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BACKGROUND Transplant recipients experience excess cardiac mortality. We compared circulatory death rates in Australian and New Zealand kidney transplant recipients to the general population and identified risk factors for circulatory death in kidney transplant recipients. METHODS The primary cause of death for kidney transplant recipients aged ≥18 was established through ICD-10-AM codes using data linkage between the Australia and New Zealand dialysis and transplant registry and national death registers. We estimated standardized mortality ratios (SMRs) and developed a Fine-Gray competing risks model to determine risk factors for cardiac mortality. RESULTS Of 5089 deaths in 16 329 kidney transplant recipients (158 325 person-years), 918 (18%) were cardiac. An increased risk of circulatory death was associated with older age (P < 0.001), male sex (P < 0.001), longer dialysis duration (P = 0.004), earlier era of transplantation (P < 0.001), ever graft failure (P < 0.001), known coronary artery disease (P = 0.002), and kidney failure from diabetes or hypertension (P < 0.001). The cardiac SMR was 5.4 [95% confidence interval (CI): 5.0-5.8], falling from 8.0 (95% CI: 4.9-13.1) in 1988 to 5.3 (95% CI: 4.0-7.0) in 2013 (P < 0.001). Females, particularly young ones, had significantly higher relative cardiac mortality than men. In recipients aged 40 years, the cardiac SMR was 26.5 (95% CI: 15.0-46.6) in females and 7.5 (95% CI: 5.0-11.1) for males. CONCLUSIONS Cardiac risks remain elevated in kidney transplant recipients and may be under-recognized, and prevention and treatment interventions less accessed, less effective or even harmful in female recipients.

ObjectiveTo evaluate sex differences in mortality among people with kidney failure compared with the general population.DesignPopulation based cohort study using data linkage.SettingThe Australian and New Zealand Dialysis and Transplant Registry (ANZDATA), which includes all patients receiving kidney replacement therapy in Australia (1980-2019) and New Zealand (1988-2019). Data were linked to national death registers to determine deaths and their causes, with additional details obtained from ANZDATA.ParticipantsOf 82 844 people with kidney failure, 33 329 were female (40%) and 49 555 were male (60%); 49 376 deaths (20 099 in female patients; 29 277 in male patients) were recorded over a total of 536 602 person years of follow-up.Main outcome measuresRelative measures of survival, including standardised mortality ratios, relative survival, and years of life lost, using general population data to account for background mortality (adjusting for country, age, sex, and year). Estimates were stratified by dialysis modality (haemodialysis or peritoneal dialysis) and for the subpopulation of kidney transplant recipients.ResultsFew differences in outcomes were found between male and female patients with kidney failure. However, compared with the general population, female patients with kidney failure had greater excess all cause deaths than male patients (female patients: standardised mortality ratio 11.3, 95% confidence interval 11.2 to 11.5, expected deaths 1781, observed deaths 20 099; male patients: 6.9, 6.8 to 6.9, expected deaths 4272, observed deaths 29 277). The greatest difference was observed among younger patients and those who died from cardiovascular disease. Relative survival was also consistently lower in female patients, with adjusted excess mortality 11% higher (95% confidence interval 8% to 13%). Average years of life lost was 3.6 years (95% confidence interval 3.6 to 3.7) greater in female patients with kidney failure compared with male patients across all ages. No major differences were found in mortality by sex for haemodialysis or peritoneal dialysis. Kidney transplantation reduced but did not entirely remove the sex difference in excess mortality, with similar relative survival (P=0.83) and years of life lost difference reduced to 2.3 years (95% confidence interval 2.2 to 2.3) between female and male patients.ConclusionsCompared with the general population, female patients had greater excess deaths, worse relative survival, and more years of life lost than male patients, however kidney transplantation reduced these differences. Future research should investigate whether systematic differences exist in access to care and possible strategies to mitigate excess mortality among female patients.

Background and Aims Initial WHO guidance advised cautious fluid administration for patients with COVID-19 due to concern about the development of acute respiratory distress syndrome (ARDS). However, as the pandemic unfolded it became apparent that patients who were admitted to hospital had high rates of AKI and this initiated a change in local clinical guidelines during early April 2020. We aimed to ascertain the impact of judicious intravenous fluid use on mortality, length of hospitalisation and AKI. Method An observational cohort study of 158 adults admitted with confirmed SARS-Cov-2 between 18th March and 9th May 2020 was conducted in a teaching hospital and designated centre for infectious diseases, London, UK. Key clinical and demographic data collected included clinical severity markers on admission, biochemical and haematological parameters as well as radiological findings. Primary outcomes were inpatient mortality, mortality at 6-weeks post discharge, length of hospitalisation and intensive care (ICU) admission. We also measured requirement for kidney replacement therapy (KRT) and AKI recovery rate at discharge. Using tests of difference, we compared key outcomes between patients treated with varying fluid regimens and then identified risk factors for AKI and mortality using multivariate logistic regression with results expressed as odds ratios (OR) with corresponding 95% confidence interval (CI). Results The median age was 74.4 (IQR 59.90 - 84.35) years, 66% were male, 53% white with hypertension and diabetes being the commonest co-morbidities. The median duration of illness prior to admission was 7 days (IQR 2 – 10) with respiratory symptoms and fever most prevalent. The people who presented with AKI on admission were more likely to receive fluids (34% vs 15%, p=0.02). 118 patients (75%) received fluids within 24-hours of admission with no difference in volume administered after local guidance change (p=0.78). Comparing patients receiving fluids with those who did not, we observed no difference in mortality (p=0.97), duration of hospital stays (p=0.26) or requirement for ICU admission (p=0.70). 18% died as an inpatient, and 52 patients were either admitted with or developed AKI. Of these 52 patients, 43 received fluids and 9 did not with no difference in KRT requirement (p=0.34), mortality (p=0.50) or AKI recovery (p=0.63). Peak AKI stage was greater among participants who received fluids though stage of AKI at presentation was also greater (p=0.04). Mortality rate in patients with an AKI is higher compared to overall inpatient mortality (31% vs 18%). Of the 36 patients with AKI who were discharged home, 25 patients (69.4%) had renal recovery by the time of discharge. Increasing age and clinical severity on admission were associated with higher mortality (see Figure 1). Older age was associated with 34 - 53 times higher risk of death compared with those aged ≤ 65 years (age 76 - 85 years: OR 34.26, 95% CI: 3.94 - 297.48, p=0.001; age > 85 years: OR 53.07, 95% CI: 5.23 - 539.03, p=0.001). Patients with NEWS2 >4 on admission has 5-fold increased risk of death than those with a score ≤4 (OR 5.26, 95% CI: 1.32 - 20.92). Black ethnicity was associated with a 16-fold increased risk of developing AKI (OR 15.86, 95% CI: 1.67 - 150.99). Conclusion To our knowledge, this is the first study to examine the impact of fluid management on inpatient mortality as well as on renal-associated outcomes of COVID-19 admission. Fluid administration regimen did not have an impact on mortality, length of hospitalisation or ICU admission, nor did it affect renal outcomes. Given the high rates of AKI and KRT in COVID-19 disease, early fluid administration is likely to be an important cornerstone of future management. Further adequately powered prospective studies are required to identify whether early fluid administration can reduce renal injury.

IntroductionFemale life expectancies consistently exceed males in the general population. Yet, this survival advantage may not persist in the presence of a chronic disease due to biological differences or healthcare inequities. Objectives and ApproachWe aimed to explore sex differences in mortality among people with end-stage kidney disease (ESKD). T he entire ESKD population in Australia, 1980-2013, and New Zealand,1988-2012, were included from the Australian and New Zealand Dialysis and Transplant Registry. Data linkage to national death registers was undertaken to ascertain deaths and their causes. We estimated relative measures of survival, including standardized mortality ratios (SMR), relative survival and expected life years lost, using general population data to account for background mortality, adjusting for country, age, sex and year. ResultsOf 60,823 ESKD patients, there were 25,042 females (41%) and 35,781 males (59%). Mortality sex differences within the ESKD population were minor, but once compared to the general population, female ESKD patients had more excess deaths, worse relative survival and greater life years lost compared to male ESKD patients. Females had 11.5 SMR (95%CI:11.3-11.7) and males had 6.7 SMR (95%CI:6.7-6.8), with greater disparity among younger ages and from certain causes. Relative survival was consistently lower in females, with adjusted excess mortality 9% higher (95%CI:7-12%) in ESKD females. Average life years lost was 4-5 years greater in ESKD females compared to males across all ages. Kidney transplantation reduced the sex differences in excess mortality, with similar relative survival (p=0.42) and average life years lost reduced to 3-4 years for females. Conclusion / ImplicationsThe impact of ESKD is more profound for women than men with greater excess mortality, however kidney transplantation attenuates these differences. Our findings show that chronic diseases and sex can compound to produce worse outcomes where women lose their survival advantage in the presence of ESKD.

Background Kidney transplant recipients are thought to experience a high risk of stroke; however, little data exist. We aimed to compare the stroke deaths in kidney transplant recipients with the general population and identify risk factors for stroke death in kidney transplant recipients. Methods Cause of death was established using data linkage between the Australian and New Zealand Dialysis and Transplant Registry and national death registers: Australia, 1980-2013, and New Zealand, 1988-2012. We estimated standardized mortality ratios (SMR) and used competing risks models to identify risk factors. Subanalysis explored those with polycystic kidney disease. Results Among 17 628 kidney transplant recipients, there were 158 stroke deaths and 5126 nonstroke deaths in 175 084 person-years. Those aged 30-49 years experienced more stroke deaths than expected, especially women (SMR in females: 19.7 [95% confidence interval, 12.9-30.3] and males: 9.1 [95% confidence interval, 5.6-14.6]). Higher risk of stroke death was associated with older age at transplant, ever graft failure, earlier era of transplant, preexisting cerebrovascular disease, and no previous malignancy. Polycystic kidney disease did not result in different SMR. Conclusions Kidney transplant recipients had excess stroke deaths, particularly at younger ages and women. Preexisting cerebrovascular disease was a potentially modifiable risk factor for stroke death, suggesting further studies of secondary stroke prevention for kidney transplant recipients.

Background: Inconsistencies in outcome reporting and frequent omission of patient-centered outcomes can diminish the value of trials in treatment decision-making. We identified critically important outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals. Methods: In a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During Round 2 and 3, participants re-rated the outcomes after reviewing their own score, the distribution of the respondents’ scores, and comments. We calculated the median, mean, and proportion rating 7-9 (critically important), and analyzed comments thematically. Results: 1018 participants (461 [45%] patients/caregivers and 557 [55%] health professionals) from 79 countries completed Round 1, and 779 (77%) completed Round 3. The top eight outcomes that met the consensus criteria in Round 3 (mean ≥7.5, median ≥8 and proportion >85%) in both groups were graft loss, graft function, chronic rejection, acute rejection, mortality, infection, cancer (excluding skin) and cardiovascular disease. Compared with health professionals, patients/caregivers gave higher priority to six outcomes (mean difference of 0.5 or more): skin cancer, surgical complications, cognition, blood pressure, depression, and ability to work. We identified five themes: capacity to control and inevitability, personal relevance, debilitating repercussions, gaining awareness of risks, and addressing knowledge gaps. Conclusions: Graft complications and severe comorbidities were critically important for both stakeholder groups. These stakeholder-prioritized outcomes will inform the core outcome set to improve the consistency and relevance of trials in kidney transplantation.

Background and Purpose— People with end-stage kidney disease (ESKD) are at greater risk of stroke. We aimed to compare stroke mortality between the ESKD population and the general population. Methods— We included all patients with incident ESKD in Australia, 1980 to 2013, and New Zealand, 1988 to 2012. The primary cause of death was ascertained using data linkage with national death registers. We produced standardized mortality ratios for stroke deaths, by age, sex, and calendar year. Results— We included 60 823 patients with ESKD, where 941 stroke deaths occurred during 381 874 person-years. Patients with ESKD had >3× the stroke deaths compared with the general population (standardized mortality ratio, 3.4; 95% CI, 3.2–3.6), markedly higher in younger people and women. The greatest excess was in intracerebral hemorrhages (standardized mortality ratio, 5.2; 95% CI, 4.5–5.9). Excess stroke deaths in patients with ESKD decreased over time, although were still double in 2013 (2013 standardized mortality ratio, 2.1; 95% CI, 1.5–2.9). Conclusions— People with ESKD experience much greater stroke mortality with the greatest difference for women and younger people. However, mortality has improved over time.

Background Cognitive impairment is associated with poorer quality of life, risk for hospitalization, and mortality. Cognitive impairment is common in people with end-stage kidney disease treated with hemodialysis, yet the severity and specific cognitive deficits are uncertain. Study Design Systematic review and meta-analysis. Setting & Population Adults receiving hemodialysis compared with the general population, people with non−dialysis-dependent chronic kidney disease (NDD-CKD), people receiving peritoneal dialysis, or people with nondialyzed chronic kidney failure. Selection Criteria for Studies Randomized controlled trials, cohort or cross-sectional studies without language restriction. Index Tests Validated neuropsychological tests of cognition. Outcomes Cognitive test scores, aggregated by cognitive domain: orientation and attention, perception, memory, language, construction and motor performance, concept formation and reasoning, and executive functions. Results 42 studies of 3,522 participants. Studies were of high or uncertain risk of bias, assessed by the Newcastle-Ottawa Scale. People treated with hemodialysis had worse cognition than the general population, particularly in attention (n=22; standardized mean difference [SMD], −0.93; 95% CI, −1.18 to −0.68). Hemodialysis patients performed better than nondialyzed patients with chronic kidney failure in attention (n=6; SMD, 0.70; 95% CI, 0.45 to 0.96) and memory (n=6; SMD, 0.36; 95% CI, 0.08 to 0.63), but had poorer memory than the general population (n=16; SMD, −0.41; 95% CI, −0.91 to 0.09) and people with NDD-CKD (n=5; SMD, −0.40; 95% CI, −0.60 to −0.21). There were insufficient data to show other differences among people receiving hemodialysis and those receiving peritoneal dialysis or with NDD-CKD. Limitations Potentially biased studies, not wholly adjusted for education. High heterogeneity, mainly due to the large variety of tests used to assess cognition. Conclusions People treated with hemodialysis have impaired cognitive function compared to the general population, particularly in the domains of orientation and attention and executive function. Cognitive deficits in specific domains should be further explored in this population and should be considered when approaching education and chronic disease management.

Background Cyclophosphamide, in combination with corticosteroids, has been first-line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end-stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. Objectives Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy-proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? Search methods We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria Randomised controlled trials (RCTs) and quasi-RCTs comparing any immunosuppressive treatment for biopsy-proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. Data collection and analysis Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. Main results In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty-nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age. Induction therapy Sixty-seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference. Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD. MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence. Maintenance therapy Nine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient-outcome data were sparse leading to imprecise estimates. Authors' conclusions In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.

This study aimed to determine absolute and excess stroke risks in people with ESRD compared with the general population.This cohort study used data linkage between the Australia and New Zealand Dialysis and Transplant Registry and hospital and death records for 10,745 people with ESRD in New South Wales from 2000 to 2010. For the general population, Australian Institute of Health and Welfare hospital usage records and Australian Bureau of Statistics census data were used. Rates and standardized incidence rate ratios of hospitalization with a stroke were calculated.People with ESRD had 640 hospitalizations with stroke in 49,472 person-years of follow-up (1294 per 100,000 person-years), and people in the general population had 338,392 hospitalizations with stroke (212 per 100,000 person-years), an incidence rate ratio of 3.32 (95% confidence interval, 3.31 to 3.33). Excess risk was greater for women (incidence rate ratio, 5.14; 95% confidence interval, 5.11 to 5.18) than men (incidence rate ratio, 2.52; 95% confidence interval, 2.51 to 2.54; P for interaction0.001) and decreased with age. People ages 35-39 years old with ESRD had an 11 times increased risk of stroke (incidence rate ratio, 11.08; 95% confidence interval, 9.41 to 13.05), and risk in people ages ≥85 years old increased 2-fold (incidence rate ratio, 2.04; 95% confidence interval, 1.87 to 2.23; P for interaction0.001). Excess risk was greater for intracerebral hemorrhage (incidence rate ratio, 4.18; 95% confidence interval, 4.11 to 4.26) than ischemic stroke (incidence rate ratio, 3.43; 95% confidence interval, 3.40 to 3.45; P for interaction0.01).People with ESRD have a substantially higher risk of stroke, particularly women and young people, and hemorrhagic stroke. Future work could investigate effective and safe interventions for primary and secondary prevention of stroke in people with ESRD.

Background: Whether abnormal myocardial perfusion scintigraphy (MPS), dobutamine stress echocardiography (DSE) or coronary angiography, performed during preoperative evaluation for potential kidney transplant recipients, predicts future cardiovascular morbidity is unclear. We assessed test performance for predicting all-cause mortality, cardiovascular mortality and major adverse cardiac events (MACE). Methods: We searched MEDLINE and EMBASE (to February 2014), appraised studies, and calculated risk differences and relative risk ratios (RRR) with 95% confidence intervals (95% CI) using random effects meta-analysis. Results: Fifty-two studies (7401 participants) contributed data to the meta-analysis. Among the different tests, similar numbers of patients experienced MACE after an abnormal test result compared with a normal result (risk difference: MPS 20 per 100 patients tested [95% CI, 0.11-0.29], DSE 24 [95% CI, 0.10-0.38], and coronary angiography 20 [95% CI, 0.08-0.32; P = 0.91]). Although there was some evidence that coronary angiography was better at predicting all-cause mortality than MPS (RRR, 0.69; 95% CI, 0.49-0.96; P = 0.03) and DSE (RRR, 0.72; 95% CI, 0.50-1.02; P = 0.06), noninvasive tests were as good as coronary angiography at predicting cardiovascular mortality (RRR, MPS, 0.89; 95% CI, 0.38-2.10; P = 0.78; DSE, 1.09; 95% CI, 0.12-10.05; P = 0.93), and MACE (RRR: MPS, 1.09; 95% CI, 0.64-1.86; P = 0.74; DSE, 1.56; 95% CI, 0.71-3.45; P = 0.25). Conclusions: Noninvasive tests are as good as coronary angiography at predicting future adverse cardiovascular events in advanced chronic kidney disease. However, a substantial number of people with negative test results go on to experience adverse cardiac events.

Background and aims Pharmacological treatments have improved survival in lupus nephritis. However, intravenous cyclophosphamide as first-line therapy has considerable toxicity and lacks evidence of efficacy to prevent end-stage kidney disease. The comparative efficacy of newer strategies compared with intravenous cyclophosphamide remains unclear. Methods We updated a random-effects meta-analysis of randomised controlled trials on induction and maintenance therapy for proliferative lupus nephritis. Evidence quality was assessed using GRADE. Results 59 trials (4465 participants) were eligible, including nine new trials. Compared with intravenous cyclophosphamide, mycophenolate mofetil (MMF) incurred similar risks of complete remission, mortality, or major infection, while risks of alopecia and ovarian failure were lower (Table 1) (evidence quality=moderate). There was no evidence combined MMF and tacrolimus had different effects on complete remission or major infection than intravenous cyclophosphamide (Table 1) (evidence quality=low-very low). In maintenance therapy (Table 2), MMF decreased risks of disease relapse compared to azathioprine (evidence quality=moderate), although there was no evidence of different effects between maintenance therapies on mortality, end-stage kidney disease, or major infection (evidence quality = very low –low). Conclusions MMF is as effective as intravenous cyclophosphamide in inducing remission in patients with proliferative lupus nephritis, with lower risks of alopecia and ovarian failure, although comparative effects of treatment on end-stage kidney disease and mortality remain uncertain. MMF is the most effective maintenance treatment to prevent relapse.

Background Cognitive impairment is common in people with chronic kidney disease (CKD) and associated with increased morbidity and mortality. Subtle changes can impact engagement with healthcare, comprehension, decision-making, and medication adherence. We aimed to systematically summarise evidence of cognitive changes in CKD. Methods We searched MEDLINE (March 2016) for cross-sectional, cohort or randomised studies that measured cognitive function in people with CKD (PROSPERO, registration number CRD42014015226). The CKD population included people with eGFR

Introduction People with end-stage kidney disease (ESKD) have up to 30-fold higher risk of stroke than the general population. Objective To determine risk factors associated with stroke death in the ESKD population. Methods We identified all patients with incident ESKD in Australia (1980–2013) and New Zealand (1988–2012) from the Australian and New Zealand Dialysis and Transplant Registry (ANZDATA) registry. We ascertained underlying cause of death from data linkage with national death registries and risk factors from ANZDATA. Using a competing risks multivariable regression model, we estimated cumulative incidence of stroke and non-stroke deaths, and risk factors for stroke deaths (adjusted sub-HR, SHR). Results We included 60 823 people with ESKD. There were 941 stroke deaths and 33 377 non-stroke deaths during 381 874 person-years of follow-up. Overall, the cumulative incidence of stroke death was 0.9% and non-stroke death was 36.8% 5 years after starting ESKD treatment. The risk of stroke death was higher at older ages (SHR 1.92, 95% CI 1.45 to 2.55), in females (SHR 1.41, 95% CI 1.21 to 1.64), in people with cerebrovascular disease (SHR 2.39, 95% CI 1.99 to 2.87), with ESKD caused by hypertensive/renovascular disease (SHR 1.39, 95% CI 1.09 to 1.78) or polycystic kidney disease (SHR 1.38, 95% CI 1.00 to 1.90), with earlier year of ESKD treatment initiation (SHR 1.93, 95% CI 1.56 to 2.39) and receiving dialysis (transplant vs haemodialysis SHR 0.27, 95% CI 0.09 to 0.84). Conclusion Patients with ESKD with higher risk of stroke death are older, women, with cerebrovascular disease, with hypertensive/renovascular or polycystic kidney disease cause of ESKD, with earlier year of ESKD treatment and receiving dialysis. These groups may benefit from targeted stroke prevention interventions. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial.

Inconsistent and incomplete outcome reporting may make estimates of treatment effects from published randomized trials unreliable. We aimed to determine outcome reporting practices and source of differences in reporting quality among randomized trials of primary immunosuppression in kidney transplantation. We searched the Cochrane Renal Group's Specialized Register, 2000-2012, specified four core outcomes we expected trials to report, and recorded if and how completely each was reported. We identified 179 trials. One hundred sixty-eight (94%) reported death, 145 (81%) as number dead and 119 (66%) as time to death. One hundred sixty-five (92%) reported graft loss, 158 (88%) as number with graft loss and 127 (71%) as time to graft loss. One hundred twenty-one (68%) reported creatinine and 114 (64%) estimated GFR (eGFR). One hundred forty-one (79%) provided complete reports of number dead, 95 (53%) censored and 99 (55%) uncensored number with graft loss. Seventy-three (41%) provided complete reports of time to death, 67 (37%) censored and 31 (17%) uncensored time to graft loss. Complete reporting of graft function was infrequent: 62 (35%) eGFR and 50 (28%) creatinine. All four outcomes were reported in any form in 61 (34%) and completely in 28 (16%) trials. No single trial or journal characteristic was consistently associated with complete outcome reporting. Outcome reporting in kidney transplant trials is inconsistent and frequently incomplete, and published estimates of treatment effects may be unreliable.

Background Lupus nephritis accounts for ∼1% of patients starting dialysis therapy. Treatment regimens combining cyclophosphamide with steroids preserve kidney function but have significant side effects. Newer immunosuppressive agents may have improved toxicity profiles. Study Design Systematic review and random-effects meta-analysis, searching MEDLINE (1966 to April 2012), EMBASE (1988-2011), and the Cochrane Renal Group Specialised Register. Setting & Population Patients with biopsy-proven proliferative lupus nephritis (classes III, IV, V+III, and V+IV). Selection Criteria Randomized controlled trials. Intervention Immunosuppressive treatment regimens used for induction and maintenance therapy of lupus nephritis. Outcomes Mortality, renal remission and relapse, doubling of creatinine level, proteinuria, incidence of end-stage kidney disease, ovarian failure, alopecia, leukopenia, infections, diarrhea, vomiting, malignancy, and bladder toxicity. Results 45 trials (2,559 participants) of induction therapy and 6 (514 participants) of maintenance therapy were included. In induction regimens comparing mycophenolate mofetil (MMF) with intravenous cyclophosphamide, there was no significant difference in mortality (7 studies, 710 patients; risk ratio [RR], 1.02; 95% CI, 0.52-1.98), incidence of end-stage kidney disease (3 studies, 231 patients; RR, 0.71; 95% CI, 0.27-1.84), complete renal remission (6 studies, 686 patients; RR, 1.39; 95% CI, 0.99-1.95), and renal relapse (1 study, 140 patients; RR, 0.97; 95% CI, 0.39-2.44). MMF-treated patients had significantly lower risks of ovarian failure (2 studies, 498 patients; RR, 0.15; 95% CI, 0.03-0.80) and alopecia (2 studies, 522 patients; RR, 0.22; 95% CI, 0.06-0.86). In maintenance therapy comparing azathioprine with MMF, the risk of renal relapse was significantly higher (3 studies, 371 patients; RR, 1.83; 95% CI, 1.24-2.71). Limitations Heterogeneity in interventions and definitions of remission and lack of long-term outcome reporting. Conclusions MMF is as effective as cyclophosphamide in achieving remission in lupus nephritis, but is safer, with a lower risk of ovarian failure. MMF is more effective than azathioprine in maintenance therapy for preventing relapse, with no difference in clinically important side effects.

Background & Aims Use of precut sphincterotomy during endoscopic retrograde cholangiopancreatography (ERCP) can increase the odds for cannulation success but is associated with increased risk of post-ERCP pancreatitis. Earlier, rather than delayed, use of precut sphincterotomy for cases with difficult biliary access might reduce this risk. We performed a meta-analysis of randomized controlled trials to determine how early use of precut sphincterotomy affects the risk of pancreatitis and rate of cannulation success compared with persistent standard cannulation. Methods We searched MEDLINE, EMBASE, and the Cochrane central register of controlled trials, along with meeting abstracts, through August 2014 for randomized controlled trials in which early precut sphincterotomy was compared with persistent standard cannulation in adults with difficult biliary access. Outcomes considered included primary cannulation success, overall cannulation success, incidence of post-ERCP pancreatitis, and overall adverse event rate. Findings from a random-effects model were expressed as pooled risk ratios (RRs) with 95% confidence intervals (CIs). Results We analyzed data from 5 studies (523 participants). The incidence of post-ERCP pancreatitis and success of overall cannulation did not differ significantly between the early precut and persistent standard therapy groups. Early use of precut sphincterotomy was associated with increased odds for primary cannulation success (RR, 1.32; 95% CI, 1.04–1.68). In subgroup analysis of studies that involved only fully qualified biliary endoscopists (not fellows), we found a significant reduction in risk of pancreatitis among patients receiving early precut vs the standard technique (RR, 0.29; 95% CI, 0.10–0.86). Conclusion Compared with standard therapy, early use of precut sphincterotomy did not increase the risk of post-ERCP pancreatitis in a meta-analysis. When the procedure is performed by qualified biliary endoscopists, early precut can reduce the risk of post-ERCP pancreatitis. Rates of primary cannulation increase with early precut. Further studies are needed to confirm these findings.

Background Atrial fibrillation (AF) often coexists with congestive cardiac failure (CCF), with multiple treatment options available. Methods Systematic review and meta-analysis of randomised control trials (RCT) comparing pulmonary vein isolation (PVI), pharmacological rate control, and atrioventricular junction ablation with pacemaker insertion (AVJAP) for AF, with a subgroup analysis in patients with CCF. We analysed changes in left ventricular ejection fraction (LVEF), Minnesota Living with Heart Failure Questionnaire (MLHFQ) score, six-minute walk distance (6MWD), treadmill exercise time, and treatment complications. Results were expressed as weighted mean differences (WMD) with 95% Confidence-Intervals (95%CI). Results We included seven RCT (425 participants). PVI was associated with a greater increase in LVEF (WMD+6.5%, 95%CI:+0.6to+12.5) and decrease in MLHFQ score (WMD-11.0, 95%CI:-2.6to-19.4) than pharmacological rate control in patients with CCF. PVI was also associated with a greater increase in LVEF (WMD+9.0%, 95%CI:+6.3to+11.7) and 6MWD (WMD+55.0metres, 95%CI:+34.9to+75.1), and decrease in MLHFQ score (WMD-22.0, 95%CI:-17.0to-27.0), compared to AVJAP in patients with CCF. Irrespective of cardiac function, pharmacological rate control had similar effects to AVJAP on LVEF (WMD+0.6%, 95%CI:-8.3to+9.4) and treadmill exercise time (WMD+0.5minutes, 95%CI:-0.4to+1.3). Conclusions Our results support the clinical implementation of PVI over AVJAP or pharmacological rate control in AF patients with CCF, who may or may not have already trialled pharmacological rhythm control.

Background Most people who receive a kidney transplant die from either cardiovascular disease or cancer before their transplant fails. The most common reason for someone with a kidney transplant to lose the function of their transplanted kidney necessitating return to dialysis is chronic kidney transplant scarring. Immunosuppressant drugs have side effects that increase risks of cardiovascular disease, cancer and chronic kidney transplant scarring. Belatacept may provide sufficient immunosuppression while avoiding unwanted side effects of other immunosuppressant drugs. However, high rates of post-transplant lymphoproliferative disease (PTLD) have been reported when belatacept is used in particular kidney transplant recipients at high dosage. Objectives 1) Compare the relative efficacy of belatacept versus any other primary immunosuppression regimen for preventing acute rejection, maintaining kidney transplant function, and preventing death. 2) Compare the incidence of several adverse events: PTLD; other malignancies; chronic transplant kidney scarring (IF/TA); infections; change in blood pressure, lipid and blood sugar control. 3) Assess any variation in effects by study, intervention and recipient characteristics, including: differences in pre-transplant Epstein Barr virus serostatus; belatacept dosage; and donor-category (living, standard criteria deceased, or extended criteria deceased). Search methods We searched the Cochrane Renal Group's Specialised Register to 1 September 2014 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. Selection criteria Randomised controlled trials (RCT) that compared belatacept versus any other immunosuppression regimen in kidney transplant recipients were eligible for inclusion. Data collection and analysis Two authors independently extracted data for study quality and transplant outcomes and synthesized results using random effects meta-analysis, expressed as risk ratios (RR) and mean differences (MD), both with 95% confidence intervals (CI). Subgroup analyses and univariate meta-regression were used to investigate potential heterogeneity. Main results We included five studies that compared belatacept and calcineurin inhibitors (CNI) that reported data from a total of 1535 kidney transplant recipients. Of the five studies, three (478 participants) compared belatacept and cyclosporin and two (43 recipients) compared belatacept and tacrolimus. Co-interventions included basiliximab (4 studies, 1434 recipients); anti-thymocyte globulin (1 study, 89 recipients); alemtuzumab (1 study, 12 recipients); mycophenolate mofetil (MMF, 5 studies, 1509 recipients); sirolimus (1 study, 26 recipients) and prednisone (5 studies, 1535 recipients). Up to three years following transplant, belatacept and CNI-treated recipients were at similar risk of dying (4 studies, 1516 recipients: RR 0.75, 95% CI 0.39 to 1.44), losing their kidney transplant and returning to dialysis (4 studies, 1516 recipients: RR 0.91, 95% CI 0.61 to 1.38), and having an episode of acute rejection (4 studies, 1516 recipients: RR 1.56, 95% CI 0.85 to 2.86). Belatacept-treated kidney transplant recipients were 28% less likely to have chronic kidney scarring (3 studies, 1360 recipients: RR 0.72, 95% CI 0.55 to 0.94) and also had better graft function (measured glomerular filtration rate (GFR) (3 studies 1083 recipients): 10.89 mL/min/1.73 m², 95% CI 4.01 to 17.77; estimated GFR (4 studies, 1083 recipients): MD 9.96 mL/min/1.73 m², 95% CI 3.28 to 16.64) than CNI-treated recipients. Blood pressure was lower (systolic (2 studies, 658 recipients): MD -7.51 mm Hg, 95% CI -10.57 to -4.46; diastolic (2 studies, 658 recipients): MD -3.07 mm Hg, 95% CI -4.83 to -1.31, lipid profile was better (non-HDL (3 studies 1101 recipients): MD -12.25 mg/dL, 95% CI -17.93 to -6.57; triglycerides (3 studies 1101 recipients): MD -24.09 mg/dL, 95% CI -44.55 to -3.64), and incidence of new-onset diabetes after transplant was reduced by 39% (4 studies (1049 recipients): RR 0.61, 95% CI 0.40 to 0.93) among belatacept-treated versus CNI-treated recipients. Risk of PTLD was similar in belatacept and CNI-treated recipients (4 studies, 1516 recipients: RR 2.79, 95% CI 0.61 to 12.66) and was no different among recipients who received different belatacept dosages (high versus low dosage: ratio of risk ratios (RRR) 1.06, 95% CI 0.11 to 9.80, test of difference = 0.96) or among those who were Epstein Barr virus seronegative compared with those who were seropositive before their kidney transplant (seronegative versus seropositive; RRR 1.49, 95% CI 0.15 to 14.76, test for difference = 0.73). The belatacept dose used (high versus low), type of donor kidney the recipient received (extended versus standard criteria) and whether the kidney transplant recipient received tacrolimus or cyclosporin made no difference to kidney transplant survival, incidence of acute rejection or estimated GFR. Selective outcome reporting meant that data for some key subgroup comparisons were sparse and that estimates of the effect of treatment in these groups of recipients remain imprecise. Authors' conclusions There is no evidence of any difference in the effectiveness of belatacept and CNI in preventing acute rejection, graft loss and death, but treatment with belatacept is associated with less chronic kidney scarring and better kidney transplant function. Treatment with belatacept is also associated with better blood pressure and lipid profile and a lower incidence of diabetes versus treatment with a CNI. Important side effects (particularly PTLD) remain poorly reported and so the relative benefits and harms of using belatacept remain unclear. Whether short-term advantages of treatment with belatacept are maintained over the medium- to long-term or translate into better cardiovascular outcomes or longer kidney transplant survival with function remains unclear. Longer-term, fully reported and published studies comparing belatacept versus tacrolimus are needed to help clinicians decide which patients might benefit most from using belatacept.

Background: People with chronic kidney disease (CKD) have an increased risk of stroke but the magnitude of increased risk and the independent effects of glomerular filtration rate (GFR) and albuminuria are unclear. We aimed to quantify the association between the independent and combined effects of GFR and albuminuria on stroke risk. Methods: We searched MEDLINE and EMBASE (February 2014) for cohort studies or randomized controlled trials (RCTs) which reported stroke incidence in adults with a baseline measurement of GFR and/or albuminuria. We extracted study and participant characteristics, risk of bias and relative risks (RR, with confidence interval; CI) of stroke associated with GFR and/or quantity of albuminuria, synthesized data using random effects meta-analysis and explored heterogeneity using meta-regression. Results: We identified 83 studies; 63 cohort studies (2 085 225 participants) and 20 RCTs (168 516 participants) reporting 30 392 strokes. There was an inverse linear relationship between GFR and risk of stroke, with risk of stroke increasing 7% (RR: 1.07, CI: 1.04-1.09) for every 10 mL/min/1.73 m(2) decrease in GFR. A 25 mg/mmol increase in albumin-creatinine ratio was associated with a 10% increased risk of stroke (RR: 1.10, 95% CI: 1.01-1.20). The effect of albuminuria was independent of GFR. Results were not different across subtypes of stroke, sex and varying prevalence of cardiovascular risk factors. Conclusions: Stroke risk increases linearly and additively with declining GFR and increasing albuminuria. CKD staging may also be a useful clinical tool for identifying people who may benefit most from interventions to reduce cardiovascular risk.

BACKGROUND: Cyclophosphamide, in combination with corticosteroids, has been first‐line treatment for inducing disease remission for proliferative lupus nephritis, reducing death at five years from over 50% in the 1950s and 1960s to less than 10% in recent years. Several treatment strategies designed to improve remission rates and minimise toxicity have become available. Treatments, including mycophenolate mofetil (MMF) and calcineurin inhibitors, alone and in combination, may have equivalent or improved rates of remission, lower toxicity (less alopecia and ovarian failure) and uncertain effects on death, end‐stage kidney disease (ESKD) and infection. This is an update of a Cochrane review first published in 2004 and updated in 2012. OBJECTIVES: Our objective was to assess the evidence and evaluate the benefits and harms of different immunosuppressive treatments in people with biopsy‐proven lupus nephritis. The following questions relating to management of proliferative lupus nephritis were addressed: 1) Are new immunosuppressive agents superior to or as effective as cyclophosphamide plus corticosteroids? 2) Which agents, dosages, routes of administration and duration of therapy should be used? 3) Which toxicities occur with the different treatment regimens? SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 2 March 2018 with support from the Cochrane Information Specialist using search terms relevant to this review. Studies in the Specialised Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi‐RCTs comparing any immunosuppressive treatment for biopsy‐proven class III, IV, V+III and V+VI lupus nephritis in adult or paediatric patients were included. DATA COLLECTION AND ANALYSIS: Data were abstracted and the risks of bias were assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) and measures on continuous scales calculated as mean differences (MD) with 95% confidence intervals (CI). The primary outcomes were death (all causes) and complete disease remission for induction therapy and disease relapse for maintenance therapy. Evidence certainty was determined using GRADE. MAIN RESULTS: In this review update, 26 new studies were identified, to include 74 studies involving 5175 participants overall. Twenty‐nine studies included children under the age of 18 years with lupus nephritis, however only two studies exclusively examined the treatment of lupus nephritis in patients less than 18 years of age. Induction therapy Sixty‐seven studies (4791 participants; median 12 months duration (range 2.5 to 48 months)) reported induction therapy. The effects of all treatment strategies on death (all causes) and ESKD were uncertain (very low certainty evidence) as this outcome occurred very infrequently. Compared with intravenous (IV) cyclophosphamide, MMF may have increased complete disease remission (RR 1.17, 95% CI 0.97 to 1.42; low certainty evidence), although the range of effects includes the possibility of little or no difference. Compared to IV cyclophosphamide, MMF is probably associated with decreased alopecia (RR 0.29, 95% CI 0.19 to 0.46; 170 less (129 less to 194 less) per 1000 people) (moderate certainty evidence), increased diarrhoea (RR 2.42, 95% CI 1.64 to 3.58; 142 more (64 more to 257 more) per 1000 people) (moderate certainty evidence) and may have made little or no difference to major infection (RR 1.02, 95% CI 0.67 to 1.54; 2 less (38 less to 62 more) per 1000 people) (low certainty evidence). It is uncertain if MMF decreased ovarian failure compared to IV cyclophosphamide because the certainty of the evidence was very low (RR 0.36, 95% CI 0.06 to 2.18; 26 less (39 less to 49 more) per 1000 people). Studies were not generally designed to measure ESKD. MMF combined with tacrolimus may have increased complete disease remission (RR 2.38, 95% CI 1.07 to 5.30; 336 more (17 to 1048 more) per 1000 people (low certainty evidence) compared with IV cyclophosphamide, however the effects on alopecia, diarrhoea, ovarian failure, and major infection remain uncertain. Compared to standard of care, the effects of biologics on most outcomes were uncertain because of low to very low certainty of evidence. Maintenance therapy Nine studies (767 participants; median 30 months duration (range 6 to 63 months)) reported maintenance therapy. In maintenance therapy, disease relapse is probably increased with azathioprine compared with MMF (RR 1.75, 95% CI 1.20 to 2.55; 114 more (30 to 236 more) per 1000 people (moderate certainty evidence). Multiple other interventions were compared as maintenance therapy, but patient‐outcome data were sparse leading to imprecise estimates. AUTHORS' CONCLUSIONS: In this review update, studies assessing treatment for proliferative lupus nephritis were not designed to assess death (all causes) or ESKD. MMF may lead to increased complete disease remission compared with IV cyclophosphamide, with an acceptable adverse event profile, although evidence certainty was low and included the possibility of no difference. Calcineurin combined with lower dose MMF may improve induction of disease remission compared with IV cyclophosphamide, but the comparative safety profile of these therapies is uncertain. Azathioprine may increase disease relapse as maintenance therapy compared with MMF.