Red Blood Cell Antigen Alloimmunization in Liver Transplant Recipients

Orthotopic liver transplantation (OLT) is a life-saving procedure for patients with end-stage liver disease. Transfusion support is an important part of OLT. Intraoperative transfusion of large volumes of blood products is recognized to be a poor prognostic factor, probably due to the negative effects of blood transfusions, such as transfusion reactions, infectious contamination of blood products, or immune modulation of the transfused patient. The aim of this study was to evaluate the frequency of alloimmunization and its specificity to red blood cell (RBC) antigens among patients undergoing OLT. We identified 74 RBC alloantibodies in 70 (23%) patients when the indirect antiglobulin test (IAT) was performed. The most common RBC alloantibodies were against Rh system antigens. The majority (41.9%) were directed against the E antigen. Despite the ethnic heterogeneity of our population there were no cases of intravascular hemolysis. The incidence of alloimmunization (23%) was slightly higher among patients than in the literature, most probably as a consequence of our ethnic heterogeneity.     

Red Blood Cell Transfusion and Transfusion Alternatives in Traumatic Brain Injury

Anemia develops in about 50% of patients hospitalized with traumatic brain injury (TBI) and is recognized as a cause of secondary brain injury. This review examines the effects of anemia and transfusion on TBI patients through a literature search to identify original research on anemia and transfusion in TBI, the effects of transfusion on brain physiology, and the role of erythropoietin or hemoglobin-based blood substitutes (HBBSs). However, the amount of high-quality, prospective data available to help make decisions about when TBI patients should be transfused is very small. Randomized transfusion trials have involved far too few TBI patients to reach definitive conclusions. Thus, it is hardly surprising that there is widespread practice variation. In our opinion, a hemoglobin transfusion threshold of 7 g/dL cannot yet be considered safe for TBI patients admitted to hospital, and in particular to the ICU, as it is for other critically ill patients. Red blood cell transfusions often have immediate, seemingly beneficial effects on cerebral physiology, but the magnitude of this effect may depend in part upon how long the cells have been stored before administration. In light of existing physiological data, we generally aim to keep hemoglobin concentrations greater than 9 g/dL during the first several days after TBI. In part, the decision is based on the patient’s risk of or development of secondary ischemia or brain injury. An increasing number of centers use multimodal neurologic monitoring, which may help to individualize transfusion goals based on the degree of cerebral hypoxia or metabolic distress. When available, brain tissue oxygen tension values less than 15–20 mm Hg or a lactate:pyruvate ratio greater than 30–40 would influence us to use more aggressive hemoglobin correction (e.g., a transfusion threshold of 10 g/dL). Clinicians can attempt to reduce transfusion requirements by limiting phlebotomy, minimizing hemodilution, and providing appropriate prophylaxis against gastrointestinal hemorrhage. Administration of exogenous erythropoietin may have a small impact in further reducing the need for transfusion, but it also may increase complications, most notably deep venous thrombosis. Erythropoietin is currently of great interest as a potential neuroprotective agent, but until it is adequately evaluated in randomized controlled trials, it should not be used routinely for this purpose. HBBSs are also of interest, but existing preparations have not been shown to be beneficial—or even safe—in the context of TBI.     

Genomic Profiles and Predictors of Early Allograft Dysfunction After Human Liver Transplantation

Early hepatic allograft dysfunction (EAD) manifests posttransplantation with high serum transaminases, persistent cholestasis, and coagulopathy. The biological mechanisms are poorly understood. This study investigates the molecular mechanisms involved in EAD and defines a gene expression signature revealing different biological pathways in subjects with EAD from those without EAD, a potential first step in developing a molecular classifier as a potential clinical diagnostic. Global gene expression profiles of 30 liver transplant recipients of deceased donor grafts with EAD and 26 recipients without graft dysfunction were investigated using microarrays of liver biopsies performed at the end of cold storage and after graft reperfusion prior to closure. Results reveal a shift in inflammatory and metabolic responses between the two time points and differences between EAD and non‐EAD. We identified relevant pathways (PPARα and NF‐κB) and targets (such as CXCL1, IL1, TRAF6, TIPARP, and TNFRSF1B) associated with the phenotype of EAD. Preliminary proof of concept gene expression classifiers that distinguish EAD from non‐EAD patients, with Area Under the Curve (AUC) >0.80 were also identified. This data may have mechanistic and diagnostic implications for EAD.     

Association of Perioperative Red Blood Cell Transfusion With Symptomatic Venous Thromboembolism Following Total Hip and Knee Arthroplasty

BackgroundPrior registry data suggest that perioperative red blood cell (RBC) transfusion may increase the incidence of venous thromboembolism (VTE) in patients status post surgery. However, there are limited data that explore VTE risk after perioperative transfusion in the setting of primary total joint arthroplasty (TJA). Our aim is to investigate the association between perioperative RBC transfusion and the development of symptomatic VTE after adjusting for confounding variables.MethodsWe retrospectively reviewed all patients undergoing primary TJA at a single institution from 2001 to 2016. The primary outcome was development of symptomatic VTE (deep vein thrombosis or pulmonary embolism) up to 90 days following primary TJA. To identify the association between RBC transfusion and development of VTE, univariate and multivariate analyses were used, as well as a sensitivity analysis using propensity score matching based on patient comorbidities.ResultsOf the 29,003 patients who underwent TJA, 2500 (8.62%) received RBC transfusion perioperatively and 302 (1.04%) developed a postoperative VTE within 90 days of surgery. While univariate analysis did suggest a slightly increased incidence of VTE in association with RBC transfusion (odds ratio [OR], 1.53; 95% confidence interval [CI], 1.09-2.16), this difference was eliminated when multivariate analysis (OR, 0.42; 95% CI, 0.12-1.39) and propensity score matching (propensity-matched OR, 1.2; 95% CI, 0.7-1.8) were employed.ConclusionPerioperative RBC transfusion does not significantly increase the incidence of symptomatic VTE following primary TJA in the 90-day postoperative period after adjustment for host VTE risk scores and other confounding variables. Perioperative RBC transfusion may be safely administered if indicated following total hip and knee arthroplasty.     

The Impact of Obesity on Long-term Outcomes in Liver Transplant Recipients—Results of the NIDDK Liver Transplant Database

The impact of obesity on outcomes following liver transplantation has been difficult to determine, in part due to the confounding effects of ascites on BMI. We evaluated the impact of pretransplant recipient obesity on outcomes following liver transplantation using the NIDDK Liver Transplantation Database. Pretransplant BMI, corrected for ascites, was categorized as underweight (BMI <18 kg/m²), normal weight (BMI 18–25 kg/m²), overweight (BMI 25.1–30 kg/m²), Class I obese (BMI 30.1–35 kg/m²), Class II obese (BMI 35.1–40 kg/m²) and Class III obese (BMI >40 kg/m²). Primary outcomes were patient and graft survival. Secondary outcomes included days in hospital and days in ICU. Data from 704 adult liver transplant recipients from the NIDDK LTD and a further 609 patients from the Mayo Clinic were analyzed. Early and late patient and graft survival was similar across all BMI categories. Correcting for ascites volume resulted in 11–20% of patients moving into a lower BMI classification. The relative risk for mortality increased by 7% for each liter of ascites removed. We conclude that corrected BMI is not independently predictive of patient or graft survival. Obesity, within the ranges observed in this study, should not be considered to be a contraindication to liver transplantation in the absence of other relative contraindications.     

The Utility of Early Allograft Dysfunction Components in Determining 90-Day Liver Graft Survival

BackgroundEarly allograft dysfunction (EAD) had been established as a useful tool to asses graft and patient survival after liver transplant. We wanted to evaluate effect of EAD components on early graft survival.MethodsThis retrospective study included 264 patients with EAD after liver transplant in the period between 2015 and 2019. The patients with retransplants were excluded from analyses. The EAD was determined with Olthoff criteria. The logistic regression model was used for analyses. The 90-day graft survival was set as a primary outcome measure.ResultsThe main indications for transplant in the analyzed group were hepatitis C virus infection (53 patients, 20.1%), hepatitis B infection (22, 8.3%), primary sclerosing cholangitis (28, 10.1%), and alcoholic liver disease (62, 23.5%), with a median model for end-stage liver disease score of 13.5 points. The 90-day graft loss occurred in 51 patients (19.3%). Each of the components used in EAD diagnosis was found to be correlated with 90-day graft loss. The bilirubin concentration on day 7 (odds ratio [OR], 3.1; 95% CI, 1.4-6.7; P < .001), international normalized ratio on day 7 (OR, 179; 95% CI, 39-815; P < .001), and the natural logarithm of alanine aminotransferase (OR, 3.1; 95% CI, 1.6-6.4) and aspartate aminotransferase (OR, 1.4; 95% CI, 0.4-4.9) predicted 90-day graft loss.ConclusionsIn patients with EAD, international normalized ratio ≥ 1.6 on day 7 was the strongest predictor of early graft-loss among all EAD components.     

Predicting Early Graft Dysfunction and Mortality After Liver Transplant Using the De Ritis Ratio

BackgroundPredicting complications after liver transplantation (LT) remains challenging. We propose incorporating the De Ritis ratio (DRR), a widely known parameter of liver dysfunction, into current or future scoring models to predict early allograft dysfunction (EAD) and mortality after LT.MethodsA retrospective chart review was conducted on 132 adults receiving a deceased donor LT from April 2015 to March 2020 and their matching donors. Donor variables, postoperative liver function, and DRR were correlated with the occurrence of EAD, post-transplant complications expressed by the Clavien-Dindo score, and 30-day mortality as outcome variables.ResultsEarly allograft dysfunction was observed in 26.5% of patients and 7.6% of patients who died within 30 days after transplant. Recipients were more likely to experience EAD when receiving grafts from donation after circulatory death (P = .04), donor risk index (DRI) >2 (P = .006), ischemic injury at time-zero biopsy (P = .02), longer secondary warm ischemia time (P < .05), or higher Clavien-Dindo scores (IIIb-V; P < .001). The DRI, total bilirubin, and DRR on postoperative day 5 yielded significant associations with the primary outcomes and were used to develop the Gala-Lopez score using a weighted scoring model. This accurately predicted EAD, high Clavien-Dindo, and 30-day mortality in 75%, 81%, and 64% of patients.ConclusionIncluding recipient and donor variables in predictive models, and for the first time DRR, as a constituent, should be regarded to predict EAD, severe complications, and 30-day mortality post-LT. Further studies will be required to validate the present findings and their applicability when using normothermic regional and machine perfusion technologies.     

The Impact of Perioperative Blood Transfusion on Cancer Recurrence and Survival Following Radical Cystectomy

Background

While the receipt of a perioperative blood transfusion (PBT) has been associated with an increased risk of mortality for a number of malignancies, the relationship between PBT and survival following radical cystectomy (RC) for bladder cancer (BCa) has not been well established.

Objective

To evaluate the association of PBT with disease recurrence and mortality following RC.

Design, setting, and participants

We identified 2060 patients who underwent RC at the Mayo Clinic between 1980 and 2005. PBT was defined as transfusion of allogenic red blood cells during RC or postoperative hospitalization.

Outcome measurements and statistical analysis

Survival was estimated using the Kaplan-Meier method and was compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of PBT with outcome, controlling for clinicopathologic variables.

Results and limitations

A total of 1279 patients (62%) received PBT. The median number of units transfused was 2 (interquartile range [IQR]: 2–4). Patients receiving PBT were significantly older (median: 69 yr vs 66 yr; p < 0.0001), had a worse Eastern Cooperative Oncology Group performance status (p < 0.0001), and were more likely to have muscle-invasive tumors (56% vs 49%; p = 0.004). Median postoperative follow-up was 10.9 yr (IQR: 7.9–15.7). Receipt of PBT was associated with significantly worse 5-yr recurrence-free survival (58% vs 64%; p = 0.01), cancer-specific survival (59% vs 72%; p < 0.001), and overall survival (45% vs 63%; p < 0.001). On multivariate analyses, PBT remained associated with significantly increased risks of postoperative tumor recurrence (hazard ratio [HR]: 1.20; p = 0.04), death from BCa (HR: 1.31; p = 0.003), and all-cause mortality (HR: 1.27; p = 0.0002). Among patients who received PBT, an increasing number of units transfused was independently associated with increased cancer-specific mortality (HR: 1.07; p < 0.0001) and all-cause mortality (HR: 1.05; p < 0.0001). Limitations include selection bias and lack of standardized transfusion criteria.

Conclusions

We found that PBT is associated with significantly increased risks of cancer recurrence and mortality following RC. While external validation is required, continued efforts to reduce the use of blood products in these patients are warranted.     

Early Prediction of Cardiac Allograft Vasculopathy and Heart Transplant Failure

Early risk‐prediction is essential to prevent cardiac allograft vasculopathy (CAV) and graft failure in heart transplant patients. We developed multivariate models to identify patients likely to experience CAV, severe CAV, and failure due to CAV, at 1, 5 and 10 years. A cohort of 172 patients was followed prospectively for 6.7 ± 3.9 years. Logistic regression models were developed and cross‐validated using bootstrap resampling. Predictive markers of atherothrombosis (myocardial fibrin deposition, and loss of vascular antithrombin and tissue plasminogen activator) and arterial endothelial activation (intercellular adhesion molecule‐1 expression) were measured in serial biopsies obtained within 3 months posttransplant. Most markers were univariately associated with outcome. Multivariate models showed that loss of tissue plasminogen activator was the dominant and, in most cases, only predictor of long‐term CAV (p < 0.001), severe CAV (p < 0.001), and graft failure due to CAV (p < 0.001). The models discriminated patients having adverse outcomes, had particularly high negative predictive values (graft failure due to CAV: 99%, 99% and 95% at 1, 5 and 10 years) and predicted event incidence and time to event. Early absence of atherothrombotic risk identifies a patient subgroup that rarely develops CAV or graft failure, implying that this low‐risk subgroup could possibly be followed with fewer invasive procedures.     

Impact of Simultaneous Kidney–Pancreas Transplant and Timing of Transplant on Kidney Allograft Survival

Since 1988 over 10 000 simultaneous cadaveric pancreas-kidney transplants (SPK) have been performed in the United States among patients with end-stage renal disease due to Type 1 diabetes (T1DM). The two aims of this study were to assess the impact on kidney allograft survival of (i) SPK versus transplantation of a kidney alone (KA), and (ii) SPK prior to versus after initiation of chronic dialysis. This retrospective, non-concurrent cohort study examined registry data collected from 8323 patients waitlisted in the United States for an SPK and transplanted with either an SPK or a KA during January 1, 1990 - October 31, 2002. SPK recipients had an adjusted hazard ratio for kidney allograft loss of 0.63 (95% CI: 0.51-0.77, p < 0.001) compared to transplantation without pancreas allograft. SPK recipients who received their allografts prior to beginning chronic dialysis had a lower rate of kidney allograft loss than SPK recipients who received their transplant after initiation of chronic dialysis (adjusted hazard rates (HR) = 0.83, 95% CI: 0.69-0.99, p = 0.042). Simultaneous transplantation of pancreas-kidney compared to kidney transplantation alone and SPK prior to the initiation of chronic dialysis compared to SPK after initiation of dialysis were both associated with longer kidney allograft survival.     

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

Infectious diseases after solid organ transplantation (SOT) are a significant cause of morbidity and reduced allograft and patient survival; however, the influence of infection on the development of chronic allograft dysfunction has not been completely delineated. Some viral infections appear to affect allograft function by both inducing direct tissue damage and immunologically related injury, including acute rejection. In particular, this has been observed for cytomegalovirus (CMV) infection in all SOT recipients and for BK virus infection in kidney transplant recipients, for community‐acquired respiratory viruses in lung transplant recipients, and for hepatitis C virus in liver transplant recipients. The impact of bacterial and fungal infections is less clear, but bacterial urinary tract infections and respiratory tract colonization by Pseudomonas aeruginosa and Aspergillus spp appear to be correlated with higher rates of chronic allograft dysfunction in kidney and lung transplant recipients, respectively. Evidence supports the beneficial effects of the use of antiviral prophylaxis for CMV in improving allograft function and survival in SOT recipients. Nevertheless, there is still a need for prospective interventional trials assessing the potential effects of preventive and therapeutic strategies against bacterial and fungal infection for reducing or delaying the development of chronic allograft dysfunction.     

Perioperative Red Blood Cell Transfusion and Outcome in Stable Patients after Elective Major Vascular Surgery

ObjectivesDefinitive evidence that red blood cell transfusion improves outcome after vascular surgery is lacking. The aims of the study were to determine, among stable consecutive patients who underwent elective major vascular surgery, (1) the association between postoperative transfusion and 30-day death, myocardial infarction, and both, and (2) and if this association differs according to the presence of postoperative anaemia (haemoglobin value less than 9.0 g/dL within 7 days after surgery).MethodsA retrospective observational study was conducted on 359 patients prospectively screened according to the ACC/AHA guidelines for preoperative risk in non-cardiac surgery. Main outcome was 30-day death; secondary outcomes 30-day myocardial infarction, and composite of 30-day myocardial infarction or death.ResultsOf the patients included, 95 (26.5%) received at least one unit of red blood cells. Patients who received transfusion had a significantly increased hazard of 30-day death (hazard ratio [HR] 11.72, 95% confidence interval [CI] 3.92–35.10; p < 0.0001), myocardial infarction (HR 3.3, 95% CI 1.7–6.1; p = 0.0003), and both (HR 4.0 95% CI 2.2–7.3; p < 0.0001). Such associations held even after adjusting for baseline characteristics, surgical risk, bleeding, and propensity to receive transfusion. There was a significant interaction between transfusion and postoperative anaemia (p = 0.012). In patients without anaemia, transfusion was associated with higher risk of 30-day death (HR 19.20, 95% CI 3.99–92.45; p = 0.007), myocardial infarction (HR 5.05, 95% CI 2.23–11.44; p = 0.0001), and both. Conversely, in patients with anaemia this association was not significant.ConclusionsIn patients who underwent elective major vascular surgery, perioperative transfusion was associated with a significantly increased risk of 30-day events which was more attributable to patients with lesser degree of anaemia. Our data caution against the use of liberal transfusion in stable vascular surgery patients.     

Correlation Between Mycophenolic Acid Blood Level and Renal Dysfunction in Stable Liver Transplant Recipients Receiving Mycophenolate Monotherapy

Purpose

Mycophenolate mofetil (MMF) is frequently used after liver transplantation (OLT). Mycophenolic acid (MPA) metabolites are eliminated primarily via the kidneys. If renal function declines, clearance is significantly impaired. The aim of this study was to reveal the renal function-dependent changes of MPA level in stable adult OLT recipients receiving MMF monotherapy.

Methods

Sixty-five OLT recipients were selected from our OLT database of >3500 cases. All had undergone MMF monotherapy with a daily MMF dose of 1000 mg or 1500 mg for more than 2 years, primarily because they could not tolerate calcineurin inhibitors. Their clinical profiles, including MPA therapeutic drug monitoring (TDM) and renal function, were analyzed as a cross-sectional study.

Results

For the group treated with 1000 mg MMF (n = 40), the 12-hour MPA trough level was 1.20 ± 0.35 μg/mL with serum creatinine (Cr) level ≤1.4 mg/dL in 13 patients; it was 2.78 ± 1.19 μg/mL with Cr >1.4 mg/dL in 16 patients not undergoing hemodialysis and 3.83 ± 0.87 μg/mL in 11 patients undergoing hemodialysis (P < .001). For the group treated with 1500 mg MMF (n = 25), the MPA trough level was 2.23 ± 0.99 μg/mL with Cr ≤1.4 mg/dL in 6 patients; it was 2.81 ± 0.99 μg/mL with Cr >1.4 mg/dL in 18 patients not undergoing hemodialysis and 3.5 μg/mL in 1 patient undergoing hemodialysis (P = .21).

Conclusions

Considering the potential therapeutic range of MPA, the suggested MMF dosage for Korean adult OLT recipients requiring hemodialysis may be set around 1000 mg per day. We suggest adjusting the MMF dosage on an individualized basis according to the results of MPA TDM, particularly for patients with markedly impaired renal function.     

Successful Blood Transfusion Management of a Living Donor Liver Transplant Recipient in the Presence of Anti-Jra: A Case Report

A 48-year-old Japanese woman was diagnosed with Budd-Chiari syndrome and transferred for possible living donor liver transplantation (LDLT). Examinations before LDLT revealed that the recipient had anti-Jr^a and preformed donor-specific anti–human leukocyte antigen (HLA) antibodies (DSA). Rituximab was administrated at 16 days prior to the patient's scheduled LDLT for the prophylaxis of antibody-mediated rejection by DSA. The clinical significance of anti-Jr^a has not been clearly established because of the rarity of this antibody, so we discussed blood transfusion strategy with the Department of Blood Transfusion Service and prepared for Jr^a-negative packed red blood cells (RBCs). Intraoperative blood salvage was used during LDLT procedures to reduce the use of packed RBCs. Although post-transplantation graft function was excellent, a total of 44 U of Jr^a-negative RBCs were transfused during the entire perioperative period. Because sufficient amounts of Jr^a-negative packed RBCs were supplied, Jr^a mismatched blood transfusion was avoided. The patient was discharged from our hospital on postoperative day 102 without clinical evidence of any blood transfusion–related adverse events. Although there are some controversies of blood transfusion related to anti-Jr^a antibodies, the current strategies of blood transfusion for liver transplantation with anti-Jr^a are as follows: (1) sufficient supply and transfusion of Jr^a-negative matched packed RBCs and (2) application of intraoperative blood salvage to reduce the total amount of rare blood type RBCs. These strategies may be changed when the mechanism of anti-Jr^a alloimmunization is fully understood in the future.     

Prevalence of Antiphospholipid Antibody Positivity and Association of Pretransplant Lupus Anticoagulant Positivity With Early Allograft Dysfunction in Liver Transplantation

Background

Antiphospholipid antibodies (aPL), including anticardiolipin (aCL), anti-β₂-glycoprotein I (anti-β2GPI), and lupus anticoagulant (LA) antibodies, are frequently found in liver cirrhosis and associated with splanchnic vein thrombosis. Although the risk factors of early allograft dysfunction (EAD) are known, the association between EAD and aPL has been poorly investigated. We hypothesized that LA, potent aPL with thrombotic potential, may be associated with EAD development after living donor liver transplantation (LDLT).