Measuring quality of life in trials including patients on dialysis: how are transplants and mortality incorporated into the analysis? A systematic review protocol.

Introduction It is estimated that 25 000 people in the UK receive dialysis. Dialysis is an intrusive and time-consuming intervention that causes significant reductions in quality of life. When enrolled in a clinical trial, often some patients drop out of the study either because they die, receive a kidney transplant or are lost to follow-up for other reasons. It is unclear how these events are dealt with when analysing quality of life measures within clinical trials. This review will assess current practice for dealing with loss to follow-up in trials including patients on haemodialysis. The methods currently used will be analysed in terms of their adequacy and will form the basis of future work assessing the most appropriate methods to employ under these circumstances. The results of this review will feed into recommendations for future nephrology trials. Methods and analysis A systematic search of electronic databases including MEDLINE and the Cochrane Library will be conducted to find clinical trials enrolling patients on haemodialysis that measure quality of life using either the kidney disease quality of life (KDQoL) or the short form 36 health survey (SF-36) (or any variation of these two measures). Ongoing trials will be identified through a search of trial registers. Articles will be screened against inclusion/exclusion criteria and data will be extracted using a predetermined data extraction form. General information such as the title, location, trial design will be extracted along with more specific information on how the study dealt with patients that died or received a transplant before the end of the follow-up period. Two independent reviewers will perform screening and extraction. Disagreements will be resolved by discussion or by a third independent reviewer. Data synthesis will be performed as a narrative summary. Ethics and dissemination Ethics approval is not required. Dissemination will be by publication in a peer-reviewed journal. PROSPERO registration number CRD42020223869.</p

Fruit and vegetable intake and incidence of type 2 diabetes mellitus: systematic review and meta-analysis.

OBJECTIVE: To investigate the independent effects of intake of fruit and vegetables on incidence of type 2 diabetes. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Medline, Embase, CINAHL, British Nursing Index (BNI), and the Cochrane library were searched for medical subject headings and keywords on diabetes, prediabetes, fruit, and vegetables. Expert opinions were sought and reference lists of relevant articles checked. STUDY SELECTION: Prospective cohort studies with an independent measure of intake of fruit, vegetables, or fruit and vegetables and data on incidence of type 2 diabetes. RESULTS: Six studies met the inclusion criteria; four of these studies also provided separate information on the consumption of green leafy vegetables. Summary estimates showed that greater intake of green leafy vegetables was associated with a 14% (hazard ratio 0.86, 95% confidence interval 0.77 to 0.97) reduction in risk of type 2 diabetes (P=0.01). The summary estimates showed no significant benefits of increasing the consumption of vegetables, fruit, or fruit and vegetables combined. CONCLUSION: Increasing daily intake of green leafy vegetables could significantly reduce the risk of type 2 diabetes and should be investigated further

Prediction of type 2 diabetes risk in people with non-diabetic hyperglycaemia: model derivation and validation using UK primary care data.

OBJECTIVE:Using primary care data, develop and validate sex-specific prognostic models that estimate the 10-year risk of people with non-diabetic hyperglycaemia developing type 2 diabetes. DESIGN:Retrospective cohort study. SETTING:Primary care. PARTICIPANTS:154 705 adult patients with non-diabetic hyperglycaemia. PRIMARY OUTCOME:Development of type 2 diabetes. METHODS:This study used data routinely collected in UK primary care from general practices contributing to the Clinical Practice Research Datalink. Patients were split into development (n=109 077) and validation datasets (n=45 628). Potential predictor variables, including demographic and lifestyle factors, medical and family history, prescribed medications and clinical measures, were included in survival models following the imputation of missing data. Measures of calibration at 10 years and discrimination were determined using the validation dataset. RESULTS:In the development dataset, 9332 patients developed type 2 diabetes during 293 238 person-years of follow-up (31.8 (95% CI 31.2 to 32.5) per 1000 person-years). In the validation dataset, 3783 patients developed type 2 diabetes during 115 113 person-years of follow-up (32.9 (95% CI 31.8 to 33.9) per 1000 person-years). The final prognostic models comprised 14 and 16 predictor variables for males and females, respectively. Both models had good calibration and high levels of discrimination. The performance statistics for the male model were: Harrell's C statistic of 0.700 in the development and 0.701 in the validation dataset, with a calibration slope of 0.974 (95% CI 0.905 to 1.042) in the validation dataset. For the female model, Harrell's C statistics were 0.720 and 0.718, respectively, while the calibration slope was 0.994 (95% CI 0.931 to 1.057) in the validation dataset. CONCLUSION:These models could be used in primary care to identify those with non-diabetic hyperglycaemia most at risk of developing type 2 diabetes for targeted referral to the National Health Service Diabetes Prevention Programme

Aspirin for the primary prevention of cardiovascular disease in individuals with chronic kidney disease: a systematic review and meta-analysis

AimsCardiovascular disease (CVD) is the major cause of morbidity and mortality in individuals with chronic kidney disease (CKD). This study assessed the risks and benefits of aspirin in the primary prevention of CVD in individuals with CKD.Methods and resultsOvid MEDLINE was searched from 2015 to 15th of September 2020 to include randomized controlled trials that assessed aspirin versus placebo in adults with non-end stage CKD without a previous diagnosis of CVD. A pre-specified protocol was registered with PROSPERO (identification number CRD42014008860). A random effects model was used to calculate a pooled hazard ratio (HR), pooled risk difference, and the number needed to treat or harm (NNT/NNH). The primary endpoint was CVD. Secondary endpoints included: all-cause mortality; coronary heart disease; stroke; and major and minor bleeding events. Five trials were identified (n = 7852 total, n = 3935 aspirin, n = 3917 placebo). Overall, 434 CVD events occurred. There was no statistically significant reduction in CVD events (HR 0.76, 95% confidence interval (CI) 0.54–1.08; P = 0.13, I2 = 63%), all-cause mortality (HR 0.94, 95% CI 0.74–1.19; P = 0.60, I2 = 21%), coronary heart disease events (HR 0.66, 95% CI 0.27–1.63; P = 0.37, I2 = 64%) or stroke (HR 0.87, 95% CI 0.6–1.27; P = 0.48, I2 = 24%) from aspirin therapy. The risk of major bleeding events were increased by approximately 50% (HR 1.53, 95% CI 1.13–2.05; P = 0.01, I2 = 0%) and minor bleeding events were more than doubled (HR 2.64, 95% CI 1.64–4.23; P ConclusionsAspirin cannot be routinely recommended for the primary prevention of CVD in individuals with CKD as there is no evidence for its benefit but there is an increased risk of bleeding.</div

Evaluation of the design, conduct and reporting of randomised controlled trials in the haemodialysis population: a scoping review and interview study.

Background: Fewer trials are conducted in nephrology than any other specialty, often failing to recruit to target, resulting in unclear evidence affecting translation to clinical practice. This mixed-methods study aims to provide guidance for designing and reporting future randomised controlled trials (RCTs) in the haemodialysis population.  Method: A scoping review was conducted. Five databases (MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Embase, Cochrane Central Register of Controlled Trials and ClinicalTrials.gov) were searched for RCTs published between 2013 and 2019 involving prevalent adult haemodialysis patients. Reporting of sample size, recruitment, retention and statistical significance of primary outcome were assessed. Face-to-face semistructured interviews were conducted with individuals from a single centre during dialysis sessions. Interviews were analysed thematically.  Results: Of 786 RCTs identified, 636 (80.9%) were parallel-group, 139 (17.7%) were crossover and 11 (1.4%) were cluster (including one stepped-wedge) design. Sample size justification was reported in 73.1%, 53.8% and 45.5% of parallel-group, crossover and cluster trials, respectively. Target recruitment was achieved by 45.5% of cluster, 53.8% of crossover and 57.7% of parallel-group trials with patient retention at 75.6%, 83.1% and 87.8%, respectively. Primary outcome reached statistical significance in 81.8% of cluster trials, 69.2% of parallel-group and 38.5% of crossover trials. Themes identified from individual interviews: perceptions of the convenience of trial participation; group allocation; perceptions of the benefits and adverse effects of taking part in clinical trials.  Conclusion: The recruitment and reporting of RCTs involving people on haemodialysis could be improved. Involvement of all stakeholders and especially participants in the trial design process may address issues around participant burden and ultimately improve the evidence base for clinical practice.</p

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 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

Effects of an Electronic Software "Prompt" With Health Care Professional Training on Cardiovascular and Renal Complications in a Multiethnic Population With Type 2 Diabetes and Microalbuminuria (the GP-Prompt Study): Results of a Pragmatic Cluster-Randomized Trial.

OBJECTIVE:Tight, targeted control of modifiable cardiovascular risk factors can reduce cardiovascular complications and mortality in individuals with type 2 diabetes (T2DM) and microalbuminuria. The effects of using an electronic "Prompt" with a treatment algorithm to support a treat-to-target approach has not been tested in primary care. RESEARCH DESIGN AND METHODS:A multicenter, cluster-randomized trial was conducted among primary care practices across Leicestershire, U.K. The primary outcome was the proportion of individuals achieving systolic and diastolic blood pressure (<130 and <80 mmHg, respectively) and total cholesterol (<3.5 mmol/L) targets at 24 months. Secondary outcomes included proportion of individuals with HbA1c <58 mmol/mol (<7.5%), changes in prescribing, change in the albumin-to-creatinine ratio, major adverse cardiovascular events, cardiovascular mortality, and coding accuracy. RESULTS:A total of 2,721 individuals from 22 practices, mean age 63 years, 41% female, and 62% from black and minority ethnic groups completed 2 years of follow-up. There were no significant differences in the proportion of individuals achieving the composite primary outcome, although the proportion of individuals achieving the prespecified outcome of total cholesterol <4.0 mmol (odds ratio 1.24; 95% CI 1.05-1.47; P = 0.01) increased with intensive intervention compared with control. Coding for microalbuminuria increased relative to control (odds ratio 2.05; 95% CI 1.29-3.25; P < 0.01). CONCLUSIONS:Greater improvements in composite cardiovascular risk factor control with this intervention compared with standard care were not achieved in this cohort of high-risk individuals with T2DM. However, improvements in lipid profile and coding can benefit patients with diabetes to alter the high risk of atherosclerotic cardiovascular events. Future studies should consider comprehensive strategies, including patient education and health care professional engagement, in the management of T2DM

The association of blood pressure variability with adverse outcomes in a primary care chronic kidney disease cohort

Background: Hypertension is common in individuals with chronic kidney disease and both conditions are associated with adverse outcomes including cardiovascular morbidity. Therefore, it is clinically important to identify methods of risk prediction in individuals with chronic kidney disease. Blood pressure variability has recently emerged as a predictor of cardiovascular events and mortality in the general population, with growing evidence indicating that it may play a similar role in individuals with chronic kidney disease. However, there have been no large studies assessing blood pressure variability in individuals with chronic kidney disease in primary care, where the majority of these patients are managed.Method: Using a retrospective observational study design, we analyzed routinely collected blood pressure readings from 16 999 individuals in The Leicester and County Chronic Kidney Disease cohort. Standard deviation, coefficient of variation and average real variability of SBP were used to calculate blood pressure variability.Results: During a median follow-up of 5.0 (IQR 3.3--5.0) years, 2053 (12.1%) patients had cardiovascular events, death occurred in 5021 (29.6%) individuals and 156 (0.9%) individuals had endstage kidney disease events. In adjusted models, standard deviation and coefficient of variation were associated with cardiovascular events, all-cause mortality and endstage kidney disease. Average real variability was associated with all-cause mortality and cardiovascular events, but not endstage kidney disease.Conclusion: Blood pressure variability may be an accessible, routinely collected, noninvasive measure for stratifying the risk of adverse events in individuals with chronic kidney disease in a primary care setting.</div

Incorporating polygenic risk into the Leicester Risk Assessment score for 10-year risk prediction of type 2 diabetes

Aims We evaluated whether incorporating information on ethnic background and polygenic risk enhanced the Leicester Risk Assessment (LRA) score for predicting 10-year risk of type 2 diabetes. Methods The sample included 202,529 UK Biobank participants aged 40–69 years. We computed the LRA score, and developed two new risk scores using training data (80% sample): LRArev, which incorporated additional information on ethnic background, and LRAprs, which incorporated polygenic risk for type 2 diabetes. We assessed discriminative and reclassification performance in a test set (20% sample). Type 2 diabetes was ascertained using primary care, hospital inpatient and death registry records. Results Over 10 years, 7476 participants developed type 2 diabetes. The Harrell's C indexes were 0.796 (95% Confidence Interval [CI] 0.785, 0.806), 0.802 (95% CI 0.792, 0.813), and 0.829 (95% CI 0.820, 0.839) for the LRA, LRArev and LRAprs scores, respectively. The LRAprs score significantly improved the overall reclassification compared to the LRA (net reclassification index [NRI] = 0.033, 95% CI 0.015, 0.049) and LRArev (NRI = 0.040, 95% CI 0.024, 0.055) scores. Conclusions Polygenic risk moderately improved the performance of the existing LRA score for 10-year risk prediction of type 2 diabetes.</p

The effect of exercise training on adipose tissue insulin sensitivity: A systematic review and meta-analysis

This systematic review and meta-analysis determined the impact of exercise training on adipose tissue insulin sensitivity in adults. Its scope extended to studies measuring whole-body and localized subcutaneous adipose tissue insulin sensitivity using validated techniques. Consensus from four studies demonstrates that exercise training improved whole-body adipose tissue insulin sensitivity when measured via stable-isotope lipid tracers (rate of appearance suppression in response to hyperinsulinemia). Meta-analysis of 20 studies (26 intervention arms) employing the adipose tissue insulin resistance index (ADIPO-IR) supported these findings (−10.63 [−14.12 to −7.15] pmol·L−1 × mmol·L−1). With ADIPO-IR, this response was greater in studies documenting weight loss and shorter sampling time (≤48 h) post-training. Overall, exercise training did not affect whole-body adipose tissue insulin sensitivity in seven studies (11 intervention arms) measuring the suppression of circulating non-esterified fatty acids in response to insulin infusion (1.51 [−0.12 to 3.14]%); however, subgroup analysis identified an enhanced suppression post-training in trials reporting weight loss. From four microdialysis studies, consensus indicates no effect of exercise training on localized (abdominal/femoral) adipose tissue insulin sensitivity, potentially suggesting that enhanced whole-body responses are related to improvements in central adipose depots. However, heterogeneity within microdialysis protocols dictates that findings must be viewed with caution