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Captain America. Vol. 1, Winter in America
\"It's winter in America! For over 70 years, Captain America has stood in stalwart defense of our country and its people. But in the aftermath of Hydra's takeover of the nation, Cap is a figure of controversy, carrying a tarnished shield--and a new enemy is rising! Who are they? And how do they intend to co-opt and corrupt the symbol that is Captain America? Distrusted by a nation that seems to have lost faith in him, Steve Rogers is a man out of time--and out of options! Where can a now-unsanctioned Captain America turn for aid and assistance in order to stem the rise of the cabal of influence brokers known as the Power Elite?\"-- Provided by publisher.
Book
Impact of deceased donor with acute kidney injury on subsequent kidney transplant outcomes–an ANZDATA registry analysis
Investigates the associations between donor acute kidney injury (AKI) and recipient transplant outcomes using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry and Organ Donation (ANZOD) Registry. Evaluates all-cause graft failure as well as death-censored graft failure, death, delayed graft function (DGF), and acute rejection. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.
Journal Article
Recurrent severe hypophosphatemia following intravenous iron administration
Key Clinical Message Hypophosphatemia postintravenous iron is frequent but under‐recognized. If prolonged or recurrent, it can cause osteomalacia. The likely mechanisms are direct toxicity to proximal tubular cells causing phosphate wasting, elevated Fibroblast growth factor‐23 (FGF‐23), and reduced 1,25‐dihydroxyvitamin D (1,25(OH)2D). Hypophosphatemia may be severe and persist for months, necessitating phosphate replacement until normalization of serum levels occurs. Hypophosphatemia postintravenous iron is frequent but under‐recognized. If prolonged or recurrent, it can cause osteomalacia. The likely mechanisms are direct toxicity to proximal tubular cells causing phosphate wasting, elevated Fibroblast growth factor‐23 (FGF‐23), and reduced 1,25‐dihydroxyvitamin D (1,25(OH)2D). Hypophosphatemia may be severe and persist for months, necessitating phosphate replacement until normalization of serum levels occurs.
Journal Article
A prospective, observational study of frailty, quality of life and dialysis in older people with advanced chronic kidney disease
Background
Frailty is prevalent in older people with chronic kidney disease (CKD) and robust evidence supporting the benefit of dialysis in this setting is lacking. We aimed to measure frailty and quality of life (QOL) longitudinally in older people with advanced CKD and assess the impact of dialysis initiation on frailty, QOL and mortality.
Methods
Outpatients aged ≥65 with an eGFR ≤ 20ml/minute/1.73m
2
were enrolled in a prospective observational study and followed up four years later. Frailty status was measured using a Frailty Index (FI), and QOL was evaluated using the EuroQol 5D-5L instrument. Mortality and dialysis status were determined through inspection of electronic records.
Results
Ninety-eight participants were enrolled. Between enrolment and follow-up, 36% of participants commenced dialysis and 59% died. Frailty prevalence increased from 47% at baseline to 86% at follow-up (change in median FI = 0.22,
p
< 0.001). Initiating dialysis was not significantly associated with change in FI. QOL declined from baseline to follow-up (mean EQ-5D-5L visual analogue score of 70 vs 63,
p
= 0.034), though commencing dialysis was associated with less decline in QOL. Each 0.1 increment in baseline FI was associated with 59% increased mortality hazard (HR = 1.59, 95%CI = 1.20 to 2.12,
p
= 0.001), and commencing dialysis was associated with 59% reduction in mortality hazard (HR = 0.41, 95%CI = 0.20 to 0.87,
p
= 0.020) irrespective of baseline FI.
Conclusions
Frailty increased substantially over four years, and higher baseline frailty was associated with greater mortality. Commencing dialysis did not affect the trajectory of FI but positively influenced the trajectory of QOL from baseline to follow-up. Within the limitations of small sample size, our data suggests that frail participants received similar survival benefit from dialysis as non-frail participants.
Journal Article
Specialized Roles of Human Natural Killer Cell Subsets in Kidney Transplant Rejection
Human natural killer (NK) cells are key functional players in kidney transplant rejection. However, the respective contributions of the two functionally distinct human NK cell subsets (CD56
cytokine-producing vs. CD56
cytotoxic effector) in episodes of allograft rejection remain uncertain, with current immunohistochemical methods unable to differentiate these discrete populations. We report the outcomes of an innovative multi-color flow cytometric-based approach to unequivocally define and evaluate NK cell subsets in human kidney allograft rejection.
We extracted renal lymphocytes from human kidney transplant biopsies. NK cell subsets were identified, enumerated, and phenotyped by multi-color flow cytometry. Dissociation supernatants were harvested and levels of soluble proteins were determined using a multiplex bead-based assay. Results were correlated with the histopathological patterns in biopsies-no rejection, borderline cellular rejection, T cell-mediated rejection (TCMR), and antibody-mediated rejection (AMR).
Absolute numbers of only CD56
NK cells were significantly elevated in TCMR biopsies. In contrast, both CD56
and CD56
NK cell numbers were significantly increased in biopsies with histopathological evidence of AMR. Notably, expression of the activation marker CD69 was only significantly elevated on CD56
NK cells in AMR biopsies compared with no rejection biopsies, indicative of a pathogenic phenotype for this cytotoxic NK cell subset. In line with this, we detected significantly elevated levels of cytotoxic effector molecules (perforin, granzyme A, and granulysin) in the dissociation supernatants of biopsies with a histopathological pattern of AMR.
Our results indicate that human NK cell subsets are differentially recruited and activated during distinct types of rejection, suggestive of specialized functional roles.
Journal Article
PREBIOTIC: a study protocol of a randomised controlled trial to assess prebiotic supplementation in kidney transplant recipients for preventing infections and gastrointestinal upset — a feasibility study
Background
Modulating the microbiota in the large intestine of kidney transplant recipients through prebiotic supplementation may prevent infectious complications from occurring. To date, there have been no interventional trials which have investigated this novel treatment in kidney transplantation. The aim of PREBIOTIC is to assess the feasibility of performing a randomised controlled trial of prebiotics in reducing infections and gastrointestinal symptoms in kidney transplant recipients.
Methods
Sixty kidney transplant patients will be recruited to a double-blind, placebo-controlled, randomised feasibility trial. Patients will be provided with prebiotic therapy or placebo for 4 to 6 weeks. Outcomes will include recruitment, adherence, tolerance, retention, laboratory parameters (including serum indoxyl sulphate, ρ-cresyl sulphate and stool collection), patients’ self-assessed quality of life, gastrointestinal symptoms and clinical outcomes.
Discussion
This trial will assess the feasibility of prebiotic supplementation in kidney transplant recipients. Prebiotics not only may alter the gut microbiota and their inherent metabolism and production of uraemic toxins but also may prevent infections from occurring in kidney transplant recipients.
Trial registration
Australian New Zealand Clinical Trials Registry number ACTRN12618001057279p. The date of registration was 25th June 2018,
https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=375370&isReview=true
.
Journal Article
Autologous Adoptive T-cell Therapy for Recurrent or Drug-resistant Cytomegalovirus Complications in Solid Organ Transplant Recipients
Autologous T-cell therapy in solid organ transplant recipients with recurrent or drug-resistant CMV-associated complications is safe and may provide clinical benefit, especially when standard therapies are not effective or are contraindicated.
Abstract
Background
Opportunistic infections including cytomegalovirus (CMV) are a major cause of morbidity and mortality in solid organ transplant (SOT) recipients. The recurrent and protracted use of antiviral drugs with eventual emergence of drug resistance represents a significant constraint to therapy. Although adoptive T-cell therapy has been successfully used in hematopoietic stem cell transplant recipients, its extension to the SOT setting poses a considerable challenge because of the inhibitory effects of immunosuppressive drugs on the virus-specific T-cell response in vivo and the perceived risk of graft rejection.
Methods
In this prospective study, 22 SOT recipients (13 renal and 8 lung and 1 heart transplants) with recurrent or ganciclovir-resistant CMV infection were recruited, and 13 of them were treated with in vitro-expanded autologous CMV-specific T cells. These patients were monitored for safety, clinical symptoms, and immune reconstitution.
Results
Autologous CMV-specific T-cell manufacture was attempted for 21 patients, and was successful in 20. The use of this adoptive immunotherapy was associated with no therapy-related serious adverse events. Eleven (84%) of the 13 treated patients showed improvement in symptoms, including complete resolution or reduction in DNAemia and CMV-associated end-organ disease and/or the cessation or reduced use of antiviral drugs. Furthermore, four of these patients showed coincident increased frequency of CMV-specific T cells in peripheral blood after completion of T-cell therapy.
Conclusions
The data presented here demonstrate for the first time the clinical safety of CMV-specific adoptive T-cell therapy and its potential therapeutic benefit for SOT recipients with recurrent and/or drug-resistant CMV infection or disease.
Clinical Trials Registration
ACTRN12613000981729.
Journal Article
Metabolite pathway alterations identified by magnetic resonance metabolomics in a proximal tubular epithelial cell line treated with TGF‐β1
Tubulointerstitial fibrosis is a characteristic hallmark of chronic kidney disease (CKD). Metabolic perturbations in cellular energy metabolism contribute to the pathogenesis of CKD, but the chemical contributors remain unclear. The aim of this investigation was to use two dimensional 1H‐nuclear magnetic resonance (2D‐COSY) metabolomics to identify the chemical changes of kidney fibrogenesis. An in vitro transforming growth factor‐β1 (TGF‐β1)‐induced model of kidney fibrogenesis with human kidney‐2 (HK‐2) proximal tubular epithelial cells (PTEC) was used. The model was validated by assaying for various pro‐fibrotic molecules, using quantitative PCR and Western blotting. 2D‐COSY was performed on treated cells. Morphological and functional changes characteristic of tubulointerstitial fibrosis were confirmed in the model; expression of fibronectin, collagen type IV, smooth muscle actin, oxidative stress enzymes increased (p < 0.05). NMR metabolomics provided evidence of altered metabolite signatures associated with glycolysis and glutamine metabolism, with decreased myo‐inositol and choline, and metabolites of the oxidative phase of the pentose phosphate pathway with increased glucose and glucuronic acid. The altered PTEC cellular metabolism likely supports the rapid fibrogenic energy demands. These results, using 2D‐COSY metabolomics, support development of a biomarker panel of fibrosis detectable using clinical magnetic resonance spectroscopy to diagnose and manage CKD.
Journal Article
Drug repurposing for glomerular diseases: an underutilized resource
Drug repurposing in glomerular disease can deliver opportunities for steroid-free regimens, enable personalized multi-target options for resistant or relapsing disease and enhance treatment options for understudied populations (for example, children) and in resource-limited settings. Identification of drug-repurposing candidates can be data driven, which utilizes existing data on disease pathobiology, drug features and clinical outcomes, or experimental, which involves high-throughput drug screens. Information from databases of approved drugs, clinical trials and PubMed registries suggests that at least 96 drugs on the market cover 49 targets with immunosuppressive potential that could be candidates for drug repurposing in glomerular disease. Furthermore, evidence to support drug repurposing is available for 191 immune drug target–glomerular disease pairs. Non-immunological drug repurposing includes strategies to reduce haemodynamic overload, podocyte injury and kidney fibrosis. Recommended strategies to expand drug-repurposing capacity in glomerular disease include enriching drug databases with glomeruli-specific information, enhancing the accessibility of primary clinical trial data, biomarker discovery to improve participant selection into clinical trials and improve surrogate outcomes and initiatives to reduce patent, regulatory and organizational hurdles.Drug repurposing could expand the therapeutic options available to patients with glomerular disease. Here, the authors examine different approaches to the identification of drug candidates, consider current immunosuppressive and non-immunological options and discuss strategies to maximize drug repurposing in glomerular disease.
Journal Article
Active PI3K Pathway Causes an Invasive Phenotype Which Can Be Reversed or Promoted by Blocking the Pathway at Divergent Nodes
The PTEN/PI3K pathway is commonly mutated in cancer and therefore represents an attractive target for therapeutic intervention. To investigate the primary phenotypes mediated by increased pathway signaling in a clean, patient-relevant context, an activating PIK3CA mutation (H1047R) was knocked-in to an endogenous allele of the MCF10A non-tumorigenic human breast epithelial cell line. Introduction of an endogenously mutated PIK3CA allele resulted in a marked epithelial-mesenchymal transition (EMT) and invasive phenotype, compared to isogenic wild-type cells. The invasive phenotype was linked to enhanced PIP(3) production via a S6K-IRS positive feedback mechanism. Moreover, potent and selective inhibitors of PI3K were highly effective in reversing this phenotype, which is optimally revealed in 3-dimensional cell culture. In contrast, inhibition of Akt or mTOR exacerbated the invasive phenotype. Our results suggest that invasion is a core phenotype mediated by increased PTEN/PI3K pathway activity and that therapeutic agents targeting different nodes of the PI3K pathway may have dramatic differences in their ability to reverse or promote cancer metastasis.
Journal Article