Ethnicity and outcomes for patients with gastrointestinal disorders attending an emergency department serving a multi-ethnic population.

BACKGROUND: Ethnic inequalities in acute health acute care are not well researched. We examined how attendee ethnicity influenced outcomes of emergency care in unselected patients presenting with a gastrointestinal (GI) disorder. METHODS: A descriptive, retrospective cohort analysis of anonymised patient level data for University Hospitals of Leicester emergency department attendees, from 1 January 2018 to 31 December 2021, receiving a diagnosis of a GI disorder was performed. The primary exposure of interest was self-reported ethnicity, and the two outcomes studied were admission to hospital and whether patients underwent clinical investigations. Confounding variables including sex and age, deprivation index and illness acuity were adjusted for in the analysis. Chi-squared and Kruskal-Wallis tests were used to examine ethnic differences across outcome measures and covariates. Multivariable logistic regression was used to examine associations between ethnicity and outcome measures. RESULTS: Of 34,337 individuals, median age 43 years, identified as attending the ED with a GI disorder, 68.6% were White. Minority ethnic patients were significantly younger than White patients. Multiple emergency department attendance rates were similar for all ethnicities (overall 18.3%). White patients had the highest median number of investigations (6, IQR 3-7), whereas those from mixed ethnic groups had the lowest (2, IQR 0-6). After adjustment for age, sex, year of attendance, index of multiple deprivation and illness acuity, all ethnic minority groups remained significantly less likely to be investigated for their presenting illness compared to White patients (Asian: aOR 0.80, 95% CI 0.74-0.87; Black: 0.67, 95% CI 0.58-0.79; mixed: 0.71, 95% CI 0.59-0.86; other: 0.79, 95% CI 0.67-0.93; p < 0.0001 for all). Similarly, after adjustment, minority ethnic attendees were also significantly less likely to be admitted to hospital (Asian: aOR 0.63, 95% CI 0.60-0.67; Black: 0.60, 95% CI 0.54-0.68; mixed: 0.60, 95% CI 0.51-0.71; other: 0.61, 95% CI 0.54-0.69; p < 0.0001 for all). CONCLUSIONS: Significant differences in usage patterns and disparities in acute care outcomes for patients of different ethnicities with GI disorders were observed in this study. These differences persisted after adjustment both for confounders and for measures of deprivation and illness acuity and indicate that minority ethnic individuals are less likely to be investigated or admitted to hospital than White patients.

The Kidney Failure Risk Equation: Evaluation of Novel Input Variables including eGFR Estimated Using the CKD-EPI 2021 Equation in 59 Cohorts.

SIGNIFICANCE STATEMENT: The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict 2- and 5-year risk of kidney failure in populations with eGFR <60 ml/min per 1.73 m 2 . However, the CKD-EPI 2021 creatinine equation for eGFR is now recommended for use but has not been fully tested in the context of KFRE. In 59 cohorts comprising 312,424 patients with CKD, the authors assessed the predictive performance and calibration associated with the use of the CKD-EPI 2021 equation and whether additional variables and accounting for the competing risk of death improves the KFRE's performance. The KFRE generally performed well using the CKD-EPI 2021 eGFR in populations with eGFR <45 ml/min per 1.73 m 2 and was not improved by adding the 2-year prior eGFR slope and cardiovascular comorbidities. BACKGROUND: The kidney failure risk equation (KFRE) uses age, sex, GFR, and urine albumin-to-creatinine ratio (ACR) to predict kidney failure risk in people with GFR <60 ml/min per 1.73 m 2 . METHODS: Using 59 cohorts with 312,424 patients with CKD, we tested several modifications to the KFRE for their potential to improve the KFRE: using the CKD-EPI 2021 creatinine equation for eGFR, substituting 1-year average ACR for single-measure ACR and 1-year average eGFR in participants with high eGFR variability, and adding 2-year prior eGFR slope and cardiovascular comorbidities. We also assessed calibration of the KFRE in subgroups of eGFR and age before and after accounting for the competing risk of death. RESULTS: The KFRE remained accurate and well calibrated overall using the CKD-EPI 2021 eGFR equation. The other modifications did not improve KFRE performance. In subgroups of eGFR 45-59 ml/min per 1.73 m 2 and in older adults using the 5-year time horizon, the KFRE demonstrated systematic underprediction and overprediction, respectively. We developed and tested a new model with a spline term in eGFR and incorporating the competing risk of mortality, resulting in more accurate calibration in those specific subgroups but not overall. CONCLUSIONS: The original KFRE is generally accurate for eGFR <45 ml/min per 1.73 m 2 when using the CKD-EPI 2021 equation. Incorporating competing risk methodology and splines for eGFR may improve calibration in low-risk settings with longer time horizons. Including historical averages, eGFR slopes, or a competing risk design did not meaningfully alter KFRE performance in most circumstances.

Major cardiovascular events and subsequent risk of kidney failure with replacement therapy: a CKD Prognosis Consortium study.

AIMS: Chronic kidney disease (CKD) increases risk of cardiovascular disease (CVD). Less is known about how CVD associates with future risk of kidney failure with replacement therapy (KFRT). METHODS AND RESULTS: The study included 25 903 761 individuals from the CKD Prognosis Consortium with known baseline estimated glomerular filtration rate (eGFR) and evaluated the impact of prevalent and incident coronary heart disease (CHD), stroke, heart failure (HF), and atrial fibrillation (AF) events as time-varying exposures on KFRT outcomes. Mean age was 53 (standard deviation 17) years and mean eGFR was 89 mL/min/1.73 m2, 15% had diabetes and 8.4% had urinary albumin-to-creatinine ratio (ACR) available (median 13 mg/g); 9.5% had prevalent CHD, 3.2% prior stroke, 3.3% HF, and 4.4% prior AF. During follow-up, there were 269 142 CHD, 311 021 stroke, 712 556 HF, and 605 596 AF incident events and 101 044 (0.4%) patients experienced KFRT. Both prevalent and incident CVD were associated with subsequent KFRT with adjusted hazard ratios (HRs) of 3.1 [95% confidence interval (CI): 2.9-3.3], 2.0 (1.9-2.1), 4.5 (4.2-4.9), 2.8 (2.7-3.1) after incident CHD, stroke, HF and AF, respectively. HRs were highest in first 3 months post-CVD incidence declining to baseline after 3 years. Incident HF hospitalizations showed the strongest association with KFRT [HR 46 (95% CI: 43-50) within 3 months] after adjustment for other CVD subtype incidence. CONCLUSION: Incident CVD events strongly and independently associate with future KFRT risk, most notably after HF, then CHD, stroke, and AF. Optimal strategies for addressing the dramatic risk of KFRT following CVD events are needed.

Estimated Glomerular Filtration Rate, Albuminuria, and Adverse Outcomes: An Individual-Participant Data Meta-Analysis.

Importance: Chronic kidney disease (low estimated glomerular filtration rate [eGFR] or albuminuria) affects approximately 14% of adults in the US. Objective: To evaluate associations of lower eGFR based on creatinine alone, lower eGFR based on creatinine combined with cystatin C, and more severe albuminuria with adverse kidney outcomes, cardiovascular outcomes, and other health outcomes. Design, Setting, and Participants: Individual-participant data meta-analysis of 27 503 140 individuals from 114 global cohorts (eGFR based on creatinine alone) and 720 736 individuals from 20 cohorts (eGFR based on creatinine and cystatin C) and 9 067 753 individuals from 114 cohorts (albuminuria) from 1980 to 2021. Exposures: The Chronic Kidney Disease Epidemiology Collaboration 2021 equations for eGFR based on creatinine alone and eGFR based on creatinine and cystatin C; and albuminuria estimated as urine albumin to creatinine ratio (UACR). Main Outcomes and Measures: The risk of kidney failure requiring replacement therapy, all-cause mortality, cardiovascular mortality, acute kidney injury, any hospitalization, coronary heart disease, stroke, heart failure, atrial fibrillation, and peripheral artery disease. The analyses were performed within each cohort and summarized with random-effects meta-analyses. Results: Within the population using eGFR based on creatinine alone (mean age, 54 years [SD, 17 years]; 51% were women; mean follow-up time, 4.8 years [SD, 3.3 years]), the mean eGFR was 90 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 11 mg/g (IQR, 8-16 mg/g). Within the population using eGFR based on creatinine and cystatin C (mean age, 59 years [SD, 12 years]; 53% were women; mean follow-up time, 10.8 years [SD, 4.1 years]), the mean eGFR was 88 mL/min/1.73 m2 (SD, 22 mL/min/1.73 m2) and the median UACR was 9 mg/g (IQR, 6-18 mg/g). Lower eGFR (whether based on creatinine alone or based on creatinine and cystatin C) and higher UACR were each significantly associated with higher risk for each of the 10 adverse outcomes, including those in the mildest categories of chronic kidney disease. For example, among people with a UACR less than 10 mg/g, an eGFR of 45 to 59 mL/min/1.73 m2 based on creatinine alone was associated with significantly higher hospitalization rates compared with an eGFR of 90 to 104 mL/min/1.73 m2 (adjusted hazard ratio, 1.3 [95% CI, 1.2-1.3]; 161 vs 79 events per 1000 person-years; excess absolute risk, 22 events per 1000 person-years [95% CI, 19-25 events per 1000 person-years]). Conclusions and Relevance: In this retrospective analysis of 114 cohorts, lower eGFR based on creatinine alone, lower eGFR based on creatinine and cystatin C, and more severe UACR were each associated with increased rates of 10 adverse outcomes, including adverse kidney outcomes, cardiovascular diseases, and hospitalizations.

Demographic and occupational determinants of anti-SARS-CoV-2 IgG seropositivity in hospital staff.

BACKGROUND: Although evidence suggests that demographic characteristics including minority ethnicity increase the risk of infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), it is unclear whether these characteristics, together with occupational factors, influence anti-SARS-CoV-2 IgG seroprevalence in hospital staff. METHODS: We conducted cross-sectional surveillance examining seroprevalence of anti-SARS-CoV-2 IgG amongst staff at University Hospitals of Leicester (UHL) NHS Trust. We quantified seroprevalence stratified by ethnicity, occupation and seniority of practitioner and used logistic regression to examine demographic and occupational factors associated with seropositivity. RESULTS: A total of 1148/10662 (10.8%) hospital staff members were seropositive. Compared to White staff (seroprevalence 9.1%), seroprevalence was higher in South Asian (12.3%) and Black (21.2%) staff. The occupations and department with the highest seroprevalence were nurses/healthcare assistants (13.7%) and the Emergency Department (ED)/Acute Medicine (17.5%), respectively. Seroprevalence decreased with seniority in medical/nursing practitioners. Minority ethnicity was associated with seropositivity on an adjusted analysis (South Asian: aOR 1.26; 95%CI: 1.07-1.49 and Black: 2.42; 1.90-3.09). Anaesthetics/ICU staff members were less likely to be seropositive than ED/Acute medicine staff (0.41; 0.27-0.61). CONCLUSIONS: Ethnicity and occupational factors, including specialty and seniority, are associated with seropositivity for anti-SARS-Cov-2 IgG. These findings could be used to inform occupational risk assessments for front-line healthcare workers.

No cases of asymptomatic SARS-CoV-2 infection among healthcare staff in a city under lockdown restrictions: lessons to inform 'Operation Moonshot'.

BACKGROUND: Leicester was the first city in the UK to have 'local lockdown' measures imposed in response to high community rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. As part of this response, a directive was issued by NHS England to offer testing of asymptomatic healthcare workers (HCWs) at University Hospitals of Leicester NHS Trust (UHL) for SARS-CoV-2 infection. METHODS: Between 20 July and 14 August 2020, we invited all HCWs at UHL to attend for SARS-CoV-2 testing by nucleic acid amplification (NAAT). We combined the result of this assay with demographic information from the electronic staff record. RESULTS: A total of 1150 staff (~8% of the workforce) volunteered. The median age was 46 years (IQR 34-55), 972 (84.5%) were female; 234 (20.4%) were of South Asian and 58 (5.0%) of Black ethnicity; 564 (49.0%) were nurses/healthcare assistants. We found no cases of asymptomatic infection. In comparison, average community test positivity rate in Leicester city was 2.6%. CONCLUSIONS: Within the context of local lockdowns due to high community transmission rates, voluntary testing of asymptomatic staff has low uptake and low yield and thus its premise and cost-effectiveness should be re-considered.

Intradialytic cycling does not exacerbate microparticles or circulating markers of systemic inflammation in haemodialysis patients.

PURPOSE: Patients receiving haemodialysis (HD) display elevated circulating microparticle (MP) concentration, tissue factor (TF) expression and markers of systemic inflammation, though regular intradialytic cycling (IDC) may have a therapeutic effect. This study investigated the impact of regular, moderate-intensity IDC on circulating MPs and inflammatory markers in unit-based HD patients. METHODS: Patients were cluster-randomised to intervention (n = 20, age: 51.4 ± 18.1 years, body mass: 77.6 ± 18.3 kg, mean ± SD) or no-exercise control (n = 20, 56.8 ± 14.0 years, 80.5 ± 26.5 kg). Intervention participants completed 30 min of moderate intensity (rating of perceived exertion [RPE] of 12-14) IDC, thrice weekly for 6 months. Pre-dialysis venous blood samples were obtained at 0, 3 and 6 months. Circulating MP phenotypes, cytokines, chemokine and MP TF expression were quantified using flow cytometry and cytometric bead array assays. RESULTS: Despite high exercise compliance (82%), no IDC-dependent effects were observed for any MP, cytokine or chemokine measure (p ≥ 0.051, ηρ2 ≤ 0.399) other than TNF-α (p = 0.001, ηρ2 = 0.186), though no significance was revealed upon post hoc analysis. CONCLUSION: Six months of regular, moderate-intensity IDC had no effect on MPs, cytokines or chemokines. This suggests that the exercise did not exacerbate thrombotic or inflammatory status, though further functional assays are required to confirm this. TRIAL REGISTRATION: ISRCTN1129707, prospectively registered on 05/03/2015.

How to design and implement a university-based COVID-19 testing programme? An evaluation of a novel RT-LAMP COVID-19 testing programme in a UK university.

BACKGROUND: Little is known about how asymptomatic testing as a method to control transmission of COVID-19 can be implemented, and the prevalence of asymptomatic infection within university populations. The objective of this study was to investigate how to effectively set-up and implement a COVID-19 testing programme using novel reverse transcriptase loop-mediated isothermal amplification (RT-LAMP) technology and to quantify the scale of asymptomatic infection on a university campus. METHODS: An observational study to describe the set-up and implementation of a novel COVID-19 testing programme on a UK university campus between September and December 2020. RT-LAMP testing was used to identify asymptomatic cases. RESULTS: A total of 1,673 tests were performed using RT-LAMP during the study period, of which 9 were positive for COVID-19, giving an overall positivity rate of 0.54%, equivalent to a rate in the tested population of 538 cases per 100,000 over the duration of testing. All positive tests were found to be positive on RT-PCR testing, giving a false positive rate of 0%. CONCLUSIONS: This study shows that it is possible to rapidly setup a universal university testing programme for COVID-19 in collaboration with local healthcare providers using RT-LAMP testing. Positive results were comparable to those in the local population, though with a different peak of infection. Further research to inform the design of the testing programme includes focus groups of those who underwent testing and further interrogation of the demographics of those opting to be tested to identify potential access problems or inequalities.

SARS-CoV-2 vaccine uptake in a multi-ethnic UK healthcare workforce: A cross-sectional study.

BACKGROUND: Healthcare workers (HCWs) and ethnic minority groups are at increased risk of COVID-19 infection and adverse outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is now available for frontline UK HCWs; however, demographic/occupational associations with vaccine uptake in this cohort are unknown. We sought to establish these associations in a large UK hospital workforce. METHODS AND FINDINGS: We conducted cross-sectional surveillance examining vaccine uptake amongst all staff at University Hospitals of Leicester NHS Trust. We examined proportions of vaccinated staff stratified by demographic factors, occupation, and previous COVID-19 test results (serology/PCR) and used logistic regression to identify predictors of vaccination status after adjustment for confounders. We included 19,044 HCWs; 12,278 (64.5%) had received SARS-CoV-2 vaccination. Compared to White HCWs (70.9% vaccinated), a significantly smaller proportion of ethnic minority HCWs were vaccinated (South Asian, 58.5%; Black, 36.8%; p < 0.001 for both). After adjustment for age, sex, ethnicity, deprivation, occupation, SARS-CoV-2 serology/PCR results, and COVID-19-related work absences, factors found to be negatively associated with vaccine uptake were younger age, female sex, increased deprivation, pregnancy, and belonging to any non-White ethnic group (Black: adjusted odds ratio [aOR] 0.30, 95% CI 0.26-0.34, p < 0.001; South Asian: aOR 0.67, 95% CI 0.62-0.72, p < 0.001). Those who had previously had confirmed COVID-19 (by PCR) were less likely to be vaccinated than those who had tested negative. Limitations include data being from a single centre, lack of data on staff vaccinated outside the hospital system, and that staff may have taken up vaccination following data extraction. CONCLUSIONS: Ethnic minority HCWs and those from more deprived areas as well as younger staff and female staff are less likely to take up SARS-CoV-2 vaccination. These findings have major implications for the delivery of SARS-CoV-2 vaccination programmes, in HCWs and the wider population, and should inform the national vaccination programme to prevent the disparities of the pandemic from widening.

A randomized controlled trial to investigate the effects of intra-dialytic cycling on left ventricular mass.

Cardiovascular disease is the leading cause of death for patients receiving hemodialysis. Since exercise mitigates many risk factors which drive cardiovascular disease for these patients, we assessed effects of a program of intra-dialytic cycling on left ventricular mass and other prognostically relevant measures of cardiovascular disease as evaluated by cardiac MRI (the CYCLE-HD trial). This was a prospective, open-label, single-blinded cluster-randomized controlled trial powered to detect a 15g difference in left ventricular mass measured between patients undergoing a six-month program of intra-dialytic cycling (exercise group) and patients continuing usual care (control group). Pre-specified secondary outcomes included measures of myocardial fibrosis, aortic stiffness, physical functioning, quality of life and ventricular arrhythmias. Outcomes were analyzed as intention-to-treat according to a pre-specified statistical analysis plan. Initially, 130 individuals were recruited and completed baseline assessments (65 each group). Ultimately, 101 patients completed the trial protocol (50 control group and 51 exercise group). The six-month program of intra-dialytic cycling resulted in a significant reduction in left ventricular mass between groups (-11.1g; 95% confidence interval -15.79, -6.43), which remained significant on sensitivity analysis (missing data imputed) (-9.92g; 14.68, -5.16). There were significant reductions in both native T1 mapping and aortic pulse wave velocity between groups favoring the intervention. There was no increase in either ventricular ectopic beats or complex ventricular arrhythmias as a result of exercise with no significant effect on physical function or quality of life. Thus, a six-month program of intradialytic cycling reduces left ventricular mass and is safe, deliverable and well tolerated.

Comorbidities and outcomes in South Asian individuals with chronic kidney disease: an observational primary care cohort.

BACKGROUND: South Asian (SA) individuals are more likely to develop end-stage renal disease (ESRD), but how chronic kidney disease (CKD) differs in relation to demographics, comorbidities and outcomes has not been studied. We aimed to study differences in SA individuals with CKD compared with White individuals. METHODS: This was an observational CKD cohort comparing SA with White individuals. Inclusion criteria were ≥18 years of age and two or more Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFRs <60 mL/min/1.73 m2 >3 months apart. Individuals with ESRD at baseline were excluded. Baseline characteristics, including eGFR formulae [CKD-EPI and CKD-EPI-Pakistan (CKD-EPI-PK)], were compared. Analysis using competing risk regression for cardiovascular (CV) and ESRD events and Cox proportional hazard model for mortality was performed. RESULTS: From an adult population of 277 248 individuals, 17 248 individuals had CKD, of whom 1990 (11.5%) were of SA ethnicity. Age-adjusted prevalence of CKD was similar between ethnicities. SA individuals were more likely to be male, younger and socioeconomically deprived, and to have diabetes mellitus, CV disease and advanced CKD. Mean CKD-EPI-PK eGFR was 6.5 mL/min/1.73 m2 lower (41.1 versus 47.6, 95% confidence interval for difference 6.47-6.56) than for CKD-EPI. During 5 years of follow-up, 5109 (29.6%) individuals died, 2072 (12.0%) had a CV and 156 (0.90%) an ESRD event. Risk for SA individuals was higher for ESRD, similar to CV events and lower for mortality. Each 1 mL/min/1.73 m2 decrease in CKD-EPI-PK was associated with a 13.1% increased ESRD risk (adjusted subdistribution hazard ratio 0.869, 95% confidence interval 0.841-0.898). CONCLUSIONS: SA individuals with CKD were younger and had more advanced disease than White individuals. Risk of ESRD was higher and CKD-EPI-PK was associated with ESRD risk in SA individuals. Specific CKD interventions, including the use of CKD-EPI-PK, should be considered in SA populations.

Correction: The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study.

[This corrects the article DOI: 10.1371/journal.pmed.1002955.].

Intravenous sildenafil citrate and post-cardiac surgery acute kidney injury: a double-blind, randomised, placebo-controlled trial.

BACKGROUND: This study assessed whether i.v. sildenafil citrate prevented acute kidney injury in at-risk patients undergoing cardiac surgery with cardiopulmonary bypass. METHODS: In a double-blind RCT, adults at increased risk of acute kidney injury undergoing cardiac surgery in a single UK tertiary centre were randomised to receive sildenafil citrate 12.5 mg kg-1 i.v. over 150 min or dextrose 5% at the commencement of surgery. The primary outcome was serum creatinine measured at six post-randomisation time points. The primary analysis used a linear mixed-effects model adjusted for the stratification variables, baseline estimated glomerular filtration rate, and surgical procedure. Secondary outcomes considered clinical events and potential disease mechanisms. Effect estimates were expressed as mean differences (MDs) or odds ratios with 95% confidence intervals. RESULTS: The analysis population comprised eligible randomised patients that underwent valve surgery or combined coronary artery bypass graft and valve surgery, with cardiopulmonary bypass, between May 2015 and June 2018. There were 60 subjects in the sildenafil group and 69 in the placebo control group. The difference between groups in creatinine concentration was not statistically significant (MD: 0.88 µmol L-1 [-5.82, 7.59]). There was a statistically significant increase in multiple organ dysfunction scores in the sildenafil group (MD: 0.54 [0.02, 1.07]; P=0.044). Secondary outcomes, and biomarkers of kidney injury, endothelial function, and inflammatory cell activation, were not significantly different between the groups. CONCLUSIONS: These results do not support the use of i.v. sildenafil citrate for kidney protection in adult cardiac surgery. CLINICAL TRIAL REGISTRATION: ISRCTN18386427.

The Primary-Secondary Care Partnership to Improve Outcomes in Chronic Kidney Disease (PSP-CKD) Study: A Cluster Randomized Trial in Primary Care.

BACKGROUND: Most patients with CKD are managed in the community. Whether nurse-led CKD management programs improve outcomes in patients with CKD in primary care is unclear. METHODS: To assess the effect of such a program on the rate of renal function decline in patients with CKD (stages 3-5) in primary care in the United Kingdom, we conducted a cluster randomized trial, the Primary-Secondary Care Partnership to Improve Outcomes in Chronic Kidney Disease study. A software program designed for the study created a data file of patients with CKD in participating practices. In 23 intervention practices (11,651 patients), a CKD nurse practitioner worked with nominated practice leads to interpret the data file and implement guideline-based patient-level CKD management interventions. The 23 control practices (11,706 patients) received a data file but otherwise, continued usual CKD care. The primary outcome was defined at the cluster (practice) level as the change from baseline of the mean eGFR of the patients with CKD at 6-month intervals up to 42 months. Secondary outcomes included numbers of patients coded for CKD, mean BP, numbers of patients achieving National Institute for Health and Care Excellence BP targets for CKD, and proteinuria measurement. RESULTS: After 42 months, eGFR did not differ significantly between control and intervention groups. CKD- and proteinuria-related coding improved significantly along with the number of patients achieving BP targets in the intervention group versus usual care. CONCLUSIONS: CKD management programs in primary care may not slow progression of CKD, but they may significantly improve processes of care and potentially decrease the cardiovascular disease burden in CKD and related costs.

Inorganic Phosphate (Pi) Signaling in Endothelial Cells: A Molecular Basis for Generation of Endothelial Microvesicles in Uraemic Cardiovascular Disease.

Hyperphosphataemia increases cardiovascular mortality in patients with kidney disease. Direct effects of high inorganic phosphate (Pi) concentrations have previously been demonstrated on endothelial cells (ECs), including generation of procoagulant endothelial microvesicles (MVs). However, no mechanism directly sensing elevated intracellular Pi has ever been described in mammalian cells. Here, we investigated the hypothesis that direct inhibition by Pi of the phosphoprotein phosphatase PP2A fulfils this sensing role in ECs, culminating in cytoskeleton disruption and MV generation. ECs were treated with control (1 mM [Pi]) vs. high (2.5 mM [Pi]), a condition that drives actin stress fibre depletion and MV generation demonstrated by confocal microscopy of F-actin and NanoSight Nanoparticle tracking, respectively. Immuno-blotting demonstrated that high Pi increased p-Src, p-PP2A-C and p-DAPK-1 and decreased p-TPM-3. Pi at 100 µM directly inhibited PP2A catalytic activity. Inhibition of PP2A enhanced inhibitory phosphorylation of DAPK-1, leading to hypophosphorylation of Tropomyosin-3 at S284 and MV generation. p-Src is known to perform inhibitory phosphorylation on DAPK-1 but also on PP2A-C. However, PP2A-C can itself dephosphorylate (and therefore inhibit) p-Src. The direct inhibition of PP2A-C by Pi is, therefore, amplified by the feedback loop between PP2A-C and p-Src, resulting in further PP2A-C inhibition. These data demonstrated that PP2A/Src acts as a potent sensor and amplifier of Pi signals which can further signal through DAPK-1/Tropomyosin-3 to generate cytoskeleton disruption and generation of potentially pathological MVs.

Mixed-effects models for health care longitudinal data with an informative visiting process: A Monte Carlo simulation study.

Electronic health records are being increasingly used in medical research to answer more relevant and detailed clinical questions; however, they pose new and significant methodological challenges. For instance, observation times are likely correlated with the underlying disease severity: Patients with worse conditions utilise health care more and may have worse biomarker values recorded. Traditional methods for analysing longitudinal data assume independence between observation times and disease severity; yet, with health care data, such assumptions unlikely hold. Through Monte Carlo simulation, we compare different analytical approaches proposed to account for an informative visiting process to assess whether they lead to unbiased results. Furthermore, we formalise a joint model for the observation process and the longitudinal outcome within an extended joint modelling framework. We illustrate our results using data from a pragmatic trial on enhanced care for individuals with chronic kidney disease, and we introduce user-friendly software that can be used to fit the joint model for the observation process and a longitudinal outcome.

The Kidney Failure Risk Equation for prediction of end stage renal disease in UK primary care: An external validation and clinical impact projection cohort study.

BACKGROUND: The Kidney Failure Risk Equation (KFRE) uses the 4 variables of age, sex, urine albumin-to-creatinine ratio (ACR), and estimated glomerular filtration rate (eGFR) in individuals with chronic kidney disease (CKD) to predict the risk of end stage renal disease (ESRD), i.e., the need for dialysis or a kidney transplant, within 2 and 5 years. Currently, national guideline writers in the UK and other countries are evaluating the role of the KFRE in renal referrals from primary care to secondary care, but the KFRE has had limited external validation in primary care. The study's objectives were therefore to externally validate the KFRE's prediction of ESRD events in primary care, perform model recalibration if necessary, and assess its projected impact on referral rates to secondary care renal services. METHODS AND FINDINGS: Individuals with 2 or more Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR values < 60 ml/min/1.73 m2 more than 90 days apart and a urine ACR or protein-to-creatinine ratio measurement between 1 December 2004 and 1 November 2016 were included in the cohort. The cohort included 35,539 (5.6%) individuals (57.5% female, mean age 75.9 years, median CKD-EPI eGFR 51 ml/min/1.73 m2, median ACR 3.2 mg/mmol) from a total adult practice population of 630,504. Overall, 176 (0.50%) and 429 (1.21%) ESRD events occurred within 2 and 5 years, respectively. Median length of follow-up was 4.7 years (IQR 2.8 to 6.6). Model discrimination was excellent for both 2-year (C-statistic 0.932, 95% CI 0.909 to 0.954) and 5-year (C-statistic 0.924, 95% 0.909 to 0.938) ESRD prediction. The KFRE overpredicted risk in lower (<20%) risk groups. Reducing the model's baseline risk improved calibration for both 2- and 5-year risk for lower risk groups, but led to some underprediction of risk in higher risk groups. Compared to current criteria, using referral criteria based on a KFRE-calculated 5-year ESRD risk of ≥5% and/or an ACR of ≥70 mg/mmol reduced the number of individuals eligible for referral who did not develop ESRD, increased the likelihood of referral eligibility in those who did develop ESRD, and referred the latter at a younger age and with a higher eGFR. The main limitation of the current study is that the cohort is from one region of the UK and therefore may not be representative of primary care CKD care in other countries. CONCLUSIONS: In this cohort, the recalibrated KFRE accurately predicted the risk of ESRD at 2 and 5 years in primary care. Its introduction into primary care for referrals to secondary care renal services may lead to a reduction in unnecessary referrals, and earlier referrals in those who go on to develop ESRD. However, further validation studies in more diverse cohorts of the clinical impact projections and suggested referral criteria are required before the latter can be clinically implemented.

Serum potassium and adverse outcomes across the range of kidney function: a CKD Prognosis Consortium meta-analysis.

Aims: Both hypo- and hyperkalaemia can have immediate deleterious physiological effects, and less is known about long-term risks. The objective was to determine the risks of all-cause mortality, cardiovascular mortality, and end-stage renal disease associated with potassium levels across the range of kidney function and evaluate for consistency across cohorts in a global consortium. Methods and results: We performed an individual-level data meta-analysis of 27 international cohorts [10 general population, 7 high cardiovascular risk, and 10 chronic kidney disease (CKD)] in the CKD Prognosis Consortium. We used Cox regression followed by random-effects meta-analysis to assess the relationship between baseline potassium and adverse outcomes, adjusted for demographic and clinical characteristics, overall and across strata of estimated glomerular filtration rate (eGFR) and albuminuria. We included 1 217 986 participants followed up for a mean of 6.9 years. The average age was 55 ± 16 years, average eGFR was 83 ± 23 mL/min/1.73 m2, and 17% had moderate- to-severe increased albuminuria levels. The mean baseline potassium was 4.2 ± 0.4 mmol/L. The risk of serum potassium of >5.5 mmol/L was related to lower eGFR and higher albuminuria. The risk relationship between potassium levels and adverse outcomes was U-shaped, with the lowest risk at serum potassium of 4-4.5 mmol/L. Compared with a reference of 4.2 mmol/L, the adjusted hazard ratio for all-cause mortality was 1.22 [95% confidence interval (CI) 1.15-1.29] at 5.5 mmol/L and 1.49 (95% CI 1.26-1.76) at 3.0 mmol/L. Risks were similar by eGFR, albuminuria, renin-angiotensin-aldosterone system inhibitor use, and across cohorts. Conclusions: Outpatient potassium levels both above and below the normal range are consistently associated with adverse outcomes, with similar risk relationships across eGFR and albuminuria.

Proinsulin C-Peptide Enhances Cell Survival and Protects against Simvastatin-Induced Myotoxicity in L6 Rat Myoblasts.

The repair capacity of progenitor skeletal muscle satellite cells (SC) in Type 1 diabetes mellitus (T1DM) is decreased. This is associated with the loss of skeletal muscle function. In T1DM, the deficiency of C-peptide along with insulin is associated with an impairment of skeletal muscle functions such as growth, and repair, and is thought to be an important contributor to increased morbidity and mortality. Recently, cholesterol-lowering drugs (statins) have also been reported to increase the risk of skeletal muscle dysfunction. We hypothesised that C-peptide activates key signaling pathways in myoblasts, thus promoting cell survival and protecting against simvastatin-induced myotoxicity. This was tested by investigating the effects of C-peptide on the L6 rat myoblast cell line under serum-starved conditions. Results: C-peptide at concentrations as low as 0.03 nM exerted stimulatory effects on intracellular signaling pathways-MAP kinase (ERK1/2) and Akt. When apoptosis was induced by simvastatin, 3 nM C-peptide potently suppressed the apoptotic effect through a pertussis toxin-sensitive pathway. Simvastatin strongly impaired Akt signaling and stimulated the reactive oxygen species (ROS) production; suggesting that Akt signaling and oxidative stress are important factors in statin-induced apoptosis in L6 myoblasts. The findings indicate that C-peptide exerts an important protective effect against death signaling in myoblasts. Therefore, in T1DM, the deficiency of C-peptide may contribute to myopathy by rendering myoblast-like progenitor cells (involved in muscle regeneration) more susceptible to the toxic effects of insults such as simvastatin.

Reduced proximal tubular expression of protein endocytic receptors in proteinuria is associated with urinary receptor shedding.

Background: Filtered proteins, including albumin, are reabsorbed in the proximal tubule (PT) mediated by megalin, cubilin and the neonatal Fc receptor (FcRn). Proteinuria is an important renal biomarker linked to poor prognosis but expression of these key receptors is not well studied. Methods: Megalin expression was determined at protein and messenger RNA (mRNA) levels in kidneys from proteinuric patients, and the expression of megalin, cubilin and FcRn was examined in the kidneys of mice with protein-overload proteinuria. The presence of receptors in the urine of proteinuric and control mice was also studied. Results: In nephrotic patients, megalin expression is reduced while mRNA is increased. In proteinuric mice megalin, cubilin and the neonatal FcRn protein are all reduced in PTs. Megalin and FcRn mRNA are increased in proteinuric mice, whereas that for cubilin was reduced. In proteinuric mice increased urinary excretion of each of these endocytic receptors was observed. Conclusions: It is concluded that in proteinuria, expression of all the key protein re-absorptive receptors is significantly reduced in the PT in association with increased turnover and urinary shedding.