Regional variation of COVID-19 admissions, acute kidney injury and mortality in England - a national observational study using administrative data.

BACKGROUND: This study explores regional variations in COVID-19 hospitalization rates, in-hospital mortality, and acute kidney injury (AKI) in England. We investigated the influence of population demographic characteristics, viral strain changes, and therapeutic advances on clinical outcomes. METHODS: Using hospital episode statistics, we conducted a retrospective cohort study with 749,844 admissions in 337,029 adult patients with laboratory-confirmed COVID-19 infection (March 1, 2020, to March 31, 2021). Multivariable logistic regression identified factors predicting AKI and mortality in COVID-19 hospitalized patients. RESULTS: London had the highest number of COVID-19 admissions (131,338, 18%), followed by the North-west region (122,683, 16%). The North-west had the highest population incidence of COVID-19 hospital admissions (21,167 per million population, pmp), while the South-west had the lowest (9,292 admissions pmp). Patients in London were relatively younger (67.0 ± 17.7 years) than those in the East of England (72.2 ± 16.8 years). The shortest length of stay was in the North-east (12.2 ± 14.9 days), while the longest was in the North-west (15.2 ± 17.9 days). All eight regions had higher odds of death compared to London, ranging from OR 1.04 (95% CI 1.00, 1.07) in the South-west to OR 1.24 (95% CI 1.21, 1.28) in the North-west. Older age, Asian ethnicity, emergency admission, transfers from other hospitals, AKI presence, ITU admission, social deprivation, and comorbidity were associated with higher odds of death. AKI incidence was 30.3%, and all regions had lower odds of developing AKI compared to London. Increasing age, mixed and black ethnicity, emergency admission, transfers from other providers, ITU care, and different levels of comorbidity were associated with higher odds of developing AKI. CONCLUSIONS: London exhibited higher hospital admission numbers and AKI incidence, but lower odds of death compared to other regions in England. TRIAL REGISTRATION: Registered on National Library of Medicine website ( www. CLINICALTRIALS: gov ) with registration number NCT04579562 on 8/10/2020.

A narrative systematic review of randomised controlled trials that compare cannulation techniques for haemodialysis.

BACKGROUND: Cannulation of arteriovenous access for haemodialysis affects longevity of the access, associates with complications and affects patients' experiences of haemodialysis. Buttonhole and rope ladder techniques were developed to reduce complications. However, studies that compare these two techniques report disparate results. This systematic review performs an in-depth exploration of RCTs, with a specific focus on cannulation as a complex intervention. METHODS: A PICO question and protocol was developed as per PRISMA-P guidance and registered on PROSPERO (CRD42018094656 https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=112895). The systematic review included any RCT performed on adult patients with end-stage kidney disease undergoing cannulation of arteriovenous fistulae or grafts for in-centre haemodialysis, as performed by healthcare staff. Assessment of quality of RCTs and data extraction were performed by two co-authors independently. Data were extracted on the study design, intervention and comparator and outcomes, including patency, infection and patients' experiences. RESULTS: The literature search identified 241 records. Ten records met inclusion criteria, which described five different RCTs that compared buttonhole to either rope ladder or usual practice. Results were disparate, with patency and infection results varying. Pain Visual Analogue scores were the only measure used to capture patients' experiences and results were inconclusive. All RCTs had differences and limitations in study design that could explain the disparity in results. CONCLUSION: Current evidence does not allow definitive conclusions as to whether buttonhole or rope ladder needling technique is superior. Future RCTs should describe interventions and comparators with adequate detail, embed process evaluation, use standardised outcome measures and build on feasibility studies to produce definitive results.

Determinants of change in arterial stiffness over 5 years in early chronic kidney disease.

BACKGROUND: Arterial stiffness (AS) is an established and potentially modifiable risk factor for cardiovascular disease associated with chronic kidney disease (CKD). There have been few studies to evaluate the progression of AS over time or factors that contribute to this, particularly in early CKD. We therefore investigated AS over 5 years in an elderly population with CKD Stage 3 cared for in primary care. METHODS: A total of 1741 persons with an estimated glomerular filtration rate of 30-59 mL/min/1.73 m2 underwent detailed clinical and biochemical assessment at baseline and Years 1 and 5. Carotid to femoral pulse wave velocity (PWV) was measured to assess AS using a Vicorder device. RESULTS: 970 participants had PWV assessments at baseline and 5 years. PWV increased significantly by a mean of 1.1 m/s (from 9.7 ± 1.9 to 10.8 ± 2.1 m/s). Multivariable linear regression analysis identified the following independent determinants of ΔPWV at Year 5: baseline age, diabetes status, baseline systolic blood pressure (SBP) and diastolic blood pressure, baseline PWV, ΔPWV at 1 year, ΔSBP over 5 years and Δserum bicarbonate over 5 years (R2 = 0.38 for the equation). CONCLUSIONS: We observed a clinically significant increase in PWV over 5 years in a cohort with early CKD despite reasonably well-controlled hypertension. Measures of BP were identified as the most important modifiable determinant of ΔPWV, suggesting that interventions to prevent arterial disease should focus on improved control of BP, particularly in those who evidence an early increase in PWV. These hypotheses should now be tested in prospective trials.

Acute kidney injury associated with COVID-19: A retrospective cohort study.

BACKGROUND: Initial reports indicate a high incidence of acute kidney injury (AKI) in Coronavirus Disease 2019 (COVID-19), but more data are required to clarify if COVID-19 is an independent risk factor for AKI and how COVID-19-associated AKI may differ from AKI due to other causes. We therefore sought to study the relationship between COVID-19, AKI, and outcomes in a retrospective cohort of patients admitted to 2 acute hospitals in Derby, United Kingdom. METHODS AND FINDINGS: We extracted electronic data from 4,759 hospitalised patients who were tested for COVID-19 between 5 March 2020 and 12 May 2020. The data were linked to electronic patient records and laboratory information management systems. The primary outcome was AKI, and secondary outcomes included in-hospital mortality, need for ventilatory support, intensive care unit (ICU) admission, and length of stay. As compared to the COVID-19-negative group (n = 3,374), COVID-19 patients (n = 1,161) were older (72.1 ± 16.1 versus 65.3 ± 20.4 years, p < 0.001), had a greater proportion of men (56.6% versus 44.9%, p < 0.001), greater proportion of Asian ethnicity (8.3% versus 4.0%, p < 0.001), and lower proportion of white ethnicity (75.5% versus 82.5%, p < 0.001). AKI developed in 304 (26.2%) COVID-19-positive patients (COVID-19 AKI) and 420 (12.4%) COVID-19-negative patients (AKI controls). COVID-19 patients aged 65 to 84 years (odds ratio [OR] 1.67, 95% confidence interval [CI] 1.11 to 2.50), needing mechanical ventilation (OR 8.74, 95% CI 5.27 to 14.77), having congestive cardiac failure (OR 1.72, 95% CI 1.18 to 2.50), chronic liver disease (OR 3.43, 95% CI 1.17 to 10.00), and chronic kidney disease (CKD) (OR 2.81, 95% CI 1.97 to 4.01) had higher odds for developing AKI. Mortality was higher in COVID-19 AKI versus COVID-19 patients without AKI (60.5% versus 27.4%, p < 0.001), and AKI was an independent predictor of mortality (OR 3.27, 95% CI 2.39 to 4.48). Compared with AKI controls, COVID-19 AKI was observed in a higher proportion of men (58.9% versus 51%, p = 0.04) and lower proportion with white ethnicity (74.7% versus 86.9%, p = 0.003); was more frequently associated with cerebrovascular disease (11.8% versus 6.0%, p = 0.006), chronic lung disease (28.0% versus 19.3%, p = 0.007), diabetes (24.7% versus 17.9%, p = 0.03), and CKD (34.2% versus 20.0%, p < 0.001); and was more likely to be hospital acquired (61.2% versus 46.4%, p < 0.001). Mortality was higher in the COVID-19 AKI as compared to the control AKI group (60.5% versus 27.6%, p < 0.001). In multivariable analysis, AKI patients aged 65 to 84 years, (OR 3.08, 95% CI 1.77 to 5.35) and ≥85 years of age (OR 3.54, 95% CI 1.87 to 6.70), peak AKI stage 2 (OR 1.74, 95% CI 1.05 to 2.90), AKI stage 3 (OR 2.01, 95% CI 1.13 to 3.57), and COVID-19 (OR 3.80, 95% CI 2.62 to 5.51) had higher odds of death. Limitations of the study include retrospective design, lack of urinalysis data, and low ethnic diversity of the region. CONCLUSIONS: We observed a high incidence of AKI in patients with COVID-19 that was associated with a 3-fold higher odds of death than COVID-19 without AKI and a 4-fold higher odds of death than AKI due to other causes. These data indicate that patients with COVID-19 should be monitored for the development of AKI and measures taken to prevent this. TRIAL REGISTRATION: ClinicalTrials.gov NCT04407156.

Health-related quality of life, functional impairment and comorbidity in people with mild-to-moderate chronic kidney disease: a cross-sectional study.

OBJECTIVES: To determine the associations between comorbidities, health-related quality of life (HRQoL) and functional impairment in people with mild-to-moderate chronic kidney disease (CKD) in primary care. DESIGN: Cross-sectional analysis at 5-year follow-up in a prospective cohort study. SETTING: Thirty-two general practitioner surgeries in England. PARTICIPANTS: 1008 participants with CKD stage 3 (of 1741 people recruited at baseline in the Renal Risk in Derby study) who survived to 5 years and had complete follow-up data for HRQoL and functional status (FS). PRIMARY AND SECONDARY OUTCOME MEASURES: HRQoL assessed using the 5-level EQ-5D version (EQ-5D-5L, with domains of mobility, self-care, usual activities, pain/discomfort and anxiety/depression and index value using utility scores calculated from the English general population), and FS using the Karnofsky Performance Status scale (functional impairment defined as Karnofksy score ≤70). Comorbidity was defined by self-reported or doctor-diagnosed condition, disease-specific medication or blood result. RESULTS: Mean age was 75.8 years. The numbers reporting some problems in EQ-5D-5L domains were: 582 (57.7%) for mobility, 166 (16.5%) for self-care, 466 (46.2%) for usual activities, 712 (70.6%) for pain/discomfort and 319 (31.6%) for anxiety/depression. Only 191 (18.9%) reported no problems in any domain. HRQoL index values showed greater variation among those with lower FS (eg, for those with Karnofsky score of 60, the median (IQR) EQ-5D index value was 0.45 (0.24 to 0.68) compared with 0.94 (0.86 to 1) for those with Karnofsky score of 90). Overall, 234 (23.2%) had functional impairment.In multivariable logistic regression models, functional impairment was independently associated with experiencing problems for all EQ-5D-5L domains (mobility: OR 16.87 (95% CI 8.70 to 32.79, p<0.001, self-care: OR 13.08 (95% CI 8.46 to 20.22), p<0.001, usual activities: OR 8.27 (95% CI 5.43 to 12.58), p<0.001, pain/discomfort: OR 2.94 (95% CI 1.86 to 4.67), p<0.001, anxiety/depression: 3.08 (95% CI 2.23 to 4.27), p<0.001). Higher comorbidity count and obesity were independently associated with problems in mobility, self-care, usual activities and pain/discomfort: for three or more comorbidities versus none: (mobility: OR 2.10 (95% CI 1.08 to 4.10, p for trend 0.002), self-care: OR 2.64 (95% CI 0.72 to 9.67, p for trend 0.05), usual activities: OR 4.20 (95% CI 2.02 to 8.74, p for trend <0.001), pain/discomfort: OR 3.06 (95% CI 1.63 to 5.73, p for trend <0.001)), and for obese (body mass index (BMI) ≥30 kg/m2) versus BMI <25 kg/m2: (mobility: OR 2.44 (95% CI 1.61 to 3.69, p for trend <0.001), self-care: OR 1.98 (95% CI 1.06 to 3.71, p for trend 0.003), usual activities: OR 1.82 (95% CI 1.19 to 2.76, p for trend 0.019), pain/discomfort: OR 2.37 (95% CI 1.58 to 3.55, p for trend <0.001)). Female sex, lower FS and lower educational attainment were independently associated with anxiety/depression (ORs 1.60 (95% CI 1.18 to 2.16, p 0.002), 3.08 (95% CI 2.23 to 4.27, p<0.001) and 1.67 (95% CI 1.10 to 2.52, p 0.009), respectively). Older age, higher comorbidity count, albuminuria (≥30 mg/mmol vs <3 mg/mmol), lower educational attainment (no formal qualifications vs degree level) and obesity were independently associated with functional impairment (ORs 1.07 (95% CI 1.04 to 1.09, p<0.001), 2.18 (95% CI 0.80 to 5.96, p for trend <0.001), 1.74 (95% CI 0.82 to 3.68, p for trend 0.005), 2.08 (95% CI 1.26 to 3.41, p for trend <0.001) and 4.23 (95% CI 2.48 to 7.20), respectively). CONCLUSIONS: The majority of persons with mild-to-moderate CKD reported reductions in at least one HRQoL domain, which were independently associated with comorbidities, obesity and functional impairment. TRIAL REGISTRATION NUMBER: National Institute for Health Research Clinical Research Portfolio Study Number 6632.

The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: A prospective cohort study.

BACKGROUND: Tissue advanced glycation end product (AGE) accumulation has been proposed as a marker of cumulative metabolic stress that can be assessed noninvasively by measurement of skin autofluorescence (SAF). In persons on haemodialysis, SAF is an independent risk factor for cardiovascular events (CVEs) and all-cause mortality (ACM), but data at earlier stages of chronic kidney disease (CKD) are inconclusive. We investigated SAF as a risk factor for CVEs and ACM in a prospective study of persons with CKD stage 3. METHODS AND FINDINGS: Participants with estimated glomerular filtration rate (eGFR) 59 to 30 mL/min/1.73 m2 on two consecutive previous blood tests were recruited from 32 primary care practices across Derbyshire, United Kingdom between 2008 and 2010. SAF was measured in participants with CKD stage 3 at baseline, 1, and 5 years using an AGE reader (DiagnOptics). Data on hospital admissions with CVEs (based on international classification of diseases [ICD]-10 coding) and deaths were obtained from NHS Digital. Cox proportional hazards models were used to investigate baseline variables associated with CVEs and ACM. A total of 1,707 of 1,741 participants with SAF readings at baseline were included in this analysis: The mean (± SD) age was 72.9 ± 9.0 years; 1,036 (60.7%) were female, 1,681 (98.5%) were of white ethnicity, and mean (±SD) eGFR was 53.5 ± 11.9 mL/min/1.73 m2. We observed 319 deaths and 590 CVEs during a mean of 6.0 ± 1.5 and 5.1 ± 2.2 years of observation, respectively. Higher baseline SAF was an independent risk factor for CVEs (hazard ratio [HR] 1.12 per SD, 95% CI 1.03-1.22, p = 0.01) and ACM (HR 1.16, 95% CI 1.03-1.30, p = 0.01). Additionally, increase in SAF over 1 year was independently associated with subsequent CVEs (HR 1.11 per SD, 95% CI 1.00-1.22; p = 0.04) and ACM (HR 1.24, 95% CI 1.09-1.41, p = 0.001). We relied on ICD-10 codes to identify hospital admissions with CVEs, and there may therefore have been some misclassification. CONCLUSIONS: We have identified SAF as an independent risk factor for CVE and ACM in persons with early CKD. These findings suggest that interventions to reduce AGE accumulation, such as dietary AGE restriction, may reduce cardiovascular risk in CKD, but this requires testing in prospective randomised trials. Our findings may not be applicable to more ethnically diverse or younger populations.

Barriers and enablers to the implementation of a complex quality improvement intervention for acute kidney injury: A qualitative evaluation of stakeholder perceptions of the Tackling AKI study.

BACKGROUND: Acute kidney injury in hospital patients is common and associated with reduced survival and higher healthcare costs. The Tackling Acute Kidney Injury (TAKI) quality improvement project aimed to reduce mortality rates in patients with acute kidney injury by implementing a multicomponent intervention comprising of an electronic alert, care bundle and education in five UK hospitals across a variety of wards. A parallel developmental evaluation using a case study approach was conducted to provide the implementation teams with insights into factors that might impact intervention implementation and fidelity. The qualitative element of the evaluation will be reported. METHODS: 29 semi-structured interviews with implementation teams across the five hospitals were carried out to identify perceived barriers and enablers to implementation. Interviews were taped and transcribed verbatim and Framework analysis was conducted. RESULTS: Interviews generated four 'barriers and enablers' to implementation themes: i) practical/contextual factors, ii) skills and make-up of the TAKI implementation team, iii) design, development and implementation approach, iv) staff knowledge, attitudes, behaviours and support. Enablers included availability of specialist teams (e.g. educational teams), multi-disciplinary implementation teams with strong leadership, team-based package completion and proactive staff. Barriers were frequently the converse of facilitators. CONCLUSIONS: Despite diversity of sites, a range of common local factors-contextual, intervention-based and individual-were identified as potential barriers and enablers to fidelity, including intervention structure/design and process of/approach to implementation. Future efforts should focus on early identification and management of barriers and tailored optimisation of known enablers such as leadership and multidisciplinary teams to encourage buy-in. Improved measures of real-time intervention and implementation fidelity would further assist local teams to target their support during such quality improvement initiatives.

An Organizational-Level Program of Intervention for AKI: A Pragmatic Stepped Wedge Cluster Randomized Trial.

BACKGROUND: Variable standards of care may contribute to poor outcomes associated with AKI. We evaluated whether a multifaceted intervention (AKI e-alerts, an AKI care bundle, and an education program) would improve delivery of care and patient outcomes at an organizational level. METHODS: A multicenter, pragmatic, stepped-wedge cluster randomized trial was performed in five UK hospitals, involving patients with AKI aged ≥18 years. The intervention was introduced sequentially across fixed three-month periods according to a randomly determined schedule until all hospitals were exposed. The primary outcome was 30-day mortality, with pre-specified secondary endpoints and a nested evaluation of care process delivery. The nature of the intervention precluded blinding, but data collection and analysis were independent of project delivery teams. RESULTS: We studied 24,059 AKI episodes, finding an overall 30-day mortality of 24.5%, with no difference between control and intervention periods. Hospital length of stay was reduced with the intervention (decreases of 0.7, 1.1, and 1.3 days at the 0.5, 0.6, and 0.7 quantiles, respectively). AKI incidence increased and was mirrored by an increase in the proportion of patients with a coded diagnosis of AKI. Our assessment of process measures in 1048 patients showed improvements in several metrics including AKI recognition, medication optimization, and fluid assessment. CONCLUSIONS: A complex, hospital-wide intervention to reduce harm associated with AKI did not reduce 30-day AKI mortality but did result in reductions in hospital length of stay, accompanied by improvements in in quality of care. An increase in AKI incidence likely reflected improved recognition.

What is the value of multidisciplinary care for chronic kidney disease?

In a Persepctive, Richard Fluck and Maarten Taal discuss the potential value of implementing multidisciplinary care programs for chronic kidney disease.

The clinical utility and cost impact of cystatin C measurement in the diagnosis and management of chronic kidney disease: A primary care cohort study.

BACKGROUND: To reduce over-diagnosis of chronic kidney disease (CKD) resulting from the inaccuracy of creatinine-based estimates of glomerular filtration rate (GFR), UK and international guidelines recommend that cystatin-C-based estimates of GFR be used to confirm or exclude the diagnosis in people with GFR 45-59 ml/min/1.73 m2 and no albuminuria (CKD G3aA1). Whilst there is good evidence for cystatin C being a marker of GFR and risk in people with CKD, its use to define CKD in this manner has not been evaluated in primary care, the setting in which most people with GFR in this range are managed. METHODS AND FINDINGS: A total of 1,741 people with CKD G3a or G3b defined by 2 estimated GFR (eGFR) values more than 90 days apart were recruited to the Renal Risk in Derby study between June 2008 and March 2010. Using Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations, we compared GFR estimated from creatinine (eGFRcreat), cystatin C (eGFRcys), and both (eGFRcreat-cys) at baseline and over 5 years of follow-up. We analysed the proportion of participants with CKD G3aA1 reclassified to 'no CKD' or more advanced CKD with the latter two equations. We further assessed the impact of using cystatin-C-based eGFR in risk prediction equations for CKD progression and all-cause mortality and investigated non-GFR determinants of eGFRcys. Finally, we estimated the cost implications of implementing National Institute for Health and Care Excellence (NICE) guidance to use eGFRcys to confirm the diagnosis in people classified as CKD G3aA1 by eGFRcreat. Mean eGFRcys was significantly lower than mean eGFRcreat (45.1 ml/min/1.73 m2, 95% CI 44.4 to 45.9, versus 53.6 ml/min/1.73 m2, 95% CI 53.0 to 54.1, P < 0.001). eGFRcys reclassified 7.7% (50 of 653) of those with CKD G3aA1 by eGFRcreat to eGFR ≥ 60 ml/min/1.73 m2. However, a much greater proportion (59.0%, 385 of 653) were classified to an eGFR category indicating more severe CKD. A similar pattern was seen using eGFRcreat-cys, but lower proportions were reclassified. Change in eGFRcreat and eGFRcys over 5 years were weakly correlated (r = 0.33, P < 0.001), but eGFRcys identified more people as having CKD progression (18.2% versus 10.5%). Multivariable analysis using eGFRcreat as an independent variable identified age, smoking status, body mass index, haemoglobin, serum uric acid, serum albumin, albuminuria, and C reactive protein as non-GFR determinants of eGFRcys. Use of eGFRcys or eGFRcreat-cys did not improve discrimination in risk prediction models for CKD progression and all-cause mortality compared to similar models with eGFRcreat. Application of the NICE guidance, which assumed cost savings, to participants with CKD G3aA1 increased the cost of monitoring by £23 per patient, which if extrapolated to be applied throughout England would increase the cost of testing and monitoring CKD by approximately £31 million per year. Limitations of this study include the lack of a measured GFR and the potential lack of ethnic diversity in the study cohort. CONCLUSIONS: Implementation of current guidelines on eGFRcys testing in our study population of older people in primary care resulted in only a small reduction in diagnosed CKD but classified a greater proportion as having more advanced CKD than eGFRcreat. Use of eGFRcys did not improve risk prediction in this population and was associated with increased cost. Our data therefore do not support implementation of these recommendations in primary care. Further studies are warranted to define the most appropriate clinical application of eGFRcys and eGFRcreat-cys.

Effect of weekend admission on mortality associated with severe acute kidney injury in England: A propensity score matched, population-based study.

BACKGROUND: Increased in-hospital mortality associated with weekend admission has been reported for many acute conditions, but no study has investigated "weekend effect" for acute kidney injury requiring dialysis (AKI-D). METHODS: In this large, propensity score matched cohort of AKI-D, we examined the impact of weekend admission and in-centre nephrology services in 53,170 AKI-D admissions between 1st April 2003 and 31st March 2015 using a hospital episode statistic dataset. Propensity score matching (PSM) was performed to match 4284 weekend admissions with AKI-D with 14,788 admissions on weekdays. RESULTS: Of the 53,170 admissions with AKI-D in the whole dataset, 12,357 (23%) were at weekends. The unadjusted mortality for weekend admissions was significantly higher compared to admissions on weekdays (40·6% versus 39·6%, p 0·046). However, in multivariable analysis of the PSM cohort, the odds of death for weekend admissions with AKI-D was 1·01 (95%CI 0·93,1·09). Mortality was higher for weekend admissions in West Midlands (odds ratio (OR) 1·32, 95% confidence interval (CI) 1·05, 1·66) and lower in East of England (OR 0·77, 95%CI 0·59, 1·00) but was not different to weekday admissions in all other regions. In 2003-04, weekend admissions had lower odds of death (OR 0·45, 95%CI 0·21, 0·96) and in 2010-11 higher odds of death (OR 1·28, 95%CI 1·00, 1·63) but in the other ten years observed, there was no significant difference in mortality between weekday and weekend admissions. Provision of in-centre nephrology services was associated with lower odds of death at 0·57 (95%CI 0·54, 0·62). CONCLUSIONS: Weekend admissions in patients with AKI-D had no effect on mortality. Further research is warranted to elucidate the reasons for the lower mortality in hospitals with in-centre nephrology services.

Associations of fibroblast growth factor 23, vitamin D and parathyroid hormone with 5-year outcomes in a prospective primary care cohort of people with chronic kidney disease stage 3.

OBJECTIVES: Vitamin D deficiency, elevated fibroblast growth factor 23 (FGF23) and elevated parathyroid hormone (PTH) have each been associated with increased mortality in people with chronic kidney disease (CKD). Previous studies have focused on the effects of FGF23 in relatively advanced CKD. This study aims to assess whether FGF23 is similarly a risk factor in people with early CKD, and how this risk compares to that associated with vitamin D deficiency or elevated PTH. DESIGN: Prospective cohort study. SETTING: Thirty-two primary care practices. PARTICIPANTS: One thousand six hundred and sixty-four people who met Kidney Disease: Improving Global Outcomes (KDIGO) definitions for CKD stage 3 (two measurements of estimated glomerular filtration rate (eGFR) between 30 and 60 mL/min/1.73 m2 at least 90 days apart) prior to study recruitment. OUTCOME MEASURES: All-cause mortality over the period of study follow-up and progression of CKD defined as a 25% fall in eGFR and a drop in GFR category, or an increase in albuminuria category. RESULTS: Two hundred and eighty-nine participants died during the follow-up period. Vitamin D deficiency (HR 1.62, 95% CI 1.01 to 2.58) and elevated PTH (HR 1.42, 95% CI 1.09 to 1.84) were independently associated with all-cause mortality. FGF23 was associated with all-cause mortality in univariable but not multivariable analysis. Fully adjusted multivariable models of CKD progression showed no association with FGF23, vitamin D status or PTH. CONCLUSIONS: In this cohort of predominantly older people with CKD stage 3 and low risk of progression, vitamin D deficiency and elevated PTH were independent risk factors for all-cause mortality but elevated FGF23 was not. While FGF23 may have a role as a risk marker in high-risk populations managed in secondary care, our data suggest that it may not be as important in CKD stage 3, managed in primary care. TRIAL REGISTRATION NUMBER: National Institute for Health Research Clinical Research Portfolio Study Number 6632.

Regional Variation in Acute Kidney Injury Requiring Dialysis in the English National Health Service from 2000 to 2015 - A National Epidemiological Study.

BACKGROUND: The absence of effective interventions in presence of increasing national incidence and case-fatality in acute kidney injury requiring dialysis (AKI-D) warrants a study of regional variation to explore any potential for improvement. We therefore studied regional variation in the epidemiology of AKI-D in English National Health Service over a period of 15 years. METHOD: We analysed Hospital Episode Statistics data for all patients with a diagnosis of AKI-D, using ICD-10-CM codes, in English regions between 2000 and 2015 to study temporal changes in regional incidence and case-fatality. RESULTS: Of 203,758,879 completed discharges between 1st April 2000 and 31st March 2015, we identified 54,252 patients who had AKI-D in the nine regions of England. The population incidence of AKI-D increased variably in all regions over 15 years; however, the regional variation decreased from 3·3-fold to 1·3-fold (p<0·01). In a multivariable adjusted model, using London as the reference, in the period of 2000-2005, the North East (odd ratio (OR) 1·38; 95%CI 1·01, 1·90), East Midlands (OR 1·38; 95%CI 1·01, 1·90) and West Midlands (OR 1·38; 95%CI 1·01, 1·90) had higher odds for death, while East of England had lower odds for death (OR 0·66; 95% CI 0·49, 0·90). The North East had higher OR in all three five-year periods as compared to the other eight regions. Adjusted case-fatality showed significant variability with temporary improvement in some regions but overall there was no significant improvement in any region over 15 years. CONCLUSIONS: We observed considerable regional variation in the epidemiology of AKI-D that was not entirely attributable to variations in demographic or other identifiable clinical factors. These observations make a compelling case for further research to elucidate the reasons and identify interventions to reduce the incidence and case-fatality in all regions.

Intensive Hemodialysis and Health-Related Quality of Life.

Diminished health-related quality of life (HRQoL) is common in dialysis patients and associated with increased risks for morbidity and mortality. Patients may present limitations in both physical and mental HRQoL. Poor physical HRQoL may be defined by limited physical function, role limitations due to physical health, dissatisfaction with physical ability, and impaired mobility. Sleep disorders such as obstructive sleep apnea, restless legs, and fatigue are typical manifestations of poor physical HRQoL in dialysis patients. Poor mental HRQoL may be defined by depressive thinking, lack of positive affect, anxiety, and feelings of social isolation. The prevalence of depression is high in dialysis patients. Intensive hemodialysis (HD) can positively address HRQoL. In 3 randomized clinical trials, relative to conventional HD, intensive HD increased physical and mental component summary scores from the 36-Item Short-Form Health Survey (SF-36), although individual treatment effects of daily nocturnal HD were not statistically significant. In another large prospective study, initiation of short daily HD therapy was followed after 12 months by improvements in all SF-36 domains, sleep quality, and restless legs symptoms. In a small study of nocturnal HD, apnea and hypopnea episodes per hour decreased by almost 70% after conversion from conventional HD. Intensive HD is also associated with a large reduction in postdialysis recovery time. In contrast, 2 randomized clinical trials failed to demonstrate statistically significant effects of intensive HD on the Beck Depression Inventory score despite a significant decrease in Beck Depression Inventory score in the prospective study of short daily HD. Furthermore, intensive HD may not improve objective physical performance and can increase burden on caregivers in the home setting. In conclusion, intensive HD potentially can address both physical and mental aspects of poor HRQoL relative to conventional HD. However, more studies are needed to understand the effects of intensive HD, including specific schedules, on HRQoL.

Intensive Hemodialysis and Treatment Complications and Tolerability.

Hemodialysis (HD) treatment can be difficult to tolerate. Common complications are intradialytic hypotension (IDH) and long time to recovery after an HD session. IDH, as defined by nadir systolic blood pressure < 90mmHg and intradialytic decline > 30mmHg, occurs in almost 8% of HD sessions. IDH may be caused by aggressive ultrafiltration in response to interdialytic weight gain, can lead to myocardial stunning and cardiac arrhythmias, and is associated with increased risk for death. Long recovery time after a treatment session is also common. In DOPPS (Dialysis Outcomes and Practice Patterns Study), recovery time was 2 to 6 hours for 41% of HD patients and longer than 6 hours for 27%; recovery time was linearly associated with increased risks for death and hospitalization. Importantly, both decreases in blood pressure and feeling washed out or drained have been identified by patients as more important outcomes than death or hospitalization. Intensive HD likely reduces the likelihood of IDH. In the Frequent Hemodialysis Network trial, short daily and nocturnal schedules reduced the per-session probability of IDH by 20% and 68%, respectively, relative to 3 sessions per week. Due to lower ultrafiltration volume and/or rate, intensive HD may reduce intradialytic blood pressure variability. In a cross-sectional study, short daily and nocturnal schedules were associated with slower ultrafiltration and less dialysis-induced myocardial stunning than 3 sessions per week. In FREEDOM (Following Rehabilitation, Economics, and Everyday-Dialysis Outcome Measurements), a prospective cohort study of short daily HD, recovery time was reduced after 12 months from 8 hours to 1 hour, according to per-protocol analysis. Recovery time after nocturnal HD may be minutes. In conclusion, intensive HD can improve the tolerability of HD treatment by reducing the risk for IDH and decreasing recovery time after HD. These changes may improve the patient centeredness of end-stage renal disease care.

Intensive Hemodialysis and Potential Risks With Increasing Treatment.

Although intensive hemodialysis (HD) can address important clinical problems, increasing treatment also introduces risks. In this review, we assess risks pertaining to 6 domains: vascular access complications, infection, mortality, loss of residual kidney function, solute balance, and patient and care partner burden. In the Frequent Hemodialysis Network (FHN) trials, short daily and nocturnal schedules increased the incidence of access complications, although the incidence of access loss was not statistically higher. Observational studies indicate that infection-related hospitalization is an ongoing challenge with short daily HD. Excess risk may be catalyzed by poor infection control practices in the home setting in which intensive HD is typically delivered, but with fixed probability of bacterial contamination per cannulation, greater treatment frequency necessarily increases the risk for infectious complications. Buttonhole cannulation may increase the risk for metastatic infections. However, intensive HD in the home setting is associated with lower risk for infection than peritoneal dialysis. Data regarding mortality are equivocal. With extended follow-up of individuals in the FHN trials, short daily HD was associated with lower risk relative to the usual schedule, whereas nocturnal HD was associated with higher risk. In many, but not all, observational studies, short daily HD has been associated with lower risk than both in-center HD and peritoneal dialysis; however, observational studies are subject to unmeasured confounding. Intensive HD can accelerate the loss of residual kidney function in new dialysis patients with substantial urine output and can deplete solutes (eg, phosphorus) to the extent that supplementation is necessary. Finally, intensive HD may increase burden on patients and caregivers, possibly leading to technique failure. Some of these problems might be addressed with careful monitoring, so that relevant interventions (eg, antibiotics, retraining, and respite care) can be delivered. Ultimately, intensive HD is not a panacea for end-stage renal disease. Potential benefits and risks of treatment should be jointly considered.

Chronic Kidney Disease in Primary Care: Outcomes after Five Years in a Prospective Cohort Study.

BACKGROUND: Chronic kidney disease (CKD) is commonly managed in primary care, but most guidelines have a secondary care perspective emphasizing the risk of end-stage kidney disease (ESKD) and need for renal replacement therapy. In this prospective cohort study, we sought to study in detail the natural history of CKD in primary care to better inform the appropriate emphasis for future guidance. METHODS AND FINDINGS: In this study, 1,741 people with CKD stage 3 were individually recruited from 32 primary care practices in Derbyshire, United Kingdom. Study visits were undertaken at baseline, year 1, and year 5. Binomial logistic regression and Cox proportional hazards models were used to model progression, CKD remission, and all-cause mortality. We used Kidney Disease: Improving Global Outcomes (KDIGO) criteria to define CKD progression and defined CKD remission as the absence of diagnostic criteria (estimated glomerular filtration rate [eGFR] >60 ml/min/1.73 m2 and urine albumin-to-creatinine ratio [uACR] <3 mg/mmol) at any study visit. Participants were predominantly elderly (mean ± standard deviation (SD) age 72.9 ± 9.0 y), with relatively mild reduction in GFR (mean ± SD eGFR 53.5 ± 11.8 mL/min/1,73 m2) and a low prevalence of albuminuria (16.9%). After 5 y, 247 participants (14.2%) had died, most of cardiovascular causes. Only 4 (0.2%) developed ESKD, but 308 (17.7%) evidenced CKD progression by KDIGO criteria. Stable CKD was observed in 593 participants (34.1%), and 336 (19.3%) met the criteria for remission. Remission at baseline and year 1 was associated with a high likelihood of remission at year 5 (odds ratio [OR] = 23.6, 95% CI 16.5-33.9 relative to participants with no remission at baseline and year 1 study visits). Multivariable analyses confirmed eGFR and albuminuria as key risk factors for predicting adverse as well as positive outcomes. Limitations of this study include reliance on GFR estimated using the Modification of Diet in Renal Disease study (MDRD) equation for recruitment (but not subsequent analysis) and a study population that was predominantly elderly and white, implying that the results may not be directly applicable to younger populations of more diverse ethnicity. CONCLUSIONS: Management of CKD in primary care should focus principally on identifying the minority of people at high risk of adverse outcomes, to allow intervention to slow CKD progression and reduce cardiovascular events. Efforts should also be made to identify and reassure the majority who are at low risk of progression to ESKD. Consideration should be given to adopting an age-calibrated definition of CKD to avoid labelling a large group of people with age-related decline in GFR and low associated risk as having CKD.