Donor-derived regulatory dendritic cell infusion modulates effector CD8+ T cell and NK cell responses after liver transplantation.

Immune cell-based therapies are promising strategies to facilitate immunosuppression withdrawal after organ transplantation. Regulatory dendritic cells (DCreg) are innate immune cells that down-regulate alloimmune responses in preclinical models. Here, we performed clinical monitoring and comprehensive assessment of peripheral and allograft tissue immune cell populations in DCreg-infused live-donor liver transplant (LDLT) recipients up to 12 months (M) after transplant. Thirteen patients were given a single infusion of donor-derived DCreg 1 week before transplant (STUDY) and were compared with 40 propensity-matched standard-of-care (SOC) patients. Donor-derived DCreg infusion was well tolerated in all STUDY patients. There were no differences in postoperative complications or biopsy-confirmed acute rejection compared with SOC patients up to 12M. DCreg administration was associated with lower frequencies of effector T-bet+Eomes+CD8+ T cells and CD16bright natural killer (NK) cells and an increase in putative tolerogenic CD141+CD163+ DCs compared with SOC at 12M. Antidonor proliferative capacity of interferon-γ+ (IFN-γ+) CD4+ and CD8+ T cells was lower compared with antithird party responses in STUDY participants, but not in SOC patients, at 12M. In addition, lower circulating concentrations of interleukin-12p40 (IL-12p40), IFN-γ, and CXCL10 were detected in STUDY participants compared with SOC patients at 12M. Analysis of 12M allograft biopsies revealed lower frequencies of graft-infiltrating CD8+ T cells, as well as attenuation of cytolytic TH1 effector genes and pathways among intragraft CD8+ T cells and NK cells, in DCreg-infused patients. These reductions may be conducive to reduced dependence on immunosuppressive drug therapy or immunosuppression withdrawal.

Design, analysis, and interpretation of treatment response heterogeneity in personalized nutrition and obesity treatment research.

It is increasingly assumed that there is no one-size-fits-all approach to dietary recommendations for the management and treatment of chronic diseases such as obesity. This phenomenon that not all individuals respond uniformly to a given treatment has become an area of research interest given the rise of personalized and precision medicine. To conduct, interpret, and disseminate this research rigorously and with scientific accuracy, however, requires an understanding of treatment response heterogeneity. Here, we define treatment response heterogeneity as it relates to clinical trials, provide statistical guidance for measuring treatment response heterogeneity, and highlight study designs that can quantify treatment response heterogeneity in nutrition and obesity research. Our goal is to educate nutrition and obesity researchers in how to correctly identify and consider treatment response heterogeneity when analyzing data and interpreting results, leading to rigorous and accurate advancements in the field of personalized medicine.

Distinct association between chronic Epstein-Barr virus infection and T cell compartments from pediatric heart, kidney, and liver transplant recipients.

Chronic Epstein-Barr virus (EBV) infection after pediatric organ transplantation (Tx) accounts for significant morbidity and mortality. The risk of complications, such as posttransplant lymphoproliferative disorders, in high viral load (HVL) carriers is the highest in heart Tx recipients. However, the immunologic signatures of such a risk have been insufficiently defined. Here, we assessed the phenotypic, functional, and transcriptomic profiles of peripheral blood CD8+/CD4+ T cells, including EBV-specific T cells, in 77 pediatric heart, kidney, and liver Tx recipients and established the relationship between memory differentiation and progression toward exhaustion. Unlike kidney and liver HVL carriers, heart HVL carriers displayed distinct CD8+ T cells with (1) up-regulation of interleukin-21R, (2) decreased naive phenotype and altered memory differentiation, (3) accumulation of terminally exhausted (TEX PD-1+T-bet-Eomes+) and decrease of functional precursors of exhausted (TPEX PD-1intT-bet+) effector subsets, and (4) transcriptomic signatures supporting the phenotypic changes. In addition, CD4+ T cells from heart HVL carriers displayed similar changes in naive and memory subsets, elevated Th1 follicular helper cells, and plasma interleukin-21, suggesting an alternative inflammatory mechanism that governs T cell responses in heart Tx recipients. These results may explain the different incidences of EBV complications and may help improve the risk stratification and clinical management of different types of Tx recipients.

Liver Transplantation vs Partial Hepatectomy for Stage T2 Multifocal Hepatocellular Carcinoma <3 cm Without Vascular Invasion: A Propensity Score-Matched Survival Analysis.

BACKGROUND: Multifocal hepatocellular carcinoma (HCC) differs biologically and immunologically from single-nodule HCC. Asian and European guidelines consider liver transplantation (LT) and partial hepatectomy (PH) as effective for T2 multifocal HCC, with preference toward LT, but few US studies compare these treatments directly. This propensity score-based observational study uses an established national cancer outcomes registry to compare overall survival in patients undergoing PH and LT for multifocal HCC. STUDY DESIGN: Data from the 2020 National Cancer Database were obtained on patients who underwent LT or PH for multifocal stage 2 HCC within Milan criteria and without vascular invasion. Propensity score matching and Cox regression analysis was applied to evaluate overall survival in an observational cohort balanced by age, sex, treatment facility type, treatment year, prothrombin time, α-fetoprotein, comorbidity burden, liver fibrosis severity, and pretreatment creatinine and bilirubin levels. RESULTS: Of 21,248 T2 HCC patients identified, 6,744 had multifocal tumors with largest tumor diameter <3 cm without major vascular invasion, with 1,267 and 181 having undergone LT and PH, respectively. Propensity score-matched Cox regression analysis associated LT with a hazard ratio of 0.39 (95% CI 0.30 to 0.50) relative to PH. Landmark analyses to account for a longer interval to LT demonstrated survival benefits of similar magnitude. CONCLUSIONS: Although early-stage HCC can be effectively treated with either LT or PH, propensity score-matched analysis comparatively shows a survival benefit for LT in patients with multifocal HCC who are within the Milan criteria.

Biomarkers in Polycystic Kidney Disease: Are We There?

This article describes the use of prognostic, predictive, and response biomarkers that have been developed for autosomal dominant polycystic kidney disease and their use in clinical care or drug development. We focus on biochemical markers that can be assayed in patients' blood and urine and their association with the outcome of decreased glomerular filtration rate. There have been several studies on prognostic biomarkers. The most promising ones have been markers of tubular injury, inflammation, metabolism, or the vasopressin-urinary concentration axis. So far, none have been shown to be superior to kidney volume-based biomarkers. Several biomarkers are additive to kidney volume and genotype in prognostic models, but there have been few direct comparisons between the biochemical markers to identify the best ones. Moreover, there is a lack of uniformity in the statistical tools used to assess and compare biomarkers. There have been few reports of predictive and response biomarkers, and none are suitable surrogate endpoints. The U.S. Food and Drug Administration's Biomarker Qualification Program provides a regulatory pathway to approve biomarkers for use across multiple drug-development programs.

Industry, occupation, and exposure history of mesothelioma patients in the U.S. National Mesothelioma Virtual Bank, 2006-2022.

BACKGROUND: Malignant mesothelioma is associated with environmental and occupational exposure to certain mineral fibers, especially asbestos. This study aims to examine work histories of mesothelioma patients and their survival time. METHOD: Using the NIOSH Industry and Occupation Computerized Coding System, we mapped occupations and industries recorded for 748 of 1444 patients in the U.S. National Mesothelioma Virtual Bank (NMVB) during the period 2006-2022. Descriptive and survival analyses were conducted. RESULTS: Among the 1023 industries recorded for those having mesothelioma, the most frequent cases were found for those in manufacturing (n = 225, 22.0%), construction (138, 13.5%), and education services (66, 6.5%); among the 924 occupation records, the most frequent cases were found for those in construction and extraction (174, 18.8%), production (145, 15.7%), and management (84, 9.1%). Males (583) or persons aged >40 years (658) at the time of diagnosis tended to have worked in industries traditionally associated with mesothelioma (e.g., construction), while females (163) or persons aged 20-40 years (27) tended to have worked in industries not traditionally associated with mesothelioma (e.g., health care). Asbestos, unknown substances, and chemical solvents were the most frequently reported exposure, with females most often reporting an unknown substance. A multi-variable Cox Hazard Regression analysis showed that significant prognostic factors associated with decreased survival in mesothelioma cases are sex (male) and work experience in utility-related industry, while factor associated with increased survival are epithelial or epithelioid histological type, prior history of surgery and immunotherapy, and industry experience in accommodation and food services. CONCLUSION: The NMVB has the potential of serving as a sentinel surveillance mechanism for identifying industries and occupations not traditionally associated with mesothelioma. Results indicate the importance of considering all potential sources of asbestos exposures including occupational, environmental, and extra-occupational exposures when evaluating mesothelioma patients and advising family members.

Perceived Hospital Stress, Severe Acute Respiratory Syndrome Coronavirus 2 Activity, and Care Process Temporal Variance During the COVID-19 Pandemic.

OBJECTIVES: The COVID-19 pandemic threatened standard hospital operations. We sought to understand how this stress was perceived and manifested within individual hospitals and in relation to local viral activity. DESIGN: Prospective weekly hospital stress survey, November 2020-June 2022. SETTING: Society of Critical Care Medicine's Discovery Severe Acute Respiratory Infection-Preparedness multicenter cohort study. SUBJECTS: Thirteen hospitals across seven U.S. health systems. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We analyzed 839 hospital-weeks of data over 85 pandemic weeks and five viral surges. Perceived overall hospital, ICU, and emergency department (ED) stress due to severe acute respiratory infection patients during the pandemic were reported by a mean of 43% ( sd , 36%), 32% (30%), and 14% (22%) of hospitals per week, respectively, and perceived care deviations in a mean of 36% (33%). Overall hospital stress was highly correlated with ICU stress (ρ = 0.82; p < 0.0001) but only moderately correlated with ED stress (ρ = 0.52; p < 0.0001). A county increase in 10 severe acute respiratory syndrome coronavirus 2 cases per 100,000 residents was associated with an increase in the odds of overall hospital, ICU, and ED stress by 9% (95% CI, 5-12%), 7% (3-10%), and 4% (2-6%), respectively. During the Delta variant surge, overall hospital stress persisted for a median of 11.5 weeks (interquartile range, 9-14 wk) after local case peak. ICU stress had a similar pattern of resolution (median 11 wk [6-14 wk] after local case peak; p = 0.59) while the resolution of ED stress (median 6 wk [5-6 wk] after local case peak; p = 0.003) was earlier. There was a similar but attenuated pattern during the Omicron BA.1 subvariant surge. CONCLUSIONS: During the COVID-19 pandemic, perceived care deviations were common and potentially avoidable patient harm was rare. Perceived hospital stress persisted for weeks after surges peaked.

Utility of new image-derived biomarkers for autosomal dominant polycystic kidney disease prognosis using automated instance cyst segmentation.

New image-derived biomarkers for patients affected by autosomal dominant polycystic kidney disease are needed to improve current clinical management. The measurement of total kidney volume (TKV) provides critical information for clinicians to drive care decisions. However, patients with similar TKV may present with very different phenotypes, often requiring subjective decisions based on other factors (e.g., appearance of healthy kidney parenchyma, a few cysts contributing significantly to overall TKV, etc.). In this study, we describe a new technique to individually segment cysts and quantify biometric parameters including cyst volume, cyst number, parenchyma volume, and cyst parenchyma surface area. Using data from the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) study the utility of these new parameters was explored, both quantitatively as well as visually. Total cyst number and cyst parenchyma surface area showed superior prediction of the slope of estimated glomerular filtration rate decline, kidney failure and chronic kidney disease stages 3A, 3B, and 4, compared to TKV. In addition, presentations such as a few large cysts contributing significantly to overall kidney volume were shown to be much better stratified in terms of outcome predictions. Thus, these new image biomarkers, which can be obtained automatically, will have great utility in future studies and clinical care for patients affected by autosomal dominant polycystic kidney disease.

Angiopoietin-Like4 Is a Novel Marker of COVID-19 Severity.

Vascular dysfunction and capillary leak are common in critically ill COVID-19 patients, but identification of endothelial pathways involved in COVID-19 pathogenesis has been limited. Angiopoietin-like 4 (ANGPTL4) is a protein secreted in response to hypoxic and nutrient-poor conditions that has a variety of biological effects including vascular injury and capillary leak. OBJECTIVES: To assess the role of ANGPTL4 in COVID-19-related outcomes. DESIGN SETTING AND PARTICIPANTS: Two hundred twenty-five COVID-19 ICU patients were enrolled from April 2020 to May 2021 in a prospective, multicenter cohort study from three different medical centers, University of Washington, University of Southern California and New York University. MAIN OUTCOMES AND MEASURES: Plasma ANGPTL4 was measured on days 1, 7, and 14 after ICU admission. We used previously published tissue proteomic data and lung single nucleus RNA (snRNA) sequencing data from specimens collected from COVID-19 patients to determine the tissues and cells that produce ANGPTL4. RESULTS: Higher plasma ANGPTL4 concentrations were significantly associated with worse hospital mortality (adjusted odds ratio per log2 increase, 1.53; 95% CI, 1.17-2.00; p = 0.002). Higher ANGPTL4 concentrations were also associated with higher proportions of venous thromboembolism and acute respiratory distress syndrome. Longitudinal ANGPTL4 concentrations were significantly different during the first 2 weeks of hospitalization in patients who subsequently died compared with survivors (p for interaction = 8.1 × 10-5). Proteomics analysis demonstrated abundance of ANGPTL4 in lung tissue compared with other organs in COVID-19. ANGPTL4 single-nuclear RNA gene expression was significantly increased in pulmonary alveolar type 2 epithelial cells and fibroblasts in COVID-19 lung tissue compared with controls. CONCLUSIONS AND RELEVANCE: ANGPTL4 is expressed in pulmonary epithelial cells and fibroblasts and is associated with clinical prognosis in critically ill COVID-19 patients.

Target Trial Emulation: A Design Tool for Cancer Clinical Trials.

PURPOSE: To apply target trial emulation to explore the potential impact of eligibility criteria on the primary outcome of a randomized controlled trial. METHODS: Simulations of a real-world explanatory trial of transarterial radioembolization for advanced unresectable hepatocellular carcinoma with portal vein invasion were performed to examine the effects of cohort specification on survival outcomes and patient sample size. Simulations comprised 24 different permutations of the trial varied on three disease nonspecific eligibility parameters. Treatment and control arms for these emulated trials were drawn from the National Cancer Database and matched by treatment propensity. Target trial emulation served as the causal framework for this analysis, allowing the architecture of a true controlled experiment to address forms of bias routinely encountered in comparative effectiveness studies involving real-world observational data. RESULTS: Twenty-four propensity score-matched cohorts comprising a wider clinical spectrum of patients than specified by the original target trial were successfully generated using the National Cancer Database. The arms for each of the emulated trials demonstrated exchangeability across all eligibility criteria and other clinical covariates. Significant treatment benefits were associated with only a narrow range of eligibility criteria, indicating that the original target trial was well specified. CONCLUSION: The impact of patient selection on treatment outcomes can be studied using target trial emulation. This analytical framework can furthermore serve to leverage existing real-world data to inform the task of cohort specification for a randomized controlled trial, facilitating a more data-driven approach for this important step in clinical trial design.

Poor Outcomes of Patients With NAFLD and Moderate Renal Dysfunction or Short-Term Dialysis Receiving a Liver Transplant Alone.

The outcomes of patients with moderate renal impairment and the impact of liver disease etiology on renal function recovery after liver transplant alone (LTA) are largely unknown. We explored whether NAFLD patients with pre-LTA moderate renal dysfunction (GFR 25-45 ml/min/1.73 m2) may be more susceptible to develop post-LTA severe renal dysfunction (GFR<15 ml/min/1.73 m2) than ALD patients, as well as other overall outcomes. Using the UNOS/OPTN database, we selected patients undergoing liver transplant for NAFLD or ALD (2006-2016), 15,103 of whom received LTA. NAFLD patients with moderate renal dysfunction were more likely to develop subsequent GFR<15 ml/min/1.73 m2 than ALD patients (11.1% vs. 7.38%, p < 0.001). Patients on short-term dialysis pre-LTA (≤12 weeks) were more likely to develop severe renal dysfunction (31.7% vs. 18.1%), especially in NAFLD patients, and were more likely to receive a further kidney transplant (15.3% vs. 3.7%) and had lower survival (48.6% vs. 50.4%) after LTA (p < 0.001 for all). NAFLD was an independent risk factor for post-LTA severe renal dysfunction (HR = 1.2, p = 0.02). NAFLD patients with moderate renal dysfunction and those receiving short-term dialysis prior to LTA are at a higher risk of developing subsequent severe renal dysfunction. Underlying etiology of liver disease may play a role in predicting development and progression of renal failure in patients receiving LTA.

SWEAT ICU-An Observational Study of Physician Workload and the Association of Physician Outcomes in Academic ICUs.

The optimal staffing model for physicians in the ICU is unknown. Patient-to-intensivist ratios may offer a simple measure of workload and be associated with patient mortality and physician burnout. To evaluate the association of physician workload, as measured by the patient-to-intensivist ratio, with physician burnout and patient mortality. DESIGN: Cross-sectional observational study. SETTING: Fourteen academic centers in the United States from August 2020 to July 2021. SUBJECTS: We enrolled ICU physicians and collected data on adult ICU patients under the physician's care on the single physician-selected study day for each physician. MEASUREMENTS and MAIN RESULTS: The primary exposure was workload (self-reported number of patients' physician was responsible for) modeled as high (>14 patients) and low (≤14 patients). The primary outcome was burnout, measured by the Well-Being Index. The secondary outcome measure was 28-day patient mortality. We calculated odds ratio for burnout and patient outcomes using a multivariable logistic regression model and a binomial mixed effects model, respectively. We enrolled 122 physicians from 62 ICUs. The median patient-to-intensivist ratio was 12 (interquartile range, 10-14), and the overall prevalence of burnout was 26.4% (n = 32). Intensivist workload was not independently associated with burnout (adjusted odds ratio, 0.74; 95% CI, 0.24-2.23). Of 1,322 patients, 679 (52%) were discharged alive from the hospital, 257 (19%) remained hospitalized, and 347 (26%) were deceased by day 28; 28-day outcomes were unknown for 39 of patients (3%). Intensivist workload was not independently associated with 28-day patient mortality (adjusted odds ratio, 1.33; 95% CI, 0.92-1.91). CONCLUSIONS: In our cohort, approximately one in four physicians experienced burnout on the study day. There was no relationship be- tween workload as measured by patient-to-intensivist ratio and burnout. Factors other than the number of patients may be important drivers of burnout among ICU physicians.

Severe Acute Respiratory Infection-Preparedness: Protocol for a Multicenter Prospective Cohort Study of Viral Respiratory Infections.

Respiratory virus infections cause significant morbidity and mortality ranging from mild uncomplicated acute respiratory illness to severe complications, such as acute respiratory distress syndrome, multiple organ failure, and death during epidemics and pandemics. We present a protocol to systematically study patients with severe acute respiratory infection (SARI), including severe acute respiratory syndrome coronavirus 2, due to respiratory viral pathogens to evaluate the natural history, prognostic biomarkers, and characteristics, including hospital stress, associated with clinical outcomes and severity. DESIGN: Prospective cohort study. SETTING: Multicenter cohort of patients admitted to an acute care ward or ICU from at least 15 hospitals representing diverse geographic regions across the United States. PATIENTS: Patients with SARI caused by infection with respiratory viruses that can cause outbreaks, epidemics, and pandemics. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Measurements include patient demographics, signs, symptoms, and medications; microbiology, imaging, and associated tests; mechanical ventilation, hospital procedures, and other interventions; and clinical outcomes and hospital stress, with specimens collected on days 0, 3, and 7-14 after enrollment and at discharge. The primary outcome measure is the number of consecutive days alive and free of mechanical ventilation (VFD) in the first 30 days after hospital admission. Important secondary outcomes include organ failure-free days before acute kidney injury, shock, hepatic failure, disseminated intravascular coagulation, 28-day mortality, adaptive immunity, as well as immunologic and microbiologic outcomes. CONCLUSIONS: SARI-Preparedness is a multicenter study under the collaboration of the Society of Critical Care Medicine Discovery, Resilience Intelligence Network, and National Emerging Special Pathogen Training and Education Center, which seeks to improve understanding of prognostic factors associated with worse outcomes and increased resource utilization. This can lead to interventions to mitigate the clinical impact of respiratory virus infections associated with SARI.

Utility of Biomarkers for Sepsis-Associated Acute Kidney Injury Staging.

Importance: The 23rd Acute Disease Quality Initiative (ADQI-23) consensus conference proposed a framework to integrate biomarkers into the staging of acute kidney injury (AKI). It is unknown whether tissue inhibitor of metalloproteinases 2 (TIMP-2) and insulinlike growth factor binding protein 7 (IGFBP7) could be used for staging. Objective: To test whether higher levels of urinary [TIMP-2] × [IGFBP7] are associated with lower survival among patients with the same functional stage of AKI. Design, Setting, and Participants: This cohort study was performed using data from the Protocolized Care for Early Septic Shock (ProCESS) trial, which enrolled critically ill patients with septic shock who presented at academic and community emergency departments and intensive care units in the US from March 2008 to May 2013. Patients with end-stage kidney disease, a reference serum creatinine level of 4 mg/dL or greater (to convert to µmol/L, multiply by 76.25), or missing data on serum creatinine levels or urinary levels of [TIMP-2] × [IGFBP7] were excluded. Data were analyzed from October 2020 to October 2021. Exposures: The presence of AKI, assessed using Kidney Disease: Improving Global Outcomes criteria within 24 hours after enrollment and the highest AKI stage as well as urinary [TIMP-2] × [IGFBP7] level at 6 hours after enrollment. A previously reported high-specificity cutoff level for [TIMP-2] × [IGFBP7] of 2.0 (ng/mL)2/1000 was used to categorize patients (including those without functional criteria of AKI) according to the new staging system proposed by the ADQI-23 as biomarker negative (urinary [TIMP-2] × [IGFBP7] level ≤2.0 [ng/mL]2/1000) or biomarker positive ([TIMP-2] × [IGFBP7] >2.0 [ng/mL]2/1000). Main Outcomes and Measures: Survival (assessed using Kaplan-Meier plots and the log-rank test) and mortality (assessed using relative risk [RR] 30 days after enrollment). Results: The analysis included 999 patients with a median age of 61 years (IQR, 50-73 years); 554 (55.5%) were male. Biomarker-positive patients had lower survival and higher mortality at 30 days in the groups with AKI stage 1 (RR, 2.20; 95% CI, 1.02-4.72), stage 2 (RR, 1.53; 95% CI, 1.04-2.27), and stage 3 (RR, 1.61; 95% CI, 1.00-2.60). The associations were specific to patients with AKI. No difference in 30-day survival was found between biomarker-positive and biomarker-negative patients in the absence of functional criteria for AKI (RR, 1.16; 95% CI, 0.45-3.01). Conclusions and Relevance: The findings suggest that assessment of the cell-cycle arrest biomarkers TIMP-2 and IGFBP7 may augment AKI staging for patients with functional criteria for AKI.

Volume Progression and Imaging Classification of Polycystic Liver in Early Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND AND OBJECTIVES: The progression of polycystic liver disease is not well understood. The purpose of the study is to evaluate the associations of polycystic liver progression with other disease progression variables and classify liver progression on the basis of patient's age, height-adjusted liver cystic volume, and height-adjusted liver volume. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Prospective longitudinal magnetic resonance images from 670 patients with early autosomal dominant polycystic kidney disease for up to 14 years of follow-up were evaluated to measure height-adjusted liver cystic volume and height-adjusted liver volume. Among them, 245 patients with liver cyst volume >50 ml at baseline were included in the longitudinal analysis. Linear mixed models on log-transformed height-adjusted liver cystic volume and height-adjusted liver volume were fitted to approximate mean annual rate of change for each outcome. The association of sex, body mass index, genotype, baseline height-adjusted total kidney volume, and Mayo imaging class was assessed. We calculated height-adjusted liver cystic volume ranges for each specific age and divided them into five classes on the basis of annual percentage increase in height-adjusted liver cystic volume. RESULTS: The mean annual growth rate of height-adjusted liver cystic volume was 12% (95% confidence interval, 11.1% to 13.1%; P<0.001), whereas that for height-adjusted liver volume was 2% (95% confidence interval, 1.9% to 2.6%; P<0.001). Women had higher baseline height-adjusted liver cystic volume than men, but men had higher height-adjusted liver cystic volume growth rate than women by 2% (95% confidence interval, 0.4% to 4.5%; P=0.02). Whereas the height-adjusted liver cystic volume growth rate decreased in women after menopause, no decrease was observed in men at any age. Body mass index, genotype, and baseline height-adjusted total kidney volume were not associated with the growth rate of height-adjusted liver cystic volume or height-adjusted liver volume. According to the height-adjusted liver cystic volume growth rate, patients were classified into five classes (number of women, men in each class): A (24, six); B (44, 13); C (43, 48); D (28, 17); and E (13, nine). CONCLUSIONS: Compared with height-adjusted liver volume, the use of height-adjusted liver cystic volume showed greater separations in volumetric progression of polycystic liver disease. Similar to the Mayo imaging classification for the kidney, the progression of polycystic liver disease may be categorized on the basis of patient's age and height-adjusted liver cystic volume.

Transarterial Radioembolization for Hepatocellular Carcinoma with Major Vascular Invasion: A Nationwide Propensity Score-Matched Analysis with Target Trial Emulation.

PURPOSE: To examine National Cancer Database (NCDB) data to comparatively evaluate overall survival (OS) between patients undergoing transarterial radioembolization (TARE) and those undergoing systemic therapy for hepatocellular carcinoma with major vascular invasion (HCC-MVI). METHODS: One thousand five hundred fourteen patients with HCC-MVI undergoing first-line TARE or systemic therapy were identified from the NCDB. OS was compared using propensity score-matched Cox regression and landmark analysis. Efficacy was also compared within a target trial framework. RESULTS: TARE usage doubled between 2010 and 2015. Intervals before treatment were longer for TARE than for systemic therapy (mean [median], 66.5 [60] days vs 46.8 (35) days, respectively, P < .0001). In propensity-score-matched and landmark-time-adjusted analyses, TARE was found to be associated with a hazard ratio of 0.74 (95 % CI, 0.60-0.91; P = .005) and median OS of 7.1 months (95 % CI, 5.0-10.5) versus 4.9 months (95 % CI, 3.9-6.5) for systemically treated patients. In an emulated target trial involving 236 patients with unilobular HCC-MVI, a low number of comorbidities, creatinine levels <2.0 mg/dL, bilirubin levels <2.0 mg/dL, and international normalized ratio <1.7, TARE was found to be associated with a hazard ratio of 0.57 (95 % CI, 0.39-0.83; P = .004) and a median OS of 12.9 months (95 % CI, 7.6-19.2) versus 6.5 months (95 % CI, 3.6-11.1) for the systemic therapy arm. CONCLUSIONS: In propensity-score-matched analyses involving pragmatic and target trial HCC-MVI cohorts, TARE was found to be associated with significant survival benefits compared with systemic therapy. Although not a substitute for prospective trials, these findings suggest that the increasing use of TARE for HCC-MVI is accompanied by improved OS. Further trials of TARE in patients with HCC-MVI are needed, especially to compare with newer systemic therapies.

T-bet+CD27+CD21- B cells poised for plasma cell differentiation during antibody-mediated rejection of kidney transplants.

Alloimmune responses driven by donor-specific antibodies (DSAs) can lead to antibody-mediated rejection (ABMR) in organ transplantation. Yet, the cellular states underlying alloreactive B cell responses and the molecular components controlling them remain unclear. Using high-dimensional profiling of B cells in a cohort of 96 kidney transplant recipients, we identified expanded numbers of CD27+CD21- activated memory (AM) B cells that expressed the transcription factor T-bet in patients who developed DSAs and progressed to ABMR. Notably, AM cells were less frequent in DSA+ABMR- patients and at baseline levels in DSA- patients. RNA-Seq analysis of AM cells in patients undergoing ABMR revealed these cells to be poised for plasma cell differentiation and to express restricted IGHV sequences reflective of clonal expansion. In addition to T-bet, AM cells manifested elevated expression of interferon regulatory factor 4 and Blimp1, and upon coculture with autologous T follicular helper cells, differentiated into DSA-producing plasma cells in an IL-21-dependent manner. The frequency of AM cells was correlated with the timing and severity of ABMR manifestations. Importantly, T-bet+ AM cells were detected within kidney allografts along with their restricted IGHV sequences. This study delineates a pivotal role for AM cells in promoting humoral responses and ABMR in organ transplantation and highlights them as important therapeutic targets.

Prognostic Value of Fibroblast Growth Factor 23 in Autosomal Dominant Polycystic Kidney Disease.

INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst growth and a loss of functioning renal mass, but a decline in glomerular filtration rate (GFR) and onset of end-stage renal disease (ESRD) occur late in the disease course. There is therefore a great need for early prognostic biomarkers in this disorder. METHODS: We measured baseline serum fibroblast growth factor 23 (FGF23) levels in 192 patients with ADPKD from the Consortium for Radiologic Imaging Studies of PKD (CRISP) cohort that were followed for a median of 13 years and tested the association between FGF23 levels and change over time in height-adjusted total kidney volume (htTKV), GFR, and time to the composite endpoints of ESRD, death, and doubling of serum creatinine. RESULTS: Patients in the highest quartile for baseline FGF23 level had a higher rate of increase in htTKV (0.95% per year, P = 0.0016), and faster rate of decline in GFR (difference of -1.03 ml/min/1.73 m2 per year, P = 0.005) compared with the lowest quartile, after adjusting for other covariates, including htTKV and genotype. The highest quartile of FGF23 was also associated with a substantial increase in risk for the composite endpoint of ESRD, death, or doubling of serum creatinine (hazard ratio [HR] of 2.45 in the fully adjusted model, P = 0.03). CONCLUSION: FGF23 is a prognostic biomarker for disease progression and clinically important outcomes in ADPKD, and has additive value to established imaging and genetic biomarkers.

Transitional B cell cytokines predict renal allograft outcomes.

Early immunological biomarkers that predict rejection and chronic allograft loss are needed to inform preemptive therapy and improve long-term outcomes. Here, we prospectively examined the ratio of interleukin-10 (IL-10) to tumor necrosis factor-α (TNFα) produced by transitional-1 B cells (T1B) 3 months after transplantation as a predictive biomarker for clinical and subclinical renal allograft rejection and subsequent clinical course. In both Training (n = 162) and Internal Validation (n = 82) Sets, the T1B IL-10/TNFα ratio 3 months after transplantation predicted both clinical and subclinical rejection anytime in the first year. The biomarker also predicted subsequent late rejection with a lead time averaging 8 months. Among biomarker high-risk patients, 60% had early rejection, of which 48% recurred later in the first posttransplant year. Among high-risk patients without early rejection, 74% developed rejection later in the first year. In contrast, only 5% of low-risk patients had early and 5% late rejection. The biomarker also predicted rejection in an External Validation Set (n = 95) and in key patient subgroups, confirming generalizability. Biomarker high-risk patients exhibited progressively worse renal function and decreased 5-year graft survival compared to low-risk patients. Treatment of B cells with anti-TNFα in vitro augmented the IL-10/TNFα ratio, restored regulatory activity, and inhibited plasmablast differentiation. To conclude, the T1B IL-10/TNFα ratio was validated as a strong predictive biomarker of renal allograft outcomes and provides a rationale for preemptive therapeutic intervention with TNF blockade.