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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.

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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.

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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.

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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.

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