Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients.

AIMS/HYPOTHESIS: The effects of successful pancreas transplant alone (PTA) on chronic complications of diabetes, in particular diabetic retinopathy, remain disputed. We prospectively studied the course of diabetic retinopathy in PTA recipients and in non-transplanted (non-PTA) type 1 diabetic patients. METHODS: The PTA and non-PTA groups consisted respectively of 33 (follow-up: 30 +/- 11 months) and 35 patients (follow-up: 28 +/- 10 months). Best corrected visual acuity, slit lamp examination, intraocular pressure measurement, ophthalmoscopy, retinal photographs, and in selected cases angiography were performed. Diabetic retinopathy and its improvement/deterioration were assessed according to criteria proposed by the Eurodiab Study. RESULTS: At baseline, 9% of PTA and 6% of non-PTA patients had no diabetic retinopathy, 24 and 29% had non-proliferative diabetic retinopathy (NPDR), whereas 67 and 66% had laser-treated and/or proliferative diabetic retinopathy (LT/PDR), respectively. No new case of diabetic retinopathy occurred in either group during follow-up. In the NPDR PTA group, 50% of patients improved by one grading, and 50% showed no change. In the LT/PDR PTA, stabilisation was observed in 86% of cases, whereas worsening of retinopathy occurred in 14% of patients. In the NPDR non-PTA group, diabetic retinopathy improved in 20% of patients, remained unchanged in 10%, and worsened in the remaining 70%. In the LT/PDR non-PTA group, retinopathy did not change in 43% and deteriorated in 57% of patients. Overall, the percentage of patients with improved or stabilised diabetic retinopathy was significantly higher in the PTA group. No differences were found between the two groups with regard to cataract lesions and intraocular pressure values. CONCLUSIONS/INTERPRETATION: Despite a relatively short follow-up, our study shows that successful PTA can positively affect the course of diabetic retinopathy.

Neoral versus prograf in simultaneous pancreas-kidney transplantation with portal venous drainage: three-year results of a single-center, open-label, prospective, randomized pilot study.

BACKGROUND: The preferential use of tacrolimus (Prograf) over cyclosporine microemulsion (Neoral) in simultaneous pancreas-kidney transplantation (SPKTx) is mainly based on historical, retrospective studies. We herein report the 3-year results of a single-center, prospective, randomized comparison of the two calcineurin inhibitors in the setting of mycophenolate mofetil (MMF)-based immunosuppression and portal drainage of pancreas allografts. METHODS: Between May 2001 and August 2004, 47 SPKTx recipients who were stratified by recipient sex, were alternatively assigned to treatment with Neoral (n = 22) or Prograf (n = 25). Concurrent immunosuppression included induction treatment with basiliximab and maintenance with MMF and steroids. RESULTS: After a median follow-up of 24.0 months, all patients remained in the study arm into which they were initially enrolled. No pancreas rejection episode was observed. One acute kidney rejection was recorded in the Neoral arm (4.5%) as compared with 7 (28.0%) including one steroid-resistant episode, in the Prograf arm (P = .03). The cumulative incidence of adverse events was 31.8% (n = 7) in the Neoral arm compared with 92.0% (n = 23) in the Prograf arm (P < .0001). One patient died in each study arm. Patient, pancreas, and kidney survivals overlapped at 1- and 3-years posttransplant, namely all 95.4% for the Neoral arm compared with 95.8%, 91.8%, and 95.8%, respectively, for the Prograf arm (P > .05). CONCLUSIONS: We conclude that in MMF-based immunosuppression there is no convincing evidence that Prograf should be preferred to Neoral in SPKTx.

Single-center, open, prospective, randomized pilot study comparing cyclosporine versus tacrolimus in simultaneous pancreas-kidney transplantation.

BACKGROUND: Although tacrolimus (Prograf) is the calcineurin inhibitor usually employed in simultaneous pancreas-kidney transplantation (SPKTx), no prospective randomized studies have compared its efficacy to cyclosporine (Neoral), when either drug is used in combination with mycophenolate mofetil (MMF) and the pancreas is drained into the portal vein. METHODS: Between May 2001 and June 2003, 16 SPKTx recipients were randomized to be prescribed Neoral and 17 Prograf in addition to basiliximab, steroids, and MMF. All pancreata were drained into the portal vein. RESULTS: After a median follow-up of 15.6 months, six kidney acute rejection episodes were observed with Prograf (36.5%; one steroid-resistant) and one Neoral (n = 1, 6.2%; P =.04). No pancreas rejection episode was recorded. Two infections occurred in two recipients from each group. No major adverse events were noted other than a severe hematological toxicity (Prograf). Metabolic parameters were equivalent in the two groups, save for higher total cholesterol (212 +/- 39 mg/dL vs 173 +/- 23 mg/dL; P =.008), LDL (129 +/- 33 mg/dL vs 101 +/- 21 mg/dL; P =.029), and triglyceride (191 +/- 86 mg/dL vs 126 +/- 40 mg/dL; P =.028), values with Neoral, although the same differences were already present at baseline. One recipient (Neoral) died with functioning grafts. Patient, pancreas, and kidney survival rates were all 94% for Neoral versus 100% for Prograf. CONCLUSIONS: Although a larger series and a longer follow-up are needed, Neoral and Prograf used in combination with MMF seem to achieve equivalent success rates among primary SPKTx when the pancreas is drained into the portal vein.

Echocardiographic evaluation in type 1 diabetic patients on waiting list for isolated pancreas or kidney-pancreas transplantation.

Type 1 diabetic patients may display abnormalities of left ventricular geometry and systolic and diastolic function. Patients on the waiting list for solitary pancreas or kidney-pancreas transplantation were evaluated by Doppler echocardiography to assess left ventricular geometry and systolic and diastolic function, and correlate these parameters with clinical characteristics. We evaluated 78 patients including 45 men with an overall mean age of 39.5 +/- 7.2 years and a disease duration of 24 +/- 9.8 years. Among these 78 patients, 13 showed isolated retinopathy, 9 isolated arterial hypertension, 45 concomitant retinopathy and hypertension and overt nephropathy, while 11 were free of complications. The results of our study showed an increased left ventricular mass and abnormal diastolic function among patients with simultaneous target organ complications and with hypertension, as has been reported in many previous studies. In contrast study patients with no complications showed normal left ventricular structure and function. This finding conflicts with data from several reports in the medical literature in which diastolic impairment was present in type 1 diabetic patients at an early stage of disease and with no evident microvascular and macrovascular complications.

Pancreas transplant alone.

Pancreas transplant alone (PTA) represents a growing proportion of overall pancreas transplantations, with 1-year patient and graft survivals of almost 100% and higher than 80%, respectively. PTA can restore normoglycemia without exogenous insulin administration and eliminate acute diabetic complications. In our series of 28 PTA, performed with portal-enteric drainage, 2-year patient and pancreas survivals were 100% and 87%, respectively. In patients with successful transplantation, rapid normalization of blood glucose level and HbA1c concentration was observed, due to restored endogenous insulin secretion. Several classical cardiovascular risk factors were measured before and after transplant, with significant improvements shortly after transplantation. Diabetic retinopathy improved in 58.8% of examined eyes, stabilized in 35.3%, and worsened in 5.9%. In conclusion, PTA represents a clinically relevant option for patients with type 1 diabetes without advanced renal disease. It restores normoglycemia in the vast majority of patients and seems to have a positive impact on late diabetic complications.

Retroperitoneal pancreas transplantation with portal-enteric drainage.

BACKGROUND: Portal-enteric drainage (PED) is the latest refinement in the surgical technique for pancreas transplantation (PTx). We herein describe the results of a modified technique for PED that places the pancreas in a totally retroperitoneal position. METHODS: Between April 2001 and June 2003, 79 PTx were performed using a retroperitoneal PED technique. RESULTS: No graft was lost due to surgical complications and the relaparotomy rate was 11.4%. Mean hospital stay averaged 25.9 days (+/-14.4 days) with a 30-day readmission rate of 12.7%. One graft was lost due to delayed (6 months) arterial thrombosis and three to acute rejection. The overall 1-year patient and graft survivals were 98.7% and 93.7%, respectively. CONCLUSIONS: Our data confirm that PED of pancreas grafts is associated with low morbidity and mortality rates. Whether retroperitoneal graft placement has actual advantages over the "classical" intraperitoneal position remains to be ascertained.

Solitary pancreas transplantation: preliminary findings about early reduction of proteinuria in incipient or evident diabetic type I nephropathy.

OBJECTIVE: Our work was aimed to evaluate the precocious reduction of proteinuria in patients suffering from diabetes mellitus type 1 with incipient and evident nephropathy after isolated pancreas transplantation (PTA). MATERIALS AND METHODS: From December 2000 to March 2003, we followed 24 PTA grafts in 24 patients with diabetes mellitus type 1 (mean age 37.8 years; mean duration of diabetes 24.8 years). The pancreas was transplanted with portal-enteric drainage in 23 patients and systemic-enteric in 1 patient. The immunosuppressive therapy used basilixmab induction and tacrolimus, mycophenolate mophetil (MMF), and low dose steroid maintenance therapy. The renal function, proteinuria, and the glucose metabolic parameters were evaluated before and during the following months after transplant. RESULTS: All patients are alive and twenty-one have a well-functioning pancreas with three grafts lost. All patients had persistence of normal renal function. Before transplantation 12 patients displayed proteinuria that was clearly reduced in 11 and gone in three patients, all of whom were insulin-independent. CONCLUSIONS: TPA seems to reduce, and in some cases to regress, the proteinuria associated with early diabetic nephropathy.

Reducing insulin resistance with metformin: the evidence today.

Insulin resistance, defined as the inability of insulin to exert a normal biological action at the level of its target tissues, is one of the principal pathogenetic defects of type 2 diabetes. Metformin, the most widely-prescribed insulin-sensitizing agent in current clinical use, improves blood glucose control mainly by improving insulin-mediated suppression of hepatic glucose production, and by enhancing insulin-stimulated glucose disposal in skeletal muscle. Experimental studies show that metformin-mediated improvements in insulin sensitivity may be associated with several mechanisms, including increased insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters. In adipose tissue, metformin promotes the re-esterification of free fatty acids and inhibits lipolysis, which may indirectly improve insulin sensitivity through reduced lipotoxicity. The improved glycaemia with metformin is not associated with increased circulating levels of insulin, and the risk of hypoglycaemia with metformin is minimal. The therapeutic profile of metformin supports its use for the control of blood glucose, in diabetic patients and for the prevention of diabetes in subjects with impaired glucose tolerance. Moreover, the improvement by metformin of cardiovascular risk factors associated with the dysmetabolic syndrome may account for the significant improvements in macrovascular outcomes observed in the UK Prospective Diabetes Study.

Dissociation between carotid artery lesions and lipid parameters in recipients of successful kidney graft.

BACKGROUND: The relationships between lipid levels and atherosclerotic lesions of carotid arteries in kidney graft recipients are still unclear. METHODS: We evaluated carotid morphology in 53 recipients of functioning renal transplantation, and studied the relationship of carotid artery wall lesions with relevant clinical and laboratory risk factors for cardiovascular disease. The patients were on stable, cyclosporine-based immunosuppressive therapy. RESULTS: The main clinical characteristics of patients were: age, 46.5 +/- 10.1 years; males/females, 40/13; body mass index, 25.8 +/- 4.4 kg/m2; duration of transplantation, 43 +/- 52 months. Ultrasonographic scanning of carotid arteries showed the presence of lesions (intimal-media thickness and/or plaque) in 28 patients (52.8%). These recipients differed from patients without carotid lesions in terms of age (50.4 +/- 9.0 vs 42.2 +/- 9.7 years, p < 0.01) and duration of pre-transplant dialysis (4.6 +/- 3.4 vs 2.3 +/- 1.9 years, p < 0.01), whereas no statistically significant difference was observed as for total cholesterol (230 +/- 44 vs 235 +/- 35 mg/dl), LDL-cholesterol (142 +/- 32 vs 143 +/- 30 mg/dl), HDL-cholesterol (52 +/- 12 vs 58 +/- 20 mg/dl) and triglycerides (178 +/- 94 vs 167 +/- 89 mg/dl). The percentage of post-transplant diabetes was 3-fold higher in patients with carotid lesions (25 vs 8%). No difference was observed as for the following parameters: body mass index, duration of transplantation, fibrinogen levels, DDimer concentrations, reactive C-protein values, prevalence of hypertension, percentage of smokers vs non-smokers. CONCLUSIONS: The present study supports the view that carotid artery lesions in kidney graft recipients on stable, cyclosporine-based immunosuppressive therapy may not be related to circulating lipid values.

Lymphokine release from human lymphomononuclear cells after co-culture with isolated pancreatic islets: effects of islet species, long-term culture, and monocyte-macrophage cell removal.

This study evaluated the release of Th1 and Th2 cytokines from human lymphomononuclear cells (LMC) in response to purified human (HI) or bovine (BI) islets, and the role of long-term (3-4 weeks) islet culture and removal of monocyte-macrophage cells. The results showed that HI and BI caused a similar increase of the release of gamma interferon (IFN), IL-2 and IL-6 from LMC, whereas BI had a more marked effect than HI on IL-10 release. Culturing the islets had possible positive effects (reduction of IFN and IL-2), but also potentially negative effects (increase of TNF). Removal of monocyte-macrophage cells determined a significant reduction of IL-6, IL-10 and TNF production in response to xeno-islets.

The biguanide compound metformin prevents desensitization of human pancreatic islets induced by high glucose.

Pancreatic islet desensitization by high glucose concentrations is a temporary and reversible state of beta-cell refractoriness to glucose (and possibly other secretagogues), due to repeated or prolonged pre-exposure to increased glucose concentrations. We evaluated whether the oral antidiabetic agent metformin affects this phenomenon in isolated, human pancreatic islets, and whether the possible effects of the biguanide are influenced by the presence of a sulphonylurea, glyburide. Islets prepared from five human pancreases were incubated for 24 h in M199 culture medium containing either 5.5 or 22.2 mmol/l glucose, with or without a therapeutic concentration (2.4 microg/ml) of metformin. Then, the islets were challenged with either 3.3 mmol/l glucose, 16.7 mmol/l glucose, or 3.3 mmol/l glucose + 10 mmol/l arginine, and insulin release was measured. After incubation in the absence of metformin, the human islets exposed to 22.2 mmol/l glucose showed no significant increase in insulin release when challenged with 16.7 mmol/l glucose (confirming that hyperglycemia desensitizes pancreatic beta-cells). In the presence of metformin, the islets fully maintained the ability to significantly increase their insulin release in response to glucose, even when previously exposed to 22.2 mmol/l glucose. No major effect on arginine-induced insulin release was observed, whatever the culture conditions. The protective action of metformin was observed also when glyburide was present in the incubation medium, whereas the sulphonylurea alone did not affect insulin release from the islets previously exposed to high glucose concentrations. These in vitro results suggest that metformin can prevent the desensitization of human pancreatic islets induced by prolonged exposure to increased glucose concentrations.