Andrew M. Posselt

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.

A clinical scoring system for predicting nonalcoholic steatohepatitis in morbidly obese patients.

Nonalcoholic steatohepatitis (NASH) is common in morbidly obese persons. Liver biopsy is diagnostic but technically challenging in such individuals. This study was undertaken to develop a clinically useful scoring system to predict the probability of NASH in morbidly obese persons, thus assisting in the decision to perform liver biopsy. Consecutive subjects undergoing bariatric surgery without evidence of other liver disease underwent intraoperative liver biopsy. The outcome was pathologic diagnosis of NASH. Predictors evaluated were demographic, clinical, and laboratory variables. A clinical scoring system was constructed by rounding the estimated regression coefficients for the independent predictors in a multivariate logistic model for the diagnosis of NASH. Of 200 subjects studied, 64 (32%) had NASH. Median body mass index was 48 kg/m2 (interquartile range, 43‐55). Multivariate analysis identified six predictive factors for NASH: the diagnosis of hypertension (odds ratio [OR], 2.4; 95% confidence interval [CI], 1‐5.6), type 2 diabetes (OR, 2.6; 95% CI, 1.1‐6.3), sleep apnea (OR, 4.0; 95% CI, 1.3‐12.2), AST > 27 IU/L (OR, 2.9; 95% CI, 1.2‐7.0), alanine aminotransferase (ALT) > 27 IU/L (OR, 3.3; 95% CI, 1.4‐8.0), and non‐Black race (OR, 8.4; 95% CI, 1.9‐37.1). A NASH Clinical Scoring System for Morbid Obesity was derived to predict the probability of NASH in four categories (low, intermediate, high, and very high). Conclusion: The proposed clinical scoring can predict NASH in morbidly obese persons with sufficient accuracy to be considered for clinical use, identifying a very high‐risk group in whom liver biopsy would be very likely to detect NASH, as well as a low‐risk group in whom biopsy can be safely delayed or avoided. (HEPATOLOGY 2008.)

Laparoscopic bariatric surgery improves candidacy in morbidly obese patients awaiting transplantation

BACKGROUND To evaluate, at a university tertiary referral center, the safety and efficacy of laparoscopic Roux-en-Y gastric bypass (LRYGB) in patients with end-stage renal disease (ESRD) and laparoscopic sleeve gastrectomy (LSG) in patients with cirrhosis or end-stage lung disease (ESLD); and to determine whether these procedures help patients become better candidates for transplantation. METHODS A retrospective review was performed of selected patients with end-stage organ failure who were not eligible for transplantation because of morbid obesity who underwent LRYGB or LSG. The prospectively collected data included demographics, operative details, complications, percentage of excess weight loss, postoperative laboratory data, and status of transplant candidacy. RESULTS Of the 15 patients, 7 with ESRD underwent LRYGB and 6 with cirrhosis and 2 with ESLD underwent LSG. Complications developed in 2 patients (both with cirrhosis); no patient died. The mean follow-up was 12.4 months, and the mean percentage of excess weight loss at > or =9 months was 61% (ESRD), 33% (cirrhosis), and 61.5% (ESLD). Obesity-associated co-morbidities improved or resolved in all patients. Serum albumin and other nutritional parameters at > or =9 months after surgery were similar to the preoperative levels in all 3 groups. At the most recent follow-up visit, 14 (93%) of 15 patients had reached our institutions body mass index limit for transplantation and were awaiting transplantation; 1 patient with ESLD underwent successful lung transplant. CONCLUSION The results of this pilot study have provided preliminary evidence that LRYGB in patients with ESRD and LSG in patients with cirrhosis or ESLD is safe, well-tolerated, and improves their candidacy for transplantation.

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

OBJECTIVE Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50–80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

Factors associated with weight loss after gastric bypass.

BACKGROUND Gastric bypass (GBP) is the most common operation performed in the United States for morbid obesity. However, weight loss is poor in 10% to 15% of patients. We sought to determine the independent factors associated with poor weight loss after GBP. DESIGN Prospective cohort study. We examined demographic, operative, and follow-up data by means of multivariate analysis. Variables investigated were age, sex, race, marital and insurance status, initial weight and body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared), comorbidities (diabetes mellitus, hypertension, joint disease, sleep apnea, hyperlipidemia, and psychiatric disease), laparoscopic vs open surgery, gastric pouch area, gastrojejunostomy technique, and alimentary limb length. SETTING University tertiary referral center. PATIENTS All patients at our institution who underwent GBP from January 1, 2003, through July 30, 2006. MAIN OUTCOME MEASURES Weight loss at 12 months defined as poor (< or =40% excess weight loss) or good (>40% excess weight loss). RESULTS Follow-up data at 12 months were available for 310 of the 361 patients (85.9%) undergoing GBP during the study period. Mean preoperative BMI was 52 (range, 36-108). Mean BMI and excess weight loss at follow-up were 34 (range, 17-74) and 60% (range, 8%-117%), respectively. Thirty-eight patients (12.3%) had poor weight loss. Of the 4 variables associated with poor weight loss in the univariate analysis (greater initial weight, diabetes, open approach, and larger pouch size), only diabetes (odds ratio, 3.09; 95% confidence interval, 1.35-7.09 [P = .007]) and larger pouch size (odds ratio, 2.77;95% confidence interval, 1.81-4.22 [P <.001]) remained after the multivariate analysis. CONCLUSIONS Gastric bypass results in substantial weight loss in most patients. Diabetes and larger pouch size are independently associated with poor weight loss after GBP.

Islet Transplantation in Type 1 Diabetics Using an Immunosuppressive Protocol Based on the Anti-LFA-1 Antibody Efalizumab

The applicability of islet transplantation as treatment for type 1 diabetes is limited by renal and islet toxicities of currently available immunosuppressants. We describe a novel immunosuppressive regimen using the antileukocyte functional antigen‐1 antibody efalizumab which permits long‐term islet allograft survival while reducing the need for corticosteroids and calcineurin inhibitors (CNI). Eight patients with type 1 diabetes and hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction followed by maintenance with efalizumab and sirolimus or mycophenolate. When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus. All patients achieved insulin independence and four out of eight patients became independent after single‐islet transplants. Insulin independent patients had no further hypoglycemic events, hemoglobin A1c levels decreased and renal function remained stable. Efalizumab was well tolerated and no serious adverse events were encountered. Although long‐term follow‐up is limited by discontinuation of efalizumab and transition to conventional imunnosuppression (including CNI in four cases), these results demonstrate that insulin independence after islet transplantation can be achieved with a CNI and steroid‐free regimen. Such an approach may minimize renal and islet toxicity and thus further improve long‐term islet allograft survival.

Laparoscopic Procurement of Kidneys with Multiple Renal Arteries is Associated with Increased Ureteral Complications in the Recipient

This study investigates the effect of renal artery multiplicity on donor and recipient outcomes after laparoscopic donor nephrectomy. Three‐hundred and sixty‐one sequential procedures were performed over a 4‐year period. Forty‐nine involved accessory renal arteries; of these, 36 required revascularization and 13 were small polar vessels and ligated. The 312 remaining kidneys with single arteries served as controls. Study variables included operative times, blood loss, hospital stay, graft function and donor and recipient complications.

Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade.

Background. The applicability of islet transplantation as treatment for type 1 diabetes is limited by long-term graft dysfunction, immunosuppressive drug toxicity, need for multiple donors, and increased risk of allosensitization. We describe two immunosuppressive regimens based on the costimulation blocker belatacept (BELA) or the antileukocyte functional antigen-1 antibody efalizumab (EFA), which permit long-term islet allograft survival and address some of these concerns. Methods. Ten patients with type 1 diabetes with hypoglycemic unawareness received intraportal allogeneic islet transplants. Immunosuppression consisted of antithymocyte globulin induction and maintenance with sirolimus or mycophenolate and BELA (n=5) or EFA (n=5). Results. All five BELA-treated patients achieved independence after single transplants; one resumed partial insulin use 305 days after transplant but is now independent after a second transplant. All five patients treated with EFA achieved independence after one (3/5) or two (2/5) islet transplants and remained independent while on EFA (392–804 days). After EFA was discontinued because of withdrawal of the drug from the market, two patients resumed intermittent insulin use; the others remain independent. No patient in either group developed significant side effects related to the study drugs, and none have been sensitized to alloantigens. All have stable renal function. Conclusions. These two novel immunosuppressive regimens are effective, well tolerated, and the first calcineurin inhibitor/steroid-sparing islet protocols resulting in long-term insulin independence. Although EFA is no longer available for clinical use, these early results demonstrate that a regimen using BELA may be an effective alternative to improve graft function and longevity while minimizing renal and &bgr;-cell toxicity.

Portomesenteric Venous Thrombosis After Laparoscopic Surgery: A Systematic Literature Review

BACKGROUND Portomesenteric venous thrombosis (PVT) is an uncommon but potentially lethal condition reported after several laparoscopic procedures. Its presentation, treatment, and outcomes remain poorly understood, and possible etiologic factors include venous stasis from increased intra-abdominal pressure, intraoperative manipulation, or damage to the splanchnic endothelium and systemic thrombophilic states. DESIGN Systematic literature review. SETTING Academic research. SUBJECTS We summarized the clinical presentation and outcomes of PVT after laparoscopic surgery other than splenectomy in 18 subjects and reviewed the treatment strategies. MAIN OUTCOME MEASURES Systematic review of the literature on PVT after laparoscopic procedures other than splenectomy. RESULTS Eighteen cases of PVT following laparoscopic procedures were identified after Roux-en-Y gastric bypass (n = 7), Nissen fundoplication (n = 5), partial colectomy (n = 3), cholecystectomy (n = 2), and appendectomy (n = 1). The mean patient age was 42 years (age range, 20-74 years). Systemic predispositions toward venous thrombosis were identified in 11 patients. Clinical symptoms consisted primarily of abdominal pain manifested, on average, 14 days (range, 3-42 days) after surgery. Thrombus location varied, but 8 patients had a combination of portal and superior mesenteric venous thrombosis. Sixteen patients were treated with anticoagulation therapy. Ten patients underwent major interventions, including exploratory laparotomy in 6 patients and thrombolytic therapy in 4 patients. Six patients had complications, and 2 patients died. CONCLUSIONS Portomesenteric venous thrombosis following laparoscopic surgery usually manifests as nonspecific abdominal pain. Computed tomography can readily provide the diagnosis and demonstrate the extent of the disease. Treatment should be individualized based on the extent of thrombosis and the presence of bowel ischemia but should include anticoagulation therapy. Venous stasis from increased intra-abdominal pressure, intraoperative manipulation of splanchnic vasculature, and systemic thrombophilic states likely converges to produce this potentially lethal condition.

Laparoscopic sleeve gastrectomy is safe and efficacious for pretransplant candidates

BACKGROUND Morbid obesity is a relative contraindication for organ transplant because it is associated with higher postoperative morbidity and mortality. The safety and efficacy of laparoscopic sleeve gastrectomy (LSG) as a weight loss method for patients awaiting transplant has not been examined. METHODS A retrospective review was performed on morbidly obese patients awaiting liver or kidney transplant who underwent LSG from 2006 to 2012. Data included patient demographic characteristics, operative details, 30-day complications, percentage of excess weight loss, postoperative laboratory data, and status of transplant candidacy. RESULTS Twenty-six pretransplant patients underwent LSG. The mean age was 57 years, and 17 (65%) were women. Six patients had end-stage renal disease, and 20 patients had end-stage liver disease. The preoperative mean body mass index was 48.3 kg/m(2) (range 38-60.4 kg/m(2)). There were no deaths, and there were 6 postoperative complications: 2 superficial wound infections, 1 staple line leak, 1 postoperative bleed requiring blood transfusion, 1 transient encephalopathy, and 1 temporary renal insufficiency. The mean percentage of excess weight loss at 1, 3, and 12 months was 17% (n = 24/26), 26% (n = 23/26), and 50% (n = 18/20), respectively. All patients met our institutions body mass index cutoffs for transplantation by 12 months after the procedure. One patients renal function stabilized, and he was taken off the transplant list. Eight patients eventually underwent solid organ transplant. Six received liver transplants, 1 patient received a combined liver and kidney transplant, and 1 received a kidney transplant. The mean time between LSG and transplant was 16.6 months. CONCLUSIONS This is the largest case series involving LSG in patients awaiting solid organ transplantation. LSG is well tolerated, is technically feasible, and improves candidacy for transplantation.