An introduction to realist evaluation and synthesis for kidney research.

Realist research describes a methodological approach that aims to explore how and why interventions work, for whom, and under what circumstances. Rather than quantifying how well an intervention works under specific conditions, realist theory explores the function of interventions in detail and specifically considers how the contexts in which interventional components are delivered influence the mechanisms that lead to outcomes. Realist methods can be applied to primary data (realist evaluation) or secondary data (realist synthesis). Although realist techniques are increasingly being used in the evaluation of complex interventions, there are relatively few published studies in the field of kidney care. In this review, we outline the theory and principles behind realist methods through discussion of a published realist synthesis describing complex interventions promoting delivery of optimal chronic kidney disease care. We discuss other kidney studies that have used realist methodology and situations where realist techniques could be applied to advance our understanding of how to best deliver care to patients with kidney disease.

Propensity Score and Instrumental Variable Techniques in Observational Transplantation Studies: An Overview and Worked Example Relating to Pre-Transplant Cardiac Screening.

Inferring causality from observational studies is difficult due to inherent differences in patient characteristics between treated and untreated groups. The randomised controlled trial is the gold standard study design as the random allocation of individuals to treatment and control arms should result in an equal distribution of known and unknown prognostic factors at baseline. However, it is not always ethically or practically possible to perform such a study in the field of transplantation. Propensity score and instrumental variable techniques have theoretical advantages over conventional multivariable regression methods and are increasingly being used within observational studies to reduce the risk of confounding bias. An understanding of these techniques is required to critically appraise the literature. We provide an overview of propensity score and instrumental variable techniques for transplant clinicians, describing their principles, assumptions, strengths, and weaknesses. We discuss the different patient populations included in analyses and how to interpret results. We illustrate these points using data from the Access to Transplant and Transplant Outcome Measures study examining the association between pre-transplant cardiac screening in kidney transplant recipients and post-transplant cardiac events.

A propensity score-matched analysis indicates screening for asymptomatic coronary artery disease does not predict cardiac events in kidney transplant recipients.

Screening for asymptomatic coronary artery disease prior to kidney transplantation aims to reduce peri- and post-operative cardiac events. It is uncertain if this is achieved. Here, we investigated whether pre-transplant screening with a stress test or coronary angiogram associated with any difference in major adverse cardiac events (MACE) up to five years post-transplantation. We examined a national prospective cohort recruited to the Access to Transplant and Transplant Outcome Measures study who received a kidney transplant between 2011-2017, and linked patient demographics and details of cardiac screening investigations to outcome data extracted from the Hospital Episode Statistics dataset and United Kingdom Renal Registry. Propensity score matched groups were analyzed using Kaplan-Meier and Cox survival analyses. Overall, 2572 individuals were transplanted in 18 centers; 51% underwent screening and the proportion undergoing screening by center ranged from 5-100%. The incidence of MACE at 90 days, one and five years was 0.9%, 2.1% and 9.4% respectively. After propensity score matching based on the presence or absence of screening, 1760 individuals were examined (880 each in screened and unscreened groups). There was no statistically significant association between screening and MACE at 90 days (hazard ratio 0.80, 95% Confidence Interval 0.31-2.05), one year (1.12, 0.51-2.47) or five years (1.31, 0.86-1.99). Age, male sex and history of ischemic heart disease were associated with MACE. Thus, there is no association between screening for asymptomatic coronary artery disease and MACE up to five years post-transplant. Practices involving unselected screening of transplant recipients should be reviewed.

Do routine hospital data accurately record comorbidity in advanced kidney disease populations? A record linkage cohort study.

BACKGROUND: Routine healthcare datasets capturing clinical and administrative information are increasingly being used to examine health outcomes. The accuracy of such data is not clearly defined. We examine the accuracy of diagnosis recording in individuals with advanced chronic kidney disease using a routine healthcare dataset in England with comparison to information collected by trained research nurses. METHODS: We linked records from the Access to Transplant and Transplant Outcome Measures study to the Hospital Episode Statistics dataset. International Classification of Diseases (ICD-10) and Office for Population Censuses and Surveys Classification of Interventions and Procedures (OPCS-4) codes were used to identify medical conditions from hospital data. The sensitivity, specificity, positive and negative predictive values were calculated for a range of diagnoses. RESULTS: Comorbidity information was available in 96% of individuals prior to starting kidney replacement therapy. There was variation in the accuracy of individual medical conditions identified from the routine healthcare dataset. Sensitivity and positive predictive values ranged from 97.7 and 90.4% for diabetes and 82.6 and 82.9% for ischaemic heart disease to 44.2 and 28.4% for liver disease. CONCLUSIONS: Routine healthcare datasets accurately capture certain conditions in an advanced chronic kidney disease population. They have potential for use within clinical and epidemiological research studies but are unlikely to be sufficient as a single resource for identifying a full spectrum of comorbidities.

Complex Interventions Across Primary and Secondary Care to Optimize Population Kidney Health: A Systematic Review and Realist Synthesis to Understand Contexts, Mechanisms, and Outcomes.

BACKGROUND: CKD affects 850 million people worldwide and is associated with high risk of kidney failure and death. Existing, evidence-based treatments are not implemented in at least a third of eligible patients, and there is socioeconomic inequity in access to care. While interventions aiming to improve delivery of evidence-based care exist, these are often complex, with intervention mechanisms acting and interacting in specific contexts to achieve desired outcomes. METHODS: We undertook realist synthesis to develop a model of these context-mechanism-outcome interactions. We included references from two existing systematic reviews and from database searches. Six reviewers produced a long list of study context-mechanism-outcome configurations based on review of individual studies. During group sessions, these were synthesized to produce an integrated model of intervention mechanisms, how they act and interact to deliver desired outcomes, and in which contexts these mechanisms work. RESULTS: Searches identified 3371 relevant studies, of which 60 were included, most from North America and Europe. Key intervention components included automated detection of higher-risk cases in primary care with management advice to general practitioners, educational support, and non-patient-facing nephrologist review. Where successful, these components promote clinician learning during the process of managing patients with CKD, promote clinician motivation to take steps toward evidence-based CKD management, and integrate dynamically with existing workflows. These mechanisms have the potential to result in improved population kidney disease outcomes and cardiovascular outcomes in supportive contexts (organizational buy-in, compatibility of interventions, geographical considerations). However, patient perspectives were unavailable and therefore did not contribute to our findings. CONCLUSIONS: This systematic review and realist synthesis describes how complex interventions work to improve delivery of CKD care, providing a framework within which future interventions can be developed. Included studies provided insight into the functioning of these interventions, but patient perspectives were lacking in available literature.

The Global Impact of COVID-19 on Solid Organ Transplantation: Two Years Into a Pandemic.

The coronavirus disease 2019 (COVID-19) pandemic has had a major global impact on solid organ transplantation (SOT). An estimated 16% global reduction in transplant activity occurred over the course of 2020, most markedly impacting kidney transplant and living donor programs, resulting in substantial knock-on effects for waitlisted patients. The increased severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection risk and excess deaths in transplant candidates has resulted in substantial effort to prioritize the safe restart and continuation of transplant programs over the second year of the pandemic, with transplant rates returning towards prepandemic levels. Over the past 2 y, COVID-19 mortality in SOT recipients has fallen from 20%-25% to 8%-10%, attributed to the increased and early availability of SARS-CoV-2 testing, adherence to nonpharmaceutical interventions, development of novel treatments, and vaccination. Despite these positive steps, transplant programs and SOT recipients continue to face challenges. Vaccine efficacy in SOT recipients is substantially lower than the general population and SOT recipients remain at an increased risk of adverse outcomes if they develop COVID-19. SOT recipients and transplant teams need to remain vigilant and ongoing adherence to nonpharmaceutical interventions appears essential. In this review, we summarize the global impact of COVID-19 on transplant activity, donor evaluation, and patient outcomes over the past 2 y, discuss the current strategies aimed at preventing and treating SARS-CoV-2 infection in SOT recipients, and based on lessons learnt from this pandemic, propose steps the transplant community could consider as preparation for future pandemics.

Burnout and long COVID among the UK nephrology workforce: results from a national survey investigating the impact of COVID-19 on working lives.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is placing a significant strain on healthcare. We conducted a national survey of the UK nephrology workforce to understand its impacts on their working lives. METHODS: An online questionnaire incorporating the Maslach Burnout Inventory score was distributed between 31 March and 1 May 2021, with a focus on COVID-19 and long COVID incidence, vaccine uptake, burnout and working patterns. Data were analysed qualitatively and quantitatively; multivariable logistic regression was used to identify associations. RESULTS: A total of 423 responses were received. Of them, 29% had contracted COVID-19, which was more common among doctors and nurses {odds ratio [OR] 2.18 [95% confidence interval (CI) 1.13-4.22]} and those <55 years of age [OR 2.60 (95% CI 1.38-4.90)]. Of those who contracted COVID-19, 36% had symptoms of long COVID, which was more common among ethnicities other than White British [OR 2.57 (95% CI 1.09-6.05)]. A total of 57% had evidence of burnout, which was more common among younger respondents [OR 1.92 (95% CI 1.10-3.35)] and those with long COVID [OR 10.31 (95% CI 1.32-80.70)], and 59% with reconfigured job plans continued to work more hours. More of those working full-time wished to retire early. A total of 59% experienced remote working, with a majority preference for continuing this in the future. In terms of vaccination, 95% had received one dose of a COVID-19 vaccine and 86% had received two doses by May 2021. CONCLUSIONS: Burnout and long COVID is prevalent with impacts on working lives. Some groups are more at risk. Vaccination uptake is high and remote and flexible working were well received. Institutional interventions are needed to prevent workforce attrition.

Novel MHC class I structures on exosomes.

Exosomes are nanometer-sized vesicles released by a number of cell types including those of the immune system, and often contain numerous immune recognition molecules including MHC molecules. We demonstrate in this study that exosomes can display a significant proportion of their MHC class I (MHC I) content in the form of disulfide-linked MHC I dimers. These MHC I dimers can be detected after release from various cell lines, human monocyte-derived dendritic cells, and can also be found in human plasma. Exosome-associated dimers exhibit novel characteristics which include 1) being composed of folded MHC I, as detected by conformational-dependent Abs, and 2) dimers forming between two different MHC I alleles. We show that dimer formation is mediated through cysteine residues located in the cytoplasmic tail domains of many MHC I molecules, and is associated with a low level of glutathione in exosomes when compared with whole cell lysates. We propose these exosomal MHC I dimers as novel structures for recognition by immune receptors.

Immunoglobulin and complement-mediated glomerular diseases with an MPGN pattern of injury: Unmasking the diagnosis of lupus in a patient with hepatitis A infection.

In cases with a broad differential or atypical features, it is important to continually review the original diagnosis. Diagnosing SLE can be challenging due to its multisystem presentations; a multidisciplinary approach is beneficial.

The Impact of Withdrawal of Maintenance Immunosuppression and Graft Nephrectomy on HLA Sensitization and Calculated Chance of Future Transplant.

BACKGROUND: The development of HLA antibodies towards a failing renal allograft is a barrier to retransplantation. This study aimed to compare the formation of HLA donor-specific antibodies (DSA) in patients undergoing graft nephrectomy and in those with a failed graft left in situ who had maintenance immunosuppression (IS) stopped, and assess the relative impact of IS cessation and graft nephrectomy on future relative chance of transplant (R-CoT). METHODS: A single-center retrospective study of patients with failed grafts between 2005 and 2015 was performed. Samples were tested for DSA pre-IS wean, post-IS wean, and post-IS cessation. Nephrectomy patients additionally had samples tested for DSA before and after nephrectomy. Calculated reaction frequency (cRF) was determined at each timepoint and entered into the UK Organ Donation and Transplant R-CoT calculator. RESULTS: Forty-one patients were included in the study: 24 with nephrectomy and 17 with a failed graft in situ. Patient demographics and duration of IS wean were similar between groups. There was a higher rate of blood transfusion (54% vs 24%) in nephrectomy patients. In patients whose graft remained in situ, cRF rose from 13% pre-IS wean to 40% post-IS wean and 62% after IS cessation. This equated to a reduction in mean R-CoT from 54% to 46% at 5 years. In patients undergoing nephrectomy mean cRF rose from 31% pre-IS wean to 69% post-IS wean and 89% post-IS cessation. Mean R-CoT fell from 54% to 42% at 5 years. CONCLUSIONS: A stepwise increase in cRF with reduced chance of transplant was observed in both groups as IS was withdrawn, with a similar pattern irrespective of graft nephrectomy. Calculated reaction frequency was higher in the nephrectomy group. The risks and benefits of stopping IS need to be carefully considered on an individual basis to maximize chance of future transplant.