Avoiding misclassification of acute kidney injury: Timing is everything.

Accurate detection of acute kidney injury (AKI) in clinical trials is important. Using a 'baseline' creatinine from trial enrolment may not be ideal for understanding a participant's true baseline kidney function. We aimed to determine if a 'pre-trial baseline creatinine' resulted in comparable creatinine concentrations to a 'trial baseline creatinine', and how the timing of baseline creatinine affected the incidence of AKI in the Combination Antibiotic therapy for MEthicillin Resistant Staphylococcus aureus (CAMERA2) randomised trial. Study sites retrospectively collected a pre-trial baseline creatinine from up to 1 year before CAMERA2 trial enrolment ideally when the patient was medically stable. Baseline creatinine from CAMERA2 (the 'trial baseline creatinine'), was the highest creatinine measurement in the 24 h preceding trial randomisation. We used Wilcoxon sign rank test to compare pre-trial and trial baseline creatinine concentrations. We included 217 patients. The median pre-trial baseline creatinine was significantly lower than the median trial baseline creatinine (82 µmol/L [IQR 65-104 µmol/L] versus 86 µmol/L [IQR 66-152 µmol/L] p = <0.001). Using pre-trial baseline creatinine, 48 of 217 patients (22%) met criteria for an AKI at CAMERA2 enrolment and only 5 of these patients met criteria for an AKI using the CAMERA2 study protocol (using baseline creatinine from trial entry). Using a baseline creatinine from the time of trial enrolment failed to detect many patients with AKI. Trial protocols should consider the optimal timing of baseline creatinine and the limitations of using a baseline creatinine during an acute illness.

Improving the accuracy of discharge medication documentation in people with kidney disease through pharmacist-led partnered prescribing.

BACKGROUND: Inaccurate medication documentation in prescriptions and discharge summaries produce poorer patient outcomes, are costly to healthcare systems and result in more readmissions to hospital. Errors in medication documentation are common in Australian hospitals. AIM: To determine whether pharmacist-led partnered prescribing (PPP) on discharge reduced errors and improved accuracy in documentation of medications in the discharge prescription and the discharge summary of people with kidney disease compared with medical prescribing (MP). METHODS: This interventional two-phase study compared current workflow (MP) with the subsequent implementation of the interventional workflow (PPP) in the renal unit of a tertiary referral hospital. Patients were included if they were discharged within pharmacy working hours and had a discharge prescription and discharge summary. The primary outcome was the percentage of discharge prescriptions with at least one error. The secondary outcome was the percentage of discharge summaries with at least one error. RESULTS: Data were collected from 185 discharged patients (95 in MP phase then 90 in PPP phase). Discharge prescriptions with at least one error reduced from 75.8% in the MP phase to 6.7% in PPP phase (P < 0.001). Discharge summaries with at least one error reduced from 53% in MP phase to 24% in the PPP phase (P < 0.001). CONCLUSION: PPP improves the accuracy of the documentation of medications in both the discharge prescription and the discharge summary of patients with kidney disease.

Impact of haemodialysis hours on outcomes in older patients.

AIM: Previous studies report an association between longer haemodialysis treatment sessions and improved survival. Worldwide, there is a trend to increasing age among prevalent patients receiving haemodialysis. This analysis aimed to determine whether the mortality benefit of longer haemodialysis treatment sessions diminishes with increasing age. METHODS: This was a retrospective cohort study of people who first commenced thrice-weekly haemodialysis aged ≥65 years, reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry from 2005 to 2015, included from 90 days after dialysis start. The primary outcome was all-cause mortality. Cox regression analysis was performed with haemodialysis session duration the exposure of interest. RESULTS: Of 8224 people who commenced haemodialysis as their first treatment for kidney failure aged ≥65 years during this period, 4727 patients died. Longer dialysis hours per session was associated with a decreased risk of death in unadjusted analyses [hazard ratio, HR, for ≥5 h versus 4 to <4.5 h: 0.81 (0.75-0.88, p < .001)]. Patients having longer dialysis sessions were younger but had greater co-morbidity. In an adjusted model including age and other variables, the survival benefit of longer hours was only partially attenuated [HR for previous comparison: 0.75 (0.69-0.82, p < .001)], and no interaction between age and hours was demonstrated (p = .89). CONCLUSION: The apparent survival benefit associated with longer haemodialysis session length appears to be preserved in patients 65 years or older. In practice, the benefit of longer dialysis hours should be carefully weighed against other factors in this patient group.

Temporal changes and risk factors for death from early withdrawal within 12 months of dialysis initiation-a cohort study.

BACKGROUND: Mortality risk is high soon after dialysis initiation in patients with kidney failure, and dialysis withdrawal is a major cause of early mortality, attributed to psychosocial or medical reasons. The temporal trends and risk factors associated with cause-specific early dialysis withdrawal within 12 months of dialysis initiation remain uncertain. METHODS: Using data from the Australia and New Zealand Dialysis and Transplant Registry, we examined the temporal trends and risk factors associated with mortality attributed to early psychosocial and medical withdrawals in incident adult dialysis patients in Australia between 2005 and 2018 using adjusted competing risk analyses. RESULTS: Of 32 274 incident dialysis patients, 3390 (11%) experienced death within 12 months post-dialysis initiation. Of these, 1225 (36%) were attributed to dialysis withdrawal, with 484 (14%) psychosocial withdrawals and 741 (22%) medical withdrawals. These patterns remained unchanged over the past two decades. Factors associated with increased risk of death from early psychosocial and medical withdrawals were older age, dialysis via central venous catheter, late referral and the presence of cerebrovascular disease; obesity and Asian ethnicity were associated with decreased risk. Risk factors associated with early psychosocial withdrawals were underweight and higher socioeconomic status. Presence of peripheral vascular disease, chronic lung disease and cancers were associated with early medical withdrawals. CONCLUSIONS: Death from dialysis withdrawal accounted for >30% of early deaths in kidney failure patients initiated on dialysis and remained unchanged over the past two decades. Several shared risk factors were observed between mortality attributed to early psychosocial and medical withdrawals.

Incremental peritoneal dialysis is a safe and feasible prescription in incident patients with preserved residual kidney function.

BACKGROUND: Incremental peritoneal dialysis (PD) is recommended as a component of high-quality care by the international society for PD; however, its feasibility and clinical outcomes have not been widely reported. The aim of this study is to describe our experience with incremental PD. METHODS: This was a retrospective cohort study of incident PD patients at Eastern Health between 2015 and 2019. Patients who stopped PD within 30 days were excluded. Incremental PD was defined in CAPD as using <8 L/day of exchange volume and in automated PD as dialysing without a last fill. Dialysis modality accorded with patient and physician preferences. RESULTS: The 96 patients were included in this study; 54 with incremental PD. Compared to full-dose PD, incremental PD patients were more likely to be female, had less comorbid diabetes (28% vs. 52%) and higher residual kidney function (RKF) (Kt/V 2.0 ± 0.7 vs. 1.4 ± 0.7). Age, BMI and starting eGFR did not differ between groups. Incremental PD exposed patients to lower exchange volumes (4.4 ± 2.1 vs. 8.5 ± 1.1 L/day), glucose load (46 ± 41 g/day vs. 119 ± 46) and was associated with a longer peritonitis-free survival. PD technique survival, rates of peritonitis or hospitalization were comparable between groups. Predictors for longer incremental PD use included older age and higher starting eGFR. CONCLUSIONS: Incremental PD is a feasible, goal-directed initial prescription in patients with RKF with comparable peritonitis rates and technique survival. Validation of this prescription in prospective studies is warranted.

Dialysis modality utilization patterns and mortality in older persons initiating dialysis in Australia and New Zealand.

AIM: The benefits of dialysis in the older population remain highly debated, particularly for certain dialysis modalities. This study aimed to explore the dialysis modality utilization patterns between in-centre haemodialysis (ICHD), peritoneal dialysis (PD) and home haemodialysis (HHD) and their association with outcomes in older persons. METHODS: Older persons (≥75 years) initiating dialysis in Australia and New Zealand from 1999 to 2018 reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) registry were included. The main aim of the study was to characterize dialysis modality utilization patterns and describe individual characteristics of each pattern. Relationships between identified patterns and survival, causes of death and withdrawal were examined as secondary analyses, where the pattern was considered as the exposure. RESULTS: A total of 10 306 older persons initiated dialysis over the study period. Of these, 6776 (66%) and 1535 (15%) were exclusively treated by ICHD and PD, respectively, while 136 (1%) ever received HHD during their dialysis treatment course. The remainder received both ICHD and PD: 906 (9%) started dialysis on ICHD and 953 (9%) on PD. Different individual characteristics were seen across dialysis modality utilization patterns. Median survival time was 3.0 (95%CI 2.9-3.1) years. Differences in survival were seen across groups and varied depending on the time period following dialysis initiation. Dialysis withdrawal was an important cause of death and varied according to individual characteristics and utilization patterns. CONCLUSION: This study showed that dialysis modality utilization patterns in older persons are associated with mortality, independent of individual characteristics.

Analysis of Serum Advanced Glycation Endproducts Reveals Methylglyoxal-Derived Advanced Glycation MG-H1 Free Adduct Is a Risk Marker in Non-Diabetic and Diabetic Chronic Kidney Disease.

Accumulation of advanced glycation endproducts (AGEs) is linked to decline in renal function, particularly in patients with diabetes. Major forms of AGEs in serum are protein-bound AGEs and AGE free adducts. In this study, we assessed levels of AGEs in subjects with and without diabetes, with normal renal function and stages 2 to 4 chronic kidney disease (CKD), to identify which AGE has the greatest progressive change with decline in renal function and change in diabetes. We performed a cross-sectional study of patients with stages 2-4 CKD, with and without diabetes, and healthy controls (n = 135). Nine protein-bound and free adduct AGEs were quantified in serum. Most protein-bound AGEs increased moderately through stages 2-4 CKD whereas AGE free adducts increased markedly. Methylglyoxal-derived hydroimidazolone MG-H1 free adduct was the AGE most responsive to CKD status, increasing 8-fold and 30-fold in stage 4 CKD in patients without and with diabetes, respectively. MG-H1 Glomerular filtration flux was increased 5-fold in diabetes, likely reflecting increased methylglyoxal glycation status. We conclude that serum MG-H1 free adduct concentration was strongly related to stage of CKD and increased in diabetes status. Serum MG-H1 free adduct is a candidate AGE risk marker of non-diabetic and diabetic CKD.

Multicenter registry analysis comparing survival on home hemodialysis and kidney transplant recipients in Australia and New Zealand.

BACKGROUND: In the era of organ shortage, home hemodialysis (HHD) has been identified as the possible preferential bridge to kidney transplantation. Data are conflicting regarding the comparability of HHD and transplantation outcomes. This study aimed to compare patient and treatment survival between HHD patients and kidney transplant recipients. METHODS: The Australia and New Zealand Dialysis and Transplant Registry was used to include incident HHD patients on Day 90 after initiation of kidney replacement therapy and first kidney-only transplant recipients in Australia and New Zealand from 1997 to 2017. Survival times were analyzed using the Kaplan-Meier product-limit method comparing HHD patients with subtypes of kidney transplant recipients using the log-rank test. Adjusted analyses were performed with multivariable Cox proportional hazards regression models for time to all-cause mortality. Time-to-treatment failure or death was assessed as a composite secondary outcome. RESULTS: The study compared 1411 HHD patients with 4960 living donor (LD) recipients, 6019 standard criteria donor (SCD) recipients and 2427 expanded criteria donor (ECD) recipients. While LD and SCD recipients had reduced risks of mortality compared with HHD patients [LD adjusted hazard ratio (HR) = 0.57, 95% confidence interval (CI) 0.46-0.71; SCD HR = 0.65 95% CI 0.52-0.79], the risk of mortality was comparable between ECD recipients and HHD patients (HR = 0.90, 95% CI 0.73-1.12). LD, SCD and ECD kidney recipients each experienced superior time-to-treatment failure or death compared with HHD patients. CONCLUSIONS: This large registry study showed that kidney transplant offers a survival benefit compared with HHD but that this advantage is not significant for ECD recipients.

Socio-economic disparity, access to care and patient-relevant outcomes after kidney allograft failure.

Social disparity is a major impediment to optimal health outcomes after kidney transplantation. In this study, we aimed to define the association between socio-economic status (SES) disparities and patient-relevant outcomes after kidney allograft failure. Using data from the Australia and New Zealand Dialysis and Transplant registry, we included patients with failed first-kidney allografts in Australia between 2005 and 2017. The association between residential postcode-derived SES in quintiles (quintile 1-most disadvantaged areas, quintile 5-most advantaged areas) with uptake of home dialysis (peritoneal or home haemodialysis) within the first 12-months post-allograft failure, repeat transplantation and death on dialysis were examined using competing-risk analysis. Of 2175 patients who had experienced first allograft failure, 417(19%) and 505(23%) patients were of SES quintiles 1 and 5, respectively. Compared to patients of quintile 5, quintile 1 patients were less likely to receive repeat transplants (adjusted subdistributional hazard ratio [SHR] 0.70,95%CI 0.55-0.89) and were more likely to die on dialysis (1.37 [1.04-1.81]), but there was no association with the uptake of home dialysis (1.02 [0.77-1.35]). Low SES may have a negative effect on outcomes post-allograft failure and further research is required into how best to mitigate this. However, small-scale variation within SES cannot be accounted for in this study.

Markers of the Endothelial Glycocalyx Are Improved following Kidney Transplantation.

INTRODUCTION: The endothelial glycocalyx on the vascular luminal surface contributes to endothelial health and function. Damage to this layer is indicative of vascular injury, reflected by increased levels of its shed constituents in serum and an increase in the perfused boundary region (PBR) when measured in sublingual capillaries using the GlycoCheck™ device. We aimed to examine the longitudinal effects of kidney transplantation on the glycocalyx by measuring biochemical markers of the glycocalyx and endothelial dysfunction and the PBR. METHODS: We recruited healthy controls and stage 5 CKD patients scheduled to undergo a kidney transplant. Investigations were performed before transplant and then 1 and 3 months after transplantation. At each point, blood was collected for hyaluronan, syndecan-1, vascular cell adhesion molecule (VCAM-1), and von Willebrand factor (vWF), and a PBR measurement was performed. RESULTS: Thirty healthy controls and 17 patients undergoing a kidney transplant were recruited (9 cadaveric and 8 live donation; 12 on dialysis and 5 pre-emptive). Before transplant, transplant recipients had greater evidence of glycocalyx damage than controls. After transplant, PBR improved from median 2.22 (range 1.29-2.73) to 1.98 (1.65-2.25) µm, p = 0.024, and syndecan-1 levels decreased from 98 (40-529) to 36 (20-328) ng/mL, p < 0.001. Similarly, VCAM-1 fell from 1,479 (751-2,428) at baseline to 823 (516-1,674) ng/mL, p < 0.001, and vWF reduced from 3,114 (1,549-5,197) to 2,007 (1,503-3,542) mIU/mL, p = 0.002. Serum levels of hyaluronan remained unchanged. CONCLUSION: The combination of reduced PBR and syndecan-1 following transplant suggests that transplantation may improve glycocalyx stability at 3 months after transplant.

Serum phosphate and mortality in incident dialysis patients in Australia and New Zealand.

AIM: Hyperphosphataemia is associated with increased adverse outcomes, including mortality. Re-examining this association using up-to-date data reflecting current and real-world practices, across different global regions and in both haemodialysis and peritoneal dialysis patients, is important. METHODS: We describe the association between serum phosphate and all-cause and cardiovascular mortality in incident dialysis patients between 2008 and 2018 using the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Time-dependent Cox proportionate hazards models were used. Models were adjusted for available covariates and fitted for the overall cohort, and also each dialysis modality. RESULTS: 31 989 patients were followed over 97 122 person-years at risk (mean age at first dialysis 61 years, 38% female, 67% haemodialysis). We observed a U-shaped association between serum phosphate and all-cause mortality. In the fully adjusted model, categories of serum phosphate above and below 1.25-1.99 mmol/L were associated with progressively higher risk, reaching a hazard ratio of 2.13 (95% CI 1.93-2.36, p < .001) for serum phosphate ≥2.75 mmol/L, and 1.56 (95% CI 1.44-1.69, p < .001) for serum phosphate <1.00 mmol/L. Low and high levels of serum phosphate were also associated with increased risk of cardiovascular mortality, however the association with high serum phosphate was more pronounced ("J-shaped relationship"). The associations were consistent across sub-analyses of patients receiving haemodialysis and peritoneal dialysis treatment. CONCLUSION: In this large contemporary dialysis cohort, both high and low levels of serum phosphate were independently associated with increased risk of mortality. Future studies are required to determine whether treatment of abnormal serum phosphate levels improves mortality.

Dialysis initiation in older persons across centres and over time in Australia and New Zealand.

AIM: With improved life expectancy over time, the burden of kidney failure resulting in kidney replacement therapy (KRT) in older persons is increasing. This study aimed to describe the age distribution at dialysis initiation in Australia and New Zealand (ANZ) across centres and over time. METHODS: Adults initiating dialysis as first KRT in ANZ from 1999 to 2018 reported to the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry were included. The primary outcomes were the age distribution and the proportion of older persons (75 years and older) initiating dialysis across centres and over time. Secondary outcomes were characterization of the older population compared with younger people and differences in dialysis modality and treatment trajectories between groups. RESULTS: Over the study period, 55 382 people initiated dialysis as first KRT, including 10 306 older persons, in 100 centres. Wide variation in age distribution across states/countries was noted, although the proportion of older persons at dialysis initiation did not significantly change over time (from 13% in 1999 to 19% in 2003, then remaining stable thereafter). Older persons were less likely to be treated with home therapies compared with younger people. Older persons were mostly Caucasians; had higher socioeconomic position, more cardiovascular comorbidities and higher eGFR at baseline; and resided in major cities. Higher proportions of older persons per centre were noted in privately funded facilities. CONCLUSION: Wide variations were noted in the proportions of older persons initiating dialysis across centres and states/country, which were associated with different case-mix across regions, particularly in terms of ethnicity, remoteness and socioeconomic advantage.

Endothelial glycocalyx damage in kidney disease correlates with uraemic toxins and endothelial dysfunction.

BACKGROUND: Damage to the endothelial glycocalyx is an early indicator of vascular damage and a potential marker of endothelial dysfunction. This study aimed to assess the relationship between markers of glycocalyx damage, endothelial dysfunction, and uraemic toxins in patients with chronic kidney disease. METHODS: Healthy controls, CKD patients, dialysis patients, and kidney transplant recipients had biochemical markers of glycocalyx damage (syndecan-1 and hyaluronan), endothelial dysfunction (von Willebrand factor; vWF and vascular cell adhesion molecule; VCAM-1), and uraemic toxins (indoxyl sulphate and p-cresyl sulphate) measured. In addition, Sidestream Darkfield imaging was performed using the novel GlycoCheck™ device to measure glycocalyx width by the perfused boundary region (PBR) in the sublingual microcirculation. RESULTS: Serum markers of glycocalyx damage were highest in the dialysis group (n = 33), followed by CKD patients (n = 32) and kidney transplant recipients (n = 30) compared to controls (n = 30): hyaluronan: 137 (16-1414), 79 (11-257), 57 (14-218) and 23 (8-116) ng/mL, respectively, p < 0.0001; syndecan-1: 81 (40-529), 46 (21-134), 39 (23-72), and 30 (12-138) ng/mL, respectively, p < 0.0001. Markers of endothelial dysfunction followed a similar pattern. No difference in the width of the PBR was detected between these groups (2.01 ± 0.35, 2.07 ± 0.27, 2.06 ± 0.28, and 2.05 ± 0.3 µm, respectively, p = 0.89). Glycocalyx damage correlated with markers of endothelial dysfunction (log-hyaluronan and log-VCAM-1: r = 0.64, p < 0.001) and levels of uraemic toxins (log-hyaluronan and log-indoxyl sulphate: r = 0.48, p < 0.001). CONCLUSIONS: Levels of biochemical markers of glycocalyx and endothelial cell damage are highest in patients receiving dialysis. Glycocalyx and endothelial damage markers correlated with each other, and with uraemic toxins. Although we could not demonstrate a change in PBR, the biochemical markers suggest that glycocalyx damage is most marked in patients with higher levels of uraemic toxins.

Effect of patient- and center-level characteristics on uptake of home dialysis in Australia and New Zealand: a multicenter registry analysis.

BACKGROUND: Home-based dialysis therapies, home hemodialysis (HHD) and peritoneal dialysis (PD) are underutilized in many countries and significant variation in the uptake of home dialysis exists across dialysis centers. This study aimed to evaluate the patient- and center-level characteristics associated with uptake of home dialysis. METHODS: The Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry was used to include incident dialysis patients in Australia and New Zealand from 1997 to 2017. Uptake of home dialysis was defined as any HHD or PD treatment reported to ANZDATA within 6 months of dialysis initiation. Characteristics associated with home dialysis uptake were evaluated using mixed effects logistic regression models with patient- and center-level covariates, era as a fixed effect and dialysis center as a random effect. RESULTS: Overall, 54 773 patients were included. Uptake of home-based dialysis was reported in 24 399 (45%) patients but varied between 0 and 87% across the 76 centers. Patient-level factors associated with lower uptake included male sex, ethnicity (particularly indigenous peoples), older age, presence of comorbidities, late referral to a nephrology service, remote residence and obesity. Center-level predictors of lower uptake included small center size, smaller proportion of patients with permanent access at dialysis initiation and lower weekly facility hemodialysis hours. The variation in odds of home dialysis uptake across centers increased by 3% after adjusting for the era and patient-level characteristics but decreased by 24% after adjusting for center-level characteristics. CONCLUSION: Center-specific factors are associated with the variation in uptake of home dialysis across centers in Australia and New Zealand.

Oral protein-based supplements versus placebo or no treatment for people with chronic kidney disease requiring dialysis.

BACKGROUND: Malnutrition is common in patients with chronic kidney disease (CKD) on dialysis. Oral protein-based nutritional supplements are often provided to patients whose oral intake is otherwise insufficient to meet their energy and protein needs. Evidence for the effectiveness of oral protein-based nutritional supplements in this population is limited. OBJECTIVES: The aims of this review were to determine the benefits and harms of using oral protein-based nutritional supplements to improve the nutritional state of patients with CKD requiring dialysis. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Register of Studies up to 12 December 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) of patients with CKD requiring dialysis that compared oral protein-based nutritional supplements to no oral protein-based nutritional supplements or placebo. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility, risk of bias, and extracted data from individual studies. Summary estimates of effect were obtained using a random-effects model, and results were expressed as risk ratios and their 95% confidence intervals (CI) for dichotomous outcomes, and mean difference and 95% CI for continuous outcomes. MAIN RESULTS: Twenty-two studies (1278 participants) were included in this review. All participants were adults on maintenance dialysis of whom 79% were on haemodialysis (HD) and 21% peritoneal dialysis. The follow-up period ranged from one to 12 months. The majority of studies were at unclear risk of selection, performance, and reporting bias. The detection bias was high for self-reported outcomes. Oral protein-based nutritional supplements probably lead to a higher mean change in serum albumin compared to the control group (16 studies, 790 participants: MD 0.19 g/dL, 95% CI 0.05 to 0.33; moderate certainty evidence), although there was considerable heterogeneity in the combined analysis (I2 = 84%). The increase was more evident in HD participants (10 studies, 526 participants: MD 0.28 g/dL, 95% CI 0.11 to 0.46; P = 0.001 for overall effect) and malnourished participants (8 studies, 405 participants: MD 0.31 g/dL, 95% CI 0.10 to 0.52, P = 0.003 for overall effect). Oral protein-based nutritional supplements also probably leads to a higher mean serum albumin at the end of the intervention (14 studies, 715 participants: MD 0.14 g/dL, 95% CI 0 to 0.27; moderate certainty evidence), however heterogeneity was again high (I2 = 80%). Again the increase was more evident in HD participants (9 studies, 498 participants: MD 0.21 g/dL, 95% CI 0.03 to 0.38; P = 0.02 for overall effect) and malnourished participants (7 studies, 377 participants: MD 0.25 g/dL, 95% CI 0.02 to 0.47; P = 0.03 for overall effect). Compared to placebo or no supplement, low certainty evidence showed oral protein-based nutritional supplements may result in a higher serum prealbumin (4 studies, 225 participants: MD 2.81 mg/dL, 95% CI 2.19 to 3.43), and mid-arm muscle circumference (4 studies, 216 participants: MD 1.33 cm, 95% CI 0.24 to 2.43) at the end of the intervention. Compared to placebo or no supplement, oral protein-based nutritional supplements may make little or no difference to weight (8 studies, 365 participants: MD 2.83 kg, 95% CI -0.43 to 6.09; low certainty evidence), body mass index (9 studies, 368 participants: MD -0.04 kg/m2, 95% CI -0.74 to 0.66; moderate certainty evidence) and lean mass (5 studies, 189 participants: MD 1.27 kg, 95% CI -1.61 to 4.51; low certainty evidence). Due to very low quality of evidence, it is uncertain whether oral protein-based nutritional supplements affect triceps skinfold thickness, mid-arm circumference, C-reactive protein, Interleukin 6, serum potassium, or serum phosphate. There may be little or no difference in the risk of developing gastrointestinal intolerance between participants who received oral protein-based nutritional supplements compared with placebo or no supplement (6 studies, 426 participants: RR 2.81, 95% CI 0.58 to 13.65, low certainty evidence). It was not possible to draw conclusions about cost or quality of life, and deaths were not reported as a study outcome in any of the included studies. AUTHORS' CONCLUSIONS: Overall, it is likely that oral protein-based nutritional supplements increase both mean change in serum albumin and serum albumin at end of intervention and may improve serum prealbumin and mid-arm muscle circumference. The improvement in serum albumin was more evident in haemodialysis and malnourished participants. However, it remains uncertain whether these results translate to improvement in nutritional status and clinically relevant outcomes such as death. Large well-designed RCTs in this population are required.

A tRial Evaluating Mid Cut-Off Value Membrane Clearance of Albumin and Light Chains in HemoDialysis Patients: A Safety Device Study.

BACKGROUND: A new class of dialysis membrane, the mid cut-off (MCO) dialyzer, has been developed to improve the clearance of uremic toxins in hemodialysis (HD). The a tRial Evaluating Mid cut-Off Value membrane clearance of Albumin and Light chains in HemoDialysis patients (REMOVAL-HD) study aimed to determine if regular use of MCO dialyzer was safe and specifically did not result in a significant loss of albumin. METHODS: This investigator initiated, crossover, longitudinal, device study was conducted across 9 centers in Australia and New Zealand (n = 89). Participants had a 4-week wash-in with high-flux HD, followed by 24-week intervention with MCO HD and a subsequent 4-week wash-out with high-flux HD. The primary outcome was change in serum albumin between weeks 4 and 28. Secondary outcomes included trends in serum albumin, changes in kappa- and lambda-free light chains (FLC), 6-min walk test (6MWT), malnutrition inflammation score (MIS), restless legs score and quality of life. RESULTS: Participants had a mean age of 66 ± 14 years, 62% were men, 45% were anuric, and 51% had -diabetes. There was no reduction in serum albumin following treatment with MCO HD (mean reduction -0.7 g/L, 95% CI -1.5 to 0.1). A sustained, unexplained reduction in serum albumin (>25%) was not observed in any participant. A reduction in FLC was observed 2 weeks into MCO HD (lambda-FLC: Δ -9.1 mg/L, 95% CI -14.4 to -3.7; kappa-FLC: Δ -5.7 mg/L, 95% CI -9.8 to -1.6) and was sustained for the rest of the study intervention. Both FLC increased after the cessation of MCO use. There was no improvement in restless legs symptoms, quality of life, 6MWT or MIS scores. CONCLUSIONS: Regular HD using the MCO dialyzer did not result in a significant fall in serum albumin. There were no effects on quality of life, functional status or nutrition. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry Number (ANZCTRN) 12616000804482.

Effect of Vancomycin or Daptomycin With vs Without an Antistaphylococcal ß-Lactam on Mortality, Bacteremia, Relapse, or Treatment Failure in Patients With MRSA Bacteremia: A Randomized Clinical Trial.

Importance: Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is associated with mortality of more than 20%. Combining standard therapy with a ß-lactam antibiotic has been associated with reduced mortality, although adequately powered randomized clinical trials of this intervention have not been conducted. Objective: To determine whether combining an antistaphylococcal ß-lactam with standard therapy is more effective than standard therapy alone in patients with MRSA bacteremia. Design, Setting, and Participants: Open-label, randomized clinical trial conducted at 27 hospital sites in 4 countries from August 2015 to July 2018 among 352 hospitalized adults with MRSA bacteremia. Follow-up was complete on October 23, 2018. Interventions: Participants were randomized to standard therapy (intravenous vancomycin or daptomycin) plus an antistaphylococcal ß-lactam (intravenous flucloxacillin, cloxacillin, or cefazolin) (n = 174) or standard therapy alone (n = 178). Total duration of therapy was determined by treating clinicians and the ß-lactam was administered for 7 days. Main Outcomes and Measures: The primary end point was a 90-day composite of mortality, persistent bacteremia at day 5, microbiological relapse, and microbiological treatment failure. Secondary outcomes included mortality at days 14, 42, and 90; persistent bacteremia at days 2 and 5; acute kidney injury (AKI); microbiological relapse; microbiological treatment failure; and duration of intravenous antibiotics. Results: The data and safety monitoring board recommended early termination of the study prior to enrollment of 440 patients because of safety. Among 352 patients randomized (mean age, 62.2 [SD, 17.7] years; 121 women [34.4%]), 345 (98%) completed the trial. The primary end point was met by 59 (35%) with combination therapy and 68 (39%) with standard therapy (absolute difference, -4.2%; 95% CI, -14.3% to 6.0%). Seven of 9 prespecified secondary end points showed no significant difference. For the combination therapy vs standard therapy groups, all-cause 90-day mortality occurred in 35 (21%) vs 28 (16%) (difference, 4.5%; 95% CI, -3.7% to 12.7%); persistent bacteremia at day 5 was observed in 19 of 166 (11%) vs 35 of 172 (20%) (difference, -8.9%; 95% CI, -16.6% to -1.2%); and, excluding patients receiving dialysis at baseline, AKI occurred in 34 of 145 (23%) vs 9 of 145 (6%) (difference, 17.2%; 95% CI, 9.3%-25.2%). Conclusions and Relevance: Among patients with MRSA bacteremia, addition of an antistaphylococcal ß-lactam to standard antibiotic therapy with vancomycin or daptomycin did not result in significant improvement in the primary composite end point of mortality, persistent bacteremia, relapse, or treatment failure. Early trial termination for safety concerns and the possibility that the study was underpowered to detect clinically important differences in favor of the intervention should be considered when interpreting the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT02365493.

Incremental and twice weekly haemodialysis in Australia and New Zealand.

BACKGROUND: Haemodialysis is usually started at a frequency of three times a week, with occasional patients starting twice weekly ('incremental dialysis'). Incremental haemodialysis (HD) may preserve residual kidney function and has been associated with reduced mortality. In the present study, we report prevalence and outcomes of incremental dialysis in Australia and New Zealand. METHODS: The cohort was all adults starting renal replacement therapy with HD in Australia and New Zealand 2004-2015. We used cox proportional hazards modelling with a primary exposure of dialysis frequency at first survey date (≥ or <3 times per week). The primary outcome was all-cause mortality (primary), cardiovascular and non-cardiovascular mortality (secondary). RESULTS: Eight-hundred fifty of 27 513 subjects were started on twice weekly HD (prevalence 3%). Compared to conventional patients, incremental dialysis patients were older (67 vs 62 years, P < 0.001), had a lower body mass index (26.1 vs 27.7 kg/m2 , P < 0.001), had a higher starting estimated glomerular filtration rate (7.59 vs 6.66 mL/min P < 0.001) and had less diabetes (39.2% vs 50.2%, P < 0.001). In a multivariate model, incremental start dialysis was not associated with all-cause mortality (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.92-1.16) or cardiovascular mortality (HR = 0.87, 95% CI = 0.71-1.07), but was associated with an increased risk of non-cardiovascular mortality (HR = 1.25, 95% CI = 1.11-1.42). CONCLUSION: Incremental dialysis was used infrequently, and there was evidence of patient level differences. All-cause mortality was similar, but there were differences in cause specific mortality. Incremental dialysis needs to be tested in prospective trials to define the safety and efficacy of this approach.

A controlled study of the effects of ferric carboxymaltose on bone and haematinic biomarkers in chronic kidney disease and pregnancy.

Background: Intravenous (IV) iron can modulate fibroblast growth factor 23 (FGF23) concentrations and cause transient but significant hypophosphataemia. However, it is unknown what other markers might be involved, especially in different patient groups. This study aimed to determine changes in bone and haematinic biomarkers following IV ferric carboxymaltose (FCM) and to identify risk factors for hypophosphataemia in pregnant subjects and those with chronic kidney disease (CKD). Methods: Changes in bone [serum FGF23, fractional excretion of phosphate urinary fractional excretion of phosphate (FEPi), serum phosphate and serum vitamin D derivatives] and haematinic [plasma hepcidin, serum ferritin and transferrin saturation (TSAT)] biomarkers after 1 g of IV FCM were followed in iron-deficient pregnant and CKD patients and compared with controls (estimated glomerular filtration rate > 60 mL/min/1.73 m2). Data were collected at baseline and up to 42 days after infusion. Risk factors for post-FCM hypophosphataemia were also assessed. Results: Sixty-five subjects completed the study (control, n = 20; pregnant, n = 20; CKD, n = 25). A uniform but variable increase across groups was seen in intact FGF23 (peak Day 2), whereas c-terminal FGF23 varied markedly. Trough serum phosphate timed with the peak FEPi at Day 7, recovering by Day 21 in the pregnant group and Day 42 in other groups. Independent predictors of a low phosphate nadir included baseline phosphate, FEPi and weight-adjusted FCM dose. All groups showed an early and marked increase in plasma hepcidin (peak Day 2), serum ferritin and TSAT (peak Day 7 for both). Conclusions: Changes in bone and haematinic biomarkers differ between patient groups following IV FCM. For patients with lower serum phosphate concentrations, limiting the dose and measuring levels 7 days after administration may mitigate clinically significant hypophosphataemia.

Lifetime risk of end-stage kidney disease in living donors for paediatric kidney transplant recipients in Australia and New Zealand - a retrospective study.

Living kidney donors (LKD) for paediatric kidney transplant recipients (KTR) have a heightened motivation to donate for emotional reasons and the clear health benefits to the KTR. We hypothesized that the cohort of LKD for paediatric KTR (LKD-P) includes motivated young parents with a higher lifetime end-stage kidney disease (ESKD) risk compared to adult KTR (LKD-A). Data from the Australia and New Zealand Dialysis and Transplant LKD Registry (2004-2015) was analysed to compare baseline characteristics and predonation ESKD risk in LKD-P (n = 315) versus LKD-A (n = 3448). LKD-P were younger (median age 42 vs. 50 years; P < 0.001) and had a marginally higher lifetime ESKD risk (median 0.44% vs. 0.40%; P < 0.01), with a similar proportion of LKD exceeding 1% risk threshold (5.4% vs. 5.6%; P = NS). Compared to grandparents as LKD-P, parents (median age 41 vs. 59 years; P < 0.001) had a higher lifetime ESKD (0.44% vs. 0.25%; P < 0.001). Although unique benefits to paediatric KTR justify the minor increase in lifetime ESKD risk in young parents, carefully selected grandparents are an alternative LKD-P option, allowing parents to donate for subsequent transplants.