Shunji Nagai

Allograft Pancreatectomy: Indications and Outcomes.

This study evaluated the indications, surgical techniques, and outcomes of allograft pancreatectomy based on a single center experience. Between 2003 and 2013, 47 patients developed pancreas allograft failure, excluding mortality with a functioning pancreas allograft. Early graft loss (within 14 days) occurred in 16, and late graft loss in 31. All patients with early graft loss eventually required allograft pancreatectomy. Nineteen of 31 patients (61%) with late graft loss underwent allograft pancreatectomy. The main indication for early allograft pancreatectomy included vascular thrombosis with or without severe pancreatitis, whereas one recipient required urgent allograft pancreatectomy for gastrointestinal hemorrhage secondary to an arterioenteric fistula. In cases of late allograft pancreatectomy, graft failure with clinical symptoms such as abdominal discomfort, pain, and nausea were the main indications (13/19 [68%]), simultaneous retransplantation without clinical symptoms in 3 (16%), and vascular catastrophes including pseudoaneurysm and enteric arterial fistula in 3 (16%). Postoperative morbidity included one case each of pulmonary embolism leading to mortality, formation of pseudoaneurysm requiring placement of covered stent, and postoperative bleeding requiring relaparotomy eventually leading to femoro‐femoral bypass surgery 2 years after allograftectomy. Allograft pancreatectomy can be performed safely, does not preclude subsequent retransplantation, and may be lifesaving in certain instances.

A Novel Approach in Combined Liver and Kidney Transplantation with Long-term Outcomes

Objective: The aim of this study was to compare the outcomes of simultaneous and delayed implantation of kidney grafts in combined liver-kidney transplantation (CLKT). Background Data: Delayed function of the renal graft (DGF), which can result from hypotension and pressor use related to the liver transplantation (LT), may cause worse outcomes in CLKT. Methods: A total of 130 CLKTs were performed at Indiana University between 2002 and 2015 and studied in an observational cohort study. All kidneys underwent continuous hypothermic pulsatile machine perfusion until transplant: 69 with simultaneous kidney transplantation (KT) (at time of LT, group 1) and 61 with delayed KT (performed at a later time as a second operation, group 2). All patients received continuous veno-venous hemodialysis during the LT. Propensity score match analysis in a 1:1 case-match was performed. Results: Mean kidney cold ischemia time was 10 ± 3 and 50 ± 15 hours, for groups 1 and 2 (P < 0.0001), respectively. The rate of DGF was 7.3% in group 1, but no DGF was seen in group 2 (P = 0.0600). Kidney function was significantly better in group 2, if the implantation of kidneys was delayed >48 hours (P < 0.01). Patient survival was greater in group 2 at 1 year (91%), and 5 year (87%) post-transplantation (P = 0.0019). On multivariate analysis, DGF [hazard ratio (HR), 165.7; 95% confidence interval (CI), 9.4–2926], extended criteria donor kidneys (HR, 15.9; 95% CI 1.8–145.2), and recipient hepatitis C (HR, 5.5; 95% CI 1.7–17.8) were significant independent risk factors for patient survival. Conclusions: Delayed KT in CLKT (especially if delayed >48 h) is associated with improved kidney function with no DGF post-KT, and improved patient and graft survival.

Immunogenicity of Renal Microvascular Endothelial Cells From Genetically Modified Pigs.

Background Disrupting the porcine GGTA1 and CMAH genes [double knockout (DKO)] that produce the gal-&agr;(1,3)-gal and N-glycolylneuraminic acid xenoantigens reduces human antibody binding to porcine peripheral blood mononuclear cells. It is important to examine rejection pathways at an organ-specific level. The object of this study is to evaluate the human preformed antibody reactivity against DKO renal microvascular endothelial cells (RMEC) in vitro. Methods Characteristics of DKO RMEC were analyzed using flow cytometry. Human IgG/M binding to primary RMEC, immortalized RMEC (iRMEC), and iRMEC-deficient in B4GALNT2 genes were examined using flow cytometric crossmatch assay. Results Porcine RMEC expressed gal-&agr;(1,3)-gal, N-glycolylneuraminic acid, and Dolichos biflorus agglutinin glycans recognized by human preexisting antibodies in humans. Antigenicity of DKO RMEC was lower than GGTA1 KO RMEC. The disruption of B4GALNT2 gene in DKO iRMEC further reduced human IgG/IgM binding. Conclusions Silencing the porcine GGTA1, CMAH, and B4GALNT2 genes is an effective strategy to reduce human preformed antibody binding to RMEC. Porcine RMEC will be a useful reagent for the further study of xenoimmunology.

Cytomegalovirus Infection After Intestinal/Multivisceral Transplantation: A Single-Center Experience With 210 Cases.

Background Cytomegalovirus (CMV) infection is the most prevalent infectious complication after solid organ transplantation, and recipients of isolated intestinal transplantation (IIT)/multivisceral transplantation (MVT) are among those at the highest risk. Limited clinical data exist regarding CMV infection after IIT/MVT. The aim of this study is to analyze risk factors for posttransplant CMV infection and to assess the efficacy and validity of our prophylaxis and treatment regimens in intestinal transplantation. Methods Medical records of 210 IIT/MVT patients were retrospectively reviewed. Posttransplant CMV prophylaxis regimen consisted of ganciclovir followed by 1 year of valganciclovir. The addition of CMV immunoglobulin (CMVIG) was decided according to donor/recipient CMV serostatus (D/R). All results of CMV PCR and/or pp65 antigenemia, and pathological reports were reviewed. Time to the incidence of CMV infection (viremia and/or tissue invasive disease) and risk factors for CMV infection were investigated. Results CMV infection was observed in 34 of 210 (16%) with a median onset of 347 days. Rejection was significantly associated with CMV infection (P = 0.01, odds ratio = 2.61). In the high-risk serostatus group (D+/R−), prophylactic CMVIG and induction with high-dose rabbit antithymocyte globulin (>10 mg/kg) were associated with a lower CMV infection rate on univariate analysis. The CMVIG remained to be an independent factor on multivariate analysis (P = 0.04, hazard ratio = 0.93/dose). Mortality associated with CMV infection occurred in 4, and CMV infection adversely affected patient survival (P = 0.001, hazard ratio = 2.71). Conclusions Prophylaxis with CMVIG and appropriate induction with rabbit antithymocyte globulin may be important to reduce CMV infection in high-risk serostatus group (D+/R−).

Intestinal Graft Failure: Should We Perform the Allograft Enterectomy Before or With Retransplantation?

BackgroundIntestinal graft dysfunction is sometimes irreversible and requires allograft enterectomy with or without retransplantation. There is no comprehensive assessment of allograft enterectomy regarding indications and outcomes. The aim of this study was to evaluate management of patients with intestinal graft failure with special reference to indications and outcomes of allograft enterectomy and the procedures validity as a bridge to retransplantation. MethodsGraft and patient survivals, reason for graft failure, and rejection episodes were evaluated in 221 intestinal recipients (primary transplantation [n = 201], retransplantation [n = 20]). Indications, surgical factors, and outcomes of allograft enterectomy were investigated. ResultsReasons for isolated enterectomy included systemic infection in 11, gastrointestinal bleeding in 1, and severe electrolyte imbalance in 1, all of which were associated with rejection. One isolated intestinal transplantation patient underwent isolated enterectomy due to cytomegalovirus enteritis. One multivisceral transplantation patient underwent isolated allograft enterectomy due to bowel necrosis. Of these 15 patients, 3 died from persistent infection postoperatively, whereas 8 underwent retransplantation with median interval of 74 days (42-252 days). Allosensitization occurred between isolated enterectomy and retransplantation in 2, one of whom lost the second graft due to rejection. Simultaneous allograft enterectomy and retransplantation was performed in 3 isolated intestinal transplantation and 9 multivisceral transplantation patients. Patient survival after retransplantation was similar between patients who underwent isolated allograft enterectomy and those who did simultaneous enterectomy with retransplantation (P = 0.82). ConclusionsIn cases of irreversible intestinal graft dysfunction, isolated allograft enterectomy successfully provides recovery from comorbidities as a lifesaving procedure and does not compromise outcomes of retransplantation.

Post-transplant persistent lymphopenia is a strong predictor of late survival in isolated intestine and multivisceral transplantation.

Absolute lymphocyte count (ALC) has been identified as a prognostic factor in liver transplantation. We hypothesized that a lower ALC may be linked to poor outcomes in isolated intestinal/multivisceral transplantation (IIT/MVT). The aim of this study was to investigate the prognostic impact of ALC in IIT/MVT. A total 141 IIT/MVT patients were eligible for the study. Post‐transplant ALCs (at 3, 6, and 12 months) were evaluated, and prognostic impact of trend of ALC during the first year was investigated. Of these 141 patients, 108 patients survived in the first year (1‐year survivors). One‐year survivors were categorized according to post‐transplant ALC at each time point. When ALC was decreased throughout the first year (post‐transplant persistent lymphopenia: <500/μl at 3, 6, and 12 months), patient survival (P < 0.001, hazard ratio = 5.09) and graft survival (P < 0.001, hazard ratio = 5.15) after the first year was significantly worse, and this remained to be an independent risk factor. Negative impact of persistent lymphopenia on patient and graft survival was significant regardless of type of intestinal graft. Infection leading to mortality occurred more frequently in the persistent lymphopenia group (43% vs. 24%). Trend of post‐transplant ALC may be a strong predictive marker for long‐term outcome in 1‐year survivors after IIT/MVT.

Prognosis after recurrence of hepatocellular carcinoma in liver transplantation: predictors for successful treatment and survival

There are no established prognostic factors or standardized therapies for hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT). The aim of this study was to investigate impact of underlying patient condition on treatment and outcomes of recurrence of HCC after LT. The medical records of 268 LT patients with HCC were evaluated. Potential prognostic factors for survival after recurrence were evaluated, including recurrent tumor characteristics, medical/radiological/surgical therapies for recurrence, and an inflammatory marker (neutrophil/lymphocyte ratio). Laboratory tests at recurrence, including albumin, absolute lymphocyte count (ALC), prognostic nutritional index (PNI: ALC(/μL) × 0.005 + Albumin(g/dL) × 10), were evaluated as surrogate markers for underlying patient conditions. A total of 51 (19%) patients developed HCC recurrence. The use of sirolimus and sorafenib significantly improved outcome (p = 0.007 and 0.04), and better nutritional status (PNI ≥ 40) enhanced their efficacy. On multivariate analysis, low ALC (<500/μL) and albumin (<2.8 g/L) remained independent prognostic factors (p = 0.03 and 0.02; hazard ratio = 3.61 [Ref. >1000/μL] and 4.97 [Ref. >3.5 g/dL], respectively). Low PNI (<40) showed significantly lower survival rate after adjusting the risk (p = 0.006, hazard ratio = 3.29). Underlying patient conditions and nutritional status, represented by ALC and albumin, are important to successful cancer treatment and strong prognostic markers for survival after HCC recurrence.