Publications by authors named "Carol A Pollock"

120 Publications

Lysyl oxidase inhibitors attenuate cyclosporin A-induced nephropathy in mouse.

Sci Rep 2021 Jun 14;11(1):12437. Epub 2021 Jun 14.

Renal Medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia.

Calcineurin inhibitors, such as Cyclosporin (CsA), are the mainstay of anti-rejection therapy in solid organ transplants but can paradoxically induce progressive nephropathy characterised by renal dysfunction and interstitial fibrosis. Lysyl oxidases (LOXs), a group of enzymes that catalyse extracellular matrix (ECM) crosslinking, were shown to implicate in tissue scarring. It is hypothesized that inhibition of these enzymes may render therapeutic effects against CsA-induced nephropathy. In this study, 6-to-8 weeks old C57BL/6 J mice were administered saline or CsA (30 mg/kg/day s.c) for 16 weeks. At 8 weeks, CsA-treated animals were divided into 5 groups respectively treated with: (1) vehicle, (2) PXS-5505 (Pan-LOX inhibitor), (3) PXS-5382 (LOX-like 2 inhibitor), (4) PXS-5505 for 4 weeks then PXS-5382 for 4 weeks (sequential therapy), and (5) Telmisartan (standard therapy). Our results indicate that CsA administration significantly increased the levels of blood urea nitrogen, glomerular and tubular injury, tubulointerstitial fibrosis, inflammation and oxidative stress in mouse kidney. These changes were associated with upregulated mRNA expression of LOX and LOXL2. Administration of Pan-LOX or LOXL2 inhibitors or the sequential therapy suppressed the expression of ECM proteins (α-SMA, FN and COL1A), matrix metalloproteases (MMP)2 and 9, inflammatory markers (TNFα and MCP-1) and TGF-β1-Smad3 signalling. Among all regimens including telmisartan, only Pan-LOX inhibitor PXS-5505 was able to attenuate uraemia. Collectively, our study suggests that Pan-LOX and LOXL2 inhibition can attenuate progressive nephropathy due to CsA administration.
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http://dx.doi.org/10.1038/s41598-021-91772-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203624PMC
June 2021

Particulate Matter, an Intrauterine Toxin Affecting Foetal Development and Beyond.

Antioxidants (Basel) 2021 May 6;10(5). Epub 2021 May 6.

Renal Research Laboratory, Kolling Institute of Medical Research, Sydney, NSW 2065, Australia.

Air pollution is the 9th cause of the overall disease burden globally. The solid component in the polluted air, particulate matters (PMs) with a diameter of 2.5 μm or smaller (PM) possess a significant health risk to several organ systems. PM has also been shown to cross the blood-placental barrier and circulate in foetal blood. Therefore, it is considered an intrauterine environmental toxin. Exposure to PM during the perinatal period, when the foetus is particularly susceptible to developmental defects, has been shown to reduce birth weight and cause preterm birth, with an increase in adult disease susceptibility in the offspring. However, few studies have thoroughly studied the health outcome of foetuses due to intrauterine exposure and the underlying mechanisms. This perspective summarises currently available evidence, which suggests that intrauterine exposure to PM promotes oxidative stress and inflammation in a similar manner as occurs in response to direct PM exposure. Oxidative stress and inflammation are likely to be the common mechanisms underlying the dysfunction of multiple systems, offering potential targets for preventative strategies in pregnant mothers for an optimal foetal outcome.
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http://dx.doi.org/10.3390/antiox10050732DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148178PMC
May 2021

Non-invasive assessment of exfoliated kidney cells extracted from urine using multispectral autofluorescence features.

Sci Rep 2021 May 20;11(1):10655. Epub 2021 May 20.

Graduate School of Biomedical Engineering, UNSW Sydney, Sydney, NSW, 2052, Australia.

Optimally preserved urinary exfoliated renal proximal tubule cells were assessed by multispectral imaging of cell autofluorescence. We demonstrated different multispectral autofluorescence signals in such cells extracted from the urine of patients with healthy or diseased kidneys. Using up to 10 features, we were able to differentiate cells from individuals with heathy kidneys and impaired renal function (indicated by estimated glomerular filtration rate (eGFR) values) with the receiver operating characteristic area under the curve (AUC) of 0.99. Using the same method, we were also able to discriminate such urine cells from patients with and without renal fibrosis on biopsy, where significant differences in multispectral autofluorescence signals (AUC = 0.90) were demonstrated between healthy and diseased patients (p < 0.05). These findings show that multispectral assessment of the cell autofluorescence in urine exfoliated proximal tubule kidney cells has the potential to be developed as a sensitive, non-invasive diagnostic method for CKD.
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http://dx.doi.org/10.1038/s41598-021-89758-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138006PMC
May 2021

Low-dose hydralazine during gestation reduces renal fibrosis in rodent offspring exposed to maternal high fat diet.

PLoS One 2021 18;16(3):e0248854. Epub 2021 Mar 18.

Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, Australia.

Background: Maternal high fat diet (HFD) promotes chronic kidney disease (CKD) in offspring. This is in accordance with the theory of fetal programming, which suggests adverse conditions occurring in utero predispose offspring to chronic conditions later in life. DNA methylation has been proposed as a key mechanism by which fetal programming occurs and is implicated in CKD progression. DNA demethylating drugs may interrupt the fetal programming of CKD by maternal obesity. Hydralazine, an antihypertensive agent, demethylates DNA at low doses which do not reduce blood pressure. We used a mouse model of maternal obesity to determine whether gestational administration of low-dose hydralazine to mothers can prevent CKD in offspring.

Methods: C57BL/6 dams received HFD or chow from 6 weeks prior to mating and were administered subcutaneous hydralazine (5mg/kg) or saline thrice weekly during gestation. Male offspring were weaned to chow and were sacrificed at either postnatal week 9 or week 32. Biometric and metabolic parameters, renal global DNA methylation, renal structural and functional changes and markers of fibrosis, oxidative stress and inflammation were measured in offspring at weeks 9 and 32.

Results: In week 9 offspring, maternal HFD consumption did not significantly alter anthropometric or metabolic parameters, or renal global DNA methylation. Week 32 offspring had increased renal global DNA methylation, together with albuminuria, glomerulosclerosis, renal fibrosis and oxidative stress. Administration of low-dose hydralazine to obese mothers during gestation reduced renal global DNA methylation and renal fibrotic markers in week 32 offspring.

Conclusion: Gestational hydralazine reduced renal global DNA methylation in offspring of obese mothers and attenuated maternal obesity-induced renal fibrosis. These data support the use of low-dose hydralazine as a demethylating agent to prevent CKD arising in offspring due to maternal HFD consumption.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0248854PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971884PMC
March 2021

KCa3.1 Mediates Dysregulation of Mitochondrial Quality Control in Diabetic Kidney Disease.

Front Cell Dev Biol 2021 19;9:573814. Epub 2021 Feb 19.

Kolling Institute, Sydney Medical School Northern, Faculty of Medicine and Health, University of Sydney, Royal North Shore Hospital, Sydney, NSW, Australia.

Mitochondrial dysfunction is implicated in the pathogenesis of diabetic kidney disease. Mitochondrial quality control is primarily mediated by mitochondrial turnover and repair through mitochondrial fission/fusion and mitophagy. We have previously shown that blockade of the calcium-activated potassium channel KCa3.1 ameliorates diabetic renal fibrosis. However, the mechanistic link between KCa3.1 and mitochondrial quality control in diabetic kidney disease is not yet known. Transforming growth factor β1 (TGF-β1) plays a central role in diabetic kidney disease. Recent studies indicate an emerging role of TGF-β1 in the regulation of mitochondrial function. However, the molecular mechanism mediating mitochondrial quality control in response to TGF-β1 remains limited. In this study, mitochondrial function was assessed in TGF-β1-exposed renal proximal tubular epithelial cells (HK2 cells) transfected with scrambled siRNA or KCa3.1 siRNA. , diabetes was induced in KCa3.1+/+ and KCa3.1-/- mice by low-dose streptozotocin (STZ) injection. Mitochondrial fission/fusion-related proteins and mitophagy markers, as well as BCL2 interacting protein 3 (BNIP3) (a mitophagy regulator) were examined in HK2 cells and diabetic mice kidneys. The results showed that TGF-β1 significantly inhibited mitochondrial ATP production rate and increased mitochondrial ROS (mtROS) production when compared to control, which was normalized by KCa3.1 gene silencing. Increased fission and suppressed fusion were found in both TGF-β1-treated HK2 cells and diabetic mice, which were reversed by KCa3.1 deficiency. Furthermore, our results showed that mitophagy was inhibited in both and models of diabetic kidney disease. KCa3.1 deficiency restored abnormal mitophagy by inhibiting BNIP3 expression in TGF-β1-induced HK2 cells as well as in the diabetic mice. Collectively, these results indicate that KCa3.1 mediates the dysregulation of mitochondrial quality control in diabetic kidney disease.
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http://dx.doi.org/10.3389/fcell.2021.573814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7933228PMC
February 2021

Metformin Attenuates Renal Fibrosis in a Mouse Model of Adenine-Induced Renal Injury Through Inhibiting TGF-β1 Signaling Pathways.

Front Cell Dev Biol 2021 4;9:603802. Epub 2021 Feb 4.

Kolling Institute, Sydney Medical School-Northern University of Sydney, Royal North Shore Hospital, St Leonards, NSW, Australia.

It is well-known that all progressive chronic kidney disease (CKD) is pathologically characterized by tubulointerstitial fibrosis process. Multiple studies have shown the critical role of inflammation and fibrosis in the development of CKD. Hence strategies that target inflammatory and fibrotic signaling pathways may provide promising opportunities to protect against renal fibrosis. Metformin has been used as the first-line glucose-lowering agent to treat patients with type 2 diabetes mellitus (T2DM) for over 50 years. Accumulating evidence suggests the potential for additional therapeutic applications of metformin, including mitigation of renal fibrosis. In this study, the anti-fibrotic effects of metformin independent of its glucose-lowering mechanism were examined in an adenine -induced mouse model of CKD. Expressions of inflammatory markers MCP-1, F4/80 and ICAM, fibrotic markers type IV collagen and fibronectin, and the cytokine TGF-β1 were increased in adenine-induced CKD when compared to control groups and significantly attenuated by metformin treatment. Moreover, treatment with metformin inhibited the phosphorylation of Smad3, ERK1/2, and P38 and was associated with activation of the AMP-activated protein kinase (AMPK) in the kidneys of adenine-treated mice. These results indicate that metformin attenuates adenine-induced renal fibrosis through inhibition of TGF-β1 signaling pathways and activation of AMPK, independent of its glucose-lowering action.
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http://dx.doi.org/10.3389/fcell.2021.603802DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889967PMC
February 2021

The Mitochondrial Kinase PINK1 in Diabetic Kidney Disease.

Int J Mol Sci 2021 Feb 3;22(4). Epub 2021 Feb 3.

Kolling Institute, Sydney Medical School, Royal North Shore Hospital, University of Sydney, St. Leonards, NSW 2065, Australia.

Mitochondria are critical organelles that play a key role in cellular metabolism, survival, and homeostasis. Mitochondrial dysfunction has been implicated in the pathogenesis of diabetic kidney disease. The function of mitochondria is critically regulated by several mitochondrial protein kinases, including the phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1). The focus of PINK1 research has been centered on neuronal diseases. Recent studies have revealed a close link between PINK1 and many other diseases including kidney diseases. This review will provide a concise summary of PINK1 and its regulation of mitochondrial function in health and disease. The physiological role of PINK1 in the major cells involved in diabetic kidney disease including proximal tubular cells and podocytes will also be summarized. Collectively, these studies suggested that targeting PINK1 may offer a promising alternative for the treatment of diabetic kidney disease.
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http://dx.doi.org/10.3390/ijms22041525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7913536PMC
February 2021

Health-Related Quality of Life in People Across the Spectrum of CKD.

Kidney Int Rep 2020 Dec 3;5(12):2264-2274. Epub 2020 Oct 3.

College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Introduction: People with chronic kidney disease (CKD) experience reduced quality of life (QoL) because of the high symptom and treatment burden. Limited data exist on the factors associated with overall and domain-specific QoL across all CKD stages.

Methods: Using data from a prospective, multinational study (Australia, New Zealand, Canada, and Spain) in 1696 participants with CKD, we measured overall and domain-specific QoL (pain, self-care, activity, mobility, anxiety/depression) using the EuroQoL, 5 dimension, 3 level. Multivariable linear regression and logistic modeling were used to determine factors associated with overall and domain-specific QoL.

Results: QoL for patients with CKD stages 3 to 5 (n = 787; mean, 0.81; SD, 0.20) was higher than in patients on dialysis (n = 415; mean, 0.76; SD, 0.24) but lower than in kidney transplant recipients (n = 494; mean, 0.84; SD, 0.21). Factors associated with reduced overall QoL (β [95% confidence intervals]) included being on dialysis (compared with CKD stages 3-5: -0.06 [-0.08 to -0.03]), female sex (-0.03 [-0.05 to -0.006]), lower educational attainment (- 0.04 [-0.06 to -0.02), lacking a partner (-0.04 [-0.06 to -0.02]), having diabetes (-0.05 [-0.07 to -0.02]), history of stroke (-0.09 [-0.13 to -0.05]), cardiovascular disease (-0.06 [-0.08 to -0.03]), and cancer (-0.03 [-0.06 to -0.009]). Pain (43%) and anxiety/depression (30%) were the most commonly affected domains, with dialysis patients reporting decrements in all 5 domains. Predictors for domain-specific QoL included being on dialysis, presence of comorbidities, lower education, female sex, and lack of a partner.

Conclusions: Being on dialysis, women with CKD, those with multiple comorbidities, lack of a partner, and lower educational attainment were associated with lower QoL across all stages of CKD.
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http://dx.doi.org/10.1016/j.ekir.2020.09.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710842PMC
December 2020

Rate of decline in residual kidney function pre and post peritoneal dialysis initiation: A post hoc analysis of the IDEAL study.

PLoS One 2020 16;15(11):e0242254. Epub 2020 Nov 16.

Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia.

Background: Residual kidney function (RKF) is associated with improved survival and quality of life in dialysis patients. Previous studies have suggested that initiation of peritoneal dialysis (PD) may slow RKF decline compared to the pre-dialysis period. We sought to evaluate the association between PD initiation and RKF decline in the Initiating Dialysis Early And Late (IDEAL) trial.

Methods: In this post hoc analysis of the IDEAL randomized controlled trial, PD participants were included if results from 24-hour urine collections had been recorded within 30 days of dialysis initiation, and at least one value pre- and one value post-dialysis commencement were available. The primary outcome was slope of RKF decline, calculated as mean of urinary creatinine and urea clearances. Secondary outcomes included slope of urine volume decline and time from PD initiation to anuria.

Results: The study included 151 participants (79 early start, 72 late start). The slope of RKF decline was slower after PD initiation (-2.69±0.18mL/min/1.73m2/yr) compared to before PD (-4.09±0.33mL/min/1.73m2/yr; change in slope +1.19 mL/min/1.73m2/yr, 95%CI 0.48-1.90, p<0.001). In contrast, urine volume decline was faster after PD commencement (-0.74±0.05 L/yr) compared to beforehand (-0.57±0.06L/yr; change in slope -0.18L/yr, 95%CI -0.34--0.01, p = 0.04). No differences were observed between the early- and late-start groups with respect to RKF decline, urine volume decline or time to anuria.

Conclusions: Initiation of PD was associated with a slower decline of RKF compared to the pre-dialysis period.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0242254PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7668577PMC
January 2021

Parental SIRT1 Overexpression Attenuate Metabolic Disorders Due to Maternal High-Fat Feeding.

Int J Mol Sci 2020 Oct 5;21(19). Epub 2020 Oct 5.

Renal medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, NSW 2065, Australia.

Maternal obesity can contribute to the development of obesity and related metabolic disorders in progeny. Sirtuin (SIRT)1, an essential regulator of metabolism and stress responses, has recently emerged as an important modifying factor of developmental programming. In this study, to elucidate the effects of parental SIRT1 overexpression on offspring mechanism, four experimental groups were included: (1) Chow-fed wild-type (WT)-dam × Chow-fed WT-sire; (2) High-fat diet (HFD)-fed WT-dam × Chow-fed WT-sire; (3) HFD-fed hemizygous SIRT1-transgenic (Tg)-dam × Chow-fed WT-sire; and (4) HFD-fed WT dam × Chow-fed Tg-sire. Our results indicate that Tg breeders had lower body weight and fat mass compared to WT counterparts and gave birth to WT offspring with reductions in body weight, adiposity and hyperlipidaemia compared to those born of WT parents. Maternal SIRT1 overexpression also reversed glucose intolerance, and normalised abnormal fat morphology and the expression of dysregulated lipid metabolism markers, including SIRT1. Despite having persistent hepatic steatosis, offspring born to Tg parents showed an improved balance of hepatic glucose/lipid metabolic markers, as well as reduced levels of inflammatory markers and TGF-β/Smad3 fibrotic signalling. Collectively, the data suggest that parental SIRT1 overexpression can ameliorate adverse metabolic programming effects by maternal obesity.
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http://dx.doi.org/10.3390/ijms21197342DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582993PMC
October 2020

A Randomized Trial on the Effect of Phosphate Reduction on Vascular End Points in CKD (IMPROVE-CKD).

J Am Soc Nephrol 2020 11 11;31(11):2653-2666. Epub 2020 Sep 11.

Australasian Kidney Trials Network, The University of Queensland, Brisbane, Queensland, Australia.

Background: Hyperphosphatemia is associated with increased fibroblast growth factor 23 (FGF23), arterial calcification, and cardiovascular mortality. Effects of phosphate-lowering medication on vascular calcification and arterial stiffness in CKD remain uncertain.

Methods: To assess the effects of non-calcium-based phosphate binders on intermediate cardiovascular markers, we conducted a multicenter, double-blind trial, randomizing 278 participants with stage 3b or 4 CKD and serum phosphate >1.00 mmol/L (3.10 mg/dl) to 500 mg lanthanum carbonate or matched placebo thrice daily for 96 weeks. We analyzed the primary outcome, carotid-femoral pulse wave velocity, using a linear mixed effects model for repeated measures. Secondary outcomes included abdominal aortic calcification and serum and urine markers of mineral metabolism.

Results: A total of 138 participants received lanthanum and 140 received placebo (mean age 63.1 years; 69% male, 64% White). Mean eGFR was 26.6 ml/min per 1.73 m; 45% of participants had diabetes and 32% had cardiovascular disease. Mean serum phosphate was 1.25 mmol/L (3.87 mg/dl), mean pulse wave velocity was 10.8 m/s, and 81.3% had abdominal aortic calcification at baseline. At 96 weeks, pulse wave velocity did not differ significantly between groups, nor did abdominal aortic calcification, serum phosphate, parathyroid hormone, FGF23, and 24-hour urinary phosphate. Serious adverse events occurred in 63 (46%) participants prescribed lanthanum and 66 (47%) prescribed placebo. Although recruitment to target was not achieved, additional analysis suggested this was unlikely to have significantly affected the principle findings.

Conclusions: In patients with stage 3b/4 CKD, treatment with lanthanum over 96 weeks did not affect arterial stiffness or aortic calcification compared with placebo. These findings do not support the role of intestinal phosphate binders to reduce cardiovascular risk in patients with CKD who have normophosphatemia.

Clinical Trial Registry Name And Registration Number: Australian Clinical Trials Registry, ACTRN12610000650099.
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http://dx.doi.org/10.1681/ASN.2020040411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608977PMC
November 2020

MicroRNA as novel biomarkers and therapeutic targets in diabetic kidney disease: An update.

FASEB Bioadv 2019 Jun 10;1(6):375-388. Epub 2019 Apr 10.

Renal Research Laboratory Kolling Institute of Medical Research, The University of Sydney, Royal North Shore hospital St Leonards, Sydney New South Wales Australia.

Diabetic kidney disease (DKD) is a life-limiting condition characterized by progressive and irreversible loss of renal function. Currently, the estimated glomerular filtration rate (eGFR) and albuminuria are used as key markers to define DKD. However, they may not accurately indicate the degree of renal dysfunction and injury. Current therapeutic approaches for DKD, including attainment of blood pressure goals, optimal control of blood glucose and lipid levels, and the use of agents to block the renin-angiotensin-aldosterone system (RAAS) can only slow the progression of DKD. Hence, early diagnosis and innovative strategies are needed to both prevent and treat DKD. In recent years, a novel class of noncoding RNA, microRNAs (miRNAs) are reported to be involved in all biological processes, including cellular proliferation, apoptosis, and differentiation. miRNAs are small noncoding RNAs that regulate gene expression by posttranscriptional and epigenetic mechanisms. They are found to be in virtually all body fluids and used successfully as biomarkers for various diseases. Urinary miRNAs correlate with clinical and histologic parameters in DKD and differential urinary miRNA expression patterns have been reported. Kidney fibrosis is the common end stage of various CKD including DKD. Transforming growth factor-β(TGF-β) is regarded as the master regulator of kidney fibrosis, which is likely at least in part through regulating miRNA expression. miRNA are widely involved in the progression of DKD via many molecular mechanisms. In this review, the involvement of miRNA in fibrosis, inflammation, hypertrophy, autophagy, endoplasmic reticulum (ER) stress, oxidative stress, insulin resistance, and podocyte injury will be discussed, as these mechanisms are believed to offer new therapeutic targets that can be exploited to develop important treatments for DKD over the next decade.
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http://dx.doi.org/10.1096/fba.2018-00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996361PMC
June 2019

Impact of maternal e-cigarette vapor exposure on renal health in the offspring.

Ann N Y Acad Sci 2019 09 17;1452(1):65-77. Epub 2019 Jul 17.

Faculty of Science, School of Life Sciences, University of Technology Sydney, Sydney, New South Wales, Australia.

Maternal smoking during pregnancy is a significant risk factor of renal pathology in the offspring. E-cigarettes are perceived to be a safe option and are increasingly used by pregnant women either continuously during pregnancy or as a replacement for tobacco cigarettes. This study aimed to determine the effects of replacing tobacco cigarettes with e-cigarettes during pregnancy, and continuous e-cigarette use during pregnancy on the offspring's kidneys. Female Balb/c mice were exposed to either air (sham) or tobacco cigarette smoke (SE) for 6 weeks prior to mating, during gestation and lactation. A subset of the "SE group" received e-cigarette vapor (containing nicotine) after mating until pups weaned. Additional female mice were continuously exposed to e-vapor (either with or without nicotine) for 6 weeks prior to mating until pups weaned. Kidneys and urine from the male offspring were assessed at postnatal day 1, day 20 (weaning), and 13 weeks of age (adulthood). E-cigarette replacement was less detrimental to renal development and albuminuria than continuous SE during pregnancy. However, continuous e-vapor exposure during pregnancy increased markers of oxidative stress, inflammation, and fibrosis in the adult offspring, independent of nicotine. E-cigarette use during pregnancy confers future risk to the offspring's kidneys.
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http://dx.doi.org/10.1111/nyas.14174DOI Listing
September 2019

One-Time Fecal Immunochemical Screening for Advanced Colorectal Neoplasia in Patients with CKD (DETECT Study).

J Am Soc Nephrol 2019 06 30;30(6):1061-1072. Epub 2019 Apr 30.

College of Medicine and Public Health, Flinders University, Adelaide, Australia.

Background: In patients with CKD, the risk of developing colorectal cancer is high and outcomes are poor. Screening using fecal immunochemical testing (FIT) is effective in reducing mortality from colorectal cancer, but performance characteristics of FIT in CKD are unknown.

Methods: To determine the detection rates and performance characteristics of FIT for advanced colorectal neoplasia (ACN) in patients with CKD, we used FIT to prospectively screen patients aged 35-74 years with CKD (stages 3-5 CKD, dialysis, and renal transplant) from 11 sites in Australia, New Zealand, Canada, and Spain. All participants received clinical follow-up at 2 years. We used a two-step reference standard approach to estimate disease status.

Results: Overall, 369 out of 1706 patients who completed FIT (21.6%) tested positive; 323 (87.5%) underwent colonoscopies. A total of 1553 (91.0%) completed follow-up; 82 (4.8%) had died and 71 (4.2%) were lost. The detection rate of ACN using FIT was 6.0% (5.6%, 7.4%, and 5.6% for stages 3-5 CKD, dialysis, and transplant). Sensitivity, specificity, and positive and negative predictive values of FIT for ACN were 0.90, 0.83, 0.30, and 0.99, respectively. Of participants who underwent colonoscopy, five (1.5%) experienced major colonoscopy-related complications, including bowel perforation and major bleeding.

Conclusions: FIT appears to be an accurate screening test for patients with CKD, such that a negative test may rule out the diagnosis of colorectal cancer within 2 years. However, the risk of major complications from work-up colonoscopy are at least ten-fold higher than in the general population.
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http://dx.doi.org/10.1681/ASN.2018121232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551781PMC
June 2019

Dialysis initiation, modality choice, access, and prescription: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2019 07 13;96(1):37-47. Epub 2019 Apr 13.

University of Sydney, Sydney, NSW, Australia. Electronic address:

Globally, the number of patients undergoing maintenance dialysis is increasing, yet throughout the world there is significant variability in the practice of initiating dialysis. Factors such as availability of resources, reasons for starting dialysis, timing of dialysis initiation, patient education and preparedness, dialysis modality and access, as well as varied "country-specific" factors significantly affect patient experiences and outcomes. As the burden of end-stage kidney disease (ESKD) has increased globally, there has also been a growing recognition of the importance of patient involvement in determining the goals of care and decisions regarding treatment. In January 2018, KDIGO (Kidney Disease: Improving Global Outcomes) convened a Controversies Conference focused on dialysis initiation, including modality choice, access, and prescription. Here we present a summary of the conference discussions, including identified knowledge gaps, areas of controversy, and priorities for research. A major novel theme represented during the conference was the need to move away from a "one-size-fits-all" approach to dialysis and provide more individualized care that incorporates patient goals and preferences while still maintaining best practices for quality and safety. Identifying and including patient-centered goals that can be validated as quality indicators in the context of diverse health care systems to achieve equity of outcomes will require alignment of goals and incentives between patients, providers, regulators, and payers that will vary across health care jurisdictions.
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http://dx.doi.org/10.1016/j.kint.2019.01.017DOI Listing
July 2019

Improving the quality of healthcare: a cross-sectional study of the features of successful clinical networks.

Public Health Res Pract 2018 Dec 6;28(4). Epub 2018 Dec 6.

Sax Institute, Sydney, NSW, Australia.

Objectives: Networks of clinical experts are being established internationally to help embed evidence based care in health systems. There is emerging evidence that these clinical networks can drive quality improvement programs, but the features that distinguish successful networks are largely unknown. We examined the factors that make clinical networks effective at improving quality of care and facilitating system-wide changes.

Methods: We conducted a retrospective cross-sectional study of 19 state-wide clinical networks that reflected a range of medical and surgical specialty care and were in operation from 2006 to 2008 in New South Wales, Australia. We conducted qualitative interviews with network leaders to characterise potential impacts, and conducted internet surveys of network members to evaluate external support and the organisational and program characteristics of their respective networks. The main outcome measures were median ratings of individual network impacts on quality of care and system-wide changes, determined through independent assessment of documented evidence by an expert panel.

Results: We interviewed 19 network managers and 32 network co-chairs; 592 network members completed internet surveys. Three networks were rated as having had high impact on quality of care, and seven as having had high impact on system-wide change. Better-perceived strategic and operational network management was significantly associated with higher ratings of impact on quality of care (coefficient estimate 0.86; 95% confidence interval [CI] 0.02, 1.69). Better-perceived leadership of the network manager (coefficient estimate 0.47; 95% CI 0.10, 0.85) and strategic and operational network management (coefficient estimate 0.23; 95% CI 0.06, 0.41) were associated with higher ratings of impact on system-wide change.

Conclusions: This study represents the largest study of clinical networks undertaken to date. The results suggest that clinical networks that span the health system can improve quality of care and facilitate system-wide change. Network management and leadership, encompassing both strategic and operational elements at the organisational level, appear to be the primary influences on network success. These findings can guide future organisational and system-wide change programs and the development or strengthening of clinical networks to help implement evidence based care to improve service delivery and outcomes.
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http://dx.doi.org/10.17061/phrp28011803DOI Listing
December 2018

SIRT1 Attenuates Kidney Disorders in Male Offspring Due to Maternal High-Fat Diet.

Nutrients 2019 Jan 11;11(1). Epub 2019 Jan 11.

Renal medicine, Kolling Institute, Royal North Shore Hospital, University of Sydney, Sydney, New South Wales 2065, Australia.

Maternal obesity has been associated with kidney disorders in male offspring. Our previous studies have demonstrated that Sirtuin (SIRT)1, an essential regulator of metabolic stress responses, is suppressed in the offspring as the result of maternal high-fat diet (HFD) consumption, which is likely to underpin the adverse metabolic and renal outcomes. To examine if SIRT1 overexpression or activation early in life can protect the offspring kidney, wild-type (WT) and transgenic (Tg) offspring were born to the same diet-induced obese female C57BL/6 mice through breeding with hemizygous SIRT1-transgenic (Tg) male mice and examined for renal pathological changes. In separate experiments, SIRT1 activator SRT1720 (25 mg/kg/2 days i.p) was administrated in WT offspring over 6 weeks of postnatal high-fat diet exposure. The results show that offspring born to obese dams have increased kidney weight, higher levels of renal triglycerides, and increased expression of oxidative stress, inflammatory, and fibrotic markers, as well as increased albuminuria compared to offspring of control dams. Both SIRT1 overexpression and SRT1720 treatment attenuated renal lipid contents and expression of lipogenesis, oxidative stress, and inflammatory markers; however, fibrosis was modestly reduced and albuminuria was not affected. The findings suggest that SIRT1 therapy can ameliorate some pathological mechanisms of kidney programming due to maternal obesity but may not be sufficient to prevent the resulting chronic kidney injury.
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http://dx.doi.org/10.3390/nu11010146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356703PMC
January 2019

Maternal L-carnitine supplementation ameliorates renal underdevelopment and epigenetic changes in male mice offspring due to maternal smoking.

Clin Exp Pharmacol Physiol 2019 02 22;46(2):183-193. Epub 2018 Nov 22.

Renal Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, New South Wales, Australia.

Objectives: Epidemiological and animal studies showed that L-carnitine (LC) supplementation can ameliorate oxidative stress-induced tissues damage. We have previously shown that maternal cigarette smoke exposure (SE) can increase renal oxidative stress in newborn offspring with postnatal kidney underdevelopment and renal dysfunction in adulthood, which were normalised by LC administration in the SE dams during pregnancy. Exposure to an adverse intrauterine environment may lead to alteration in the epigenome, a mechanism by which adverse prenatal conditions increase the susceptibility to chronic disease later in life. The current study aimed to determine whether maternal SE induces epigenetic changes in the offspring's kidney are associated with renal underdevelopment, and the protective effect of maternal LC supplementation.

Method: Female Balb/c mice (7 weeks) were exposed to cigarette smoke (SE) or air (Sham) for 6 weeks prior to mating, during gestation and lactation. A subgroup of the SE dams received LC via drinking water (SE + LC, 1.5 mmol/L) throughout gestation and lactation. Male offspring were studied at postnatal day (P)1, P20, and 13 weeks.

Results: Maternal SE altered the expression of renal development markers glial cell line-derived neurotrophic factor and fibroblast growth factor 2, which were associated with increased renal global DNA methylation and DNA methyltransferase 1 mRNA expression at birth. These disorders were reversed by maternal LC administration.

Conclusion: The effect of maternal SE on renal underdevelopment involves global epigenetic alterations from birth, which can be prevented by maternal LC supplementation.
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http://dx.doi.org/10.1111/1440-1681.13038DOI Listing
February 2019

Lysyl oxidase-like 2 inhibition ameliorates glomerulosclerosis and albuminuria in diabetic nephropathy.

Sci Rep 2018 06 21;8(1):9423. Epub 2018 Jun 21.

Renal Research, Kolling Institute, Northern Sydney Local Health District, St Leonards, NSW, Sydney, Australia.

Diabetic nephropathy is characterised by the excessive amount of extracellular matrix in glomeruli and tubulointerstitial space. Lysyl oxidase-like 2 (LOXL2) is elevated in renal fibrosis and known to play key roles in ECM stabilisation by facilitating collagen cross-links, epithelial to mesenchymal transition and myofibroblast activation. Thus, targeting LOXL2 may prove to be a useful strategy to prevent diabetic nephropathy. We explored the renoprotective effect of a selective small molecule LOXL2 inhibitor (PXS-S2B) in a streptozotocin-induced diabetes model. Diabetic mice were treated with PXS-S2B for 24 weeks and outcomes compared with untreated diabetic mice and with telmisartan treated animals as comparator of current standard of care. Diabetic mice had albuminuria, higher glomerulosclerosis scores, upregulation of fibrosis markers and increased renal cortical LOXL2 expression. Treatment with PXS-S2B reduced albuminuria and ameliorated glomerulosclerosis. This was associated with reduced expression of glomerular fibronectin and tubulointerstitial collagen I. The renoprotective effects of both PXS-S2B and telmisartan were more marked in the glomerular compartment than in the tubulointerstitial space. The study reveals that LOXL2 inhibition was beneficial in preserving glomerular structure and function. Thus, LOXL2 may be a potential therapeutic target in diabetic nephropathy.
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http://dx.doi.org/10.1038/s41598-018-27462-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013429PMC
June 2018

MitoQ supplementation prevent long-term impact of maternal smoking on renal development, oxidative stress and mitochondrial density in male mice offspring.

Sci Rep 2018 04 26;8(1):6631. Epub 2018 Apr 26.

School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, 2007, Australia.

To investigate the effect of maternal MitoQ treatment on renal disorders caused by maternal cigarette smoke exposure (SE). We have demonstrated that maternal SE during pregnancy increases the risk of developing chronic kidney disease (CKD) in adult offspring. Mitochondrial oxidative damage contributes to the adverse effects of maternal smoking on renal disorders. MitoQ is a mitochondria-targeted antioxidant that has been shown to protect against oxidative damage-related pathologies in many diseases. Female Balb/c mice (8 weeks) were divided into Sham (exposed to air), SE (exposed to cigarette smoke) and SEMQ (exposed to cigarette smoke with MitoQ supplemented from mating) groups. Kidneys from the mothers were collected when the pups weaned and those from the offspring were collected at 13 weeks. Maternal MitoQ supplementation during gestation and lactation significantly reversed the adverse impact of maternal SE on offspring's body weight, kidney mass and renal pathology. MitoQ administration also significantly reversed the impact of SE on the renal cellular mitochondrial density and renal total reactive oxygen species in both the mothers and their offspring in adulthood. Our results suggested that MitoQ supplementation can mitigate the adverse impact of maternal SE on offspring's renal pathology, renal oxidative stress and mitochondrial density in mice offspring.
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http://dx.doi.org/10.1038/s41598-018-24949-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5919980PMC
April 2018

DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease.

FASEB J 2018 10 24;32(10):5215-5226. Epub 2018 Apr 24.

Renal Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia.

Chronic kidney disease (CKD) is a global epidemic, and its major risk factors include obesity and type 2 diabetes. Obesity not only promotes metabolic dysregulation and the development of diabetic kidney disease but also may independently lead to CKD by a variety of mechanisms, including endocrine and metabolic dysfunction, inflammation, oxidative stress, altered renal hemodynamics, and lipotoxicity. Deleterious renal effects of obesity can also be transmitted from one generation to the next, and it is increasingly recognized that offspring of obese mothers are predisposed to CKD. Epigenetic modifications are changes that regulate gene expression without altering the DNA sequence. Of these, DNA methylation is the most studied. Epigenetic imprints, particularly DNA methylation, are laid down during critical periods of fetal development, and they may provide a mechanism by which maternal-fetal transmission of chronic disease occurs. Our current review explores the evidence for the role of DNA methylation in the development of CKD, diabetic kidney disease, diabetes, and obesity. DNA methylation has been implicated in renal fibrosis-the final pathophysiologic pathway in the development of end-stage kidney disease-which supports the notion that demethylating agents may play a potential therapeutic role in preventing development and progression of CKD.-Larkin, B. P., Glastras, S. J., Chen, H., Pollock, C. A., Saad, S. DNA methylation and the potential role of demethylating agents in prevention of progressive chronic kidney disease.
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http://dx.doi.org/10.1096/fj.201800205RDOI Listing
October 2018

Improving the prognosis of patients with severely decreased glomerular filtration rate (CKD G4+): conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Kidney Int 2018 06 12;93(6):1281-1292. Epub 2018 Apr 12.

Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Patients with severely decreased glomerular filtration rate (GFR) (i.e., chronic kidney disease [CKD] G4+) are at increased risk for kidney failure, cardiovascular disease (CVD) events (including heart failure), and death. However, little is known about the variability of outcomes and optimal therapeutic strategies, including initiation of kidney replacement therapy (KRT). Kidney Disease: Improving Global Outcomes (KDIGO) organized a Controversies Conference with an international expert group in December 2016 to address this gap in knowledge. In collaboration with the CKD Prognosis Consortium (CKD-PC) a global meta-analysis of cohort studies (n = 264,515 individuals with CKD G4+) was conducted to better understand the timing of clinical outcomes in patients with CKD G4+ and risk factors for different outcomes. The results confirmed the prognostic value of traditional CVD risk factors in individuals with severely decreased GFR, although the risk estimates vary for kidney and CVD outcomes. A 2- and 4-year model of the probability and timing of kidney failure requiring KRT was also developed. The implications of these findings for patient management were discussed in the context of published evidence under 4 key themes: management of CKD G4+, diagnostic and therapeutic challenges of heart failure, shared decision-making, and optimization of clinical trials in CKD G4+ patients. Participants concluded that variable prognosis of patients with advanced CKD mandates individualized, risk-based management, factoring in competing risks and patient preferences.
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http://dx.doi.org/10.1016/j.kint.2018.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5998808PMC
June 2018

Maternal obesity increases the risk of metabolic disease and impacts renal health in offspring.

Biosci Rep 2018 04 29;38(2). Epub 2018 Mar 29.

Department of Medicine, Kolling Institute, University of Sydney, Sydney, Australia.

Obesity, together with insulin resistance, promotes multiple metabolic abnormalities and is strongly associated with an increased risk of chronic disease including type 2 diabetes (T2D), hypertension, cardiovascular disease, non-alcoholic fatty liver disease (NAFLD) and chronic kidney disease (CKD). The incidence of obesity continues to rise in astronomical proportions throughout the world and affects all the different stages of the lifespan. Importantly, the proportion of women of reproductive age who are overweight or obese is increasing at an alarming rate and has potential ramifications for offspring health and disease risk. Evidence suggests a strong link between the intrauterine environment and disease programming. The current review will describe the importance of the intrauterine environment in the development of metabolic disease, including kidney disease. It will detail the known mechanisms of fetal programming, including the role of epigenetic modulation. The evidence for the role of maternal obesity in the developmental programming of CKD is derived mostly from our rodent models which will be described. The clinical implication of such findings will also be discussed.
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http://dx.doi.org/10.1042/BSR20180050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874265PMC
April 2018

The KCa3.1 blocker TRAM34 reverses renal damage in a mouse model of established diabetic nephropathy.

PLoS One 2018 9;13(2):e0192800. Epub 2018 Feb 9.

Kolling Institute, Sydney Medical School-Northern, University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Despite optimal control of hyperglycaemia, hypertension, and dyslipidaemia, the number of patients with diabetic nephropathy (DN) continues to grow. Strategies to target various signaling pathways to prevent DN have been intensively investigated in animal models and many have been proved to be promising. However, targeting these pathways once kidney disease is established, remain unsatisfactory. The clinical scenario is that patients with diabetes mellitus often present with established kidney damage and need effective treatments to repair and reverse the kidney damage. In this studies, eNOS-/- mice were administered with streptozotocin to induce diabetes. At 24 weeks, at which time we have previously demonstrated albuminuria and pathological changes of diabetic nephropathy, mice were randomised to receive TRAM34 subcutaneously, a highly selective inhibitor of potassium channel KCa3.1 or DMSO (vehicle) for a further 14 weeks. Albuminuria was assessed, inflammatory markers (CD68, F4/80) and extracellular matrix deposition (type I collagen and fibronectin) in the kidneys were examined. The results clearly demonstrate that TRAM34 reduced albuminuria, decreased inflammatory markers and reversed extracellular matrix deposition in kidneys via inhibition of the TGF-β1 signaling pathway. These results indicate that KCa3.1 blockade effectively reverses established diabetic nephropathy in this rodent model and provides a basis for progressing to human studies.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192800PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806905PMC
April 2018

Metformin attenuates folic-acid induced renal fibrosis in mice.

J Cell Physiol 2018 09 25;233(9):7045-7054. Epub 2018 Mar 25.

Kolling Institute, Sydney Medical School-Northern University of Sydney, Royal North Shore Hospital, St Leonards, New South Wales, Australia.

Progressive tubulointerstitial fibrosis has been recognized as a common pathological process that leads to the progression of all chronic kidney disease (CKD). Innovative strategies are needed to both prevent and treat CKD. Inflammatory and fibrotic signaling pathways play central roles in the progression of CKD regardless of aetiology. Hence, targeting inflammatory and fibrotic responses holds promise to limit renal fibrosis. Metformin has been the most prescribed glucose-lowering medicine worldwide, and its potential for many other therapeutic applications is also being explored intensively. Increasing evidence indicates metformin may limit renal fibrosis. However, the exact mechanisms whereby metformin limits renal injury are not fully understood. The anti-fibrotic effects of metformin, independent of improved glycaemic control was examined in a folic acid-induced mouse model of nephropathy for 14 days. Human proximal tubular cells (HK2 cells) exposed to TGF-β1 were used in in vitro models to examine mechanistic pathways. Folic acid induced nephropathy was associated with the overexpression of inflammatory markers MCP-1, F4/80, type IV collagen, fibronectin and TGF-β1 compared to control groups, which were partially attenuated by metformin treatment. In vitro studies confirmed that metformin inhibited TGF-β1 induced inflammatory and fibrotic responses through Smad3, ERK1/2, and P38 pathways in human renal proximal tubular cells. These results suggest that metoformin attenuates folic acid-induced renal interstitial fibrogenesis through TGF-β1 signaling pathways.
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http://dx.doi.org/10.1002/jcp.26505DOI Listing
September 2018

An Interview Study of Patient and Caregiver Perspectives on Advance Care Planning in ESRD.

Am J Kidney Dis 2018 02 11;71(2):216-224. Epub 2017 Nov 11.

Sydney School of Public Health, The University of Sydney, Sydney, Australia; Centre for Kidney Research, The Children's Hospital at Westmead, NSW, Australia.

Background: Advance care planning (ACP) empowers patients to consider and communicate their current and future treatment goals. However, it can be an emotionally charged process for patients with kidney disease and their caregivers. This study aimed to describe the perspectives and attitudes of patients with end-stage renal disease (ESRD) and their caregivers toward ACP.

Study Design: Qualitative study.

Setting & Participants: Patients with ESRD (n=24) and their caregivers (n=15) aged 36 to 91 years at various stages of ACP ("not commenced," "in progress," or "completed") from 3 renal services.

Methodology: Semistructured interviews.

Analytical Approach: Transcripts were analyzed using thematic analysis.

Results: 5 major themes were identified: articulating core values (avoiding futile and undignified treatment, reevaluating terms of dialysis, framing a life worth living, and refusing to be a burden), confronting conversations (signifying death and defeat, accepting inevitable death, and alleviating existential tension), negotiating mutual understanding (broaching taboos and assisting conflicted caregivers), challenging patient autonomy (family pressures to continue dialysis, grief diminishing caregivers' capacity, and leveraging support), and decisional disempowerment (lacking medical transparency and disappointment with clinical disinterest).

Limitations: Only English-speaking patients/caregivers participated in the interview.

Conclusions: ACP provides patients with ESRD and their caregivers a conduit for accepting and planning for impending death and to express treatment preferences based on self-dignity and value of living. However, ACP can be considered taboo, may require caregivers to overcome personal and decisional conflict, and may be complex if patients and caregivers are unable to accept the reality of the patient's illness. We suggest that ACP facilitators and clinicians make ACP more acceptable and less confrontational to patients and caregivers and that strategies be put in place to support caregivers who may be experiencing overwhelming grief or who have conflicting goals, particularly when they are called on to make end-of-life decisions.
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http://dx.doi.org/10.1053/j.ajkd.2017.07.021DOI Listing
February 2018

The renal consequences of maternal obesity in offspring are overwhelmed by postnatal high fat diet.

PLoS One 2017 22;12(2):e0172644. Epub 2017 Feb 22.

Department of Medicine, Kolling Institute, University of Sydney, Sydney, Australia.

Aims/hypothesis: Developmental programming induced by maternal obesity influences the development of chronic disease in offspring. In the present study, we aimed to determine whether maternal obesity exaggerates obesity-related kidney disease.

Methods: Female C57BL/6 mice were fed high-fat diet (HFD) for six weeks prior to mating, during gestation and lactation. Male offspring were weaned to normal chow or HFD. At postnatal Week 8, HFD-fed offspring were administered one dose streptozotocin (STZ, 100 mg/kg i.p.) or vehicle control. Metabolic parameters and renal functional and structural changes were observed at postnatal Week 32.

Results: HFD-fed offspring had increased adiposity, glucose intolerance and hyperlipidaemia, associated with increased albuminuria and serum creatinine levels. Their kidneys displayed structural changes with increased levels of fibrotic, inflammatory and oxidative stress markers. STZ administration did not potentiate the renal effects of HFD. Though maternal obesity had a sustained effect on serum creatinine and oxidative stress markers in lean offspring, the renal consequences of maternal obesity were overwhelmed by the powerful effect of diet-induced obesity.

Conclusion: Maternal obesity portends significant risks for metabolic and renal health in adult offspring. However, diet-induced obesity is an overwhelming and potent stimulus for the development of CKD that is not potentiated by maternal obesity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172644PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5321436PMC
August 2017

Clinicians' Perspectives on Advance Care Planning for Patients With CKD in Australia: An Interview Study.

Am J Kidney Dis 2017 Sep 17;70(3):315-323. Epub 2017 Feb 17.

Sydney Medical School, The University of Sydney, Sydney, Australia; Improving Palliative Care through Clinical Trials (ImPaCCT) New South Wales, Australia; HammondCare Palliative & Supportive Care Service, Greenwich Hospital, Sydney, Australia. Electronic address:

Background: Advance care planning (ACP) empowers patients to consider and communicate their current and future treatment goals. However, ACP is not widely implemented in chronic kidney disease (CKD) care settings. This study aims to describe clinicians' beliefs, challenges, and perspectives of ACP in patients with CKD.

Study Design: Qualitative study.

Setting & Participants: Nephrologists (n=20), nurses (n=7), and social workers (n=4) with a range of experience in facilitating ACP for patients with CKD across Australia.

Methodology: Semistructured interviews were digitally recorded and transcribed verbatim.

Analytical Approach: Transcripts were analyzed using thematic analysis.

Results: 5 major themes were identified: facilitating informed decision making (avoiding preconceptions, conveying complete truths, focusing on supportive care, and synchronizing with evolving priorities), negotiating moral boundaries (contending with medical futility and respecting patient vs family autonomy), navigating vulnerable conversations (jeopardizing the therapeutic relationship, compromising professional confidence, emotionally invested, and enriching experiences), professional disempowerment (unsupportive culture, doubting logistical feasibility, and making uncertain judgments), and clarifying responsibilities (governing facilitation, managing tensions, and transforming multidisciplinary relationships).

Limitations: Some findings may be specific to the Australian context.

Conclusions: The tensions among themes reflect that ACP is paradoxically rewarding for clinicians because ACP empowers patients yet can expose personal and professional vulnerabilities. Clinicians believe that a more collaborative approach is needed, with increased efforts to identify the evolving and individualized needs and goals of patients with CKD. Models of ACP that address clinicians' personal and professional vulnerabilities when initiating ACP may foster greater confidence and cultural acceptance of ACP in the CKD setting.
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http://dx.doi.org/10.1053/j.ajkd.2016.11.023DOI Listing
September 2017

Fluorescent Labeling and Biodistribution of Latex Nanoparticles Formed by Surfactant-Free RAFT Emulsion Polymerization.

Macromol Biosci 2017 10 14;17(10). Epub 2016 Dec 14.

Key Centre for Polymers & Colloids, School of Chemistry, The University of Sydney, Building F11, NSW, 2006, Australia.

The authors report the preparation of a novel range of functional polyacrylamide stabilized polystyrene nanoparticles, obtained by surfactant-free reversible addition-fragmentation chain transfer (RAFT) emulsion polymerization, their fluorescent tagging, cellular uptake, and biodistribution. The authors show the versatility of the RAFT emulsion process for the design of functional nanoparticles of well-defined size that can be used as drug delivery vectors. Functionalization with a fluorescent tag offers a useful visualization tool for tracing, localization, and clearance studies of these carriers in biological models. The studies are carried out by labeling the sterically stabilized latex particles chemically with rhodamine B. The fluorescent particles are incubated in a healthy human renal proximal tubular cell line model, and intravenously injected into a mouse model. Cellular localization and biodistribution of these particles on the biological models are explored.
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http://dx.doi.org/10.1002/mabi.201600366DOI Listing
October 2017
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