Heart-liver-kidney transplantation for AL amyloidosis using normothermic recovery and storage from a donor following circulatory death: Short-term outcome in a first-in-world experience.

AL amyloidosis is a rare condition characterized by the overproduction of an unstable free light chain, protein misfolding and aggregation, and extracellular deposition that can progress to multiorgan involvement and failure. To our knowledge, this is the first worldwide report to describe triple organ transplantation for AL amyloidosis and triple organ transplantation using thoracoabdominal normothermic regional perfusion recovery with a donation from a circulatory death (DCD) donor. The recipient was a 40-year-old man with multiorgan AL amyloidosis with a terminal prognosis without multiorgan transplantation. An appropriate DCD donor was selected for sequential heart, liver, and kidney transplants via our center's thoracoabdominal normothermic regional perfusion pathway. The liver was additionally placed on an ex vivo normothermic machine perfusion, and the kidney was maintained on hypothermic machine perfusion while awaiting implantation. The heart transplant was completed first (cold ischemic time [CIT]: 131 minutes), followed by the liver transplant (CIT: 87 minutes, normothermic machine perfusion: 301 minutes). Kidney transplantation was performed the following day (CIT: 1833 minutes). He is 8 months posttransplant without evidence of heart, liver, or kidney graft dysfunction or rejection. This case highlights the feasibility of normothermic recovery and storage modalities for DCD donors, which can expand transplant opportunities for allografts previously not considered for multiorgan transplantations.

Outcomes of patients with acute liver failure listed for liver transplantation: A multicenter prospective cohort analysis.

Liver transplantation (LT) is a life-saving treatment for patients with acute liver failure (ALF). Currently, there are few detailed data regarding long-term outcomes after LT for ALF. We combined prospective data from the Acute Liver Failure Study Group (ALFSG) Registry with those of the Scientific Registry of Transplant Recipients (SRTR) to assess outcomes among consecutive patients with ALF listed for LT. Cohort analysis of detailed pretransplantation data for patients listed for LT for ALF in the ALFSG Registry between January 1998 and October 2018 matched with transplantation-related data from the SRTR. Primary outcomes were 1- and 3-year post-LT patient survival. Secondary outcome was receipt of LT; independent associations with successful receipt of LT were determined using multivariable logistic regression. Of 624 patients with ALF listed for LT, 398 (64%) underwent LT, 100 (16%) died without LT, and 126 (20%) recovered spontaneously. Among LT recipients, etiologies included seronegative/indeterminate (22%), drug-induced liver injury (18%), acetaminophen overdose (APAP; 16%), and viral hepatitis (15%). The 1- and 3-year post-LT patient survival rates were 91% and 90%, respectively. Comparing those dying on the waiting list versus with those who received LT, the former had more severe multiorgan failure, reflected by increased vasopressor use (65% vs. 22%), mechanical ventilation (84% vs. 57%), and renal replacement therapy (57% vs. 30%; p < 0.0001 for all). After adjusting for relevant covariates, age (adjusted odds ratio [aOR] 1.02, 95% confidence interval [CI] 1.00-1.04), APAP etiology (aOR 2.72, 95% CI 1.42-5.23), requirement for vasopressors (aOR 4.19, 95% CI 2.44-7.20), Grade III/IV hepatic encephalopathy (aOR 2.47, 95% CI 1.29-4.72), and Model for End-Stage Liver Disease (MELD) scores (aOR 1.05, 95% CI 1.02-1.09; p < 0.05 for all) were independently associated with death without receipt of LT. Post-LT outcomes for ALF are excellent in this cohort of very ill patients. The development of multiorgan failure while on the transplantation list and APAP ALF etiology were associated with a lower likelihood of successful receipt of LT.

Rescue liver re-transplantation after graft loss due to severe rejection in the setting of pre-transplant nivolumab therapy.

Immune checkpoint inhibitors (ICI) have been used to treat hepatocellular carcinoma (HCC) since 2017. The safety of ICIs in the setting of solid organ transplantation remains controversial. When used in the post-transplant setting, ICIs have been associated with high allograft rejection rates, but there are few published reports on the use of ICIs prior to transplant. We present the first reported case of rescue liver re-transplantation after loss of the first allograft due to severe acute rejection with extensive hepatic necrosis in the setting of pre-transplant ICI therapy with the PD-1 inhibitor nivolumab. It is likely that the durable immune response triggered by nivolumab contributes to graft rejection, therefore extreme caution should be taken when using ICIs before transplant until further investigation has been conducted on their safety in the pre-transplant setting.

Impact of diabetes and chronic dialysis on post-transplant survival in combined heart-kidney transplant recipients.

Growing research supports an increased survival benefit of combined heart and kidney transplantation in patients with both heart and renal failure. As a result, the frequency of these combined transplants continues to increase. Despite this trend, little has been done to quantify the impact of chronic illness in this population. We identified adult recipients of combined heart-kidney transplant from the Scientific Registry of Transplant Recipients (SRTR) database between 2005 and 2018. We focused on renal disease secondary to diabetes and duration of dialysis as markers of chronic illness. The primary outcome was post-transplant mortality. Our final multivariable Cox proportional hazard model found that diabetes-associated renal disease (HR 1.57, 95% CI 1.14-2.15, p = .01) and dialysis duration (HR 1.08, 95% CI 1.01-1.15, p = .02) were significant predictors of post-transplant mortality. Given the significant impact of dialysis duration and renal disease secondary to diabetes mellitus, these chronically ill patients should be closely examined for conditions such as peripheral vascular disease and frailty, which have been shown to affect mortality in heart transplant recipients and are prevalent in the chronic dialysis population.

Understanding the Impact of Pneumonia and Other Complications in Elderly Liver Transplant Recipients: An Analysis of NSQIP Transplant.

Despite an increasing demand for liver transplantation in older patients, our understanding of posttransplant outcomes in older recipients is limited to basic recipient and graft survival. Using National Surgical Quality Improvement Program Transplant, we tracked early outcomes after liver transplantation for patients >65. METHODS: We conducted a retrospective analysis of patients in National Surgical Quality Improvement Program Transplant between March 1, 2017 and March 31, 2019. Recipients were followed for 1 y after transplant with follow-up at 30, 90, and 365 d. Data were prospectively gathered using standard definitions across all sites. RESULTS: One thousand seven hundred thirty-one adult liver transplants were enrolled; 387 (22.4%) were >65 y old. The majority of older recipients were transplanted for hepatocellular carcinoma. The older cohort had a lower lab Model for End-Stage Liver Disease and was less likely to be hospitalized at time of transplant. Overall, older recipients had higher rates of pneumonia but no difference in intensive care unit length of stay (LOS), total LOS, surgical site infection, or 30-d readmission. Subgroup analysis of patients with poor functional status revealed a significant difference in intensive care unit and total LOS. Pneumonia was even more common in older patients and had a significant impact on overall survival. CONCLUSIONS: By targeting patients with hepatocellular carcinoma and lower Model for End-Stage Liver Diseases, transplant centers can achieve nearly equivalent outcomes in older recipients. However, older recipients with poor functional status require greater resources and are more likely to develop pneumonia. Pneumonia was strongly associated with posttransplant survival and represents an opportunity for improvement. By truly understanding the outcomes of elderly and frail recipients, transplant centers can improve outcomes for these higher-risk recipients.

Understanding the Final Disposition of Livers Declined After the Start of Procurement: A Nationwide Organ Procurement Organization Effort.

Declining a liver offer during organ procurement likely increases the risk of discard, but the specifics around late reallocation remain obscure. This voluntarily submitted, prospectively collected data describe late declines and the ultimate disposition of 893 livers. Once a liver suffered an intraoperative decline, only 49% of recovered livers were transplanted. Livers declined ≥80 minutes prior to cross-clamp were transplanted 80% of the time versus livers declined ≥80 minutes after cross-clamp, which were transplanted 45% of the time. The final disposition of these livers was into a predetermined backup patient (51%) or required an out-of-sequence expedited allocation (42%). Prerecovery imaging and prerecovery biopsy did not influence the ability to reallocate a liver, and livers from donors after circulatory death are rarely successfully reallocated. In conclusion, this study begins to shed light on this seemingly common practice. A total of 85% of centers had an intraoperative decline, but 4% of centers accounted for 25% of the declines. Organ procurement organizations often enter expedited liver allocation, and instituting a cross-clamp delay to allow for reallocation may influence the disposition of these liver grafts. Expedited allocation was more time consuming than allocation into a predetermined backup. Although a certain number of intraoperative declines probably suggests a healthy amount of donor selection aggressiveness at the time of the initial organ offer, the 47% risk of discard of livers declined intraoperatively suggests that United Network for Organ Sharing should consider systematically collecting data about intraoperative declines so we can learn more about this event that influences organ utilization.

Comparison of Clinical Outcomes of Induction Regimens in Patients Undergoing Liver Transplantation for Acute Liver Failure.

Spontaneous survival rates in acute liver failure (ALF) are vastly improved by liver transplantation (LT). However, the value of induction agents beyond steroids continues to be debated. To understand the potential benefit of different induction regimens in the ALF population, we compared overall survival of recipients undergoing LT in the United States for ALF. Using the Scientific Registry of Transplant Recipients, we assessed the impact of induction immunosuppression (IS) in a cohort of 3754 first-time LT recipients with a diagnosis of ALF from 2002 to 2018. Induction IS therapy was grouped into steroid-only induction, use of antithymocyte globulin (ATG), or interleukin 2 receptor antibody. Other regimens were excluded from analysis. Survival analysis was estimated via Cox proportional hazards models and expressed as hazard ratios (HRs). In LT for ALF, the use of induction agents beyond steroids is increasingly frequent over the last 2 decades. The use of ATG is associated with worse overall survival, even after adjusting for donor and recipient factors, with HR of 1.24 (95% confidence interval, 1.00-1.53; P = 0.05). An elevated serum creatinine, recipient and donor age, and Black ethnicity, were all associated with reduced survival, whereas maintenance IS with calcineurin inhibitors (CNIs) was associated with improved survival. Although adjunct induction therapy has become more common, our analysis shows that compared with a steroid-only induction regimen, the addition of ATG is associated with worse overall survival after LT for ALF. CNI maintenance was highly protective, suggesting that an IS strategy focusing on corticosteroid-only induction followed by CNI maintenance may offer the best overall survival rate.

Somatic Mutations Increase Hepatic Clonal Fitness and Regeneration in Chronic Liver Disease.

Normal tissues accumulate genetic changes with age, but it is unknown if somatic mutations promote clonal expansion of non-malignant cells in the setting of chronic degenerative diseases. Exome sequencing of diseased liver samples from 82 patients revealed a complex mutational landscape in cirrhosis. Additional ultra-deep sequencing identified recurrent mutations in PKD1, PPARGC1B, KMT2D, and ARID1A. The number and size of mutant clones increased as a function of fibrosis stage and tissue damage. To interrogate the functional impact of mutated genes, a pooled in vivo CRISPR screening approach was established. In agreement with sequencing results, examination of 147 genes again revealed that loss of Pkd1, Kmt2d, and Arid1a promoted clonal expansion. Conditional heterozygous deletion of these genes in mice was also hepatoprotective in injury assays. Pre-malignant somatic alterations are often viewed through the lens of cancer, but we show that mutations can promote regeneration, likely independent of carcinogenesis.

Beyond death and graft survival-Variation in outcomes after kidney transplantation. Results from the NSQIP Transplant beta phase.

The National Surgical Quality Program (NSQIP) Transplant was designed by transplant surgeons from the ground up to track posttransplant outcomes beyond basic recipient and graft survival. After an initial pilot phase, the program has expanded to 29 participating sites and enrolled more than 4300 recipient-donor pairs into the database, including 2876 complete kidney transplant cases. In this analysis, surgical site infection (SSI), urinary tract infection (UTI), and reoperation/intervention were evaluated for kidney transplant recipients. We observed impressive variation in the crude incidence between sites for SSI (0%-17%), UTI (0%-14%), and reoperation/intervention (0%-25%). After adjustment for donor and recipient factors, 2 sites were outliers with respect to their incidence of UTI. For the first time, the field of transplantation has data that demonstrate variation in kidney recipient surgical outcomes between sites. More importantly, NSQIP Transplant provides a powerful platform to improve care beyond basic patient and graft survival.

Two-stage liver transplant for ruptured hepatic adenoma: A case report.

BACKGROUND: Only one case of liver transplantation for hepatic adenoma has previously been reported for patients with rupture and uncontrolled hemorrhage. We present the case of a massive ruptured hepatic adenoma with persistent hemorrhagic shock and toxic liver syndrome which resulted in a two-stage liver transplantation. This is the first case of a two-stage liver transplantation performed for a ruptured hepatic adenoma. CASE SUMMARY: A 23 years old African American female with a history of pre-diabetes and oral contraceptive presented to an outside facility complaining of right-sided chest pain and emesis for one day. She was found to be in hemorrhagic shock due to a massive ruptured hepatic hepatic adenoma. She underwent repeated embolizations with interventional radiology with ongoing hemorrhage and the development of renal failure, hepatic failure, and hemodynamic instability, known as toxic liver syndrome. In the setting of uncontrolled hemorrhage and toxic liver syndrome, a hepatectomy with porto-caval anastomosis was performed with liver transplantation 15 h later. She tolerated the anhepatic stage well, and has done well over one year later. CONCLUSION: When toxic liver syndrome is recognized, liver transplantation with or without hepatectomy should be considered before the patient becomes unstable.

Beyond death and graft survival-Variation in outcomes after liver transplant. Results from the NSQIP transplant beta phase.

The National Surgical Quality Program (NSQIP) Transplant program was designed by transplant surgeons from the ground up to track posttransplant outcomes beyond basic recipient and graft survival. After an initial pilot phase, the program has expanded to 29 participating sites and enrolled more than 4300 recipient-donor pairs into the database, including 1444 completed liver transplant cases. In this analysis, surgical site infection (SSI), urinary tract infection (UTI), and unplanned reoperation/intervention after liver transplantation were evaluated. We observed impressive variation in the crude incidence between sites for SSI (0%-29%), UTI (0%-10%), and reoperation/intervention (0%-57%). After adjustment for donor and recipient factors, at least 1 site was identified as an outlier for each of the analyzed outcomes. For the first time, the field of transplantation has data that demonstrate variation in liver recipient outcomes beyond death and graft survival between sites. More importantly, NSQIP Transplant provides a powerful platform to improve care beyond basic patient and graft survival.

Should more donation after cardiac death livers be used in pediatric transplantation?

INTRODUCTION: There is a mismatch that exists in donor liver organ supply and demand. DCD livers represents a potential source to increase the number of liver grafts available for use in pediatric recipients; however, there has been hesitancy to use such organs. We evaluated patient and allograft outcomes in pediatric liver transplant recipients of DCD livers. METHODS: The UNOS database was queried to examine outcomes in all liver transplant recipients from 1993 to 2017. Patients were then divided according to adult and pediatric status, DBD or DCD allograft status, and era of transplant. Donor and recipient demographic data were examined, and patient and allograft survival were calculated. A P-value of <0.05 was considered to be significant. RESULTS: A total of 57 pediatric recipients received a DCD liver allograft. DCD recipients were older than DBD recipients. There was no difference in the final PELD score between the groups. There were no differences in causes of allograft failure between the DCD and DBD groups. Importantly, the overall allograft survival in the DCD and DBD groups was similar, as was allograft survival based on era. CONCLUSION: Pediatric liver transplant recipients of DCD allografts have comparable patient and allograft survival when compared to DBD allograft recipients. Use of DCD allografts in the pediatric liver transplant population should be strongly considered to increase the donor organ pool.

Acute Rejection Rates and Graft Outcomes According to Induction Regimen among Recipients of Kidneys from Deceased Donors Treated with Tacrolimus and Mycophenolate.

BACKGROUND AND OBJECTIVES: IL-2 receptor antagonist (IL2-RA) is recommended as a first-line agent for induction therapy in renal transplantation. However, this remains controversial in deceased donor renal transplantation (DDRT) maintained on tacrolimus (TAC)/mycophenolic acid (MPA) with or without steroids. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We studied the United Network for Organ Sharing Registry for patients receiving DDRT from 2000 to 2012 maintained on TAC/MPA at transplantation hospital discharge (n=74,627) to compare outcomes of IL2-RA and other induction agents. We initially divided the cohort into two groups on the basis of steroid use at the time of discharge: steroid (n=59,010) versus no steroid (n=15,617). Each group was stratified into induction categories: IL2-RA, rabbit antithymocyte globulin (r-ATG), alemtuzumab, and no induction. The main outcomes were incidence of acute rejection within the first year and overall graft failure (defined as graft failure and/or death) post-transplantation. Propensity score (PS), specifically inverse probability of treatment weight, analysis was used to minimize selection bias caused by nonrandom assignment of induction therapies. RESULTS: Median (25th, 75th percentiles) follow-up times were 3.9 (1.1, 5.9) and 3.2 (1.1, 4.9) years for steroid and no steroid groups, respectively. Acute rejection within the first year and overall graft failure within 5 years of transplantation were more common in the no induction category (13.3%; P<0.001 and 28%; P=0.01, respectively) in the steroid group and the IL2-RA category (11.1%; P=0.16 and 27.4%; P<0.001, respectively) in the no steroid group. Compared with IL2-RA, PS-weighted and covariate-adjusted multivariable logistic and Cox analyses showed that outcomes in the steroid group were similar among induction categories, except that acute rejection was significantly lower with r-ATG (odds ratio [OR], 0.68; 95% confidence interval [95% CI], 0.62 to 0.74). In the no steroid group, compared with IL2-RA, odds of acute rejection with r-ATG (OR, 0.80; 95% CI, 0.60 to 1.00) and alemtuzumab (OR, 0.68; 95% CI, 0.53 to 0.88) were lower, and r-ATG was associated with better graft survival (hazard ratio, 0.86; 95% CI, 0.75 to 0.99). CONCLUSIONS: In DDRT, compared with IL2-RA induction, no induction was associated with similar outcomes when TAC/MPA/steroids were used. r-ATG seems to offer better graft survival over IL2-RA in steroid avoidance protocols.

A Pilot Study Evaluating Serum MMP7 as a Preoperative Prognostic Marker for Pancreatic Ductal Adenocarcinoma Patients.

BACKGROUND: Current preoperative risk stratification modalities for pancreatic ductal adenocarcinoma (PDA) patients are inadequate. Elevated serum matrix metalloproteinase 7 (MMP7) is associated with metastatic PDA. We evaluated preoperative MMP7 level as a prognostic marker in patients with resectable PDA. METHODS: From a prospectively maintained database, we identified PDA patients who underwent operation with curative intent from 2004 to 2008 and had serum collected preoperatively. MMP7 was measured by enzyme-linked immunosorbent assay. Patients were defined as having advanced disease if they were found to be unresectable at the time of operation or had nodal involvement on final pathology. RESULTS: Preoperative serum samples were available for 134 patients. Using a cutoff of 13.5 ng/mL, MMP7 was highly predictive for advanced disease. For patients who underwent R0 resection, MMP7 > 13.5 ng/mL was strongly associated with N1 status, T3/T4 stage, moderate/poor differentiation, and perineural invasion. The median recurrence-free survival was 5.0 months in patients with MMP7 > 13.5 ng/mL versus 9.9 months for patients with lower values (P = 0.004). CONCLUSIONS: Very elevated serum MMP7 was highly predictive of unresectable disease and nodal involvement despite favorable preoperative cross-sectional imaging. MMP7 should be further evaluated as a biomarker to risk-stratify PDA patients prior to operation.

Islet transplantation for Type 1 diabetes: where are we now?

Pancreatic islet transplantation is a minimally invasive procedure that can restore normoglycemia and insulin independence in Type 1 diabetics without the surgical complications associated with vascularized pancreas transplantation. The advances made in this field over the past decade have dramatically improved patient outcomes, and the procedure is now transitioning from an experimental treatment to a clinical reality. Nonetheless, a number of important issues continue to hamper the success of islet transplantation and must be addressed before there is widespread clinical acceptance. These include the relative inefficiency of the islet isolation process, the progressive loss of islet function over time and the need for multiple donors to achieve insulin independence. Here, we discuss the current status of islet transplantation and examine its future as a treatment for Type 1 diabetes.

Left hepatectomy versus right hepatectomy for living donor liver transplantation: shifting the risk from the donor to the recipient.

Living donor liver transplantation (LDLT), originally used in children with left lateral segment grafts, has been expanded to adults who require larger grafts to support liver function. Most adult LDLT procedures have been performed with right lobe grafts, and this means a significant risk of morbidity for the donors. To minimize the donor risk for adults, there is renewed interest in smaller left lobe grafts. The smaller graft size increases the recipient risk in the form of small-for-size syndrome (SFSS) and essentially transfers the risk from the donor to the recipient. We review the donor and recipient risks of LDLT and pay particular attention to the different types of liver grafts and the use of graft inflow modification to ameliorate the risk of SFSS. Finally, a new metric is proposed for quantifying the recipient benefit in exchange for a specific donor risk.

Lymph node sampling rates and predictors of nodal metastasis in pancreatic neuroendocrine tumor resections: the UCSF experience with 149 patients.

OBJECTIVES: The decision to perform pancreas-preserving procedures or standard resections for pancreatic neuroendocrine tumors (PNETs) is often based on the perceived risk of malignancy, including potential nodal involvement. We sought to identify clinicopathological factors that predict nodal disease. METHODS: This is a retrospective review of pathology database for PNET resections from January 1, 1988, to March 15, 2010. Univariate analysis and multivariate logistic regression were used to identify predictors of nodal metastasis. RESULTS: A total of 149 patients were identified. Enucleations had lower lymph node sampling rates compared to major resections. Excluding enucleations, 23% of patients had no lymph nodes sampled. For patients who did have lymph nodes evaluated, a median of 5 lymph nodes were examined. On multivariate analysis, only distant disease predicted nodal metastasis (odds ratio = 3.80, P = 0.02); tumor size did not (P = 0.48). One third of patients with lymph node metastasis had tumors less than 3 cm. CONCLUSIONS: Lymph nodes are not evaluated in many major pancreatic resections for PNET, and preoperative prediction of nodal metastasis is difficult, even when tumor size is considered. Consequently, many patients may be understaged and undergo potentially inadequate resection. Inconsistent lymph node sampling may explain conflicting conclusions in the literature regarding the prognostic value of lymph node involvement in PNET patients.

Identification of unknown primary tumors in patients with neuroendocrine liver metastases.

BACKGROUND: For patients with neuroendocrine tumor (NET) liver metastases, resection of the primary tumor may prevent local complications (obstruction, ischemia, and bleeding) and improve survival. Despite preoperative evaluation, the primary tumor location may remain unknown. DESIGN: Retrospective cohort analysis of pathology database from January 1, 1993, to August 15, 2008. SETTING: Academic medical center. PATIENTS: One hundred twenty-three patients with NET liver metastases. MAIN OUTCOME MEASURES: Successful identification and resection of the primary tumor. RESULTS: Fifteen patients underwent surgical exploration. The primary tumor was located in 13 patients (86.7%) in the small intestine and resected in 12 patients. Primary tumors in the small intestine found during surgical exploration were significantly smaller than those identified preoperatively (1.38 vs 1.91 cm, P = .03) and were often multifocal (54.2% [n = 15]). Computed tomography (34.6% [n = 78]) and somatostatin receptor scintigraphy (26.2% [n = 42]) were not sensitive in locating a primary NET in the gastrointestinal tract. Colonoscopy was sensitive in detecting colonic NETs (86.7% [n = 15]). CONCLUSION: For patients with NET liver metastases and unknown primary tumor, surgical exploration effectively identifies and resects occult primary tumors that are often located in the small intestine. Primary tumors are usually small and multifocal, so careful palpation of the small intestine is essential. Before patients are considered for surgery, a multidisciplinary team assessment and evaluation consisting of computed tomography, somatostatin receptor scintigraphy, and upper and lower endoscopy should be done.