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Background: Non-anaemic iron deficiency is highly prevalent in people living with chronic kidney disease (CKD) but is underdiagnosed and undertreated, especially in earlier stages of CKD. A multicentre trial assessing the effect of intravenous iron supplementation in iron-deficiency but not anaemic people with CKD included a qualitative sub-study that aimed to explore the patient experience and psychosocial impact of living with CKD and iron deficiency, and the experience of the therapeutic intervention (intravenous iron and exercise)., Methods: Semi-structured interviews were conducted with 23 trial participants blinded to treatment. Topics explored included experiences of living with CKD and iron deficiency, symptoms, social and leisure activities, quality of life, and participants' views and experiences of receiving the therapeutic intervention. Thematic analysis was used to identify and report themes., Results: Six overarching themes were identified: lack of awareness of iron deficiency; overwhelming feelings of tiredness; feeling limited; balancing emotions; perceptions and experiences of therapeutic treatment received; and impact of trial participation on life participation. Trial participation, specifically the exercise training, was perceived to be beneficial, with improvements in life participation and psychological wellbeing experienced. However, there were no clear differences between treatment groups, with mixed perceptions about which therapeutic treatment was received., Conclusions: The impact of tiredness on individuals with CKD is profound and can result in reduced vitality, impaired ability to engage in life activities and emotional conflict. Improved communication and support about psychosocial impact and management of symptoms, particularly fatigue, for people with CKD may be required, alongside effective therapeutic interventions, to improve symptom management and quality of life., Competing Interests: S.B. was a previous Trustee for Kidney Research UK and has served on the advisory board of CSL Vifor. P.A.K. has served on advisory boards and lectured for CSL Vifor, and Salford Royal has received research funding from this company. D.C.W. has received honoraria from CSL Vifor. D.B. has lectured for CSL Vifor. All other authors declare that they have no competing interests., (© The Author(s) 2025. Published by Oxford University Press on behalf of the ERA.)

Background and Hypothesis: Mild cognitive impairment and dementia (CI) are common in patients with CKD. We aim to clarify whether and how CKD and CI coexistence increases adverse health outcomes., Methods: This retrospective observational cohort study was conducted on CKD patients (stages 3-5) from the TriNetX platform. CKD patients with and without pre-existing CI were included from 115 healthcare organizations, and their outcomes were compared. The two cohorts were propensity score matched (PSM) for age, sex, ethnicity, comorbidities, BMI, blood parameters, and medications. The proportional hazard assumption was tested with a 95% confidence interval. Kaplan-Meier analysis was used to calculate survival probability. Outcomes were included from 1 day after the CKD diagnosis until 10 years afterwards., Results: We identified 533 772 CKD patients, and 8184 had co-existent CI. Two cohorts of 8170 PSM patients each were generated. The mean age was 60.5 ± 7.0 years and the eGFR was 52.1±19 mL/min. Mean follow-up was 23.2 months. CKD patients with CI had higher all-cause mortality (18.5% vs 12.6%), higher risk of cerebrovascular disease (11.3% vs 6.9%), transient cerebral ischemic attacks (2.7% vs 1.6%), hypotension (16.5%-12.5%), malnutrition (6.7% vs 4.0%), pneumonia (10.7% vs 7.9%), urinary infections (13.2% vs 9.3%), encephalopathy (9.9% vs 5.0%), mood disorders (13.6% vs 9.7%), psychosis (9.8% vs 4.6%), and epilepsy (4.3% vs 1.5%). Higher use of antidepressants (26.3% vs 16.3%), anticonvulsants (19.5% vs 15.1%), antipsychotics (18.6% vs 9.1%), anticholinesterase (5.6% vs 0.1%), and benzodiazepines (30.6% vs 26.6%) was noted in those with CI. All these findings were statistically significant., Conclusion: Despite the limitations of a retrospective study, real-world data demonstrate that concomitant CI is a decisive risk factor for higher mortality and increased adverse outcomes in patients with CKD. These results highlight the need for routine comprehensive cognitive assessments in patients at any stage of CKD., Competing Interests: L.M., F.R., R.C., G.H., G.G.B., P.M.C., and M.T. declare no competing interests. R.A.D. received grants from NIHR, Alzheimer's Society, and Lilly, received consulting fees and honoraria from Lilly, and is on an advisory board for Otsuka. J.T. received consulting fees from Astra-Zeneca and the Royal College of GPs, received honoraria from Astra-Zeneca and Bayer, and received support for attending meetings from Bayer. S.S. received a grant from Kidney Research UK. P.A.K. received grants from Vifor, Astellas, Pharmacosmos, and Unicyte, received consulting fees and honoraria from Vifor, Astra-Zeneca, Pfizer, Pharmacosmos, Napp, GSK, Novartis, and Bayer, received consulting fees from Astra-Zeneca, Vifor, Unicyte, UCB, and Otsuka, and received support for attending meetings from Pharmacosmos, Vifor, and Medice. Prior presentation: Data included in this manuscript were presented in a focused oral presentation to the European Renal Association Annual Meeting of 2024., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background and Aims: What is the relationship between blood tests for iron deficiency, including anaemia, and the response to intravenous iron in patients with heart failure?, Methods: In the IRONMAN trial, 1137 patients with heart failure, ejection fraction ≤ 45%, and either serum ferritin < 100 µg/L or transferrin saturation (TSAT) < 20% were randomized to intravenous ferric derisomaltose (FDI) or usual care. Relationships were investigated between baseline anaemia severity, ferritin and TSAT, to changes in haemoglobin from baseline to 4 months, Minnesota Living with Heart Failure (MLwHF) score and 6-minute walk distance achieved at 4 months, and clinical events, including heart failure hospitalization (recurrent) or cardiovascular death., Results: The rise in haemoglobin after administering FDI, adjusted for usual care, was greater for lower baseline TSAT (Pinteraction < .0001) and ferritin (Pinteraction = .028) and more severe anaemia (Pinteraction = .014). MLwHF scores at 4 months were somewhat lower (better) with FDI for more anaemic patients (overall Pinteraction = .14; physical Pinteraction = .085; emotional Pinteraction = .043) but were not related to baseline TSAT or ferritin. Blood tests did not predict difference in achieved walking distance for those randomized to FDI compared to control. The absence of anaemia or a TSAT ≥ 20% was associated with lower event rates and little evidence of benefit from FDI. More severe anaemia or TSAT < 20%, especially when ferritin was ≥100 µg/L, was associated with higher event rates and greater absolute reductions in events with FDI, albeit not statistically significant., Conclusions: This hypothesis-generating analysis suggests that anaemia or TSAT < 20% with ferritin > 100 µg/L might identify patients with heart failure who obtain greater benefit from intravenous iron. This interpretation requires confirmation., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Due to the high correlation of chronic kidney disease (CKD) with other comorbidities, the sole effect of CKD on deprived people is not clear. In addition, there is a paucity of evidence in the literature linking isolated domains of deprivation to outcomes. This study aimed to examine whether deprivation was associated with adverse outcomes in patients with CKD, independent of cardiometabolic morbidities. Individual domains of deprivation were also evaluated., Methods: A retrospective study of patients with non-dialysis-dependent CKD (ND-CKD) in the Salford Kidney Study to investigate the association of deprivation with outcomes. The English Indices of Deprivation was used for the comparative analysis of the five quintiles of deprivation. Two propensity score methods were used to attenuate the confounding effect of cardiometabolic morbidities between the least and the most deprived groups., Results: People living in the least deprived areas ( n  = 319) had a lower risk of combined outcomes (all-cause mortality and renal replacement therapy) when compared with the most deprived group ( n  = 813) [hazard ratio (HR) 0.83; 95% confidence interval (CI) 0.71-0.98]. The negative association of deprivation remained after matching but with mixed statistical significance when using different propensity methods (HR 0.85; 95% CI 0.70-1.03 for propensity score matching and HR 0.77; 95% CI 0.61-0.98 for inverse probability weighting). The association of combined outcomes varied across component index of multiple deprivation domains with wide CIs. However, areas with lower scores for education, income and employment were significantly associated with a higher risk., Conclusions: This study has identified that in people with ND-CKD, unemployment, poor educational attainment and lower household income were associated with poor outcomes. The association of deprivation with adverse outcomes persists despite adjustment for cardiometabolic morbidities., Competing Interests: This research was part funded by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (NIHR203308). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. Professor Sinha reports grants from AstraZeneca, Johnson & Johnson, and Amgen; consultant fees from Sanifit, Novartis, AstraZeneca, GSK, Boehringer Ingelheim, Bayer, Sanofi-Genzyme, Inozyme Pharma, and CSL Vifor; honoraria from Bayer, Menarini, AstraZeneca, GSK, Novartis, Sanofi-Genzyme, CSL Vifor, and Medscape; and support for attending meetings from AstraZeneca, Novartis, and CSL Vifor. Professor Sinha is the National Clinical Director for renal services, NHS England. Professor Kalra reports grants from Vifor and Astellas; consulting fees from AstraZeneca, Vifor, Unicyte, and UCB; honoraria from Vifor, AstraZeneca, and Pfizer; and support to attend meetings from Pharmacosmos and Vifor. No other authors have anything else to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Many non-modifiable factors are associated with poorer health-related quality of life (HRQoL) experienced by people with chronic kidney disease (CKD). We hypothesize that potentially modifiable factors for poor HRQoL can be identified among CKD patients, providing potential targets for intervention., Method: The National Unified Renal Translational Research Enterprise Chronic Kidney Disease (NURTuRE-CKD) cohort study recruited 2996 participants from nephrology centres with all stages of non-dialysis-dependent CKD. Baseline data collection for sociodemographic, anthropometric, biochemical and clinical information, including Integrated Palliative care Outcome Scale renal, Hospital Anxiety and Depression score (HADS) and the 5-level EuroQol-5D (EQ-5D-5L) as HRQoL measure, took place between 2017 and 2019. EQ-5D-5L dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) were mapped to an EQ-5D-3L value set to derive index value. Multivariable mixed effects regression models, adjusted for known factors affecting HRQoL with recruitment region as a random effect, were fit to assess potentially modifiable factors associated with index value (linear) and within each dimension (logistic)., Results: Among the 2958/2996 (98.7%) participants with complete EQ-5D data, 2201 (74.4%) reported problems in at least one EQ-5D-5L dimension. Multivariable linear regression identified independent associations between poorer HRQoL (EQ-5D-3L index value) and obesity (body mass index ≥30.0 kg/m 2 , β -0.037, 95% CI -0.058 to -0.016, P  = .001), HADS depression score ≥8 (β -0.159, -0.182 to -0.137, P  < .001), anxiety score ≥8 (β -0.090, -0.110 to -0.069, P  < .001), taking ≥10 medications (β -0.065, -0.085 to -0.046, P  < .001), sarcopenia (β -0.062, -0.080 to -0.043, P  < .001) haemoglobin <100 g/L (β -0.047, -0.085 to -0.010, P  = .012) and pain (β -0.134, -0.152 to -0.117, P  < .001). Smoking and prescription of prednisolone independently associated with problems in self-care and usual activities respectively. Renin-angiotensin system inhibitor (RASi) prescription associated with fewer problems with mobility and usual activities., Conclusion: Potentially modifiable factors including obesity, pain, depression, anxiety, anaemia, polypharmacy, smoking, steroid use and sarcopenia associated with poorer HRQoL in this cohort, whilst RASi use was associated with better HRQoL in two dimensions., Competing Interests: T.P. receives funding from Kidney Research UK (Charity number: 252 892) who are also funders of the NURTuRE-CKD study. S.H. has no conflicts of interest to declare. O.L.A. receives funding from the National Institute for Health Research (NIHR) Birmingham Biomedical Research Centre (BRC), NIHR Applied Research Collaboration (ARC), West Midlands, NIHR Blood and Transplant Research Unit (BTRU) in Precision Transplant and Cellular Therapeutics at the University of Birmingham and University Hospitals Birmingham NHS Foundation, The Health Foundation, Innovate UK (part of UK Research and Innovation), Gilead Sciences Ltd, Merck, Anthony Nolan, and Sarcoma UK. O.L.A. declares personal fees from Gilead Sciences Ltd, GlaxoSmithKline (GSK) and Merck outside the submitted work. B.L. is funded by the NIHR. M.B. has no conflicts of interest to declare. P.J.R. has no conflicts of interest to declare. P.C. reports a leadership role in the UK Kidney Association and a non-remunerated research consultancy with Boehringer Ingelheim. P.A.K. has received honoraria for lecturing and advisory board attendance from AstraZeneca and UCB, which are both funders of the NURTuRE study. D.C.W. has an ongoing consultancy contract with AstraZeneca. In the last 3 years, he has received payments from the following companies in relation to consultancy work, speaker engagements or service on trials committees: Astellas, Bayer, Boehringer Ingelheim, Eledon, GSK, Galderma, Janssen, Menarini, Merck, Pharmacosmos, Mineralys, ProKidney, Tricida and Vifor. M.W.T. reports consulting fees from Boehringer Ingelheim, honoraria from Bayer and support to attend conferences from Bayer and a leadership role in the International Society of Nephrology. S.D.S.F. has no conflicts of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Chronic kidney disease (CKD) is common but heterogenous and is associated with multiple adverse outcomes. The National Unified Renal Translational Research Enterprise (NURTuRE)-CKD cohort was established to investigate risk factors for clinically important outcomes in persons with CKD referred to secondary care., Methods: Eligible participants with CKD stages G3-4 or stages G1-2 plus albuminuria >30 mg/mmol were enrolled from 16 nephrology centres in England, Scotland and Wales from 2017 to 2019. Baseline assessment included demographic data, routine laboratory data and research samples. Clinical outcomes are being collected over 15 years by the UK Renal Registry using established data linkage. Baseline data are presented with subgroup analysis by age, sex and estimated glomerular filtration rate (eGFR)., Results: A total of 2996 participants was enrolled. Median (interquartile range) age was 66 (54-74) years, eGFR 33.8 (24.0-46.6) mL/min/1.73 m2 and urine albumin to creatinine ratio 209 (33-926) mg/g; 58.5% were male. Of these participants, 1883 (69.1%) were in high-risk CKD categories. Primary renal diagnosis was CKD of unknown cause in 32.3%, glomerular disease in 23.4% and diabetic kidney disease in 11.5%. Older participants and those with lower eGFR had higher systolic blood pressure and were less likely to be treated with renin-angiotensin system inhibitors (RASi) but were more likely to receive a statin. Female participants were less likely to receive a RASi or statin., Conclusions: NURTuRE-CKD is a prospective cohort of persons who are at relatively high risk of adverse outcomes. Long-term follow-up and a large biorepository create opportunities for research to improve risk prediction and to investigate underlying mechanisms to inform new treatment development., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: The recombinant protein-based vaccine, NVX-CoV2373, demonstrated 89.7% efficacy against coronavirus disease 2019 (COVID-19) in a phase 3, randomized, observer-blinded, placebo-controlled trial in the United Kingdom. The protocol was amended to include a blinded crossover. Data to the end of the placebo-controlled phase are reported., Methods: Adults aged 18-84 years received 2 doses of NVX-CoV2373 or placebo (1:1) and were monitored for virologically confirmed mild, moderate, or severe COVID-19 (onset from 7 days after second vaccination). Participants who developed immunoglobulin G (IgG) against nucleocapsid protein but did not show symptomatic COVID-19 were considered asymptomatic. Secondary outcomes included anti-spike (S) IgG responses, wild-type virus neutralization, and T-cell responses., Results: Of 15 185 participants, 13 989 remained in the per-protocol efficacy population (6989 NVX-CoV2373, 7000 placebo). At a maximum of 7.5 months (median, 4.5) postvaccination, there were 24 cases of COVID-19 among NVX-CoV2373 recipients and 134 cases among placebo recipients, a vaccine efficacy of 82.7% (95% confidence interval [CI], 73.3%-88.8%). Vaccine efficacy was 100% (95% CI, 17.9%-100.0%) against severe disease and 76.3% (95% CI, 57.4%-86.8%) against asymptomatic disease. High anti-S and neutralization responses to vaccination were evident, together with S-protein-specific induction of interferon-γ secretion in peripheral blood T cells. Incidence of serious adverse events and adverse events of special interest were similar between groups., Conclusions: A 2-dose regimen of NVX-CoV2373 conferred a high level of ongoing protection against asymptomatic, symptomatic, and severe COVID-19 through >6 months postvaccination. A gradual decrease of protection suggests that a booster may be indicated., Clinical Trials Registration: EudraCT, 2020-004123-16., Competing Interests: Potential conflicts of interest. K. A., I. C., L. F., G. G., I. Mc., E. J. R., A. R., K. S., and S. T. are employees of Novavax Inc and receive a salary for their work. K. S. reports stock received as part of employment compensation from Novavax. A. R. reports stock or stock options from Novavax. E. J. R. and I. Mc. report Novavax stock. K. A. reports vested and unvested Novavax stock/restricted stock units. I. C. reports Novavax stock and stock options and salary and bonus as an employee of Novavax. L. F. reports consulting fees as a prior full-time employee, now contractor to, Novavax reimbursed hourly for work performed on this study and in analyses and drafting this report, and shares and stock options from Novavax. G. G. reports stock-related compensations from Novavax. S. T. reports royalties or licenses, salary and stock, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events, and a leadership or fiduciary role in other board, society, committee, or advocacy group, paid or unpaid, as an employee of Novavax. Guy's and St Thomas' National Health Service (NHS) Foundation Trust (with which A. L. G. is affiliated) received funding from Novavax for this trial. Oxford University has entered into a partnership with AstraZeneca for further development of ChAdOx1 nCoV-19. A. L. G. is named as an inventor on a patent covering use of a particular promoter construct that is often used in vectored vaccines and is incorporated in the ChAdOx1 nCoV-19 vaccine, and may benefit from royalty income paid to the University of Oxford from sales of this vaccine by AstraZeneca and its sublicensees under the university's revenue sharing policy. M. B. reports a research grant to institution from Novavax related to this manuscript, advisory/speaker fees or grants to the institution from GSK, ViiV, Gilead, Janssen, Moderna, Pfizer, Valneva, MSD, Roche, Cipla, and Mylan and support for attending the online World AIDS conference from ViiV. D. R. C. reports a research grant to institution from Gilead Sciences, unpaid participation as an Independent Data Monitoring Board (IDMB) member for the FLARE Trial, and unpaid role as a British HIV Association trustee member. J. G. reports a research contract with institution from Novavax. C. A. C. reports a research grant to institution from Novavax related to this manuscript, and a research grant to institution from Moderna. P. T. H. reports a research grant to institution from Novavax related to this manuscript, research grants to institution from Pfizer, AstraZeneca, Moderna, Valneva, and Janssen, and payment to institution for educational events from Novavax. P. A. K. reports a research grant to institution from Novavax related to this manuscript, grants or contracts unrelated to this work from Vifor, Astellas, Evotec, Pharmacosmos, and Unicyte; consulting fees from AstraZeneca, Vifor, Unicyte, and UCB; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Vifor, AstraZeneca, Pfizer, Pharmacosmos, Napp, and Bayer; and support for attending meetings and/or travel from Pharmacosmos and Vifor. J. P. reports a research grant to institution from Novavax related to this manuscript, and being co-applicant for a Haywood Foundation grant and for a National Institute for Health and Care Research (NIHR)/Clinical Research Network (CRN) COVID Innovation and Insight grant. P. A. S. reports a research grant to institution from Novavax related to this manuscript, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Bayer and AstraZeneca; support for attending meetings and/or travel from Bayer; and participation on a DSMB or advisory board for Bayer. E. C. T. reports a research grant to institution from Novavax related to this manuscript, research grants to institution from Valneva, COV-BOOST, Medical Research Council (MRC), Wellcome, and Public Health Scotland; payment to author for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Wellcome Connecting Science—Sanger Institute; support for attending meetings and/or travel, paid to author, from Wellcome Connecting Science—Sanger Institute, University of Oxford, University of Cambridge, and University of Manchester; and unpaid leadership or fiduciary roles with the Scottish Committee for Pandemic Preparedness, UK Health Security Agency (HSA) technical groups, and the Scottish Genomics Oversight Group. J. T. reports Quin Technologies consulting fees; participation as chair of the Data Monitoring and Ethics Committee (DMEC) for the NIFTY Trial, an NIHR-funded trial; and a role as clinical advisor to Parathyroid UK, a patient support charity. S. I., C. J., H. N., D. B., A. Hi., R. S., I. M., A. M., R. C., D. N. B., D. S., E. P. G., J. B., R. L. S., A. He., C. M., C. P., and F. B. report a research grant to institution from Novavax related to this manuscript. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: The iron-based phosphate binder (PB), sucroferric oxyhydroxide (SFOH), is indicated to control serum phosphorus levels in patients with chronic kidney disease on dialysis., Methods: This non-interventional, prospective, multicentre, cohort study conducted in seven European countries evaluated the safety and effectiveness of SFOH in dialysis patients with hyperphosphataemia in routine practice. Safety outcomes included adverse drug reactions (ADRs) and changes in iron-related parameters. SFOH effectiveness was evaluated by changes-from-baseline (BL) in serum phosphorus and percentage of patients achieving in-target phosphorus levels., Results: The safety analysis set included 1365 patients (mean observation: 420.3 ± 239.3 days). Overall, 682 (50.0%) patients discontinued the study. Mean SFOH dose during the observation period was 1172.7 ± 539.9 mg (2.3 pills/day). Overall, 617 (45.2%) patients received concomitant PB(s) during SFOH treatment. ADRs and serious ADRs were observed for 531 (38.9%) and 26 (1.9%) patients. Most frequent ADRs were diarrhoea (194 patients, 14.2%) and discoloured faeces (128 patients, 9.4%). Diarrhoea generally occurred early during SFOH treatment and was mostly mild and transient. Small increases from BL in serum ferritin were observed (ranging from +12 to +75 µg/L). SFOH treatment was associated with serum phosphorus reductions (6.3 ± 1.6 mg/dL at BL versus 5.3 ± 1.8 mg/dL at Month 30; ΔBL: -1.0 mg/dL, P < 0.01). Percentage of patients achieving serum phosphorus ≤4.5 mg/dL increased from 12.0% at BL to 34.8% at Month 30, while the percentage achieving serum phosphorus ≤5.5 mg/dL increased from 29.9% to 63.0%., Conclusions: SFOH has a favourable safety and tolerability profile in a real-world setting, consistent with results of the Phase 3 study. Moreover, SFOH improved serum phosphorus control with a low daily pill burden., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: The optimal intravenous (IV) iron would allow safe correction of iron deficiency at a single infusion over a short time. The FERWON-NEPHRO trial evaluated the safety and efficacy of iron isomaltoside 1000/ferric derisomaltose (IIM) in patients with non-dialysis-dependent chronic kidney disease and iron deficiency anaemia., Methods: In this randomized, open-label and multi-centre trial conducted in the USA, patients were randomized 2:1 to a single dose of 1000 mg IIM or iron sucrose (IS) administered as 200 mg IV injections up to five times within a 2-week period. The co-primary endpoints were serious or severe hypersensitivity reactions and change in haemoglobin (Hb) from baseline to Week 8. Secondary endpoints included incidence of composite cardiovascular adverse events (AEs)., Results: A total of 1538 patients were enrolled (mean estimated glomerular filtration rate 35.5 mL/min/1.73 m2). The co-primary safety objective was met based on no significant difference in the incidence of serious or severe hypersensitivity reactions in the IIM and IS groups [0.3% versus 0%; risk difference: 0.29% (95% confidence interval: -0.19; 0.77; P > 0.05)]. Incidence of composite cardiovascular AEs was significantly lower in the IIM versus IS group (4.1% versus 6.9%; P = 0.025). Compared with IS, IIM led to a more pronounced increase in Hb during the first 4 weeks (P ≤ 0.021), and change in Hb to Week 8 showed non-inferiority, confirming that the co-primary efficacy objective was met., Conclusions: Compared with multiple doses of IS, a single dose of IIM induced a non-inferior 8-week haematological response, comparably low rates of hypersensitivity reactions, and a significantly lower incidence of composite cardiovascular AEs., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Cognitive impairment in chronic kidney disease (CKD) is common and underrecognized [1, 2]. Determining risk factors for cognitive impairment and whether speed of CKD progression is an important consideration may help identify cognitive impairment by nephrologists. Vascular disease is thought to underpin cognitive impairment in CKD and by segregating CKD patients with proven vascular disease, we may also be able to discover other important associations with cognitive impairment in CKD patients., Method: A total of 250 patients in a UK prospective cohort of CKD patients underwent two cognitive assessments: Montreal Cognitive Assessment test and Trail Making Test. Cognitive impairment was defined using validated population cut-offs (cognitive impairment) and relative cognitive impairment. Relative cognitive impairment was defined by <1 standard deviation below the mean Z -score on any completed test. Two multivariable logistical regression models identified variables associated with cognitive impairment and realtive cognitive impairment., Results: About 44 and 24.8% of patients suffered cognitive impairment and relative cognitive impairment, respectively. Depression, previous stroke and older age were significantly associated with cognitive impairment. Older age was significantly associated with relative cognitive impairment (P ≤ 0.05) and higher proteinuria and the use of psychodynamic medications were also significantly associated with relative cognitive impairment (P = 0.05). Delta estimated glomerular filtration rate (eGFR) in patients with cognitive impairment and relative cognitive impairment compared with those having normal cognition was similar (-0.77 versus -1.35 mL/min/1.73 m 2 /year, P = 0.34 for cognitive impairment and -1.12 versus -1.02 mL/min/1.73 m 2 /year, P = 0.89 for relative cognitive impairment)., Conclusion: Risk factors for cognitive impairment in CKD include previous stroke, depression or anxiety, higher proteinuria and prescription of psychodynamic medications. Patients with a faster eGFR decline do not represent a group of patients at increased risk of cognitive impairment., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Exercise interventions designed to improve physical function and reduce sedentary behaviour in haemodialysis (HD) patients might improve exercise capacity, reduce fatigue and lead to improved quality of life (QOL). The PrEscription of intraDialytic exercise to improve quAlity of Life study aimed to evaluate the effectiveness of a 6-month intradialytic exercise programme on QOL and physical function, compared with usual care for patients on HD in the UK., Methods: We conducted a prospective, pragmatic multicentre randomized controlled trial in 335 HD patients and randomly (1:1) assigned them to either (i) intradialytic exercise training plus usual care maintenance HD or (ii) usual care maintenance HD. The primary outcome of the study was the change in Kidney Disease Quality of Life Short Form (KDQOL-SF 1.3) Physical Component Score between baseline and 6 months. Additional secondary outcomes included changes in peak aerobic capacity, physical fitness, habitual physical activity levels and falls (International Physical Activity Questionnaire, Duke's Activity Status Index and Tinetti Falls Efficacy Scale), QOL and symptom burden assessments (EQ5D), arterial stiffness (pulse wave velocity), anthropometric measures, resting blood pressure, clinical chemistry, safety and harms associated with the intervention, hospitalizations and cost-effectiveness. A nested qualitative study investigated the experience and acceptability of the intervention for both participants and members of the renal health care team., Results: At baseline assessment, 62.4% of the randomized cohort were male, the median age was 59.3 years and 50.4% were white. Prior cerebrovascular events and myocardial infarction were present in 8 and 12% of the cohort, respectively, 77.9% of patients had hypertension and 39.4% had diabetes. Baseline clinical characteristics and laboratory data for the randomized cohort were generally concordant with data from the UK Renal Registry., Conclusion: The results from this study will address a significant knowledge gap in the prescription of exercise interventions for patients receiving maintenance HD therapy and inform the development of intradialytic exercise programmes both nationally and internationally., Trial Registration: ISRCTN N83508514; registered on 17 December 2014., (© The Author(s) 2020. Published by Oxford University Press on behalf of ERA-EDTA.)

Patients with chronic kidney disease are at increased risk of cardiovascular disease and this often manifests clinically like heart failure. Conversely, patients with heart failure frequently have reduced kidney function. The links between the kidneys and cardiovascular system are being elucidated, with blood pressure being a key risk factor. Patients with heart failure have benefitted from many trials which have now established a strong evidence based on which to base management. However, patients with advanced kidney disease have often been excluded from these trials. Nevertheless, there is little evidence that the benefits of such treatments are modified by the presence or absence of kidney disease, but more direct evidence among patients with advanced kidney disease is required. Neprilysin inhibition is the most recent treatment to be shown to improve outcomes among patients with heart failure. The UK HARP-III trial assessed whether neprilysin inhibition improved kidney function in the short- to medium-term and its effects on cardiovascular biomarkers. Although no effect (compared to irbesartan control) was found on kidney function, allocation to neprilysin inhibition (sacubitril/valsartan) did reduce cardiac biomarkers more than irbesartan, suggesting that this treatment might improve cardiovascular outcomes in this population. Larger clinical outcomes trials are needed to test this hypothesis., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Risk stratification in atherosclerotic renovascular disease (ARVD) can influence treatment decisions and facilitate patient selection for revascularization. In this study, we aim to use variables with the best predictive value to design a risk calculator that can assist clinicians with risk stratification and outcome prediction., Methods: Patients with a radiological diagnosis of ARVD referred to our tertiary renal centre were recruited into this prospective cohort study between 1986 and 2014. Primary clinical endpoints included: death, progression to end-stage kidney disease and cardiovascular events (CVE). A stepwise regression model was used to select variables with the most significant hazard ratio for each clinical endpoint. The risk calculator was designed using Hypertext Markup Language. Survival and CVE-free survival were estimated at 1, 5 and 10 years., Results: In total, 872 patients were recruited into the Salford ARVD study with a median follow-up period of 54.9 months (interquartile range 20.2-96.0). Only models predicting death and CVE showed good performance (C-index >0.80). Survival probabilities obtained from the risk calculator show that most patients with ARVD have reduced long-term survival. Revascularization improved outcomes in patients with higher baseline estimated glomerular filtration rate and lower proteinuria but not in those with co-existing comorbidities and higher levels of baseline proteinuria., Conclusions: Although this risk calculator requires further independent validation in other ARVD cohorts, this study shows that a small number of easily obtained variables can help predict clinical outcomes and encourage a patient-specific therapeutic approach., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Cardiovascular mortality is very high in chronic and end-stage kidney disease (ESKD). However, risk stratification data are lacking. Sudden cardiac deaths are among the most common cardiovascular causes of death in these populations. As a result, many studies have assessed the prognostic potential of various electrocardiographic parameters in the renal population. Recent data from studies of implantable loop recordings in haemodialysis patients from five different countries have shed light on a pre-eminent bradyarrhythmic risk of mortality. Importantly, heart block addressed by permanent pacing system was detected in a proportion of patients during the prolonged recording periods. Standard electrocardiogram is inexpensive, non-invasive and easily accessible. Hence, risk prediction models using this simple investigation tool could easily translate into clinical practice. We believe that electrocardiographic assessment is currently under-valued in renal populations. For this review, we identified studies from the preceding 10 years that assessed the use of conventional and novel electrocardiographic biomarkers as risk predictors in chronic and ESKD. The review indicates that conventional electrocardiographic markers are not reliable for risk stratification in the renal populations. Novel parameters have shown promising results in smaller studies, but further validation in larger populations is required., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Non-alcoholic fatty liver disease (NAFLD) is an independent risk factor associated with cardiovascular disease (CVD) and incidence of chronic kidney disease (CKD). NAFLD is threatening to become a major public health problem in association with the metabolic syndrome. The association of NAFLD with outcomes in patients with advanced CKD has not been evaluated. In this study, the prevalence of NAFLD and its impact on cardiovascular and renal outcomes and mortality were determined in a large secondary care CKD cohort., Methods: The study was conducted on 1148 CKD patients within a cohort of 3061 CKD patients, who had undergone ultrasound imaging of the liver over a 15-year period. A propensity-matched population from within the cohort was also included. Cox regression analysis was used to study the association of NAFLD with cardiovascular events, end-stage renal disease and mortality and linear regression analysis for CKD progression., Results: The prevalence of NAFLD was 17.9%. The median duration of follow-up after scanning was 5.4 years, with a median estimated glomerular filtration rate (eGFR) of 33.5 mL/min/1.73 m2 in this population. NAFLD proved to be a strong independent risk factor for cardiovascular events [hazard ratio (HR) 2.03; 95% confidence interval (CI) 1.33-3.13; P < 0.01] but it was not associated with all-cause mortality (HR 0.79; 95% CI 0.58-1.08; P = 0.14) or CKD progression (P = 0.09 for rate of decline of eGFR slope). Patients with CKD are known to have high cardiovascular risk; the propensity-matched analysis showed that NAFLD increased this cardiovascular risk (HR 2.00; CI 1.10-3.66; P < 0.05)., Conclusions: NAFLD has a strong independent association with cardiovascular events, even in an advanced CKD cohort with high comorbidity. The implication is that routine screening for NAFLD may be warranted in CKD populations to enable targeted interventions for CVD prevention in higher risk patients., (© The Author(s) 2018. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Functional renal magnetic resonance imaging (MRI) has seen a number of recent advances, and techniques are now available that can generate quantitative imaging biomarkers with the potential to improve the management of kidney disease. Such biomarkers are sensitive to changes in renal blood flow, tissue perfusion, oxygenation and microstructure (including inflammation and fibrosis), processes that are important in a range of renal diseases including chronic kidney disease. However, several challenges remain to move these techniques towards clinical adoption, from technical validation through biological and clinical validation, to demonstration of cost-effectiveness and regulatory qualification. To address these challenges, the European Cooperation in Science and Technology Action PARENCHIMA was initiated in early 2017. PARENCHIMA is a multidisciplinary pan-European network with an overarching aim of eliminating the main barriers to the broader evaluation, commercial exploitation and clinical use of renal MRI biomarkers. This position paper lays out PARENCHIMA's vision on key clinical questions that MRI must address to become more widely used in patients with kidney disease, first within research settings and ultimately in clinical practice. We then present a series of practical recommendations to accelerate the study and translation of these techniques.

Background: Patients with atherosclerotic renovascular disease (ARVD) and high-risk clinical presentations have largely been excluded from randomized controlled trials comparing renal revascularization and optimal medical therapy. Here, we explore the effect of revascularization on death, progression to end-stage kidney disease (ESKD) and cardiovascular events (CVE) in a highly selected cohort of patients with ARVD., Methods: All patients with a radiological diagnosis of ARVD referred to our tertiary centre have been recruited into a single-centre cohort study between 1986 and 2014. Patients with ≥70% unilateral or bilateral ARVD together with one or more of the following putative high-risk presentations were designated 'high-risk': flash pulmonary oedema (FPE), severe hypertension, rapidly deteriorating renal function. The effect of revascularization on clinical outcomes in high-risk patients, patients with bilateral severe ARVD and those with <1 g proteinuria at baseline was compared with 'control' patients who had the same degree of renal artery stenosis (RAS) but did not exhibit these features., Results: Median follow-up was 58.4 months [interquartile range (IQR) 25.4-97.3]. Revascularization was associated with a reduced risk of progression to ESKD, CVE and all combined events in patients with rapidly deteriorating renal function [ESKD: hazard ratio (HR) 0.47 (95% confidence interval, CI, 0.25-0.85), P = 0.01; CVE: HR 0.51 (95% CI 0.29-0.91), P = 0.02; Any: HR 0.51 (95% CI 0.29-0.90), P = 0.02]. High-risk patients with bilateral ≥70% RAS and those with <1 g/day baseline proteinuria also had significantly better renal and cardiovascular outcomes post-revascularization when compared with controls., Conclusion: Our results indicate that revascularization may be of benefit in patients with anatomically significant RAS who present with rapidly deteriorating renal function, especially in the presence of severe bilateral ARVD or <1 g/day proteinuria., (© The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Cardiac abnormalities are frequent in patients with atherosclerotic renovascular disease (ARVD). The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial studied the effect of percutaneous renal revascularization combined with medical therapy compared with medical therapy alone in 806 patients with ARVD., Methods: This was a pre-specified sub-study of ASTRAL (clinical trials registration, current controlled trials number: ISRCTN59586944), designed to consider the effect of percutaneous renal artery angioplasty and stenting on change in cardiac structure and function, measured using cardiac magnetic resonance (CMR) imaging. Fifty-one patients were recruited from six selected ASTRAL centres. Forty-four completed the study (medical therapy n = 21; revascularization n = 23). Full analysis of CMR was possible in 40 patients (18 medical therapy and 22 revascularization). CMR measurements of left and right ventricular end systolic (LV and RVESV) and diastolic volume (LV and RVEDV), ejection fraction (LVEF) and mass (LVM) were made shortly after recruitment and before revascularization in the interventional group, and again after 12 months. Reporting was performed by CMR analysts blinded to randomization arm., Results: Groups were well matched for mean age (70 versus 72 years), blood pressure (148/71 versus 143/74 mmHg), degree of renal artery stenosis (75 versus 75%) and comorbid conditions. In both randomized groups, improvements in cardiac structural parameters were seen at 12 months, but there were no significant differences between treatment groups. Median left ventricular changes between baseline and 12 months (medical versus revascularization) were LVEDV -1.9 versus -5.8 mL, P = 0.4; LVESV -2.1 versus 0.3 mL, P = 0.7; LVM -5.4 versus -6.3 g, P = 0.8; and LVEF -1.5 versus -0.8%, P = 0.7. Multivariate regression also found that randomized treatment assignment was not associated with degree of change in any of the CMR measurements., Conclusions: In this sub-study of the ASTRAL trial, renal revascularization did not offer additional benefit to cardiac structure or function in unselected patients with ARVD., (© The Author 2016. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Over the past decades, management of atherosclerotic renovascular disease (ARVD) has undergone significant progress, in parallel with increased knowledge about the complex pathophysiology of this condition. Modern multi-targeted medical management of atherosclerosis has driven a change in both the natural history and the clinical outcomes of ARVD. Progression to total renal artery occlusion is a much less common occurrence and while early studies have reported that up to 41% of patients reached renal end-points over a mean follow-up of 44 months, the latest randomized controlled trials have shown that progressive renal impairment occurs in 16-22% of patients, with <8% of patients reaching end-stage kidney disease (ESKD) over a similar time-frame. However, the results of the latest large ARVD trials investigating the effect of renal stenting upon clinical outcomes have been influenced by selection bias as high-risk patients with clinically significant renal artery stenosis (RAS) have largely been excluded from these studies. Although the neutral results of these trials have shown uncertainty about the role of revascularization in the management of patients with ARVD, there is evidence that revascularization can optimize outcomes in selected patients with a high-risk clinical phenotype. Future challenges lie in identifying important subgroups of patients with critical RAS and viable kidneys, while continuing to develop strategies to protect the renal parenchyma and hence improve clinical outcomes., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Iron deficiency anaemia is common in patients with non-dialysis-dependent chronic kidney disease (NDD-CKD) and is often treated with oral or intravenous (IV) iron therapy. This trial compared the efficacy and safety of IV iron isomaltoside 1000 (Monofer®) and oral iron in NDD-CKD patients with renal-related anaemia., Methods: The trial was a Phase III open-label, comparative, multicentre, non-inferiority trial conducted in 351 iron-deficient NDD-CKD patients, randomized 2:1 to either iron isomaltoside 1000 (Group A) or iron sulphate administered as 100 mg elemental oral iron twice daily (200 mg daily) for 8 weeks (Group B). The patients in Group A were randomized into A1 (infusion of max. 1000 mg single doses over 15 min) and A2 (bolus injections of 500 mg over 2 min). A modified Ganzoni formula was used to calculate IV iron need. The primary end point was change in haemoglobin concentrations from baseline to Week 4., Results: Iron isomaltoside 1000 was both non-inferior to oral iron at Week 4 (P < 0.001) and sustained a superior increase in haemoglobin from Week 3 until the end of the study at Week 8 (P = 0.009 at Week 3). The haemoglobin response was more pronounced with iron isomaltoside 1000 doses ≥1000 mg (P < 0.05). Serum-ferritin and transferrin saturation concentrations were also significantly increased with IV iron. Adverse drug reactions were observed in 10.5% in the iron isomaltoside 1000 group and 10.3% in the oral iron group. More patients treated with oral iron sulphate withdrew from the study due to adverse events (4.3 versus 0.9%, P = 0.2)., Conclusions: Iron isomaltoside 1000 was more efficacious than oral iron for increase in haemoglobin and proved to be well tolerated at the tested dose levels in NDD-CKD patients., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.)

Background: Iron deficiency anaemia is common in patients with chronic kidney disease, and intravenous iron is the preferred treatment for those on haemodialysis. The aim of this trial was to compare the efficacy and safety of iron isomaltoside 1000 (Monofer®) with iron sucrose (Venofer®) in haemodialysis patients., Methods: This was an open-label, randomized, multicentre, non-inferiority trial conducted in 351 haemodialysis subjects randomized 2:1 to either iron isomaltoside 1000 (Group A) or iron sucrose (Group B). Subjects in Group A were equally divided into A1 (500 mg single bolus injection) and A2 (500 mg split dose). Group B were also treated with 500 mg split dose. The primary end point was the proportion of subjects with haemoglobin (Hb) in the target range 9.5-12.5 g/dL at 6 weeks. Secondary outcome measures included haematology parameters and safety parameters., Results: A total of 351 subjects were enrolled. Both treatments showed similar efficacy with >82% of subjects with Hb in the target range (non-inferiority, P = 0.01). Similar results were found when comparing subgroups A1 and A2 with Group B. No statistical significant change in Hb concentration was found between any of the groups. There was a significant increase in ferritin from baseline to Weeks 1, 2 and 4 in Group A compared with Group B (Weeks 1 and 2: P < 0.001; Week 4: P = 0.002). There was a significant higher increase in reticulocyte count in Group A compared with Group B at Week 1 (P < 0.001). The frequency, type and severity of adverse events were similar., Conclusions: Iron isomaltoside 1000 and iron sucrose have comparative efficacy in maintaining Hb concentrations in haemodialysis subjects and both preparations were well tolerated with a similar short-term safety profile., (© The Author 2015. Published by Oxford University Press on behalf of ERA-EDTA.)

Backgound: The term 'joint modelling' is used in the statistical literature to refer to methods for simultaneously analysing longitudinal measurement outcomes, also called repeated measurement data, and time-to-event outcomes, also called survival data. A typical example from nephrology is a study in which the data from each participant consist of repeated estimated glomerular filtration rate (eGFR) measurements and time to initiation of renal replacement therapy (RRT). Joint models typically combine linear mixed effects models for repeated measurements and Cox models for censored survival outcomes. Our aim in this paper is to present an introductory tutorial on joint modelling methods, with a case study in nephrology., Methods: We describe the development of the joint modelling framework and compare the results with those obtained by the more widely used approaches of conducting separate analyses of the repeated measurements and survival times based on a linear mixed effects model and a Cox model, respectively. Our case study concerns a data set from the Chronic Renal Insufficiency Standards Implementation Study (CRISIS). We also provide details of our open-source software implementation to allow others to replicate and/or modify our analysis., Results: The results for the conventional linear mixed effects model and the longitudinal component of the joint models were found to be similar. However, there were considerable differences between the results for the Cox model with time-varying covariate and the time-to-event component of the joint model. For example, the relationship between kidney function as measured by eGFR and the hazard for initiation of RRT was significantly underestimated by the Cox model that treats eGFR as a time-varying covariate, because the Cox model does not take measurement error in eGFR into account., Conclusions: Joint models should be preferred for simultaneous analyses of repeated measurement and survival data, especially when the former is measured with error and the association between the underlying error-free measurement process and the hazard for survival is of scientific interest., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Acute flash pulmonary oedema (AFPO) is a life-threatening syndrome almost unique to patients with atheromatous renovascular disease (ARVD). Although recurrent AFPO is a widely accepted indication to consider renal revascularization, this is based on a number of case reports/series describing a successful outcome post-procedure. There is limited literature on the pathophysiological mechanisms and treatment effects of revascularization to support this clinical decision making. We report the case of a 65-year-old lady who presented with three episodes of AFPO. Investigations revealed severe bilateral renal artery stenosis. Post-revascularization, she experienced substantial improvement in energy levels and New York Heart Association class, with improvement in her blood pressure and renal function. Post-procedure, there were dramatic improvements in her cardiac morphology and function that were sustained at 1 year (ejection fraction improved from 39 to 65%, left ventricular mass decreased from 161 to 116 g) as well as renal function (isotopic glomerular filtration rate increased from 22.4 to 34.2 mL/min). This report provides new insights into the pathophysiological relationships between renal and cardiac changes in AFPO; the extent of the cardiac morphological changes was striking and unexpected.

Background: Hyperkalaemia is a common potentially fatal complication of chronic kidney disease (CKD). It may manifest as electrocardiogram (ECG) changes, the earliest of which is T-wave 'tenting'. However, this occurs in less than half of episodes of hyperkalaemia. The aim of this study was to determine what other clinical features relate to the probability of T-wave tenting; and if there is a longer-term survival difference between patients who develop tenting and those who do not., Method: One hundred and forty-five patients with end-stage renal disease who had standard 12-lead ECG and concurrent serum potassium measurement were enrolled. The presence of tenting and the ratio of the amplitude of the tallest precordial T-wave and R-wave were determined (T:R)., Results: Tenting was as common in normal range serum potassium as hyperkalaemia (33 versus 31%) and less common than in left ventricular hypertrophy (44%). T:R was less sensitive (24 versus 33%) but more specific (85 versus 67%) than tenting at correctly identifying hyperkalaemia ≥ 6.0 mmol/L. Tenting became less common with increasing age. Dialysis patients were more likely to show increased T:R that pre-dialysis Stage 5 CKD. Elevated T:R was not associated with worse cardiovascular outcome but was associated with increased risk of sudden death over a mean follow-up of 3.8 years (hazard ratio = 8.3, P = 0.021)., Conclusions: The reason for the variability in T-wave changes is not clear. The ratio of precordial T-wave to R-wave amplitude is a more specific measure than tenting but both are poorly sensitive at detecting hyperkalaemia. The greater risk for sudden death may represent a susceptibility to cardiac arrhythmia during repolarization.

Background: Chronic kidney disease (CKD) is increasingly prevalent worldwide. Furthermore, obesity is now a global problem with major health implications. There is a clear association between obesity and the development of CKD but it is not known whether obesity is a risk factor for the progression of pre-existing kidney disease. We examined the relationship between the body mass index (BMI) and the rate of progression of CKD in non-diabetic adults., Methods: The Chronic Renal Insufficiency Standards Implementation Study (CRISIS) is a prospective observational study in a predominantly white population in Greater Manchester. From the CRISIS database, we assessed rate of progression of CKD in 499 adults attending the hospital. Baseline measurements including BMI were obtained and estimated glomerular filtration rate (eGFR) was monitored. The rate of deterioration of eGFR was derived over time, defined as ΔeGFR (mL/min/1.73 m2/year) and assessed using univariate analysis of variance., Results: In the groups as a whole, no relationship between BMI and ΔeGFR was shown. Dividing the subjects into obese (BMI≥30) and non-obese (BMI<30) groups and further breakdown into CKD stages 3, 4 and 5, also showed no relationship between BMI and ΔeGFR. Univariate analysis of variance was used., Conclusions: Neither BMI as a continuous variable nor obesity (BMI≥30) as a categorical variable was associated with an increased rate of progression of existing CKD in this predominantly white population.

Background: Many physicians retain reservations regarding the routine prescription of renin-angiotensin blockade (RAB) in patients with atheromatous renovascular disease (ARVD). Conversely, these patients are in most need of the cardio- and renal protection offered by RAB. This reservation is mostly because of fear of precipitating acute renal deterioration. We aimed to study whether RAB can be used safely in ARVD patients and whether it altered their outcome., Methods: Prospective observational study of all ARVD patients presenting to our tertiary referral centre from 1999-2009. Data capture included usage and tolerability of RAB, and correlation with endpoints of cardiovascular events, dialysis or death., Results: Six hundred and twenty-one subjects were available for analysis. Mean age (SD) of the cohort was 71.3 (8.8) years, median (interquartile range) follow-up 3.1 (2.1, 4.8), range 0.2-10.61 years. Seventy-four patients had an intolerance to RAB at study entry. When utilized prospectively, RAB was tolerated in 357 of 378 patients (92%), and this was even seen in 54/69 (78.3%) patients with bilateral>60% renal artery stenosis (RAS) or occlusion. Patients (4/21) who were intolerant of RAB during follow-up (and 12 retrospectively intolerant), underwent renal revascularization which facilitated safe use of these medications post-procedure. On multivariate time-adjusted analysis, patients receiving RAB were significantly less likely to die (P=0.02)., Conclusion: RAB is well tolerated even in patients with bilateral severe RAS and reduced mortality in a large group of ARVD patients. We recommend all ARVD patients be considered for RAB therapy unless an absolute contra-indication exists. Intolerance of these agents due to renal dysfunction should be considered an emerging indication for renal revascularization to facilitate their re-introduction.

Background: Stenting of the stenosed renal artery is commonly employed in atheromatous renovascular disease (ARVD) in order to revascularize the affected kidney. However, it is still far from clear which patient subgroups should be revascularized as stenting carries small but significant risks. We have previously demonstrated that the ratio of magnetic resonance-measured renal volume to isotopic single kidney glomerular filtration rate (isoSK-GFR) is higher in kidneys which show functional improvement after revascularization. Blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) does not require contrast administration and is sensitive to changes in tissue concentration of deoxyhaemoglobin., Methods: In this study, we test the hypothesis that baseline BOLD R2* map signal and R2*:isoSK-GFR ratio will provide an additional independent predictive biomarker of response to revascularization., Results: Studies were performed in 28 subjects (16 ARVD and 12 controls). All subjects had R2* mapping and isoSK-GFR measured at baseline and at 4-month follow-up. MRI data were collected on a 3 T whole-body MRI scanner using a coronal dual-echo, 2D gradient-echo breath-hold acquisition. Parenchymal regions of interest (ROIs) were drawn on a representative slice through the middle of the kidney. Parametric maps of R2* were generated and mean values of R2* were calculated for every ROI. The ratio of R2*:isoSK-GFR at baseline was significantly greater in kidneys where renal function improved (5.91 ± 6.51) versus stable (1.78 ± 1.11), deteriorated (2.15 ± 1.79) or controls (1.5 ± 0.91), P = 0.003. R2*:isoSK-GFR ratio that was greater than 95% confidence interval of the control kidneys was 66.7% sensitive, but 85.7% specific in predicting a positive renal functional outcome., Conclusions: These pilot data show that BOLD R2* imaging, presumably by detecting intra-renal deoxyhaemoglobin in still viable 'hibernating' parenchyma, coupled with isoSK-GFR may provide an effective predictive biomarker for positive renal functional response to revascularization. R2* imaging is non-invasive, quick to perform and could provide further insight into reversible parenchymal changes in ARVD kidneys.

Patients with chronic kidney disease (CKD) often suffer from iron deficiency anaemia necessitating treatment with intravenous (IV) iron. Several studies demonstrate that oral iron is insufficient in these patients and that IV supplementation is a more effective treatment. Until now, use of available parenteral iron preparations has been limited by dosing schedules and the need, in some cases, for a test dose, and despite the availability of a range of different IV iron compounds, there is still a need for improved compounds. The new IV iron, iron isomaltoside 1000 Monofer®, is composed of iron and chemically modified isomalto-oligosaccharides which have a mean molecular weight of 1000 Da and consist predominantly of 3-5 glucose units. In contrast to dextrans, the carbohydrate isomaltoside 1000 is a linear and unbranched structure with theoretically a low immunological potential. Hence, a test dose is not necessary. Iron isomaltoside 1000 contains strongly bound iron within the iron-isomaltoside formulation, which enables a controlled slow release of bioavailable iron to the iron-binding proteins, with potentially a reduced risk of free iron toxicity. This allows flexible dosing including high and rapid dosing securing convenient iron therapy for a wide range of patients. The development of Monofer® has been enthusiastically acknowledged by clinicians, and in 2009, there has been fast approval by European authorities via a decentralized registration procedure. This new IV iron is currently being marketed in several European countries. This article describes the development rationale and summarizes the clinical data assessing the use of iron isomaltoside 1000 administered without a test dose by either repeated bolus injections or fast high single iron infusions [defined as total dose infusion (TDI)] to patients suffering from CKD. Since CKD is associated with a high prevalence of cardiovascular disease, data from a small trial applying high single doses of iron isomatoside 1000 in patients with chronic heart failure (CHF) are also reviewed. Collectively, the available data demonstrate adequate efficacy and a good safety profile of iron isomaltoside 1000 in CKD and CHF patients even when administered without a test dose and as single rapid high-dose infusions.

Background: There have been few attempts to estimate progression of kidney disease in people with diabetes in a single large population with predictive modelling. The aim of this study was to investigate the rate of progression of chronic kidney disease in people with diabetes according to their estimated glomerular filtration rate (eGFR) and presence of albuminuria., Methods: Data were collected on all people with diabetes in Salford, UK, where an eGFR could be calculated using the four-variable MDRD formula and urinary albumin-creatinine ratio (uACR) was available. All data between 2001 and 2007 were used in the model. Classification of albuminuria status was based on the average of their first two uACR measurements. A longitudinal mixed effect dynamic regression model was fitted to the data. Parameters were estimated by maximum likelihood., Results: For the analysis of the population, average progression of eGFR, uACR and drug prescribing were available in 3431 people. The regression model showed that in people with diabetes and macroalbuminuria, eGFR declined at 5.7% per annum, while the eGFR of those with microalbuminuria or without albuminuria declined at 1.5% and 0.3% per annum, respectively, independently of age (P < 0.0001)., Conclusions: The longitudinal effect of time on eGFR showed that people with diabetes and macroalbuminuria have an estimated 19 times more rapid decline in renal function compared with those without albuminuria. This study demonstrates that the progression of kidney disease in diabetic people without albuminuria is relatively benign compared with those with albuminuria.

Background: Renal functional outcome is unpredictable after revascularization of high-grade atherosclerotic renal artery stenosis (RAS). 'Hibernating' parenchyma describes acute parenchymal injury where renal dysfunction is potentially reversible with treatment of the stenosis. We analysed renal parenchymal volume (PV) and single-kidney glomerular filtration rate (SK-GFR) characteristics to identify kidneys with hibernating parenchyma and hence determine renal functional outcome after revascularization., Methods: Fifty patients with > or =50% RAS underwent baseline analyses: (i) PV using magnetic resonance imaging; (ii) radioisotopic SK-GFR. Twenty-one patients (27 kidneys) underwent renal revascularization and 29 medical therapy alone., Results: Patients with revascularized kidneys manifesting high PV:SK-GFR showed improvement in global estimated GFR compared to conservatively managed counterparts at 6 months and 1 year (6 months: 6.2 +/- 2.9 versus -3.7 +/- 6.8, P = 0.038; 1 year: 3.5 +/- 3.0 versus -5.1 +/- 5.1 ml/min/1.73 m(2), P = 0.021). Twelve revascularized patients (16 kidneys) underwent repeat SK-GFR 4 months post-revascularization. Six of 16 revascularized kidneys had high baseline PV:SK-GFR and showed improved SK-GFR compared to kidneys with low or normal PV:SK-GFR (6.3 +/- 2.0 versus -0.9 +/- 4.2 ml/min, P = 0.002)., Conclusions: Our data suggest that, after revascularization, GFR improvement is likely if there is a disproportionately higher baseline PV:SK-GFR in the RAS kidney. Analysing these parameters can potentially identify these 'hibernating' kidneys and aid determination of renal functional outcome in RAS.

Background: Sevelamer carbonate is an improved, buffered form of sevelamer hydrochloride developed for the treatment of hyperphosphataemia in CKD patients. Sevelamer carbonate formulated as a powder for oral suspension presents a novel, patient-friendly alternative to tablet phosphate binders. This study compared the safety and efficacy of sevelamer carbonate powder with sevelamer hydrochloride tablets in CKD patients on haemodialysis., Methods: This was a multi-centre, open-label, randomized, crossover design study. Thirty-one haemodialysis patients were randomly assigned to either sevelamer carbonate powder or sevelamer hydrochloride tablets for 4 weeks followed by a crossover to the other regimen for an additional 4 weeks., Results: The mean serum phosphorus was 1.6 +/- 0.5 mmol/L (5.0 +/- 1.5 mg/dL) during sevelamer carbonate powder treatment and 1.7 +/- 0.4 mmol/L (5.2 +/- 1.1 mg/dL) during sevelamer hydrochloride tablet treatment. Sevelamer carbonate powder and sevelamer hydrochloride tablets are equivalent in controlling serum phosphorus; the geometric least square mean ratio was 0.95 (90% CI 0.87-1.03). No statistically significant or clinically meaningful differences were observed in calcium x phosphorus product and lipid levels between sevelamer carbonate powder and sevelamer hydrochloride tablets. Serum bicarbonate levels increased 2.7 +/- 3.7 mmol/L (2.7 +/- 3.7 mEq/L) during sevelamer carbonate treatment. No statistically significant change in bicarbonate was observed during sevelamer hydrochloride treatment. Sevelamer carbonate powder and sevelamer hydrochloride were well tolerated during this study., Conclusions: Sevelamer carbonate powder and sevelamer hydrochloride tablets are equivalent in controlling serum phosphorus and well tolerated in CKD patients on haemodialysis. Bicarbonate levels improved only during sevelamer carbonate treatment. Sevelamer carbonate powder should provide a welcomed new option for the treatment of hyperphosphataemia for CKD patients on dialysis.

Background: Urine protein strip tests are often used in the ward or clinic as first-line measures of proteinuria. The ability of a semi-quantitative meter-read strip test for the protein:creatinine ratio, Multistix* PRO 10LS (Siemens Medical Solutions, Tarrytown, USA), was assessed as a first-line test to exclude significant proteinuria in the monitoring of patients with established chronic kidney disease., Methods: Eighty-six patients attending a hospital renal outpatient clinic collected three random urine samples during a 24-h period. Random urine protein:creatinine ratios measured by the strip test were compared to the laboratory estimation of 24-h protein excretion on that same day., Results: At significant protein excretion of 0.3 g/24 h, the strips elicited negative predictive values in the range of 91.2-94.1% and negative likelihood ratios of 0.01-0.12, using all the random urines. Receiver-operator characteristic curve analysis also demonstrated good performance with all samples., Conclusions: The strip test allows the physician to rule out significant proteinuria at the patient consultation on a random urine sample, obviating the need for specially collected samples, and with the added benefit of reducing the need for a lengthy and costly quantitative laboratory follow-up by approximately 40-48%.