ORCID Profile
0000-0002-4376-9720
Current Organisation
Deakin University
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Publisher: Wiley
Date: 12-2017
DOI: 10.1111/IMJ.13640
Publisher: Royal Society of Chemistry (RSC)
Date: 2021
DOI: 10.1039/D1MA00859E
Abstract: This review article critically assesses materials engineering advances across blood separation technologies which addresses operating challenges such as surface fouling and material biocompatibility.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2017
Publisher: Elsevier BV
Date: 03-2006
DOI: 10.1016/J.BCMD.2005.12.025
Abstract: Extracellular nucleotide P2-receptor-mediated effects on platelets, leukocytes and endothelium are modulated by ecto-nucleotidases. These ecto-enzymes hydrolyze extracellular nucleotides to the respective nucleosides. The dominant ecto-nucleotidase expressed by the endothelium, by monocytes and vascular smooth muscle cells is CD39/NTPDase1. Ecto-nucleotidase biochemical activity of CD39 is lost at sites of acute vascular injury, such as in ischemia reperfusion and immune graft rejection. CD39L(Like)1/NTPDase2, a related protein, is associated with the basolateral surface of endothelium, the adventitia of vessels and microvascular pericytes. CD39/NTPDase1 hydrolyzes both tri- and diphosphonucleosides and blocks platelet aggregation responses to ADP. In contrast, CD39L1/NTPDase2, a preferential nucleoside triphosphatase, activates platelets by preferentially converting ATP to ADP, the major agonist of platelet P2 receptors. Spatial and temporal expression of NTPDases in the vasculature appears to control platelet activation, thrombus size and stability by regulating phosphohydrolytic activity and consequent P2 receptor signaling. Constitutively circulating microparticles appear to be associated with functional NTPDases, and accumulation of these at sites of vascular injury might influence local thrombus formation and evolution. The phenotype of the cd39-null mouse is in keeping with disordered thromboregulation with heightened susceptibility to inflammatory vasculary reactions, increased permeability and high levels of tissue fibrin. Paradoxically, these mutant mice also exhibit a bleeding phenotype with differential platelet P2Y1 desensitization. Over-expression of CD39 at sites of vascular injury and inflammation by adenoviral vectors, by transgenesis or by the use of pharmacological modalities with soluble derivatives has been shown to have major potential in several animal models tested to date. Future clinical applications will involve the development of new therapeutic strategies to various inflammatory vascular diseases and in transplantation.
Publisher: Frontiers Media SA
Date: 28-02-2022
Abstract: We investigated a cross-sectional metabolomic analysis of plasma and urine of patients with early and late stage diabetes associated chronic kidney disease (CKD), inclusive of stages 1–5 CKD, to identify potential metabolomic profiles between the two groups. This cross-sectional study recruited 119 adults. Metabolomic biomarkers were quantified in 119 non-fasted plasma and 57 urine s les using a high-throughput proton Nuclear Magnetic Resonance platform. Analyses were conducted using R with the ggforestplot package. Linear regression models were minimally adjusted for age, sex, and body mass index and p -values were adjusted for multiple comparisons using the Benjamini-Hockberg method with a false discovery rate of 0.05. Apolipoprotein A1 concentration (ApoA1) was reduced (adj. p = 0.04) and apolipoprotein B/apolipoprotein A1 ratio (ApoB/ApoA1) was increased (adj. p = 0.04) in late CKD compared with early CKD. Low-density lipoprotein triglyceride (LDL-TG) had an increased concentration (adj. p = 0.01), while concentrations of high-density lipoprotein cholesterol (HDL-C) were reduced (adj. p = 0.04) in late CKD compared to early stages of disease. Our results highlight the presence of abnormal lipid metabolism namely significant reduction in the protective ApoA1 and significant increase in atherogenic ApoB/ApoA1 ratio. The study also demonstrates significantly elevated levels of triglyceride-rich lipoproteins such as LDL-TG. We illustrate the significant reduction in protective HDL-C in in iduals with diabetic CKD. It explores a detailed plasma lipid profile that significantly differentiates between the late and early CKD groups as well as each CKD stage. The study of complex metabolite profiles may provide additional data required to enable more specific cardiovascular risk stratification.
Publisher: Wiley
Date: 03-2008
DOI: 10.1038/BJP.2008.23
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/951423
Publisher: Springer Science and Business Media LLC
Date: 11-03-2019
DOI: 10.1038/S41598-019-41009-3
Abstract: Maternal hyperglycaemia has a profound impact on the developing foetus and increases the risk of developing abnormalities like obesity, impaired glucose tolerance and insulin secretory defects in the post-natal life. Increased levels of glucose in the blood stream due to diabetes causes visual disorders like retinopathy. However, the impact of maternal hyperglycaemia due to pre-existing or gestational diabetes on the developing foetal retina is unknown. The aim of this work was to study the effect of hyperglycaemia on the developing retina using zebrafish as a vertebrate model. Wild-type and transgenic zebrafish embryos were exposed to 0, 4 and 5% D-Glucose in a pulsatile manner to mimic the fluctuations in glycaemia experienced by the developing foetus in pregnant women with diabetes. The zebrafish embryos displayed numerous ocular defects associated with altered retinal cell layer thickness, increased presence of macrophages, and decreased number of Müeller glial and retinal ganglion cells following high-glucose exposure. We have developed a model of gestational hyperglycaemia using the zebrafish embryo to study the effect of hyperglycaemia on the developing embryonic retina. The data suggests that glucose exposure is detrimental to the development of embryonic retina and the legacy of this exposure may extend into adulthood. These data suggest merit in retinal assessment in infants born to mothers with pre-existing and gestational diabetes both in early and adult life.
Publisher: Rockefeller University Press
Date: 14-05-2007
DOI: 10.1084/JEM.20062512
Abstract: The study of T regulatory cells (T reg cells) has been limited by the lack of specific surface markers and an inability to define mechanisms of suppression. We show that the expression of CD39/ENTPD1 in concert with CD73/ecto-5′-nucleotidase distinguishes CD4+/CD25+/Foxp3+ T reg cells from other T cells. These ectoenzymes generate pericellular adenosine from extracellular nucleotides. The coordinated expression of CD39/CD73 on T reg cells and the adenosine A2A receptor on activated T effector cells generates immunosuppressive loops, indicating roles in the inhibitory function of T reg cells. Consequently, T reg cells from Cd39-null mice show impaired suppressive properties in vitro and fail to block allograft rejection in vivo. We conclude that CD39 and CD73 are surface markers of T reg cells that impart a specific biochemical signature characterized by adenosine generation that has functional relevance for cellular immunoregulation.
Publisher: Springer Science and Business Media LLC
Date: 25-03-2017
Publisher: Wiley
Date: 03-2022
DOI: 10.1111/IMJ.15708
Publisher: Elsevier BV
Date: 02-2010
Publisher: Wiley
Date: 12-2001
Publisher: Wiley
Date: 11-2022
DOI: 10.1111/IMJ.15931
Abstract: The COVID‐19 pandemic has exposed the deficiencies of the current healthcare system in terms of a disconnect between primary and tertiary care and increasing subspecialisation, the focus on acute episodic care rather than on prevention in a time where chronic disease prevails and an inefficient use of healthcare resources. Herein, we present the case for an alternative model of healthcare delivery – shared medical appointments – which are efficient, effective and empowering and can be transitioned to the virtual environment successfully. We highlight the barriers to implementation and how these can be overcome.
Publisher: Informa UK Limited
Date: 2013
Publisher: Proceedings of the National Academy of Sciences
Date: 04-01-2010
Abstract: Extracellular adenosine is a potent immunosuppressor that accumulates during tumor growth. We performed proof-of-concept studies investigating the therapeutic potential and mechanism of action of monoclonal antibody (mAb)-based therapy against CD73, an ecto-enzyme overexpressed on breast-cancer cells that catalyzes the dephosphorylation of adenosine monophosphates into adenosine. We showed that anti-CD73 mAb therapy significantly delayed primary 4T1.2 and E0771 tumor growth in immune-competent mice and significantly inhibited the development of spontaneous 4T1.2 lung metastases. Notably, anti-CD73 mAb therapy was essentially dependent on the induction of adaptive anti-tumor immune responses. Knockdown of CD73 in 4T1.2 tumor cells confirmed the tumor-promoting effects of CD73. In addition to its immunosuppressive effect, CD73 enhanced tumor-cell chemotaxis, suggesting a role for CD73-derived adenosine in tumor metastasis. Accordingly, administration of adenosine-5′-N-ethylcarboxamide to tumor-bearing mice significantly enhanced spontaneous 4T1.2 lung metastasis. Using selective adenosine-receptor antagonists, we showed that activation of A2B adenosine receptors promoted 4T1.2 tumor-cell chemotaxis in vitro and metastasis in vivo. In conclusion, our study identified tumor-derived CD73 as a mechanism of tumor immune escape and tumor metastasis, and it also established the proof of concept that targeted therapy against CD73 can trigger adaptive anti-tumor immunity and inhibit metastasis of breast cancer.
Publisher: Wiley
Date: 22-05-2022
DOI: 10.1111/IMJ.15812
Abstract: The post‐COVID‐19 care era is likely to see a burgeoning of metabolic dysfunction and chronic kidney disease. Attention to self‐care, including nutrition, will underpin the management of those affected. The damaging effects of sugar‐sweetened beverages are well documented and profound and counter many accepted medical treatments. Government leadership is urgently required with explicit and strong messaging to avoid sugar‐sweetened beverages.
Publisher: Wiley
Date: 19-04-2013
DOI: 10.1111/NEP.12058
Abstract: CD39 (NTPDase1), a critical immune and vascular ecto-nucleotidase, hydrolyses pro-inflammatory and pro-thrombotic nucleotides (adenosine-5'-triphosphate (ATP) and adenosine diphosphate) to adenosine. In humans, CD39 is the dominant ecto-nucleotidase in placental trophoblastic tissues and modulates ATP-dependent trophoblastic functions. CD39 is an integral component of regulatory T cells (Treg), which are central to immunological tolerance and maintenance of normal pregnancy. We examined the impact of CD39 overexpression in a mouse model of preecl sia. Matings were performed between virginal BALB/c female (wild-type (WT) or CD39 transgenic (CD39TG)) and C57BL/6 male mice. On days 10 and 12 of pregnancy BALB/c Th1-polarized cells were injected. Systolic blood pressure (SBP) was measured throughout pregnancy. Mice were sacrificed at day 15 of pregnancy. Following transfer of Th1-polarized cells, SBP of pregnant WT mice increased (118 ± 3 mmHg to 142 ± 5 mmHg). Although ultrastructural changes were evident in the kidney this was not accompanied by significant proteinuria. SBP remained unchanged (115 ± 2 mmHg to 114 ± 3 mmHg) in pregnant CD39TG mice without evidence of renal lesions. We conclude that gestational hypertension can be induced in mice following transfer of maternally derived Th1-polarized cells and that overexpression of CD39 is protective in this model.
Publisher: Elsevier BV
Date: 12-2021
DOI: 10.1177/24726303211024562
Abstract: This review discusses the field of coprocytobiology, defined as a combined method of cell preservation, isolation, and cytology, which has applications to the investigation of noninvasive fecal screening for colorectal cancer. In the decade since the field was last reviewed, cell isolation has progressed rapidly via the development of technologies such as microfluidic and magnetic cell sorting. The landscape of cytology has also advanced in this time with the emergence of novel cytological methods and cell preservation strategies. Previous reviews present an outdated and incomplete view of coprocytobiology, summarizing a limited number of early publications, ignoring the principle of cell preservation and focusing on a single method of isolation rather than the field as a whole. In contrast to these publications, this review presents an updated, comprehensive, and unbiased representation of the technical aspects of coprocytobiology and provides unique insight into the common methodological pitfalls, best practice, and future directions of cytological screening for colorectal cancer. This review discusses the field of coprocytobiology, defined as a combined method of cell preservation, isolation, and cytology, which has applications to the investigation of noninvasive fecal screening for colorectal cancer. In the decade since the field was last reviewed, cell isolation has progressed rapidly via the development of technologies such as microfluidic and magnetic cell sorting. The landscape of cytology has also advanced in this time with the emergence of novel cytological methods and cell preservation strategies. Previous reviews present an outdated and incomplete view of coprocytobiology, summarizing a limited number of early publications, ignoring the principle of cell preservation and focusing on a single method of isolation rather than the field as a whole. In contrast to these publications, this review presents an updated, comprehensive, and unbiased representation of the technical aspects of coprocytobiology and provides unique insight into the common methodological pitfalls, best practice, and future directions of cytological screening for colorectal cancer.
Publisher: MDPI AG
Date: 12-09-2018
DOI: 10.3390/NU10091291
Abstract: The contribution of cows’ milk containing beta-casein protein A1 variant to the development of type 1 diabetes (T1D) has been controversial for decades. Despite epidemiological data demonstrating a relationship between A1 beta-casein consumption and T1D incidence, direct evidence is limited. We demonstrate that early life exposure to A1 beta-casein through the diet can modify progression to diabetes in non-obese diabetic (NOD) mice, with the effect apparent in later generations. Adult NOD mice from the F0 generation and all subsequent generations (F1 to F4) were fed either A1 or A2 beta-casein supplemented diets. Diabetes incidence in F0–F2 generations was similar in both cohorts of mice. However, diabetes incidence doubled in the F3 generation NOD mice fed an A1 beta-casein supplemented diet. In F4 NOD mice, subclinical insulitis and altered glucose handling was evident as early as 10 weeks of age in A1 fed mice only. A significant decrease in the proportion of non-conventional regulatory T cell subset defined as CD4+CD25−FoxP3+ was evident in the F4 generation of A1 fed mice. This feeding intervention study demonstrates that dietary A1 beta-casein may affect glucose homeostasis and T1D progression, although this effect takes generations to manifest.
Publisher: Wiley
Date: 11-11-2021
DOI: 10.5694/MJA2.51337
Publisher: Elsevier BV
Date: 07-2012
Publisher: Springer Science and Business Media LLC
Date: 13-01-2018
Publisher: Wiley
Date: 02-2000
Publisher: BMJ
Date: 02-2022
DOI: 10.1136/BMJOPEN-2021-052315
Abstract: People with chronic kidney disease requiring dialysis or kidney transplantation in rural areas have worse outcomes, including an increased risk of hospitalisation and mortality and encounter many barriers to accessing kidney replacement therapy. We aim to describe clinicians’ perspectives of equity of access to dialysis and kidney transplantation in rural areas. Qualitative study with semistructured interviews. Twenty eight nephrologists, nurses and social workers from 19 centres across seven states in Australia. We identified five themes: the tyranny of distance (with subthemes of overwhelming burden of travel, minimising relocation distress, limited transportation options and concerns for patient safety on the roads) supporting navigation of health systems (reliance on local ch ions, variability of health literacy, providing flexible models of care and frustrated by gatekeepers) disrupted care (without continuity of care, scarcity of specialist services and fluctuating capacity for dialysis) pervasive financial distress (crippling out of pocket expenditure and widespread socioeconomic disadvantage) and understanding local variability (lacking availability of safe and sustainable resources for dialysis, sensitivity to local needs and dependence on social support). Clinicians identified geographical barriers, dislocation from homes and financial hardship to be major challenges for patients in accessing kidney replacement therapy. Strategies such as telehealth, outreach services, increased service provision and patient navigators were suggested to improve access.
Publisher: Springer Science and Business Media LLC
Date: 26-08-2016
Publisher: Georg Thieme Verlag KG
Date: 04-2005
Abstract: Transplantation results in exposure of the graft vasculature to warm and cold ischemia, followed by perfusion by circulating blood constituents and obligatory oxidant stress. Further graft injury occurs as consequences of acute humoral cellular rejection or chronic transplant vasculopathy, or both. Extracellular nucleotide stimulation of purinergic type 2 (P2) receptors are key components of platelet, endothelial cell (EC), and leukocyte activation resulting in vascular thrombosis and inflammation in vivo. CD39, the prototype nucleoside triphosphate diphosphohydrolase (NTPDase-1) is highly expressed on endothelium in contrast, CD39L1/NTPDase-2 (a preferential adenosine triphosphatase [ATPase]) is found on vascular adventitial cells. Both ectoenzymes influence thrombogenesis by the regulated hydrolysis of extracellular nucleotides that differentially regulate P2-receptor activity and function in platelets and vascular cells. The intracytoplasmic domains of NTPDase-1 may also independently influence cellular activation and proliferation. NTPDase activity is substantively lost in the vasculature of injured or rejected grafts. A role for NTPDase-1 in thromboregulation has been validated by generation of mutant mice either null for cd39 or overexpressing human CD39. Administration of soluble NTPDase or induction of CD39 by adenoviral vectors, or both, are also of benefit in several models of transplantation. Administration of soluble CD39 or targeted expression may have future therapeutic application in transplantation-associated and other vascular diseases.
Publisher: The American Association of Immunologists
Date: 15-06-2017
Abstract: Deficiency in the membrane-bound complement regulators CD55 and CD59 exacerbates renal ischemia-reperfusion injury (IRI) in mouse models, but the effect of increasing CD55 and CD59 activity has not been examined. In this study, we investigated the impact of overexpression of human (h) CD55 ± hCD59 or treatment with soluble rhCD55 in a mouse model of renal IRI. Unilaterally nephrectomised mice were subjected to 18 (mild IRI) or 22 min (moderate IRI) warm renal ischemia, and analyzed 24 h after reperfusion for renal function (serum creatinine and urea), complement deposition (C3b/c and C9), and infiltration of neutrophils and macrophages. Transgenic mice expressing hCD55 alone were protected against mild renal IRI, with reduced creatinine and urea levels compared with wild type littermates. However, the renal function of the hCD55 mice was not preserved in the moderate IRI model, despite a reduction in C3b/c and C9 deposition and innate cell infiltration. Mice expressing both hCD55 and hCD59, on the other hand, were protected in the moderate IRI model, with significant reductions in all parameters measured. Wild type mice treated with rhCD55 immediately after reperfusion were also protected in the moderate IRI model. Thus, manipulation of CD55 activity to increase inhibition of the C3 and C5 convertases is protective against renal IRI, and the additional expression of hCD59, which regulates the terminal complement pathway, provides further protection. Therefore, anti-complement therapy using complement regulatory proteins may provide a potential clinical option for preventing tissue and organ damage in renal IRI.
Publisher: Wiley
Date: 03-2015
DOI: 10.1111/NEP.12422
Abstract: Primary focal segmental glomerulosclerosis is an important cause of end-stage kidney disease with a high rate of recurrent disease after kidney transplantation. Current therapy achieves remission in only half of patients. Recent interest has focused on the potential role of galactose in binding and inactivating the putative circulating permeability factor, supported by in vitro and clinical case report studies. Orally active and without major adverse effects, galactose has a favourable treatment profile compared with current immunosuppressive treatment options. We describe our experience using galactose therapy in two patients with recurrent focal segmental glomerulosclerosis after renal transplantation. Galactose was associated with symptomatic improvement and stabilization of graft function in one case the other case was complicated by concurrent malignancy. In both cases, we observed a marked reduction in proteinuria with galactose treatment.
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.PAN.2018.06.006
Abstract: Insulin, a key hormone produced by pancreatic beta cells precisely regulates glucose metabolism in vertebrates. In type 1 diabetes, the beta cell mass is destroyed, a process triggered by a combination of environmental and genetic factors. This ultimately results in absolute insulin deficiency and dysregulated glucose metabolism resulting in a number of detrimental pathophysiological effects. The traditional focus of treating type 1 diabetes has been to control blood sugar levels through the administration of exogenous insulin. Newer approaches aim to replace the beta cell mass through pancreatic or islet transplantation. Type 2 diabetes results from a relative insulin deficiency for the prevailing insulin resistance. Treatments are generally aimed at reducing insulin resistance and/or augmenting insulin secretion and the use of insulin itself is often required. It is increasingly being recognized that the beta cell mass is dynamic and increases insulin secretion in response to beta cell mitogens and stress signals to maintain glycemia within a very narrow physiological range. This review critically discusses the role of adrenergic, adenosine and opioid pathways and their interrelationship in insulin secretion, beta cell proliferation and regeneration.
Publisher: Proceedings of the National Academy of Sciences
Date: 20-08-2013
Abstract: CD73 inhibits antitumor immunity through the activation of adenosine receptors expressed on multiple immune subsets. CD73 also enhances tumor metastasis, although the nature of the immune subsets and adenosine receptor subtypes involved in this process are largely unknown. In this study, we revealed that A 2A /A 2B receptor antagonists were effective in reducing the metastasis of tumors expressing CD73 endogenously (4T1.2 breast tumors) and when CD73 was ectopically expressed (B16F10 melanoma). A 2A −/− mice were strongly protected against tumor metastasis, indicating that host A 2A receptors enhanced tumor metastasis. A 2A blockade enhanced natural killer (NK) cell maturation and cytotoxic function in vitro, reduced metastasis in a perforin-dependent manner, and enhanced NK cell expression of granzyme B in vivo, strongly suggesting that the antimetastatic effect of A 2A blockade was due to enhanced NK cell function. Interestingly, A 2B blockade had no effect on NK cell cytotoxicity, indicating that an NK cell-independent mechanism also contributed to the increased metastasis of CD73 + tumors. Our results thus revealed that CD73 promotes tumor metastasis through multiple mechanisms, including suppression of NK cell function. Furthermore, our data strongly suggest that A 2A or A 2B antagonists may be useful for the treatment of metastatic disease. Overall, our study has potential therapeutic implications given that A 2A /A 2B receptor antagonists have already entered clinical trials in other therapeutic settings.
Publisher: Oxford University Press (OUP)
Date: 04-11-2021
DOI: 10.1093/NDT/GFAA226
Abstract: We investigated a cross-sectional epigenome-wide association study of patients with early and late diabetes-associated chronic kidney disease (CKD) to identify possible epigenetic differences between the two groups as well as changes in methylation across all stages of diabetic CKD. We also evaluated the potential of using a panel of identified 5′-C-phosphate-G-3′ (CpG) sites from this cohort to predict the progression of diabetic CKD. This cross-sectional study recruited 119 adults. DNA was extracted from blood using the Qiagen QIA DNA Mini Spin Kit. Genome-wide methylation analysis was performed using Illumina Infinium MethylationEPIC BeadChips (HM850K). Intensity data files were processed and analysed using the minfi and MissMethyl packages for R. We examined the degree of methylation of CpG sites in early versus late diabetic CKD patients for CpG sites with an unadjusted P-value & .01 and an absolute change in methylation of 5% (n = 239 CpG sites). Hierarchical clustering of the 239 CpG sites largely separated the two groups. A heat map for all 239 CpG sites demonstrated distinct methylation patterns in the early versus late groups, with CpG sites showing evidence of progressive change. Based on our differentially methylated region (DMR) analysis of the 239 CpG sites, we highlighted two DMRs, namely the cysteine-rich secretory protein 2 (CRISP2) and piwi-like RNA-mediated gene silencing 1 (PIWIL1) genes. The best predictability for the two groups involved a receiver operating characteristics curve of eight CpG sites alone and achieved an area under the curve of 0.976. We have identified distinct DNA methylation patterns between early and late diabetic CKD patients as well as demonstrated novel findings of potential progressive methylation changes across all stages (1–5) of diabetic CKD at specific CpG sites. We have also identified associated genes CRISP2 and PIWIL1, which may have the potential to act as stage-specific diabetes-associated CKD markers, and showed that the use of a panel of eight identified CpG sites alone helps to increase the predictability for the two groups.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2013
Publisher: Oxford University Press (OUP)
Date: 06-10-2011
Publisher: Wiley
Date: 09-2012
Abstract: CD39 is an ecto-enzyme that degrades extracellular nucleotides, such as ATP, and is highly expressed on by the vasculature and circulating cells including Foxp3+ regulatory T (Treg) cells. To study the role of purinergic regulation in renal disease, we used the adriamycin nephropathy (AN) mouse model of chronic renal injury, using human CD39-transgenic (hCD39Tg) and wild-type (WT) BALB/c mice. Effects of CD39 expression by Treg cells were assessed in AN by adoptive transfer of CD4(+) CD25(+) and CD4(+) CD25(-) T cells isolated from hCD39Tg and WT mice. hCD39Tg mice were protected from renal injury in AN with decreased urinary protein and serum creatinine, and significantly less renal injury compared with WT mice. While WT CD25(+) and hCD39Tg CD25(-) T cells conferred some protection against AN, hCD39Tg CD25(+) Treg cells offered greater protection. In vitro studies showed direct pro-apoptotic effects of ATP on renal tubular cells. In conclusion, hCD39 expressed by circulating leukocytes and intrinsic renal cells limits innate AN injury. Specifically, CD39 expression by Treg cells contributes to its protective role in renal injury. These findings suggest that extracellular nucleotides mediate AN kidney injury and that CD39, expressed by Treg cells and other cells, is protective in this model.
Publisher: Oxford University Press (OUP)
Date: 28-05-2013
DOI: 10.1093/CKJ/SFT043
Publisher: Frontiers Media SA
Date: 05-03-2017
DOI: 10.1111/TRI.12925
Abstract: Klotho is predominantly expressed in the kidney and reported to have antioxidant and antifibrotic properties. Soluble Klotho (sKl), the circulating protein cleaved from membrane-bound Klotho, is reduced significantly with kidney disease and inversely associated with mortality. sKl has not been thoroughly evaluated prospectively after kidney transplantation. Incident kidney transplant recipients (KTRs) were prospectively evaluated pretransplantation, 1, 12 and 52 weeks post-transplantation. Basic biochemistry, sKl and intact FGF23 were measured. Within-subject comparisons were evaluated using repeat-measure anova or Friedman's analysis. Effects of immunosuppression and biochemical parameters on sKl and FGF-23 over time were analysed using mixed-effects modelling. Median serum creatinine (sCr) at 1 week was 116 (92-142) μmol/l, and at 52 weeks, all 29 KTRs had a functioning graft with median sCr of 111 (97-131) μmol/l. Compared with baseline, sKl was increased at 52 weeks following an initial decline at 1 week (P < 0.005 and P < 0.01, respectively), while FGF23 was considerably reduced at 52 weeks (P < 0.001). In a mixed-effects model, an increased sKl was not associated with reduction in immunosuppression or evaluated biochemical parameters. Modest increase in sKl is observed one-year postkidney transplantation with excellent early graft function suggesting factors beyond renal capacity may influence circulating sKl. FGF23 normalization was observed. Longer term evaluation in transplantation, specifically addressing the effects of immunosuppression, is required to understand the pathophysiology of the sKl/FGF23 axis and potential for modification.
Publisher: Elsevier BV
Date: 05-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-03-2013
DOI: 10.1002/HEP.25985
Abstract: Ischemia-reperfusion injury (IRI) is a major limiting event for successful liver transplantation, and CD4+ T cells and invariant natural killer T (iNKT) cells have been implicated in promoting IRI. We hypothesized that hepatic overexpression of CD39, an ectonucleotidase with antiinflammatory functions, will protect liver grafts after prolonged cold ischemia. CD39-transgenic (CD39tg) and wildtype (WT) mouse livers were transplanted into WT recipients after 18 hours cold storage and pathological analysis was performed 6 hours after transplantation. Serum levels of alanine aminotransferase and interleukin (IL)-6 were significantly reduced in recipients of CD39tg livers compared to recipients of WT livers. Furthermore, less severe histopathological injury was demonstrated in the CD39tg grafts. Immune analysis revealed that CD4+ T cells and iNKT cells were significantly decreased in number in the livers of untreated CD39tg mice. This was associated with a peripheral CD4+ T cell lymphopenia due to defective thymocyte maturation. To assess the relative importance of liver-resident CD4+ T cells and iNKT cells in mediating liver injury following extended cold preservation and transplantation, WT mice depleted of CD4+ T cells or mice genetically deficient in iNKT cells were used as donors. The absence of CD4+ T cells, but not iNKT cells, protected liver grafts from early IRI. Hepatic CD4+ T cells, but not iNKT cells, play a critical role in early IRI following extended cold preservation in a liver transplant model.
Publisher: Wiley
Date: 06-03-2022
DOI: 10.1111/IMJ.15670
Abstract: The number of Australians affected by kidney disease will increase as the impacts of COVID‐19 infection on kidney health are realised. Chronic kidney disease (CKD) imposes significant health and economic burdens from dialysis costs, loss of employment, premature death and increased admissions to hospital. Screening for kidney disease must be integrated into post‐COVID‐19 care however, currently there is no reimbursement for kidney health checks in primary care. Early detection can reduce the progression of CKD by as much as 50% and thus the imperative to fund the Kidney Health Check is now.
Publisher: JMIR Publications Inc.
Date: 16-09-2019
Abstract: he importance of identifying people with diabetes and progressive kidney dysfunction relates to the excess morbidity and mortality of this group. Rates of cardiovascular disease are much higher in people with both diabetes and kidney dysfunction than in those with only one of these conditions. By the time these people are identified in current clinical practice, proteinuria and renal dysfunction are already established, limiting the effectiveness of therapeutic interventions. The identification of an epigenetic or blood metabolite signature or gut microbiome profile may identify those with diabetes at risk of progressive chronic kidney disease, in turn providing targeted intervention to improve patient outcomes. his study aims to identify potential biomarkers in people with diabetes and chronic kidney disease (CKD) associated with progressive renal injury and to distinguish between stages of chronic kidney disease. Three sources of biomarkers will be explored, including DNA methylation profiles in blood lymphocytes, the metabolomic profile of blood-derived plasma and urine, and the gut microbiome. he cross-sectional study recruited 121 people with diabetes and varying stages (stages 1-5) of chronic kidney disease. Single-point data collection included blood, urine, and fecal s les in addition to clinical data such as anthropometric measurements and biochemical parameters. Additional information obtained from medical records included patient demographics, medical comorbidities, and medications. ata collection commenced in January 2018 and was completed in June 2018. At the time of submission, 121 patients had been recruited, and 119 s les remained after quality control. There were 83 participants in the early diabetes-associated CKD group with a mean estimated glomerular filtration rate (eGFR) of 61.2 mL/min/1.73 m2 (early CKD group consisting of stage 1, 2, and 3a CKD), and 36 participants in the late diabetic CKD group with a mean eGFR of 23.9 mL/min/1.73 m2 (late CKD group, consisting of stage 3b, 4, and 5), i P /i .001. We have successfully obtained DNA for methylation and microbiome analyses using the biospecimens collected via this protocol and are currently analyzing these results together with the metabolome of this cohort of in iduals with diabetic CKD. ecent advances have improved our understanding of the epigenome, metabolomics, and the influence of the gut microbiome on the incidence of diseases such as cancers, particularly those related to environmental exposures. However, there is a paucity of literature surrounding these influencers in renal disease. This study will provide insight into the fundamental understanding of the pathophysiology of CKD in in iduals with diabetes, especially in novel areas such as epigenetics, metabolomics, and the kidney-gut axis. ERR1-10.2196/16277
Publisher: Springer Science and Business Media LLC
Date: 06-02-2007
Publisher: Frontiers Media SA
Date: 2014
Publisher: Springer Science and Business Media LLC
Date: 17-07-2017
DOI: 10.1007/S40266-017-0478-2
Abstract: Post-transplant diabetes mellitus occurs in 30-50% of cases during the first year post-renal transplantation. It is associated with increased morbidity, mortality and healthcare costs. Risk factors include age and specific immunosuppression regimens. At the same time, renal transplantation is increasingly indicated in elderly (aged >65 years) patients as this proportion of older patients in the prevalent dialysis population has increased. The immune system and β cells undergo senescence and this impacts on the risk for developing post-transplant diabetes and our ability to prevent such development. It may, however, be possible to identify patients at risk of developing post-transplant diabetes, enabling treatment protocols that prevent or reduce the impact of post-transplant diabetes. Much work remains to be completed in this area and is facilitated by the growing base of knowledge regarding the pathophysiology of post-transplant diabetes. Should post-transplant diabetes develop, there are a range of treatment options available. There is increasing interest in using newer agents, although their safety and efficacy in transplant recipients remains to be conclusively established.
Publisher: Wiley
Date: 29-06-2023
DOI: 10.1111/DOM.15195
Publisher: Elsevier BV
Date: 2019
DOI: 10.1016/J.NUT.2018.05.011
Abstract: Objective Beta-casein is a major protein in breast milk and an important source for several bioactive peptides that are encrypted within the sequence. Beta-casomorphins (BCMs) are short-chain proteolytic peptides that are derived from the beta-casein protein and have opioid effects in newborns. Human milk is known to contain naturally occurring milk-protein-derived bioactive peptides but the identification of naturally occurring beta-casein-derived BCMs in human breast milk has been limited due to difficulties in the detection of BCM peptides, which are small and circulate in low concentrations. Methods The present study aimed to identify the naturally occurring BCM peptides from beta-casein in human breast milk using liquid chromatography-tandem mass spectrometry. The BCM peptides identified in the breast milk were analysed to predict the milk proteases responsible for the cleavage patterns using a computational tool EnzymePredictor. Results In-depth peptidomics analysis of breast milk s les that were collected at different lactation stages during human lactation revealed the presence of BCMs including BCM-8, -9, -10, and -11 as well as precursors and truncated forms of the original peptide, which suggests that milk protease activity in the mammary gland generates biologically relevant BCMs. Conclusions To our knowledge, this is the first report to describe the presence of naturally occurring human BCM-10 and -11 in breast milk. Our study provides evidence of beta-casein-derived BCM peptides in human milk before infant digestion. Proteases that are present in milk are likely specific in their proteolysis of beta-casein. The identified bioactive BCM-8, -9, -10, and -11 as well as the precursor peptides meet the structural requirements to elicit opioid, immunomodulatory, antioxidative, and satiety functions in newborns.
Publisher: Portland Press Ltd.
Date: 24-05-2005
DOI: 10.1042/CS20040312
Abstract: In a cross-sectional study, oxidative stress in high vascular disease risk groups, ESRD (end-stage renal disease) and Type I diabetes, was assessed by measuring plasma protein carbonyls and comparing antioxidant capacity of HDL (high-density lipoprotein) as pertaining to PON1 (paraoxonase 1) activity and in vitro removal of LPO (lipid peroxides). ESRD subjects on haemodialysis (n=22), Type I diabetes subjects (n=20) without vascular complications and healthy subjects (n=23) were compared. Plasma protein carbonyls were higher in ESRD patients [0.16 (0.050) nmol/mg of protein P=0.001 value is mean (SD)] relative to subjects with Type I diabetes [0.099 (0.014) nmol/mg of protein] and healthy subjects [0.093 (0.014) nmol/mg of protein]. Plasma PON1 activity, with and without correction for HDL-cholesterol, was lower in diabetes but did not differ in ESRD compared with healthy subjects. Plasma PON1 activity, without correction for HDL, did not differ between the three groups. In ESRD, plasma PON1 activity and plasma protein carbonyl concentrations were inversely related (r=−0.50, P& .05). In an in vitro assay, LPO removal by HDL in ESRD subjects was greater than HDL from healthy subjects (P& .01), whereas HDL from patients with Type I diabetes was less effective (P& .01). Efficacy of LPO removal was unrelated to plasma PON1 activity, in vitro glycation or mild oxidation, but was impaired by marked oxidation and glycoxidation. Protein carbonyl levels are increased in ESRD but not in complication-free Type I diabetes. HDL antioxidant function is increased in ESRD, perhaps a compensatory response to increased oxidative stress, but is lower in Type I diabetes. HDL dysfunction is related to glycoxidation rather than glycation or PON1 activity.
Publisher: Elsevier BV
Date: 2002
DOI: 10.1046/J.1444-2892.2002.00110.X
Abstract: Xenotransplantation offers a potential solution to the shortfall in donor organs for human transplantation. This review describes the barriers to xenotransplantation and the progress that has been made towards making it a clinical reality. Data from preclinical pig-to-primate cardiac and pulmonary xenografts are highlighted.
Publisher: Public Library of Science (PLoS)
Date: 09-01-2012
Publisher: Elsevier BV
Date: 2002
DOI: 10.1080/003130201201117945
Abstract: The reported association of glomerular disease with chronic lymphocytic leukaemia (CLL) is rare despite the relative frequency of this type of leukaemia. Hence, we have examined the renal biopsies in three patients with CLL and glomerulonephritis. Renal biopsies were examined by light microscopy, immunofluorescence microscopy and electron microscopy. One of two patients with mild impairment of renal function and an active urinary sediment had ultrastructural features of idiopathic type I membranoproliferative glomerulonephritis (MPGN), and the other had features of fibrillary/ immunotactoid glomerulonephritis with deposits of IgG and C3. One patient with nephrotic syndrome had characteristic electron microscopic appearances of type III MPGN. In all three there was an association with monoclonal gammopathy. The parameters of glomerular damage improved in association with response to drug treatment of the CLL. There is a spectrum of types of MPGN seen in patients with CLL and there appears to be an association with the presence of monoclonal gammopathy. This is the first reported case of type III MPGN in CLL.
Publisher: American Physiological Society
Date: 15-06-2015
DOI: 10.1152/AJPRENAL.00125.2014
Abstract: Extracellular nucleotides acting through P2 receptors facilitate natriuresis. To define how purinergic mechanisms are involved in sodium homeostasis, we used transgenic (TG) mice that globally overexpress human CD39 (hCD39, NTPDase1), an ectonucleotidase that hydrolyzes extracellular ATP/ADP to AMP, resulting in an altered extracellular purine profile. On a high-sodium diet (HSD, 3.5% Na + ), urine volume and serum sodium were significantly higher in TG mice but sodium excretion was unaltered. Furthermore, TG mice showed an attenuated fall in urine aldosterone with HSD. Western blot analysis revealed significantly lower densities (∼40%) of the β-subunit of the epithelial sodium channel (ENaC) in medulla, and the major band (85-kDa) of γ-ENaC in TG mice cortex. To evaluate aldosterone-independent differences, in a second experiment, aldosterone was cl ed by osmotic minipump at 20 μg/day, and mice were fed either an HSD or a low-sodium diet (LSD, 0.03% Na + ). Here, no differences in urine volume or osmolality, or serum aldosterone were found, but TG mice showed a modest, yet significant impairment in late natriuresis ( days 3 and 4). Several major sodium transporters or channel subunits were differentially expressed between the genotypes. HSD caused a downregulation of Na-Cl cotransporter (NCC) in both genotypes and had higher cortical levels of NCC, Na-K-ATPase (α-1 subunit), and α- and γ-ENaC. The Na-K-2Cl cotransporter (NKCC2) was downregulated by HSD in wild-type mice, but it increased in TG mice. In summary, our data support the concept that extracellular nucleotides facilitate natriuresis they also reveal an aldosterone-independent downregulation of major renal sodium transporters and channel subunits by purinergic signaling.
Publisher: The Company of Biologists
Date: 2020
DOI: 10.1242/BIO.049304
Abstract: Several epidemiological studies support the protective role of breast-feeding in reducing the risk for type 1 diabetes. Human breast milk is the perfect nutrition for infants and contains many complex proteins, lipids and carbohydrates. In this study, we examined the physiological effects of human milk-derived opioid peptides, beta casomorphins (BCM), and compared them with bovine milk-derived opioid peptides on pancreatic hormone regulation and β-cell regeneration. Exposure of wild-type zebrafish embryos to 50 µg/mL of human BCM -5 and -7 from 3 days post fertilisation until 6 days post fertilisation resulted in an increased insulin domain of expression while exposure to bovine BCM -5 and -7 significantly reduced the insulin domain of expression as analysed by whole-mount in-situ hybridisation. These changes may be accounted for by reduced insulin expression or β-cell number and were mitigated by the µ-opioid receptor antagonist, naloxone. The effect of BCM on β-cell regeneration was assessed following ablation of β-cells in Tg (ins: CFP-NTR) zebrafish from 3 days post fertilisation to 4 days post fertilisation, followed by exposure of bovine and human BCM -5 and -7 (50 µg/mL) from 4 days post fertilisation until 7 days post fertilisation. The regenerative capacity of β-cells was not impeded following exposure to human BCM -5 and -7, whereas the capacity of β-cells to regenerate following bovine BCM -5 and -7 exposure was reduced. Our data suggests that human BCM -5 and -7 may promote β-cell development and enable the regeneration of β-cells, while the bovine milk derived peptides, BCM -5 and -7 play an opposite role. These data may provide some biological explanation for the protective effect of breastfeeding on the development of Type 1 Diabetes.
Publisher: Wiley
Date: 15-10-2023
DOI: 10.5694/MJA2.52114
Publisher: Elsevier BV
Date: 2007
Publisher: American Physiological Society
Date: 09-2013
DOI: 10.1152/AJPRENAL.00407.2012
Abstract: Salt reabsorption is the major energy-requiring process in the kidney, and AMP-activated protein kinase (AMPK) is an important regulator of cellular metabolism. Mice with targeted deletion of the β1-subunit of AMPK (AMPK-β1 −/− mice) had significantly increased urinary Na + excretion on a normal salt diet. This was associated with reduced expression of the β-subunit of the epithelial Na + channel (ENaC) and increased subapical tubular expression of kidney-specific Na + -K + -2Cl − cotransporter 2 (NKCC2) in the medullary thick ascending limb of Henle. AMPK-β1 −/− mice fed a salt-deficient diet were able to conserve Na + , but renin secretion increased 180% compared with control mice. Cyclooxygenase-2 mRNA also increased in the kidney cortex, indicating greater signaling through the macula densa tubular salt-sensing pathway. To determine whether the increase in renin secretion was due to a change in regulation of fatty acid metabolism by AMPK, mice with a mutation of the inhibitory AMPK phosphosite in acetyl-CoA carboxylase 1 [ACC1-knockin (KI) S79A mice] were examined. ACC1-KI S79A mice on a normal salt diet had no increase in salt loss or renin secretion, and expression of NKCC2, Na + -Cl − cotransporter, and ENaC-β were similar to those in control mice. When mice were placed on a salt-deficient diet, however, renin secretion and cortical expression of cyclooxygenase-2 mRNA increased significantly in ACC1-KI S79A mice compared with control mice. In summary, our data suggest that renin synthesis and secretion are regulated by AMPK and coupled to metabolism by phosphorylation of ACC1.
Publisher: Elsevier BV
Date: 2018
DOI: 10.1016/J.BMCL.2017.11.019
Abstract: Adenosine is considered the canonical ligand for the adenosine 2B receptor (A
Publisher: Springer Science and Business Media LLC
Date: 15-05-2017
DOI: 10.1038/NUTD.2017.16
Abstract: Globally type 1 diabetes incidence is increasing. It is widely accepted that the pathophysiology of type 1 diabetes is influenced by environmental factors in people with specific human leukocyte antigen haplotypes. We propose that a complex interplay between dietary triggers, permissive gut factors and potentially other influencing factors underpins disease progression. We present evidence that A1 β-casein cows’ milk protein is a primary causal trigger of type 1 diabetes in in iduals with genetic risk factors. Permissive gut factors (for ex le, aberrant mucosal immunity), intervene by impacting the gut’s environment and the mucosal barrier. Various influencing factors (for ex le, breastfeeding duration, exposure to other dietary triggers and vitamin D) modify the impact of triggers and permissive gut factors on disease. The power of the dominant trigger and permissive gut factors on disease is influenced by timing, magnitude and/or duration of exposure. Within this framework, removal of a dominant dietary trigger may profoundly affect type 1 diabetes incidence. We present epidemiological, animal-based, in vitro and theoretical evidence for A1 β-casein and its β-casomorphin-7 derivative as dominant causal triggers of type 1 diabetes. The effects of ordinary milk containing A1 and A2 β-casein and milk containing only the A2 β-casein warrant comparison in prospective trials.
Publisher: Elsevier BV
Date: 06-2002
DOI: 10.1034/J.1600-6143.2002.20605.X
Abstract: Delayed rejection of pig kidney xenografts by primates is associated with vascular injury that may be accompanied by a form of consumptive coagulopathy in recipients. Using a life-supporting pig-to-baboon renal xenotransplantation model, we have tested the hypothesis that treatment with recombinant human antithrombin III would prevent or at least delay the onset of rejection and coagulopathy. Non-immunosuppressed baboons were transplanted with transgenic pig kidneys expressing the human complement regulators CD55 and CD59. Recipients were treated with an intravenous infusion of antithrombin III eight hourly (250 units per kg body weight), with or without low molecular weight heparin. Antithrombin-treated recipients had preservation of normal renal function for 4-5 days, which was twice as long as untreated animals, and developed neither thrombocytopenia nor significant coagulopathy during this period. Thus, recombinant antithrombin III may be a useful therapeutic agent to ameliorate both early graft damage and the development of systemic coagulation disorders in pig-to-human xenotransplantation.
Publisher: Springer Science and Business Media LLC
Date: 09-10-2011
DOI: 10.1007/S10620-010-1425-9
Abstract: Dysregulation of immune responses in inflammatory bowel diseases (IBD) results in intestinal inflammation and vascular injury while exacerbating systemic disease. CD39 is an ectonucleotidase, expressed by T regulatory cells and dendritic cells, that hydrolyzes extracellular nucleotides to modify those cellular immune responses implicated in IBD. Genetic polymorphisms of CD39 have been linked to Crohn's disease while gene deletion in mice exacerbates dextran sodium sulphate-induced colitis. The aim of this study was to test how global deletion of CD39 in mice impacts other models of experimental colitis. Colitis was induced in CD39-null and -wt mice, using trinitrobenzene sulfonic acid (TNBS, 125 mg/kg) administered intrarectally. Oxazolone colitis (1.5% oxazolone in 50% alcohol) was induced in comparable groups. Morphology, clinical and molecular parameters, and FACS analyses of lamina propria mononuclear cells (LPMC) were examined in CD39-null mice. CD39 expression was analyzed in human IBD biopsies. Paradoxically, TNBS colitis in CD39-null mice was characterized by improved survival, favorable clinical scores, and decreased MPO activity, when compared to wt mice (P < 0.05). LPMC from TNBS colitis contained significantly increased amounts of T-cells (CD3(+) and CD4(+)) and TNF-α mRNA expression were increased over those in CD39 null mice (P < 0.05). In contrast, oxazolone treated CD39-null and wt mice had comparable outcomes. In both ulcerative colitis and Crohn's disease, CD39 is present at high levels in intestinal tissue biopsies. TNBS colitis was attenuated in CD39-null mice whereas oxazolone-induced colitis was not impacted. Impaired adaptive cellular immune reactivity in the CD39-null environment appears protective in hapten-mediated Th1-type colitis. CD39 is expressed at high levels in clinical IBD tissues.
Publisher: American Society for Clinical Investigation
Date: 15-05-2004
DOI: 10.1172/JCI19560
Publisher: Elsevier BV
Date: 08-2009
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 14-09-2013
DOI: 10.1002/LT.23720
Abstract: Donor passenger leukocytes (PLs) from transplanted livers migrate to recipient lymphoid tissues, where they are thought to induce the deletion of donor-specific T cells and tolerance. Difficulties in tracking alloreactive T cells and PLs in rats and in performing this complex surgery in mice have limited progress in identifying the contribution of PL subsets and sites and the kinetics of T cell deletion. Here we developed a mouse liver transplant model in which PLs, recipient cells, and a reporter population of transgenic CD8 T cells specific for the graft could be easily distinguished and quantified in allografts and recipient organs by flow cytometry. All PL subsets circulated rapidly via the blood as soon as 1.5 hours after transplantation. By 24 hours, PLs were distributed differently in the lymph nodes and spleen, whereas donor natural killer and natural killer T cells remained in the liver and blood. Reporter T cells were activated in both liver and lymphoid tissues, but their numbers dramatically decreased within the first 48 hours. These results provide the first unequivocal demonstration of the differential recirculation of liver PL subsets after transplantation, and show that alloreactive CD8 T cells are deleted more rapidly than initially reported. This model will be useful for dissecting early events leading to the spontaneous acceptance of liver transplants.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2011
Publisher: Oxford University Press (OUP)
Date: 07-06-2012
DOI: 10.1093/CKJ/SFS053
Publisher: Elsevier BV
Date: 08-2002
Abstract: A number of well-documented renal lesions have been associated with intravenous drug use. Recently, investigators reported three cases of granulomatous glomerulonephritis in association with intravenous injection of oxycodone suppositories. We report 2 patients with similar glomerular pathology who presented with chronic renal failure. However, we also highlight the widespread tubulointerstitial involvement in this renal lesion. The fibrillar deposits seen within the glomeruli and extensively within tubular basement membranes on electron microscopy do not have the staining characteristics of amyloid and are not associated with immunoglobulin (Ig) deposition. Is this a new form of non-Ig-associated fibrillary glomerulopathy with its pathogenesis linked to some component of the oxycodone suppositories? One of the patients had a history of narcotic addiction but denied intravenous injection of suppositories. In both patients there was progressive deterioration of renal function with 1 patient requiring dialysis within 3 months of initial presentation.
Publisher: Wiley
Date: 12-2018
DOI: 10.1111/IMJ.14129
Abstract: The metabolic abnormalities affecting bone in the setting of chronic kidney disease (CKD) are complex with overlapping and interacting aetiologies and have challenging diagnostic and management strategies. Disturbances in calcium, phosphate, fibroblast growth factor 23, parathyroid hormone concentrations and vitamin D deficiency are commonly encountered and contribute to the clinical syndromes of bone disorders in CKD, including hyperparathyroidism, osteomalacia, osteoporosis and adynamic bone disease. Mineral and bone abnormalities may also persist or arise de novo post-renal transplantation. The Kidney Disease Improving Global Outcomes organisation describes these mineral metabolism derangements and skeletal abnormalities as 'CKD Mineral and Bone Disorder'. Patients with this disorder have an increased risk of fracture, cardiovascular events and overall increased mortality. In light of the recently updated 2017 guidelines from the Kidney Disease Improving Global Outcomes, we present a clinical case-based discussion to highlight the complexities of investigating and managing the bone health of patients with CKD with a focus on these updates.
Publisher: Wiley
Date: 15-06-2017
DOI: 10.1111/NEP.12894
Abstract: Regulatory T cells (Treg) are important in mediating immune tolerance and outcomes of allotransplantation. CD4 CD4 CD4 CD4
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2006
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2016
DOI: 10.1161/ATVBAHA.116.307374
Abstract: Circulating blood cells and endothelial cells express ectonucleoside triphosphate diphosphohydrolase-1 (CD39) and ecto-5′-nucleotidase (CD73). CD39 hydrolyzes extracellular ATP or ADP to AMP. CD73 hydrolyzes AMP to adenosine. The goal of this study was to examine the interplay between CD39 and CD73 cascade in arterial thrombosis. To determine how CD73 activity influences in vivo thrombosis, the time to ferric chloride–induced arterial thrombosis was measured in CD73-null mice. In response to 5% FeCl 3 , but not to 10% FeCl 3 , there was a significant decrease in the time to thrombosis in CD73-null mice compared with wild-type mice. In mice overexpressing CD39, ablation of CD73 did not inhibit the prolongation in the time to thrombosis conveyed by CD39 overexpression. However, the CD73 inhibitor α-β-methylene-ADP nullified the prolongation in the time to thrombosis in human CD39 transgenic (hC39-Tg)/CD73-null mice. To determine whether hematopoietic-derived cells or endothelial cell CD39 activity regulates in vivo arterial thrombus, bone marrow transplant studies were conducted. FeCl 3 -induced arterial thrombosis in chimeric mice revealed a significant prolongation in the time to thrombosis in hCD39-Tg reconstituted wild-type mice, but not on wild-type reconstituted hCD39-Tg mice. Monocyte depletion with clodronate-loaded liposomes normalized the time to thrombosis in hCD39-Tg mice compared with hCD39-Tg mice treated with control liposomes, demonstrating that increased CD39 expression on monocytes protects against thrombosis. These data demonstrate that ablation of CD73 minimally effects in vivo thrombosis, but increased CD39 expression on hematopoietic-derived cells, especially monocytes, attenuates in vivo arterial thrombosis.
Publisher: Elsevier BV
Date: 10-2014
DOI: 10.1038/KI.2014.244
Abstract: Renal fibrosis, the key histopathological lesion in the development and progression of chronic kidney disease (CKD), has been the focus of much research in recent decades. The growing burden of CKD in both developed and developing nations highlights a need for novel therapies to halt the progression of renal disease. Insights into the pathogenesis of renal fibrosis and the key cellular and molecular mediators have been critical in the process of identifying potential targets of therapy. Adenosine signaling is an innate biological autocrine and paracrine cellular signaling pathway involving several key mediators: ectonucleotidases, adenosine, and adenosine receptors. Short-term activation of the adenosine A2A and A2B receptors decreases inflammation, which precedes renal fibrosis. However, in conditions of persistent, excessive adenosine exposure, such as in patients born with adenosine deaminase (ADA) deficiency, adenosine signaling via A2B receptor promotes renal fibrosis, as seen in chronic inflammation. This review will describe the increasingly recognized complex role of adenosine signaling in the development of renal fibrosis. We will speculate how the knowledge gained may be employed in the search for more effective therapies based on these complex signaling pathways.
Publisher: Portland Press Ltd.
Date: 26-04-2006
DOI: 10.1042/BJ20051568
Abstract: CD39/ecto-NTPDase 1 (nucleoside triphosphate diphosphohydrolase 1) is an ecto-nucleotidase that influences P2 receptor activation to regulate vascular and immune cell adhesion and signalling events pivotal in inflammation. Whether CD39 interacts with other membrane or cytoplasmic proteins has not been established to date. Using the yeast two-hybrid system, we note that the N-terminus of CD39 binds to RanBPM (Ran binding protein M also known as RanBP9), a multi-adaptor scaffolding membrane protein originally characterized as a binding protein for the small GTPase Ran. We confirm formation of complexes between CD39 and RanBPM in transfected mammalian cells by co-immunoprecipitation studies. Endogenous CD39 and RanBPM are also found to be co-expressed and abundant in cell membranes of B-lymphocytes. NTPDase activity of recombinant CD39, but not of N-terminus-deleted-CD39 mutant, is substantially diminished by RanBPM co-expression in COS-7 cells. The conserved SPRY [repeats in splA and RyR (ryanodine receptor)] moiety of RanBPM is insufficient alone for complete physical and functional interactions with CD39. We conclude that CD39 associations with RanBPM have the potential to regulate NTPDase catalytic activity. This intermolecular interaction may have important implications for the regulation of extracellular nucleotide-mediated signalling.
Publisher: American Physiological Society
Date: 08-2012
DOI: 10.1152/AJPRENAL.00060.2012
Abstract: Ectonucleoside triphosphate diphosphohydrolase-1 hydrolyzes extracellular ATP and ADP to AMP. Previously, we showed that CD39 is expressed at several sites within the kidney and thus may impact the availability of type 2 purinergic receptor (P2-R) ligands. Because P2-Rs appear to regulate urinary concentrating ability, we have evaluated renal water handling in transgenic mice (TG) globally overexpressing hCD39. Under basal conditions, TG mice exhibited significantly impaired urinary concentration and decreased protein abundance of AQP2 in the kidney compared with wild-type (WT) mice. Urinary excretion of total nitrates/nitrites was significantly higher in TG mice, but the excretion of AVP or PGE 2 was equivalent to control WT mice. There were no significant differences in electrolyte-free water clearance or fractional excretion of sodium. Under stable hydrated conditions (gelled diet feeding), the differences between the WT and TG mice were negated, but the decrease in urine osmolality persisted. When water deprived, TG mice failed to adequately concentrate urine and exhibited impaired AVP responses. However, the increases in urinary osmolalities in response to subacute dDAVP or chronic AVP treatment were similar in TG and WT mice. These observations suggest that TG mice have impaired urinary concentrating ability despite normal AVP levels. We also note impaired AVP release in response to water deprivation but that TG kidneys are responsive to exogenous dDAVP or AVP. We infer that heightened nucleotide scavenging by increased levels of CD39 altered the release of endogenous AVP in response to dehydration. We propose that ectonucleotidases and modulated purinergic signaling impact urinary concentration and indicate potential utility of targeted therapy for the treatment of water balance disorders.
Publisher: Elsevier BV
Date: 07-2002
Abstract: Renovascular disease is a common cause of renal impairment and hypertension, particularly in the older population. Oligoanuric acute renal failure secondary to renal artery occlusion is not well recognized however, it is potentially reversible if identified and treated. Five patients presented to our institution with oligoanuric acute renal failure. Each had evidence of vascular disease, and a prerenal insult was identified. They were investigated with renal artery Doppler ultrasound or nuclear imaging before proceeding to percutaneous angioplasty and stent placement. The targeted kidney had relatively well-preserved renal size, and potential viability of the renal tissue was determined by nuclear scanning with parenchymal uptake of tracer. Percutaneous angioplasty and stent placement resulted in brisk reperfusion of the kidney and an immediate diuresis with improvement of renal function, avoiding supportive dialysis after the procedure. Contrast nephrotoxicity was identified in two of the five cases. Renal artery occlusion should be considered as a cause of oliguric acute renal failure, particularly in patients at high risk who present with a sudden deterioration of renal function, with nuclear imaging showing potentially viable renal tissue with relatively well-preserved renal size. Percutaneous revascularization should be considered in this group.
Publisher: Oxford University Press (OUP)
Date: 13-06-2012
DOI: 10.1093/CKJ/SFS061
Publisher: Public Library of Science (PLoS)
Date: 20-02-2018
Publisher: Springer Science and Business Media LLC
Date: 08-07-2020
Publisher: Elsevier BV
Date: 12-2010
Publisher: Wiley
Date: 06-2019
DOI: 10.1111/IMJ.14317
Publisher: American Physiological Society
Date: 05-2011
DOI: 10.1152/AJPHEART.01285.2010
Abstract: Antioxidant enzymatic pathways form a critical network that detoxifies ROS in response to myocardial stress or injury. Genetic alteration of the expression levels of in idual enzymes has yielded mixed results with regard to attenuating in vivo myocardial ischemia-reperfusion injury, an extreme oxidative stress. We hypothesized that overexpression of an antioxidant network (AON) composed of SOD1, SOD3, and glutathione peroxidase (GSHPx)-1 would reduce myocardial ischemia-reperfusion injury by limiting ROS-mediated lipid peroxidation and oxidative posttranslational modification (OPTM) of proteins. Both ex vivo and in vivo myocardial ischemia models were used to evaluate the effect of AON expression. After ischemia-reperfusion injury, infarct size was significantly reduced both ex vivo and in vivo, ROS formation, measured by dihydroethidium staining, was markedly decreased, ROS-mediated lipid peroxidation, measured by malondialdehyde production, was significantly limited, and OPTM of total myocardial proteins, including fatty acid-binding protein and sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA)2a, was markedly reduced in AON mice, which overexpress SOD1, SOD3, and GSHPx-1, compared with wild-type mice. These data demonstrate that concomitant SOD1, SOD3, and GSHPX-1 expression confers marked protection against myocardial ischemia-reperfusion injury, reducing ROS, ROS-mediated lipid peroxidation, and OPTM of critical cardiac proteins, including cardiac fatty acid-binding protein and SERCA2a.
Publisher: AMPCo
Date: 08-2013
DOI: 10.5694/MJA12.11554
Publisher: MDPI AG
Date: 10-09-2020
DOI: 10.3390/BIOMEDICINES8090341
Abstract: Diabetes-associated chronic kidney disease is a pandemic issue. Despite the global increase in the number of in iduals with this chronic condition together with increasing morbidity and mortality, there are currently only limited therapeutic options to slow disease progression. One of the reasons for this is that the current-day “gold standard” biomarkers lack adequate sensitivity and specificity to detect early diabetic chronic kidney disease (CKD). This review focuses on the rapidly evolving areas of epigenetics, metabolomics, and the gut microbiome as potential sources of novel biomarkers in diabetes-associated CKD and discusses their relevance to clinical practice. However, it also highlights the problems associated with many studies within these three areas—namely, the lack of adequately powered longitudinal studies, and the lack of reproducibility of results which impede biomarker development and clinical validation in this complex and susceptible population.
Publisher: JMIR Publications Inc.
Date: 31-07-2020
DOI: 10.2196/16277
Abstract: The importance of identifying people with diabetes and progressive kidney dysfunction relates to the excess morbidity and mortality of this group. Rates of cardiovascular disease are much higher in people with both diabetes and kidney dysfunction than in those with only one of these conditions. By the time these people are identified in current clinical practice, proteinuria and renal dysfunction are already established, limiting the effectiveness of therapeutic interventions. The identification of an epigenetic or blood metabolite signature or gut microbiome profile may identify those with diabetes at risk of progressive chronic kidney disease, in turn providing targeted intervention to improve patient outcomes. This study aims to identify potential biomarkers in people with diabetes and chronic kidney disease (CKD) associated with progressive renal injury and to distinguish between stages of chronic kidney disease. Three sources of biomarkers will be explored, including DNA methylation profiles in blood lymphocytes, the metabolomic profile of blood-derived plasma and urine, and the gut microbiome. The cross-sectional study recruited 121 people with diabetes and varying stages (stages 1-5) of chronic kidney disease. Single-point data collection included blood, urine, and fecal s les in addition to clinical data such as anthropometric measurements and biochemical parameters. Additional information obtained from medical records included patient demographics, medical comorbidities, and medications. Data collection commenced in January 2018 and was completed in June 2018. At the time of submission, 121 patients had been recruited, and 119 s les remained after quality control. There were 83 participants in the early diabetes-associated CKD group with a mean estimated glomerular filtration rate (eGFR) of 61.2 mL/min/1.73 m2 (early CKD group consisting of stage 1, 2, and 3a CKD), and 36 participants in the late diabetic CKD group with a mean eGFR of 23.9 mL/min/1.73 m2 (late CKD group, consisting of stage 3b, 4, and 5), P .001. We have successfully obtained DNA for methylation and microbiome analyses using the biospecimens collected via this protocol and are currently analyzing these results together with the metabolome of this cohort of in iduals with diabetic CKD. Recent advances have improved our understanding of the epigenome, metabolomics, and the influence of the gut microbiome on the incidence of diseases such as cancers, particularly those related to environmental exposures. However, there is a paucity of literature surrounding these influencers in renal disease. This study will provide insight into the fundamental understanding of the pathophysiology of CKD in in iduals with diabetes, especially in novel areas such as epigenetics, metabolomics, and the kidney-gut axis. DERR1-10.2196/16277
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-12-2008
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-12-2010
Publisher: American Diabetes Association
Date: 20-05-2013
DOI: 10.2337/DB12-0625
Abstract: Islet allograft survival limits the long-term success of islet transplantation as a potential curative therapy for type 1 diabetes. A number of factors compromise islet survival, including recurrent diabetes. We investigated whether CD39, an ectonucleotidase that promotes the generation of extracellular adenosine, would mitigate diabetes in the T cell–mediated multiple low-dose streptozotocin (MLDS) model. Mice null for CD39 (CD39KO), wild-type mice (WT), and mice overexpressing CD39 (CD39TG) were subjected to MLDS. Adoptive transfer experiments were performed to delineate the efficacy of tissue-restricted overexpression of CD39. The role of adenosine signaling was examined using mutant mice and pharmacological inhibition. The susceptibility to MLDS-induced diabetes was influenced by the level of expression of CD39. CD39KO mice developed diabetes more rapidly and with higher frequency than WT mice. In contrast, CD39TG mice were protected. CD39 overexpression conferred protection through the activation of adenosine 2A receptor and adenosine 2B receptor. Adoptive transfer experiments indicated that tissue-restricted overexpression of CD39 conferred robust protection, suggesting that this may be a useful strategy to protect islet grafts from T cell–mediated injury.
Publisher: Elsevier BV
Date: 12-2011
Publisher: Elsevier BV
Date: 09-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2017
Publisher: SAGE Publications
Date: 07-2000
DOI: 10.1191/096120300678828505
Abstract: We report the case of a woman with systemic lupus erythematosus initially manifesting with fever, rash and arthritis, and two years later with Class IV lupus nephritis. Following treatment with cyclophosphamide she developed symptoms and signs of chronic intestinal pseudo-obstruction (CIPO) that was initially thought to be due to a neutropenic enterocolitis. However, persistence of symptoms resulted in segmental resection of the ileum which showed widespread myocyte necrosis and active inflammation within the muscularis propria. A subsequent, more extensive ileocolic resection showed severe diffuse atrophy and fibrosis of the muscularis propria throughout the resected bowel. The absence of mesenteric vasculitis and the clinical response of the CIPO to the immunosupressive regimen of prednisolone and cyclosporin A suggest that the bowel muscle coat changes reflect an intestinal myopathy secondary to systemic lupus erythematosus, and may have an auto-immune etiology.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2017
Publisher: AMPCo
Date: 20-12-1414
DOI: 10.5694/MJA2.12068
Publisher: Elsevier BV
Date: 03-2018
DOI: 10.1016/J.JAUT.2017.10.009
Abstract: Antiphospholipid syndrome (APS) is a systemic autoimmune disorder of young adults associated with devastating pregnancy complications (recurrent miscarriages, preecl sia and low birth weight) and vascular complications including thrombosis. The key components implicated in pathogenesis of APS are the complement cascade and tissue factor (TF) activity causing inflammation and coagulation. Purinergic signalling involving catabolism of ATP to adenosine by cell-surface enzymes CD39 and CD73 has anti-inflammatory and anti-thrombotic effects. We studied whether activities of CD39 and CD73 are important in preventing the development of miscarriages in APS. We studied frequency of miscarriages and decidual pathology following passive transfer of human aPL-ab to pregnant wildtype mice, and mice deficient in CD39 and CD73, and also transgenic mice exhibiting 2-3X higher CD39 activity. aPL-ab infusion in pregnant CD39-or CD73-knockout mice triggers an increase in miscarriages, associated with increased TF expression and complement deposition as well as elevated oxidative stress and pro-inflammatory TNF-α and IL-10 expression within the placental decidua. In contrast, aPL-ab induced miscarriages are prevented in mice over-expressing CD39, with reduced decidual TF expression and C3d deposition, diminished lipid peroxidation (4-hydroxynonenal or 4-HNE positive lipid adducts), and reduced TNF-α expression. We demonstrate a protective role for CD39 in APS and provide rationale for both the development of endothelial cell-targeted soluble CD39 as a novel therapeutic for APS and analysis of perturbations in the purinergic pathway to explain human disease.
Publisher: MDPI AG
Date: 29-12-2020
DOI: 10.3390/BIOMEDICINES9010019
Abstract: (1) Background: In iduals with diabetes and chronic kidney disease display gut dysbiosis when compared to healthy controls. However, it is unknown whether there is a change in dysbiosis across the stages of diabetic chronic kidney disease. We investigated a cross-sectional study of patients with early and late diabetes associated chronic kidney disease to identify possible microbial differences between these two groups and across each of the stages of diabetic chronic kidney disease. (2) Methods: This cross-sectional study recruited 95 adults. DNA extracted from collected stool s les were used for 16S rRNA sequencing to identify the bacterial community in the gut. (3) Results: The phylum Firmicutes was the most abundant and its mean relative abundance was similar in the early and late chronic kidney disease group, 45.99 ± 0.58% and 49.39 ± 0.55%, respectively. The mean relative abundance for family Bacteroidaceae, was also similar in the early and late group, 29.15 ± 2.02% and 29.16 ± 1.70%, respectively. The lower abundance of Prevotellaceae remained similar across both the early 3.87 ± 1.66% and late 3.36 ± 0.98% diabetic chronic kidney disease groups. (4) Conclusions: The data arising from our cohort of in iduals with diabetes associated chronic kidney disease show a predominance of phyla Firmicutes and Bacteroidetes. The families Ruminococcaceae and Bacteroidaceae represent the highest abundance, while the beneficial Prevotellaceae family were reduced in abundance. The most interesting observation is that the relative abundance of these gut microbes does not change across the early and late stages of diabetic chronic kidney disease, suggesting that this is an early event in the development of diabetes associated chronic kidney disease. We hypothesise that the dysbiotic microbiome acquired during the early stages of diabetic chronic kidney disease remains relatively stable and is only one of many risk factors that influence progressive kidney dysfunction.
Publisher: Wiley
Date: 14-03-2014
DOI: 10.1111/NEP.12193
Abstract: Mycobacterium haemophilum is a rare isolate of non-tuberculous Mycobacterium which has been reported to affect immunocompromised patients. We report a case of a 32-year-old renal transplant patient with M. haemophilum infection initially involving his left sinus which was treated with appropriate antimicrobial therapy for thirteen months. Two weeks after cessation of antibiotics the infection rapidly recurred in his skin and soft tissues of his hands and feet. This case highlights the difficult diagnostic and therapeutic implications of atypical infections in transplant patients. To our knowledge this is the first reported case of relapsed M. haemophilum infection in a renal transplant recipient.
Publisher: Elsevier BV
Date: 11-2010
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-03-2013
Publisher: Hindawi Limited
Date: 2012
DOI: 10.1155/2012/320495
Abstract: Diabetes mellitus encompasses two distinct disease processes: autoimmune Type 1 (T1D) and nonimmune Type 2 (T2D) diabetes. Despite the disparate aetiologies, the disease phenotype of hyperglycemia and the associated complications are similar. In this paper, we discuss the role of the CD39-adenosinergic axis in the pathogenesis of both T1D and T2D, with particular emphasis on the role of CD39 and CD73.
Publisher: Wiley
Date: 22-04-2016
DOI: 10.1111/NEP.12624
Abstract: The phospholipase A2 receptor (PLA2R) is the major target antigen in idiopathic membranous nephropathy (iMN). The aim of this prospective study was to determine the prevalence of anti-PLA2R in iMN in an Australian cohort. Serum anti-PLA2R was measured using two techniques, an enzyme-linked immunosorbent assay (ELISA) and a cell-based indirect immunofluorescence test. Kidney biopsies were also examined for the presence of PLA2R using a polyclonal antibody. A group of 21 patients with iMN were compared with a group of 19 patients with secondary MN and other glomerular diseases. Seventeen of 21 patients with iMN were positive for anti-PLA2R on both ELISA and indirect immunofluorescence test, and 14 of these patients also had positive staining for PLA2R in the biopsy (tissue was unavailable in two patients). Three patients with iMN had positive staining in the biopsy only, and one patient was negative in both the serum and the biopsy. None of the patients with secondary MN or other glomerular diseases had anti-PLA2R antibodies or PLA2R in the biopsy. There was wide inter-in idual variation in titre on ELISA, but serial levels within an in idual patient enabled monitoring of disease, and a fall in titre correlated with clinical remission. This is the first Australian series to examine the incidence of anti-PLA2R in iMN. It is also unique in examining sera by two separate techniques in conjunction with tissue localization of PLA2R. We have shown 100% specificity of both serum anti-PLA2R and glomerular PLA2R in iMN, with a sensitivity of 81.0%. When serum testing is combined with tissue localization of PLA2R, the sensitivity increases to 95.2%.
Publisher: Springer Science and Business Media LLC
Date: 26-04-2022
DOI: 10.1007/S11302-022-09865-3
Abstract: Kidney transplantation is the preferred treatment for in iduals with kidney failure offering improved quality and quantity of life. Despite significant advancements in short term graft survival, longer term survival rates have not improved greatly mediated in large by chronic antibody mediated rejection. Strategies to reduce the donor kidney antigenic load may translate to improved transplant survival. CD39 on the vascular endothelium and on circulating cells, in particular regulatory T cells (Treg), is upregulated in response to hypoxic stimuli and plays a critical role in regulating the immune response removing proinflammatory ATP and generating anti-inflammatory adenosine. Herein, the role of CD39 in reducing ischaemia–reperfusion injury (IRI) and on Treg within the context of kidney transplantation is reviewed.
Publisher: Elsevier BV
Date: 12-2014
DOI: 10.1016/J.TRANSPROCEED.2014.09.151
Abstract: Long-term renal allograft survival has not improved despite improvements in short term outcomes. Graft loss is characterized histologically by the development of interstitial fibrosis and tubular atrophy (IFTA). Mechanisms underlying the development of IFTA are multifactorial and include ischemia-reperfusion injury (IRI). Therapeutic options to reduce IFTA include management of immunologic causes, such as rejection, but despite these efforts IFTA can still occur and leads to the inexorable destruction of the transplanted kidney. The adenosine A2B receptor (A2BR) has recently been implicated in the development of renal fibrosis. We performed an observational study to examine the mRNA expression of the adenosine receptors after renal ischemia up to the development of renal fibrosis in a mouse model of unilateral IRI. A2BR was the only adenosine receptor that showed elevated expression following ischemia until the development of renal fibrosis 4 weeks after injury. At 2 weeks after ischemia, increased expression of the fibrotic markers transforming growth factor β and Collagen-1α was observed. Expression of hypoxia inducible factor 1α and endothelin-1, which lie downstream of A2BR activation and have been recognized to promote renal fibrosis, were also significantly up-regulated at 2 weeks after ischemia. Expression of fibrotic markers returned to baseline by 4 weeks after ischemia, indicating resolution of injury with the concurrent development of renal fibrosis and reduced renal function. Our data suggest that A2BR may be a therapeutic target in reducing the development of renal fibrosis after ischemia.
No related grants have been discovered for Karen Dwyer.