Quantitative analysis of microvasculature of rat pancreas transplants in acute rejection.

The changes of the microvasculature of rat pancreas transplants during acute rejection were investigated and quantitatively analyzed. The vessels in pancreas transplants increased in caliber and decreased in density during acute rejection. These changes were marked in the exocrine pancreas, especially in central zones, whereas changes in islets were mild. These results indicate that the early deterioration of exocrine function is closely related to vascular destruction.

Effect of troglitazone on blood insulin levels after pancreas transplantation with systemic venous drainage in rats.

BACKGROUND: Troglitazone is a new oral antidiabetic agent and has been reported to reduce insulin resistance and improve peripheral hyperinsulinemia in patients with noninsulin-dependent diabetes mellitus. To examine the effect of troglitazone on insulin regulation after pancreas transplantation with systemic venous drainage, we measured peripheral glucose and insulin levels and performed an intravenous glucose tolerance test. METHODS: We divided the rats into four groups: diabetic rats with a pancreas graft and administration of troglitazone at 40 mg/day orally (group P+T, n=4), rats with a pancreas graft only (group P, n=4), age-matched normal rats (group N, n=5), and diabetic rats (group DM, n=4). RESULTS: Fasting insulin levels in group P were relatively higher than those in group N, whereas the values in group P+T were normalized. In the intravenous glucose tolerance test, troglitazone clearly regulates sigma immunoreactive insulin levels of pancreas transplanted rats (P vs. P+T: 244+/-23 vs. 145+/-14 microU/ml, P<0.05). CONCLUSION: Hyperinsulinemia induced by systemic venous drainage, which may progress atherosclerosis, can be controlled with troglitazone treatment.

Differential effects of preexisting uremia and a synchronous kidney graft on pancreas allograft functional survival in rats.

Pancreas transplant results have been better in uremic recipients of a simultaneous kidney than in nonuremic recipients of a pancreas alone. We studied the relative effect of uremia versus a double transplant on functional survival by performing bladder-drained pancreas transplants alone (PTA), kidney transplants alone (KTA), and simultaneous pancreas/kidney (SPK) transplants from Buffalo donors to diabetic Lewis rat recipients that were or were not made uremic 2-3 weeks before by 1 4/5 native nephrectomy. Pancreas graft exocrine function was monitored by urinary amylase (UA). In the PTA and SPK recipients made diabetic by streptozotocin, endocrine function was monitored by measuring nonfasting plasma glucose (PG) levels. Kidney graft function was monitored by plasma creatinine (Cr). Rejection of the endocrine pancreas was defined as an increase of PG to greater than 200 mg/dl; of the exocrine pancreas, as a decline in UA to less than 6000 U/L or to less than 100 U/24 hr; and of the kidney, as an elevation of Cr to greater than 3 mg/dl. The mean functional survival times (MST) of both the endocrine (12.0 +/- 2.1 versus 10.1 +/- 1.1 days, P = 0.036) and exocrine (8.0 +/- 2.1 versus 6.3 +/- 1.3 days, P = 0.016) components of the pancreas grafts were significantly longer in SPK than in PTA recipients. The MST of kidney allografts, however, was not significantly longer in nonuremic SPK than nonuremic KTA recipients (6.7 +/- 1.4 versus 5.7 +/- 0.7 days, P = 0.13). In parallel experiments in recipients immunosuppressed with cyclosporine, the graft survival times were longer, but the relative differences between the PTA, SPK, and KTA groups persisted. Histologically, lymphocyte infiltration began in the two organs almost simultaneously, but the severity of the rejection was more vigorous in the kidney than in the pancreas in doubly grafted rats, and destruction of pancreas grafts progressed more slowly in SPK than in PTA recipients. Preexisting uremia delayed pancreas rejection in both SPK (exocrine 10.6 +/- 2.3, P = 0.032, and endocrine 14.8 +/- 3.4 days, P = 0.065, versus nonuremics) and PTA (exocrine 8.5 +/- 1.7, P = 0.007, and endocrine 12.6 +/- 2.5, P = 0.026, versus nonuremics) nonimmunosuppressed recipients. The MST of kidney grafts was not significantly longer in uremic (8.9 +/- 2.8 days) than in nonuremic (6.7 +/- 1.4 days) SPK recipients (P = 0.081). A synchronous kidney transplant and uremia independently down-modulate the rejection response to a pancreas graft, and a simultaneous pancreas graft has no detrimental effect on the survival of a kidney graft.(ABSTRACT TRUNCATED AT 400 WORDS)

Evaluation of intrathymic islet transplantation in the prediabetic period.

BACKGROUND: Beta-cell destruction in type I diabetes mellitus results from a chronic autoimmune process. Exposure of thymic T cells to islet antigens during the prehyperglycemic phase of diabetes may alter the likelihood of autoimmune damage to beta cells in the native pancreas. Thus we evaluated whether prophylactic major histocompatibility complex (MHC)-incompatible intrathymic islet allografts could prevent hyperglycemia and native pancreatic beta-cell destruction. METHODS: At 4 to 6 weeks of age, diabetes-prone BioBreeding rats received intrathymic injection of 1500 to 2000 noncultured MHC-incompatible Lewis islets. No immunosuppression was administered. Age-matched littermates underwent intrathymic injection of saline solution. RESULTS: None of 13 BioBreeding rat recipients of prophylactic intrathymic Lewis islet allografts became hyperglycemic versus 13 of 13 control rats (p less than 0.001). The age at onset of diabetes in the control group ranged from 77 to 104 days (mean, 86 days). Normoglycemia in recipients of intrathymic islet allografts persisted for greater than 8 months after transplantation, and thymectomy (graft removal) did not precipitate hyperglycemia. CONCLUSIONS: Prophylactic intrathymic MHC-incompatible islet allografts effectively prevent hyperglycemia and native beta-cell destruction in an animal model of autoimmune diabetes. Rejection and autoimmune destruction of intrathymic MHC-incompatible islet allografts were not seen after transplantation in the prediabetic (prehyperglycemic) period. Intrathymic islet allografts at an early age (before puberty) preserve native beta-cell function and may prevent or retard thymic atrophy.

Effect of soybean flour on exocrine function in rat pancreas transplant with bladder drainage.

The urinary output of trypsin, chymotrypsin, elastase, and amylase by rats with a pancreas transplant and bladder drainage was determined after injection with cholecystokinin (CCK) or by feeding diets containing high (raw soy flour) or low (heated soy flour) trypsin inhibitor activity. The injection of CCK produced a significant increase in the urinary output of all four enzymes. Rats were fed heated or raw soy flour in three consecutive 10-day periods in the following sequence: period 1, heated soy flour; period 2, raw soy flour; period 3, heated soy flour. Replacing heated soy flour in period 1 with raw soy flour in period 2 caused a significant increase in the output of the four enzymes. Subsequent feeding with heated soy flour in period 3 resulted in a reduction in the output of trypsin, chymotrypsin, and elastase to levels that were not significantly different from that observed in period 1. Although amylase output was also reduced in period 3, it did not return to the level noted in period 1. These results are consistent with the roles that CCK and trypsin inhibitors are believed to play in the negative feedback control of pancreatic exocrine function. A similar approach might be employed with humans who have undergone a pancreas transplant with bladder drainage.

Experimental hybrid islet transplantation: application of polyvinyl alcohol membrane for entrapment of islets.

In this study, we first examined in vitro a polyvinyl alcohol membrane to be used to contain hybrid islet cells, and second we tested a bioartificial pancreas with entrapment of pancreatic islets in polyvinyl alcohol membrane in rats with experimentally induced diabetes. The permeability of the polyvinyl alcohol membrane to different substances was studied in a two-cell chamber system. Glucose, insulin, and nutrients passed through the membrane easily, whereas the passage of immunoglobulin G was completely prevented, indicating that this membrane could be effective in protecting the bioartificial pancreas from immunorejection. Approximately 2,000 islets collected from three Sprague-Dawley rats were enclosed in a mesh-reinforced polyvinyl alcohol tube and transplanted into the peritoneal cavity of six Wistar rats with streptozotocin-induced diabetes. Their nonfasting serum glucose levels were significantly decreased for at least 12 days. Six diabetic rats receiving intraperitoneal transplantation of free islets without the tube showed a slight but significant decrease in nonfasting serum glucose levels for only 3 days. One diabetic rat with transplantation of the bioartificial pancreas had a significant and sustained decrease in nonfasting glucose levels from pretransplanted levels of 440-500 mg/dl to a mean value of 162 +/- 13 mg/dl for over 3 months without immunosuppression. The bioartificial pancreas was then removed, and glucose levels gradually increased to over 500 mg/dl. The results of the present study suggest that a bioartificial pancreas with entrapment of islets in a polyvinyl alcohol membrane could be a promising therapeutic approach to diabetes mellitus.

[The effect of portal venous drainage on graft survival and function in rat whole pancreaticoduodenal transplantation].

A whole pancreaticoduodenal transplant model with portal venous drainage was achieved in the rat, and effect of venous drainage from pancreas grafts into the portal vein on the functional graft survival and long-term glucose metabolism was investigated. In allogeneic series between ACI (RT1a) donors and streptozotocin-induced diabetic Lewis (RT1l) recipients (nonfasting plasma glucose greater than or equal to 400 mg/dl), the mean survival time of pancreas transplants determined by recurrent hyperglycemia (greater than or equal to 200 mg/gl) in rats with portal venous drainage (PV-group: 8.9 +/- 1.3 days) was slightly longer than that in rats with systemic venous drainage (SV-group: 8.3 +/- 0.9 days), but statistically insignificant. In the syngeneic series using Lewis rats, K-values (%/min) in IV-GTT at 1, 2 and 3 months after pancreas transplantation were, respectively, 1.5 +/- 1.0, 2.0 +/- 0.6 and 2.3 +/- 0.7 in PV-group, and 1.2 +/- 0.3, 1.2 +/- 0.4 and 1.8 +/- 0.5 in SV-group. Peripheral IRI (microU/ml) levels before glucose load were higher in both groups (PV-group, 15.1 +/- 10.5: SV-group, 22.8 +/- 16.2) at 3 months than in normal control (7.9 +/- 1.6: p greater than 0.05). These results indicate that the portal venous drainage in pancreas transplants has no remarkable profit in graft survival and that it can provide more physiological glucose control but cannot normalize insulin concentration.

[Problems and management in kidney transplant recipients with impaired glucose metabolism].

Fourty two (12%: Group-I) out of 358 kidney transplant (Tx) recipients showed impaired glucose tolerance in pre-Tx O-GTT and the other 49 (14%: Group-II) showed that only after Tx. Insulin therapy was more frequently required and earlier started after Tx in Group-I than in Group-II, and total dosages of steroids before the initiation of insulin therapy were also smaller in Group-I. These trends were more markedly observed in the patients treated with ciclosporin (CsA) than in those with the conventional therapy. Poor graft survival rate of Group-I in long-term follow-up (> 5 years) was demonstrated. Thus, pre-Tx impaired glucose tolerance and the subsequent immunosuppressants, especially steroids and CsA, were the key factors for deteriorating glucose metabolism after Tx, and meticulous controls of drug doses and glucose levels are needed in diabetic patients, since diabetes could change the fate of kidney grafts.

[De novo malignancy following renal transplantation].

The characteristics and incidence of de novo malignancy was analyzed in 376 renal transplant recipients transplanted between April 1970 and December 1992. Malignancies developed in 21 recipients of living related donor renal allografts. The total number of malignancies was 23, with 2 patients developing 2 malignancies. The mean age at the time of diagnosis was 42 years. The average interval from transplantation to the time of diagnosis was 129 months. Malignancy developed in 12 of 21 patients who survived 10 years with a functioning graft. Nine patients died of their malignancy. The risk of developing malignancy is increased following renal transplantation. Compared with sex- and age-matched Japanese control, the incidence is 6.1 times greater for male, 10.5 times greater for female, and 7.3 times greater overall. The risk was increased at all sites except the stomach. The risk rate of acquiring malignancies at 5-year intervals following transplantation was 6.5 times greater from 0 to 5 years, 10.0 times greater from 5 to 10 years, and 9.3 times greater from 10 to 15 years. These results suggest that annual medical examinations should be performed as part of the routine log-term follow-up of renal transplant recipients to detect malignancies in the early stage.