Darsy Darssan

Measures of kidney function by minimally invasive techniques correlate with histological glomerular damage in SCID mice with adriamycin-induced nephropathy

Maximising the use of preclinical murine models of progressive kidney disease as test beds for therapies ideally requires kidney function to be measured repeatedly in a safe, minimally invasive manner. To date, most studies of murine nephropathy depend on unreliable markers of renal physiological function, exemplified by measuring blood levels of creatinine and urea, and on various end points necessitating sacrifice of experimental animals to assess histological damage, thus counteracting the principles of Replacement, Refinement and Reduction. Here, we applied two novel minimally invasive techniques to measure kidney function in SCID mice with adriamycin-induced nephropathy. We employed i) a transcutaneous device that measures the half-life of intravenously administered FITC-sinistrin, a molecule cleared by glomerular filtration; and ii) multispectral optoacoustic tomography, a photoacoustic imaging device that directly visualises the clearance of the near infrared dye, IRDye 800CW carboxylate. Measurements with either technique showed a significant impairment of renal function in experimental animals versus controls, with significant correlations with the proportion of scarred glomeruli five weeks after induction of injury. These technologies provide clinically relevant functional data and should be widely adopted for testing the efficacies of novel therapies. Moreover, their use will also lead to a reduction in experimental animal numbers.

Multicenter Registry Analysis of Center Characteristics Associated with Technique Failure in Patients on Incident Peritoneal Dialysis

BACKGROUND AND OBJECTIVES Technique failure is a major limitation of peritoneal dialysis. Our study aimed to identify center- and patient-level predictors of peritoneal dialysis technique failure. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS All patients on incident peritoneal dialysis in Australia from 2004 to 2014 were included in the study using data from the Australia and New Zealand Dialysis and Transplant Registry. Center- and patient-level characteristics associated with technique failure were evaluated using Cox shared frailty models. Death-censored technique failure and cause-specific technique failure were analyzed as secondary outcomes. RESULTS The study included 9362 patients from 51 centers in Australia. The technique failure rate was 0.35 (95% confidence interval, 0.34 to 0.36) episodes per patient-year, with a sevenfold variation across centers that was mainly associated with center-level characteristics. Technique failure was significantly less likely in centers with larger proportions of patients treated with peritoneal dialysis (>29%; adjusted hazard ratio, 0.83; 95% confidence interval, 0.73 to 0.94) and more likely in smaller centers (<16 new patients per year; adjusted hazard ratio, 1.10; 95% confidence interval, 1.00 to 1.21) and centers with lower proportions of patients achieving target baseline serum phosphate levels (<40%; adjusted hazard ratio, 1.15; 95% confidence interval, 1.03 to 1.29). Similar results were observed for death-censored technique failure, except that center target phosphate achievement was not significantly associated. Technique failure due to infection, social reasons, mechanical causes, or death was variably associated with center size, proportion of patients on peritoneal dialysis, and/or target phosphate achievement, automated peritoneal dialysis exposure, icodextrin use, and antifungal use. The variation of hazards of technique failure across centers was reduced by 28% after adjusting for patient-specific factors and an additional 53% after adding center-specific factors. CONCLUSIONS Technique failure varies widely across centers in Australia. A significant proportion of this variation is related to potentially modifiable center characteristics, including peritoneal dialysis center size, proportion of patients on peritoneal dialysis, and proportion of patients on peritoneal dialysis achieving target phosphate level.

Predictors of residual renal function decline in peritoneal dialysis patients: the balANZ trial

♦ Objective: Preservation of residual renal function (RRF) is associated with improved survival. The aim of the present study was to identify independent predictors of RRF and urine volume (UV) in incident peritoneal dialysis (PD) patients. ♦ Methods: The study included incident PD patients who were balANZ trial participants. The primary and secondary outcomes were RRF and UV, respectively. Both outcomes were analyzed using mixed effects linear regression with demographic data in the first model and PD-related parameters included in a second model. ♦ Results: The study included 161 patients (mean age 57.9 ± 14.1 years, 44% female, 33% diabetic, mean follow-up 19.5 ± 6.6 months). Residual renal function declined from 7.5 ± 2.9 mL/min/1.73 m2 at baseline to 3.3 ± 2.8 mL/min/1.73 m2 at 24 months. Better preservation of RRF was independently predicted by male gender, higher baseline RRF, higher time-varying systolic blood pressure (SBP), biocompatible (neutral pH, low glucose degradation product) PD solution, lower peritoneal ultrafiltration (UF) and lower dialysate glucose exposure. In particular, biocompatible solution resulted in 27% better RRF preservation. Each 1 L/day increase in UF was associated with 8% worse RRF preservation (p = 0.007) and each 10 g/day increase in dialysate glucose exposure was associated with 4% worse RRF preservation (p < 0.001). Residual renal function was not independently predicted by body mass index, diabetes mellitus, renin angiotensin system inhibitors, peritoneal solute transport rate, or PD modality. Similar results were observed for UV. ♦ Conclusions: Common modifiable risk factors which were consistently associated with preserved RRF and residual UV were use of biocompatible PD solutions and achievement of higher SBP, lower peritoneal UF, and lower dialysate glucose exposure over time.

Vitamin D status and mortality risk among patients on dialysis: a systematic review and meta-analysis of observational studies

Background Vitamin D deficiency is highly prevalent in patients on dialysis. Although vitamin D deficiency is closely associated with cardiovascular disease (CVD) and high mortality in the general population, the relationship between serum 25-hydroxyvitamin D [25(OH)D] and all-cause and cardiovascular mortality in dialysis patients is uncertain. We aim to explore the relationship between serum 25(OH)D levels and all-cause and cardiovascular mortality in dialysis patients. Methods This is a systematic review and meta-analysis of clinical studies among patients receiving maintenance dialysis. We did a systematic literature search in PubMed and Embase to identify studies reporting the relationship between serum 25(OH)D levels and all-cause and cardiovascular mortality in patients on dialysis. The search was last updated on 10 February 2017. Results The study included 18 moderate to high-quality cohort studies with an overall sample of 14 154 patients on dialysis. The relative risk of all-cause mortality per 10 ng/mL increase in serum 25(OH)D level was 0.78 [95% confidence interval (CI) 0.71-0.86], although there was marked heterogeneity (I2=96%, P < 0.01) that was partly explained by differences in CVD prevalence, baseline parathyroid hormone level and dialysis duration among included studies. The relative risk of cardiovascular mortality per 10 ng/mL increase in serum 25(OH)D level was 0.71 (95% CI 0.63-0.79), with substantial heterogeneity (I2=74%, P=0.004) that was largely explained by differences in study type and serum 25(OH)D measurement method. Conclusions In the present study, increased serum 25(OH)D level was significantly associated with lower all-cause mortality and lower cardiovascular mortality in dialysis patients.

Outcomes of Corynebacterium Peritonitis: A Multicenter Registry Analysis

Background: Corynebacterium is a rare cause of peritonitis that is increasingly being recognized in peritoneal dialysis (PD) patients. The aims of this study were to compare Corynebacterium peritonitis outcomes with those of peritonitis caused by other organisms and to examine the effects of type and duration of antibiotic therapy on outcomes of Corynebacterium peritonitis. Methods: Using Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data, we included all PD patients who developed peritonitis in Australia between 2004 and 2014. The primary outcome was peritonitis cure by antibiotic therapy, defined as resolution of a peritonitis episode with antibiotics alone and without being complicated by recurrence, relapse, catheter removal, hemodialysis transfer, or death. Peritonitis outcomes were analyzed using multivariable logistic regression. Results: A total of 11,122 episodes of peritonitis in 5,367 patients were included. Of these, 162 episodes (1.5%) were due to Corynebacterium. Compared with Corynebacterium peritonitis, the odds of cure were lower in peritonitis due to Staphylococcus aureus (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.45 – 0.97), Pseudomonas (OR 0.22, 95% CI 0.14 – 0.33), other gram-negative organisms (OR 0.52, 95% CI 0.35 – 0.75), fungi (OR 0.02, 95% CI 0.01 – 0.03), polymicrobial organisms (OR 0.32, 95% CI 0.22 – 0.47), and other organisms (OR 0.66, 95% CI 0.44 – 0.99) but similar for culture-negative and other gram-positive peritonitis. Similar results were observed for hemodialysis transfer and death. The outcomes of Corynebacterium peritonitis were not associated with the type of initial antibiotic selected (vancomycin vs cefazolin) or the duration of antibiotic therapy (≤ 14 days vs > 14 days). Conclusions: Outcomes for Corynebacterium peritonitis are generally favorable compared with other forms of peritonitis. Cure rates did not appear to differ if peritonitis was treated initially with vancomycin or cefazolin or if treatment duration was prolonged beyond 14 days.

EARLY PERITONITIS AND ITS OUTCOME IN INCIDENT PERITONEAL DIALYSIS PATIENTS

BACKGROUND Early-onset peritonitis is a serious complication of peritoneal dialysis (PD) and is associated with heightened risks of technique failure and death. The risk factors for early peritonitis and its outcomes are unknown. METHODS This registry study examined all incident Australian PD patients between 2003 and 2014. The primary outcome was early peritonitis, defined as onset within 12 months of starting therapy. Secondary outcomes were medical cure, relapse/recurrence, catheter removal, peritonitis-associated technique failure, and peritonitis-associated death. RESULTS Of 9,845 patients, 2,615 experienced 3,827 early-peritonitis episodes (0.50 episodes per patient-year). Early peritonitis was more common in patients who were male, obese, had a history of cigarette smoking or cerebrovascular disease, used continuous ambulatory PD, and had received prior renal replacement therapy for > 90 days. Remoteness was a risk modifier for the association between race and early peritonitis; remote Aboriginal, Torres Strait Islander, Maori and Pacific Islander patients had the highest risk. Obese patients were more likely to achieve medical cure. Older patients were less likely to achieve cure and more likely to experience peritonitis-associated death. CONCLUSIONS In summary, several factors predicted early peritonitis in incident PD patients. Modified approaches to patient selection, training techniques, and prevention strategies should be considered in high-risk individuals.

A comparison of characteristics of patients seen in a tertiary hospital diabetes telehealth service versus specialist face-to-face outpatients

This study aimed to describe patient-related characteristics of those attending the diabetes telehealth service delivered from a tertiary hospital and compare these with the characteristics of patients attending face-to-face visits at the same hospital’s diabetes outpatient service. This analysis could inform diabetes telehealth service improvements. To our knowledge, there has been no prior evaluation of a diabetes telehealth service in Australia. A cross-sectional survey was conducted as part of the Australian National Diabetes Audit in May 2016 for all patients attending the diabetes telehealth service and diabetes outpatient service. The diabetes telehealth service was serving a greater proportion of females, indigenous people and patients with a longer mean duration of type 2 diabetes mellitus. Type 2 diabetes mellitus patients in the diabetes telehealth service group had a higher average glycated haemoglobin of 9.1% (76 mmol/mol) vs 8.1% (65 mmol/mol) in the diabetes outpatient service group. The diabetes telehealth service had more people with initial visits; had higher self-reported smoking rates in type 2 diabetes mellitus patients; and had adequate access to allied health supports as recommended for diabetes management. Diabetes telehealth service patients had more complex diabetes as evidenced by a higher proportion of indigenous clients, higher glycated haemoglobin and longer mean duration of diabetes.

Center Effects and Peritoneal Dialysis Peritonitis Outcomes: Analysis of a National Registry

BACKGROUND Peritonitis is a common cause of technique failure in peritoneal dialysis (PD). Dialysis center-level characteristics may influence PD peritonitis outcomes independent of patient-level characteristics. STUDY DESIGN Retrospective cohort study. SETTING & PARTICIPANTS Using Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data, all incident Australian PD patients who had peritonitis from 2004 through 2014 were included. PREDICTORS Patient- (including demographic data, causal organisms, and comorbid conditions) and center- (including center size, proportion of patients treated with PD, and summary measures related to type, cause, and outcome of peritonitis episodes) level predictors. OUTCOMES & MEASUREMENT The primary outcome was cure of peritonitis with antibiotics. Secondary outcomes were peritonitis-related catheter removal, hemodialysis therapy transfer, peritonitis relapse/recurrence, hospitalization, and mortality. Outcomes were analyzed using multilevel mixed logistic regression. RESULTS The study included 9,100 episodes of peritonitis among 4,428 patients across 51 centers. Cure with antibiotics was achieved in 6,285 (69%) peritonitis episodes and varied between 38% and 86% across centers. Centers with higher proportions of dialysis patients treated with PD (>29%) had significantly higher odds of peritonitis cure (adjusted OR, 1.21; 95% CI, 1.04-1.40) and lower odds of catheter removal (OR, 0.78; 95% CI, 0.62-0.97), hemodialysis therapy transfer (OR, 0.78; 95% CI, 0.62-0.97), and peritonitis relapse/recurrence (OR, 0.68; 95% CI, 0.48-0.98). Centers with higher proportions of peritonitis episodes receiving empirical antibiotics covering both Gram-positive and Gram-negative organisms had higher odds of cure with antibiotics (OR, 1.22; 95% CI, 1.06-1.42). Patient-level characteristics associated with higher odds of cure were younger age and less virulent causative organisms (coagulase-negative staphylococci, streptococci, and culture negative). The variation in odds of cure across centers was 9% higher after adjustment for patient-level characteristics, but 66% lower after adjustment for center-level characteristics. LIMITATIONS Retrospective study design using registry data. CONCLUSIONS These results suggest that center effects contribute substantially to the appreciable variation in PD peritonitis outcomes that exist across PD centers within Australia.

The Relationship Between Body Mass Index and Organism-Specific Peritonitis

Background: Obesity is increasingly prevalent worldwide, and a greater number of patients initiate renal replacement therapy with a high body mass index (BMI). This study aimed to evaluate the association between BMI and organism-specific peritonitis. Methods: All adult patients who initiated peritoneal dialysis (PD) in Australia between January 2004 and December 2013 were included. Data were accessed through the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. The co-primary outcomes of this study were time to first organism-specific peritonitis episode, specifically gram-positive, gram-negative, culture-negative, and fungal. Secondary outcomes were individual rates of organism-specific peritonitis for the same 4 microbiological categories. Results: There were 7,381 peritonitis episodes among the 8,343 incident PD patients evaluated. After multivariable adjustment, obese patients (BMI 30 – 34.9 kg/m2) had an increased risk of fungal peritonitis (adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.18 – 2.42), very obese patients (BMI ≥ 35 kg/m2) had a significantly higher risk of gram-positive peritonitis (HR 1.15, 95% CI 1.02 – 1.30), while both obese and very obese patients experienced significantly higher risks of gram-negative peritonitis (HR 1.29, 95% CI 1.11 – 1.50 and HR 1.30, 95% CI 1.08 – 1.57, respectively) compared with patients with normal BMI (20 – 24.9 kg/m2). Obesity and severe obesity were independently associated with increased incidence rate ratios of all forms of organism-specific peritonitis with a non-significant trend for severe obesity and gram-negative peritonitis association. Conclusion: Among Australian patients, obesity and severe obesity are associated with significantly increased rates of gram-positive, gram-negative, fungal, and culture-negative peritonitis.

ASSOCIATIONS BETWEEN PERITONEAL GLUCOSE EXPOSURE, GLUCOSE DEGRADATION PRODUCT EXPOSURE, AND PERITONEAL MEMBRANE TRANSPORT CHARACTERISTICS IN PERITONEAL DIALYSIS PATIENTS: SECONDARY ANALYSIS OF THE balANZ TRIAL

Background: Glucose is the most commonly used osmotic medium in peritoneal dialysis (PD) solutions, and its use has been associated with both local and systemic adverse effects. Previous, single-center, observational cohort studies have reported conflicting findings regarding whether a relationship exists between peritoneal glucose exposure and peritoneal small solute transport rate. Methods: In this secondary analysis of the balANZ multicenter, multinational, randomized controlled trial of a neutral pH, ultra-low glucose degradation product (biocompatible) versus conventional PD solutions over a 2-year period, the relationship between time varying peritoneal glucose exposure and change in peritoneal solute transport rate, (measured as dialysate to plasma creatinine ratio at 4 hours [D:PCr4h]), was evaluated using multivariable, multilevel linear regression. Baseline peritoneal glucose exposure was also assessed as either a continuous or categorical variable. Results: The study included 165 patients (age 58.1 ± 14.2 years, 55% male, 33% diabetic). Peritoneal glucose exposure increased over time (coefficient 1.49, 95% confidence interval [CI] 1.07 – 1.92 and was not significantly associated with change in D:PCr4h (coefficient 0.00004, 95% CI -0.0001 – 0.0002, p = 0.68). Similar results were found when peritoneal glucose exposure was examined as a baseline continuous or categorical variable. A significant 2-way interaction was observed with PD solution type, whereby a progressive increase in D:PCr4h was seen in the patients receiving conventional PD solution, but not in those receiving biocompatible solution. Conclusions: Increases in peritoneal solute transport rate in PD patients over time were not associated with peritoneal glucose exposure, although a strong and positive association with PD solution glucose degradation product content was identified. Peritoneal glucose exposure may be a less important consideration than peritoneal glucose degradation product exposure with respect to peritoneal membrane function over time.