DEVELOPING CONSENSUS-BASED OUTCOME DOMAINS FOR TRIALS IN PERITONEAL DIALYSIS: AN INTERNATIONAL DELPHI SURVEY

K MANERA1,2, A TONG1,2, J CRAIG1,2, J SHEN3, S JESUDASON4,5, Y CHO6,7,8, B SAUTENET1,2,9,M HOWELL1,2, A WANG10, E BROWN11, G BRUNIER12, J PERL13, J DONG14, M WILKIE15, R MEHROTRA16, R PECOITS-FILHO17, S NAICKER18, T DUNNING19, D JOHNSON6,7,8,20,21
1Sydney School of Public Health, The University Of Sydney, Sydney, Australia, 2Centre for Kidney Research, The Children’s Hospital at Westmead, Westmead, Australia, 3Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrence, USA, 4Central and Northern Adelaide Renal and Transplantation Service (CNARTS), Royal Adelaide Hospital, Adelaide, Australia, 5School of Medicine, University of Adelaide, Adelaide, Australia, 6Department of Nephrology, Princess Alexandra Hospital, Brisbane, Australia, 7Australian Kidney Trials Network, University of Queensland, Brisbane, Australia, 8Translational Research Institute, Brisbane, Australia, 9Department of Nephrology and Clinical Immunology, , France, 10Department of Medicine, Queen Mary Hospital, University of Hong Kong, , Hong Kong, 11Imperial College Renal and Transplant Centre, Hammersmith Hospital, , United Kingdom, 12Lawrence S. Bloomberg Faculty of Nursing, University of Toronto, Toronto, Canada, 13Division of Nephrology, Department of Medicine, St. Michael’s Hospital, University of Toronto, Toronto, Canada, 14Renal Division, Department of Medicine, Peking University First Hospital, , China, 15Department of Nephrology, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, United Kingdom, 16Kidney Research Institute and Harborview Medical Center, Division of Nephrology/Department of Medicine, University of Washington, Seattle, USA, 17School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba, Brazil, 18Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, , South Africa, 19South Bank TAFE, Brisbane, Austalia, 20Metro South and Ipswich Nephrology and Transplant Services (MINTS), Brisbane, Australia, 21Centre for Kidney Disease Research, University of Queensland at Princess Alexandra Hospital, Brisbane, Australia

Background: Major inconsistencies in the reporting of outcomes, the omission of patient-reported outcomes, and frequent reporting of surrogate outcomes in trials impedes evidence-informed decision making by patients and their clinicians.
Aim: To generate a consensus-based prioritised list of outcome domains for trials in peritoneal dialysis (PD).
Methods: In an international online 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcomes using a 9-point Likert scale and provided comments. In rounds 2 and 3, participants re-rated the outcomes after reviewing the scores and comments of other respondents. For each outcome we calculated the mean, median, and proportion rating 7-9 (critically important).
Results: In total, 873 participants (207 [24%] patients/caregivers and 666 [76%] health professionals) from 68 countries completed round 1, and 530 (61%) completed round 3. The top outcomes based on a threshold (mean >8; median ≥8; proportion >85% in both groups) were PD-infection, membrane functioning, PD failure, cardiovascular disease, mortality, catheter complications, and ability to do usual activities. Compared with health professionals, patients/caregivers gave higher priority to 6 outcomes: blood pressure (mean difference of 0.4), fatigue (0.3), membrane functioning (0.3), impact on family/friends (0.1), peritoneal thickening [EPS] (0.1), and usual activities (0.1).
Conclusion: Clinical outcomes were highly prioritised by both stakeholder groups. Patients/caregivers gave higher priority to lifestyle-related outcomes than health professionals. This process will inform a core outcome set to improve the consistency and relevance of outcomes reported in trials in peritoneal dialysis.


Biography:
Karine Manera is a PhD candidate with The University of Sydney and research officer at the Centre for Kidney Research. She uses qualitative and quantitative research methods to generate evidence for improving shared decision-making in the area of peritoneal dialysis. She has applied this approach in global and multi-language studies.

 

ASSOCIATIONS OF COGNITIVE FUNCTION AND EDUCATIONAL LEVEL WITH ALL-CAUSE MORTALITY IN ADULTS ON HAEMODIALYSIS: THE COGNITIVE-HD COHORT STUDY

A VAN ZWIETEN1,2, G WONG1,2,3, M RUOSPO4,5, S PALMER6, A TEIXEIRA-PINTO1,2, M BARULLI7, A IURILLO7, V SAGLIMBENE1,4, P NATALE4,8, L GARGANO4, M MURGO4, C LOY1,9, R TORTELLI7, J CRAIG1,2,10, D JOHNSON11,12, M TONELLI13, J  HEGBRANT4, C WOLLHEIM4, G LOGROSCINO7,14, G STRIPPOLI1,4,8
1Sydney School of Public Health, University of Sydney, Sydney, Australia, 2Centre for Kidney Research, Children’s Hospital at Westmead, Westmead, Australia, 3Department of Renal Medicine, Westmead Hospital, Westmead, Australia, 4Diaverum Medical-Scientific Office, Lund, Sweden, 5Division of Nephrology and Transplantation, Amedeo Avogadro University of Eastern Piedmont, Novara, Italy, 6Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand, 7Neurodegenerative Diseases Unit, Department of Clinical Research in Neurology, University of Bari “A. Moro”, “Pia Fondazione Cardinale G. Panico”, Tricase, Italy, 8Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare, Bari, Italy, 9Huntington Disease Service, Westmead Hospital, Westmead, Australia, 10Department of Nephrology, Children’s Hospital at Westmead, Westmead, Australia, 11Department of Nephrology, Princess Alexandra Hospital, Woolloongabba, Australia, 12Translational Research Institute, University of Queensland, Woolloongabba, Australia, 13Cumming School of Medicine, University of Calgary, Calgary, Canada, 14Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “A. Moro”, Bari, Italy

Aim: To determine the association between cognitive function and all-cause mortality in adults on haemodialysis, and the independent and interactive effects of educational level.
Background: Cognitive impairment is common in dialysis patients, and is associated with lower levels of education. Associations of cognitive impairment and education with mortality in dialysis populations are understudied.
Methods: We recruited adult haemodialysis patients from 20 centres in Italy, assessing their cognitive function across 5 domains (memory, attention, executive function, language, perceptual-motor function) with a neuropsychological battery of 10 tests, and their self-reported educational level. Associations of cognition and education with all-cause mortality were examined in multivariable Cox regression models.
Results: Of 958 patients in the network, 676 participated (70.6%). Patients’ median age was 70.9 years (IQR: 59.9-78.1) and 262 (38.8%) were female. Educational levels were 338 (50.0%) primary or less, 163 (24.1%) lower secondary, 175 (25.9%) upper secondary or higher. Of 664 with data, 527 (79.4%) were impaired on at least 1 cognitive domain. Median follow-up was 3.29 years (IQR: 1.90-3.58) and there were 206 deaths over 1874.22 person-years. Adjusted HR (95% CI) for mortality on cognition were: 1.77 (1.07-2.93) for any impairment (compared to none, N=630); 1.48 (0.82-2.68) for 1 domain impaired, 1.88 (1.01-3.53) for 2 domains, 2.01 (1.14-3.55) for 3 or more (compared to none, N=564); and 0.68 (0.51-0.92) per standard deviation increase in global cognitive score from principal components analysis (N=429). Adjusted HR (95% CI) for education were 0.94 (0.61-1.45) for lower secondary and 1.49 (1.02-2.18) for upper secondary or higher (relative to primary/less, N=630). The cognition-by-education interaction was not significant (p=.691).
Conclusions: Cognitive impairment appears to be a risk factor for mortality in haemodialysis patients.


Biography:
Anita is a PhD Candidate at the University of Sydney School of Public Health and Centre for Kidney Research with a background in psychology and public health. She is interested in the dynamic interactions between education, economic disadvantage and health across the life-course with a specific focus on kidney disease.

 

IMPACT OF EXTENDED HOURS DIALYSIS ON UTILITY-BASED QUALITY OF LIFE: RESULTS FROM THE ACTIVE DIALYSIS TRIAL

B SMYTH1,2, K HOWARD1, L ZUO3, J DE ZOYSA4,5, C CHAN6, N GRAY7,8, A CASS9, M GALLAGHER2,10,11, V PERKOVIC2, M JARDINE2,11
1Sydney School of Public Health, University of Sydney, Sydney, Australia, 2The George Institute for Global Health, UNSW, Sydney, Australia, 3Peking University People’s Hospital, Beijing, China, 4North Shore Hospital, Auckland, New Zealand, 5Department of Medicine, University of Auckland, Auckland, New Zealand, 6University Health Network, Toronto, Canada, 7Sunshine Coast University Hospital, Birtinya, Australia, 8Sunshine Coast Clinical School, University of Queensland, , Australia, 9Menzies School of Health Research, Charles Darwin University, Darwin, Australia, 10Sydney Medical School, University of Sydney, Sydney, Australia, 11Renal Unit, Concord Repatriation General Hospital, Sydney, Australia

Aim: To estimate the effect of extended hours dialysis on utility-based quality of life (QOL) using two distinct multi-attribute utility instruments.
Background: Health economic evaluations often rely on measurements of health utility. Validated health utility assessment tools are available but whether they perform similarly is rarely assessed.
Methods: The ACTIVE Dialysis trial randomised 200 participants to extended hours (≥24 hours/week) or standard hours (≤18 hours/week) haemodialysis for 12 months. Utility-based QOL was assessed every three months by the EuroQOL-5 Dimensions (EQ-5D) and Short Form-6 Dimensions (SF-6D). The mean difference in utility weights between groups was obtained by mixed linear regression. Quality adjusted life years (QALYs), a measure that combines survival and quality of life, were calculated.
Results: Extended dialysis hours did not improve utility-based QOL measured by the EQ-5D (0.036 [95%CI -0.022, 0.093]; p=0.223) but did significantly improve it when measured by the SF-6D (0.027 [95%CI 0.003, 0.052]; p=0.026). There was no significant difference in mean QALYs gained per patient from extended over standard dialysis as measured by the SF-6D (0.015 [95%CI -0.070, 0.041]) or the EQ-5D (0.029 [95%CI -0.108, 0.049]) – equivalent to a mean per patient gain of 5.5 (95%CI -25.6, 15.0) and 10.6 (95%CI -39.4, 17.9) days of perfect health, respectively.
Conclusions: The EQ-5D and SF-6D resulted in different interpretations of utility-based QOL effects of extended hours dialysis, although the significant improvement in utility-based QOL found with the SF-6D did not translate into a significant gain in QALYs. These results emphasise the need for a better understanding of the impact of different scoring algorithms and instrument properties on the performance of multi-attribute utility instruments to measure QOL in dialysis patients.


Biography:
Dr Smyth is a nephrologist and PhD candidate at The George Institute for Global Health. His research interests include dialysis, especially randomised controlled trial methodology and evidence as well as patient reported outcomes in dialysis patients.

ANNUAL SCREENING VERSUS NO SCREENING FOR ASYMPTOMATIC CORONARY ARTERY DISEASE IN WAIT-LISTED KIDNEY TRANSPLANT CANDIDATES: A MODELLED COST-EFFECTIVENESS ANALYSIS

T YING1,2,A TRAN2, AC WEBSTER2, H PILMORE3, P KELLY2, JS GILL4, S KLARENBACH5, S CHADBAN1,2, RL MORTON2
1Royal Prince Alfred Hospital, Camperdown, Australia, 2University of Sydney, Camperdown, Australia, 3Auckland City Hospital, Auckland, New Zealand, 4University of British Columbia, Vancouver, Canada, 5University of Alberta, Edmonton, Canada

Aim: To calculate the cost-effectiveness of repeated screening of kidney transplant candidates (KTC) for asymptomatic coronary artery disease (CAD) versus no screening (after wait-listing) from a health system perspective, and identify areas of current evidence uncertainty to be addressed in a forthcoming randomised trial.
Background: KTC often wait 2-6 years on the deceased-donor wait-list; cardiovascular fitness must be maintained prior to transplantation. Regular screening by non-invasive methods for CAD is routinely performed at many transplant centres; however the cost-effectiveness of this practice is unclear.
Methods: We developed a Markov model over a lifetime horizon to simulate a cohort of KTCs to undergo annual CAD screening compared with no further screening. We obtained quality-of-life utilities and probabilities of important clinical events including myocardial infarction, transplantation and death using published data. Resource use and costs were obtained from Australian Refined Diagnosis Related Groups, Medicare Benefits Schedule, the Australian Institute of Health and Welfare reports and the literature.
Results: In the base model, no further screening resulted in a cost-saving of $91,025 and additional 2.26 quality-adjusted life-years (QALYs) compared to annual screening. The lifetime costs of an average 40-year old undergoing annual screening was $1,467,078 compared with $1,376,052 for no screening. Annual screening yielded 11.16 QALYs vs 13.42 QALYs in the no-screening arm. Results were most sensitive to the costs of cardiovascular-death and the costs of transplantation in the first and subsequent years.
Conclusion: No further screening for asymptomatic CAD in KTCs is likely to be cost-saving. Detailed data on the real costs of cardiovascular events is required to reduce uncertainty in the results. The Canadian-Australasian Randomised trial of Screening Kidney transplant candidates seeks to answer this question.


BIOGRAPHY:
Tracey Ying is a nephrologist and a PhD candidate in kidney transplantation at the Kidney Node, Charles Perkins Centre at the University of Sydney

TLR AGONISTS EXCERBATE ACUTE KIDNEY INJURY MIMICKING AHUS IN A CFH MUTANT MOUSE WITH A KNOWN HUMAN MUTATION

V SHEN1, G ZHANG1, M HU2, J ZHOU1, S ROBINSON1, H MCCARTHY1, Y WANG2, Q CAO2, G ZHENG2, N ROGERS2, T BARBOUR3, I ALEXANDER4, D HARRIS2, S ALEXANDER1, Y WANG1
1Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, Australia, 2Centre for Transplant and Renal Research, University of Sydney at Westmead Hospital, Sydney, Australia, 3Department of Nephrology, Royal Melbourne Hospital, Melbourne, Australia, 4Gene Therapy Research Unit, The Children’s Hospital at Westmead, Sydney, Australia

Aim: To evaluate whether TLR4 and TLR7 agonists induce acute kidney injury in CFH mutant mice.
Background: Atypical haemolytic uremic syndrome (aHUS) is associated with mutations in the complement alternative pathway, most commonly complement factor H (CFH), a negative regulator of C3 activation. Mice carrying CFH mutations associated with functionally impaired CFH protein in human aHUS have been generated by ENU mutagenesis. The role of infection in triggering disease in these mice was tested by treatment with lipopolysaccharide (LPS, TLR4 agonist) and Imiquimod (IMQ, TLR7 agonist).
Methods: For LPS, a single low dose (4mg/kg) was administrated intraperitoneally to homozygous, heterozygous and wild type (WT) mice. For IMQ, 25μg was administered on alternate days for 3 weeks in the corresponding groups. After treatment, kidney function, histology and C3 immunofluorescence were assessed. Serum and liver CFH levels were measured using western blot.
Results: Homozygous mice showed spontaneous deposition of glomerular C3 and had minimal serum concentrations of CFH compared to WT and heterozygous mice. Following LPS treatment, homozygous mice showed significantly higher levels of proteinuria (3.1±0.2mg/16h) and serum creatinine (28.3±3umol/L) compared to heterozygous (1.3±0.4mg/16h, 20.3±2umol/L, p<0.01 and p<0.05 respectively) and WT mice (1.2±0.2mg/16h, 17.6±1.6umol/L, p<0.01 and p<0.05 respectively). IMQ treatment also had a worse effect on renal function in homozygous mice. LPS or IMQ treated homozygous mice exhibited significantly more glomerulosclerosis, tubular damage and interstitial inflammation than heterozygous and WT mice (p<0.01).
Conclusions: Mice homozygous for the aHUS-associated CFH mutation develop glomerular C3 deposition and are sensitive to LPS or IMQ, developing acute kidney injury and renal histological damage. This suggests a significant role for infection in triggering aHUS in susceptible individuals.


Biography:
Victor completed his Bachelor of Medical Science studies at the University of Sydney, majoring in immunobiology and physiology. He is currently studying his Honours year at the Centre for Kidney Research, The Children’s Hospital at Westmead under the supervision of Prof Stephen Alexander and Dr Yuan Min Wang. His area of interest involves hematology and role of complement regulators in glomerular injuries.

 

INABILITY TO REGULATE FATTY ACID OXIDATION OR GLYCOLYSIS INCREASES RENAL FIBROSIS

M LEE1,2, P MOUNT1, M KATERELOS1, K GLEICH1, D POWER1,2
1Austin Health, Heidelberg, Australia, 2Department of Medicine, The University of Melbourne, Heidelberg, Australia

Aim: To determine the roles of fatty acid oxidation (FAO) and glycolysis in renal fibrosis.
Background: Changes in energy metabolism are emerging as a key contributor in renal fibrosis. Expression of genes regulating fatty acid metabolism is reduced in fibrotic kidneys and aerobic glycolysis increases in renal disease models.
Methods: Mice with knock-in mutations of phosphosites in acetyl CoA carboxylase 1 and 2 (ACC1/2KI mice), the major regulator of FAO, and 6-phosphofructo-2kinase/fructose-2,6-biphosphatase (PFKFB2KI mice), the major regulator of glycolysis, were used to assess the roles of FAO and glycolysis, respectively. The folic acid nephropathy (FAN) and unilateral ureteric obstruction (UUO) models were induced in male ACC1/2KI and PFKFB2KI mice. Metformin was administered to mice with FAN.
Results: ACC Ser79 phosphorylation was reduced in folate-treated tubular epithelial cells (p<0.01) and WT mice with FAN (p<0.05). Mutation of these sites in ACC1/2 KI mice with FAN or UUO caused lipid accumulation (Oil Red O p<0.01), increased triglyceride (p<0.01), increased collagen (PicroSirius red p<0.001; Masson’s Trichrome p<0.01; qRT-PCR p<0.01) and increased α-SMA (Western blot p<0.05; qRT-PCR p<0.01). Metformin administration was associated with reduced fibrosis (PicroSirius red p<0.01) and lipid accumulation (Oil Red O p<0.05) in WT mice, but not in ACC1/2KI mice. To determine the role of glycolysis, UUO was induced in PFKFB2KI mice. WT mice with UUO had reduced PFKFB2 Ser483 phosphorylation (p<0.01). PFKFB2KI UUO mice had increased collagen (Picrosirius red p<0.001), increased fibronectin (Western blot p<0.05; qRT-PCR p<0.05) increased α-SMA (Western blot, p<0.05) and glycogen accumulation (PAS, p<0.05).
Conclusions: These data suggest reduced FAO and glycolysis is deleterious following renal injury. Phosphorylation of ACC reduces renal fibrosis and is essential for the anti-fibrotic effect of metformin.


Biography:
Mardiana Lee completed her advanced training in nephrology through  the Austin and the Royal Melbourne Hospital. She received her fellowship from the Royal Australasian College of Physician in 2015. She is currently completing her PhD at the University of Melbourne.

KCA3.1 MEDIATED DYSREGULATION OF MITOCHONDRIAL QUALITY CONTROL IN DIABETIC NEPHROPATHY

C HUANG1, H YI1, Y SHI1, Q CAO1, X-M CHEN1, C POLLOCK1
1University of Sydney, St Leonards, Australia

Aim: To identify the role of KCa3.1 in mitochondrial quality control in diabetic nephropathy.
Background: Mitochondrial dysfunction is involved in the pathogenesis of diabetic nephropathy. Mitochondrial quality control is characterized by repairing of mitochondrial damage through mitophagy and fission/fusion. It has been shown that blockade of KCa3.1, a potassium channel, ameliorates diabetic renal fibrosis and KCa3.1 activation contributes to dysfunctional tubular autophagy in diabetic nephropathy through PI3K/Akt/mTOR signaling pathways. However, the role of KCa3.1 in mitochondrial quality control is not yet known.
Methods: In vitro human proximal tubular cells (HK2 cells) transfected with scrambled siRNA or KCa3.1 siRNA were exposed to TGF-β1 for 48h. Mitochondrial function and mitochondrial ROS (mtROS) production were assessed. In vivo, diabetes was induced in KCa3.1+/+ and KCa3.1-/- mice by streptozotocin injection. The pro-fission protein dynamin-related protein 1 (Drp1) and pro-fussion protein mitofusin 2 (Mfn2) as well as BCL2 interacting protein 3 (BNIP3) (a mitophagy regulator) were examined by western blotting in HK2 cells and mice kidneys.
Results: The in vitro results showed that TGF-β1 significantly inhibited mitochondrial ATP production rate, compared to the controls, which were significantly reversed by KCa3.1 siRNA in HK2 cells. KCa3.1 gene silencing inhibited TGF-β1-induced significant increase in MitoSOX Red fluorescence in HK2 cells. TGF-β1 significantly increased the expression of Drp1 and BNIP3 in HK2 cells, which were attenuated by KCa3.1 gene silencing. The expression of Mfn2 was not overtly apparent on TGF-β1 stimulation. Consistently, the in vivo results showed significantly increased Drp1 and BNIP3 expression in diabetic KCa3.1 +/+ mice, which were significantly reduced in diabetic KCa3.1-/- mice.
Conclusions: KCa3.1 mediates dysregulation of mitochondrial quality control in diabetic nephropathy.


Biography:
Dr Chunling Huang is a NHMRC early career research fellow in the renal lab at Kolling Institute, University of Sydney. She has expertise in diabetic kidney disease, animal models of diabetic nephropathy and kidney fibrosis. Her research focuses on the novel therapeutic targets for chronic kidney diseases and the underling mechanisms including inflammation, fibrosis, fibroblast activation and autophagy.

 

A CRUCIAL ROLE FOR INTERLEUKIN-18 IN THE DEVELOPMENT OF RENAL INFLAMMATION AND ELEVATED BLOOD PRESSURE IN 1 KIDNEY/DOCA/SALT-INDUCED HYPERTENSION

J THOMAS1, Y LING1, S KRISHNAN2, D FERENS2, B KEMP-HARPER2, C SOBEY1, G DRUMMOND1, B HUUSKES1, A VINH1
1Department of Physiology, Anatomy and Microbiology, La Trobe University, Bundoora, Australia, 2Department of Pharmacology, Monash University, Clayton, Australia

Aim: To test the hypothesis that Interleukin-18 (IL-18) signalling contributes to the development of experimental hypertension and renal inflammation.
Background: Clinical studies have shown that levels of IL-18 are elevated in hypertensive patients. However, whether IL-18 plays a causal role in hypertension is unknown.
Methods: Hypertension was induced in male wild-type (WT) and IL-18-/- mice by uninephrectomy and treatment with deoxycorticosterone acetate (2.4 mg/d, s.c.) and saline (0.9%) drinking water (1K/DOCA/salt). Blood pressure (BP) was measured via tail cuff and radiotelemetry, and after 21 days kidneys were harvested for histopathological, mRNA and flow cytometric analyses.
Results: 1K/DOCA/salt-treated mice had higher BPs (140±3mmHg vs 118±2mmHg; n≥17; P≤0.0001) and renal weights (390±8mg vs. 291±7mg; n≥17; P<0.05) than 1K/placebo mice, and more than double the number of CD45+ leukocytes in their kidneys. 1K/DOCA/salt-treated mice also displayed >2-fold increases in renal mRNA expression of pro-IL-18 and its receptor, IL-18R (n≥6; P<0.01), with the latter due partly to an increased number of IL-18R-expressing T cells within the kidneys (22039±3246 vs 2958±1100; n≥7; P< 0.001). Phenotypic profiling of IL-18R+ T cells revealed that they were an important source of IL-17 in the kidneys of 1K/DOCA/salt mice (P<0.05 vs IL-18R-T cells). T cell-dependent production of IL-17 was abolished in IL-18-/- mice (n=3-8; P<0.05) and this was associated with protection from the development of renal fibrosis and a blunted hypertensive response to 1K/DOCA/salt (122±3 vs 143±4mmHg in WT mice; n≥9; P≤0.001).
Conclusions: Experimental hypertension is associated with upregulation of IL-18 signalling in the kidney. IL-18 deficiency protected against renal T cell activation and fibrosis and the development of high BP, highlighting the IL-18 system as a potential target for future anti-hypertensive therapies.


Biography:
Jordyn Thomas is a PhD student in the Vascular Biology and Immunopharmacology Group at La Trobe University. Her project aims to elucidate how inflammasome activation and subsequent production of IL-18 contributes to hypertension and chronic kidney disease. Although only 12 months into her candidature, Jordyn has already presented at a national conference, and she recently delivered an oral presentation at Experimental Biology 2018 (San Diego, USA). Jordyn has also written a comprehensive review on “The diagnostic and therapeutic potential of the IL-18 signalling pathway in chronic kidney disease” which is under consideration at the British Journal of Pharmacology.

BLOCKADE OF RIPK3 ATTENUATES FOLIC ACIDINDUCED KIDENY FIBROSIS OF C57BL/6 MOUSE

Y SHI1, Y ZHAO2, CL HUANG1, X CHEN1, C POLLOCK1

1Kolling Institute, University of Sydney, Royal North Shore Hospital, Sydney, New South Wales; 2The Second Hospital, Dalian Medical University, China

Aim: To define the role of RIPK3 blocking in alleviating renal fibrogenesis.

Background: Current therapies for renal fibrosis are largely ineffective. Therefore, identification of novel therapeutic targets is essential. RIPK3 is identified as a crucial regulator of necrosis, apoptosis and inflammation, which have been well recognized to be involved in renal fibrogenesis. To date, the role of RIPK3 in renal fibrosis has not been reported.

Methods: C57BL/6 wild-type and RIPK3 gene knock out (RIPK3-/-) mice and two interventional strategies were used in the study. 1. Folic acid was administrated i.p. to induce kidney injury in both WT and RIPK3-/- mice for 28 days; 2. C57BL/6 WT mice injected with folic acid were treated with Dabrafenib (RIPK3 inhibitor) or vehicle respectively for 28 days. Kidneys were harvested from above experiments and kidney function was assessed by measuring 24 hour of urinary albumin excretion and urinary albumin creatinine ratio (UACR) by ELISAs. Kidney histological change and collagen deposition was assessed by PAS, Masson’s trichrome and picrosirius red staining. MCP-1, TGF-β and a-SMA RNA expression level were detected by quantitative RTPCR analysis.

Results: RIPK3 blockade reversed folic acid increased 24 hour urinary albumin excretion and decreased UACR compared to WT or vehicle control groups treated with folic acid. Histological analysis has shown that folic acid
resulted in increased collagen accumulation and ECM deposition, whereas, RIPK3 inhibition attenuated ECM deposition and renal fibrosis. In addition, quantitative RT-PCR demonstrated Dabrafenib treated mice and RIPK3-/-
mice inhibited RNA expression of MCP-1 TGF-β and a-SMA. Conclusions: These results suggest that RIPK3 blockade may be a potential novel target in renal fibrosis.

IDENTIFYING IMPORTANT OUTCOMES FOR CHILDREN WITH CHRONIC KIDNEY DISEASE AND THEIR CAREGIVERS: FOCUS GROUPS WITH NOMINAL GROUP TECHNIQUE

CS HANSON1,2, G RAMAN2, Y ZHANG2, AF RALPH1,2, AJU1,2, LJ JAMES1,2,  AK VIECELLI3, S MCTAGGART4, A WALKER5, J DIONNE6, T BLYDTHANSEN6, H CURRIER7, M MICHAEL7, S WENDERFER7, M ZAPPITELLI9, A DART10, S FURTH11, AA EDDY6, S SAMUEL, J GROOTHOFF12, NJA WEBB13, Y HUI-KIM14, D BOCKENHAUER15, A SINHA16, SI ALEXANDER2, SL GOLDSTEIN17, DS GIPSON18, JC CRAIG1,2, A TONG1,2, FOR THE SONG-KIDS INITIATIVE

1Sydney School of Public Health, University of Sydney, Sydney, New South Wales; 2Centre for Kidney Research, The Children’s Hospital at Westmead, Sydney, New South Wales; 3Deparment of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland; 4Queensland Child and Adolescent Renal Service, Queensland; 5Department of Nephrology, Royal Children’s Hospital Melbourne, Parkville, Victoria; 6Department of Pediatrics, BC Children’s Hospital and University of British Columbia, Vancouver; 7Renal Section, Department of Pediatrics, Texas Children’s Hospital/Baylor College of Medicine, Houston, Texas; 8Department of Pediatrics, Section of
Nephrology, University of Calgary, Calgary, Canada; 9Division of Pediatric Nephrology, Department of Pediatrics, Montreal Children’s Hospital, McGill University Health Centre, McGill University, Montreal; 10Department of Pediatrics and Child Health, The Children’s Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg; 11Departments of Pediatrics and Epidemiology, Perelman School of Medicine and Division of Nephrology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; 12Department of Pediatric Nephrology, Academic Medical Center (AMC), Emma Children’s Hospital, Amsterdam, The Netherlands; 13Department of Pediatric Nephrology and NIHR/Wellcome Trust Clinical Research Facility, University of Manchester, Manchester Academic Health Science Centre, Royal Manchester Children’s Hospital, Manchester, UK; 14Department of Pediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; 15UCL Centre for Nephrology and Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK; 16Division of
Nephrology, Department of Pediatrics, All India Institute of Medical Sciences, India; 17Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA; 18University of Michigan, Ann Arbor, USA Department of Pediatrics, School of Medicine

Aim: To identify outcomes that are important to children with chronic kidney disease (CKD) and their caregivers, and ultimately to inform clinical care and a patient-focussed research agenda.

Background: CKD has a devastating impact on the lives of children and their families, due to delayed development, debilitating symptoms and lifethreatening complications. Trials frequently report surrogate outcomes, rather than clinical and patient-centred outcomes, and children and caregivers are rarely involved in determining what outcomes should be reported.

Methods: Children and adolescents with CKD (Stage 1-5, dialysis, transplant) and caregivers were purposively sampled from 4 centres across Australia, the United States and Canada. Participants identified and ranked outcomes, and discussed the reasons for their priorities. The mean rank score was determined, and qualitative data were analysed thematically.

Results: Twenty-five patients (aged 10 – 21 years, mean 14 years) and 35 caregivers participated in 10 groups, and identified 41 outcomes. The five highest ranked outcomes for patients were: kidney function (mean rank score 7.6/10), physical activity (7.1), survival (6.9), growth (6.9) and fatigue (6.9). Caregiver’s five highest ranked outcomes were: kidney function (8.8), weight gain (8.2), impact on family (7.5), cardiovascular disease (7.0) and anxiety (6.7). The themes underpinning their choices were a desire to thrive and survive; managing ‘normal’ daily living; preserving health; seeking control and certainty of future.

Conclusions: Children prioritized their kidney health and survival, physical function, appearance, and social, sport, and school participation. Caregivers were concerned about cardiovascular disease, the child’s kidney function, family life, and the child’s anxiety. Trials that include outcomes important to children with CKD and their caregivers can better inform shared decision making.

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About ANZSN

The ASM is hosted by Australian and New Zealand Society of Nephrology.

The aims of the Society are to promote and support the study of the kidney and urinary tract in health and disease, and to ensure the highest professional standards for the practice of nephrology in Australia and New Zealand.

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