Eduardo Peixoto

Ten years of preserved kidney function after islet transplant graft failure

Several studies in patients with type 1 diabetes have examined the impact of islet transplantation (ITx) on renal function (1–3). Our group and others (1,4) have reported the beneficial effect of ITx. Equally relevant, however, is the assessment of renal function in patients with graft failure (GF) who are exposed to the well-known potential toxicity from immunosuppressive drugs and risk of development or progression of diabetic nephropathy related to unstable glycemic control (5). In this study, we examined the renal function of 12 recipients of allogeneic ITx who developed GF (stimulated C-peptide <0.3 ng/mL) but had at least 1 year (range 1.0–5.1) of graft function. Maintenance immunosuppression consisted of sirolimus and tacrolimus, which were discontinued after GF. Patients were enrolled in the ongoing Long Term Surveillance of Islet Transplant Recipients Following Complete Graft Loss study at the University of Miami, 6.0 ± 1.8 years (range 2.9–8.8) after GF. In this interim report, we provide data on renal function for a mean of 10.7 years after islet GF (Fig. 1 A ). The estimated glomerular filtration rate (eGFR) at the end of follow-up was comparable to …

The use of 1.5-anhydroglucitol for monitoring glycemic control in islet transplant recipients.

We evaluated whether 1,5-anhydroglucitol (1,5-AG) (GlycoMark®), a test for measuring postprandial glucose and glucose variability, could be a tool for assessing short-term glycemic control in islet cell transplant (ICT) subjects. Data of 21 subjects, with type 1 DM and allogenic islet transplantation, who had concomitant fructosamine, HbA1c, 1,5-AG (n = 85 samples), and capillary glucose self-monitoring measurements (n = 2,979) were analyzed retrospectively at different time points after ICT. A significant negative association was observed between 1,5-AG and HbA1c (p = 0.02), but not with fructosamine. When HbA1c was divided in quartiles as <5.6, 5.6–5.9, 5.9–6.2, and >6.2, a decrease of an estimated 0.70 ± 0.30 μg/ml in 1,5-AG was associated with each quartile of increase in HbA1c (p < 0.0001). There was a significant decline of 1.64 ± 0.3mg/dl in postprandial glucose values for each 1 unit increase in 1,5-AG (p < 0.0001). For those with HbA1c ≥ 6.0% when 1,5-AG was ≥8.15 μg/ml, the mean estimated glucose level was 103.71 ± 3.66 mg/dl, whereas it was 132.12 ± 3.71 mg/ dl when 1,5-AG was <8.15 μg/ml. The glucose variability (Glumax - Glumin) in subjects with 1,5-AG <8.15 μg/ml was 46.23 mg/dl greater than the subjects with 1,5-AG ≥8.15 μg/ml (HbA1c ≥ 6.0%). There was no significant association between GlycoMark and glucose variability where HbA1c < 6%. 1,5-AG significantly associated with postprandial glucose levels and glucose variability in ICT recipients with near-normal HbA1c (6.0–6.5%) levels. These findings suggest that 1,5-AG can be used to differentiate those ICT subjects with higher glucose variability despite having near-normal HbA1c. However, prospective studies are needed to evaluate the association between GlycoMark levels and the parameters of graft dysfunction/failure.

G-CSF and Exenatide Might Be Associated with Increased Long-Term Survival of Allogeneic Pancreatic Islet Grafts

Background Allogeneic human islet transplantation is an effective therapy for the treatment of patients with Type 1 Diabetes (T1D). The low number of islet transplants performed worldwide and the different transplantation protocols used limit the identification of the most effective therapeutic options to improve the efficacy of this approach. Methods We present a retrospective analysis on the data collected from 44 patients with T1D who underwent islet transplantation at our institute between 2000 and 2007. Several variables were included: recipient demographics and immunological characteristics, donor and transplant characteristics, induction protocols, and additional medical treatment received. Immunosuppression was induced with anti-CD25 (Daclizumab), alone or in association with anti-tumor necrosis factor alpha (TNF-α) treatments (Etanercept or Infliximab), or with anti-CD52 (Alemtuzumab) in association with anti-TNF-α treatments (Etanercept or Infliximab). Subsets of patients were treated with Filgrastim for moderate/severe neutropenia and/or Exenatide for post prandial hyperglycemia. Results The analysis performed indicates a negative association between graft survival (c-peptide level ≥ 0.3 ng/ml) and islet infusion volume, with the caveat that, the progressive reduction of infusion volumes over the years has been paralleled by improved immunosuppressive protocols. A positive association is instead suggested between graft survival and administration of Exenatide and Filgrastim, alone or in combination. Conclusion This retrospective analysis may be of assistance to further improve long-term outcomes of protocols for transplant of islets and other organs.

Hepatic hematoma after islet cell transplantation.

Allogeneic islet cell transplantation (ICT) is an alternative treatment in a selected group of subjects with type 1 diabetes mellitus (T1DM)(1). Percutaneous trans-hepatic portal access (PTHA) is a minimally invasive technique for ICT which avoids open or laparoscopic surgery, general anesthesia and prolonged hospitalization(2,3). Bleeding, portal vein thrombosis and portal hypertension are the most reported complications(5-7)(8) . The potential risk of acute bleeding may be less with a controlled operative (laparoscopic) approach, however the feasibility of the percutaneous approach has made it preferable to date in most centers (9,10) Improvements in islet purification, smaller infused volume, infusion by gravity, and addition of heparin are factors that have reduced the incidence of portal vein thrombosis(11,12). Bleeding complications are rare, but when they occur, typically originate from the parenchymal tract after removal of the infusion catheter. This may be exacerbated with heparin administration, however sealing of the intrahepatic tract using gelfoam slurry (collagen suspension); collagen-thrombin paste (D-stat™ or Avitene™-contrast paste), thrombostatic coils, and/or cautery has been shown to reduce risks of bleeding (13-15). We describe a case of a massive subcapsular hepatic hematoma after intra-portal ICT secondary to arterial bleeding (Case#1) and review procedure-related hemorrhages at DRI-Miami. Case#1: a 50 year-old female with T1DM for 21 years who was on an insulin pump with severe hypoglycemia episodes, hypoglycemia unawareness and unstable glucose control received, her first allogeneic ICT under an immunosuppressive regimen consisting of induction thymoglobulin-etanercept (1st ICT), basiliximab-etanercept (2nd ICT) and maintenance with sirolimus/tacrolimus. Six months after the 1st ICT (7.281 IEQ/kg) insulin dose was reduced by 50%. A second ICT (11,748 IEQ/kg) was performed 241 days after initial infusion utilizing the PTHA approach (11). A packed cell volume of 6ml (total 303ml with diluents), mixed with 3871 units of heparin (70U/Kg) according to protocol was infused by gravity. There was no significant elevation in mean portal vein pressure, measuring 2 ,3 and 5mmHg before, during and after ICT respectively;. The catheter tract was sealed with Gelfoam pledgets and D-STAT™ (15). a continuous heparin infusion was commenced according to protocol to achieve and maintain partial thromboplastin time (PTT) between 50-60 seconds which was substituted by enoxaparin 30mg BID at 48h after ICT. Abdominal ultrasound at 24 hours post procedure showed no significant abnormality, specifically no evidence of intra- or extra-hepatic bleeding (Hb:12.5g/dl; hematocrit (Hct):37.5). The Subject was discharged at 48 hours post infusion. The subject was readmitted via the ER on POD 4, describing progressive dull abdominal pain that had started shortly after discharge, and culminated in severe right upper quadrant pain, a syncopal episode, nausea and vomiting on the day of admission. A CT scan showed a subcapsular hematoma with 15cm (cranio-caudad dimension) adjacent to the right hepatic lobe, active extravasation of contrast, and large amounts of free abdominal and pelvic fluid. Hb and Hct had fallen to 7.5g/dl and 21.5% respectively. A hepatic angiogram was performed which demonstrated a pseudoaneurysm, concluded to be the cause of the bleeding. The pseudoaneurysm was successfully treated using coil embolization, the patient received a five unit blood transfusion and was discharged in stable condition (Hb:11.1g/dl-Htc:31.4%). The patient continued to suffer with right upper quadrant pain, percutaneous drainage was offered but the patient opted for non-operative management with opiate analgesics. Serial repeat cross-sectional CT at 1and 6 months revealed a 14.6×14.4×5.8cm hepatic hematoma which shrunk to 5.0 × 2.5cm, by which time the subject had achieved insulin independence. Analgesics were weaned and discontinued. An MRI at 12 months showed a 3.7 × 1.8cm residual cyst, and the surrounding liver was normal with no periportal or generalized steatosis. The subject remains insulin free (>475 days) with HbA1c 5.1%. On previous reports, the risk of bleeding after ITC varied from 0-3.6%, and originated from the liver parenchymal tract (2,3,13-15). At DRI-Miami, 52 subjects received 89 ICT from 100 donors (March, 2012). We retrospectively evaluated demographics and laboratory findings of ICT (Fig-1). The bleeding incidence (6.7%) is similar to other ICT centers (15). Overall, 3/6 required blood transfusions, 5/6 bleedings occurred on ICT procedures utilizing gelfoam only. There have been no further bleeding complications since D-stat was introduced (12) until the present case described . Case#1 had the highest hemoglobin drop after ICT at our center. The number of needle passes and heparin dose did not differ from Case#1 to former ICT cases. Figure 1 Demographics and ICT Characteristics. Case#1: CT-Scan image of hepatic hematoma at 1st month (14.6×5.8 cm) at 6th month (5.0×2.5 cm). MRI at 12th month (3.7 × 1.8cm). Multiple needle passes to access the portal vein, elevated portal pressure, heparin dose (≥45U/kg), platelet <150.000/mm3 and aspirin use are associated with ICT bleedings. False-aneurysms of the hepatic artery and its branches are rare but well recognized potential complications after invasive transhepatic procedures (16,17). The complications described in this case report was a delayed event, not evident on ultrasound imaging at 24 hours. While most ICT patients may have mild residual right upper quadrant pain when they are ready for discharge, usually the day after their procedure, the pain should not be severe as in this case. Pain which worsens after discharge should prompt an immediate careful investigation to detect rare but potentially life threatening complications such as this one. Non-operative management of hepatic hematomas for hemodynamically stable patients without signs of infection include: blood transfusion, pain control, prophylactic antibiotics and bed rest. Subcapsular-hematomas/asymptomatic-intraperitoneal bleeds often resolve spontaneously, but may occasionally extend and cause hepatic compartment syndromes (14). Hemorrhage with hemodynamic instability, tachycardia and/or hypotension requiring blood transfusion may need urgent surgical or laparoscopic interventions(5,14). Pseudoaneurysms are rare complications occurring in less than 1% percutaneous transhepatic procedures, however when detected should be treated due to their risk of late bleeding. Depending on size and location, false-aneurysms are treated either by percutaneous embolization, or by direct thrombin injection(18,19). A large hepatic hematoma caused by an arterial bleeding, might be controlled by angiographic embolization and managed non-operatively. We present this case to demonstrate a rare complication and its management, occurring as a result of ICT.