Publications by authors named "Daniel G Maluf"

68 Publications

Artificial Intelligence May Predict Early Sepsis After Liver Transplantation.

Front Physiol 2021 6;12:692667. Epub 2021 Sep 6.

University of Maryland School of Medicine, Baltimore, MD, United States.

Sepsis, post-liver transplantation, is a frequent challenge that impacts patient outcomes. We aimed to develop an artificial intelligence method to predict the onset of post-operative sepsis earlier. This pilot study aimed to identify "physiomarkers" in continuous minute-by-minute physiologic data streams, such as heart rate, respiratory rate, oxygen saturation (SpO2), and blood pressure, to predict the onset of sepsis. The model was derived from a cohort of 5,748 transplant and non-transplant patients across intensive care units (ICUs) over 36 months, with 92 post-liver transplant patients who developed sepsis. Using an alert timestamp generated with the Third International Consensus Definition of Sepsis (Sepsis-3) definition as a reference point, we studied up to 24 h of continuous physiologic data prior to the event, totaling to 8.35 million data points. One hundred fifty-five features were generated using signal processing and statistical methods. Feature selection identified 52 highly ranked features, many of which included blood pressures. An eXtreme Gradient Boost (XGB) classifier was then trained on the ranked features by 5-fold cross validation on all patients ( = 5,748). We identified that the average sensitivity, specificity, positive predictive value (PPV), and area under the receiver-operator curve (AUC) of the model after 100 iterations was 0.94 ± 0.02, 0.9 ± 0.02, 0.89 ± 0.01, respectively, and 0.97 ± 0.01 for predicting sepsis 12 h before meeting criteria. The data suggest that machine learning/deep learning can be applied to continuous streaming data in the transplant ICU to monitor patients and possibly predict sepsis.
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http://dx.doi.org/10.3389/fphys.2021.692667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8450439PMC
September 2021

Recent progress and remaining hurdles toward clinical xenotransplantation.

Xenotransplantation 2021 05 23;28(3):e12681. Epub 2021 Mar 23.

Transplantation Center, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland.

Background: Xenotransplantation has made tremendous progress over the last decade.

Methods: We discuss kidney and heart xenotransplantation, which are nearing initial clinical trials.

Results: Life sustaining genetically modified kidney xenografts can now last for approximately 500 days and orthotopic heart xenografts for 200 days in non-human primates. Anti-swine specific antibody screening, preemptive desensitization protocols, complement inhibition and targeted immunosuppression are currently being adapted to xenotransplantation with the hope to achieve better control of antibody-mediated rejection (AMR) and improve xenograft longevity. These newest advances could probably facilitate future clinical trials, a significant step for the medical community, given that dialysis remains difficult for many patients and can have prohibitive costs. Performing a successful pig-to-human clinical kidney xenograft, that could last for more than a year after transplant, seems feasible but it still has significant potential hurdles to overcome. The risk/benefit balance is progressively reaching an acceptable equilibrium for future human recipients, e.g. those with a life expectancy inferior to two years. The ultimate question at this stage would be to determine if a "proof of concept" in humans is desirable, or whether further experimental/pre-clinical advances are still needed to demonstrate longer xenograft survival in non-human primates.

Conclusion: In this review, we discuss the most recent advances in kidney and heart xenotransplantation, with a focus on the prevention and treatment of AMR and on the recipient's selection, two aspects that will likely be the major points of discussion in the first pig organ xenotransplantation clinical trials.
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http://dx.doi.org/10.1111/xen.12681DOI Listing
May 2021

Epigenetic modifications and the development of kidney graft fibrosis.

Curr Opin Organ Transplant 2021 02;26(1):1-9

Division of Transplant, Department of Surgery, School of Medicine, University of Maryland, Baltimore, Maryland, USA.

Purpose Of Review: To outline recent discoveries in epigenetic regulatory mechanisms that have potential implications in the development of renal fibrosis following kidney transplantation.

Recent Findings: The characterization of renal fibrosis following kidney transplantation has shown TGFβ/Smad signaling to play a major role in the progression to chronic allograft dysfunction. The onset of unregulated proinflammatory pathways are only exacerbated by the decline in regulatory mechanisms lost with progressive patient age and comorbidities such as hypertension and diabetes. However, significant developments in the recognition of epigenetic regulatory markers upstream of aberrant TGFβ-signaling has significant clinical potential to provide therapeutic targets for the treatment of renal fibrosis. In addition, discoveries in extracellular vesicles and the characterization of their cargo has laid new framework for the potential to evaluate patient outcomes independent of invasive biopsies.

Summary: The current review summarizes the main findings in epigenetic machinery specific to the development of renal fibrosis and highlights therapeutic options that have significant potential to translate into clinical practice.
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http://dx.doi.org/10.1097/MOT.0000000000000839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059991PMC
February 2021

Characterization of Gut Microbiome in Liver Transplant Recipients With Nonalcoholic Steatohepatitis.

Transplant Direct 2020 Dec 10;6(12):e625. Epub 2020 Nov 10.

Division of Transplant Surgery, Department of Surgery, University of Tennessee Health Science Center, Memphis, TN.

Nonalcoholic fatty liver disease (NAFLD) and its progressive form nonalcoholic steatohepatitis (NASH) are a growing problem globally and recur even after liver transplant (LT). We aim to characterize the gut dysbiosis in patients who developed recurrent NAFLD compared with patients without recurrence following LT.

Methods: Twenty-one patients who received LT for NASH and had a protocol liver biopsy performed beyond 1-y post-LT were included prospectively (January 2018-December 2018). Genomic DNA extraction, next-generation sequencing, and quantitative PCR analysis were performed on stool samples collected within 1.1 ± 1.6 y from time of liver biopsy.

Results: Recurrent NAFLD was noted in 15 of the 21 included patients. Stool microbiome analysis at the genus level showed significant loss of and increasing associated with NAFLD recurrence. Quantitative PCR analysis revealed significantly decreased relative abundance of Firmicutes in patients with NAFLD activity scores (NASs) ≥5 as compared with patients with lower NAS scores, whereas Bacteroidetes were significantly increased with higher NAS ( < 0.05). Firmicutes ( = 0.007) and group ( = 0.037) were inversely correlated, whereas Bacteroidetes ( = 0.001) showed a positive correlation with higher hepatic steatosis content. The Firmicutes/Bacteroidetes ratios were higher in patients without NAFLD or NASH as compared with patients diagnosed with NAFLD or NASH at the time of sample collection.

Conclusions: , Firmicutes, and may play protective roles in the development of recurrent NAFLD in LT recipients, whereas Fusobacteria and Bacteroidetes may play pathogenic roles. These findings highlight the potential role of the "gut-liver" axis in the pathogenesis of NAFLD recurrence after LT.
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http://dx.doi.org/10.1097/TXD.0000000000001033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665248PMC
December 2020

Achieving Solid Organ Transplant Tolerance: New Findings, More Questions and the Search Continues.

Transplantation 2020 08;104(8):1531-1532

Research Transplant Institute, James D Eason Transplant Institute, Department of Surgery, School of Medicine, The University of Tennessee Health Science Center, Memphis, TN.

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http://dx.doi.org/10.1097/TP.0000000000003264DOI Listing
August 2020

Living donor program crisis management plans: Current landscape and talking point recommendations.

Am J Transplant 2020 02 28;20(2):546-552. Epub 2019 Oct 28.

Medstar Georgetown Transplant Institute, Washington, District of Columbia.

Although minimized by expert evaluation, operative technique, and postoperative care, the extremely low risk of perioperative mortality following living kidney or liver donation will never be eliminated. Furthermore, anticipation of poor donor outcome may simultaneously be a source of anxiety for physicians and programs and also be a circumstance for which they are unprepared. We conducted a national survey of US transplant surgeons to understand experiences with and systemic preparedness for the event of a living donor death. Respondents represented 87 unique transplant programs (71 kidney and 16 liver donor programs). Perioperative deaths were rare, as expected. Although most respondents (N = 57, 64% of total respondents; 88% of liver programs) reported being moderately to extremely concerned about a future living donor death at their institution, only 30 (33% of total program respondents) had a written plan available in the case of such an event; 63% of programs would find guidance and recommendations useful. To help address this gap, the American Society of Transplantation Live Donor Community of Practice (AST LDCOP) developed Living Donor Crisis Management Plan Talking Points suitable to guide crisis plan development at transplant programs.
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http://dx.doi.org/10.1111/ajt.15618DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984987PMC
February 2020

Mechanistic analyses in kidney transplant recipients prospectively randomized to two steroid free regimen-Low dose Tacrolimus with Everolimus versus standard dose Tacrolimus with Mycophenolate Mofetil.

PLoS One 2019 28;14(5):e0216300. Epub 2019 May 28.

Department of Medicine-Nephrology, Northwestern University, Chicago, IL, United States of America.

Calcineurin inhibitors (CNI), the cornerstone of immunosuppression after transplantation are implicated in nephrotoxicity and allograft dysfunction. We hypothesized that combined low doses of CNI and Everolimus (EVR) may result in better graft outcomes and greater tolerogenic milieu. Forty adult renal transplant recipients were prospectively randomized to (steroid free) low dose Tacrolimus (TAC) and EVR or standard dose TAC and Mycophenolate (MMF) after Alemtuzumab induction. Baseline characteristics were statistically similar. EVR levels were maintained at 3-8 ng/ml. TAC levels were 4.5±1.9 and 6.4±1.5 ng/ml in the TAC+EVR and TAC+MMF group respectively. Follow up was 14±4 and 17±5 months respectively and included protocol kidney biopsies at 3 and 12 months post-transplantation. Rejection-rate was lower in the TAC+EVR group. However patient and overall graft survival, eGFR and incidence of adverse events were similar. TAC+EVR induced expansion of CD4+CD25hiFoxp3+ regulatory T cells as early as 3 months and expansion of IFN-γ+CD4+CD25hiFoxp3+ regulatory T cells at 12 months post-transplant. Gene expression profile showed a trend toward decreased inflammation, angiogenesis and connective tissue growth in the TAC+EVR Group. Thus, greater tolerogenic mechanisms were found to be operating in patients with low dose TAC+EVR and this might be responsible for the lower rejection-rate than in patients on standard dose TAC+MMF. However, further studies with longer follow up and evaluating impact on T regulatory cells are warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0216300PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538151PMC
January 2020

Adenosine 2A Receptor Activation Attenuates Ischemia Reperfusion Injury During Extracorporeal Cardiopulmonary Resuscitation.

Ann Surg 2019 06;269(6):1176-1183

Department of Surgery, University of Virginia, Charlottesville, VA.

Objective: We tested the hypothesis that systemic administration of an A2AR agonist will reduce multiorgan IRI in a porcine model of ECPR.

Summary Background Data: Advances in ECPR have decreased mortality after cardiac arrest; however, subsequent IRI contributes to late multisystem organ failure. Attenuation of IRI has been reported with the use of an A2AR agonist.

Methods: Adult swine underwent 20 minutes of circulatory arrest, induced by ventricular fibrillation, followed by 6 hours of reperfusion with ECPR. Animals were randomized to vehicle control, low-dose A2AR agonist, or high-dose A2AR agonist. A perfusion specialist using a goal-directed resuscitation protocol managed all the animals during the reperfusion period. Hourly blood, urine, and tissue samples were collected. Biochemical and microarray analyses were performed to identify differential inflammatory markers and gene expression between groups.

Results: Both the treatment groups demonstrated significantly higher percent reduction from peak lactate after reperfusion compared with vehicle controls. Control animals required significantly more fluid, epinephrine, and higher final pump flow while having lower urine output than both the treatment groups. The treatment groups had lower urine NGAL, an early marker of kidney injury (P = 0.01), lower plasma aspartate aminotransferase, and reduced rate of troponin rise (P = 0.01). Pro-inflammatory cytokines were lower while anti-inflammatory cytokines were significantly higher in the treatment groups.

Conclusions: Using a novel and clinically relevant porcine model of circulatory arrest and ECPR, we demonstrated that a selective A2AR agonist significantly attenuated systemic IRI and warrants clinical investigation.
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http://dx.doi.org/10.1097/SLA.0000000000002685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6757347PMC
June 2019

Ex Situ Liver Machine Perfusion as an Emerging Graft Protective Strategy in Clinical Liver Transplantation: the Dawn of a New Era.

Transplantation 2019 10;103(10):2003-2011

Department of Surgery, University of Tennessee Health System, Memphis, TN.

The disparity between the number of available donor livers and patients awaiting a liver transplant has led transplant centers to accept suboptimal livers. There has been no universally accepted tool to predict the posttransplant function of these organs to safely increase the donor pool, protect these livers against ischemia-reperfusion injury, or improve their quality before implantation. Ex situ liver machine preservation has emerged as a promising novel graft protective strategy in the field of liver transplantation, with remarkable ongoing research and evolving clinical trials within Europe and the United States. This technology has been shown to be safe and feasible in the clinical liver transplantation field, has shown to reduce liver ischemia-reperfusion injury, and has shown to decrease the graft discard rate compared with conventional static cold storage. This review focuses on the current status of ex situ machine preservation in clinical liver transplantation, describing the most important technical aspects with the emphasis on the findings of the most recent clinical studies.
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http://dx.doi.org/10.1097/TP.0000000000002772DOI Listing
October 2019

Messengers of tolerance.

Hum Immunol 2018 May 2;79(5):362-372. Epub 2018 Feb 2.

Translational Genomics and Transplant Laboratory, Department of Surgery, University of Virginia, Charlottesville 22903, United States. Electronic address:

The use of immunosuppressant drugs after organ transplantation has brought great success in the field of organ transplantation with respect to short-term outcome. However, major challenges (i.e., limited improvement of long-term survival, immunosuppressant toxicity, infections and carcinoma) demand alternate treatment approaches that minimizes the use of immunosuppressants. Interestingly, few studies have identified groups of transplant patients who developed operational tolerance and thereby keep their allograft without complications in absence of immunosuppressants. These rare groups of patients are of particular interest as study subjects for understanding mechanisms of graft tolerance that could be leveraged in future for inducing tolerance and for understanding mechanisms involved in improving long-term allograft outcomes. Also, biomarkers from these studies could benefit the larger transplant population by their application in immunosuppressant tailoring and identification of tolerant patients among patients with stably functioning allografts. This review compiles several gene expression studies performed in samples from tolerant patients in different solid organ transplantations to identify key genes and associated molecular pathways relevant to tolerance. This review is aimed at putting forth all this important work done thus far and to identify research gaps that need to be filled, in order to achieve the greater purpose of these studies.
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http://dx.doi.org/10.1016/j.humimm.2018.01.008DOI Listing
May 2018

Intragraft Molecular Pathways Associated with Tolerance Induction in Renal Transplantation.

J Am Soc Nephrol 2018 02 30;29(2):423-433. Epub 2017 Nov 30.

Translational Genomics Transplant Laboratory, Department of Surgery, University of Virginia, Charlottesville, Virginia.

The modern immunosuppression regimen has greatly improved short-term allograft outcomes but not long-term allograft survival. Complications associated with immunosuppression, specifically nephrotoxicity and infection risk, significantly affect graft and patient survival. Inducing and understanding pathways underlying clinical tolerance after transplantation are, therefore, necessary. We previously showed full donor chimerism and immunosuppression withdrawal in highly mismatched allograft recipients using a bioengineered stem cell product (FCRx). Here, we evaluated the gene expression and microRNA expression profiles in renal biopsy samples from tolerance-induced FCRx recipients, paired donor organs before implant, and subjects under standard immunosuppression (SIS) without rejection and with acute rejection. Unlike allograft samples showing acute rejection, samples from FCRx recipients did not show upregulation of T cell- and B cell-mediated rejection pathways. Gene expression pathways differed slightly between FCRx samples and the paired preimplantation donor organ samples, but most of the functional gene networks overlapped. Notably, compared with SIS samples, FCRx samples showed upregulation of genes involved in pathways, like B cell receptor signaling. Additionally, prediction analysis showed inhibition of proinflammatory regulators and activation of anti-inflammatory pathways in FCRx samples. Furthermore, integrative analyses (microRNA and gene expression profiling from the same biopsy sample) identified the induction of regulators with demonstrated roles in the downregulation of inflammatory pathways and maintenance of tissue homeostasis in tolerance-induced FCRx samples compared with SIS samples. This pilot study highlights the utility of molecular intragraft evaluation of pathways related to FCRx-induced tolerance and the use of integrative analyses for identifying upstream regulators of the affected downstream molecular pathways.
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http://dx.doi.org/10.1681/ASN.2017030348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5791065PMC
February 2018

Geographic variation in liver transplantation persists despite implementation of Share35.

Hepatol Res 2018 Mar 30;48(4):225-232. Epub 2017 Aug 30.

Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia, USA.

Aim: Geographic disparities persist in the USA despite locoregional organ sharing policies. The impact of national organ sharing policies on waiting-list mortality on a regional basis remains unknown.

Methods: Data on all adult liver transplants between 1 February 2002 and 31 March 2015 were obtained from the United Network for Organ Sharing/Organ and Transplantation Network. Multivariable Cox proportional hazards models were constructed in a time-to-event analysis to estimate waiting-list mortality for the pre- and post-Share35 eras.

Results: In the analyzed time period, 134 247 patients were listed for transplantation and 54 510 received organs (42.8%). Listing volume increased following the introduction of the Share35 organ sharing policy (15 976 candidates pre- vs. 18 375 post) without significant regional changes as did the number of transplants (7210 pre- vs. 8224 post). Waiting-list mortality improved from 12.2% to 8.1% (P < 0.001). Adjusted waiting-list mortality ratios remained geographically disparate. Region 10 and region 11 had lower hazard ratios (HR) but still had increased mortality (1.46, 95% confidence interval [CI] 1.34-1.60, P < 0.001; and HR 1.49, 95% CI 1.37-1.62, P < 0.001, respectively). Regions 3 and 6 had increased HR with persistently elevated waiting-list mortality (1.79, 95% CI 1.66-1.93, P < 0.001; and HR 1.29, 95% CI 1.16-1.45, P < 0.001, respectively). Model for End-state Liver Disease (MELD) exception continued to propagate a survival benefit (HR 0.65, 95% CI 0.63-0.68, P < 0.001).

Conclusions: Although overall waiting-list mortality has decreased, geographic disparities persist, but appear reduced despite broader sharing policies enacted by Share35. The advantage afforded by MELD exception, while still present, was diminished by Share35 as organs are being shifted to MELD >35 candidates. The disparities highlighted by our findings imply a need to review current allocation policies to best balance local, regional, and national transplant environments.
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http://dx.doi.org/10.1111/hepr.12922DOI Listing
March 2018

Advanced non-alcoholic steatohepatitis cirrhosis: A high-risk population for pre-liver transplant portal vein thrombosis.

World J Hepatol 2017 Jan;9(3):139-146

Jonathan G Stine, Curtis K Argo, Stephen H Caldwell, Patrick G Northup, Division of Gastroenterology and Hepatology, Department of Medicine, Center for the Study of Coagulation Disorders in Liver Disease, University of Virginia, Charlottesville, VA 22908-0708, United States.

Aim: To examine if liver transplant recipients with high-risk non-alcoholic steatohepatitis (NASH) are at increased risk for pre-transplant portal venous thrombosis.

Methods: Data on all liver transplants in the United States from February 2002 through September 2014 were analyzed. Recipients were sorted into three distinct groups: High-risk (age > 60, body mass index > 30 kg/m, hypertension and diabetes), low-risk and non-NASH cirrhosis. Multivariable logistic regression models were constructed.

Results: Thirty-five thousand and seventy-two candidates underwent liver transplantation and of those organ recipients, 465 were transplanted for high-risk and 2775 for low-risk NASH. Two thousand six hundred and twenty-six (7.5%) recipients had pre-transplant portal vein thrombosis; 66 (14.2%) of the high-risk NASH group had portal vein thrombosis 328 (11.8%) of the low-risk NASH group. In general, all NASH recipients were less likely to be male or African American and more likely to be obese. In adjusted multivariable regression analyses, high-risk recipients had the greatest risk of pre-transplant portal vein thrombosis with OR = 2.11 (95%CI: 1.60-2.76, < 0.001) when referenced to the non-NASH group.

Conclusion: Liver transplant candidates with high-risk NASH are at the greatest risk for portal vein thrombosis development prior to transplantation. These candidates may benefit from interventions to decrease their likelihood of clot formation and resultant downstream hepatic decompensating events. Prospective study is needed.
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http://dx.doi.org/10.4254/wjh.v9.i3.139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295147PMC
January 2017

Cellular and molecular profiling of graft injury post renal transplantation.

Curr Opin Organ Transplant 2017 Feb;22(1):36-45

aTransplant Division, Translational Genomics Transplant Laboratory bNephrology Division, Center for Immunity, Inflammation and Regenerative Medicine cTransplant Surgery, University of Virginia, Charlottesville, Virginia, USA.

Purpose Of Review: Continues advancements in assessing methods for biomolecules that have assisted to identify surrogate candidate biomarkers that can be used to monitor the transplanted organ. These high-throughput methods can help researchers to significantly speed up the identification and the validation steps, which are crucial factors for biomarker discovery efforts. However, this task in transplantation confronts multiple limitations. The review summarizes main findings using 'omics approaches in the evaluation of different types of allograft injury with the overarching aim of evaluating the next steps for transferring the available data to the clinical setting.

Recent Findings: Significant discoveries have been made about the molecular and cellular mechanisms that associate with graft injury that may lead to early biomarkers of graft injury (prediction and diagnosis) with the goal of improving long-term outcomes by extending the lifespan of the graft and/or identifying new therapeutic targets.

Summary: Common efforts among researchers are needed for transferring biomarkers to the clinical setting and, moreover, elucidate pathways that may allow for early interventions to avoid fibrosis progression and graft loss. Large and prospective studies for validation of current available data under strict analytical evaluation are needed to move biomarkers from the discovery phase to validation and clinical implementation.
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http://dx.doi.org/10.1097/MOT.0000000000000377DOI Listing
February 2017

Liver transplant recipients with portal vein thrombosis receiving an organ from a high-risk donor are at an increased risk for graft loss due to hepatic artery thrombosis.

Transpl Int 2016 Dec 6;29(12):1286-1295. Epub 2016 Oct 6.

Division of Gastroenterology & Hepatology, Department of Medicine, Center for the Study of Coagulation Disorders in Liver Disease, University of Virginia, Charlottesville, VA, USA.

We hypothesize that recipients with pretransplant portal vein thrombosis (PVT) receiving organs from high-risk donors (HRD) are at an increased risk of HAT. Data on all liver transplants in the United States from February 2002 to March 2015 were analyzed. Recipients were sorted into two groups: those with PVT and those without. HRDs were defined by donor risk index (DRI) >1.7. Multivariable logistic regression models were constructed to assess the independent risk factors for HAT with the resultant graft loss ≤90 days from transplantation. A total of 60 404 candidates underwent liver transplantation; of those recipients, 623 (1.0%) had HAT, of which 66.0% (n = 411) received organs from HRDs compared with 49.3% (n = 29 473) in recipients without HAT (P < 0.001); 2250 (3.7%) recipients had pretransplantation PVT and received organs from HRDs. On adjusted multivariable analysis, PVT with a HRD organ was the most significant independent risk factor (OR 3.56, 95% CI 2.52-5.02, P < 0.001) for the development of HAT. Candidates with pretransplant PVT who receive an organ from a HRD are at the highest risk for postoperative HAT independent of other measurable factors. Recipients with pretransplant PVT would benefit from careful donor selection and possibly anticoagulation perioperatively.
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http://dx.doi.org/10.1111/tri.12855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5154764PMC
December 2016

Biomarkers of Transplant Tolerance: A Provisional Analysis for an Unmet Need.

Transplantation 2016 Apr;100(4):705-6

1 Department of Surgery, University of Virginia, Charlottesville, VA. 2 Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia Health System, Charlottesville, VA.

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http://dx.doi.org/10.1097/TP.0000000000001106DOI Listing
April 2016

Epigenetics in Kidney Transplantation: Current Evidence, Predictions, and Future Research Directions.

Transplantation 2016 Jan;100(1):23-38

1 Translational Genomics Transplant Laboratory, Division of Transplant, Department of Surgery, University of Virginia, Charlottesville, VA. 2 Division of Nephrology, Department of Medicine, University of Virginia, Charlottesville, VA. 3 Transplant Surgery, Division of Transplant, Department of Surgery, University of Virginia, Charlottesville, VA.

Epigenetic modifications are changes to the genome that occur without any alteration in DNA sequence. These changes include cytosine methylation of DNA at cytosine-phosphate diester-guanine dinucleotides, histone modifications, microRNA interactions, and chromatin remodeling complexes. Epigenetic modifications may exert their effect independently or complementary to genetic variants and have the potential to modify gene expression. These modifications are dynamic, potentially heritable, and can be induced by environmental stimuli or drugs. There is emerging evidence that epigenetics play an important role in health and disease. However, the impact of epigenetic modifications on the outcomes of kidney transplantation is currently poorly understood and deserves further exploration. Kidney transplantation is the best treatment option for end-stage renal disease, but allograft loss remains a significant challenge that leads to increased morbidity and return to dialysis. Epigenetic modifications may influence the activation, proliferation, and differentiation of the immune cells, and therefore may have a critical role in the host immune response to the allograft and its outcome. The epigenome of the donor may also impact kidney graft survival, especially those epigenetic modifications associated with early transplant stressors (e.g., cold ischemia time) and donor aging. In the present review, we discuss evidence supporting the role of epigenetic modifications in ischemia-reperfusion injury, host immune response to the graft, and graft response to injury as potential new tools for the diagnosis and prediction of graft function, and new therapeutic targets for improving outcomes of kidney transplantation.
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http://dx.doi.org/10.1097/TP.0000000000000878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6843994PMC
January 2016

Donor Hepatic Steatosis Induce Exacerbated Ischemia-Reperfusion Injury Through Activation of Innate Immune Response Molecular Pathways.

Transplantation 2015 Dec;99(12):2523-33

1 Transplant Division, Department of Surgery, University of Virginia, Charlottesville, VA. 2 Department of Pathology, Virginia Commonwealth University, Richmond, VA. 3 Department of Pathology, University of Virginia, Charlottesville, VA.

Background: Severe liver steatosis is a known risk factor for increased ischemia-reperfusion injury (IRI) and poor outcomes after liver transplantation (LT). This study aimed to identify steatosis-related molecular mechanisms associated with IRI exacerbation after LT.

Methods: Paired graft biopsies (n = 60) were collected before implantation (L1) and 90 minutes after reperfusion (L2). The LT recipients (n = 30) were classified by graft macrosteatosis: without steatosis (WS) of 5% or less (n = 13) and with steatosis (S) of 25% or greater (n = 17). Plasma samples were collected at L1, L2, and 1 day after LT (postoperative [POD]1) for cytokines evaluation. Tissue RNA was isolated for gene expression microarrays. Probeset summaries were obtained using robust multiarray average algorithm. Pairwise comparisons were fit using 2-sample t test. P values 0.01 or less were significant (false discovery rate <5%). Molecular pathway analyses were conducted using Ingenuity Pathway Analysis tool.

Results: Significantly differentially expressed genes were identified for WS and S grafts after reperfusion. Comprehensive comparison analysis of molecular profiles revealed significant association of S grafts molecular profile with innate immune response activation, macrophage production of nitric oxide and reactive oxygen species, IL-6, IL-8, IL-10 signaling activation, recruitment of granulocytes, and accumulation of myeloid cells. Postreperfusion histological patterns of S grafts revealed neutrophilic infiltration surrounding fat accumulation. Circulating proinflammatory cytokines after reperfusion and 24 hours after LT concurred with intragraft-deregulated molecular pathways. All tested cytokines were significantly increased in plasma of S grafts recipients after reperfusion when compared with WS group at same time.

Conclusions: Increases of graft steatosis exacerbate IRI by exacerbation of innate immune response after LT. Preemptive strategies should consider it for safety usage of steatotic livers.
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http://dx.doi.org/10.1097/TP.0000000000000857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4668234PMC
December 2015

A step closer to individualization of hepatocellular carcinoma therapy.

J Vasc Interv Radiol 2015 May;26(5):733-4

Translational Research Laboratory, Department of Surgery, University of Virginia, 409 Lane Rd., P.O. Box 800709, Charlottesville, VA 22908.

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http://dx.doi.org/10.1016/j.jvir.2015.01.034DOI Listing
May 2015

Combined transmesenteric and transhepatic recanalization of chronic portal and mesenteric vein occlusion to treat bleeding duodenal varices.

J Vasc Interv Radiol 2014 Aug;25(8):1295-9

Division of Interventional Radiology, Department of Radiology and Medical Imaging, University of Virginia Health System, Box 800170, 1215 Lee Street, Charlottesville, VA 22908.

Two patients presented with bleeding duodenal varices secondary to mesenteric and portal vein chronic occlusion. After a failed transhepatic recanalization, a combined transmesenteric and transhepatic approach was used to recanalize the chronic portal and mesenteric venous obstruction. The occluded segment was treated with transmesenteric stent placement in one patient and stent placement and coil embolization of varices in the second patient. Follow-up imaging and endoscopy showed decompression of the duodenal varices in both patients and absence of further bleeding episodes.
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http://dx.doi.org/10.1016/j.jvir.2013.11.021DOI Listing
August 2014

Liver transplant complications in hepatitis C infected recipients: recurrence versus rejection.

Expert Rev Gastroenterol Hepatol 2014 Jul 18;8(5):453-6. Epub 2014 Mar 18.

Department of Surgery, University of Virginia, P.O. Box 800625, 904 Lane Rd, Charlottesville, VA 22908-0625, USA.

Despite improvement on outcomes post liver transplantation (LT), complications such as HCV recurrence (HCV-rec) and acute cellular rejection (ACR) continue to be a challenge for transplant physicians. Accurate diagnostic tools to better dissect between those complications post-LT are crucial for prompt and correct diagnosis and treatment. It is well known that the overlapping features of clinical and histo-pathological characteristics between these conditions turn difficult the appropriate differential diagnosis. Recently, new technological advances had supported the field of biomarker discovery in many diseases. Disease biomarkers capable to differentiate ACR versus HCV-rec post-LT is a long waited task in the transplant community. This editorial describes and discusses potential biomarkers of disease differentiation including recent reports in the field of genomics, proteomics, immunohistochemistry among other technologies.
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http://dx.doi.org/10.1586/17474124.2014.898562DOI Listing
July 2014

The urine microRNA profile may help monitor post-transplant renal graft function.

Kidney Int 2014 Feb 11;85(2):439-49. Epub 2013 Sep 11.

Translational Genomics Transplant Laboratory, Transplant Division, Department of Surgery, University of Virginia, Charlottesville, Virginia, USA.

Noninvasive, cost-effective biomarkers that allow accurate monitoring of graft function are needed in kidney transplantation. Since microRNAs (miRNAs) have emerged as promising disease biomarkers, we sought to establish an miRNA signature in urinary cell pellets comparing kidney transplant patients diagnosed with chronic allograft dysfunction (CAD) with interstitial fibrosis and tubular atrophy and those recipients with normal graft function. Overall, we evaluated 191 samples from 125 deceased donor primary kidney transplant recipients in the discovery, initial validation, and the longitudinal validation studies for noninvasive monitoring of graft function. Of 1733 mature miRNAs studied using microarrays, 22 were found to be differentially expressed between groups. Ontology and pathway analyses showed inflammation as the principal biological function associated with these miRNAs. Twelve selected miRNAs were longitudinally evaluated in urine samples of an independent set of 66 patients, at two time points after kidney transplant. A subset of these miRNAs was found to be differentially expressed between groups early after kidney transplant before histological allograft injury was evident. Thus, a panel of urine miRNAs was identified as potential biomarkers for monitoring graft function and anticipating progression to CAD in kidney transplant patients.
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http://dx.doi.org/10.1038/ki.2013.338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3946645PMC
February 2014

Regulation of molecular pathways in ischemia-reperfusion injury after liver transplantation.

Transplantation 2013 Nov;96(10):926-34

1 Transplant Division, Department of Surgery, University of Virginia, Charlottesville, VA. 2 Department of Pathology, Virginia Commonwealth University, Richmond, VA. 3 Address correspondence to Daniel G. Maluf, M.D., Liver Transplant Program, Transplant Division, Department of Surgery, University of Virginia, 1300 Jefferson Park Avenue, Barringer 5, Room 5417, Charlottesville, VA.

Background: Ischemia-reperfusion (I/R) injury is a multifactorial phenomenon that occurs during the transplant event and frequently compromises early graft function after liver transplantation (LT). Current comprehension of molecular mechanisms and regulation processes of I/R injury lacks clarity. MicroRNA (miRNA) regulation results critical in several biological processes.

Methods: This study evaluated gene expression and miRNA expression profiles using microarrays in 34 graft biopsies collected at preimplantation (L1) and at 90 min postreperfusion (L2) from consecutives deceased-donor LT recipients. miRNA profiles were first analyzed. Data integration analysis (gene expression/miRNA expression) aimed to identify potential target genes for each identified miRNA from the L1/L2 differential gene expression profile.

Results: Pairwise comparison analyses identified 40 miRNAs and 3168 significantly differentially expressed genes at postreperfusion time compared with preimplantation time. Pathway analysis of miRNAs associated these profiles with antiapoptosis, inhibition of cellular proliferation, and proinflammatory processes. Target analysis identified an miRNA-associated molecular profile of 2172 genes involved in cellular growth and proliferation modulation by cell cycle regulation, cell death and survival, and proinflammatory and anti-inflammatory processes. miRNA-independent genes involved proinflammatory molecules.

Conclusion: We identified a miRNA profile involved in posttranscriptional regulatory mechanisms in I/R injury post-LT. A better understanding of these molecular processes involved in I/R may contribute to develop new strategies to minimize graft injury.
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http://dx.doi.org/10.1097/TP.0b013e3182a20398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4377108PMC
November 2013

Hepatic disease biomarkers and liver transplantation: what is the potential utility of microRNAs?

Expert Rev Gastroenterol Hepatol 2013 Feb;7(2):157-70

Department of Surgery, University of Virginia, Transplant Division, PO Box 800625, 409 Lane Rd, Charlottesville, VA 22908-0625, USA.

Liver transplantation represents the treatment of choice for acute hepatic failure or chronically induced end stage of liver disease. Molecular characterization of hepatic injury and recovery processes encloses the key for biomarker discovery in the liver transplantation field. Several pathological hepatic processes were demonstrated to be associated with deregulated miRNA profiles. Moreover, abnormal concentration levels of circulating cell-free miRNAs correlate with specific hepatic injury. The high molecular stability and emerging rapid assessment techniques invite further consideration of miRNAs as feasible monitoring and outcome predictive biomarkers for liver disease and liver transplantation. The present review aims to provide an overview of recent achievements in research on the potential applicability of miRNAs as biomarkers in liver disease and liver transplantation.
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http://dx.doi.org/10.1586/egh.12.71DOI Listing
February 2013

MiRNAs in kidney transplantation: potential role as new biomarkers.

Expert Rev Mol Diagn 2013 Jan;13(1):93-104

University of Virginia, Department of Surgery, PO Box 800679, Charlottesville, VA, USA.

MiRNAs (miRNAs) are a class of small endogenous, noncoding RNAs with important roles in regulating gene expression known to play a role in many cellular functions including cellular differentiation, cell proliferation, cell development and functional regulation of the immune system, among others. As such, miRNAs are emerging not only as potential biomarkers but also as potential therapeutic targets. Here, we review the currently published work on miRNAs and renal transplantation as it pertains to ischemia-reperfusion injury, acute kidney injury, delayed graft function, calcineurin inhibitor toxicity, acute rejection, chronic allograft dysfunction and kidney fibrosis.
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http://dx.doi.org/10.1586/erm.12.131DOI Listing
January 2013

Identification of biomarkers to assess organ quality and predict posttransplantation outcomes.

Transplantation 2012 Oct;94(8):851-8

Division of Transplantation, Department of Surgery, University of Virginia School of Medicine, Charlottesville, VA 22908-0679, USA.

Unlabelled: The increased disparity between organ supply and need has led to the use of extended criteria donors and donation after cardiac death donors with other comorbidities.

Methods: We have examined the preimplantation transcriptome of 112 kidney transplant recipient samples from 100 deceased-donor kidneys by microarray profiling. Subject groups were segregated based on estimated glomerular filtration rate (eGFR) at 1 month after transplantation: the GFR-high group (n=74) included patients with eGFR 45 mL/min per 1.73 m(2), whereas the GFR-low group (n=35) included patients with eGFR 45 mL/min or less per 1.73 m(2).

Results: Gene expression profiling identified higher expression of 160 probe sets (140 genes) in the GFR-low group, whereas expression of 37 probe sets (33 genes) was higher in the GFR-high group (P<0.01, false discovery rate <0.2). Four genes (CCL5, CXCR4, ITGB2, and EGF) were selected based on fold change and P value and further validated using an independent set of samples. A random forest analysis identified three of these genes (CCL5, CXCR4, and ITGB2) as important predictors of graft function after transplantation.

Conclusions: Inclusion of pretransplantation molecular gene expression profiles in donor quality assessment systems may provide the necessary information for better donor organ selection and function prediction. These biomarkers would further allow a more objective and complete assessment of procured renal allografts at pretransplantation time.
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http://dx.doi.org/10.1097/TP.0b013e318263702bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3927314PMC
October 2012

Molecular profiles of HCV cirrhotic tissues derived in a panel of markers with clinical utility for hepatocellular carcinoma surveillance.

PLoS One 2012 5;7(7):e40275. Epub 2012 Jul 5.

University of Virginia, Department of Surgery, Transplant Division. Charlottesville, Virginia, United States of America.

Background: Early hepatocellular carcinoma (HCC) detection is difficult because low accuracy of surveillance tests. Genome-wide analyses were performed using HCV-cirrhosis with HCC to identify predictive signatures.

Methodology/principal Findings: Cirrhotic liver tissue was collected from 107 HCV-infected patients with diagnosis of HCC at pre-transplantation and confirmed in explanted livers. Study groups included: 1) microarray hybridization set (n = 80) including patients without (woHCC = 45) and with (wHCC = 24) HCC, and with incidental HCC (iHCC = 11); 2) independent validation set (n = 27; woHCC = 16, wHCC = 11). Pairwise comparisons were performed using moderated t-test. FDR<1% was considered significant. L(1)-penalized logistic regression model was fit for woHCC and wHCC microarrays, and tested against iHCC. Prediction model genes were validated in independent set by qPCR. The genomic profile was associated with genetic disorders and cancer focused on gene expression, cell cycle and cell death. Molecular profile analysis revealed cell cycle progression and arrest at G2/M, but progressing to mitosis; unregulated DNA damage check-points, and apoptosis. The prediction model included 17 molecules demonstrated 98.6% of accuracy and correctly classified 6 out of 11 undiagnosed iHCC cases. The best model performed even better in the additional independent set.

Conclusions/significances: The molecular analysis of HCV-cirrhotic tissue conducted to a prediction model with good performance and high potential for HCC surveillance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0040275PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390353PMC
April 2013

Reduced expression of inflammatory genes in deceased donor kidneys undergoing pulsatile pump preservation.

PLoS One 2012 24;7(4):e35526. Epub 2012 Apr 24.

Translational Genomics Transplant Laboratory, University of Virginia, Charlottesville, Virginia, United States of America.

Background: The use of expanded criteria donor kidneys (ECD) had been associated with worse outcomes. Whole gene expression of pre-implantation allograft biopsies from deceased donor kidneys (DDKs) was evaluated to compare the effect of pulsatile pump preservation (PPP) vs. cold storage preservation (CSP) on standard and ECD kidneys.

Methodology/principal Findings: 99 pre-implantation DDK biopsies were studied using gene expression with GeneChips. Kidneys transplant recipients were followed post transplantation for 35.8 months (range = 24-62). The PPP group included 60 biopsies (cold ischemia time (CIT) = 1,367+/-509 minutes) and the CSP group included 39 biopsies (CIT = 1,022+/-485 minutes) (P<0.001). Donor age (42.0±14.6 vs. 34.1±14.2 years, P = 0.009) and the percentage of ECD kidneys (PPP = 35% vs. CSP = 12.8%, P = 0.012) were significantly different between groups. A two-sample t-test was performed, and probe sets having a P<0.001 were considered significant. Probe set level linear models were fit using cold ischemia time and CSP/PPP as independent variables to determine significant probe sets (P<0.001) between groups after adjusting for cold ischemia time. Thus, 43 significant genes were identified (P<0.001). Over-expression of genes associated with inflammation (CD86, CD209, CLEC4, EGFR2, TFF3, among others) was observed in the CSP group. Cell-to-cell signaling and interaction, and antigen presentation were the most important pathways with genes significantly over-expressed in CSP kidneys. When the analysis was restricted to ECD kidneys, genes involved in inflammation were also differentially up-regulated in ECD kidneys undergoing CSP. However, graft survival at the end of the study was similar between groups (P = 0.2). Moreover, the incidence of delayed graft function was not significant between groups.

Conclusions/significance: Inflammation was the most important up-regulated pattern associated with pre-implantation biopsies undergoing CSP even when the PPP group has a larger number of ECD kidneys. No significant difference was observed in delayed graft function incidence and graft function post-transplantation. These findings support the use of PPP in ECD donor kidneys.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035526PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3335841PMC
August 2012
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