harvested on the same aortic patch; in 10 cases the splenic artery was divided at its origin during the harvesting, requiring bench surgery for reconstruction.