Chandrashekhar A. Kubal

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.

Prospective monitoring of donor-specific anti-HLA antibodies after intestine/multivisceral transplantation: Significance of De novo antibodies

Background Presence of circulating donor-specific antibodies (DSA) may be associated with worse clinical outcomes after intestine/multivisceral transplantation. Methods In 79 intestine/multivisceral recipients, sera were prospectively screened for DSA by Luminex Single antigen test at 1, 3, 6, 9, 12, 18, 24, and 36 months after transplantation. Standard immunosuppression included thymoglobulin-rituximab induction and tacrolimus-prednisone maintenance. C4d staining was performed retrospectively on biopsies in patients that developed acute rejection (AR). Results Twenty-two (28%) patients developed de novo DSA at a median posttransplant period of 3 (1-36) months. De novo DSA were observed in 10 of 40 liver-including and 12 of 39 liver-excluding transplants (P = 0.57). Occurrence of AR was slightly higher in patients with de novo DSA (45% vs 33%, respectively; P = 0.41). Similarly, chronic rejection (14% vs 5%; P = 0.21) and graft loss due to AR (18% vs 7%; P = 0.14) were numerically higher in patients with de novo DSA. Only 35% patients experiencing AR had circulating de novo DSA at the time of AR. Antibody-mediated rejection was diagnosed in 6 patients based on C4d staining, of these 2 patients had circulating de novo DSA at the time of biopsy. Conclusions De novo DSA formation, particularly early in the posttransplant course may be associated with trends toward worse outcomes. However, its significance in the pathophysiology of AR remains uncertain. Studies focusing mechanisms of DSA-related graft injury and intragraft DSA detection might provide further insight into this issue.

Impact of Positive Flow Cytometry Crossmatch on Outcomes of Intestinal/Multivisceral Transplantation: Role Anti-IL-2 Receptor Antibody

Background Positive crossmatch may be associated with an increased risk of acute rejection (AR) and worse overall outcomes after intestinal/multivisceral (MV) transplantation. However, the evidence from published studies in this setting is sparse and contradictory. This study reports the impact of positive flow cytometry crossmatch on clinical outcomes after intestinal/MV transplantation and the use of anti–interleukin (IL)-2 receptor antibody as a maintenance immunosuppressant. Methods Records of all intestinal/MV transplants from 2003 to 2010 were reviewed. Flow cytometry was used to evaluate T- and B-cell crossmatch status. Standard immunosuppression included rabbit anti-thymocyte globulin–rituximab induction with tacrolimus and steroid maintenance. From 2008 onwards (second era), monthly anti-IL-2 receptor antibody was added to the maintenance immunosuppression in patients receiving liver-excluding transplants. Results Of 131 intestinal/MV transplants, 27 (21%) had a positive crossmatch. Positive crossmatch was not associated with an increased incidence of AR and graft loss (30% and 37% vs. 29% and 47%; P=0.94 and 0.35, respectively). This effect was maintained in liver-excluding transplants. Overall rate of AR decreased from 39% to 22% in the second era. In liver-excluding transplants, there was a significant decrease in AR from 75% to 44% with the use of anti-IL-2 receptor antibody therapy. Conclusions With rabbit anti-thymocyte globulin–rituximab induction, positive crossmatch status is not associated with worse outcomes after intestinal/MV transplantation. Use of anti-IL-2 receptor antibody as a part of maintenance immunosuppression may be beneficial in liver-excluding transplants.

Crossmatch-positive liver transplantation in patients receiving thymoglobulin-rituximab induction.

Background Positive crossmatch (CM) in liver transplantation (LT) is associated with worse outcomes. Role of induction immunosuppression in this setting remains to be studied. Methods One thousand consecutive LT patients receiving rabbit antithymocyte globulin±rituximab induction were studied. Pretransplantation sera of 55 CM-positive (CM+) patients were tested for C1q-fixing donor-specific antibodies (DSA). Diagnosis of antibody-mediated rejection required presence of diffuse vascular C4d expression on liver biopsies. Results CM was positive in 112 (11%) recipients. Antibody-mediated rejection was observed in 3 (0.03%) patients, whereas acute cellular rejection (ACR) occurred in 31 (3%) patients. CM+ status was associated with a higher incidence of ACR (9% in CM+ vs. 2% in CM-negative [CM−]; P<0.01) and chronic rejection (4% in CM+ vs. 1% in CM−; P<0.01). Graft survival was slightly lower in CM+ patients (at 1 year; 85% in CM+ vs. 89% in CM−; P=0.26). Patients with autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis as a group had a tendency toward CM+ status as well as developing ACR. Upon multivariate analysis, CM status was the strongest predictor of ACR (B=1.14; P=0.02). Only half of CM+ patients harbored C1q-fixing DSA. Presence of C1q-fixing DSA was not associated with increased incidence of ACR. Conclusions In LT, CM+ status is associated with an increased incidence of acute rejection, chronic rejection, and slightly worse graft survival. With the use of rabbit antithymocyte globulin±rituximab induction, overall low rejection rates can be achieved in CM+ LT.

Optimization of Perioperative Conditions to Prevent Ischemic Cholangiopathy in Donation After Circulatory Death Donor Liver Transplantation

Background Donation after circulatory death (DCD) donor pool remains underutilized for liver transplantation (LT). We describe optimizing “modifiable risk factors,” such as cold ischemia time (CIT) recipient warm ischemia time (WIT) and the use of thrombolytic flush at the time of procurement to minimize ischemic cholangiopathy (IC). Methods From July 2011 (era II), to improve outcomes after DCD LT, measures were taken to minimize CIT, operative time and recipient WIT along with the use of tissue plasminogen activator (tPA) flush during DCD procurements. Thirty consecutive DCD LTs were performed prospectively in era II. Outcomes were compared with 61 historic controls (era I). Reperfusion biopsies were evaluated for the presence of necrosis and biliary epithelial damage. Results Median CIT (4.9 [3.5-5.9] vs 6.4 [4.3-12]; P < 0.001), hepatectomy time (70 [42-120] vs 81 [58-207]; P = 0.02), and recipient WIT (16 [13-31] vs 24[15-40]; P < 0.001) were significantly shorter in era II. All patients in era II received tPA flushed liver grafts. None of the patients in era II developed IC (0% vs 18%; P = 0.013). There were fewer biliary complications in era II, and there was no increased risk of bleeding associated with the use of tPA. One-year graft survival was slightly better in era II (n = 24 patients with 1 year follow-up) (88% vs 80%; P = 0.14). Conclusions Optimizing peritransplant conditions, such as shortening ischemic times with the use of thrombolytic donor flush, may prevent IC after DCD LT. With this approach, the DCD donor pool may be expanded.

Retrieval of the pancreas allograft for whole-organ transplantation.

Proper pancreas retrieval during multi‐organ recovery is one of the cornerstones of technically successful whole‐organ pancreas transplantation. With evolving surgical approaches for organ retrieval and implantation, it has become standard to procure the pancreas in conjunction with other abdominal organs without compromising either vasculature, graft quality, or transplant outcomes. This review summarizes the major steps required for proper whole‐organ retrieval of the pancreas allograft with suggestions and tips whenever alternative approaches are available.

Worse Long-term Patient Survival and Higher Cancer Rates in Liver Transplant Recipients With a History of Smoking.

Background This study is a retrospective review of liver transplant (LT) recipients to determine the impact of tobacco exposure on 10-year survival and de novo cancer (CA) incidence. Methods The records of 1275 consecutive LT patients were reviewed (2001 to 2011). Patients were categorized as current, previous, or never smokers (NS) at listing for LT. Additionally, smokers were stratified by pack-years of tobacco exposure. Events included patient death, cardiovascular events, and de novo cancers. Cox regression analysis was used to evaluate survival. A complete cause of death analysis is provided, as well as a detailed tumor registry. Results Current (n = 279) and previous smokers (n = 323) were more likely to have hepatocellular carcinoma (HCC) at transplant (25%, 29% vs 18% [NS], P < 0.001), and these 2 groups had higher HCC recurrence rates (21%, 14% vs 11% [NS], P = 0.18). De novo non-HCC CA was higher for current and previous smokers, compared to NS (18%, 16% vs 12% [NS], P = 0.05). Among those with de novo CA (n = 180), the 2 smoking groups were more likely to have non-skin CA (60%, 54% vs 27% [NS], P < 0.001). Patient survival at 10 years was worse for current smokers than the other study groups (55% vs 70%, P < 0.01). These results were largely mirrored with increased tobacco exposure. Conclusions The LT outcomes are uniformly worse for patients with a history of smoking, and the risk of negative events increases with increasing tobacco use. Smokers have higher rates of HCC and recurrence, de novo cancer, and worse long-term survival. Summary statement This study summarizes the clinical outcomes for 1275 LT patients over 10 years, analyzing the impact of pre transplant recipient tobacco use. There are 47% of patients with a history of smoking. Because of demonstrated higher cancer rates and decreased survival, patients with a significant smoking history should be carefully scrutinized for liver transplantation.

Intestine and Multivisceral Transplantation: Current Status and Future Directions

Intestinal failure and associated parenteral nutrition-induced liver failure cause significant morbidity, mortality, and health care burden. Intestine transplantation is now considered to be the standard of care in patients with intestinal failure who fail intestinal rehabilitation. Intestinal failure-associated liver disease is an important sequela of intestinal failure, caused by parenteral lipids, requiring simultaneous liver-intestine transplant. Lipid minimization and, in recent years, the emergence of fish oil-based lipid emulsions have been shown to reverse parenteral nutrition-associated hyperbilirubinemia, but not fibrosis. Significant progress in surgical techniques and immunosuppression has led to improved outcomes after intestine transplantation. Intestine in varying combination with liver, stomach, and pancreas, also referred to as multivisceral transplantation, is performed for patients with intestinal failure along with liver disease, surgical abdominal catastrophes, neuroendocrine and slow-growing tumors, and complete portomesenteric thrombosis with cirrhosis of the liver. Although acute and chronic rejection are major problems, long-term survivors have excellent quality of life and remain free of parenteral nutrition.

Elevated alanine aminotransferase (ALT) in the deceased donor: impact on early post‐transplant liver allograft function

Serum alanine aminotransferase (ALT) levels are frequently elevated with liver injury and such elevations are common in deceased organ donors. The impact of this injury on early liver allograft function has not been well described. This study analyses the immediate function and 1‐year graft and patient survival for liver allografts stratified by peak serum ALT levels in the deceased donor.

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.