Effect of Dialysate and Plasma Sodium on Mortality in a Global Historical Hemodialysis Cohort.

SIGNIFICANCE STATEMENT: This large observational cohort study aimed to investigate the relationship between dialysate and plasma sodium concentrations and mortality among maintenance hemodialysis patients. Using a large multinational cohort of 68,196 patients, we found that lower dialysate sodium concentrations (≤138 mmol/L) were independently associated with higher mortality compared with higher dialysate sodium concentrations (>138 mmol/L). The risk of death was lower among patients exposed to higher dialysate sodium concentrations, regardless of plasma sodium levels. These results challenge the prevailing assumption that lower dialysate sodium concentrations improve outcomes in hemodialysis patients. The study confirms that until robust evidence from randomized trials that are underway is available, nephrologists should remain cautious in reconsideration of dialysate sodium prescribing practices to optimize cardiovascular outcomes and reduce mortality in this population. BACKGROUND: Excess mortality in hemodialysis (HD) patients is largely due to cardiovascular disease and is associated with abnormal fluid status and plasma sodium concentrations. Ultrafiltration facilitates the removal of fluid and sodium, whereas diffusive exchange of sodium plays a pivotal role in sodium removal and tonicity adjustment. Lower dialysate sodium may increase sodium removal at the expense of hypotonicity, reduced blood volume refilling, and intradialytic hypotension risk. Higher dialysate sodium preserves blood volume and hemodynamic stability but reduces sodium removal. In this retrospective cohort, we aimed to assess whether prescribing a dialysate sodium ≤138 mmol/L has an effect on survival outcomes compared with dialysate sodium >138 mmol/L after adjusting for plasma sodium concentration. METHODS: The study population included incident HD patients from 875 Fresenius Medical Care Nephrocare clinics in 25 countries between 2010 and 2019. Baseline dialysate sodium (≤138 or >138 mmol/L) and plasma sodium (<135, 135-142, >142 mmol/L) concentrations defined exposure status. We used multivariable Cox regression model stratified by country to model the association between time-varying dialysate and plasma sodium exposure and all-cause mortality, adjusted for demographic and treatment variables, including bioimpedance measures of fluid status. RESULTS: In 2,123,957 patient-months from 68,196 incident HD patients with on average three HD sessions per week dialysate sodium of 138 mmol/L was prescribed in 63.2%, 139 mmol/L in 15.8%, 140 mmol/L in 20.7%, and other concentrations in 0.4% of patients. Most clinical centers (78.6%) used a standardized concentration. During a median follow-up of 40 months, one third of patients ( n =21,644) died. Dialysate sodium ≤138 mmol/L was associated with higher mortality (multivariate hazard ratio for the total population (1.57, 95% confidence interval, 1.25 to 1.98), adjusted for plasma sodium concentrations and other confounding variables. Subgroup analysis did not show any evidence of effect modification by plasma sodium concentrations or other patient-specific variables. CONCLUSIONS: These observational findings stress the need for randomized evidence to reliably define optimal standard dialysate sodium prescribing practices.

Conservative kidney management and kidney supportive care: core components of integrated care for people with kidney failure.

Integrated kidney care requires synergistic linkage between preventative care for people at risk for chronic kidney disease and health services providing care for people with kidney disease, ensuring holistic and coordinated care as people transition between acute and chronic kidney disease and the 3 modalities of kidney failure management: conservative kidney management, transplantation, and dialysis. People with kidney failure have many supportive care needs throughout their illness, regardless of treatment modality. Kidney supportive care is therefore a vital part of this integrated framework, but is nonexistent, poorly developed, and/or poorly integrated with kidney care in many settings, especially in low- and middle-income countries. To address this, the International Society of Nephrology has (i) coordinated the development of consensus definitions of conservative kidney management and kidney supportive care to promote international understanding and awareness of these active treatments; and (ii) identified key considerations for the development and expansion of conservative kidney management and kidney supportive care programs, especially in low resource settings, where access to kidney replacement therapy is restricted or not available. This article presents the definitions for conservative kidney management and kidney supportive care; describes their core components with some illustrative examples to highlight key points; and describes some of the additional considerations for delivering conservative kidney management and kidney supportive care in low resource settings.

Geographic and racial variability in kidney, cardiovascular and safety outcomes with canagliflozin: A secondary analysis of the CREDENCE randomized trial.

AIM: To explore the effect of canagliflozin on kidney and cardiovascular events and safety outcomes in individuals with type 2 diabetes and chronic kidney disease across geographic regions and racial groups. MATERIALS AND METHODS: A stratified Cox proportional hazards model was used to assess efficacy and safety outcomes by geographic region and racial group. The primary composite outcome was a composite of end-stage kidney disease (ESKD), doubling of the serum creatinine (SCr) level, or death from kidney or cardiovascular causes. Secondary outcomes included: (i) cardiovascular death or heart failure (HF) hospitalization; (ii) cardiovascular death, myocardial infarction (MI) or stroke; (iii) HF hospitalization; (iv) doubling of the SCr level, ESKD or kidney death; (v) cardiovascular death; (vi) all-cause death; and (vii) cardiovascular death, MI, stroke, or hospitalization for HF or for unstable angina. RESULTS: The 4401 patients were divided into six geographic region subgroups: North America (n = 1182, 27%), Central and South America (n = 941, 21%), Eastern Europe (n = 947, 21%), Western Europe (n = 421, 10%), Asia (n = 749, 17%) and Other (n = 161, 4%). The analyses included four racial groups: White (n = 2931, 67%), Black or African American (n = 224, 5%), Asian (n = 877, 20%) and Other (n = 369, 8%). Canagliflozin reduced the relative risk of the primary composite outcome in the overall trial by 30% (hazard ratio 0.70, 95% confidence interval 0.59-0.82; P = 0.00001). Across geographic regions and racial groups, canagliflozin consistently reduced the primary composite endpoint without evidence of heterogeneity (interaction P values of 0.39 and 0.91, respectively) or significant safety outcome differences. CONCLUSIONS: Canagliflozin reduces the risk of kidney and cardiovascular events similarly across geographic regions and racial groups.

Estimating a Minimal Important Difference for the EQ-5D-5L Utility Index in Dialysis Patients.

OBJECTIVES: The EQ-5D-5L is a commonly used health-related quality of life instrument for evaluating interventions in patients receiving dialysis; however, the minimal important difference (MID) that constitutes a meaningful treatment effect for this population has not been established. This study aims to estimate the MID for the EQ-5D-5L utility index in dialysis patients. METHODS: 6-monthly EQ-5D-5L measurements were collected from adult dialysis patients between April 2017 and November 2020 at a renal network in Sydney, Australia. EQ-VAS and Integrated Palliative care Outcome Scale Renal symptom burden scores were collected simultaneously and used as anchors. MID estimates for the EQ-5D-5L utility index were derived using anchor-based and distribution-based methods. RESULTS: A total of 352 patients with ≥1 EQ-5D-5L observation were included, constituting 1127 observations. Mean EQ-5D-5L utility index at baseline was 0.719 (SD ± 0.267), and mean EQ-5D-5L utility decreased over time by -0.017 per year (95% CI -0.029 to -0.006, P = .004). Using cross-sectional anchor-based methods, MID estimates ranged from 0.073 to 0.107. Using longitudinal anchor-based methods, MID for improvement and deterioration ranged from 0.046 to 0.079 and -0.111 to -0.048, respectively. Using receiver operating characteristic curves, MID for improvement and deterioration ranged from 0.037 to 0.122 and -0.074 to -0.063, respectively. MID estimates from distribution-based methods were consistent with anchor-based estimates. CONCLUSIONS: Anchor-based and distribution-based approaches provided EQ-5D-5L utility index MID estimates ranging from 0.034 to 0.134. These estimates can inform the target difference or "effect size" for clinical trial design among dialysis populations.

Dual inhibition of the endothelin and angiotensin receptor ameliorates renal and inner ear pathologies in Alport mice.

Alport syndrome (AS), a type IV collagen disorder, leads to glomerular disease and, in some patients, hearing loss. AS is treated with inhibitors of the renin-angiotensin system; however, a need exists for novel therapies, especially those addressing both major pathologies. Sparsentan is a single-molecule dual endothelin type-A and angiotensin II type 1 receptor antagonist (DEARA) under clinical development for focal segmental glomerulosclerosis and IgA nephropathy. We report the ability of sparsentan to ameliorate both renal and inner ear pathologies in an autosomal-recessive Alport mouse model. Sparsentan significantly delayed onset of glomerulosclerosis, interstitial fibrosis, proteinuria, and glomerular filtration rate decline. Sparsentan attenuated glomerular basement membrane defects, blunted mesangial filopodial invasion into the glomerular capillaries, increased lifespan more than losartan, and lessened changes in profibrotic/pro-inflammatory gene pathways in both the glomerular and the renal cortical compartments. Notably, treatment with sparsentan, but not losartan, prevented accumulation of extracellular matrix in the strial capillary basement membranes in the inner ear and reduced susceptibility to hearing loss. Improvements in lifespan and in renal and strial pathology were observed even when sparsentan was initiated after development of renal pathologies. These findings suggest that sparsentan may address both renal and hearing pathologies in Alport syndrome patients. © 2023 Travere Therapeutics, Inc and The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The Association of Frailty and Malnutrition With Dietary Intake and Gastrointestinal Symptoms in People With Kidney Failure: 2-Year Prospective Study.

BACKGROUND: Frailty and malnutrition are both associated with worsening morbidity and mortality and become more prevalent in the elderly and as kidney function declines. Anorexia and reduced oral intake are common features of both frailty and malnutrition. However, there are sparse data evaluating the impact of other gastrointestinal (GI) symptoms, such as taste changes, on rates of frailty and malnutrition in people with kidney failure. The aim of this study is to describe the prevalence of frailty and malnutrition and their association with dietary intake and nutrition-related symptoms in people with kidney failure. METHODS: This observational study recruited people with kidney failure who were commencing Conservative Kidney Management or elderly people (aged > 75 years) newly commenced on dialysis from 3 renal units. Participants underwent assessments of frailty, nutritional status, dietary intake, and GI symptom burden when they attended clinic appointments, approximately every 6 months. RESULTS: Of the 85 participants, 57% were assessed as being frail and 33% were assessed as being malnourished. Participants assessed as frail reported more GI symptoms (3 vs. 2, P < .001) that were more severe (1.75 vs. 1.0, P < .001) compared to nonfrail participants. Being malnourished was associated with a 5 times higher chance of being frail (odds ratio 5.8; 95% confidence interval 1.5, 21.8; P = .015) and having more severe symptoms was associated with a 2 times higher chance (odds ratio 2.8; 95% CI 1.1, 7.0; P = .026) of being frail. In addition to experiencing more GI symptoms, that were more severe, participants who were malnourished consumed significantly less energy (1234 kcal vs. 1400 kcal, P = .01) and protein (51 g vs. 74 g, P < .001). CONCLUSIONS: Frailty and malnutrition are common and are associated with a higher GI symptom burden and poorer dietary intake. Future research is needed to determine effective interventions targeting frailty and malnutrition, including nutrition-related symptoms and optimal protein intake.

Sex and Gender in Randomized Controlled Trials of Adults Receiving Maintenance Dialysis: A Meta-epidemiologic Study.

RATIONALE & OBJECTIVE: How sex and gender concepts are incorporated into randomized controlled trials (RCTs) in adults with kidney failure receiving maintenance dialysis is largely unknown. We describe these practices in published journal articles as well as investigate the proportion of women and female participants in these studies. STUDY DESIGN: Meta-epidemiologic study. SETTING & STUDY POPULATIONS: RCTs in maintenance dialysis. SELECTION CRITERIA FOR STUDIES: Trials published in high-impact journals in 2000-2020. DATA EXTRACTION: Implemented in duplicate with conflicts resolved by a third reviewer. ANALYTICAL APPROACH: Meta-regression was performed to identify trial characteristics independently associated with the proportion of women and female participants. RESULTS: Among 561 included RCTs, 69.7% were parallel and 28.0% were crossover in design; 80.6% were conducted in the hemodialysis population; and 25% of trials compared the treatment of interest with a placebo arm, 25% with a usual care treatment arm, and 50% with an active alternative therapy arm. Of the RCTS, 37.6% were masked. The median size was 60 (IQR, 26-151) participants, and the median follow-up period was 154 (IQR, 42-365) days. The mean proportion of women or female participants was 0.40±0.13 (SD): 39.0% of trials reported sex, and 26.6% reported the gender of the participants. Also, 56.2% referred to participants as females, 25.3% referred to participants as women, and 15.5% referred to both females and women. No trial characteristic other than region (ß of 0.062 [95% CI, 0.007-0.117] for Asia) was associated with the proportion of women or female participants. Considering trial design and conduct, 2.7% of trials used sex and/or gender as an inclusion criterion, 26.6% as an exclusion criterion, 4.5% for randomization, 4.8% for subgroup analyses, and 15.7% for covariate adjustment. LIMITATIONS: Only high-impact journal articles were studied; and the included studies lacked pediatric trials, those addressing chronic kidney disease or kidney transplantation, any trials from Africa and underrepresentation of other regions, and missing data. CONCLUSIONS: RCTs in dialysis are representative of the general dialysis population with regard to sex and gender but they uncommonly report both and often do not include either in their reporting or analysis.

Kidney and Cardiovascular Effects of Canagliflozin According to Age and Sex: A Post Hoc Analysis of the CREDENCE Randomized Clinical Trial.

RATIONALE & OBJECTIVE: It is unclear whether the effect of canagliflozin on adverse kidney and cardiovascular events in those with diabetic kidney disease varies by age and sex. We assessed the effects of canagliflozin among age group categories and between sexes in the Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study. STUDY DESIGN: Secondary analysis of a randomized controlled trial. SETTING & PARTICIPANTS: Participants in the CREDENCE trial. INTERVENTION: Participants were randomly assigned to receive canagliflozin 100mg/d or placebo. OUTCOMES: Primary composite outcome of kidney failure, doubling of serum creatinine concentration, or death due to kidney or cardiovascular disease. Prespecified secondary and safety outcomes were also analyzed. Outcomes were evaluated by age at baseline (<60, 60-69, and≥70 years) and sex in the intention-to-treat population using Cox regression models. RESULTS: The mean age of the cohort was 63.0±9.2 years, and 34% were female. Older age and female sex were independently associated with a lower risk of the composite of adverse kidney outcomes. There was no evidence that the effect of canagliflozin on the primary outcome (a composite of kidney failure, a doubling of serum creatinine concentration, or death from kidney or cardiovascular causes) differed between age groups (HRs, 0.67 [95% CI, 0.52-0.87], 0.63 [0.48-0.82], and 0.89 [0.61-1.29] for ages<60, 60-69, and≥70 years, respectively; P=0.3for interaction) or sexes (HRs, 0.71 [95% CI, 0.54-0.95] and 0.69 [0.56-0.84] in women and men, respectively; P=0.8for interaction). No differences in safety outcomes by age group or sex were observed. LIMITATIONS: This was a post hoc analysis with multiple comparisons. CONCLUSIONS: Canagliflozin consistently reduced the relative risk of kidney events in people with diabetic kidney disease in both sexes and across age subgroups. As a result of greater background risk, the absolute reduction in adverse kidney outcomes was greater in younger participants. FUNDING: This post hoc analysis of the CREDENCE trial was not funded. The CREDENCE study was sponsored by Janssen Research and Development and was conducted collaboratively by the sponsor, an academic-led steering committee, and an academic research organization, George Clinical. TRIAL REGISTRATION: The original CREDENCE trial was registered at ClinicalTrials.gov with study number NCT02065791.

The sodium-glucose cotransporter-2 inhibitor canagliflozin does not increase risk of non-genital skin and soft tissue infections in people with type 2 diabetes mellitus: A pooled post hoc analysis from the CANVAS Program and CREDENCE randomized double-blind trials.

AIMS: To assess whether the sodium-glucose cotransporter-2 (SGLT2) inhibitor canagliflozin affects risk of non-genital skin and soft tissue infections (SSTIs). MATERIALS AND METHODS: We performed a post hoc pooled individual participant analysis of the CANVAS Program and CREDENCE trials that randomized people with type 2 diabetes at high cardiovascular risk and/or with chronic kidney disease to either canagliflozin or placebo. Investigator-reported adverse events were assessed by two blinded authors following predetermined criteria for non-genital SSTIs. Risks of non-genital SSTIs, overall and within prespecified subgroups, and risk of non-genital fungal SSTIs, were analysed using Cox regression models. Factors associated with non-genital SSTIs were assessed using multivariable Cox regression models. RESULTS: Overall, 903 of 14 531 participants (6%) experienced non-genital SSTIs over a median follow-up of 26 months. No difference was observed in non-genital SSTI rates between canagliflozin and placebo (24.0 events/1000 person-years vs. 23.9 events/1000 person-years, respectively; hazard ratio [HR] 0.97, 95% confidence interval [CI] 0.85-1.11; P = 0.70), with consistent results across subgroups (all P interaction > 0.05). The risk of recurrent events and non-genital fungal infection also did not differ significantly between canagliflozin and placebo (HR 1.06, 95% CI 0.94-1.19 [P = 0.32] and HR 1.18, 95% CI 0.88-1.60 [P = 0.27], respectively). Baseline factors independently associated with non-genital SSTIs were younger age, male sex, higher body mass index, higher glycated haemoglobin, lower estimated glomerular filtration rate (eGFR), established peripheral vascular disease, and history of neuropathy. CONCLUSIONS: Canagliflozin did not affect risk of non-genital SSTIs or non-genital fungal SSTIs compared with placebo. These findings suggest that any SGLT2 inhibitor-mediated change in skin microenvironment is unlikely to have meaningful clinical consequences.

Carbon emissions and hospital pathology stewardship: a retrospective cohort analysis.

BACKGROUND: As healthcare is responsible for 7% of Australia's carbon emissions, it was recognised that a policy implemented at St George Hospital, Sydney, to reduce non-urgent pathology testing to 2 days per week and, on other days only if essential, would also result in a reduction in carbon emissions. The aim of the study was to measure the impact of this intervention on pathology collections and associated carbon emissions and pathology costs. AIMS: To measure the impact of an intervention to reduce unnecessary testing on pathology collections and associated carbon emissions and pathology costs. METHODS: The difference in the number of pathology collections, carbon dioxide equivalents (CO2 e) for five common blood tests and pathology cost per admission were compared between a 6-month reference period and 6-month intervention period. CO2 e were estimated from published pathology CO2 e impacts. Cost was derived from pathology billing records. Outcomes were modelled using multivariable negative binomial, generalised linear and logistic regression. RESULTS: In total, 24 585 pathology collections in 5695 patients were identified. In adjusted analysis, the rate of collections was lower during the intervention period (rate ratio 0.90; 95% confidence interval (CI), 0.86-0.95; P < 0.001). This resulted in a reduction of 53 g CO2 e (95% CI, 24-83 g; P < 0.001) and $22 (95% CI, $9-$34; P = 0.001) in pathology fees per admission. The intervention was estimated to have saved 132 kg CO2 e (95% CI, 59-205 kg) and $53 573 (95% CI, 22 076-85 096). CONCLUSIONS: Reduction in unnecessary hospital pathology collections was associated with both carbon emission and cost savings. Pathology stewardship warrants further study as a potentially scalable, cost-effective and incentivising pathway to lowering healthcare associated greenhouse gas emissions.

Comparing survival in patients with chronic kidney disease across three countries - Results from the study of heart and renal protection-extended review.

AIM: This study examined whether survival and causes of death differed between participants enrolled from Australia (AUS), Malaysia (MYL), and New Zealand (NZ) in extended follow-up of the Study of Heart and Renal Protection (SHARP), a randomized controlled trial (RCT) of participants with moderate to severe chronic kidney disease comparing placebo to combination therapy with Simvastatin and Ezetimibe. METHODS: All participants alive at final SHARP study visit in participating centres were eligible for inclusion. Consenting participants were re-enrolled following final SHARP Study visit and followed for 5 years. Data collection included: significant medical events, hospital admissions and requirement for kidney replacement therapy. Data linkage was performed to national kidney and mortality registries. The primary outcome was all-cause mortality compared across the three countries. RESULTS: The SHARP trial randomized 2029 participants from AUS (1043/2029, 51%), MYL (701/2029, 35%), and NZ (285/2029, 14%), with 1136 participants alive and eligible for extended follow-up at the end of SHARP. In multivariable analysis, risk of death was increased for participants in MYL (HR 1.37, 95% CI 1.17-1.61, p < .001) and NZ (HR 1.28, 95% CI 1.04-1.57, p = .02) when compared to AUS participants. Adjustment for kidney transplantation as a competing risk did not explain the variation seen between countries. CONCLUSION: This study allows a better understanding of the differences in long-term mortality risk across participants from AUS, MYL, and NZ in extended follow-up of the SHARP study and demonstrates the feasibility and value of extended follow-up of participants enrolled in RCTs.

Feasibility of Symptom monitoring WIth Feedback Trial (SWIFT) for adults on hemodialysis: a registry-based cluster randomized pilot trial.

BACKGROUND: Patients with kidney failure on hemodialysis (HD) experience considerable symptom burden and poor health-related quality of life (HRQoL). There is limited use of patient reported outcome measures (PROMs) in facility HD units to direct immediate care, with response rates in other studies between 36 to 70%. The aim of this pilot study was to evaluate feasibility of electronic PROMs (e-PROMs) in HD participants, with feedback 3-monthly to the participants' treating team, for severe or worsening symptoms as identified by the Integrated Palliative Outcome Scale (IPOS-Renal), with linkage to the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, compared with usual care. METHODS: This is a registry-based cluster-randomized controlled pilot trial involving all adults receiving HD in 4 satellite units in Australia over a 6-month period. HD units were cluster randomized 1:1 to the control (HRQoL data collection only) or intervention arm (symptom monitoring with feedback to treating team every 3 months). Feasibility was assessed by participant response rate (percentage of eligible HD participants, including new incident participants, who completed the questionnaire at each time point); retention rate (percentage of participants who completed the baseline questionnaire and all subsequent measures); and completion time. HRQoL and symptom burden scores are described. RESULTS: There were 226 unique participants who completed the e-PROMs (mean age 62 years, 69% males, 78% White-European, median dialysis vintage 1.62 years). At 6 months, response rate and retention rate for the intervention arm were 54% and 68%, respectively, and 89% and 97% in the control arm. Median time to complete IPOS-Renal was 6.6 min (5.3, 10.1) at 3 months, and when combined with the outcome measure (EQ-5D-5L), the median time was 9.4 min (6.9, 13.6) at 6 months. CONCLUSIONS: Electronic symptom monitoring among HD participants with feedback to clinicians is feasible. Variations in response and retention rates could be potentially explained by the lengthier questionnaire, and higher frequency of data collection time points for participants in the intervention arm. A definitive national RCT is underway. TRIAL REGISTRATION: ACTRN12618001976279 (07/12/2018).

Digital health and artificial intelligence in kidney research: a report from the 2020 Kidney Disease Clinical Trialists (KDCT) meeting.

The exponential growth in digital technology coupled with the global coronavirus disease 2019 pandemic is driving a profound change in the delivery of medical care and research conduct. The growing availability of electronic monitoring, electronic health records, smartphones and other devices and access to ever greater computational power provides not only new opportunities, but also new challenges. Artificial intelligence (AI) exemplifies the potential of this digital revolution, which also includes other tools such as mobile health (mHealth) services and wearables. Despite digital technology becoming commonplace, its use in medicine and medical research is still in its infancy, with many clinicians and researchers having limited experience with such tools in their usual practice. This article, derived from the 'Digital Health and Artificial Intelligence' session of the Kidney Disease Clinical Trialists virtual workshop held in September 2020, aims to illustrate the breadth of applications to which digital tools and AI can be applied in clinical medicine and research. It highlights several innovative projects incorporating digital technology that range from streamlining medical care of those with acute kidney injury to the use of AI to navigate the vast genomic and proteomic data gathered in kidney disease. Important considerations relating to any new digital health project are presented, with a view to encouraging the further evolution and refinement of these new tools in a manner that fosters collaboration and the generation of robust evidence.

Retrospective study on the epidemiology of antineutrophil cytoplasmic autoantibodies-associated vasculitis in two Australian health districts.

BACKGROUND: Antineutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV) is more prevalent in rural Australia compared with metropolitan areas, suggesting a role of environment in disease pathogenesis. However, the prevalence of environmental risk factors in Australian AAV patients has not been described. AIMS: To compare the incidence of AAV between two health districts (Illawarra Shoalhaven Local Health District (ISLHD), a mixed rural/metropolitan region, and South Eastern Sydney Local Health District (SESLHD), a metropolitan region) in Australia and its relationship to environmental exposures. METHODS: Cases of AAV from 2002 to 2017 were retrospectively identified from ISLHD and SESLHD using electronic medical records. Eligible participants were invited to complete a standardised questionnaire examining their exposure to silica, solvents, metal, dust, farming, gardening and sunlight. RESULTS: One hundred and fifty-six cases of AAV were identified from 2002 to 2017. A higher cumulative incidence of AAV was observed in the ISLHD (184.2 (95% confidence interval (CI) 143.6-232.7) per million) compared with SESLHD (102.6 (95% CI 82.1-126.8) per million). Over 50% of the cohort had high levels of silica and solvents exposure, based on self-reported questionnaires. There was no significant relationship between region and exposure to silica (P = 0.96), solvents (P = 0.44), metal (P = 0.33), dust (P = 0.25), farming (P = 0.90), gardening (P = 0.93) or sunlight (P = 0.55). CONCLUSIONS: We found a higher incidence of AAV in ISLHD compared with SESLHD with high levels of exposure to silica and solvents in both regions based on self-reported questionnaires. Prospective systematic collection of data, such as a registry of AAV, is warranted to further explore the relationship between environmental exposures and AAV.

Relationship between measured and prescribed dialysate sodium in haemodialysis: a systematic review and meta-analysis.

BACKGROUND: Dialysate sodium (DNa) prescription policy differs between haemodialysis (HD) units, and the optimal DNa remains uncertain. We sought to summarize the evidence on the agreement between prescribed and delivered DNa, and whether the relationship varied according to prescribed DNa. METHODS: We searched MEDLINE and PubMed from inception to 26 February 2020 for studies reporting measured and prescribed DNa. We analysed results reported in aggregate with random-effects meta-analysis. We analysed results reported by individual sample, using mixed-effects Bland-Altman analysis and linear regression. Pre-specified subgroup analyses included method of sodium measurement, dialysis machine manufacturer and proportioning method. RESULTS: Seven studies, representing 908 dialysate samples from 10 HD facilities (range 16-133 samples), were identified. All but one were single-centre studies. Studies were of low to moderate quality. Overall, there was no statistically significant difference between measured and prescribed DNa {mean difference = 0.73 mmol/L [95% confidence interval (CI) -1.12 to 2.58; P = 0.44]} but variability across studies was substantial (I2 = 99.3%). Among individually reported samples (n = 295), measured DNa was higher than prescribed DNa by 1.96 mmol/L (95% CI 0.23-3.69) and the 95% limits of agreement ranged from -3.97 to 7.88 mmol/L. Regression analysis confirmed a strong relationship between prescribed and measured DNa, with a slope close to 1:1 (ß = 1.16, 95% CI 1.06-1.27; P < 0.0001). CONCLUSIONS: A limited number of studies suggest that, on average, prescribed and measured DNa are similar. However, between- and within-study differences were large. Further consideration of the precision of delivered DNa is required to inform rational prescribing.

From Proteinuria to Fibrosis: An Update on Pathophysiology and Treatment Options.

BACKGROUND: Proteinuria is a key biomarker in nephrology. It is central to diagnosis and risk assessment and the primary target of many important therapies. Etiologies resulting in pathological proteinuria include congenital and acquired disorders, as well as both glomerular (immune/non-immune mediated) and tubular defects. SUMMARY: Untreated proteinuria is strongly linked to progressive loss of kidney function and kidney failure. Excess protein reaching the renal tubules is ordinarily resorbed by the tubular epithelium. However, when these mechanisms are overwhelmed, a variety of inflammatory and fibrotic pathways are activated, causing both interstitial fibrosis and glomerulosclerosis. Nevertheless, the specific mechanisms underlying this are complex and remain incompletely understood. Recently, a number of treatments, in addition to angiotensin system blockade, have been shown to effectively slow the progression of proteinuric chronic kidney disease. However, additional therapies are clearly needed. Key message: This review provides an update on the pathophysiology of proteinuria, the pathways leading to fibrosis, and an overview of current and emerging therapies.

Chronic Kidney Disease-Associated Pruritus: A Review.

BACKGROUND: Chronic kidney disease-associated pruritus (CKD-aP), also known as uraemic pruritus, is a disabling symptom for patients and a challenging condition for clinicians. Despite being common amongst end-stage kidney disease (ESKD) patients, it remains underestimated and underdiagnosed. The exact pathogenesis remains largely elusive, which hampers the synthesis of a definite treatment approach. SUMMARY: Chronic pruritus (lasting 6 weeks or more in duration) is a common and potentially disabling symptom in patients with advanced CKD. A unified hypothesis of pathogenesis has not yet been concluded. Studies have shown changes in the immunochemical milieu of the skin in patients with CKD-aP with several inciting stimuli identified. However, other unrecognized factors are likely to be involved. This article will review the current observations and understanding of the postulated pathogenesis of CKD-aP, as well as the evidence for current management strategies. Key Messages: CKD-aP is a common and troubling symptom amongst ESKD patients that is associated with decreased quality of life and poor prognosis. Its exact pathogenesis, at the time of writing, is not well-understood. A stepwise approach is recommended for management. Systematic reviews show the largest body of evidence was found for the effectiveness of gabapentin. Comparison is needed between newly emerging pharmacological agents such as kappa-opioid receptor agonists and more established agents, such as the gabapentinoids. Finally, renal transplantation should be considered in severe and refractory cases who are suitable transplant candidates as it has shown an excellent outcome in most cases.

Predictors of Change in Left-Ventricular Structure and Function in a Trial of Extended Hours Hemodialysis.

BACKGROUND: Myocardial pathology is common in patients undergoing hemodialysis. To explore the effects of differing aspects of dialysis treatment on its evolution, we examined the impact of change in markers of volume status, hemodynamics and solute clearance on left ventricular (LV) parameters in a randomized trial of extended hours dialysis. METHODS AND RESULTS: A Clinical Trial of IntensiVE (ACTIVE) Dialysis randomized 200 patients undergoing hemodialysis to extended dialysis hours (≥ 24 hours/week) or standard hours (12-18 hours/week) for 12 months. In a prespecified substudy, 95 participants underwent cardiac magnetic resonance imaging (CMR) at baseline and at the study's end. Generalized linear regression was used to model the relationship between changes in LV parameters and markers of volume status (normalized ultrafiltration rate and total weekly interdialytic weight gain), hemodynamic changes (systolic and diastolic blood pressure) and solute control (urea clearance, dialysis hours and phosphate). Randomization to extended hours dialysis was not associated with change in any CMR parameter. Reduction in ultrafiltration rate was associated with reduction in LV mass index (P = 0.049) and improved ejection fraction (P = 0.024); reduction in systolic blood pressure was also associated with improvement in ejection fraction (P = 0.045); reduction in interdialytic weight gain was associated with reduced stroke volume (P = 0.038). There were no associations between change in urea clearance, phosphate or total hours per week and CMR parameters. CONCLUSIONS: Reduction in ultrafiltration rate and blood pressure are associated with improved myocardial parameters in hemodialysis recipients independently of solute clearance or dialysis time. These findings underscore the importance of fluid status and related parameters as potential treatment targets in this population.

No evidence of a legacy effect on survival following randomization to extended hours dialysis in the ACTIVE Dialysis trial.

AIM: Extended hours haemodialysis is associated with superior survival to standard hours. However, residual confounding limits the interpretation of this observation. We aimed to determine the effect of a period of extended hours dialysis on long-term survival among participants in the ACTIVE Dialysis trial. METHODS: Two-hundred maintenance haemodialysis recipients were randomized to extended hours dialysis (median 24 h/wk) or standard hours dialysis (median 12 h/wk) for 12 months. Further pre-specified observational follow up occurred at 24, 36 and 60 months. Vital status and modality of renal replacement therapy were ascertained. RESULTS: Over the 5 years, 38 participants died, 30 received a renal transplant, and 6 were lost to follow up. Total weekly dialysis hours did not differ between standard and extended groups during the follow-up period (14.1 hours [95%CI 13.4-14.8] vs 14.8 hours [95%CI 14.1-15.6]; P = .16). There was no difference in all-cause mortality (hazard ratio for extended hours 0.91 [95%CI 0.48-1.72]; P = .77). Similar results were obtained after censoring participants at transplantation, and after adjusting for potential confounding variables. Subgroup analysis did not reveal differences in treatment effect by region, dialysis setting or vintage (P-interaction .51, .54, .12, respectively). CONCLUSION: Twelve months of extended hours dialysis did not improve long-term survival nor affect dialysis hours after the intervention period. An urgent need remains to further define the optimal dialysis intensity across the broad range of dialysis recipients.