REDUCING PATHOLOGY COST IN DIALYSIS

C WILKINSON1, M MANTHA1, S DHEDA1
1Cairns Base Hospital (Queensland Health), Cairns, Australia

Aim: To explore the cost saving and clinical impact of abbreviated testing schedule.
Background: Dialysis patients undergo routine monthly blood tests. Most units have a monthly schedule of testing. We amended our unit’s schedule by making simple changes. Routine 20 analyte chemistry (chem20) was replaced by chem5 but quarterly chem20 was retained. Quarterly B12/folate and PTH were reduced to biannually. Viral serologies and urea was reduced to annually. Quarterly CRP was removed from routine testing. We hypothesised these changes would not have significant clinical impact.
Methods: Cost of routine pathology testing was provided by Pathology Queensland. We then calculated the cost per patient/year and the cost difference for both our old and new schedule. The hospital database was used to quantify all hospital admissions 12 months before and after the schedule change. We defined a significant hospital stay as > 1day. Paired T testing was used to compare the difference.
Results: The cost of the original pathology test regime was $555.58 per patient per year. The cost of the new pathology testing regime was $306.31 per patient per year. There were 287 prevalent dialysis patients. This represented a total cost reduction of $71540.49 over 12 months.
There was no significant difference in mean hospital admissions for each patient, before and after the testing schedule change (1.54 in 2016 vs 1.31 in 2017; t = 1.8612, p = 0.06).
Conclusion: Rationalising the pathology testing schedule in dialysis can result in significant cost savings for the health service. These data suggest that outcomes can be monitored less frequently, and biochemistry can be removed from routine monitoring without adversely altering admission rates.


Biography:
Dr Catherine Wilkinson is a advanced trainee in nephrology, currently based at Cairns Hospital.

THE INTERPLAY BETWEEN SECONDARY CALCIPROTEIN PARTICLES AND OSTEOBLASTIC DIFFERENTIATION

M CAI1,2, E SMITH1,2,N TOUSSAINT1,2,  T HEWITSON1,2, S HOLT1,2
1Department of Nephrology, Royal Melbourne Hospital, Parkville, Australia, 2Department of Medicine (RMH), University of Melbourne, Parkville, Australia

Aim: To determine the effects of phosphate and CPP2 on markers of osteoblast differentiation and viability, and to assess the effect of osteoblast differentiation on CPP2 metabolism.
Background: Adynamic bone disease (ABD) occurs in chronic kidney disease (CKD) and is often associated vascular calcification (VC). Phosphate feeding causes ABD in CKD animal models, but mechanisms of action are unclear. Secondary calciprotein particles (CPP2) are calcium phosphate colloidal nanoparticles which circulate in extracellular fluid. Given phosphate promotes CPP2 formation, high phosphate may potentially cause ABD via CPP2. Conversely, ABD may also cause VC via CPP2.
Methods: MC3T3-E1 cells were treated with control (ConM) media, high phosphate media (PiM), CPP2 containing media (CPP2M) or high phosphate and CPP2 containing media (Pi+CPP2M). Osteocalcin expression, alkaline phosphatase (ALP) expression and activity were analysed as markers of osteoblastic differentiation. Cell viability and apoptosis was assessed. To determine the effect of osteoblastic differentiation on CPP2 metabolism, CPP2 uptake and conditioned media CPP quantity and quality was assessed in differentiated and non-differentiated MC3T-E1 cells treated with Osteosense labelled CPP2.
Results: Pi+CPP2M increased osteocalcin expression, but decreased ALP expression and activity. Pi+CPP2M also reduced osteoblast viability and increased apoptosis. MC3T3-E1 cells took up CPP2. This was further enhanced by osteoblastic differentiation. Osteoblastic differentiation affected conditioned media CPP2 characteristics. CPP2 size was significantly increased in non-differentiated cells treated with high phosphate media.
Conclusion: The combination of high phosphate and CPP2 affected clinically relevant markers of ABD in vitro. Reduced osteoblastic differentiation and high phosphate increased CPP2 size, an important contributor to VC. These results suggest that CPP2 plays an important role in the interplay between high phosphate, ABD and VC.


Biography:
Dr Michael Cai is a nephrologist with Royal Melbourne Hospital. His main research interest is in CKD-MBD, especially on the role of calciprotein particles in mediating the CKD-MBD phenotypes.

A 2-YEAR STUDY EVALUATING THE EFFICACY OF DENOSUMAB FOR THE TREATMENT OF MALE HEMODIALYSIS PATIENTS WITH LOW BONE MINERAL DENSITY

H TAKAMI1, K WASHIO2, T SHIMIZU2, H GOTO3
1Saitama Honoka Clinic, Futtono Minuma Saitama, Japan, 2Saiyuu Kawaguchi Clinic, Totsukahigashi Kawaguchi, Japan, 3Saiyuu Souka Hospital, Matsubara Souka, Japan

Aim: Although denosumab increased bone mineral density (BMD) in men without renal failure, effects in hemodialysis male patients are not well known. The efficacy of denosumab for male hemodialysis patients was evaluated.
Background: Bone fractures are relatively common among hemodialysis patients and pose a significant health burden. Some studies suggested that bone mineral density was lower in patients with chronic kidney disease who had fractures.
Methods: This was an observational retrospective case-control study.
Thirty two male hemodialysis patients with low BMD (<70% of the young adult mean) were enrolled. Sixteen patients were treated with denosumab 60 mg every six months (denosumab group) (mean age 71.3 years), and another sixteen patients (control group) (mean age 67.2 years) were not treated with denosumab. BMD at the distal third of the radius was measured by X-ray absorptiometry.
Results: BMD was 57.5 ± 6.6 % of young adult mean in the denosumab group, 52.9 ± 9.5 % of young adult mean in the control group at baseline. The administration of the drug was clinically well tolerated. Episodes of hypocalcemia associated with PTH increase were seen, but easily overcome by increase carbonate calcium, calcitriol or alfacalcidol.
At one year, BMD increased 3.0 ± 3.8 % in denosumab group, decreased 4.4 ± 6.5 % in control group (P<0.001). At two year, BMD increased 2.7 ± 4.9 % in the denosumab group, decreased 6.6 ± 7.2 % in the control group (P<0.001).
Conclusion: In this observational study, denosumab therapy represents an effective treatment for male hemodialysis patients with low BMD.


Biography:
1985 Tokyo Medical and Dental University M.D.
1990 Tokyo Medical and Dental University Ph. D
1992 to 1995 National Institutes of Health, Maryland USA
1996 to 1998 Tokyo metropolitan Fucyu Hospital
1998 to 2000 Saiyuu Clinic, Saitama
2000 to 2017 Saiyuu Kawaguchi Clinic, Saitama
2017 Saitama Honoka Clinic, Saitama

EFFECTIVE SOLUTE CLEARANCE KINETICS ACROSS SEQUENTIAL HIGH-FLUX HAEMODIALYSIS (HD) TREATMENTS BY TIME-SERIES ANALYSIS OF FREQUENTLY SAMPLED EFFLUENT DIALYSATE ALIQUOTS

R SLACK1, O YOUDELL1 R WALKER1,2, S WILSON1,2,3

1ALFRED HEALTH, Melbourne, Victoria; 2Monash University, Melbourne, Victoria 3 BAKER IDI, Melbourne, Victoria

Aim: To quantify and describe the effective clearance kinetics of solutes across both a single treatment and one-week of high-flux (HF) HD.

Background: Contemporary understanding of HD solute clearances is drawn from low-flux hollow-fibre dialyser data. HF HD clears solute by both diffusive and convective means, abrogated to some extent by back-filtration. In the era where HF HD is convention, differential clearance dynamics of common solutes is uncharacterised –particularly the degree of variation across 1-week of HD.

Methods: Prospective observational study (n=9) sampling aliquots of post-dialyser effluent at 30-minute intervals across three sequential HD (2.2m2 HF membranes, Qd 500ml/min, mean HD time 4.5hours). Samples were analysed using Abbot Archicentre ci16200 after validation against fluid of known composition. Time-series modelling of solute clearance was undertaken on aggregate and at an intra-individual level.

Results: Cumulative proportion of total dialytic clearance per-hour was similar across each solute with mean (+SEM) of 37 + 2%, 63 + 2.5%, 84+1% across the first three treatment hours respectively. Removal closely followed an exponential decay regression model with median post-log transformation Pearson-coefficients below -0.75 for all solutes (p<0.01). Total estimated clearance strongly correlated with serum level preHD (median Pearson-R 0.73 (p<0.01)) and more modestly with ultrafiltration rates for creatinine, urea and phosphate (median Pearson-R 0.52 (p<0.01)). Effective equilibration fraction from serum into first dialysate sample differed across solutes but did not exceed 45% and did not correlate to ultrafiltration or blood-flow rate. Absolute levels of clearance across the first and third HD of the week were significantly different for urea and phosphate only (p<0.01).

Conclusions: We provide the first detailed time-series analysis of in-vivo HF HD solute clearance dynamics using timed effluent aliquot sampling.

DETERIORATION OF CORTICAL BONE MICROARCHITECTURE IN RENAL OSTEODYSTROPHY – UNDER-REPRESENTED IN THE ‘TURNOVER MINERALISATION VOLUME’ (TMV) CLASSIFICATION?

AK SHARMA1,2, ND TOUSSAINT1,2, GJ ELDER3,4, SG HOLT1,2, P ROBERTSON1,2, PR EBELING5, P BALDOCK4, CS RAJAPAKSE6, R MASTERSON1,2   

1The Royal Melbourne Hospital, Parkville, Australia; 2Department of Medicine (RMH), University of Melbourne, Parkville, Australia; 3Westmead Hospital, Westmead, Australia; 4Garvan Institute of Medical Research, Australia; 5Monash University, Clayton, Australia; 6University of Pennsylvania, PA, USA

Aim: To assess trabecular and cortical bone microarchitecture in patients with chronic kidney disease (CKD) by classical histomorphometry and microcomputed tomography (mCT) of iliac crest biopsies.

Background: Cortical bone contributes significantly to mechanical strength of bone and its deterioration is associated with non-vertebral fractures. Recent imaging and histomorphometric studies demonstrate prevalence of thin cortices and increased cortical porosity in CKD which may have diagnostic and therapeutic implications. Changes in bone microarchitecture as measured by TMV classification do not completely reflect deterioration in cortical parameters.

Methods: Iliac crest bone biopsies were performed in 14 patients undergoing kidney transplantation (n=12) and parathyroidectomy (n=2). Trabecular structural parameters were analyzed by histomorphometry and 3D mCT and included trabecular bone volume, thickness, number and separation. Cortical thickness (CtTh) and porosity (CtPo) were measured by 3D mCT. Bone mineral density (BMD) was measured by peripheral quantitative CT (radius) and dual energy x-ray absorptiometry. Associations were determined by analysis with Spearman’s rank correlation coefficients.

Results: Trabecular parameters from bone biopsy were within normally accepted ranges in most patients. In contrast, all patients showed decreased CtTh and significantly increased CtPo at the iliac crest. CtPo was unrelated to turnover status but demonstrated positive relationship with PTH levels (r=0.62; p=0.021) and was inversely related to trabecular thickness (r=-0.60; p=0.024) at the iliac crest and cortical area (r=-0.59; p=0.045) at the radius. CtTh was also associated with lumbar spine (r=-0.72; p=0.013) and femoral neck BMD (r=-0.55; p=0.07)

Conclusions: Marked deterioration of cortical microarchitecture in the setting of relatively normal trabecular parameters in our cohort reinforces the importance of comprehensive cortical bone evaluation in CKD.

CHANGES IN BONE AND MINERAL METABOLISM MARKERS AFTER CESSATION OF CINACALCET IN DIALYSIS PATIENTS WITH SECONDARY HYPERPARATHYROIDISM

I RUDERMAN1,2, S HOLT1,2, T HEWITSON1,2, E SMITH1,2, R KRISHNASAMY5,N GRAY5, C HAWLEY4, V OLIVER4, G TALAULIKAR6 , G KIRKLAND3, S MASLEN3, N TOUSSAINT1,2

1Department of Nephrology, The Royal Melbourne Hospital, Melbourne, Victoria; 2Department of Medicine (RMH), The University of Melbourne, Melbourne, Victoria; 3Department of Nephrology, Royal Hobart Hospital, Hobart, Tasmania; 4Department of Nephrology, Princess Alexandra Hospital, Brisbane, Queensland; 5Department of Nephrology, Sunshine Coast Hospital and Health Service, Sunshine Coast, Queensland; 6Department of Nephrology, Canberra Hospital, Canberra, Australian Capital Territory

Aim: Removal of PBS funding for the calcimimetic agent cinacalcet in Australia has provided a unique opportunity to assess changes to biochemical and clinical outcomes in dialysis patients following the cessation of this medication.

Background: Secondary hyperparathyroidism (SHPT) is a common complication of chronic kidney disease and is associated with significant abnormalities in bone metabolism and associated cardiovascular disease. Management of SHPT is challenging and involves correction of mineral abnormalities or more direct interventions with either cinacalcet or parathyroidectomy.

Methods: Retrospective data was collected from dialysis patients whom had ceased cinacalcet therapy after August 2015 from five different institutions in Australia. Clinical outcomes and changes in biochemical parameters were assessed over a 12-month period of follow up from cessation of cinacalcet.

Results: 168 patients were included, mean age 64.5±15 years. 157 patients were on haemodialysis and 11 on peritoneal dialysis. Biochemical changes from baseline to 12 months after cessation included increased serum parathyroid hormone (PTH) from 51 (IQR 24.5-92.8) pmol/L to 74 (IQR 31.7-138.5) pmol/L (p<0.0005) and increased serum calcium from 2.33±0.22mmol/L to 2.41±0.17mmol/L (p<0.0005). Over the 12-month period following cessation of cinacalcet, there were 17 parathyroidectomies, one episode of calciphylaxis and 33 deaths. Seven patients recommenced cinacalcet, meeting criteria under a special access scheme.

Conclusion: Significant increases in serum PTH and calcium occurred over a 12-month period following withdrawal of cinacalcet. Longer term follow-up will allow us to identify if these biochemical changes are associated with increased rates of parathyroidectomies and cardiovascular mortality and morbidity.

A NOVEL AND UNIQUE PROTEIN I-BODY AD-114 INHIBITED TGFβ1-INDUCED EXPRESSION OF FIBRONECTIN AND COLLAGEN 4 IN RENAL PROXIMAL TUBULAR CELLS

Q CAO1, C HUANG1, H YI1, S STANGENBERG1, M FOLEY2,3, X-M CHEN1, CA POLLOCK1

1Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia; 2AdAlta Pty. Ltd., 15/2 Park Dr., Bundoora, Victoria, Australia; 3Department of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, Victoria, Australia

Aim: To define the role of i-body AD-114 in renal fibrosis.

Background: Fibrosis is the final common pathway of various types of chronic kidney disease (CKD). CXCR4 has been demonstrated to be a central player in the development of tissue fibrosis. i-body AD-114, which binds CXCR4 with high specificity and affinity, has shown anti-fibrotic effects in lung, liver and eye fibrosis. However, the role of AD-114 in renal fibrosis has not been studied.

Methods: To detect CXCR4 expression in the kidney, biopsies from patients with diabetic nephropathy (DN) and kidneys from three mouse models of CKD were collected and CXCR4 expression was detected using immunohistochemistry.  To determine the role of TGFβ1 in AD-114 binding with CXCR4 in human renal proximal tubular cells (PTCs), PTCs were incubated with/without TGFβ1 (2ng/ml) for 48 hours, and AD-114 binding with PTC was detected using immunocytochemistry.  To examine whether AD-114 blocks TGFβ1-induced fibrotic responses in PTCs, PTCs were incubated with TGFβ1 (2ng/ml) in the absence or presence of AD-114 (1mM or 3mM) for 48 hours. The supernatant and cell lysis protein were collected and fibronectin (FN) and collagen 4 (Col 4) were measured by Western-blotting.

Results: CXCR4 expression was significantly upregulated in patients with DN and fibrotic kidneys of three mouse models of CKD compared to control groups (P<0.001, n=6). TGFβ1 significantly increased AD-114 binding to renal PTCs compared to negative control i-body and normal controls (P<0.001, n=4). AD-114 (3µM) suppressed TGFβ1-induced overexpression of FN and Col 4 compared to a lower concentration of AD-114 (1µM) and negative control i-body (P<0.001, n=4).

Conclusions: Blocking CXCR4 using the i-body AD-114 is a promising therapeutic strategy to prevent the development of CKD.

A RARE CASE OF GENE CYP11B1 DEFICIENCY CAUSING HYPERALDOSTERONISM

M KAYES1, S TARAFDAR1, 2

1Department of Renal Medicine, Blacktown Hospital, Sydney, New South Wales; 2Western Sydney University, Sydney, New South Wales

Background: Defect in the gene CYP11B1 and the subsequent deficiency in the enzyme 11-beta-hydroxylase 1(11β-OH1) is a rare cause of congenital adrenal hyperplasia (CAH). 11β-OH1 plays a major role in cortisol synthesis by converting 11-deoxycortisol to cortisol. It also has a supportive role for 11β-OH2 in aldosterone synthesis by converting 11-deoxycorticosterone to corticosterone.

Clinical features of 11β-OH1 deficiency include ambiguous genitalia, accelerated skeletal maturation, short stature, precocious puberty due to androgen excess and hypokalaemic hypertension from excess 11-deoxycorticosterone.

Case Report: A 27 year old male presented with hypertensive urgency, hypokalaemia and metabolic alkalosis on a background of hypertension from age 21. Known to be noncompliant with treatment, investigations revealed a plasma aldosterone level of 547pmol/L with plasma renin concentration of <2.2mIU/L indicating an aldosterone to renin ratio of more than 200 (normal <30).  CT imaging of the adrenal glands were unremarkable. Given his young age and strong family history of early onset hypertension, patient had genetic testing revealing a large deletion in CYP11B1. There was no evidence of hyperandrogenism.

Conclusions: 11β-OH1 associated CAH is characterised by hyperandrogenism with accumulation of 11-deoxycortisol and 11-deoxycorticosterone. 11-deoxycorticosterone (which has intrinsic mineralocorticoid activity) causes hypokalaemic hypertension and supressed aldosterone production. However, our patient had a significantly elevated aldosterone to renin ratio suggesting that blockage of the cortisol pathway caused activation of the mineralocorticoid pathway instead of the androgen pathway.

This is the first documented case of a deletion in gene CYP11B1 presenting with both hypertension and hyperaldosteronism instead of hypertension, hyperandrogenism and hypoaldosteronism. This case suggests that depending on which pathway is predominantly activated (aldosterone or androgens), deletion of CYP11B1 can lead to either CAH or a novel hyperaldosteronism.

LIPID-LOWERING THERAPY AMONG CKD PATIENTS IN AUSTRALIAN GENERAL PRACTICE

MA KHANAM1, J RADFORD2, R CASTELINO2, MD JOSE2, A KITSOS2, J STANKOVICH2, ST ZAIDI2, L KINSMAN1, GM PETERSON2,3

1School of Health Sciences, University of Tasmania; 2School of Medicine, University of Tasmania; 3Faculty of Health, University of Tasmania, Sandy Bay, Tasmania

Aim: To examine the prescription patterns of lipid-lowering treatment among chronic kidney disease (CKD) patients within Australian general practice.

Background: A significant proportion of patients with early stages of CKD die of cardiovascular disease (CVD) before they develop end-stage kidney disease. Furthermore, abnormal lipid levels contribute to the progression of CKD. Lipid-lowering therapy reduces both kidney disease progression and the incidence of CVD in people with CKD.

Methods: MedicineInsight data 01/01/2013 to 01/06/2016 was used for this analysis. MedicineInsight is a primary care quality improvement initiative of NPS MedicineWise, that collects de-identified patient information, including prescriptions, from 557 participating general practices, providing a database of over 3.5 million Australians. We analysed the use of lipid-lowering therapy (at least one prescription during the study period) among CKD patients, with or without co-morbid conditions.

Results: 61,102 adult patients met the definition of CKD (two or more eGFR results <60ml/min/1.73m2, at least 90 days apart). The proportion of CKD patients (without co-morbidities) who had been prescribed lipid-lowering therapy was 42.7% (M41.2%, W43.7%), while prevalence of use was 69.7% among the CKD+CVD patient group (M75.3%, W64.7%), 72.2% among the CKD+Diabetes group (M70.4%, W73.6%), and 83.0% among the CKD+CVD+Diabetes group (M84.6%, W81.0%). With co-morbidities of CKD and CVD, women were 37.8% less likely to be prescribed lipid-lowering therapy compared to men (p <0.001). The use of lipid-lowering medication steadily increased with age in both genders until 80 years, then declined.

Conclusions: The rate of prescribing lipid-lowering medication in general practice-based CKD patients appears to be relatively high. However, there may be room for improvement, especially in patients without high-risk comorbidities, and females with co-existing CVD.

BLOOD PRESSURE AND RESPIRATORY SYMPATHETIC MODULATION IN AN ANIMAL MODEL OF CHRONIC KIDNEY DISEASE AFTER BILATERAL CAROTID SINUS DENERVATION

M SAHA1 2 3, QJ SUN1, CM HILDRETH1, JK PHILLIPS1

1Department of Biomedical Sciences, Macquarie University, Sydney NSW; 2Department of Nephrology, National Institute of Kidney Disease and Urology, Bangladesh; 3Department of General Medicine, Shoalhaven District Memorial Hospital, NSW

Aim:  To identify if inhibition of peripheral chemoreceptors influence respiratory sympathetic modulation and blood pressure in an animal model of chronic kidney disease (CKD).

Background: Peripheral chemoreceptor hypersensitivity is believed to contribute to sympathetic overactivity in hypertension associated with various diseases including CKD. One mechanism by which this may occur is through enhanced respiratory sympathetic modulation, whereby respiratory activity amplifies nerve activity (SNA). Inhibition of peripheral chemoreceptor input could reduce this respiratory sympathetic modulation and therefore blood pressure in CKD.

Methods: Experiments were performed in anaesthetised, vagotomised, paralysed and ventilated hypertensive Lewis Polycystic Kidney (LPK) and normotensive control Lewis rats (n = 6-8/strain). Blood pressure, phrenic nerve activity (PNA) and splanchnic SNA (sSNA) were measured in animals that had undergone bilateral CSN surgical denervation to inhibit peripheral chemoreceptor input to the brain. For technical reasons, only blood pressure of these animals could be measured before CSN denervation.

Results: LPK rats were hypertensive before CSN denervation (LPK: 136±5 vs Lewis: 90±5mmHg; p<0.0001). Following CSN denervation, when compared to Lewis control rats, LPK rats showed higher sSNA (LPK: 5.9±0.6 vs Lewis: 3.4±0.3 µv; p<0.01) and larger respiratory related SNA (area under the curve in PNA triggered average of SNA: LPK: 5.09±1.4 vs Lewis: 2.5±0.4 µvxs; P<0.05). Blood pressure was normalised by CSN denervation in the LPK (LPK: 108±4 vs Lewis: 94±8 mmHg; p=0.24).

Conclusions: Our findings suggest that while removal of peripheral chemoreceptor input can normalize blood pressure in the LPK model of CKD, it does not mediate this effect through a normalisation of respiratory sympathetic modulation. Inhibition of peripheral chemoreceptors may be a therapeutic target for CKD however the mechanism remains to be determined.

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