Shari Messinger

Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010

OBJECTIVE To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010. RESEARCH DESIGN AND METHODS A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years. RESULTS Insulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001). CONCLUSIONS The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.

Induction Therapy With Autologous Mesenchymal Stem Cells in Living-Related Kidney Transplants A Randomized Controlled Trial

CONTEXT Antibody-based induction therapy plus calcineurin inhibitors (CNIs) reduce acute rejection rates in kidney recipients; however, opportunistic infections and toxic CNI effects remain challenging. Reportedly, mesenchymal stem cells (MSCs) have successfully treated graft-vs-host disease. OBJECTIVE To assess autologous MSCs as replacement of antibody induction for patients with end-stage renal disease who undergo ABO-compatible, cross-match-negative kidney transplants from a living-related donor. DESIGN, SETTING, AND PATIENTS One hundred fifty-nine patients were enrolled in this single-site, prospective, open-label, randomized study from February 2008-May 2009, when recruitment was completed. INTERVENTION Patients were inoculated with marrow-derived autologous MSC (1-2 x 10(6)/kg) at kidney reperfusion and two weeks later. Fifty-three patients received standard-dose and 52 patients received low-dose CNIs (80% of standard); 51 patients in the control group received anti-IL-2 receptor antibody plus standard-dose CNIs. MAIN OUTCOME MEASURES The primary measure was 1-year incidence of acute rejection and renal function (estimated glomerular filtration rate [eGFR]); the secondary measure was patient and graft survival and incidence of adverse events. RESULTS Patient and graft survival at 13 to 30 months was similar in all groups. After 6 months, 4 of 53 patients (7.5%) in the autologous MSC plus standard-dose CNI group (95% CI, 0.4%-14.7%; P = .04) and 4 of 52 patients (7.7%) in the low-dose group (95% CI, 0.5%-14.9%; P = .046) compared with 11 of 51 controls (21.6%; 95% CI, 10.5%-32.6%) had biopsy-confirmed acute rejection. None of the patients in either autologous MSC group had glucorticoid-resistant rejection, whereas 4 patients (7.8%) in the control group did (95% CI, 0.6%-15.1%; overall P = .02). Renal function recovered faster among both MSC groups showing increased eGFR levels during the first month after surgery than the control group. Patients receiving standard-dose CNI had a mean difference of 6.2 mL/min per 1.73 m(2) (95% CI, 0.4-11.9; P=.04) and those in the low-dose CNI of 10.0 mL/min per 1.73 m(2) (95% CI, 3.8-16.2; P=.002). Also, during the 1-year follow-up, combined analysis of MSC-treated groups revealed significantly decreased risk of opportunistic infections than the control group (hazard ratio, 0.42; 95% CI, 0.20-0.85, P=.02) CONCLUSION Among patients undergoing renal transplant, the use of autologous MSCs compared with anti-IL-2 receptor antibody induction therapy resulted in lower incidence of acute rejection, decreased risk of opportunistic infection, and better estimated renal function at 1 year. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00658073.

A novel method for the assessment of cellular composition and beta-cell viability in human islet preparations

Current methodologies to evaluate islet cell viability are largely based on tests that assess the exclusion of DNA‐binding dyes. While these tests identify cells that have lost selective membrane permeability, they do not allow us to recognize apoptotic cells, which do not yet stain with DNA‐binding dyes. Furthermore, current methods of analysis do not discriminate between cell subsets in the preparation and, in particular, they do not allow for selectively defining β‐cell viability.

HIV Transmission Risk Behaviors among HIV-Infected Persons Who Are Successfully Linked to Care

OBJECTIVES We examined the relationship between receipt of medical care for human immunodeficiency virus (HIV) infection and HIV transmission risk behavior among persons who had received a recent diagnosis of HIV infection. METHODS We enrolled 316 participants from 4 US cities and prospectively followed up participants for 1 year. Generalized estimating equations were used to examine whether having at least 3 medical care visits in a 6-month period was associated with unprotected vaginal or anal intercourse with an HIV-negative partner or partner with unknown HIV status. RESULTS A total of 27.5% of the participants (84 of 305) self-reported having unprotected sex with an HIV-negative or unknown status partner at enrollment, decreasing to 12% (31 of 258) and 14.2% (36 of 254) at 6-month and 12-month follow-ups, respectively. At follow-up, people who had received medical care for HIV infection at least 3 times had reduced odds of engaging in risk behavior, compared with those with fewer visits. Other factors associated with reduced risk behavior were being >30 years of age, male sex, not having depressive symptoms, and not using crack cocaine. CONCLUSIONS Being in HIV care is associated with a reduced prevalence of sexual risk behavior among persons living with HIV infection. Persons linked to care can benefit from prevention services available in primary care settings.

Immunosuppression and procedure-related complications in 26 patients with type 1 diabetes mellitus receiving allogeneic islet cell transplantation

Background. The success of sirolimus and low-dose tacrolimus in islet cell transplantation has influenced many transplant centers to utilize this novel regimen. The long-term safety and tolerability of this steroid-free immunosuppressive protocol for allogeneic islet transplantation has yet to be determined. Methods. We transplanted 26 adult patients with long standing type 1 diabetes mellitus between April 2000 and June 2004. Immunosuppression consisted of induction with daclizumab and maintenance therapy with tacrolimus and sirolimus. Adverse events (AEs) in patients were followed and graded using the Common Terminology Criteria for Adverse Events, version 3.0 (National Cancer Institute). Results. To date, the majority of patients were able to remain on the immunosuppression combination for up to 22±11 months. Four patients were successfully converted to Mycophenolate Mofetil due to tacrolimus-related toxicity. Withdrawal from immunosuppression was decided in four patients due to hypereosinophilic syndrome, parvovirus infection, aspiration pneumonia, and severe depression, respectively. Six patients required filgrastim therapy for neutropenia. Transient elevation of liver enzymes was observed in most patients early after islet infusion. Increased LDL in 20 patients required medical treatment. Conclusion. There was a varying range of AEs, most of them mild and self-limiting; however, some required urgent medical attention. The majority of patients were able to tolerate and remain on this effective regimen. To date, no deaths, cytomegalovirus disease, graft-versus-host disease, or posttransplant lymphoproliferative disease has been observed.

Long-term insulin independence and improvement in insulin secretion after supplemental islet infusion under exenatide and etanercept.

Background. Progressive graft dysfunction (GDF) and loss of insulin independence (II) have been invariably observed in islet transplant recipients under the “Edmonton protocol.” To reestablish II, we performed supplemental islet infusions (SI) in recipients of allogeneic islet transplant alone, displaying GDF. To improve the engraftment and long-term graft function of SI, exenatide (EXN) and etanercept treatment at islet infusion, and long-term EXN treatment were tested in a non-randomized pilot clinical trial. Methods. Patients with GDF received SI under Edmonton-like immunosuppression with daclizumab induction, either without interventions (SI-control; n=5) or with EXN and etanercept treatment (SI-EXN; n=4). Clinical and metabolic profiles were assessed during 18-month follow-up. Results. Long-term II (18 months) was observed in 100% of SI-EXN and in 20% of SI-control (P=0.04). SI-EXN subjects demonstrated restoration of function better than that seen after initial islet infusions. Comparison of SI-EXN and SI-control groups demonstrated better responses in SI-EXN subjects at 3 months post-SI. During the 18 months of follow-up, function was sustained in the SI-EXN subjects better than in SI-controls. Acute effects of EXN during mixed meal tolerance test and intravenous glucose tolerance test results in improved first and second phase insulin release in response to intravenous glucose tolerance test and suppressed postprandial hyperglucagonemia after mixed meal tolerance test. Conclusion. These results suggest that the combination of EXN and etanercept improve engraftment and long-term islet survival and function in subjects undergoing SI. This data, however, must be interpreted with some caution because of small sample size, lack of randomization, and sequential comparison with historical controls.

The Use of Exenatide in Islet Transplant Recipients with Chronic Allograft Dysfunction: Safety, Efficacy and Metabolic Effects

Background. A current limitation of islet transplantation is reduced long-term graft function. The glucagon-like peptide-1 receptor agonist, exenatide (Byetta, Amylin Pharmaceuticals, CA) has properties that could improve existing islet function, prevent further loss of islet mass and possibly even stimulate islet regeneration. Methods. This prospective study evaluated the safety, efficacy, and metabolic effects of exenatide in subjects with type 1 diabetes mellitus and islet allograft dysfunction requiring exogenous insulin. Results. Sixteen subjects commenced exenatide, 12 continue (follow-up 214±57 days; range 108–287), four (25%) discontinued medication because of side effects. At 6 months, exogenous insulin was significantly reduced with stable glycemic control (0.15±0.02 vs. 0.11±0.025 U/kg per day; P<0.0001); three subjects discontinued insulin from 4, 5, and 9 U/day, respectively, two sustained insulin independence with A1c reduction below graft dysfunction criteria. Postprandial capillary blood glucose was significantly decreased (129.4±3.8 vs. 118.7±4.6 mg/dL; P<0.001), C-peptide and C-peptide-to-glucose ratio increased significantly by 5th and 6th months of treatment (ratio, 1.09±0.15 vs. 1.52±0.18; P<0.05). Weight loss more than 3 kg occurred in 8 of 12 (67%) subjects. Stimulation testing demonstrated improved glucose disposal and C-peptide secretion (glucose area under the curve 52,332±3,219 vs. 42,072±1,965; P=0.002 mg·min−1·dL−1, mixed meal stimulation index 0.50±0.06 vs. 0.66±0.09; P=0.03 pmol·mL−1), with marked suppression of glucagon secretion and progressive increase in amylin secretion. Side effects were more frequent and severe compared with published reports in type 2 diabetes, tolerated doses were lower. Conclusions. Exenatide was tolerated in this patient population after appropriate dose titration and there appeared to be gradual but sustained positive effects on glycemic control and islet graft function.

Toward maximizing the success rates of human islet isolation: influence of donor and isolation factors.

In order to make islet transplantation a therapeutic option for patients with diabetes there is an urgent need for more efficient islet cell processing to maximize islet recovery. Improved donor management, organ recovery techniques, implementation of more stringent donor criteria, and improved islet cell processing techniques may contribute to enhance organ utilization for transplantation. We have analyzed the effects of donor and islet processing factors on the success rate of human islet cell processing for transplantation performed at a single islet cell processing center. Islet isolation outcomes improved when vasopressors, and in particular pitressin, and steroids were used for the management of multiorgan donors. Higher islet yields were obtained from adult male donors, BMI >25 kg/m2, adequate glycemic control during hospital stay, and when the pancreas was retrieved by a local surgical team. Successful isolations were obtained in 58% of the cases when ≥ 4 donor criteria were met, and even higher success rates (69%) were observed when considering ≥ 5 criteria. Our data suggest that a sequential, integrated approach is highly desirable to improve the success rate of islet cell processing.

Simple Measures to Monitor β-Cell Mass and Assess Islet Graft Dysfunction

The aim of this study was to develop a simple test for the assessment of islet graft dysfunction based on measures involving fasting C‐peptide. Calculations were made to account for the dependence of C‐peptide secretion on glucose concentration (C‐peptide/glucose ratio [CP/G]) and adjusted for renal function by calculating the C‐peptide/glucose‐creatinine ratio (CP/GCr). Values from 22 recipients were analyzed at different times post‐last islet infusion. Receiver operating characteristic curves were used to determine which of these measures best predicts high 90‐minute glucose (90 min‐Glc; >10 mmol/L) after a Mixed Meal Tolerance Test (MMTT). In this initial analysis, CP/G was found to be superior predicting high 90 min‐Glc with a larger area under the ROC curve than C‐peptide (p = 0.01) and CP/GCr (p = 0.06). We then correlated C‐peptide and CP/G with islet equivalents‐IEQ/kg infused, 90 min‐Glc after MMTT and clinical outcome (β‐score). C‐peptide and CP/G in the first 3 months post‐last islet infusion correlated with IEQ/kg infused. CP/G correlated with 90 min‐Glc and β‐score. C‐peptide and CP/G are good indicators of islet mass transplanted. CP/G is more indicative of graft dysfunction and clinical outcome than C‐peptide alone. The ease of calculation and the good correlation with other tests makes this ratio a practical tool when monitoring and managing islet transplant recipients.

Improved Metabolic Control and Quality of Life in Seven Patients With Type 1 Diabetes Following Islet After Kidney Transplantation

Background. The beneficial effects of glycemic control on both survival and function of transplanted kidneys in patients with type 1 diabetes mellitus (T1DM) and end-stage renal disease (ESRD) have been recognized. Methods. Herein, we present the clinical outcome of a single-center pilot trial of islet after kidney (IAK) transplantation in seven patients with T1DM. The immunosuppression protocol for the kidney graft was converted to sirolimus+tacrolimus regimen 6 months before islet transplantation to exclude negative effects on kidney graft function. Primary endpoint was achievement of insulin independence after transplantation. Clinical outcome, metabolic control, severe hypoglycemia, kidney function, Quality of Life (QOL) psychometric measures, and adverse events were monitored. Results. Seven patients showed graft function with improved metabolic control (A1c, fasting glycemia, and metabolic tests) after IAK (14,779±3,800 IEQ/kg). One-year insulin independence was 30% with persistent graft function in 86% (C-peptide-positive). A1c reduction was 1.95±0.31% from baseline (P<0.0001). No episodes of severe hypoglycemia were observed, even after resuming insulin. The direct consequence of these benefits was a significant improvement in diabetes QOL. Adverse events included procedure-related pleural effusion (n=2), cholecystitis (n=1), and additional immunosuppression-related, all resolved without sequelae. Kidney function (by estimated glomerular filtration rate) remained stable during follow-up in six of seven patients. Conclusions. Islet transplantation represents a feasible therapeutic option for patients with T1DM bearing a stable kidney allograft. Insulin independence at 1 year is lower than what reported in islet transplant alone. Nevertheless, clear benefits in terms of optimal metabolic control and absence of severe hypoglycemia are invariably present.