Impact of ABCB1 and ABCG2 Transporter in Outcome of Gallbladder Cancer.

Background: Gallbladder cancer (GBC) is a biologically aggressive malignancy requiring appropriate biomarkers to improve its outcome. Role of ABC transporters (ABCB1 and ABCG2) has been linked to cancer aggressiveness, tumorigenesis and multidrug resistance. Herein, we studied the prognostic implication of ABCB1 and ABCG2 in GBC. Methods: Fresh tissue (tumour & normal) samples collected from 54 patients who underwent R0 resection, were analysed for mRNA and protein expression of ABCB1 and ABCG2 by quantitative Real-Time PCR and western blotting, respectively, in this prospective study. The molecular findings were correlated with clinical-pathological parameters using χ2 and fisher exact test. The molecular changes in ABCB1 and ABCG2 were analysed for predicting overall survival (OS), disease-free survival (DFS) and response to chemotherapy using Kaplan-Meier log-rank test and Cox regression multivariate analysis. Results: The mean age of the cohort was 50 ± 13.2 with 26 (48.1%) in patients having early stage gallbladder cancer (GBC). Over-expression of ABCB1 and ABCG2 was noted in 32/54 (59%) and 40/54 (74%) cases, respectively. The protein expression of ABCB1(P-glycoprotein) and ABCG2 (BCRP) was higher in 27/54 (50%) and 37/54 (59%) cases, respectively. The mean OS and DFS was 20.7 ± 11.5 and 19.3 ± 12.2 months at median follow-up of 24 months. The TNM stage, lymph node metastasis, and presence of gallstone were significant factors for predicting OS and DFS on multivariate analysis. Both ABCB1 and ABCG2 did not show any significant correlation with OS and DFS with similar incidences of late death and recurrence among over-expression and down-expression. Sub-group comparison suggests that change in expression pattern of ABCB1 and ABCG2 may not affect response to chemotherapy in GBC. Conclusion: Altered expression of ABCB1 and ABCG2 may not be a useful prognostic marker for survival or response to chemotherapy in GBC. Presently, histo-pathological characteristics and associated gallstones are the important predictors for survival and recurrence in GBC.

The Banff 2022 Kidney Meeting Work Plan: Data-driven refinement of the Banff Classification for renal allografts.

The XVIth Banff Meeting for Allograft Pathology was held in Banff, Alberta, Canada, from September 19 to 23, 2022, as a joint meeting with the Canadian Society of Transplantation. In addition to a key focus on the impact of microvascular inflammation and biopsy-based transcript analysis on the Banff Classification, further sessions were devoted to other aspects of kidney transplant pathology, in particular T cell-mediated rejection, activity and chronicity indices, digital pathology, xenotransplantation, clinical trials, and surrogate endpoints. Although the output of these sessions has not led to any changes in the classification, the key role of Banff Working Groups in phrasing unanswered questions, and coordinating and disseminating results of investigations addressing these unanswered questions was emphasized. This paper summarizes the key Banff Meeting 2022 sessions not covered in the Banff Kidney Meeting 2022 Report paper and also provides an update on other Banff Working Group activities relevant to kidney allografts.

Scalable and interpretable alternative to chart review for phenotype evaluation using standardized structured data from electronic health records.

OBJECTIVES: Chart review as the current gold standard for phenotype evaluation cannot support observational research on electronic health records and claims data sources at scale. We aimed to evaluate the ability of structured data to support efficient and interpretable phenotype evaluation as an alternative to chart review. MATERIALS AND METHODS: We developed Knowledge-Enhanced Electronic Profile Review (KEEPER) as a phenotype evaluation tool that extracts patient's structured data elements relevant to a phenotype and presents them in a standardized fashion following clinical reasoning principles. We evaluated its performance (interrater agreement, intermethod agreement, accuracy, and review time) compared to manual chart review for 4 conditions using randomized 2-period, 2-sequence crossover design. RESULTS: Case ascertainment with KEEPER was twice as fast compared to manual chart review. 88.1% of the patients were classified concordantly using charts and KEEPER, but agreement varied depending on the condition. Missing data and differences in interpretation accounted for most of the discrepancies. Pairs of clinicians agreed in case ascertainment in 91.2% of the cases when using KEEPER compared to 76.3% when using charts. Patient classification aligned with the gold standard in 88.1% and 86.9% of the cases respectively. CONCLUSION: Structured data can be used for efficient and interpretable phenotype evaluation if they are limited to relevant subset and organized according to the clinical reasoning principles. A system that implements these principles can achieve noninferior performance compared to chart review at a fraction of time.

The Association of Dialysis Facility Payer Mix With Access to Kidney Transplantation.

Importance: Insurance coverage for patients with end-stage kidney disease has shifted toward more commercially insured patients at dialysis facilities. The associations among insurance status, facility-level payer mix, and access to kidney transplantation are unclear. Objective: To determine the association of dialysis facility commercial payer mix and 1-year incidence of wait-listing for kidney transplantation, and to delineate the association of commercial insurance at the patient vs facility level. Design, Setting, and Participants: This retrospective population-based cohort study used data from the United States Renal Data System from 2013 to 2018. Participants included patients aged 18 to 75 years initiating chronic dialysis between 2013 and 2017, excluding patients with a prior kidney transplant or with major contraindications to kidney transplant. Data were analyzed from August 2021 and May 2023. Exposure: Dialysis facility commercial payer mix, calculated as the proportion of patients with commercial insurance per facility. Main Outcomes and Measures: The primary outcome was patients added to a waiting list for kidney transplant within 1 year of dialysis initiation. Multivariable Cox regression, censoring for death, was used to adjust for patient-level (demographic, socioeconomic, and medical) and facility-level factors. Results: A total of 233 003 patients (97 617 [41.9%] female patients; mean [SD] age, 58.0 [12.1] years) across 6565 facilities met inclusion criteria. Participants included 70 062 Black patients (30.1%), 42 820 Hispanic patients (18.4%), 105 368 White patients (45.2%), and 14 753 patients (6.3%) who identified as another race or ethnicity (eg, American Indian or Alaskan Native, Asian, Native Hawaiian or Pacific Islander, and multiracial). Of 6565 dialysis facilities, the mean (SD) commercial payer mix was 21.2% (15.6 percentage points). Patient-level commercial insurance was associated with increased incidence of wait-listing (adjusted hazard ratio [aHR], 1.86; 95% CI, 1.80-1.93; P < .001). At the facility-level and before covariate adjustment, higher commercial payer mix was associated with increased wait-listing (fourth vs first payer mix quartile [Q]: HR, 1.79; 95% CI, 1.67-1.91; P < .001). However, after covariate-adjustment, including adjusting for patient-level insurance status, commercial payer mix was not significantly associated with outcome (Q4 vs Q1: aHR, 1.02; 95% CI, 0.95-1.09; P = .60). Conclusions and Relevance: In this national cohort study of patients newly initiated on chronic dialysis, although patient-level commercial insurance was associated with higher access to the kidney transplant waiting lists, there was no independent association of facility-level commercial payer mix with patients being added to waiting lists for transplant. As the landscape of insurance coverage for dialysis evolves, the potential downstream impact on access to kidney transplant should be monitored.

Increased volume of organ offers and decreased efficiency of kidney placement under circle-based kidney allocation.

The newest kidney allocation policy kidney allocation system 250 (KAS250) broadened geographic distribution while increasing allocation system complexity. We studied the volume of kidney offers received by transplant centers and the efficiency of kidney placement since KAS250. We identified deceased-donor kidney offers (N = 907,848; N = 36,226 donors) to 185 US transplant centers from January 1, 2019, to December 31, 2021 (policy implemented March 15, 2021). Each unique donor offered to a center was considered a single offer. We compared the monthly volume of offers received by centers and the number of centers offered before the first acceptance using an interrupted time series approach (pre-/post-KAS250). Post-KAS250, transplant centers received more kidney offers (level change: 32.5 offers/center/mo, P < .001; slope change: 3.9 offers/center/mo, P = .003). The median monthly offer volume post-/pre-KAS250 was 195 (interquartile range 137-253) vs. 115 (76-151). There was no significant increase in deceased-donor transplant volume at the center level after KAS250, and center-specific changes in offer volume did not correlate with changes in transplant volume (r = -0.001). Post-KAS250, the number of centers to whom a kidney was offered before acceptance increased significantly (level change: 1.7 centers/donor, P < .001; slope change: 0.1 centers/donor/mo, P = .014). These findings demonstrate the logistical burden of broader organ sharing, and future allocation policy changes will need to balance equity in transplant access with the operational efficiency of the allocation system.

Phytocompounds targeting epigenetic modulations: an assessment in cancer.

For centuries, plants have been serving as sources of potential therapeutic agents. In recent years, there has been a growing interest in investigating the effects of plant-derived compounds on epigenetic processes, a novel and captivating Frontier in the field of epigenetics research. Epigenetic changes encompass modifications to DNA, histones, and microRNAs that can influence gene expression. Aberrant epigenetic changes can perturb key cellular processes, including cell cycle control, intercellular communication, DNA repair, inflammation, stress response, and apoptosis. Such disruptions can contribute to cancer development by altering the expression of genes involved in tumorigenesis. However, these modifications are reversible, offering a unique avenue for therapeutic intervention. Plant secondary compounds, including terpenes, phenolics, terpenoids, and sulfur-containing compounds are widely found in grains, vegetables, spices, fruits, and medicinal plants. Numerous plant-derived compounds have demonstrated the potential to target these abnormal epigenetic modifications, including apigenin (histone acetylation), berberine (DNA methylation), curcumin (histone acetylation and epi-miRs), genistein (histone acetylation and DNA methylation), lycopene (epi-miRs), quercetin (DNA methylation and epi-miRs), etc. This comprehensive review highlights these abnormal epigenetic alterations and discusses the promising efficacy of plant-derived compounds in mitigating these deleterious epigenetic signatures in human cancer. Furthermore, it addresses ongoing clinical investigations to evaluate the therapeutic potential of these phytocompounds in cancer treatment, along with their limitations and challenges.

The New Distance-Based Kidney Allocation System: Implications for Patients, Transplant Centers, and Organ Procurement Organizations.

Purpose of Review: The goal of deceased donor kidney allocation policy is to provide objective prioritization for donated kidneys, and policy has undergone a series of revisions in the past decade in attempt to achieve equity and utility in access to kidney transplantation. Most recently, to address geographic disparities in access to kidney transplantation, the Kidney Allocation System changed to a distance-based allocation system-colloquially termed "KAS 250"-moving away from donor service areas as the geographic basis of allocation. We review the early impact of this policy change on access to transplant for patients, and on complexity of organ allocation and transplantation for transplant centers and organ procurement organizations. Recent Findings: Broader sharing of kidneys has increased complexity of the allocation system, as transplant centers and OPOs now interact in larger networks. The increased competition resulting from this system, and the increased operational burden on centers and OPOs resulting from greater numbers of organ offers, may adversely affect organ utilization. Preliminary results suggest an increase in transplant rate overall but a trend toward higher kidney discard and increased cold ischemia time. Summary: The KAS 250 allocation policy changed the geographic basis of deceased donor kidney distribution in a manner that is intended to reduce geographic disparities in access to kidney transplantation. Close monitoring of this policy's impact on patients, transplant center behavior, and process measures is critical to the aim of maximizing access to transplant while achieving transplant equity.

Previous SARS-CoV-2 infection or a third dose of vaccine elicited cross-variant neutralising antibodies in vaccinated solid-organ transplant recipients.

Objectives: The SARS-CoV-2 pandemic poses a great threat to global health, particularly in solid organ transplant recipients (SOTRs). A 3-dose mRNA vaccination protocol has been implemented for the majority of SOTRs, yet their immune responses are less effective compared to healthy controls (HCs). Methods: We analyzed the humoral immune responses against the vaccine strain and variants of concern (VOC), including the highly mutated-omicron variant in 113 SOTRs, of whom 44 had recovered from COVID-19 (recovered-SOTRs) and 69 had not contracted the virus (COVID-naïve). In addition, 30 HCs, 8 of whom had recovered from COVID-19, were also studied. Results: Here, we report that three doses of the mRNA vaccine had only a modest effect in eliciting anti-viral antibodies against all viral strains in the fully vaccinated COVID-naive SOTRs (n = 47). Only 34.0% of this group of patients demonstrated both detectable anti-RBD IgG with neutralization activities against alpha, beta, and delta variants, and only 8.5% of them showed additional omicron neutralizing capacities. In contrast, 79.5% of the recovered-SOTRs who received two doses of vaccine demonstrated both higher anti-RBD IgG levels and neutralizing activities against all VOC, including omicron. Conclusion: These findings illustrate a significant impact of previous infection on the development of anti-SARS-CoV-2 immune responses in vaccinated SOTRs and highlight the need for alternative strategies to protect a subset of a lesser-vaccine responsive population.

Kidney nonprocurement in deceased donors with acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is common in deceased organ donors and is associated with high rates of kidney discard by transplant centers. High discard rates may consequently drive nonprocurement of these kidneys by organ procurement organizations. We aimed to study the relationship between donor AKI and kidney nonprocurement. METHODS: Using U.S. registry data, we identified donors with at least one organ recovered from 2008 to 2018. We compared characteristics of donors with no kidneys procured across AKI stages, and used multivariable logistic regression to evaluate the relationship between AKI severity and kidney nonprocurement. RESULTS: Overall 14 543 kidneys from 7620 donors were not procured, among which 93% were from donors with AKI. For 6945 donors with no kidneys procured but an extrarenal organ recovered, most had stage 3 (51%), followed by stage 1 (27%) and stage 2 AKI (15%). Nonprocured stage 3 donors were the youngest and had the lowest Kidney Donor Risk Index of all nonprocured donors. Adjusted odds of kidney nonprocurement were 1.14 (95%CI 1.02-1.27) for stage 1, 1.25 (95%CI 1.12-1.41) for stage 2, and 10.37 (95%CI 9.30-11.56) for stage 3 donors, compared to non-AKI donors. Among donors with minimum creatinine <1.5 mg/dl, stage 2 and 3 AKI were still associated with significantly higher odds of nonprocurement. CONCLUSIONS: AKI severity is a strong risk factor for kidney nonprocurement. Efforts to address the organ shortage should focus on encouraging procurement and utilization of kidneys from deceased donors with severe AKI, given the large and rising prevalence of donor AKI and excellent transplant outcomes with these kidneys.

Deceased Donor Procurement Biopsy Practices, Interpretation, and Histology-Based Decision-Making: A Survey of US Kidney Transplant Centers.

Introduction: The utility of kidney procurement biopsies is controversial. Understanding the current landscape of how clinicians obtain and use biopsies in organ evaluation may help inform consensus-building efforts. Methods: An electronic survey was distributed to clinicians at US kidney transplant programs (April 22, 2021-June 30, 2021) to evaluate donor biopsy indications, frequency, processing and interpretation, and impact of findings on practices. Results: Responses from staff involved in organ acceptance (73% surgeons, 20% nephrologists, 6% coordinators) at 95 transplant centers were analyzed, representing 40% of US transplant centers and 50% of recent deceased donor kidney transplant volume. More than a third of centers (35%) reported obtaining procurement biopsies on most-to-all kidneys. Most clinicians decided when to biopsy jointly with the Organ Procurement Organization (OPO) (82%) based on formal criteria for the decision (72%), although 41% reported having requested a biopsy outside of the criteria. Most respondents used a semiquantitative scoring system for interpretation (57%). Many respondents reported rarely or never having access to renal specialty pathologists (37%) or to telepathology (59%). Most respondents reported that a favorable biopsy result would encourage them to accept a "marginal" donor kidney (72%); nearly half (46%) indicated that an unfavorable biopsy result would lead to decline of a standard criteria kidney. Conclusion: Procurement biopsies are commonly used in organ acceptance decisions despite inconsistent access to experienced renal pathologists and heterogeneous approaches to criteria, scoring, and interpretation. Ongoing study and consensus building are needed to direct procurement biopsy practice toward increasing organ utilization and reducing allocation inefficiency.

The difference between cystatin C- and creatinine-based assessment of kidney function in acute heart failure.

AIMS: Acute heart failure (HF) is associated with muscle mass loss, potentially leading to overestimation of kidney function using serum creatinine-based estimated glomerular filtration rate (eGFRsCr ). Cystatin C-based eGFR (eGFRCysC ) is less muscle mass dependent. Changes in the difference between eGFRCysC and eGFRsCr may reflect muscle mass loss. We investigated the difference between eGFRCysC and eGFRsCr and its association with clinical outcomes in acute HF patients. METHODS AND RESULTS: A post hoc analysis was performed in 841 patients enrolled in three trials: Diuretic Optimization Strategy Evaluation (DOSE), Renal Optimization Strategies Evaluation (ROSE), and Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF). Intra-individual differences between eGFRs (eGFRdiff ) were calculated as eGFRCysC -eGFRsCr at serial time points during HF admission. We investigated associations of (i) change in eGFRdiff between baseline and day 3 or 4 with readmission-free survival up to day 60; (ii) index hospitalization length of stay (LOS) and readmission with eGFRdiff at day 60. eGFRCysC reclassified 40% of samples to more advanced kidney dysfunction. Median eGFRdiff was -4 [-11 to 1.5] mL/min/1.73 m2 at baseline, became more negative during admission and remained significantly different at day 60. The change in eGFRdiff between baseline and day 3 or 4 was associated with readmission-free survival (adjusted hazard ratio per standard deviation decrease in eGFRdiff : 1.14, P = 0.035). Longer index hospitalization LOS and readmission were associated with more negative eGFRdiff at day 60 (both P ≤ 0.026 in adjusted models). CONCLUSIONS: In acute HF, a marked difference between eGFRCysC and eGFRsCr is present at baseline, becomes more pronounced during hospitalization, and is sustained at 60 day follow-up. The change in eGFRdiff during HF admission and eGFRdiff at day 60 are associated with clinical outcomes.

Association of transplant center market concentration and local organ availability with deceased donor kidney utilization.

Although there is a shortage of kidneys available for transplantation, many transplantable kidneys are not procured or are discarded after procurement. We investigated whether local market competition and/or organ availability impact kidney procurement/utilization. We calculated the Herfindahl-Hirschman Index (HHI) for deceased donor kidney transplants (2015-2019) for 58 US donation service areas (DSAs) and defined 4 groups: HHI ≤ 0.32 (high competition), HHI = 0.33-0.51 (medium), HHI = 0.53-0.99 (low), and HHI = 1 (monopoly). We calculated organ availability for each DSA as the number kidneys procured per incident waitlisted candidate, grouped as: <0.42, 0.42-0.69, >0.69. Characteristics of procured organs were similar across groups. In adjusted logistic regression, the HHI group was inconsistently associated with composite export/discard (reference: high competition; medium: OR 1.16, 95% CI 1.11-1.20; low 1.01, 0.96-1.06; monopoly 1.19, 1.13-1.26) and increasing organ availability was associated with export/discard (reference: availability <0.42; 0.42-0.69: OR 1.35, 95% CI 1.30-1.40; >0.69: OR 1.83, 95% CI 1.73-1.93). When analyzing each endpoint separately, lower competition was associated with higher export and only market monopoly was weakly associated with lower discard, whereas higher organ availability was associated with export and discard. These results indicate that local organ utilization is more strongly influenced by the relative intensity of the organ shortage than by market competition between centers.

Patients with High Priority for Kidney Transplant Who Are Not Given Expedited Placement on the Transplant Waiting List Represent Lost Opportunities.

BACKGROUND: Kidney transplantation is associated with the best outcomes for most patients with ESKD. The national Kidney Allocation System prioritizes patients with Estimated Post-Transplant Survival (EPTS) scores in the top 20% for expedited access to optimal deceased donor kidneys. METHODS: We studied adults aged ≥18 years in the United States Renal Data System with top 20% EPTS scores who had been preemptively waitlisted or initiated dialysis in 2015-2017. We evaluated time to waitlist placement, transplantation, and mortality with unadjusted and multivariable survival models. RESULTS: Of 42,445 patients with top 20% EPTS scores (mean age, 38.0 years; 57% male; 59% White patients, and 31% Black patients), 7922 were preemptively waitlisted. Among 34,523 patients initiating dialysis, the 3-year cumulative waitlist placement incidence was 37%. Numerous factors independently associated with waitlisting included race, income, and having noncommercial insurance. For example, waitlisting was less likely for Black versus White patients, and for patients in the lowest-income neighborhoods versus those in the highest-income neighborhoods. Among patients initiating dialysis, 61% lost their top 20% EPTS status within 30 months versus 18% of patients who were preemptively listed. The 3-year incidence of deceased and living donor transplantation was 5% and 6%, respectively, for patients who initiated dialysis and 26% and 44%, respectively, for patients who were preemptively listed. CONCLUSIONS: Many patients with ESKDqualifying with top 20% EPTS status are not placed on the transplant waiting list in a timely manner, with significant variation on the basis of demographic and social factors. Patients who are preemptively listed are more likely to receive benefits of top 20% EPTS status. Efforts to expedite care for qualifying candidates are needed, and automated transplant referral for patients with the best prognoses should be considered. PODCAST: This article contains a podcast athttps://www.asn-online.org/media/podcast/JASN/2021_07_30_JASN2020081146.mp3.

Febrile neutropenia after kidney transplantation.

Neutropenia is common after kidney transplant. There are few data on febrile neutropenia episodes (FNE) after kidney transplant. We studied FNE in a single-center retrospective cohort of 1682 kidney transplant recipients. Neutropenia (absolute neutrophil count [ANC] <1000) occurred in 32% and FNE in 3%. There were 56 FNE. Median time to FNE was 143 days, and median time from onset of neutropenia to onset of FNE was 5.5 days. The most common sources of infection were urine, blood, and lungs, and in 20% of FNE no source was identified. No infectious organism was identified in 46% of FNE, and opportunistic infections were uncommon. Patient survival was similar among those with and without FNE, but FNE was associated with increased death-censored graft failure (DCGF). Following FNE, acute rejection occurred in 31% and DCGF in 15%, often in the setting of persistent reduced immunosuppression. In conclusion, FNE are common after kidney transplant and are associated with inferior long-term outcomes.