Blood Management in a Liver Transplant Recipient with Kidd (Jka) and Rhesus (D) Antibodies: A Case Report.

A 67-year-old man presented for urgent liver transplantation (LT). Screening revealed the rare combination of antiRhesus (D) and antiKidd Jk(a) antibodies, requiring antigen-negative red blood cells (RBC) for both phenotypes. This combination has not been reported during LT. Compatible RBCs were initially limited, requiring continued communication between the blood bank/blood supplier to obtain more, including frozen, units. Additional strategies included the use of cell salvage and intentional management of coagulopathy to limit bleeding and RBC requirement. This case highlights blood management during LT when D and Jk(a) antibodies may limit RBC supply and emphasizes the need for effective communication with the blood bank.

Seroprevalence of Measles, Mumps, Rubella, and Varicella-Zoster Virus and Seroresponse to the Vaccinations in Adult Solid Organ Transplant Candidates.

BACKGROUND: Updating live vaccines such as measles, mumps, rubella, and varicella (MMRV) is an important step in preparing patients for solid organ transplant (SOT) to prevent morbidity from these preventable diseases. However, data for this approach are scarce. Thus, we aimed to describe the seroprevalence of MMRV and the efficacy of the vaccines in our transplant center. METHODS: Pre-SOT candidates >18 y of age were retrospectively retrieved from SOT database in Memorial Hermann Hospital Texas Medical Center. MMRV serologies are routinely screened at the time of pretransplant evaluation. We divided patients into 2 groups: MMRV-positive group versus MMRV-negative group, patients with positive all MMRV serologies and with negative immunity to at least 1 dose of MMRV, respectively. RESULTS: A total of 1213 patients were identified. Three hundred ninety-four patients (32.4%) did not have immunity to at least 1 dose of MMRV. Multivariate analysis was conducted. Older age (odds ratio [OR]: 1.04) and liver transplant candidates (OR: 1.71) were associated with seropositivity. Previous history of SOT (OR: 0.54) and pancreas/kidney transplant candidates (OR: 0.24) were associated with seronegativity. Among 394 MMRV seronegative patients, 60 patients received 1 dose of MMR vaccine and 14 patients received 1 dose of varicella-zoster virus vaccine without severe adverse events. A total of 35% (13/37) of patients who had follow-up serologies did not have a serological response. CONCLUSIONS: A significant number of pre-SOT candidates were not immune to at least 1 dose of MMRV. This highlights the importance of MMRV screening and vaccinations pre-SOT. Postvaccination serological confirmation should be performed to evaluate the necessity for a second dose.

CD73-Dependent Adenosine Signaling through Adora2b Drives Immunosuppression in Ductal Pancreatic Cancer.

The microenvironment that surrounds pancreatic ductal adenocarcinoma (PDAC) is profoundly desmoplastic and immunosuppressive. Understanding triggers of immunosuppression during the process of pancreatic tumorigenesis would aid in establishing targets for effective prevention and therapy. Here, we interrogated differential molecular mechanisms dependent on cell of origin and subtype that promote immunosuppression during PDAC initiation and in established tumors. Transcriptomic analysis of cell-of-origin-dependent epithelial gene signatures revealed that Nt5e/CD73, a cell-surface enzyme required for extracellular adenosine generation, is one of the top 10% of genes overexpressed in murine tumors arising from the ductal pancreatic epithelium as opposed to those rising from acinar cells. These findings were confirmed by IHC and high-performance liquid chromatography. Analysis in human PDAC subtypes indicated that high Nt5e in murine ductal PDAC models overlaps with high NT5E in human PDAC squamous and basal subtypes, considered to have the highest immunosuppression and worst prognosis. Multiplex immunofluorescent analysis showed that activated CD8+ T cells in the PDAC tumor microenvironment express high levels of CD73, indicating an opportunity for immunotherapeutic targeting. Delivery of CD73 small-molecule inhibitors through various delivery routes reduced tumor development and growth in genetically engineered and syngeneic mouse models. In addition, the adenosine receptor Adora2b was a determinant of adenosine-mediated immunosuppression in PDAC. These findings highlight a molecular trigger of the immunosuppressive PDAC microenvironment elevated in the ductal cell of origin, linking biology with subtype classification, critical components for PDAC immunoprevention and personalized approaches for immunotherapeutic intervention. SIGNIFICANCE: Ductal-derived pancreatic tumors have elevated epithelial and CD8+GZM+ T-cell CD73 expression that confers sensitivity to small-molecule inhibition of CD73 or Adora2b to promote CD8+ T-cell-mediated tumor regression. See related commentary by DelGiorno, p. 977.

Refractory thrombocytopenia during liver transplantation requiring splenectomy.

Although thrombocytopenia is common in end-stage liver disease, severe, refractory thrombocytopenia during liver transplantation is rare, and if immune based, usually presents months or years later. This case describes an adult woman in whom preoperative evaluation had not determined an immune-related cause of thrombocytopenia. Clot strength was dramatically impaired as measured by thrombelastography during the transplant. Following a lack of response to repeat platelet transfusions, splenectomy was performed after graft reperfusion with rapid temporal restoration of clot strength. This case shows a severe manifestation of perioperative thrombocytopenia during liver transplantation and clinically guided management when measured clot strength is too low for accurate determination.

Seroprevalence of Strongyloides stercoralis and Evaluation of Universal Screening in Kidney Transplant Candidates: A Single-Center Experience in Houston (2012-2017).

BACKGROUND: Disseminated strongyloidiasis in solid organ transplant recipients is a rare but devastating infection. In our center, we implemented a universal screening of all candidates for kidney transplantation. We assessed the seroprevalence and utility of universal screening for strongyloidiasis in our center. METHODS: Patients were identified from our transplant referral list (from July 2012 to June 2017). Demographics, pretransplant laboratory, and serological screenings were retrospectively collected. For Strongyloides-seropositive (SSp) patients, data on travel history, symptoms, treatment, and stool ova and parasite examinations were extracted. Logistic regression and multiple imputation for missing data were performed. RESULTS: A total of 1689 patients underwent serological screening, of whom 168 (9.9%) were SSp. Univariate analysis revealed that SSp patients had higher rates of eosinophilia, diabetes mellitus, latent tuberculosis and were likely to be either Hispanic or Asian (P < .05). In multivariate analysis, eosinophilia (P = .01), diabetes mellitus (P = .02), and Asian race (P = .03) were associated with being SSp, but 45 (27%) of the SSp patients did not have any of these 3 factors, and 18 SSp patients (11%) had no epidemiological risk factors. All patients received ivermectin, and none developed disseminated strongyloidiasis. Of patients who underwent serological screening on multiple occasions, 6.8% seroconverted while waiting for kidney transplantation. CONCLUSIONS: We found a high rate of Strongyloides seropositivity among our kidney transplantation candidates. No epidemiological risk factors effectively predicted SSp status in our population, and universal screening identified a large number of patients without such factors. Serial screening should be considered when a long wait time is expected before transplantation.

Exploration of the Stanford Integrated Psychosocial Assessment for Transplantation With Psychosocial and Medical Outcomes in Kidney and Kidney-Pancreas Transplant Recipients.

INTRODUCTION: The Stanford Integrated Psychosocial Assessment for Transplantation (SIPAT) is a psychometric instrument designed to assess patient risk for transplant. We investigated the association between SIPAT scores and demographic data with psychosocial and medical outcomes within a diverse kidney/kidney-pancreas transplant population. DESIGN: The SIPAT was administered to all pretransplant candidates. A retrospective review of transplanted patients who had at least 6 months of follow-up was completed. RESULTS: The sample included 136 patients: male (n = 77 [57%]) with a mean age of 47 years old. Thirty-eight percent were black (n = 51), 55% had less than a high school education (n = 74), and 65% had low socioeconomic status (n = 89). Statistical difference was found among SIPAT scores and substance use and support system instability (P = .035, P = .012). Females (P = .012) and patients with a history of psychopathology (P = .002) developed or had a relapse of psychopathology following transplant. Patients with more than a high school education (P = .025) and who were less than 30 years (P = .026) had higher rejection incidence rates. Risk factors for rehospitalizations included Hispanic race, diabetes, and low socioeconomic status (P = .036, P = .038, P = .014). African American/Black and male patients had higher incidence of infection events (P = .032, P = .049). Mortality and treatment nonadherence were not significantly associated with SIPAT scores or demographic variables. CONCLUSION: The SIPAT was associated with posttransplant substance use and support system instability, while demographic variables were associated with the development and/or relapse of psychopathology, graft loss, rejection, infection events, and medical rehospitalizations. Revision of the SIPAT to include additional demographic components may lend to improved prediction of transplant outcomes.

Mutant p53R175H promotes cancer initiation in the pancreas by stabilizing HSP70.

Pancreatic cancer remains a highly lethal malignancy. We have recently shown that simultaneous expression of Kras and mutant Tp53R175H promotes invasive ductal adenocarcinoma from pancreatic ductal cells. We hypothesized specific mutations in TP53 have divergent mechanisms of transforming ductal cells. In order to understand the role of mutant TP53 in transforming pancreatic ductal cells, we used a lentiviral system to express mutant TP53R175H and TP53R273H, two of the most frequently mutated TP53 alleles in pancreatic cancer patients, in immortalized, but not transformed, pancreatic ductal epithelial cells carrying a KRAS mutation (HPNE:KRASG12D). Mutant TP53 expression enhanced colony formation and an RPPA assay results revealed TP53R175H uniquely induced HSP70 expression in HPNE:KRASG12D cells. In the context of TP53R175H expression; we observed nuclear localization of HSP70. We performed immunoprecipitation experiments to show mutant p53R175H binds to HSP70. We also provide evidence mutant p53R175H is important for HSP70 stability and, more importantly, HSP70 is required for mutant p53 stability. These data are critical in the context of events leading to cellular transformation in the pancreas.

Ischaemia reperfusion injury in liver transplantation: Cellular and molecular mechanisms.

Liver disease causing end organ failure is a growing cause of mortality. In most cases, the only therapy is liver transplantation. However, liver transplantation is a complex undertaking and its success is dependent on a number of factors. In particular, liver transplantation is subject to the risks of ischaemia-reperfusion injury (IRI). Liver IRI has significant effects on the function of a liver after transplantation. The cellular and molecular mechanisms governing IRI in liver transplantation are numerous. They involve multiple cells types such as liver sinusoidal endothelial cells, hepatocytes, Kupffer cells, neutrophils and platelets acting via an interconnected network of molecular pathways such as activation of toll-like receptor signalling, alterations in micro-RNA expression, production of ROS, regulation of autophagy and activation of hypoxia-inducible factors. Interestingly, the cellular and molecular events in liver IRI can be correlated with clinical risk factors for IRI in liver transplantation such as donor organ steatosis, ischaemic times, donor age, and donor and recipient coagulopathy. Thus, understanding the relationship of the clinical risk factors for liver IRI to the cellular and molecular mechanisms that govern it is critical to higher levels of success after liver transplantation. This in turn will help in the discovery of therapeutics for IRI in liver transplantation - a process that will lead to improved outcomes for patients suffering from end-stage liver disease.

Special Considerations in Pediatric Kidney Transplantation.

Universally accepted as the treatment of choice for children needing renal replacement therapy, kidney transplantation affords children the opportunity for an improved quality of life over dialysis therapy. Immunologic and surgical advances over the last 15 years have improved the pediatric patient and kidney graft survival. Unique to pediatrics, congenital genitourinary anomalies are the most common primary diseases leading to kidney failure, many with urological issues. Early urological evaluation for post-transplant bladder dysfunction and emphasis on immunization adherence are the mainstays of pediatric pretransplant and post-transplant evaluations. A child's height can be challenging, sometimes requiring an intra-abdominally placed graft, particularly if the patient is <20 kg. Maintenance immunosuppression regimens are similar to adult kidney graft recipients, although distinctive pharmacokinetics may change dosing intervals in children from twice a day to thrice a day. Viral infections and secondary malignancies are problematic for children relative to adults. Current trends to reduce/remove corticosteroid therapy from post-transplant protocols have produced improved linear growth with less steroid toxicity; although these studies are still ongoing, graft function and survival are considered acceptable. Finally, all children with a kidney transplant need a smooth transition to adult clinics. Future research in pertinent psychosocial aspects and continued technological advances will only serve to optimize the transition process. Although some aspects of kidney transplantation are similar in children and adults, for instance immunosuppression and immunosuppressive regimens, and rejection mechanisms and their diagnosis using the Banff criteria, there are important differences this review will focus on and which continue to drive innovation.

Retrograde Flushing of Living Donor Renal Allografts via the Renal Vein: A Simple, Effective Technique.

BACKGROUND: Prograde flushing (PF) of living donor renal allografts with preservation solution via the renal artery or arteries is standard practice. PF may be difficult and potentially injurious to the donor kidney, especially in grafts with small or multiple arteries. In this report, we present our experience with retrograde flushing (RF) of 7 living donor kidneys via the renal vein. METHODS: Retrospective review of 7 consecutive living donor renal transplants performed using the RF technique was performed. The 7 preceding living donor renal transplants performed using the standard arterial PF technique served as a control group. RESULTS: All 7 recipients of RF kidneys experienced immediate graft function. At postoperative days 3 and 30, there was no difference in estimated glomerular filtration rate between the RF study group and PF controls. CONCLUSIONS: The RF technique is simple and safe, with results equivalent to the PF technique. The RF technique may be especially useful after recovering kidneys with small and/or multiple arteries.

Case of hepatocellular carcinoma in a patient with hereditary tyrosinemia in the post-newborn screening era.

Hereditary tyrosinemia type 1 (HT-1) is a metabolic disorder caused by a defect in tyrosine degradation. Without treatment, symptoms of hepatomegaly, renal tubular dysfunction, growth failure, neurologic crises resembling porphyrias, rickets and possible hepatocellular carcinoma can develop. The use of 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione and early diagnosis through newborn screening initiatives have resulted in a sharp decline in morbidity and mortality associated with this disease. We present a case report of a 7-year-old patient with HT-1 who was born prior to the addition of tyrosinemia to the newborn screening in her birth area. At her time of diagnosis, the patient had developed many of the symptoms associated with her disease, including chronic kidney disease, rickets, and myopathy that left her non-ambulatory. During her initial evaluation, she was also noted to have hepatocellular carcinoma. With cadaveric liver transplantation and nutritional support, her symptoms all either resolved or stabilized. Her case illustrates the severity of the disease if left untreated, the need for vigilance in populations who do not routinely receive newborn screens, and the markedly improved outcomes in patients following transplant.

The impact of left ventricular hypertrophy on survival in candidates for liver transplantation.

Left ventricular hypertrophy (LVH) occurs in 12% to 30% of patients with cirrhosis; however, its prognostic significance is not well studied. We assessed the association of LVH with survival in patients undergoing a liver transplantation (LT) evaluation. We performed a multicenter cohort study of patients undergoing an evaluation for LT. LVH was defined with transthoracic echocardiography. The outcome of interest was all-cause mortality. LVH was present in 138 of 485 patients (28%). Patients with LVH were older, more likely to be male and African American, and were more likely to have hypertension. Three hundred forty-five patients did not undergo transplantation (212 declined, and 133 were waiting): 36 of 110 patients with LVH (33%) died, whereas 57 of 235 patients without LVH (24%) died (P = 0.23). After LT, 8 of 28 patients with LVH (29%) died over the course of 3 years, whereas 9 of 112 patients without LVH (8%) died (P = 0.007). This finding was independent of conventional risk factors for LVH, and all deaths for patients with LVH occurred within 9 months of LT. No clinical or demographic characteristics were associated with mortality among LVH patients. In conclusion, the presence of LVH is associated with an early increase in mortality after LT, and this is independent of conventional risk factors for LVH. Further studies are needed to confirm these findings and identify factors associated with mortality after transplantation to improve outcomes.

Hypertrophic obstructive cardiomyopathy in liver transplant patients.

The optimal treatment strategy for patients with symptomatic hypertrophic obstructive cardiomyopathy (HOCM) and end-stage liver disease (ESLD) is not well defined. Although medical management is the accepted first line treatment, patients who are unresponsive to medication require further interventions. Since ESLD patients have a high operative risk for surgical myomectomy, alcohol septal ablation (ASA) emerges as a good alternative in these cases. The timing of ASA in relation to liver transplantation is still unclear. We report here on the first case of an orthotopic liver transplant-recipient undergoing ASA and the second of a cirrhotic patient requiring ASA as a bridge to liver transplantation. Both patients had a good clinical outcome and we argue that ASA in HOCM patients should be driven by symptom onset, and that in the asymptomatic patient it can be safely deferred until after liver transplantation.

Two-dose daclizumab induction therapy in 209 liver transplants: a single-center analysis.

BACKGROUND: Patient and graft survival after liver transplantation are adversely affected by early posttransplant renal dysfunction. Therefore, our immunosuppressive strategies should be as "renal sparing" as possible. This is the largest published series to date using daclizumab induction therapy in a renal-sparing regimen. METHODS: This is a retrospective, nonrandomized study comparing 209 adult liver transplants with daclizumab induction to 115 transplants with no induction. RESULTS: Patient and graft survival were similar, despite higher pretransplant acuity of illness and older age in the induction group. Acute rejection within the first 6 months occurred less commonly in the induction group (25.4% vs. 39.1%, P=0.01), despite significantly delayed initiation and lower doses of a calcineurin inhibitor. Mycophenolate mofetil was used more commonly in induction patients, but the efficacy of daclizumab in preventing rejection was independent of this. Patients with a pretransplant creatinine concentration 1.5 mg/dL or less had less rejection if they received induction. Renal function worsened in noninduction patients but showed sustained improvement throughout follow-up in induction patients with a pretransplant creatinine concentration greater than 1.5 mg/dL. Induction therapy provided better rejection prophylaxis among those requiring temporary calcineurin inhibitor cessation because of renal dysfunction. The incidences of histologic hepatitis C recurrence and cytomegalovirus infection were similar in each group. CONCLUSIONS: Liver recipients with and without pretransplant renal dysfunction have less acute rejection with daclizumab induction therapy. This is not associated with an increased risk of over-immunosuppression. Sustained renal improvement in recipients with pretransplant renal dysfunction is possible with daclizumab induction.

Usefulness of preoperative stress perfusion imaging in predicting prognosis after liver transplantation.

The role of preoperative stress single-photon emission computed tomographic (SPECT) imaging in patients with end-stage liver disease who underwent liver transplantation is not well established. We reviewed medical records of patients who had liver transplantation at our institution between January 1998 and November 2001. During this time, 339 patients (213 men, aged 51 +/- 11 years) underwent liver transplantation. Of these, 87 patients had preoperative stress SPECT imaging. Diabetes mellitus (30% vs 11%), hypertension (26% vs 12%), and coronary artery disease (15% vs 7%) were more prevalent in those with than without SPECT (p <0.01 each). The stress SPECT perfusion images were normal in 78 patients (91%) and the left ventricular ejection fraction was 72 +/- 10%. SPECT images revealed ascites in 66% and splenomegaly in 83% of patients. There were 35 total deaths (10%) and 5 nonfatal myocardial infarctions over a mean follow-up of 21 +/- 13 months. Most deaths (32 of 35) were noncardiac and sepsis was the most common cause of death. A normal SPECT study had a 99% negative predictive value for perioperative cardiac events. Kaplan-Meier survival curves showed an 87% 2-year cumulative survival rate in the total group. Thus, in patients undergoing liver transplantation, 2-year survival depends on early noncardiac events. A normal stress SPECT study identified patients at a very low risk for early and late cardiac events despite a higher risk profile. SPECT images also revealed unique findings, such as ascites and splenomegaly, which could produce image artifacts and may interfere with accurate image interpretation.