Publications by authors named "Matthew Griffin"

179 Publications

Ultrafine Particles Emitted through Routine Operation of a Hairdryer.

Environ Sci Technol 2021 Jun 9. Epub 2021 Jun 9.

Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States.

Particulate matter is a large concern for human health. Fine and ultrafine particulate matter has been shown to negatively impact human health; for example, it causes cardiopulmonary diseases. Current regulation targets the size of the particles, but composition also impacts toxicity. Indoor sources of air pollution pose unique challenges for human health due to the potential for human exposure to high concentrations in confined spaces. In this work, six hairdryers were each operated within a plexiglass chamber, and their emissions were analyzed with transmission electron microscopy and energy-dispersive spectroscopy. All hairdryers were found to emit ultrafine iron, carbon, and copper. In addition, emissions from two hairdryers primarily contained silver nanoparticles in the ultrafine range (<100 nm). The ultrafine particle emission rates for the hairdryers that did not contain silver were measured and found to be lower than ultrafine particle emissions by gas stoves and electric burners. Based on their size, these particles can either remain in the lung or enter the bloodstream after inhalation and potentially cause long-term health effects.
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http://dx.doi.org/10.1021/acs.est.0c08564DOI Listing
June 2021

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

Lancet Oncol 2021 06 14;22(6):813-823. Epub 2021 May 14.

Radiotherapy Department, Gustave Roussy University Hospital, Villejuif, Cedex, France.

Background: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.

Methods: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.

Findings: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported.

Interpretation: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.

Funding: Merck Sharpe & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00090-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191233PMC
June 2021

Could NAD Precursor Supplements Induce a Legacy of Protection against Diabetic Nephropathy?

J Am Soc Nephrol 2021 Jun 14;32(6):1270-1273. Epub 2021 Apr 14.

Regenerative Medicine Institute at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, Ireland.

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http://dx.doi.org/10.1681/ASN.2021020275DOI Listing
June 2021

Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.

Acta Neuropathol 2021 Jun 19;141(6):945-957. Epub 2021 Mar 19.

Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute Rotterdam, PO Box 2040, 3000 CA, Rotterdam, The Netherlands.

Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1 mutations. Patients harbouring IDH1 mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1 have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1 mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.
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http://dx.doi.org/10.1007/s00401-021-02291-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113211PMC
June 2021

Reference intervals for commonly requested biochemical and haematological parameters in a healthy Irish adult Caucasian population.

Ir J Med Sci 2021 Feb 11. Epub 2021 Feb 11.

Department of Clinical Biochemistry, Saolta University Health Care Group (SUHCG), Galway University Hospitals, Newcastle Road, Galway, Ireland.

Introduction: In laboratory medicine, reference intervals (RIs) are key decision support tools used to guide the clinical interpretation of numerical test results. Best practice suggests each laboratory establishes RIs in the local population prior to introducing an assay into routine clinical practice.

Aim: The aim of this study was to define RIs for frequently requested biochemical/haematological parameters in a healthy adult Irish Caucasian population.

Methods: A cross-sectional study of non-pregnant apparently healthy volunteers was conducted. Baseline demographics, anthropometric and laboratory measurements were recorded. In total, 37 commonly requested biochemical (serum, n = 26) and haematological (venous blood, n = 11) ISO15189:2012 accredited tests were analysed, using the Roche Cobas® Sebia Capillarys 3 Tera and Siemens Advia® 2120i platforms following standard operating procedures. RIs were defined according to the International Federation of Clinical Chemistry (IFCC) recommended method.

Results: Of 208 apparently healthy volunteers, 76 failed to meet the study inclusion criteria. The reference population comprised of 132 participants (males: n = 65, 49.2%) with a median age of 29.7 (18.1-62.2) years. RIs for the majority of biochemical/haematological parameters were broadly in accord with those provided by Pathology Harmony (UK)/Irish RI Harmonisation Project and the manufacturer Roche Diagnostics. However, the established RI defined for HbA: 27-37 mmol/mol was markedly different from that quoted nationally, HbA: 20-42 mmol/mol.

Conclusion: Normative biological intervals established in a healthy adult Irish population for 37 commonly requested biochemical/haematological parameters will be a valuable aid to result interpretation in clinical laboratories after appropriate verification in accordance with ISO 15189: 2012.
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http://dx.doi.org/10.1007/s11845-021-02535-0DOI Listing
February 2021

Natriuretic Equation to Predict Loop Diuretic Response in Patients With Heart Failure.

J Am Coll Cardiol 2021 Feb;77(6):695-708

Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. Electronic address:

Background: Most acute decompensated heart failure admissions are driven by congestion. However, residual congestion is common and often driven by the lack of reliable tools to titrate diuretic therapy. The authors previously developed a natriuretic response prediction equation (NRPE), which predicts sodium output using a spot urine sample collected 2 h after loop diuretic administration.

Objectives: The purpose of this study was to validate the NRPE and describe proof-of-concept that the NRPE can be used to guide diuretic therapy.

Methods: Two cohorts were assembled: 1) the Diagnosing and Targeting Mechanisms of Diuretic Resistance (MDR) cohort was used to validate the NRPE to predict 6-h sodium output after a loop diuretic, which was defined as poor (<50 mmol), suboptimal (<100 mmol), or excellent (>150 mmol); and 2) the Yale Diuretic Pathway (YDP) cohort, which used the NRPE to guide loop diuretic titration via a nurse-driven automated protocol.

Results: Evaluating 638 loop diuretic administrations, the NRPE showed excellent discrimination with areas under the curve ≥0.90 to predict poor, suboptimal, and excellent natriuretic response, and outperformed clinically obtained net fluid loss (p < 0.05 for all cutpoints). In the YDP cohort (n = 161) using the NRPE to direct therapy mean daily urine output (1.8 ± 0.9 l vs. 3.0 ± 0.8 l), net fluid output (-1.1 ± 0.9 l vs. -2.1 ± 0.9 l), and weight loss (-0.3 ± 0.3 kg vs. -2.5 ± 0.3 kg) improved substantially following initiation of the YDP (p < 0.001 for all pre-post comparisons).

Conclusions: Natriuretic response can be rapidly and accurately predicted by the NRPE, and this information can be used to guide diuretic therapy during acute decompensated heart failure. Additional study of diuresis guided by the NRPE is warranted.
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http://dx.doi.org/10.1016/j.jacc.2020.12.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8114781PMC
February 2021

The genetic landscape of polycystic kidney disease in Ireland.

Eur J Hum Genet 2021 May 16;29(5):827-838. Epub 2021 Jan 16.

School of Pharmacy and Biomolecular Science, Royal College of Surgeons in Ireland, Dublin, Ireland.

Polycystic kidney diseases (PKDs) comprise the most common Mendelian forms of renal disease. It is characterised by the development of fluid-filled renal cysts, causing progressive loss of kidney function, culminating in the need for renal replacement therapy or kidney transplant. Ireland represents a valuable region for the genetic study of PKD, as family sizes are traditionally large and the population relatively homogenous. Studying a cohort of 169 patients, we describe the genetic landscape of PKD in Ireland for the first time, compare the clinical features of patients with and without a molecular diagnosis and correlate disease severity with autosomal dominant pathogenic variant type. Using a combination of molecular genetic tools, including targeted next-generation sequencing, we report diagnostic rates of 71-83% in Irish PKD patients, depending on which variant classification guidelines are used (ACMG or Mayo clinic respectively). We have catalogued a spectrum of Irish autosomal dominant PKD pathogenic variants including 36 novel variants. We illustrate how apparently unrelated individuals carrying the same autosomal dominant pathogenic variant are highly likely to have inherited that variant from a common ancestor. We highlight issues surrounding the implementation of the ACMG guidelines for variant pathogenicity interpretation in PKD, which have important implications for clinical genetics.
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http://dx.doi.org/10.1038/s41431-020-00806-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110806PMC
May 2021

Frontiers in cancer immunotherapy-a symposium report.

Ann N Y Acad Sci 2021 04 13;1489(1):30-47. Epub 2020 Nov 13.

Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford, California.

Cancer immunotherapy has dramatically changed the approach to cancer treatment. The aim of targeting the immune system to recognize and destroy cancer cells has afforded many patients the prospect of achieving deep, long-term remission and potential cures. However, many challenges remain for achieving the goal of effective immunotherapy for all cancer patients. Checkpoint inhibitors have been able to achieve long-term responses in a minority of patients, yet improving response rates with combination therapies increases the possibility of toxicity. Chimeric antigen receptor T cells have demonstrated high response rates in hematological cancers, although most patients experience relapse. In addition, some cancers are notoriously immunologically "cold" and typically are not effective targets for immunotherapy. Overcoming these obstacles will require new strategies to improve upon the efficacy of current agents, identify biomarkers to select appropriate therapies, and discover new modalities to expand the accessibility of immunotherapy to additional tumor types and patient populations.
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http://dx.doi.org/10.1111/nyas.14526DOI Listing
April 2021

Targeting stromal cell Syndecan-2 reduces breast tumour growth, metastasis and limits immune evasion.

Int J Cancer 2021 Mar 2;148(5):1245-1259. Epub 2020 Dec 2.

Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.

Tumour stromal cells support tumourigenesis. We report that Syndecan-2 (SDC2) is expressed on a nonepithelial, nonhaematopoietic, nonendothelial stromal cell population within breast cancer tissue. In vitro, syndecan-2 modulated TGFβ signalling (SMAD7, PAI-1), migration and immunosuppression of patient-derived tumour-associated stromal cells (TASCs). In an orthotopic immunocompromised breast cancer model, overexpression of syndecan-2 in TASCs significantly enhanced TGFβ signalling (SMAD7, PAI-1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGFβ signalling (SMAD7, PAI-1, CXCR4), tumour growth and metastasis. To explore the potential for therapeutic application, a syndecan-2-peptide was generated that inhibited the migratory and immunosuppressive properties of TASCs in association with reduced expression of TGFβ-regulated immunosuppressive genes, such as CXCR4 and PD-L1. Moreover, using an orthotopic syngeneic breast cancer model, overexpression of syndecan-2-peptide in TASCs reduced tumour growth and immunosuppression within the TME. These data provide evidence that targeting stromal syndecan-2 within the TME inhibits tumour growth and metastasis due to decreased TGFβ signalling and increased immune control.
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http://dx.doi.org/10.1002/ijc.33383DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839764PMC
March 2021

Association of Volume Overload With Kidney Function Outcomes Among Patients With Heart Failure With Reduced Ejection Fraction.

Kidney Int Rep 2020 Oct 23;5(10):1661-1669. Epub 2020 Jul 23.

Division of Nephrology, Tufts Medical Center, Boston, Massachusetts, USA.

Introduction: In patients with heart failure with reduced ejection fraction (HFrEF), volume overload is associated with mortality. Few studies that have examined the relation between volume and long-term kidney function outcomes in HFrEF.

Methods: Using data from the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan (EVEREST) trial, we used multivariable Cox regression models to evaluate the association between volume overload as evaluated by B-type natriuretic peptide (BNP) and N-terminal pro B-type natriuretic peptide (NT-proBNP), and a clinical congestion score (scale of 0-12) composed of pedal edema, jugular venous distension, rales, and orthopnea with the occurrence of estimated glomerular filtration rate (eGFR) decline by >40%, and incident chronic kidney disease (CKD) stage ≥4 defined by eGFR of <30 ml/min per 1.73 m, over a median 10-month follow-up.

Results: Among 3718 patients (mean eGFR 59 ± 22 ml/min per 1.73 m), 340 (9%) reached an eGFR decline >40% and 337 (10%) developed incident CKD stage ≥4. In multivariable models, compared with those in the quartile of lowest NT-proBNP, those within the highest quartile had a significantly higher risk of eGFR decline by >40% (hazard ratio [HR] = 2.62 [95% confidence interval {CI} = 1.62, 4.23]) and incident CKD stage ≥4 (HR = 2.66 [95% CI = 1.49, 4.77]), with similar trends for BNP. Similarly in multivariable models, patients in the quartile of highest congestion score had a 48% increased risk for eGFR decline by >40% (HR = 1.48 [95% CI = 1.07, 2.06]) and a 42% increased risk for CKD stage ≥4 (HR = 1.42 [95% CI = 1.01, 1.99]), compared with the lowest quartile.

Conclusion: Volume overload, as indicated both by elevated natriuretic peptides and clinical signs and symptoms, is associated with increased risk for clinically important kidney function outcomes in HFrEF.
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http://dx.doi.org/10.1016/j.ekir.2020.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569703PMC
October 2020

A multidisciplinary approach to online support for device research translation: regulatory change and clinical engagement.

Health Policy Technol 2020 Oct 15. Epub 2020 Oct 15.

Clinical Research Development Ireland, Mount St., Dublin 2, Ireland.

Objectives: To promote medical device EU regulatory understanding in the biomedical research community and encourage greater levels of clinical engagement to further medical device research innovation, translation and effective clinical trials.

Methods: An interdisciplinary, iterative, needs-based design approach was used to develop medical device regulatory training, information and clinical expertise resources.

Results: A multimedia based self-paced e-Learning course focusing on the 'Fundamentals of Medical Device Design and Regulation' was produced in tandem with an interactive online web portal: Medtech Translate.

Conclusions: Health research translation relies on both clinical input and regulation to drive progress and to ensure quality and safety standards from concept development to clinical investigation. A lack of regulatory awareness and access to clinical expertise has the potential to significantly impact on health research translation and ambition for market. Our interdisciplinary academic-regulator-clinical-industry led approach meets the need for a coordinated stakeholder response to support innovation and promote growth in the medical technology sector.
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http://dx.doi.org/10.1016/j.hlpt.2020.10.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560120PMC
October 2020

Sulfated glycans engage the Ang-Tie pathway to regulate vascular development.

Nat Chem Biol 2021 02 5;17(2):178-186. Epub 2020 Oct 5.

Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA, USA.

The angiopoietin (Ang)-Tie pathway is essential for the proper maturation and remodeling of the vasculature. Despite its importance in disease, the mechanisms that control signal transduction through this pathway are poorly understood. Here, we demonstrate that heparan sulfate glycosaminoglycans (HS GAGs) regulate Ang-Tie signaling through direct interactions with both Ang ligands and Tie1 receptors. HS GAGs formed ternary complexes with Ang1 or Ang4 and Tie2 receptors, resulting in potentiation of endothelial survival signaling. In addition, HS GAGs served as ligands for the orphan receptor Tie1. The HS-Tie1 interaction promoted Tie1-Tie2 heterodimerization and enhanced Tie1 stability within the mature vasculature. Loss of HS-Tie1 binding using CRISPR-Cas9-mediated mutagenesis in vivo led to decreased Tie protein levels, pathway suppression and aberrant retinal vascularization. Together, these results reveal that sulfated glycans use dual mechanisms to regulate Ang-Tie signaling and are important for the development and maintenance of the vasculature.
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http://dx.doi.org/10.1038/s41589-020-00657-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8087285PMC
February 2021

Antisense Oligonucleotide Remodels the Suppressive Tumor Microenvironment to Enhance Immune Activation in Combination with Anti-PD-L1.

Clin Cancer Res 2020 12 17;26(23):6335-6349. Epub 2020 Sep 17.

Translational Medicine, Research and Early Development, Oncology R&D, AstraZeneca, Waltham, Massachusetts.

Purpose: Danvatirsen is a therapeutic antisense oligonucleotide (ASO) that selectively targets and has shown clinical activity in two phase I clinical studies. We interrogated the clinical mechanism of action using danvatirsen-treated patient samples and conducted back-translational studies to further elucidate its immunomodulatory mechanism of action.

Experimental Design: Paired biopsies and blood samples from danvatirsen-treated patients were evaluated using immunohistochemistry and gene-expression analysis. To gain mechanistic insight, we used mass cytometry, flow cytometry, and immunofluorescence analysis of CT26 tumors treated with a mouse surrogate ASO, and human immune cells were treated with danvatirsen.

Results: Within the tumors of treated patients, danvatirsen uptake was observed mainly in cells of the tumor microenvironment (TME). Gene expression analysis comparing baseline and on-treatment tumor samples showed increased expression of proinflammatory genes. In mouse models, ASO demonstrated partial tumor growth inhibition and enhanced the antitumor activity when combined with anti-PD-L1. Immune profiling revealed reduced STAT3 protein in immune and stromal cells, and decreased suppressive cytokines correlating with increased proinflammatory macrophages and cytokine production. These changes led to enhanced T-cell abundance and function in combination with anti-PD-L1.

Conclusions: ASO treatment reverses a suppressive TME and promotes proinflammatory gene expression changes in patients' tumors and mouse models. Preclinical data provide evidence that ASO-mediated inhibition of STAT3 in the immune compartment is sufficient to remodel the TME and enhance the activity of checkpoint blockade without direct STAT3 inhibition in tumor cells. Collectively, these data provide a rationale for testing this combination in the clinic.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1066DOI Listing
December 2020

Mechanisms of Diuretic Resistance Study: design and rationale.

ESC Heart Fail 2020 Sep 6. Epub 2020 Sep 6.

Yale University School of Medicine, New Haven, CT, USA.

Introduction: Diuretic resistance is a common complication impairing decongestion during hospitalization for acute decompensated heart failure (ADHF). The current understanding of diuretic resistance mechanisms in ADHF is based upon extrapolations from other disease states and healthy volunteers. However, accumulating evidence suggests that the dominant mechanisms in other populations have limited influence on diuretic response in ADHF. Additionally, the ability to rapidly and reliably diagnose diuretic resistance is inadequate using currently available tools.

Aims: The Mechanisms of Diuretic Resistance (MDR) Study is designed to rigorously investigate the mechanisms of diuretic resistance and develop tools to rapidly predict diuretic response in a prospective cohort hospitalized with ADHF.

Methods: Study assessments occur serially during the ADHF hospitalization and after discharge. Each assessment includes a supervised 6-hour urine collection with baseline blood and timed spot urine collections following loop diuretic administration. Patient characteristics, medications, physical exam findings, and both in-hospital and post-discharge HF outcomes are collected. Patients with diuretic resistance are eligible for a randomized sub-study comparing an increased loop diuretic dose with combination diuretic therapy of loop diuretic plus chlorothiazide.

Conclusions: The Mechanisms of Diuretic Resistance Study will establish a prospective patient cohort and biorepository to investigate the mechanisms of diuretic resistance and urine biomarkers to rapidly predict loop diuretic resistance.
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http://dx.doi.org/10.1002/ehf2.12949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754741PMC
September 2020

Cystatin C and Muscle Mass in Patients With Heart Failure.

J Card Fail 2021 Jan 1;27(1):48-56. Epub 2020 Aug 1.

Department of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Background: The estimated glomerular filtration rate (eGFR) from cystatin C (eGFRcys) is often considered a more accurate method to assess GFR compared with an eGFR from creatinine (eGFRcr) in the setting of heart failure (HF) and sarcopenia, because cystatin C is hypothesized to be less affected by muscle mass than creatinine. We evaluated (1) the association of muscle mass with cystatin C, (2) the accuracy of eGFRcys, and (3) the association of eGFRcys with mortality given muscle mass.

Methods And Results: We included 293 patients admitted with HF. Muscle mass was estimated with a validated creatinine excretion-based equation. Accuracy of eGFRcys and eGFRcr was compared with measured creatinine clearance. Cystatin C and creatinine were 31.7% and 59.9% higher per 14 kg higher muscle mass at multivariable analysis (both P < .001). At lower muscle mass, eGFRcys and eGFRcr overestimated the measured creatinine clearance. At higher muscle mass, eGFRcys underestimated the measured creatinine clearance, but eGFRcr did not. After adjusting for muscle mass, neither eGFRcys nor eGFRcr were associated with mortality (both P > .19).

Conclusions: Cystatin C levels were associated with muscle mass in patients with HF, which could potentially decrease the accuracy of eGFRcys. In HF where aberrations in body composition are common, eGFRcys, like eGFRcr, may not provide accurate GFR estimations and results should be interpreted cautiously.
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http://dx.doi.org/10.1016/j.cardfail.2020.07.013DOI Listing
January 2021

Human Monocyte Subset Distinctions and Function: Insights From Gene Expression Analysis.

Front Immunol 2020 4;11:1070. Epub 2020 Jun 4.

Regenerative Medical Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland.

Monocytes are a highly plastic innate immune cell population that displays significant heterogeneity within the circulation. Distinct patterns of surface marker expression have become accepted as a basis for distinguishing three monocyte subsets in humans. These phenotypic subsets, termed classical, intermediate and nonclassical, have also been demonstrated to differ in regard to their functional properties and disease associations when studied and . Nonetheless, for the intermediate monocyte subset in particular, functional experiments have yielded conflicting results and some studies point to further levels of heterogeneity. Developments in genetic sequencing technology have provided opportunities to more comprehensively explore the phenotypic and functional differences among conventionally-recognized immune cell subtypes as well as the potential to identify novel subpopulations. In this review, we summarize the transcriptomic evidence in support of the existence of three separate monocyte subsets. We also critically evaluate the insights into subset functional distinctions that have been garnered from monocyte gene expression analysis and the potential utility of such studies to unravel subset-specific functional changes which arise in disease states.
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http://dx.doi.org/10.3389/fimmu.2020.01070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287163PMC
March 2021

Acute Kidney Function Declines in the Context of Decongestion in Acute Decompensated Heart Failure.

JACC Heart Fail 2020 07 10;8(7):537-547. Epub 2020 Jun 10.

Division of Nephrology, Tufts Medical Center, Boston, Massachusetts. Electronic address:

Objectives: This study aimed to examine whether incorporation of a comprehensive set of measures of decongestion modifies the association of acute declines in kidney function with outcomes.

Background: In-hospital acute declines in kidney function occur in approximately 20% to 30% of patients admitted with acute decompensated heart failure (ADHF) and may be associated with adverse outcomes.

Methods: Using data from EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study With Tolvaptan), we used multivariable Cox regression models to evaluate the association between in-hospital changes in estimated glomerular filtration rate (eGFR) with death and a composite outcome of cardiovascular death and hospitalization for heart failure. We evaluated eGFR declines within the context of changes in markers of volume overload including b-type natriuretic peptide (BNP), N-terminal prohormone of B-type natriuretic peptide (NT-proBNP), and weight, as well as changes in measures of hemoconcentration including hematocrit, albumin, and total protein.

Results: Among 3,715 patients over a median follow-up of 9.9 months, every 30% decline in eGFR was associated with higher risk of both death (hazard ratio [HR]: 1.19; 95% confidence interval [CI]: 1.07 to 1.31) and the composite outcome (HR: 1.09; 95% CI: 1.01 to 1.18) in adjusted models. The acute decline in eGFR was no longer associated with higher risk of either outcome as long as there was evidence of decongestion, either by declines in BNP, NT-proBNP, or weight or by increases in hematocrit, albumin or total protein. Interaction testing between decline in eGFR and changes in hematocrit, albumin, and total protein was statistically significant (p interaction of <0.01 for death and p interaction of ≤0.01 for composite for all 3 biomarkers). Interaction between change in eGFR and changes in BNP (p interaction = 0.07 for death; p interaction = 0.08 for composite), NT-proBNP (p interaction = 0.15 for death; p interaction = 0.18 for composite) and weight (p interaction = 0.13 for death; p interaction = 0.19 for composite) did not meet statistical significance.

Conclusions: Overall, acute declines in eGFR are associated with adverse outcomes, with evidence of modification by changes in markers of decongestion, suggesting that they are no longer associated with adverse outcomes if these markers are concomitantly improving.
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http://dx.doi.org/10.1016/j.jchf.2020.03.009DOI Listing
July 2020

TGF-β1-Licensed Murine MSCs Show Superior Therapeutic Efficacy in Modulating Corneal Allograft Immune Rejection In Vivo.

Mol Ther 2020 09 30;28(9):2023-2043. Epub 2020 May 30.

Regenerative Medicine Institute (REMEDI), School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland Galway, Galway, Ireland; CÚRAM, SFI Research Centre for Medical Devices, National University of Ireland Galway, Galway, Ireland. Electronic address:

Mesenchymal stromal cells (MSCs) are a promising therapeutic option for multiple immune diseases/disorders; however, efficacy of MSC treatments can vary significantly. We present a novel licensing strategy to improve the immunosuppressive capacity of MSCs. Licensing murine MSCs with transforming growth factor-β1 (TGF-β MSCs) significantly improved their ability to modulate both the phenotype and secretome of inflammatory bone marrow-derived macrophages and significantly increased the numbers of regulatory T lymphocytes following co-culture assays. These TGF-β MSC-expanded regulatory T lymphocytes also expressed significantly higher levels of PD-L1 and CD73, indicating enhanced suppressive potential. Detailed analysis of T lymphocyte co-cultures revealed modulation of secreted factors, most notably elevated prostaglandin E2 (PGE2). Furthermore, TGF-β MSCs could significantly prolong rejection-free survival (69.2% acceptance rate compared to 21.4% for unlicensed MSC-treated recipients) in a murine corneal allograft model. Mechanistic studies revealed that (1) therapeutic efficacy of TGF-β MSCs is Smad2/3-dependent, (2) the enhanced immunosuppressive capacity of TGF-β MSCs is contact-dependent, and (3) enhanced secretion of PGE2 (via prostaglandin EP4 [E-type prostanoid 4] receptor) by TGF-β MSCs is the predominant mediator of Treg expansion and T cell activation and is associated with corneal allograft survival. Collectively, we provide compelling evidence for the use of TGF-β1 licensing as an unconventional strategy for enhancing MSC immunosuppressive capacity.
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http://dx.doi.org/10.1016/j.ymthe.2020.05.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7474271PMC
September 2020

Sodium glucose cotransporter 2 inhibitors as diuretic adjuvants in acute decompensated heart failure: a case series.

ESC Heart Fail 2020 08 31;7(4):1966-1971. Epub 2020 May 31.

Section of Cardiovascular Medicine, Yale University School of Medicine, 135 College Street, Suite 230, New Haven, CT, 06520, USA.

Aims: Diuretic resistance is common in acute decompensated heart failure (ADHF). When loop diuretic monotherapy is ineffective, thiazides are often recommended as adjunctive therapy, but these agents have many side effects and are associated with worsened survival. In contrast, sodium glucose cotransporter 2 inhibitors (SGLT-2i's), initially developed as glucose-lowering medications for type 2 diabetes, improve heart failure outcomes. A candidate contributory mechanism for this benefit is their diuretic effects. We sought to describe the safety and efficacy of SGLT-2i's as loop diuretic adjuvants in ADHF.

Methods And Results: We retrospectively analysed patients who received adjuvant SGLT-2i therapy between August 2016 and June 2018 at Yale-New Haven Hospital. Thirty-one patients comprised the cohort, 58% of whom had type 2 diabetes. Compared with the 24 h prior to SGLT-2i initiation, average weight loss improved (1.0 ± 2.2 kg, P = 0.03 at Day 1; 1.7 ± 4.9 kg, P = 0.08 at Day 2; and 2.1 ± 5.6 kg, P = 0.06 at Day 3), as did urine output (3.7 ± 2.0 L, P = 0.002 at Day 1; 3.4 ± 1.7 L, P = 0.02 at Day 2; and 3.1 ± 1.7 L, P = 0.02 at Day 3) while loop diuretic dosing remaining stable. Creatinine remained unchanged during the 3 days after initiation, as did blood pressure and the incidence of hypokalaemia (P = NS for all).

Conclusions: In this cohort of patients with ADHF, SGLT-2i's improved weight loss, urine output, and diuretic efficiency without worsening of creatinine, potassium, or blood pressure. Further study of SGLT-2i's as a loop diuretic adjuvant is warranted.
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http://dx.doi.org/10.1002/ehf2.12759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373933PMC
August 2020

Empagliflozin in Heart Failure: Diuretic and Cardiorenal Effects.

Circulation 2020 Sep 15;142(11):1028-1039. Epub 2020 May 15.

Department of Internal Medicine, Section of Endocrinology (S.E.I.), Yale University School of Medicine, New Haven, CT.

Background: Sodium-glucose cotransporter-2 inhibitors improve heart failure-related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics such as furosemide induce substantial neurohormonal activation, contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the sodium-glucose cotransporter-2 inhibitors may help circumvent these limitations.

Methods: Twenty patients with type 2 diabetes mellitus and chronic, stable heart failure completed a randomized, placebo-controlled crossover study of empagliflozin 10 mg daily versus placebo. Patients underwent an intensive 6-hour biospecimen collection and cardiorenal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with the above protocol repeated.

Results: Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (<0.0001). Fractional excretion of sodium increased significantly with empagliflozin monotherapy versus placebo (fractional excretion of sodium, 1.2±0.7% versus 0.7±0.4%; =0.001), and there was a synergistic effect in combination with bumetanide (fractional excretion of sodium, 5.8±2.5% versus 3.9±1.9%; =0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208 mL [interquartile range, -536 to 153 mL] versus -14 mL [interquartile range, -282 to 335 mL]; =0.035) and plasma volume (-138 mL, interquartile range, -379 to 154±453 mL; =0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation because the change in norepinephrine was superior (=0.02) and all other neurohormones were similar (<0.34) during the empagliflozin versus placebo period. Furthermore, there was no evidence of potassium wasting (=0.20) or renal dysfunction (>0.11 for all biomarkers), whereas both serum magnesium (<0.001) and uric acid levels (=0.008) improved.

Conclusions: Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in patients with heart failure and may represent a mechanism contributing to the superior long-term heart failure outcomes observed with these agents. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03027960.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521417PMC
September 2020

Validation of a quantitative PCR assay for the detection of 2 genomovars.

J Vet Diagn Invest 2020 May 20;32(3):356-362. Epub 2020 Apr 20.

Fish Health Services, Oregon Department of Fish and Wildlife, Department of Microbiology, Oregon State University, Corvallis, OR (Gibbs).

is the causative agent of columnaris disease in a variety of fish hosts. Using modifications to previously established protocols, a quantitative PCR (qPCR) assay was validated for the detection of 2 predominant genomovars. The oligonucleotide primer and probe combination was designed to amplify a 203-bp region of the chondroitin AC lyase gene (GenBank AY912281) of . There were no significant differences in amplification between genomovars. Comparable quantities of genomic DNA from 10 strains, 5 representatives of each genomovar, produced similar results. Serial dilutions of purified PCR product demonstrated the limit of sensitivity for the assay was ~ 10 copies per reaction. The presence of gill and spleen tissue did not significantly affect the sensitivity of the assay. Comparably, bacterial DNA detected from the liver and kidney was less sensitive than pure bacterial DNA. However, detection from these tissues was within one order of magnitude of other tissues, indicating this reduction may have minimal analytic significance. This validated assay was used to approximate the minimum infectious dose for isolate 94-081 in channel catfish and assess bacterial loads in gill and kidney tissues 48 h post-infection.
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http://dx.doi.org/10.1177/1040638720915760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7377616PMC
May 2020

Mesenchymal stromal cell-based therapies for acute kidney injury: progress in the last decade.

Kidney Int 2020 06 29;97(6):1130-1140. Epub 2020 Jan 29.

Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, Ireland; Department of Nephrology, Saolta University Health Care Group, Galway University Hospitals, Galway, Ireland. Electronic address:

A little over 10 years ago, the therapeutic potential of mesenchymal stromal cells (MSCs) for the treatment of acute kidney injury (AKI) was becoming widely recognized. Since then, there has been further intensive study of this topic with a clear translational intent. Over the past decade, many more animal model studies have strengthened the evidence that systemically or locally delivered MSCs ameliorate renal injury in sterile and sepsis-associated AKI. Some of these preclinical studies have also provided a range of compelling new insights into the in vivo fate and mechanisms of action of MSCs in the setting of AKI and other inflammatory conditions. Coupled with increased knowledge of the functional roles of resident and infiltrating immune cell mediators in determining the severity and outcome of AKI, the progress made in the past decade would appear to have significantly strengthened the translational pathway for MSC-based therapies. In contrast, however, the extent of the clinical experience with MSC administration in human subjects with AKI or sepsis-associated AKI has been limited to a small number of early-phase clinical trials, which appear to demonstrate safety but have not thus far delivered a strong signal of efficacy. In this review, we summarize the most significant new developments in the field of MSC-based therapies as they relate to AKI and reflect on the key gaps in knowledge and technology that remain to be addressed for the true clinical potential of MSCs and, perhaps, other emerging cellular therapies to be realized.
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http://dx.doi.org/10.1016/j.kint.2019.12.019DOI Listing
June 2020

Celiac Disease Symptoms in Athletes: Prevalence Indicators of Perceived Quality of Life.

Sports Health 2020 May/Jun;12(3):246-255. Epub 2020 Apr 9.

Department of Psychology, Bridgewater State University, Bridgewater, Massachusetts.

Background: Celiac disease (CD) is a common gastrointestinal pathology; however, prevalence and comorbidities are unknown in collegiate athletics.

Hypotheses: (1) Athletes will have similar odds of CD as general population estimates (approximately 1 in 141) based on self-report and signs and symptoms, (2) athletes scoring higher on the Celiac Symptom Index (CSI) will have lower self-reported quality of life (QoL), (3) athletes scoring higher on the CSI will have higher depression scores, and (4) athletes scoring higher on the CSI will have higher perceived stress scores.

Study Design: Epidemiological cross-sectional study.

Level Of Evidence: Level 4.

Methods: The CSI, WHO Quality of Life-BREF, Beck Depression Inventory, and Perceived Stress Scale were used to assess patients' signs and symptoms of CD and psychosocial measures/QoL in male and female National Collegiate Athletic Association (all divisions) athletes (N = 141). Participants also self-reported a formal diagnosis of CD. Chi-square analyses determined CD prevalence. Odds ratios determined risk for either being diagnosed with CD or reporting more symptoms than the general population. Correlational analyses determined whether symptoms correlated with QoL and psychosocial measures.

Results: Athletes were 3.85 times (95% CI, 0.42-34.89) more likely to report a CD diagnosis and were 18.36 times (95% CI, 2.40-140.48) more likely to report a high degree of CD symptoms than the general population. Athletes with more symptoms had worse physical, psychological, social, and environmental QoL indicators and higher depression and perceived stress scores.

Conclusion: Athletes may be a higher risk population for experiencing CD and report greater signs/symptoms compared with general population estimates. Additionally, athletes with higher CD symptom scores also reported poorer QoL.

Clinical Relevance: Allied health care professionals should be aware of the diversity of CD symptoms and be prepared to refer athletes when gastrointestinal symptoms persist to ensure proper care and unhampered performance.
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http://dx.doi.org/10.1177/1941738120905137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222663PMC
May 2020

The impact of chronic kidney disease on developed countries from a health economics perspective: A systematic scoping review.

PLoS One 2020 24;15(3):e0230512. Epub 2020 Mar 24.

Centre for Public Health, Queen's University Belfast, Belfast, Northern Ireland, United Kingdom.

Chronic kidney disease (CKD) affects over 10% of the global population and poses significant challenges for societies and health care systems worldwide. To illustrate these challenges and inform cost-effectiveness analyses, we undertook a comprehensive systematic scoping review that explored costs, health-related quality of life (HRQoL) and life expectancy (LE) amongst individuals with CKD. Costs were examined from a health system and societal perspective, and HRQoL was assessed from a societal and patient perspective. Papers published in English from 2015 onward found through a systematic search strategy formed the basis of the review. All costs were adjusted for inflation and expressed in US$ after correcting for purchasing power parity. From the health system perspective, progression from CKD stages 1-2 to CKD stages 3a-3b was associated with a 1.1-1.7 fold increase in per patient mean annual health care cost. The progression from CKD stage 3 to CKD stages 4-5 was associated with a 1.3-4.2 fold increase in costs, with the highest costs associated with end-stage renal disease at $20,110 to $100,593 per patient. Mean EuroQol-5D index scores ranged from 0.80 to 0.86 for CKD stages 1-3, and decreased to 0.73-0.79 for CKD stages 4-5. For treatment with renal replacement therapy, transplant recipients incurred lower costs and demonstrated higher HRQoL scores with longer LE compared to dialysis patients. The study has provided a comprehensive updated overview of the burden associated with different CKD stages and renal replacement therapy modalities across developed countries. These data will be useful for the assessment of new renal services/therapies in terms of cost-effectiveness.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0230512PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092970PMC
June 2020

Editorial: Innovative Biologics and Drugs to Target Renal Inflammation.

Front Pharmacol 2020 6;11:38. Epub 2020 Feb 6.

Division of Nephrology, University of Virginia Health System, Charlottesville, VA, United States.

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http://dx.doi.org/10.3389/fphar.2020.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016012PMC
February 2020

Real World Use of Hypertonic Saline in Refractory Acute Decompensated Heart Failure: A U.S. Center's Experience.

JACC Heart Fail 2020 03 5;8(3):199-208. Epub 2020 Feb 5.

Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Objectives: The purpose of this study was to investigate real world safety and efficacy of hypertonic saline therapy in cases of refractory acute decompensated heart failure (ADHF) at a large U.S. academic medical center.

Background: Hypertonic saline therapy has been described as a potential management strategy for refractory ADHF, but experience in the United States is limited.

Methods: A retrospective analysis was performed in all patients receiving hypertonic saline for diuretic therapy-resistant ADHF at the authors' institution since March 2013. The primary analytic approach was a comparison of the trajectory of clinical variables prior to and after administration of hypertonic saline, with secondary focus on predictors of treatment response.

Results: A total of 58 hypertonic saline administration episodes were identified across 40 patients with diuretic-therapy refractory ADHF. Prior to hypertonic saline administration, serum sodium, chloride, and creatinine concentrations were worsening but improved after hypertonic saline administration (p < 0.001, all). Both total urine output and weight loss significantly improved with hypertonic saline (p = 0.01 and <0.001, respectively). Diuretic efficiency, defined as change in urine output per doubling of diuretic dose, also improved over this period (p < 0.01). There were no significant changes in respiratory status or overcorrection of serum sodium with the intervention.

Conclusions: In a cohort of patients who were refractory to ADHF, hypertonic saline administration was associated with increased diuretic efficiency, fluid and weight loss, and improvement of metabolic derangements, and no adverse respiratory or neurological signals were identified. Additional study of hypertonic saline as a diuretic adjuvant is warranted.
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http://dx.doi.org/10.1016/j.jchf.2019.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814403PMC
March 2020

Effect of Loop Diuretics on the Fractional Excretion of Urea in Decompensated Heart Failure.

J Card Fail 2020 May 30;26(5):402-409. Epub 2020 Jan 30.

Division of Internal Medicine, Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, Connecticut. Electronic address:

Background: Fractional excretion of urea (FEUrea) is often used to understand the etiology of acute kidney injury (AKI) in patients receiving diuretics. Although FEUrea demonstrates diagnostic superiority over fractional excretion of sodium (FENa), clinicians often assume FEUrea is not affected by diuretics.

Objective: To assess the intravenous loop diuretic effect on FEUrea.

Methods: We analyzed a prospective cohort (n=297) hospitalized with hypervolemic heart failure at Yale New Haven Hospital System. FENa and FEUrea were calculated at baseline and serially after diuretics. The change in FEUrea at peak diuresis was compared with the pre-diuretic baseline.

Results: Mean baseline FEUrea was 35.2% ± 10.5% and increased by a mean 5.6% ± 10.5% following 80 mg (40-160 mg) of furosemide equivalents (P < .001). The magnitude of change in FEUrea was clinically important as the distribution of change in FEUrea was similar to the overall distribution of baseline FEUrea. Change in FEUrea was related to the diuretic response (r = 0.61, P < .001), with a larger FEUrea increase in diuretic responders (8.8%, interquartile range [IQR]: 1.8-16.9) than non-responders (1.2%, IQR: -3.2 to 5.5; P < .001). Diuretic administration reclassified 27% of patients between low and high FEUrea groups across a 35% threshold. Neither change in FEUrea nor percentage reclassified out of a low FEUrea category differed between patients with and without AKI (P > .63 for both).

Conclusions: FEUrea is meaningfully affected by loop diuretics. The degree of change in FEUrea is highly variable between patients and commonly of a magnitude that could reclassify across categories of FEUrea.
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http://dx.doi.org/10.1016/j.cardfail.2020.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798124PMC
May 2020

Effects of mesenchymal stromal cells on regulatory T cells: Current understanding and clinical relevance.

Stem Cells 2020 05 3;38(5):596-605. Epub 2020 Feb 3.

Regenerative Medicine Institute (REMEDI) at CÚRAM Centre for Research in Medical Devices, School of Medicine, National University of Ireland Galway, Galway, Ireland.

The immunomodulatory potential of mesenchymal stromal cells (MSCs) and regulatory T cells (T-reg) is well recognized by translational scientists in the field of regenerative medicine and cellular therapies. A wide range of preclinical studies as well as a limited number of human clinical trials of MSC therapies have not only shown promising safety and efficacy profiles but have also revealed changes in T-reg frequency and function. However, the mechanisms underlying this potentially important observation are not well understood and, consequently, the optimal strategies for harnessing MSC/T-reg cross-talk remain elusive. Cell-to-cell contact, production of soluble factors, reprogramming of antigen presenting cells to tolerogenic phenotypes, and induction of extracellular vesicles ("exosomes") have emerged as possible mechanisms by which MSCs produce an immune-modulatory milieu for T-reg expansion. Additionally, these two cell types have the potential to complement each other's immunoregulatory functions, and a combinatorial approach may exert synergistic effects for the treatment of immunological diseases. In this review, we critically assess recent translational research related to the outcomes and mechanistic basis of MSC effects on T-reg and provide a perspective on the potential for this knowledge base to be further exploited for the treatment of autoimmune disorders and transplants.
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http://dx.doi.org/10.1002/stem.3151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217190PMC
May 2020

First-in-Human Experience With Peritoneal Direct Sodium Removal Using a Zero-Sodium Solution: A New Candidate Therapy for Volume Overload.

Circulation 2020 03 8;141(13):1043-1053. Epub 2020 Jan 8.

Department of Internal Medicine, Section of Cardiovascular Medicine (V.S.R., M.G., D.M., N.B., J.M. Testani), Yale University School of Medicine, New Haven, CT.

Background: Loop diuretics have well-described toxicities, and loss of response to these agents is common. Alternative strategies are needed for the maintenance of euvolemia in heart failure (HF). Nonrenal removal of sodium directly across the peritoneal membrane (direct sodium removal [DSR]) with a sodium-free osmotic solution should result in extraction of large quantities of sodium with limited off-target solute removal.

Methods: This article describes the preclinical development and first-in-human proof of concept for DSR. Sodium-free 10% dextrose was used as the DSR solution. Porcine experiments were conducted to investigate the optimal dwell time, safety, and scalability and to determine the effect of experimental heart failure. In the human study, participants with end-stage renal disease on peritoneal dialysis (PD) underwent randomization and crossover to either a 2-hour dwell with 1 L DSR solution or standard PD solution (Dianeal 4.25% dextrose, Baxter). The primary end point was completion of the 2-hour dwell without significant discomfort or adverse events, and the secondary end point was difference in sodium removal between DSR and standard PD solution.

Results: Porcine experiments revealed that 1 L DSR solution removed 4.1±0.4 g sodium in 2 hours with negligible off-target solute removal and overall stable serum electrolytes. Increasing the volume of DSR solution cycled across the peritoneum increased sodium removal and substantially decreased plasma volume (=0.005). In the setting of experimental heart failure with elevated right atrial pressure, sodium removal was ≈4 times greater than in healthy animals (<0.001). In the human proof-of-concept study, DSR solution was well tolerated and not associated with significant discomfort or adverse events. Plasma electrolyte concentrations were stable, and off-target solute removal was negligible. Sodium removal was substantially higher with DSR (4.5±0.4 g) compared with standard PD solution (1.0±0.3 g; <0.0001).

Conclusions: DSR was well tolerated in both animals and human subjects and produced substantially greater sodium removal than standard PD solution. Additional research evaluating the use of DSR as a method to prevent and treat hypervolemia in heart failure is warranted. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03801226.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7331276PMC
March 2020

Senescence marker activin A is increased in human diabetic kidney disease: association with kidney function and potential implications for therapy.

BMJ Open Diabetes Res Care 2019 15;7(1):e000720. Epub 2019 Dec 15.

Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.

Objective: Activin A, an inflammatory mediator implicated in cellular senescence-induced adipose tissue dysfunction and profibrotic kidney injury, may become a new target for the treatment of diabetic kidney disease (DKD) and chronic kidney diseases. We tested the hypothesis that human DKD-related injury leads to upregulation of activin A in blood and urine and in a human kidney cell model. We further hypothesized that circulating activin A parallels kidney injury markers in DKD.

Research Design And Methods: In two adult diabetes cohorts and controls (Minnesota, USA; Galway, Ireland), the relationships between plasma (or urine) activin A, estimated glomerular filtration rate (eGFR) and DKD injury biomarkers were tested with logistic regression and correlation coefficients. Activin A, inflammatory, epithelial-mesenchymal-transition (EMT) and senescence markers were assayed in human kidney (HK-2) cells incubated in high glucose plus transforming growth factor-β1 or albumin.

Results: Plasma activin A levels were elevated in diabetes (n=206) compared with controls (n=76; 418.1 vs 259.3 pg/mL; p<0.001) and correlated inversely with eGFR (r=-0.61; p<0.001; diabetes). After eGFR adjustment, only albuminuria (OR 1.56, 95% CI 1.16 to 2.09) and tumor necrosis factor receptor-1 (OR 6.40, 95% CI 1.08 to 38.00) associated with the highest activin tertile. Albuminuria also related to urinary activin (r=0.65; p<0.001). Following in vitro HK-2 injury, activin, inflammatory, EMT genes and supernatant activin levels were increased.

Conclusions: Circulating activin A is increased in human DKD and correlates with reduced kidney function and kidney injury markers. DKD-injured human renal tubule cells develop a profibrotic and inflammatory phenotype with activin A upregulation. These findings underscore the role of inflammation and provide a basis for further exploration of activin A as a diagnostic marker and therapeutic target in DKD.
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http://dx.doi.org/10.1136/bmjdrc-2019-000720DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936543PMC
August 2020