Treatment decision-making and care among older adults with kidney failure: protocol for a multicentre, prospective observational cohort study with nested substudies and linked qualitative research (the Elderly Advanced CKD Programme).

INTRODUCTION: Shared treatment decision-making and planning of care are fundamental in advanced chronic kidney disease (CKD) management. There are limited data on several key outcomes for the elderly population including survival, quality of life, symptom burden, changes in physical functioning and experienced burden of healthcare. Patients, caregivers and clinicians consequently face significant uncertainty when making life-impacting treatment decisions. The Elderly Advanced CKD Programme includes quantitative and qualitative studies to better address challenges in treatment decision-making and planning of care among this increasingly prevalent elderly cohort. METHODS AND ANALYSIS: The primary component is OUTcomes of Older patients with Kidney failure (OUTLOOK), a multicentre prospective observational cohort study that will enrol 800 patients ≥75 years with kidney failure (estimated glomerular filtration rate ≤15 mL/min/1.73 m2) across a minimum of six sites in Australia. Patients entered are in the decision-making phase or have recently made a decision on preferred treatment (dialysis, conservative kidney management or undecided). Patients will be prospectively followed until death or a maximum of 4 years, with the primary outcome being survival. Secondary outcomes are receipt of short-term acute dialysis, receipt of long-term maintenance dialysis, changes in biochemistry and end-of-life care characteristics. Data will be used to formulate a risk prediction tool applicable for use in the decision-making phase. The nested substudies Treatment modalities for the InfirM ElderLY with end stage kidney disease (TIMELY) and Caregivers of The InfirM ElderLY with end stage kidney disease (Co-TIMELY) will longitudinally assess quality of life, symptom burden and caregiver burden among 150 patients and 100 caregivers, respectively. CONsumer views of Treatment options for Elderly patieNts with kiDney failure (CONTEND) is an additional qualitative study that will enrol a minimum of 20 patients and 20 caregivers to explore experiences of treatment decision-making and care. ETHICS AND DISSEMINATION: Ethics approval was obtained through Sydney Local Health District Human Research Ethics Committee (2019/ETH07718, 2020/ETH02226, 2021/ETH01020, 2019/ETH07783). OUTLOOK is approved to have waiver of individual patient consent. TIMELY, Co-TIMELY and CONTEND participants will provide written informed consent. Final results will be disseminated through peer-reviewed journals and presented at scientific meetings.

Risk factors for incident kidney disease in older adults: an Australian prospective population-based study.

BACKGROUND AND AIM: To determine risk factors for incident chronic kidney disease (CKD) in a large population-based cohort. METHODS: This prospective opt-in population-based cohort study is based on the 45 and Up Study, where New South Wales residents aged ≥45 years were randomly sampled from the Services Australia database and agreed to complete the 45 and Up Study baseline questionnaire and have their responses linked to their health data in routinely collected databases. The primary outcome was the development of incident CKD, defined as eGFR < 60 mL/min/1.73 m2 . CKD incidence was calculated using Poisson regression. Risk factors for incident CKD were assessed using Cox regression in multivariable models. RESULTS: In 39 574 participants who did not have CKD at enrolment, independent factors associated with developing CKD included: older age, regional residence (HR 1.38 (1.27-1.50) for outer regional vs major city), smoking (1.13 (1.00-1.27) for current smoker vs non-smoker), obesity (1.25 (1.16-1.35) for obese vs normal body mass index), diabetes mellitus (1.41 (1.33-1.50)), hypertension (1.53 (1.44-1.62)), coronary heart disease (1.13 (1.07-1.20)), depression/anxiety (1.16 (1.09-1.24)) and cancer (1.29 (1.20-1.39)). Migrants were less likely to develop CKD compared with people born in Australia (0.88 (0.83-0.94)). Gender, partner status and socioeconomic factors were not independently associated with developing CKD. CONCLUSIONS: This large population-based study found multiple modifiable and non-modifiable factors were independently associated with developing CKD. In the Australian setting, the risk of CKD was higher with regional residence. Differences according to socioeconomic status were predominantly explained by age, comorbidities and harmful health-related behaviours.

Prevalence, incidence and risk factors of diabetes in Australian adults aged ≥45 years: A cohort study using linked routinely-collected data.

AIMS: To use linked routinely-collected health data to estimate diabetes prevalence and incidence in an Australian cohort of adults aged ≥45 years, and examine risk factors associated with incident disease. RESEARCH DESIGN AND METHODS: The EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45) Study is a linked data study that combines baseline questionnaire responses from the population-based 45 and Up Study (2006-2009, n = 267,153) with multiple routinely-collected health databases up to December 2014. Among participants with ≥1 linked result for any laboratory test, diabetes status was determined from multiple data sources according to standard biochemical criteria, use of glucose-lowering medication or self-report, and the prevalence and incidence rate calculated. Independent risk factors of incident diabetes were examined using multivariable Cox regression. RESULTS: Among 152,169 45 and Up Study participants with ≥1 linked laboratory result in the EXTEND45 database (mean age 63.0 years; 54.9% female), diabetes prevalence was 10.8% (95% confidence interval [CI] 10.6%-10.9%). Incident disease in those without diabetes at baseline (n = 135,810; mean age 62.5 years; 56.1% female) was 10.0 per 1,000 person-years (95% CI 9.8-10.2). In all age groups, diabetes incidence was lower in women compared to men, an association that persisted in the fully adjusted analyses. Other independent risk factors of diabetes were older age, being born outside of Australia (with the highest rate of 19.2 per 1,000 person-years observed in people born in South and Central Asia), lower education status, lower annual household income, residence in a major city, family history of diabetes, personal history of cardiovascular disease or hypertension, higher body mass index, smoking and long sleeping hours. CONCLUSIONS: Our study represents an efficient approach to assessing diabetes frequency and its risk factors in the community. The infrastructure provided by the EXTEND45 Study will be useful for diabetes surveillance and examining other important clinical and epidemiological questions.

EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (the EXTEND45 Study): Protocol for an Australian Linked Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) and diabetes are the major causes of death and disability worldwide. They are associated with high health service utilization persisting over many years. Their slow progression and wide clinical variation make them eminently suitable for study in population-based cohorts. However, current understanding of their prevalence, incidence, and progression is largely based on studies conducted in clinical populations. OBJECTIVE: This study aims to establish a novel link between an existing population-based cohort (the 45 and Up Study) and routinely collected laboratory and administrative data to facilitate research across the full disease spectrum of CKD and diabetes. METHODS: In the EXTEND45 Study (EXamining OuTcomEs in chroNic Disease in the 45 and Up Study), baseline questionnaire responses of over 260,000 participants of the 45 and Up Study aged ≥45 years living in New South Wales (NSW), collected between January 2006 and December 2009, are linked to data from laboratory service providers as well as national- and state-based administrative datasets via probabilistic linkage. Routinely collected data were obtained for participants who could be linked between January 2005 and July 2013. Laboratory data will enable the identification of early cases of chronic disease and the assessment of clinically relevant biochemical targets during the disease course. Health administrative datasets will allow for the examination of health service use, pharmacological management, and clinical outcomes. RESULTS: The study received ethics approval from the NSW Population and Health Services Research Ethics Committee in February 2014. Data linkage for 267,153 of the 45 and Up Study participants was completed in June 2016, with congruent linkage achieved for 265,086 (99.23%) individuals. To date, the CKD and diabetes cohorts have been identified (published elsewhere), and a diverse portfolio of research projects relating to disease burden, risk factors, health outcomes, and health service utilization is in development. CONCLUSIONS: The EXTEND45 Study represents an unparalleled opportunity to perform extensive research into diseases of considerable public health and clinical importance. Strengths include the population-based nature of the cohort and the availability of longitudinal information on the complete disease pathway for affected individuals. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR1-10.2196/15646.

Incidence and Associations of Chronic Kidney Disease in Community Participants With Diabetes: A 5-Year Prospective Analysis of the EXTEND45 Study.

OBJECTIVE: To determine the incidence of and factors associated with an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 in people with diabetes. RESEARCH DESIGN AND METHODS: We identified people with diabetes in the EXamining ouTcomEs in chroNic Disease in the 45 and Up Study (EXTEND45), a population-based cohort study (2006-2014) that linked the Sax Institute's 45 and Up Study cohort to community laboratory and administrative data in New South Wales, Australia. The study outcome was the first eGFR measurement <60 mL/min/1.73 m2 recorded during the follow-up period. Participants with eGFR < 60 mL/min/1.73 m2 at baseline were excluded. We used Poisson regression to estimate the incidence of eGFR <60 mL/min/1.73 m2 and multivariable Cox regression to examine factors associated with the study outcome. RESULTS: Of 9,313 participants with diabetes, 2,106 (22.6%) developed incident eGFR <60 mL/min/1.73 m2 over a median follow-up time of 5.7 years (interquartile range, 3.0-5.9 years). The eGFR <60 mL/min/1.73 m2 incidence rate per 100 person-years was 6.0 (95% CI 5.7-6.3) overall, 1.5 (1.3-1.9) in participants aged 45-54 years, 3.7 (3.4-4.0) for 55-64 year olds, 7.6 (7.1-8.1) for 65-74 year olds, 15.0 (13.0-16.0) for 75-84 year olds, and 26.0 (22.0-32.0) for those aged 85 years and over. In a fully adjusted multivariable model incidence was independently associated with age (hazard ratio 1.23 per 5-year increase; 95% CI 1.19-1.26), geography (outer regional and remote versus major city: 1.36; 1.17-1.58), obesity (obese class III versus normal: 1.44; 1.16-1.80), and the presence of hypertension (1.52; 1.33-1.73), coronary heart disease (1.13; 1.02-1.24), cancer (1.30; 1.14-1.50), and depression/anxiety (1.14; 1.01-1.27). CONCLUSIONS: In participants with diabetes, the incidence of an eGFR <60 mL/min/1.73 m2 was high. Older age, remoteness of residence, and the presence of various comorbid conditions were associated with higher incidence.

Retrospective chart review to assess domains of quality of death (recognition of dying, appropriate limitations, symptom monitoring, anticipatory prescribing) of patients dying in the acute hospital under the care of a nephrology service with renal supportive care support over time.

AIM: To explore the quality of deaths in an acute hospital under a nephrology service at two teaching hospitals in Sydney with renal supportive care services over time. METHODS: Retrospective chart review of all deaths in the years 2004, 2009 and 2014 at St George Hospital (SGH) and in 2014 at the Concord Repatriation General Hospital. Domains assessed were recognition of dying, invasive interventions, symptom assessment, anticipatory prescribing, documentation of spiritual needs and bereavement information for families. End-of-life care plan (EOLCP) use was also evaluated at SGH. RESULTS: Over 90% of patients were recognized to be dying in all 3 years at SGH. Rates of interventions in the last week of life were low and did not differ across the 3 years. There was a significant increase in the prescription of anti-psychotic, anti-emetic and anti-cholinergic medication over the years at SGH. Use of EOLCP was significantly higher at SGH, and their use improved several quality domains. Of all deaths, 68% were referred to palliative care at SGH and 33% at Concord Repatriation General Hospital (not significant). Cessation of observations and non-essential medications and documentation of bereavement information given to families was low across both sites in all years, although this significantly improved when EOLCP were used. CONCLUSION: While acute teams are good at recognizing dying, they need support to care for dying patients. The use of EOLCP in acute services can facilitate improvements in caring for the dying. Renal supportive care services need time to become embedded in the culture of the acute hospital.

Burden of Care and Quality of Life Among Caregivers for Adults Receiving Maintenance Dialysis: A Systematic Review.

RATIONALE & OBJECTIVE: Dialysis is a burdensome and complex treatment for which many recipients require support from caregivers. The impact of caring for people dependent on dialysis on the quality of life of the caregivers has been incompletely characterized. STUDY DESIGN: Systematic review of quantitative studies of quality of life and burden to caregivers. SETTING & STUDY POPULATION: Caregivers of adults receiving maintenance dialysis. SELECTION CRITERIA FOR STUDIES: The Cochrane Library, Embase, PsycINFO, CINAHL, PubMed, and MEDLINE were systematically searched from inception until December 2016 for quantitative studies of caregivers. Pediatric and non-English language studies were excluded. Study quality was assessed using a modified Newcastle-Ottawa scale. DATA EXTRACTION: 2 independent reviewers selected studies and extracted data using a prespecified extraction instrument. ANALYTICAL APPROACH: Descriptive reports of demographics, measurement scales, and outcomes. Quantitative meta-analysis using random effects when possible. RESULTS: 61 studies were identified that included 5,367 caregivers from 21 countries and assessed the impact on caregivers using 70 different scales. Most (85%) studies were cross-sectional. The largest identified group of caregivers was female spouses who cared for recipients of facility-based hemodialysis (72.3%) or peritoneal dialysis (20.6%). Caregiver quality of life was poorer than in the general population, mostly comparable with caregivers of people with other chronic diseases, and often better than experienced by the dialysis patients cared for. Caregiver quality of life was comparable across dialysis modalities. LIMITATIONS: Heterogeneity in study design and outcome measures made comparisons between studies difficult and precluded quantitative meta-analysis. Study quality was generally poor. CONCLUSIONS: Quality of life of caregivers of dialysis recipients is poorer than in the general population and comparable to that of caregivers of individuals with other chronic diseases. The impact of caring for recipients of home hemodialysis or changes in the impact of caring over time have not been well studied. Further research is needed to optimally inform dialysis programs how to educate and support caregivers.

Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes - A systematic review.

AIM: Sodium glucose co-transporter 2 (SGLT2) inhibitors appear to protect against increased risks of cardiovascular and kidney disease in patients with type 2 diabetes but also cause some harms. Whether effects are comparable across drug class or specific to individual compounds is unclear. This meta-analysis assessed the class and individual compound effects of SGLT2 inhibition versus control on cardiovascular events, death, kidney disease and safety outcomes in patients with type 2 diabetes. METHODS: MEDLINE, EMBASE, the Cochrane Library and regulatory databases were systematically searched for data from randomized clinical trials that included reporting of cardiovascular events, deaths or safety outcomes. We used fixed effects models and inverse variance weighting to calculate relative risks with the 95% confidence intervals. RESULTS: The analyses included data from 82 trials, four overviews and six regulatory reports and there were 1,968 major cardiovascular events identified for analysis. Patients randomly assigned to SGLT2 had lower risks of major cardiovascular events (RR 0.85, 95%CI 0.77-0.93), heart failure (RR 0.67, 95%CI 0.55-0.80), all-cause death (RR 0.79, 95%CI 0.70-0.88) and serious decline in kidney function (RR 0.59, 0.49-0.71). Significant adverse effects were observed for genital infections (RR 3.06, 95%CI 2.73-4.43), volume depletion events (RR 1.24, 95%CI 1.07-1.43) and amputation (RR 1.44 95%CI 1.13-1.83). There was a high likelihood of differences in the associations of the individual compounds with cardiovascular death, hypoglycaemia and amputation (all I2 > 80%) and a moderate likelihood of differences in the associations with non-fatal stroke, all-cause death, urinary tract infection and fracture (all I2 > 30%). CONCLUSION: There are strong overall associations of SGLT2 inhibition with protection against major cardiovascular events, heart failure, serious decline in kidney function and all-cause death. SGLT2 inhibitors were also associated with infections, volume depletion effects and amputation. Some associations appear to differ between compounds.

Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: a systematic review and meta-analysis.

BACKGROUND: In patients with type 2 diabetes, sodium-glucose cotransporter-2 (SGLT2) inhibitors are known to reduce glucose concentrations, blood pressure, and weight, but to increase LDL cholesterol and the incidence of urogenital infections. Protection against cardiovascular events has also been reported, as have possible increased risks of adverse outcomes such as ketoacidosis and bone fracture. We aimed to establish the effects of SGLT2 inhibitors on cardiovascular events, death, and safety outcomes in adults with type 2 diabetes, both overall and separately for individual drugs. METHODS: In this systematic review and meta-analysis, we searched MEDLINE, Embase, the Cochrane Library, and websites of US, European, and Japanese regulatory authorities from Jan 1, 1950, to Sept 30, 2015, for data from prospective randomised controlled trials assessing the effects of SGLT2 treatment compared with controls. We excluded duplicate reports, trials of compound drugs, trials that lasted 7 days or fewer, trials that did not report on outcomes of interest, and articles that presented pooled trial data for which the individual trials could not be identified. We extracted data in duplicate using a standardised approach. The primary outcome was major adverse cardiovascular events. Secondary outcomes were cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, admission to hospital for unstable angina, heart failure, and all-cause mortality. We estimated summary relative risks with fixed-effects meta-analysis, with the I(2) statistic used to estimate heterogeneity of results beyond chance. FINDINGS: The analyses included data from six regulatory submissions (37 525 participants) and 57 published trials (33 385 participants), which provided data for seven different SGLT2 inhibitors. SGLT2 inhibitors protected against the risk of major adverse cardiovascular events (relative risk 0·84 [95% CI 0·75-0·95]; p=0·006), cardiovascular death (0·63 [0·51-0·77]; p<0·0001), heart failure (0·65 [0·50-0·85]; p=0·002), and death from any cause (0·71 [0·61-0·83]; p<0·0001). No clear effect was apparent for non-fatal myocardial infarction (0·88 [0·72-1·07]; p=0·18) or angina (0·95 [0·73-1·23]; p=0·70), but we noted an adverse effect for non-fatal stroke (1·30 [1·00-1·68]; p=0·049). We noted no clear evidence that the individual drugs had different effects on cardiovascular outcomes or death (all I(2)<43%). Safety analyses showed consistent increased risks of genital infections (regulatory submissions 4·75 [4·00-5·63]; scientific reports 2·88 [2·48-3·34]), but findings for some safety outcomes varied depending on whether anlayses were based on data extracted from regulatory submissions or trials reported in the scientific literature. INTERPRETATION: These data suggest net protection of SGLT2 inhibitors against cardiovascular outcomes and death. The efficacy results were driven by findings for empagliflozin (the only SGLT2 inhibitor for which data from a dedicated long-term cardiovascular safety trial have been reported), although results for the other drugs in the class were not clearly different. Adverse events were more difficult to quantify than was efficacy, with the effects of individual drugs in the class seeming to differ for some safety outcomes. Results from ongoing studies will be crucial to substantiate these findings across the drug class, but the available data provide a strong rationale to expect benefit from use of SGLT2 inhibitors in patients with type 2 diabetes at high risk of cardiovascular events. FUNDING: National Health and Medical Research Council of Australia.

Survival outcomes of supportive care versus dialysis therapies for elderly patients with end-stage kidney disease: A systematic review and meta-analysis.

AIM: Elderly people comprise a large and growing proportion of the global dialysis population. Regional differences in rates of dialysis in the elderly suggest multiple factors influence treatment decision-making including beliefs about the relative benefits and harms of dialysis and supportive (non-dialysis) care. We therefore systematically reviewed the literature reporting survival of elderly patients treated with either treatment pathway. METHODS: Systematic review and meta-analysis of cohort studies or randomized controlled trials identified in MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials published before July 2014. Survival by treatment modality was calculated. Subgroup analyses by study design, study size, patient age and cohort era were conducted. RESULTS: Eighty-nine studies published between 1976 and 2014 reported on 294 921 elderly end-stage kidney disease (ESKD) patients. There was a paucity of data for supportive care (724 patients or 0.2% of the total patients) and supportive care studies were susceptible to lead-time bias. One-year survival for elderly patients treated with undifferentiated dialysis was 73.0% (95% confidence interval (CI) 66.3-79.7%), 78.4% (95% CI 75.2-81.6) for haemodialysis and 77.9% (95% CI 73.8-81.9) for peritoneal dialysis. Supportive care patients had a 1-year survival of 70.6% (95% CI 63.3-78.0%). Residual heterogeneity remained within individual treatment modalities despite subgroup analyses. CONCLUSIONS: While the available literature demonstrates a broadly similar 1-year survival in elderly ESKD patients, it does not allow a confident estimate of the relative survival benefits of dialysis or supportive care. This uncertainty needs urgent attendance by further prospective data, which avoid bias and allow comparisons of quality of life and survival.

CKD in elderly patients managed without dialysis: survival, symptoms, and quality of life.

BACKGROUND AND OBJECTIVES: Survival, symptom burden, and quality of life (QOL) are uncertain for elderly patients with advanced CKD managed without dialysis. We examined these outcomes in patients managed with renal supportive care without dialysis (RSC-NFD) and those planned for or commencing dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this prospective observational study, symptoms were measured using the Memorial Symptom Assessment Scale and the Palliative care Outcomes Scale - Symptoms (renal) inventory and QOL was measured using the Short Form-36 survey. This study comprised 273 predialysis patients who had usual nephrology care and 122 nondialysis pathway patients who also attended a renal supportive care clinic adding the skills of a palliative medicine team. A further 72 patients commenced dialysis during this period without attending either clinic. RESULTS: Nondialysis patients were older than the predialysis group (82 versus 67 years; P<0.001) but had similar eGFR at the first clinic visit (16 ml/min per 1.73 m(2); P=0.92). Of the predialysis patients, 92 (34%) commenced dialysis. Compared with the RSC-NFD group, the death rate was lower in the predialysis group who did not require dialysis (hazard ratio, 0.23; 95% confidence interval, 0.12 to 0.41] and in those requiring dialysis (0.30; 0.13 to 0.67) but not in dialysis patients who had not attended the predialysis clinic (0.60; 0.35 to 1.03). Median survival in RSC-NFD patients was 16 (interquartile range, 9, 37) months and 32% survived >12 months after eGFR fell below 10 ml/min per 1.73 m(2). For the whole group, age, serum albumin, and eGFR <15 ml/min per 1.73 m(2) were associated with poorer survival. Of the nondialysis patients, 57% had stable or improved symptoms over 12 months and 58% had stable or improved QOL. CONCLUSIONS: Elderly patients who choose not to have dialysis as part of shared decision making survive a median of 16 months and about one-third survive 12 months past a time when dialysis might have otherwise been indicated. Utilizing the skills of palliative medicine helps provide reasonable symptom control and QOL without dialysis.

COnsiderations of Nephrologists when SuggestIng Dialysis in Elderly patients with Renal failure (CONSIDER): a discrete choice experiment.

BACKGROUND: Nephrologists often face difficult decisions when recommending dialysis or non-dialysis (supportive) care for elderly patients, given the uncertainty around survival and the burden of dialysis. Discrete choice experiments (DCEs) mimic real-world decisions through simultaneous consideration of multiple variables. We aimed to determine the relative influence of patient characteristics on dialysis recommendations. METHODS: We conducted a DCE among Australasian nephrologists consisting of 12 scenarios of two patients (described in terms of age, gender, cognition, comorbidity, life expectancy, current quality of life (QOL), expected QOL with dialysis, social support, patient and family inclination). Nephrologists indicated which patient they preferred recommending dialysis for, or whether they preferred 'neither'. Mixed logit models determined the odds of recommending dialysis over no dialysis. Trade-offs between QOL and survival were calculated. RESULTS: A total of 159 nephrologists participated (34% aged 40-49 years, 62% male and 69% Caucasian). All patient characteristics except gender significantly affected the likelihood of dialysis recommendation. Nephrologists were more likely to recommend dialysis for patients with preserved cognition (odds ratio [OR]: 68.3; 95% confidence interval [CI]: 33.4-140.0), lower comorbidity (OR: 2.1; 95% CI: 1.1-4.1), increased life expectancy (OR: 2.8; 95% CI: 2.1-3.7), high current QOL (OR: 2.8; 95% CI: 2.0-3.8) and positive patient and family dialysis inclination (OR: 27.5; 95% CI: 16.2-46.8 and OR: 2.0; 95% CI: 1.3-3.3, respectively). Nephrologists aged >65 were more likely (OR: 11.7; 95% CI: 1.8-77.2) to recommend dialysis. Nephrologists were willing to forgo 12 months of patient survival to avoid substantial QOL decrease with dialysis. CONCLUSION: Nephrologists avoided dialysis recommendation if it was expected to considerably reduce QOL. To inform elderly patients' dialysis decisions, systematic and longitudinal cognition and QOL evaluations are needed as well as better research into understanding patient preferences.

Impact of estimated GFR reporting on late referral rates and practice patterns for end-stage kidney disease patients: a multilevel logistic regression analysis using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA).

BACKGROUND: Late referral for renal replacement therapy (RRT) leads to worse outcomes. In 2005, estimated glomerular filtration rate (eGFR) reporting began in Australasia, with an aim of substantially increasing earlier disease detection. STUDY DESIGN: Observational cohort study using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA) data. SETTING & PARTICIPANTS: All patients commencing RRT in Australasia between January 1, 1999, and December 31, 2010. We excluded the period between December 31, 2004, and January 1, 2007, to allow for practice change. FACTOR: Introduction of eGFR reporting. OUTCOMES: Primary outcome was late referral defined as commencing RRT within 3 months of nephrology referral. Secondary outcomes included initial RRT modality and prepared access at hemodialysis therapy initiation. MEASUREMENTS: Late referral rates per era were determined and multilevel logistic regression was used to identify late referral predictors. RESULTS: We included 25,009 patients. Overall, 3,433 (25.3%) patients were referred late in the pre-eGFR era compared with 2,464 (21.6%) in the post-eGFR era, for an absolute reduction of 3.7% (95% CI, 2.7%-4.8%; P<0.001). After adjustments for age, body mass index, race, comorbid conditions, and primary kidney disease, adjusted late referral rates were 25.8% (95% CI, 23.3%-28.3%) and 21.8% (95% CI, 19.2%-24.4%) in the pre- and post-eGFR eras, respectively, for a difference of 4.0% (95% CI, 1.2%-6.8%; P=0.005). Late referral risk was attenuated significantly post-eGFR reporting (OR, 1.30; 95% CI, 1.12-1.51) compared to pre-eGFR reporting (OR, 2.15; 95% CI, 1.88-2.46) for indigenous patients. Late referral rates decreased for older patients but increased slightly for younger patients (P=0.001 for interaction between age and era). There was no impact on initial RRT modality or prepared access rates at hemodialysis therapy initiation between eras. LIMITATIONS: Residual confounding could not be excluded. CONCLUSIONS: eGFR reporting was associated with small reductions in late referral, but more than 1 in 5 patients are still referred late. Other initiatives to increase timely referral warrant investigation.

Effects of intensive blood pressure lowering on the progression of chronic kidney disease: a systematic review and meta-analysis.

BACKGROUND: Recent guidelines suggest lowering the target blood pressure for patients with chronic kidney disease, although the strength of evidence for this suggestion has been uncertain. We sought to assess the renal and cardiovascular effects of intensive blood pressure lowering in people with chronic kidney disease. METHODS: We performed a systematic review and meta-analysis of all relevant reports published between 1950 and July 2011 identified in a search of MEDLINE, Embase and the Cochrane Library. We included randomized trials that assigned patients with chronic kidney disease to different target blood pressure levels and reported kidney failure or cardiovascular events. Two reviewers independently identified relevant articles and extracted data. RESULTS: We identified 11 trials providing information on 9287 patients with chronic kidney disease and 1264 kidney failure events (defined as either a composite of doubling of serum creatinine level and 50% decline in glomerular filtration rate, or end-stage kidney disease). Compared with standard regimens, a more intensive blood pressure-lowering strategy reduced the risk of the composite outcome (hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.68-0.98) and end-stage kidney disease (HR 0.79, 95% CI 0.67-0.93). Subgroup analysis showed effect modification by baseline proteinuria (p = 0.006) and markers of trial quality. Intensive blood pressure lowering reduced the risk of kidney failure (HR 0.73, 95% CI 0.62-0.86), but not in patients without proteinuria at baseline (HR 1.12, 95% CI 0.67-1.87). There was no clear effect on the risk of cardiovascular events or death. INTERPRETATION: Intensive blood pressure lowering appears to provide protection against kidney failure events in patients with chronic kidney disease, particularly among those with proteinuria. More data are required to determine the effects of such a strategy among patients without proteinuria.

Perspective - the issues surrounding ESKD and dialysis in the elderly and those with co-morbidities.

There is a disproportionate increase in the number of elderly patients, many with multiple co-morbidities, commencing dialysis. Predictors of survival for elderly patients on dialysis include age, comorbidity score, malnutrition, poor functional status and late referral. Patients with high co morbidity scores may not gain a survival advantage with dialysis vs a non dialysis pathway. Late referral and lack of dialysis access are independent predictors of mortality in elderly patients commencing dialysis. Hospital free survival may be similar in dialysis and non-dialysis treated groups We have little data on those choosing not to start dialysis in terms of numbers, clinical course and survival. Most available data is not from an Australian or New Zealand source. The effects on quality of life of different management pathways on patients, carers and staff still need to be addressed.

Antihypertensive agents for preventing diabetic kidney disease.

BACKGROUND: Various blood pressure-lowering agents, and particularly inhibitors of the renin-angiotensin system (RAS), are widely used for people with diabetes to prevent the onset of diabetic kidney disease (DKD) and adverse cardiovascular outcomes. This is an update of a Cochrane review first published in 2003 and updated in 2005. OBJECTIVES: This systematic review aimed to assess the benefits and harms of blood pressure lowering agents in people with diabetes mellitus and a normal amount of albumin in the urine (normoalbuminuria). SEARCH METHODS: In January 2011 we searched the Cochrane Renal Group's Specialised Register through contact with the Trials Search Co-ordinator. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing any antihypertensive agent with placebo or another agent in hypertensive or normotensive patients with diabetes and no kidney disease (albumin excretion rate < 30 mg/d) were included. DATA COLLECTION AND ANALYSIS: Two investigators independently extracted data on kidney and other patient-relevant outcomes (all-cause mortality and serious cardiovascular events), and assessed study quality. Analysis was by a random effects model was applied to analyse results which were expressed as risk ratio (RR) and 95% confidence intervals (CI). MAIN RESULTS: We identified 26 studies that enrolling 61,264 participants. Angiotensin-converting enzyme inhibitors (ACEi) reduced the risk of new onset of microalbuminuria, macroalbuminuria or both when compared to placebo (8 studies, 11,906 patients: RR 0.71, 95% CI 0.56 to 0.89), with similar benefits in people with and without hypertension (P = 0.74), and when compared to calcium channel blockers (5 studies, 1253 participants: RR 0.60, 95% CI 0.42 to 0.85). ACEi reduced the risk of death when compared to placebo (6 studies, 11,350 participants: RR 0.84, 95% CI 0.73 to 0.97). No effect was observed for angiotensin receptor blockers (ARB) when compared to placebo for new microalbuminuria, macroalbuminuria or both (5 studies, 7653 participants: RR 0.90, 95% CI 0.68 to 1.19) or death (5 studies, 7653 participants: RR 1.12, 95% CI 0.88 to 1.41); however, meta-regression suggested possible benefits from ARB for preventing kidney disease in high risk patients. There was a trend towards benefit from use of combined ACEi and ARB for prevention of DKD compared with ACEi alone (2 studies, 4171 participants: RR 0.88, 95% CI 0.78 to 1.00).The risk of cough was significantly increased with ACEi when compared to placebo (6 studies, 11,791 patients: RR 1.84, 95% CI 1.24 to 2.72), however there was no significant difference in the risk of headache or hyperkalaemia. There was no significant difference in the risk of cough, headache or hyperkalaemia when ARB was to placebo. On average risk of bias was judged to be either low (27% to 69%) or unclear (i.e. no information available) (8% to 73%). Blinding of participants, incomplete outcome data and selective reporting were judged to be high in 23%, 31% and 31% of studies, respectively. AUTHORS' CONCLUSIONS: ACEi were found to prevent new onset DKD and death in normoalbuminuric people with diabetes, and could therefore be used in this population. More data are needed to clarify the role of ARB and other drug classes in preventing DKD.

Survival of elderly dialysis patients is predicted by both patient and practice characteristics.

BACKGROUND: Increasing numbers of elderly patients face decisions about the management of end-stage kidney disease. Improved understanding of contemporary patient and practice factors influencing prognosis may assist decision making for individual patients and their care providers. METHODS: This is a prospective registry study using multivariable proportional hazards models. A total of 1781 patients aged ≥ 75 years at dialysis initiation recorded in ANZDATA, the Australia and New Zealand renal replacement registry, between January 2002 and December 2005. The patient characteristics were demographic and comorbid conditions. The practice characteristics were late referral, access at dialysis initiation and intended dialysis modality (modality established by 90 days). The study outcome was mortality censored at 31 December 2007 or at recovery of renal function (of at least 30 days), transplantation or loss to follow-up. RESULTS: Median follow-up was 2.3 years (interquartile range 1.1-3.3 years) during which time, 65% of the patients died. Baseline factors independently associated with mortality were older age [hazard ratio (HR) 1.24 for 5-year increase, 95% confidence interval (CI) 1.13-1.36], body mass index <18.5 (HR 1.78, 95% CI 1.33-2.38), number of comorbidities (one comorbidity HR 1.38, 95% CI 1.13-1.69; two comorbidities HR 1.55, 95% CI 1.27-1.89; three or more comorbidities HR 1.89, 95% CI 1.55-2.31), late referral (HR 1.19, 95% CI 1.02-1.39), peritoneal dialysis as intended modality (HR 1.26, 95% CI 1.08-1.47) and unprepared access (HR 1.43, 95% CI 1.23-1.67). The limitations of the study were the observational nature of the analysis, potential selection bias introduced through analysis of a group who actually commenced dialysis and the potential confounding from unmeasured factors or dichotomous reporting of comorbidities. CONCLUSIONS: Within the elderly cohort, other patient characteristics have a greater association with mortality than 5-year age increments. Even after consideration of patient characteristics, practice factors have a striking impact on the survival of elderly patients commencing dialysis. In the absence of randomized studies, efforts to enhance the identification and preparation of elderly patients for dialysis may improve outcomes within current settings.

Effects of SGLT2 inhibitors on cardiovascular outcomes.

Glucose in the glomerular ultrafiltrate is actively reabsorbed by sodium glucose transporters (SGLT) in the proximal tubule. The SGLT2 protein is a high capacity molecule responsible for the majority of glucose reuptake with pharmacological inhibition, resulting in the loss of about 80g of glucose in the urine each day. About a dozen inhibitors of SGLT2 have entered clinical development, and the first has recently been submitted for registration with the United States Food and Drug Administration. The rationale for the clinical evaluation of these agents is their beneficial effects on glycaemia, blood pressure and body weight. No adequately powered trial has yet determined the effects of an SGLT2 inhibitor on either macrovascular or microvascular outcomes, although a number of large-scale trials are now ongoing. Evidence that will define the overall balance of benefits and risks of this new drug class is anticipated within the next 5 years.