Recurrence of type 1 diabetes after simultaneous pancreas-kidney transplantation in the absence of GAD and IA-2 autoantibodies.

We report herein the patterns of type 1 diabetes recurrence in a simultaneous pancreas-kidney transplant (SPK) recipient, in the absence of rejection. A 38-year-old female underwent SPK for end-stage nephropathy secondary to type 1 diabetes. Fasting blood glucose, HbA1c, fructosamine, C-peptide and autoantibodies (GAD-65, IA-2) were monitored throughout follow-up. At 3.5 years post-SPK, HbA1c and fructosamine increased sharply, indicating loss of perfect metabolic control, despite C-peptide levels in the normal-high range. Exogenous insulin was restarted 4 months later. C-peptide levels abruptly fell and became undetectable at 5.5 years. Autoantibody levels, which were undetectable at the time of SPK, never converted to positivity. Pancreas retranspantation was performed at 6 years. The failed pancreas graft had a normal macroscopic appearance. On histology, there were no signs of cellular or humoral rejection in the kidney or pancreas. A selective peri-islet lymphocytic infiltrate was observed, together with near-total destruction of ß cells. At 2.5 years post retransplantation, pancreatic graft function is perfect. This observation indicates unequivocally that pancreas graft can be lost to recurrence of type 1 diabetes in the absence of rejection. GAD-65 and IA-2 autoantibodies are not reliable markers of autoimmunity recurrence.

Clinical magnetic resonance imaging of pancreatic islet grafts after iron nanoparticle labeling.

There is a crucial need for noninvasive assessment tools after cell transplantation. This study investigates whether a magnetic resonance imaging (MRI) strategy could be clinically applied to islet transplantation. The purest fractions of seven human islet preparations were labeled with superparamagnetic iron oxide particles (SPIO, 280 microg/mL) and transplanted into four patients with type 1 diabetes. MRI studies (T2*) were performed prior to and at various time points after transplantation. Viability and in vitro and in vivo functions of labeled islets were similar to those of control islets. All patients could stop insulin after transplantation. The first patient had diffuse hypointense images on her baseline liver MRI, typical for spontaneous high iron content, and transplant-related modifications could not be observed. The other three patients had normal intensity on pretransplant images, and iron-loaded islets could be identified after transplantation as hypointense spots within the liver. In one of them, i.v. iron therapy prevented subsequent visualization of the spots because of diffuse hypointense liver background. Altogether, this study demonstrates the feasibility and safety of MRI-based islet graft monitoring in clinical practice. Iron overload (spontaneous or induced) represents the major obstacle to the technique.

Detection of insulin mRNA in the peripheral blood after human islet transplantion predicts deterioration of metabolic control.

Recent updates of the Edmonton trial have shown that insulin independence is progressively lost in approximately 90% of islet transplant recipients over the first 5 years. Early prediction of islet graft injury could prompt the implementation of strategies attempting to salvage the transplanted islets. We hypothesize that islet damage is associated with the release and detection of insulin mRNA in the circulating blood. Whole blood samples were prospectively taken from 19 patients with type 1 diabetes receiving 31 islet transplants, immediately prior to transplantation and at regular time-points thereafter. After RNA extraction, levels of insulin mRNA were determined by quantitative reverse tran-scriptase-polymerase chain reaction. All patients exhibited a primary peak of insulin mRNA immediately after transplantation, without correlation of duration and amplitude with graft size or outcome. Twenty-five subsequent peaks were observed during the follow-up of 17 transplantations. Fourteen secondary peaks (56%) were closely followed by events related to islet graft function. Duration and amplitude of peaks were higher when they heralded occurrence of an adverse event. Peaks of insulin mRNA can be detected and are often associated with alterations of islet graft function. These data suggest that insulin mRNA detection in the peripheral blood is a promising method for the prediction of islet graft damage.

Effect of HLA matching in simultaneous pancreas-kidney transplantation.

UNLABELLED: Simultaneous pancreas-kidney (SPK) transplantation has become the therapy of choice for type 1 diabetic patients with end-stage renal disease. The current analysis examined the impact of HLA matching on graft outcome following SPK transplantation. The study population was obtained from patients enrolled in the Euro-SPK 001 study. PATIENTS AND METHODS: The effect of HLA matching on graft function and survival was assessed in 180 SPK recipients in whom complete donor-recipient HLA data were available. A group of 45 patients with 0 to 3 HLA mismatches (MM) was compared to 135 patients with 4 to 6 MM. RESULTS: There were no differences in 3-year kidney, pancreas, or patient survival rates between the 0 to 3 and 4 to 6 MM groups. Biological parameters of kidney and pancreas graft function were similar in both groups. Significantly more patients with 0 to 3 MM (66%) were rejection free at 3 years than those with 4 to 6 MM (41%; P = .003). The relative risk of acute rejection was 2.6 times higher among patients with 4 to 6 MM than among those with 0 to 3 MM. In conclusion, there was no evidence that HLA matching was associated with improved kidney or pancreas survival. However, a higher rate of acute rejection was observed with poor HLA matches, which may impact long-term survival.

Impact of a sirolimus/tacrolimus-based immunosuppressive regimen on kidney function after islet transplantation.

AIM: Islet transplantation is gaining recognition as a therapeutic option for selected diabetic patients. The immunosuppressive regimen based on sirolimus/low-dose tacrolimus is considered a major breakthrough that allowed considerable improvement in graft survival. A high incidence of side effects associated with such a regimen has been reported in the literature, but this immunosuppressive protocol is generally considered safe or even protective to the kidney. Herein, we analyze the impact of the sirolimus/low-dose tacrolimus-based protocol on kidney function. PATIENTS AND METHODS: Five islet-after-kidney and 5 islet-transplant-alone patients were enrolled and followed up. Renal function was assessed by the periodic measurement of serum creatinine and by the presence of albuminuria. Metabolic control markers and graft function were followed, as well as immunosuppressive whole blood trough levels. RESULTS: Kidney function significantly decreased in 6 of 10 patients. Neither metabolic markers nor immunosuppressive drugs levels were significantly associated with the decreased kidney function. CONCLUSION: Although a specific etiology was not identified, subsets of patients presented a higher risk for decrease of kidney function. The presence of low creatinine clearance, albuminuria, and long-established kidney graft were associated with poorer outcomes.

Islet autotransplantation for the prevention of surgical diabetes after extended pancreatectomy for the resection of benign tumors of the pancreas.

OBJECTIVE: The objective of this article is to report a single-center experience with islet autotransplantation after extensive pancreatic resection for benign tumors of the pancreas. MATERIALS AND METHODS: Seven patients underwent extensive left pancreatectomy for benign lesions located at the neck of the pancreas. Once an unequivocal diagnosis of a benign nature was ascertained, the rest of the specimen was processed and the unpurified pancreatic digest was infused into the portal vein. The results were compared with those of 8 autotransplantations performed for chronic pancreatitis over the same period. RESULTS: Tumors were 4 cystadenomas, 2 insulinomas and 1 neuroendocrine tumor. Mean islet yields were 275,000 islet equivalents (IEQ) versus 129,000 in chronic pancreatitis (P =.04) or 6700 IEQ/g of tissue versus 1900 (P =.002), resulting in transplantation of 4200 IEQ/kg body weight vs 2150 in chronic pancreatitis (P =.03), respectively at 4-month to 7.5-year follow-up, all patients are alive and 6 of 7 are off insulin. All patients off insulin after at least 1 year currently have a normal IVGTT, with K values ranging between -1.19 and -2.36 (normal < -1.00). All patients, including 1 on insulin, display positive basal and glucagon-stimulated C-peptide levels. CONCLUSIONS: Compared with chronic pancreatitis tissue resected for benign tumors is more likely to achieve good islet yields, and thus insulin independence after autotransplantation. Islet autotransplantation should be considered when extensive pancreatectomy is required for resection of a benign tumor, and only if the benign nature of the lesion is demonstrated unequivocally.