Richard S. Mangus

Use of extended criteria livers decreases wait time for liver transplantation without adversely impacting posttransplant survival.

Introduction:The use of extended criteria donors (ECDs) could minimize shortage of suitable donor livers for transplantation. In 3 years, the aggressive use of ECD livers has reduced the wait list at our center from 257 to 30 patients with a median wait time of 18 days without using living donors. This study compares the graft/patient survival from standard (SD) and ECD for our transplant population between 2001 and 2005. Methods:Records of all adult liver transplant recipients over 4 years were reviewed (n = 571). ECD criteria included: age >59 years, BMI >34.9, maximum AST/ALT >500, maximum bilirubin >2.0, peak serum sodium >170, HBV/HCV/HTLV reactive, donation after cardiac death, cold ischemia time >12 hours, ICU stay >5 days, 3 or more pressors simultaneously, extensive alcohol abuse, cancer history (nonskin), active meningitis/bacteremia, or significant donor liver trauma. Outcomes included graft and patient survival at 90 days, 1 year, and 2 years. Results:Sixty-eight percent of recipients (n = 388) received ECD livers. Primary factors accounting for ECD-liver status included: elevated liver function tests (20%), hypernatremia (12.6%), and extensive alcohol abuse (11.4%). Graft survival was (SD, ECD): 90-day 91%, 88%; 1-year 84%, 80%; 2-year 78%, 77%; patient survival was: 90-day 93%, 90%; 1-year 87%, 82%; 2-year 83%, 79%. Kaplan-Meier survival analysis failed to demonstrate an overall difference in graft or patient survival at any time point. Only donor age >60 years was associated with decreased graft and patient survival. Conclusions:Liver grafts from ECD can be used to dramatically reduce wait list time with outcomes comparable to those for SD without resorting to living donor liver transplantation.

Stented versus nonstented extravesical ureteroneocystostomy in renal transplantation: a metaanalysis.

Stenting of the extravesical ureteroneocystostomy in renal transplantation is controversial. This study is a metaanalysis of 49 published studies over 30 years time in which the extravesical technique was used. Stented and nonstented anastomoses were compared. One‐hundred six articles published between 1973 and 2002 were reviewed and 49 met criteria for inclusion. Articles were required to list original, numeric, previously unpublished data and to report or to describe the use of an extravesical ureteroneocystostomy, with or without stent. Data were analyzed within separate groups, (1) randomized, controlled trials and (2) case series. Data were included from five randomized, controlled trials and 44 case series. In the controlled trials group, there were urologic complications in 6 of 407 stented (1.5%), and 35 of 389 nonstented subjects (9.0%) (p < 0.0001, OR 0.24, 95% CI 0.10–0.57). In the case‐series group, there were urologic complications in 137 of 4245 stented (3.2%) and 433 of 9077 nonstented subjects (4.8%) (p = 0.007, OR 0.58, 95% CI 0.39–0.86). Renal transplants with stented extravesical ureteroneocystostomy have a significantly lower urologic complication rate than those with nonstented anastomoses. All five randomized, controlled trials individually found stented anastomoses to have a lower complication rate and this was confirmed by metaanalysis of these trials and of case‐series data.

Comparison of histidine‐tryptophan‐ketoglutarate solution (HTK) and University of Wisconsin solution (UW) in adult liver transplantation

Histidine‐tryptophan‐ketoglutarate solution (HTK) and University of Wisconsin solution (UW) have been shown to have similar outcomes in cadaveric kidney, pancreas, and liver transplantation. Our institution changed from UW to HTK as the primary preservation solution for liver, kidney and pancreas transplantation. This study compares the perioperative and first year outcomes of liver transplantation using UW or HTK. Primary use of HTK began on May 1, 2003. We reviewed the records of all adult liver transplant recipients from July 1, 2002 to December 31, 2004. Recipients were compared based on organ preservation solution (UW n=204, HTK n=174). Outcomes included 1‐, 6‐ and 12‐month graft and patient survival and 1‐, 7‐, 14‐, and 30‐day liver function and serum creatinine. During the entire study period, the two groups were managed similarly in operative technique, immunosuppressive regimens, and donor liver criteria. Over 30 months, 378 adult patients underwent liver transplantation. There were no significant differences between UW and HTK in 1‐, 6‐, or 12‐month graft or patient survival. The HTK group had a higher day 1 median AST, ALT, and total bilirubin, but the two groups were similar thereafter. An anticipated difference in infused volume between UW and HTK was demonstrated. In conclusion, to our knowledge, this is the first reported large case series from North America comparing HTK and UW in liver transplantation with 2‐ to 12‐month follow‐up. There were no significant differences between HTK and UW in this population when comparing 1 month graft function and first‐year graft and patient survival. Liver Transpl 12:226–230, 2006.

Comparison of histidine-tryptophan-ketoglutarate solution and University of Wisconsin solution in extended criteria liver donors

Liver, pancreas, and kidney allografts preserved in histidine‐tryptophan‐ketoglutarate (HTK) and University of Wisconsin (UW) solutions have similar clinical outcomes. This study compares HTK and UW in a large number of standard criteria donor (SCD) and extended criteria donor (ECD) livers at a single center over 5 years. All adult, cadaveric liver and liver‐kidney transplants performed between July 1, 2001 and June 30, 2006 were reviewed (n = 698). There were 435 livers (62%) categorized as ECD for severe physiologic stress and 70 (10%) because of old age. Recipient outcomes included perioperative death or graft loss and overall survival. Liver enzymes were analyzed for the first month post‐transplant. Biliary complications were assessed through chart review. Overall, 371 donor livers were preserved in HTK (53%), and 327 were preserved in UW (47%). There were no statistically significant differences in any of the primary outcome measures comparing HTK and UW. The HTK group overall had a higher day 1 median aspartate aminotransferase and alanine aminotransferase, but the two groups were similar in function thereafter. HTK was superior to UW in protection against biliary complications. Kaplan‐Meier graft survival curves failed to demonstrate a significant difference in SCD or ECD livers. In conclusion, HTK and UW are not clinically distinguishable in this large sample of liver transplants, although HTK may be protective against biliary complications when compared to UW. These findings persisted for both SCD and ECD livers. Given the lower cost per donor for HTK, this preservation solution may be preferable for general use. Liver Transpl 14:365–373, 2008.

Promising early results with immunosuppression using rabbit anti-thymocyte globulin and steroids with delayed introduction of tacrolimus in adult liver transplant recipients

Induction therapy with T‐cell depleting drugs in liver transplantation is controversial. This study examined the use of rabbit antithymocyte globulin (RATG) with delayed introduction of tacrolimus in liver transplant recipients. Additional subgroup analysis compared patients with or without hepatitis C (HCV) cirrhosis. Over 17 months, 116 adults received 120 liver allografts. Four patients who died before receiving RATG were excluded. Immunosuppression included steroids, 3 doses of RATG (2 mg/kg), and tacrolimus started on postoperative day 3 to 4. Ninety‐six percent of patients were alive with a mean follow‐up of 12.9±4.5 months. No graft was lost to rejection. Two patients developed hepatic artery thrombosis. Six percent of patients had acute rejection. No patient had steroid resistant or recurrent rejection. RATG related drug events were limited to fever, chills, tachycardia, and oxygen desaturation. There were no cases of lymphoproliferative disease. Forty‐two percent of patients were transplanted for HCV. Thirty‐two percent of HCV‐patients had biopsy proven hepatitis C recurrence occurring at 4 weeks to 10 months posttransplant. RATG induction therapy is associated with good patient and graft survival, a low incidence of rejection, and minimal side effects. In addition, RATG induction is safe in patients transplanted for HCV. (Liver Transpl 2004;10:404–407.)

Multivisceral transplantation for diffuse portomesenteric thrombosis

Objective:To evaluate the clinical outcomes of multivisceral transplantation (MVT) in the setting of diffuse thrombosis of the portomesenteric venous system. Background:Liver transplantation (LT) in the face of cirrhosis and diffuse portomesenteric thrombosis (PMT) is controversial and contraindicated in many transplant centers. LT using alternative techniques such as portocaval hemitransposition fails to eliminate complications of portal hypertension. MVT replaces the liver and the thrombosed portomesenteric system. Methods:A database of intestinal transplant patients was maintained with prospective analysis of outcomes. The diagnosis of diffuse PMT was established with dual-phase abdominal computed tomography or magnetic resonance imaging with venous reconstruction. Results:Twenty-five patients with grade IV PMT received 25 MVT. Eleven patients underwent simultaneous cadaveric kidney transplantation. Biopsy-proven acute cellular rejection was noted in 5 recipients, which was treated successfully. With a median follow-up of 2.8 years, patient and graft survival were 80%, 72%, and 72% at 1, 3, and 5 years, respectively. To date, all survivors have good graft function without any signs of residual/recurrent features of portal hypertension. Conclusions:MVT can be considered as an option for the treatment of patients with diffuse PMT. MVT is the only procedure that completely reverses portal hypertension and addresses the primary disease while achieving superior survival results in comparison to the alternative options.

Induction Immunosuppression With Thymoglobulin and Rituximab in Intestinal and Multivisceral Transplantation

Background. Induction immunosuppression is now a common practice after intestinal and multivisceral transplantation. We report our experience in 27 adult recipients who received rituximab and rabbit antithymocyte globulin (rATG) in combination as induction agents. Material and Methods. Twenty-seven adult patients received 29 intestinal transplants between July 2004 and March 2007. All patients received induction immunosuppression therapy with rATG, rituximab, and steroids. Tacrolimums and a steroid taper were used for maintenance therapy. Patient and graft survival, episodes of rejection as well as posttransplant lymphoproliferative disease (PTLD) and graft-versus-host disease were analyzed. Results. One-year patient and graft survival was 81% and 76%, respectively. Thirteen patients (48%) experienced 19 episodes of acute rejection (9 mild episodes, 2 moderate, and 8 severe). Patients with a multivisceral graft experienced less episodes of severe acute rejection (1 of 19, 5%) when compared with isolated intestinal transplants and modified multivisceral transplants (7 of 10, 70%). Two patients had episodes of skin graft-versus-host disease that responded to steroid boluses. PTLD was not seen in our series. Two patients developed cytomegalovirus enteritis. Conclusions. The combination of rATG and rituximab was an effective induction therapy in our preliminary data. The number and severity of rejection episodes increased when the liver was not included as part of the graft. An immunosuppression regimen including rATG, rituximab, and steroids may have a protective effect against PTLD and chronic rejection.

Immunosuppression induction with rabbit anti‐thymocyte globulin with or without rituximab in 1000 liver transplant patients with long‐term follow‐up

Rabbit anti‐thymocyte globulin (rATG)–based immunosuppression induction is being increasingly used in liver transplantation (LT) in conjunction with steroid‐free protocols to delay the initiation of calcineurin inhibitors. This study reports a single‐center comparison of transplant outcomes and complications in 3 immunosuppression eras. Data were obtained retrospectively from a center research database, and the analysis included LT patients from 2001 to 2008. The immunosuppression consisted of rATG induction in 3 doses (6 mg/kg in all): (1) the first dose was administered perioperatively [the rabbit anti‐thymocyte globulin in the operating room (rATG‐OR) era]; (2) the first dose was delayed until 48 hours after transplantation [the rabbit anti‐thymocyte globulin after a delay (rATG‐D) era]; or (3) the first dose was delayed until 48 hours after transplantation, and a single dose of rituximab was added 72 hours after transplantation [the rabbit anti‐thymocyte globulin after a delay plus rituximab (rATG‐D‐Ritux) era]. The initial maintenance immunosuppression was tacrolimus monotherapy, which was started on postoperative day 2. There were 166 patients (16%) in the rATG‐OR era, 259 patients (26%) in the rATG‐D era, and 588 patients (58%) in the rATG‐D‐Ritux era (1013 patients in all). Demographically, the latter eras were characterized by higher recipient and donor ages; greater percentages of liver‐kidney transplants, hepatocellular carcinoma (HCC), donation after cardiac death (DCD), and imported organs; and shorter graft ischemia times. There were no significant differences between the 3 immunosuppression groups in unadjusted patient survival 3 and 5 years after transplantation (80% and 75% for the rATG‐OR era, 75% and 67% for the rATG‐D era, and 79% and 71% for the rATG‐D‐Ritux era, P = 0.15). The 5‐year survival rates for patients with hepatitis C virus (HCV) and HCC were 65% and 68%, respectively. The factors included in the Cox regression model for patient death included the Model for End‐Stage Liver Disease score [hazard ratio (HR) = 1.03, P = 0.001], HCV (HR = 1.28, P = 0.04), donor age (HR = 1.01, P = 0.001), recipient age (HR = 1.01, P = 0.05), and DCD (HR = 1.55, P = 0.11). rATG‐based induction immunosuppression can be safely used in adult LT recipients with excellent survival and low rejection rates and without increases in immunosuppression‐related side effects. Liver Transpl, 2012.

The case for pancreas after kidney transplantation

Abstract:  Pancreas after kidney (PAK) transplantation has historically demonstrated inferior pancreas allograft survival compared to simultaneous pancreas and kidney (SPK) transplantation. Under our current immunosuppression protocol, we have noted excellent outcomes and rare immunological graft loss. The goal of this study was to compare pancreas allograft survival in PAK and SPK recipients using this regimen. This was a single center retrospective review of all SPK and PAK transplants performed between January 2003 and November 2007. All transplants were performed with systemic venous drainage and enteric exocrine drainage. Immunosuppression included induction with rabbit anti‐thymocyte globulin (thymoglobulin), early steroid withdrawal, and maintenance with tacrolimus and sirolimus or mycophenolate mofetil. Study end points included graft and patient survival and immunosuppression related complications. Transplants included PAK 61 (30%) and SPK 142 (70%). One‐yr patient survival was PAK 98% and SPK 95% (p = 0.44) and pancreas graft survival was PAK 95% and SPK 90% (p = 0.28). Acute cellular rejection was uncommon with 2% requiring treatment in each group. Survival for PAK using thymoglobulin induction, early steroid withdrawal and tacrolimus‐based immunosuppression is at least comparable to SPK and should be pursued in the recipient with a potential living donor.

Comparison of Histidine-Tryptophan-Ketoglutarate Solution and University of Wisconsin Solution in Intestinal and Multivisceral Transplantation

Background. Previous studies have failed to demonstrate a clinical difference between histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) preservation solutions in clinical transplant outcomes for liver, pancreas, and kidney transplantation. This study compares HTK and UW in bowel transplantation with primary outcomes being graft and patient survival, early graft function, and episodes of rejection. Methods. Data were extracted using a retrospective chart and medical record review of all bowel transplants between 2003 and 2007, and included both pediatric and adult grafts. Transplanted organs included isolated small bowel, modified multivisceral (bowel, pancreas, and stomach) and multivisceral (bowel, pancreas, stomach, and liver). Immunosuppression included induction with a steroid taper and antithymocyte globulin and anti-CD20 monoclonal antibody (rituximab), followed by maintenance with prograf monotherapy. Bowel surveillance was performed with twice weekly zoom endoscopy and biopsy. Results. There were 54 patients transplanted with 57 grafts, 22 preserved in UW, and 37 in HTK. No differences were noted between the two solutions in initial graft function, appearance of bowel on initial endoscopy, and number of rejection episodes. There were no episodes of pancreatitis in the 44 multivisceral grafts which included a transplant pancreas (14 UW and 30 HTK). Kaplan-Meier survival analysis did not demonstrate a significant difference in graft or patient survival at 30- or 90-days posttransplant. Conclusions. Intestinal grafts preserved in UW and HTK demonstrate no difference in graft and patient survival at 30- and 90-days posttransplant. There were no differences noted in initial function, endoscopic appearance, rejection episodes, or transplant pancreatitis.