Status of clinical pancreas transplantation

Since 1977 and especially within the latest 5 years there was a volatile development in the pancreas transplantation. If we had only 60 transplants between 1966-1977, prevalent duodeno-pancreas-transplants, the cases rose to 215 up to 1982 and to 447 transplantations between 1983 to 1985. Altogether there were 722 pancreas transplants, up to November, 15, 1985 registered. Before 1977 only 2 patients had a 1 year function rate of the transplant and of the 447 transplantations within the latest 3 years 201 transplants functioned more than 12 months. That was a 1-year function rate of 45% in contrast to 3% before 1977. The clear improvement of the results in pancreas transplantation can be attributed to operative aspects and to the employment of Cyclosporine A. The segmental pancreas transplantation with duct occlusion and intestinal or external drainage of the duct system were the most sure operative procedures. The combination of Azathioprine and Cyclosporin A brought with a 1-year function rate of 54% better results in comparison to the singular application of Azathioprine (22%) and Cyclosporin A (41%). The simultaneous pancreas-kidney transplantation had a 1-year function rate of 39%, the pancreas transplantation after kidney of 31% and the pancreas transplantation alone of 20%.     

Current status of clinical pancreas transplantation

Pancreas transplantation (PT) has become increasingly effective for the treatment of human diabetes. Islet transplants have been successful only in the laboratory; clinical human islet transplantation needs to be improved with a search to reduce islet cells immunogenicity. Up to now, the only effective method of endocrine replacement therapy in diabetic patients is vascularized pancreas transplantation. Analysis of the International Human Pancreas Registry shows that the best options in 1985 are enteric diversion of the exocrine function, simultaneous kidney graft from the same donor and cyclosporin combined with other immunosuppressive agents in the recipient.     

Long-term effect of pancreas transplantation on diabetic hyperglucagonemia

Pancreas isotransplantation was performed on streptozotocin-diabetic Wistar rats. To study the influence of the graft on diabetic hyperglucagonemia, immunoreactive glucagon (IRG) and its response to alanine (peak IRG) were determined in peripheral blood at intervals for up to 8 months after the transplantation. Concentrations of IRG and immunoreactive insulin (IRI) in effluent blood from host pancreas (portal vein) and graft (caval vein) were measured 4 months after the transplantation to estimate the hormone release from both organs. Following transplantation, caval IRI increased sixfold. Portal IRI increased 180% and reached 65% of the concentration observed in control rats. Peripheral basal and peak IRG were initially restored to normal, but were later increased to levels equal to those of diabetic rats. Also portal and caval IRG concentrations were similar in recipients and diabetic rats. The results show that relatively small amounts of glucagon are released from the graft, and that the exaggerated glucagon release from the host pancreas is only transiently normalized following pancreas transplantation.     

Effect of pancreas transplantation on diabetic somatic neuropathy

To determine whether pancreas transplantation is capable of preventing diabetic somatic neuropathy, metabolic studies and electron microscopic morphometry of the sciatic nerve were performed monthly for 2 years in four groups of highly inbred rats: (1) NC-28 nondiabetic controls; (2) DC-82 untreated alloxan-diabetic controls; (3) WPT-122 diabetic rats that received a syngeneic whole-pancreas transplant; and (4) IT-90 diabetic rats that received intraportal injections of 1500 to 2000 syngeneic pancreatic islets. Five diabetic nerve lesions were quantitated by a "blind" protocol: intra-axonal glycogen deposits, axons with glycogen deposits, demyelinated axons, intact axoglial junctions in paranodal terminal myelin loops, and basal lamina thickness of vasa nervorum. Untreated diabetic control animals had significant and progressive increases in all five nerve lesions compared to nondiabetic controls (p less than 0.01). Whole pancreas transplants produced precise metabolic control of diabetes and prevented development and progression of all five diabetic nerve lesions throughout the 2-year study period. Pancreatic islet transplantation produced strict metabolic control and prevented diabetic neuropathy for the first 6 months, but then diabetes recurred and nerve lesions that were similar in severity to those in untreated diabetic rats developed. The finding that whole pancreas transplantation prevents diabetic somatic neuropathy adds to and extends our previous studies showing that whole-pancreas transplants prevent diabetic nephropathy.     

The effect of pancreas transplantation on diabetic polyneuropathy

Neuromuscular function was evaluated in long-term type I diabetic patients who retained a functioning pancreas graft. A group of 34 patients was examined at 1 year and another group of 11 patients at 2 years after pancreas transplantation. In this report the clinical and electrophysiological course of motor features of polyneuropathy are described. Before pancreas transplantation, clinical evidence of polyneuropathy was present in all patients. The mean motor nerve conduction velocities (NCV) were below normal and the mean amplitude of the evoked muscle action potentials (MAP) were in the low normal range. The observed abnormalities of muscle strength and tendon reflexes had not progressed in these intervals. Motor NCV improved slightly and MAP amplitude was essentially unchanged. These preliminary results indicate that the progression of diabetic polyneuropathy may be halted by successful pancreas transplantation.     

Neutrophil oxidative metabolism in diabetic patients undergoing pancreas transplantation

A pancreas transplantation is the only therapy capable of returning a constant, physiological euglycemic state to diabetic patients. Considering the clinical controversies in the study of infection in diabetes and the recognized effect of insulin on the oxidative metabolism of glucose in phagocytes, the present study sought to evaluate the formation of intraphagocytic oxygen-free radicals in diabetic patients undergoing simultaneous pancreas kidney transplantation (SPK). METHODS: Twenty-five diabetic patients undergoing SPK were compared with 25 normal individuals. Evaluation of the oxidative metabolism of leukocytes was performed using the NBT test. RESULTS: The abnormality in the pretransplant counts (19.32%-28.2%) reached normal levels at 48 hours after transplantation (45.11%-76.25%) and was maintained to the 5th day (46.28%-76.20%). CONCLUSION: An SPK in a diabetic patient normalized the formation of intraphagocytic oxygen-free radicals.     

Duplex-Doppler ultrasonography in monitoring clinical pancreas transplantation

Abstract. The findings are reported that were obtained with duplex-Doppler ultrasonography (US) in seven diabetic patients who underwent pancreatic grafting with pancreaticocystostomy. Five normal functioning grafts showed homogenous echostructure and pulsed Doppler spectrum characteristics of low impedance vascular beds. Four of these patients developed graft rejection (five episodes). The remaining two grafts had pulsed Doppler evidence of venous thrombosis. It was not possible to differentiate graft rejection from venous thrombosis using real-time US. In both circumstances a heterogeneous pancreatic echostructure with a small amount of peripancreatic fluid and an increase in pancreas size were observed. Pulsed Doppler, however, showed absence of venous flow in both cases of venous thrombosis whereas all rejection episodes were characterized by an increase in arterial impedance. We conclude that duplex-Doppler US is a promising noninvasive method of detecting surgical complications and graft rejection in pancreatic transplant recipients.     

Duplex-Doppler ultrasonography in monitoring clinical pancreas transplantation

The findings are reported that were obtained with duplex-Doppler ultrasonography (US) in seven diabetic patients who underwent pancreatic grafting with pancreaticocystostomy. Five normal functioning grafts showed homogenous echostructure and pulsed Doppler spectrum characteristics of low impedance vascular beds. Four of these patients developed graft rejection (five episodes). The remaining two grafts had pulsed Doppler evidence of venous thrombosis. It was not possible to differentiate graft rejection from venous thrombosis using real-time US. In both circumstances a heterogeneous pancreatic echostructure with a small amount of peripancreatic fluid and an increase in pancreas size were observed. Pulsed Doppler, however, showed absence of venous flow in both cases of venous thrombosis whereas all rejection episodes were characterized by an increase in arterial impedance. We conclude that duplex-Doppler US is a promising noninvasive method of detecting surgical complications and graft rejection in pancreatic transplant recipients.     

Metabolic effect of pancreas transplantation on long-term diabetic rats

Thirty-six male Lewis rats rendered diabetic using alloxan received syngeneic pancreaticoduodenal grafts. Seven days prior to and 7, 30, and 90 days posttransplantation, the animals were housed in metabolic cages for periods of 48 hours. During this time, body weight, water intake, food intake, urine output, and fecal output were recorded every 24 hours. Blood sugar, plasma insulin, glucosuria, and proteinuria were determined at 3-month intervals prior to the transplant and at monthly intervals posttransplantation. These parameters were also concurrently recorded for diabetic control rats. Pancreaticoduodenal transplantation produces immediate relief of hyperglycemia, glucosuria, polyuria, polyphasia, and polydypsia, resulting in good health of the animals until the time of sacrifice. A significantly increased insulin level was also recorded. The transplanted animals showed a weight gain reflecting that of a normal growth curve.     

Reversal of diabetic nephropathy: lessons from pancreas transplantation

Pancreas transplantation is the only therapeutic intervention able to achieve and maintain long-term euglycemia, without risks of hypoglycemia; this makes it possible to test the impact of normoglycemia in the different stages of diabetic nephropathy. Pancreas and islet transplantation in animal models prevent the development of diabetic nephropathy lesions and ameliorate or reverse established glomerular lesions. In type 1 diabetic patients, pancreas transplantation, performed simultaneously or after kidney transplantation, has been shown to prevent the recurrence of diabetic glomerulopathy lesions. The established lesions of diabetic nephropathy have been considered to be irreversible; pancreas transplantation alone allows us to test whether this is true. To this end, we studied renal structure before and 5 and 10 years after pancreas transplantation in 8 nonuremic type 1 diabetic patients. These patients, with a long diabetes duration, had established diabetic nephropathy lesions at the time of transplantation. We report that diabetic glomerulopathy lesions, unchanged at 5 years post pancreas transplantation, significantly improved after 10 years, with complete normalization of glomerular structure in most patients. Thus this study demonstrates that the lesions of diabetic nephropathy are reversed by long-term normoglycemia and that the human kidney has the potential in humans to obtain a substantial architectural remodeling of the glomerular and tubular structures toward healing.     

The time interval between kidney and pancreas transplantation and the clinical outcomes of pancreas after kidney transplantation

Pancreas after kidney (PAK) transplantation is one of the accepted pancreas transplant modalities. We studied the impact of time interval between kidney and pancreas transplantation on the outcomes of PAK transplantation. Using OPTN/SRTR data, we included 1853 PAK transplants performed between 1996 and 2005 with follow-up until November 1, 2008. Kaplan-Meier survival and multivariate Cox regression analyses were performed using the time interval between kidney and pancreas transplantation either as a categorical (less than one yr, between one and less than three yr, and greater than or equal to three yr) or as a continuous variable (months) to assess kidney graft and patient survival. Patients who received a pancreas transplant three yr or later after kidney transplantation had higher risk of death-censored kidney graft loss (HR 1.56, 95% CI 1.04, 2.32, p = 0.03). Each month beyond three yr between kidney and pancreas transplantation incurred 1% higher risk of subsequent death-censored kidney graft loss (HR 1.01, 95% CI 1.001, 1.02, p = 0.03). In conclusion, time interval between pancreas and kidney transplantation is an independent risk factor of kidney graft loss following pancreas transplantation. Shortening the time interval between pancreas and kidney transplantation to less than three yr may reduce the risk of kidney graft loss in qualified PAK transplant candidates.     

胰腺移植对大鼠糖尿病早期肾病的治疗

通过对大鼠肌注链脲霉素制成稳定的糖尿病模型后，尿中２４小时β２－微球蛋白、白蛋白排泄总量的检测，发现其均明显地高于正常水平，最高可达正常倍左右；并对胰腺移植后尿中增高的β２－微球蛋白、白蛋白，能重／１００克体重恢复情况进行观察，认为成功的胰腺移植可以使糖水病早期肾病的微量蛋白尿和增大的肾脏体积恢复正常。