Mehdi Tavakol

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 When efalizumab was withdrawn from the market in mid 2009, all patients were transitioned to regimens consisting of mycophenolate and sirolimus or mycophenolate and tacrolimus.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.

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.

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.

Multivessel coronary artery disease predicts mortality, length of stay, and pressor requirements after liver transplantation

The optimal preoperative cardiac evaluation strategy for patients with end‐stage liver disease (ESLD) undergoing liver transplantation remains unknown. Patients are frequently referred for cardiac catheterization, but the effects of coronary artery disease (CAD) on posttransplant mortality are also unknown. We sought to determine the contribution of CAD and multivessel CAD in particular to posttransplant mortality. We performed a retrospective study of ESLD patients undergoing cardiac catheterization before liver transplant surgery between August 1, 2004 and August 1, 2007 to determine the effects of CAD on outcomes after transplantation. Among 83 patients who underwent left heart catheterization, 47 underwent liver transplantation during the follow‐up period. Twenty‐one of all ESLD patients who underwent liver transplantation (45%) had CAD. Fifteen of the transplant patients with CAD (71%) had multivessel disease. Among transplant patients, the presence of multivessel CAD (versus no CAD) was predictive of mortality (27% versus 4%, P = 0.046), increased length of stay (22 versus 15 days, P = 0.050), and postoperative pressor requirements (27% versus 4%, P = 0.029). Interestingly, neither the presence of any CAD nor the severity of stenosis in any single coronary artery predicted mortality. Furthermore, none of the traditional clinical predictors (age, gender, diabetes, creatinine, ejection fraction, and Model for End‐Stage Liver Disease score) were predictive of mortality among transplant recipients. In conclusion, multivessel CAD is associated with higher mortality after liver transplantation when it is documented angiographically before transplantation, even in the absence of severe coronary artery stenosis. This study provides preliminary evidence showing that there may be significant prognostic value in coronary angiography as a part of the pretransplant workup. Liver Transpl 16:1242‐1248, 2010.

Donor Liver Small Droplet Macrovesicular Steatosis is Associated With Increased Risk for Recipient Allograft Rejection.

Although donor livers with <30% large droplet macrovesicular steatosis (MaS) and/or small droplet MaS (irrespective of percentage) are considered safe to use, this consensus is based on variable definitions of MaS subtypes and/or without a reproducible scoring system. We analyzed 134 donor liver biopsies from allografts transplanted at University of California at San Francisco between 2000 and 2015 to determine whether large and/or small droplet MaS is a risk factor for poor outcomes. Large droplet MaS was defined as a fat droplet occupying greater than one half of an individual hepatocyte, with nuclear displacement, and scored as the percentage of total parenchymal area replaced by large fat droplets on ×40 magnification. Small droplet MaS was defined as 1 to several discrete fat droplets, each occupying less than one half of an individual hepatocyte, and scored as the percentage of remaining hepatocytes (ie, hepatocytes not occupied by large fat droplets) containing small fat droplets on ×200 magnification (ie, small droplet MaS is the percentage of “remaining hepatocytes” with small fat droplets, and “remaining hepatocytes” is defined as 100% minus percent large droplet MaS). Thus, total MaS equals the sum of large and small droplet MaS, which cannot exceed 100%. Electronic medical records were reviewed to determine outcomes. There was an increased risk for acute cellular rejection (hazard ratio=2.5, P=0.0108) and bile duct loss suggestive of chronic ductopenic rejection (hazard ratio=2.4, P=0.0130) in donor livers with ≥30% small droplet MaS. Large droplet MaS (up to 60%) was not associated with adverse outcomes. Patient survival was not adversely affected by steatosis. Excellent agreement on the estimation of large (weighted &kgr;=0.682) and small droplet MaS (weighted &kgr;=0.780) was achieved. Our approach to donor steatosis scoring can identify liver allograft recipients at increased risk for rejection and highlights the importance of distinguishing between small and large droplet MaS in this evaluation.

A Single Perioperative Injection of Dexamethasone Decreases Nausea, Vomiting, and Pain after Laparoscopic Donor Nephrectomy

Background. A single dose of perioperative dexamethasone (8–10 mg) reportedly decreases postoperative nausea, vomiting, and pain but has not been widely used in laparoscopic donor nephrectomy (LDN). Methods. We performed a retrospective cohort study of living donors who underwent LDN between 2013 and 2015. Donors who received a lower dose (4–6 mg)  (n = 70) or a higher dose (8–14 mg) of dexamethasone (n = 100) were compared with 111 donors who did not receive dexamethasone (control). Outcomes and incidence of postoperative nausea, vomiting, and pain within 24 h after LDN were compared before and after propensity-score matching. Results. The higher dose of dexamethasone reduced postoperative nausea and vomiting incidences by 28% (P = 0.010) compared to control, but the lower dose did not. Total opioid use was 29% lower in donors who received the higher dose than in control (P = 0.004). The higher dose was identified as an independent factor for preventing postoperative nausea and vomiting. Postoperative complication rates and hospital stays did not differ between the groups. After propensity-score matching, the results were the same as for the unmatched analysis. Conclusion. A single perioperative injection of 8–14 mg dexamethasone decreases antiemetic and narcotic requirements in the first 24 h, with no increase in surgical complications.

Utility of Preoperative Non-Contrast Computed Tomography (CT) to Guide Perioperative Management for Renal Transplantation

Background Peripheral artery disease is highly prevalent among patients with end stage renal disease. Non-contrast CT scans of the abdomen and pelvis (CT A/P) are performed for pre-transplant (tx) evaluation in patients at high risk for cardiovascular events. The purpose of this study is to examine the severity and distribution of common iliac artery (CIA) and external iliac artery (EIA) calcifications and the associations with operative complications and clinical outcomes following renal tx. Methods Retrospective analysis of 202 renal tx recipients between 2/2013-11/2014 who underwent pre-operative CT A/P within 3 years of their surgery. All CT scans were assessed using a previously described scoring system (Table 1). Results The mean age was 57.2±11.2 years and 132/202 (65%) were men. 189/202 (94%) had hypertension, 124/202 (61%) had diabetes mellitus (DM), and 77/202 (38%) had coronary artery disease (CAD). There was no significant difference in calcification scores between sides (Table 2). In a regression analysis, previous cerebrovascular accident (CVA) (OR 5.43, p=0.03), CAD (OR 3.56, p<0.001), history of smoking (OR 2.08, p=0.02), DM (OR 2.23, p=0.01), and older age (OR 1.10, p<0.001) were significantly associated with moderate/severe CIA plaque (morphology score ≥ 2). One patient could not undergo tx due to severe, diffuse calcifications. 7 patients required arterial reconstruction during renal tx, all of whom had tx to the right EIA. Patients with moderate/severe right EIA plaque were more likely to require arterial reconstruction compared to those with none/mild plaque (4/34 [11.7%] v. 3/130 [2.3%]; p=0.03). There were 58 cases of delayed graft function (DGF), 51 of which occurred in transplants to the right EIA. In these cases, DGF was significantly associated with moderate/severe right EIA plaque (OR 2.82, p=0.009). Post-operative cardiac events occurred in 17/201 (8.5%) patients. In a multivariable logistic regression model, history of CAD (OR 3.79, p=0.03), congestive heart failure (OR 5.54, p=0.009), and severe CIA plaque (morphology score=3) (OR 4.98, p=0.04) were significantly associated with post-operative cardiac complications. 21 patients died during a mean follow-up of 1153 ± 1784 days. In a multivariable model, DM (p=0.05) and previous CVA (p=0.02) were significantly associated with increased risk of death. Conclusions Local calcified plaque of the recipient iliac artery is associated with increased operative complexity and higher rates of DGF. Plaque burden in the CIA is associated with both patient demographic factors and post-operative cardiac events, and is likely indicative of a greater severity of systemic atherosclerotic disease. Routine pre-tx CT scans in high risk patients may guide operative strategy and facilitate perioperative management to improve clinical outcomes. Table. No title available. Table. No title available. Research reported in this publication was supported in part by an NIAID T32 training grant from the National Institutes of Health under an award to the University of California, San Francisco (T32AI125222). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Inferior long-term graft survival after end-to-side reconstruction for two renal arteries in living donor renal transplantation

Living donor kidneys with two arteries can be revascularized using various techniques depending on anatomy. We hypothesized that the revascularization technique could impact long-term outcomes. We retrospectively analyzed 1714 living donor renal transplants at our institution between 1999 and 2015. Three hundred and eleven kidneys had dual arteries, and these were categorized into 5 groups; end-to-side (n = 18), inferior epigastric artery (n = 21), direct anastomosis (n = 65), side-to-side (n = 126) and ligated (n = 81). We then compared the outcomes with that of a control group (single artery, n = 1403) using Kaplan-Meier and Cox regression analyses. Cox regression was adjusted by age, sex and race/ethnicity of donor and recipient, side of kidney, transplant period and recipient surgeon. Compared to the control group, the end-to-side group had increased all-cause graft loss (10 years: 77.2% vs 24.5%, adjusted hazard ratio [aHR] 3.02, 95% confidence interval [CI] 1.30–7.03, p = 0.010) and death-censored graft loss (10 years: 82.0% vs 55.9%, aHR 4.17, 95% CI 1.63–10.68, p = 0.003), whereas the other groups did not. Our study shows that 10-year overall survival and death-censored graft survival were significantly worse for end-to-side arterial reconstruction than for other techniques. Alternative techniques to the end-to-side method should be used for accessory arteries that require revascularization.