ORCID Profile
0000-0002-3973-5114
Current Organisations
John Curtin School of Medical Research
,
Canberra Hospital
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Publisher: Springer Science and Business Media LLC
Date: 18-11-2012
DOI: 10.1007/S11255-012-0328-4
Abstract: Peritonitis can be a severe complication of peritoneal dialysis (PD) due to associated morbidity and mortality. Non-tuberculous mycobacteria (NTM) are a rare cause of PD peritonitis, with high rates of catheter removal and conversion to haemodialysis, and a reported mortality as high as 40 %. The incidence, culprit NTM species, and outcomes associated with PD peritonitis have not been described in many countries, including Australia. We examined the Australia and New Zealand Dialysis and Transplant Registry from 1 October 2003 to 31 December 2009 for all prevalent peritoneal dialysis patients. Patient characteristics, organisms, treatment and outcome for all NTM PD peritonitis episodes were obtained. Twelve cases of NTM PD peritonitis were reported, including the first reports of infection due to Mycobacterium hassiacum and Mycobacterium neoaurum. The incidence of NTM PD peritonitis was approximately 1 per 1000 PD patient-years. Recovery occurred in 11 patients, including 3 without removal of their Tenckhoff catheters. A range of antibiotics were utilised. One patient died of sclerosing peritonitis 5 months after diagnosis of PD peritonitis. Non-tuberculous mycobacteria PD peritonitis is a rare cause of peritonitis, and mortality may be lower than previously reported. Catheter removal occurred in the majority of patients, and adverse outcomes were not observed for those in whom it was retained.
Publisher: Elsevier BV
Date: 03-2011
DOI: 10.1038/KI.2010.518
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.COI.2015.09.003
Abstract: T follicular helper (Tfh) cells are crucial to induce protective extrafollicular and germinal center antibody responses against protein antigens. Over the last decade, control of Tfh cell numbers has emerged as an important regulatory checkpoint which, when perturbed, may lead to production of autoantibodies. Recent progress in understanding how Tfh cells are kept limiting has revealed an important role for posttranscriptional control of gene expression mediated by microRNAs such as miR-17 ∼ 92, miR-155 and miR-146a, and the RNA-binding proteins Roquin and Regnase. Additionally, T cell microRNAs dysregulated in patients with systemic lupus erythematosus have been shown to influence processes such as DNA hypomethylation, IL-2 and CCL5 secretion, and Treg function, which contribute to autoantibody formation and tissue damage.
Publisher: Springer Science and Business Media LLC
Date: 17-01-2017
Publisher: Springer Science and Business Media LLC
Date: 12-2018
Publisher: Springer Science and Business Media LLC
Date: 08-06-2012
Abstract: Peritoneal dialysis-associated peritonitis (PD-peritonitis) due to Mycobacterium spp is uncommon. Non-tuberculous Mycobacterium (NTB) PD-peritonitis can present in a similar fashion to more common causes of bacterial PD-peritonitis. We describe the first reported case of multiresistant Mycobacterium fortuitum PD-peritonitis in an Australian patient. A 38 year-old woman developed mild PD-peritonitis during an overseas holiday. Treatment was complicated by delayed diagnosis, requirement for special investigations, treatment with multiple antibiotics, and conversion to haemodialysis following removal of her Tenckhoff catheter. This case demonstrates the diagnostic yield of pursuing further investigations in cases of initially culture-negative, problematic PD-peritonitis. A systematic review of the literature identified only 17 reports of M. fortuitum PD-peritonitis. Similar to our case, a delay in microbiological diagnosis was frequently noted and the Tenckhoff catheter was commonly removed at the time of diagnosis. The type and duration of antibiotic therapy also varied widely so the optimum treatment appears to be poorly defined.
Publisher: Informa UK Limited
Date: 04-04-2011
Publisher: AME Publishing Company
Date: 12-2016
Publisher: Wiley
Date: 26-10-2017
Publisher: Therapeutic Guidelines Limited
Date: 02-06-2020
Publisher: Wiley
Date: 16-05-2020
DOI: 10.1111/IMCB.12339
Publisher: Wiley
Date: 05-03-2019
DOI: 10.1002/PATH.5242
Abstract: Acute kidney injury (AKI) remains a global challenge and, despite the availability of dialysis and transplantation, can be fatal. Those that survive an AKI are at increased risk of developing chronic kidney disease and end stage renal failure. Understanding the fundamental mechanisms underpinning the pathophysiology of AKI is critical for developing novel strategies for diagnosis and treatment. A growing body of evidence indicates that lifying type 2 immunity may have therapeutic potential in kidney injury and disease. Of particular interest are the recently described subset of innate immune cells, termed group 2 innate lymphoid cells (ILCs). Group 2 ILCs are crucial tissue-resident immune cells that maintain homeostasis and regulate tissue repair at multiple organ sites, including the kidney. They are critical mediators of type 2 immune responses following infection and injury. The existing literature suggests that activation of group 2 ILCs and production of a local type 2 immune milieu is protective against renal injury and associated pathology. In this review, we describe the emerging role for group 2 ILCs in renal homeostasis and repair. We provide an in-depth discussion of the most recent literature that use preclinical models of AKI and assess the therapeutic effect of modulating group 2 ILC function. We debate the potential for targeting these cells as novel cellular therapies in AKI and discuss the implications for future studies and translation. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: Dustri-Verlgag Dr. Karl Feistle
Date: 12-2011
DOI: 10.5414/CN107128
Abstract: It has been recommended that patients should be admitted for 24 h of observation after percutaneous renal biopsy. This may be performed in the ambulatory outpatient setting, though its safety in this setting is an area of debate. We aim to demonstrate the safety of biopsy in the ambulatory outpatient setting. We performed a retrospective cohort study of 475 biopsies performed in the ambulatory outpatient setting to examine safety and risk factors for complications. Transplant and native kidney biopsies performed at the Canberra Hospital, a tertiary referral university hospital, from 2006 until 2010 were included. Patients were observed for 6 h before discharge. Study outcomes were minor complications, defined as pain, hemorrhage or postural hypotension or major complications, defined as complications requiring therapeutic intervention including blood product transfusion. The overall complication rate was 8.2%. There were 33 minor complications (6.9%) and 6 major complications (1.3%). All complications occurring outside the period of observation were safely managed. Significant predictors of any complication was hemoglobin (OR 1.03, 95% CI 1.01 - 1.06), kidney size (OR 0.93, 95% CI 0.89 - 0.98), and proceduralist. Percutaneous renal biopsy is safe in the ambulatory outpatient setting. Establishing ongoing quality assurance programs may be helpful in early identification of operator-dependent factors.
Publisher: Wiley
Date: 09-2021
DOI: 10.1002/RAI2.12010
Abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by extraordinary heterogeneity, due to the complex pathogenesis and erse manifestations. Stratification of patients for therapy and prognosis represents a major challenge to manage SLE. Conventional biomarkers for disease diagnosis and activity assessment provide very limited insight into immunological pathogenesis and therapeutic response rates. The advancement of “omics” technologies including genomics, transcriptomics, proteomics, and metabolomics has constituted an unprecedented opportunity to characterize the immunopathological landscape in in idual patients with SLE. Indeed, genomic studies reveal a subset of SLE patients carrying one or more functional single nucleotide polymorphisms (SNPs) underlying immune dysregulation while transcriptomic studies have revealed subgroups in SLE patients showing distinct signatures for Type I interferon (TI‐IFN) pathway activation or aberrant differentiation of B cells into plasma cells. This review will summarize results from the latest studies using omics technology to understand SLE heterogeneity. In addition, we propose that the application of artificial intelligence, such as by machine learning‐based nonlinear dimensionality reduction method uniform manifold approximation and projection (UMAP) can further strengthen the analysis of omics big data. The combination of new technology and novel analysis pipeline can lead to breakthroughs in stratifying SLE patients for a better monitoring of disease activity and more precise design of treatment regime, not only for conventional immunosuppression but also novel immunotherapies targeting B‐cell activating factor (BAFF), TI‐IFN, and interleukin 2 (IL‐2).
Publisher: Frontiers Media SA
Date: 16-04-2019
Publisher: Elsevier BV
Date: 08-2020
Publisher: SAGE Publications
Date: 16-07-2021
DOI: 10.1177/09612033211033979
Abstract: To compare the frequency of rare variants in genes of the pathophysiologically relevant endosomal Toll-like receptor (eTLR) pathway and any quantifiable differences in variant rarity, predicted deleteriousness, or molecular proximity in patients with systemic lupus erythematosus (SLE) and healthy controls. 65 genes associated with the eTLR pathway were identified by literature search and pathway analysis. Using next generation sequencing techniques, these were compared in two randomised cohorts of patients with SLE (n = 114 and n = 113) with 197 healthy controls. Genetically determined ethnicity was used to normalise minor allele frequencies (MAF) for the identified genetic variants and these were then compared by their frequency: rare (MAF 0.005), uncommon (MAF 0.005–0.02), and common (MAF .02). This was compared to the results for 65 randomly selected genes. Patients with SLE are more likely to carry a rare nonsynonymous variant affecting proteins within the eTLR pathway than healthy controls. Furthermore, in iduals with SLE are more likely to have multiple rare variants in this pathway. There were no differences in rarity, Combined Annotation Dependent Depletion (CADD) score, or molecular proximity for rare eTLR pathway variants. Rare non-synonymous variants are enriched in patients with SLE in the eTLR pathway. This supports the hypothesis that SLE arises from several rare variants of relatively large effect rather than many common variants of small effect.
Publisher: Oxford University Press (OUP)
Date: 26-12-2016
DOI: 10.1093/CKJ/SFW111
Publisher: Elsevier BV
Date: 06-2022
Publisher: Elsevier BV
Date: 2021
DOI: 10.2139/SSRN.3808293
Publisher: S. Karger AG
Date: 2011
DOI: 10.1159/000323554
Abstract: Monitoring of blood flows in arteriovenous fistulae and arteriovenous grafts is recommended to predict access thrombosis. The ultrasound dilution technique (UDT) is the gold standard. We compare a recently described haemoglobin dilution technique (HDT) with the UDT in measurement of vascular access flow. Access blood flow was measured in 67 stable dialysis patients using HDT by bedside Hemocue (Hemocue AB, Ängelholm, Sweden) and laboratory measurement. Access blood flow was then measured by UDT in the same dialysis session. Median flow rate by UDT was 950 ml/min (IQR 490–1,440 ml/min), by Hemocue HDT 935 ml/min (IQR 475–1,395 ml/min, p = 0.534), and by laboratory haemoglobin HDT 920 ml/min (IQR 463–1,378 ml/min). Bland-Altman plots demonstrated poor agreement between UDT and HDT (limits of agreement for Hemocue HDT –22.7 to 20.1%, for laboratory HDT –21.2 to 20.4%). HDT can be used to measure vascular access flow but requires validation against clinical outcomes before being recommended as an alternative to UDT.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2019
DOI: 10.1038/S41467-019-10242-9
Abstract: Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease. It is thought that many common variant gene loci of weak effect act additively to predispose to common autoimmune diseases, while the contribution of rare variants remains unclear. Here we describe that rare coding variants in lupus-risk genes are present in most SLE patients and healthy controls. We demonstrate the functional consequences of rare and low frequency missense variants in the interacting proteins BLK and BANK1, which are present alone, or in combination, in a substantial proportion of lupus patients. The rare variants found in patients, but not those found exclusively in controls, impair suppression of IRF5 and type-I IFN in human B cell lines and increase pathogenic lymphocytes in lupus-prone mice. Thus, rare gene variants are common in SLE and likely contribute to genetic risk.
Publisher: Frontiers Media SA
Date: 11-09-2019
Publisher: Wiley
Date: 04-2012
Publisher: Wiley
Date: 25-11-2014
DOI: 10.1002/ART.38824
Abstract: Objective. Systemic lupus erythematosus (SLE) isa chronic and heterogeneous autoimmune disease. Both twin and sibling studies indicate a strong genetic contribution to lupus, but in the majority of cases the pathogenic variant remains to be identified. The genetic contribution to disease is likely to be greatest in cases with early onset and severe phenotypes. Whole-exome sequencing now offers the possibility of identifying rare alleles responsible for disease in such cases. This study was undertaken to identify genetic causes of SLE using whole-exome sequencing.Methods. We performed whole-exome sequencing in a 4-year-old girl with early-onset SLE and conducted biochemical analysis of the putative defect.Results. Whole-exome sequencing in a 4-year-old girl with cerebral lupus identified a rare, homozygous mutation in the three prime repair exonuclease 1 gene(TREX1) that was predicted to be highly deleterious.The TREX1 R97H mutant protein had a 20-fold reduction in exonuclease activity and was associated with an elevated interferon-alpha signature in the patient.The discovery and characterization of a pathogenic TREX1 variant in our proband has therapeutic implications.The patient is now a candidate for therapy. Conclusion. Our study is the first to demonstrate that whole-exome sequencing can be used to identify rare or novel deleterious variants as genetic causes of SLE and, through a personalized approach, improve therapeutic options.
Publisher: Wiley
Date: 17-12-2012
DOI: 10.1111/J.1440-1797.2012.01658.X
Abstract: A significant proportion of peritoneal dialysis (PD) patients will have abrupt technique failure requiring conversion to haemodialysis, often using temporary vascular catheters as bridging access. However, vascular catheter use has been associated with increased mortality and great effort has been made to reduce their use. Just under two decades ago, a trial of dual arteriovenous fistula (AVF) formation and Tenckhoff catheter insertion reported only 4% of those in whom back-up fistulae were formed ever used them. Patient demographic, surgical technique and fistula care over those decades have changed substantially, potentially making this practice feasible. Thirty-five selected patients at Concord Repatriation and General Hospital had AVF formed at the time of Tenckhoff insertion and were entered prospectively into a vascular access database. We retrospectively examined this database with a median follow up of 345 days (interquartile range 183-658). Thirty-one per cent of all patients used the preformed AVF, and a further 19% who were still on PD had clinically functioning AVF. The vast majority (62%) had abrupt PD technique failure. This is a marked difference to dated reports of AVF use after concurrent PD and AVF formation. It raises the possibility that the formation of back-up fistula may be another method to reduce the need for vascular catheter use.
Publisher: Frontiers Media SA
Date: 16-03-2022
Abstract: Chronic kidney disease progression to ESKD is associated with a marked increase in mortality and morbidity. Its progression is highly variable and difficult to predict. This is an observational, retrospective, single-centre study. The cohort was patients attending hospital and nephrology clinic at The Canberra Hospital from September 1996 to March 2018. Demographic data, vital signs, kidney function test, proteinuria, and serum glucose were extracted. The model was trained on the featurised time series data with XGBoost. Its performance was compared against six nephrologists and the Kidney Failure Risk Equation (KFRE). A total of 12,371 patients were included, with 2,388 were found to have an adequate density (three eGFR data points in the first 2 years) for subsequent analysis. Patients were ided into 80%/20% ratio for training and testing datasets. ML model had superior performance than nephrologist in predicting ESKD within 2 years with 93.9% accuracy, 60% sensitivity, 97.7% specificity, 75% positive predictive value. The ML model was superior in all performance metrics to the KFRE 4- and 8-variable models. eGFR and glucose were found to be highly contributing to the ESKD prediction performance. The computational predictions had higher accuracy, specificity and positive predictive value, which indicates the potential integration into clinical workflows for decision support.
Publisher: AMPCo
Date: 02-2011
Publisher: Elsevier BV
Date: 12-2021
Publisher: Springer Science and Business Media LLC
Date: 11-07-2020
DOI: 10.1186/S12882-020-01923-5
Abstract: C3 glomerulonephritis is a recently described entity with heterogeneous histopathological features. This study was conducted to assess the effect of reclassification of C3 glomerulopathies on renal outcomes, mortality, and response to therapy. We undertook a retrospective analysis of 857 renal biopsies collected at The Canberra Hospital. S les with predominant C3 staining were reviewed by a renal histopathologist. Of 31 biopsies with predominant C3 staining, 10 fulfilled histological criteria for C3 glomerulonephritis, while the remaining 21 cases were used as C3 Controls. Aside from a higher incidence of C3 glomerulonephritis in Torres Strait islanders (40% vs 5% C3 Controls, p = 0.04), presentation demographics were similar between the two groups. Median creatinine at diagnosis was higher in patients with C3 glomerulonephritis (253 umol/L IQR 103–333 vs 127 umol/L C3 Controls, IQR 105–182, p = 0.01). Prior to reclassification, a majority of C3 glomerulonephritis cases were diagnosed as membranoproliferative glomerulonephritis (60% vs 5% (C3 Controls) p 0.01). Electron microscopy demonstrated all C3 glomerulonephritis patients had C3 deposition (100% vs 38% p = 0.02), these deposits were amorphous in nature (50% vs 5% respectively p = 0.007). C3 glomerulonephritis patients had shorter median follow-up (405 days IQR 203–1197 vs 1822 days respectively, IQR 1243–3948, p = 0.02). Mortality was higher in C3 glomerulonephritis patients (30% vs 14% in C3 Controls (log rank p = 0.02)). We have devised a diagnostic and treatment algorithm based on the results of literature review and our current study. Further prospective assessment is required to review diagnostic and treatment outcomes for this disease in Australian centres.
Publisher: Wiley
Date: 21-09-2012
DOI: 10.1111/SDI.12005
Abstract: Establishing and maintaining hemodialysis access are major challenges in dialysis patient care. The impact of implementing guideline recommendations around vascular access surveillance, which lacks strong evidence, is poorly understood. We report the results of a vascular access surveillance and early intervention program upon hemodialysis thrombosis rates for all patients hemodialyzing in a single center between January 2005 and March 2011. Data were derived from hospital records and the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA). Data were collected of 227 prevalent patients over the 6-year period. Crude ultrasound and angiography intervention rates increased from 23 and 57 per 100 prevalent patients per quarter (/100 pts/qtr) to 31 and 83/100 pts/qtr, respectively, during the study. Crude thrombosis rates fell from 21 to 2/100 pts/qtr during the study. After adjustment for comorbidities, mean ultrasound use increased by 4.6% per quarter (95% CI: 2.4-6.9, p<0.001), mean interventional angiography increased by 2.6% per quarter (95% CI: 1.1-4.2, p=0.001), and the predicted mean of the number of thromboses decreased by 8.4% per quarter (95% CI: 5.6-11.1, p<0.001). Implementation of a vascular access surveillance increases service utilization and is associated with a reduction in vascular access thrombosis.
Publisher: Rockefeller University Press
Date: 10-12-2021
DOI: 10.1084/JEM.20211004
Abstract: B cell self-tolerance is maintained through multiple checkpoints, including restraints on intracellular signaling and cell trafficking. P2RY8 is a receptor with established roles in germinal center (GC) B cell migration inhibition and growth regulation. Somatic P2RY8 variants are common in GC-derived B cell lymphomas. Here, we identify germline novel or rare P2RY8 missense variants in lupus kindreds or the related antiphospholipid syndrome, including a “de novo” variant in a child with severe nephritis. All variants decreased protein expression, F-actin abundance, and GPCR-RhoA signaling, and those with stronger effects increased AKT and ERK activity and cell migration. Remarkably, P2RY8 was reduced in B cell subsets from some SLE patients lacking P2RY8 gene variants. Low P2RY8 correlated with lupus nephritis and increased age-associated B cells and plasma cells. By contrast, P2RY8 overexpression in cells and mice restrained plasma cell development and reinforced negative selection of DNA-reactive developing B cells. These findings uncover a role of P2RY8 in immunological tolerance and lupus pathogenesis.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 27-10-2012
Publisher: Wiley
Date: 23-11-2022
DOI: 10.1002/RAI2.12060
Abstract: Systemic lupus erythematosus (SLE) is a complex systemic autoimmune disease characterized by development of autoantibodies and multiorgan involvement. Kidney involvement, termed lupus nephritis, has major impact on life expectancy. It is increasingly recognized that SLE is likely a common clinical manifestation of pathophysiologically erse processes, and lupus nephritis has similarly been associated with several distinct immunological processes. We compared the immune cell phenotypes of in iduals with SLE in the presence or absence of nephritis. Cryopreserved peripheral blood mononuclear cells from SLE patients with and without kidney involvement underwent flow cytometric analysis to identify major populations in T cells, B cells and myeloid lineages. We compared the frequencies of lymphocyte populations in 69 SLE patients without nephritis, 20 SLE patients with nephritis, and 92 healthy blood donors. Patients with SLE and lupus nephritis (LN) had reduced marginal zone B cells ( P 0.0001 in SLE P = 0.001 in LN), memory B cells ( P = 0.002 in SLE P = 0.001 in LN) and circulating T follicular helper (Tfh) memory cells ( P 0.0001 in SLE and LN) compared to healthy donors. Patients with lupus nephritis had increase Th2 ( P 0.0001) and T regulatory cells ( P 0.0001) compared to both SLE patients without nephritis and healthy donors. SLE patients with and without lupus nephritis have distinct immunologic differences that may reflect the unique pathophysiological processes contributing to disease manifestations.
Start Date: 2017
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2017
End Date: 2021
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2020
End Date: 2021
Funder: Royal Australasian College of Physicians
View Funded ActivityStart Date: 2020
End Date: 2025
Funder: Australian National University
View Funded ActivityStart Date: 2014
End Date: 2015
Funder: National Health and Medical Research Council
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