Post-kidney Transplant Delirium: The Vulnerable Brain and Kidney Exposed—A Commentary on Ruck et al “Association of Postoperative Delirium With Incident Dementia and Graft Outcomes Among Kidney Transplant Recipients”

Nephrologists evaluating patients with end-stage kidney disease (ESKD) for kidney transplant (KT) suitability use guidelines to ensure patients selected have the optimal chance of benefit and to reduce the potential harms of surgery and immunosuppression. Mostly, these guidelines focus on objective and familiar areas of comorbidity including malignancy, vascular disease, and infection. Severe psychiatric and progressive neurocognitive disorders are usually cause for exclusion. Lesser degrees of cognitive disease are harder to quantify risk and benefit yet occur in up to 40% of patients with ESKD because of an aging population with a high prevalence of hypertension and diabetes.1 The prevalence of neurogenerative disorders (Alzheimer’s Dementia, AD) are similar to those without ESKD, but vascular and mixed dementias are increased because of the high prevalence of these common vascular risk factors. The cognitive effects in ESKD particularly effect processing and executive functions, which are required for optimal self-management after transplant. Following transplant, there is initial improvement in these higher level functions, perhaps because of early benefit from resolution of “uremia,” although this benefit is not always sustained.2 Delirium is associated with aging and has a bidirectional relationship with dementia and increases morbidity and risk of death in hospitalized patients. In the general population, up to 20% of hospitalized patients may have an episode of delirium often arising in those with known dementia.3 What is the risk of delirium and the consequences for KT recipients? Ruck et al performed a USRDS registry analysis of 35 800 incident KT recipients ≥55 y of age without a diagnosis of prior delirium or dementia and evaluated the association between post-KT delirium and incident dementia, graft loss, and death.4 A diagnosis of delirium was made in 0.9% of KT recipients, and risk factors associated with delirium were age, diabetes, and cerebrovascular disease but not years on dialysis. Delirium was associated with a significantly increased risk of delayed graft function (DGF 42% versus 27%) and twice the length of hospital stay (10 d versus 5 d). Delirium associated with a higher risk of death-censored graft loss (19.4% versus 13.3%), all-cause mortality (35% versus 23%), and risk of incident dementia (32% versus 7%) over a median of around 3 y follow-up. KT recipients in the 55–64 age group with delirium had an even higher risk of incident dementia. Notably, only mixed and vascular dementia subtypes but not AD was increased. Adjustment for measured variables including diabetes, cerebrovascular disease, and educational status did not modify these conclusions. The study benefits from large population and follow-up and adjustment for competing risks analysis but is limited by accuracy of coding. In particular, the rate of delirium is very low, suggesting either extremely careful patient selection, or more likely, underreporting. The accuracy of coding of dementia subtypes, and their continued clinical validity also remain uncertain, and it is likely significant overlap is present.5 The authors confined themselves to establishing only pre-KT risks with outcomes and the data are plausible, consistent, and expands their earlier single-center studies.2 It is an important finding that delirium portends significant immediate and long-term consequences. It is likely delirium unmasks the vulnerable or previously unrecognized neurocognitively impaired susceptible individuals. Surgery, immunosuppressive agents, diabetes, and environmental stimuli are possible triggers and the finding of an increased risk of diagnosed dementia is established in accordance with the general population findings. What is less clear and challenging is why should an isolated episode of delirium lead to an increased risk of graft loss and death? The high rate of DGF in this report is therefore of interest. Is delirium the cause or the consequence of DGF? There are striking similarities between DGF and delirium. Each is characterized by localized inflammation and systemic effects via innate immunity activation in response to a foreign stimulus and each is associated with increased graft loss and premature death.6,7 The pathophysiology of delirium involves microglial dysfunction via systemic and local neuroinflammation mediated by proinflammatory cytokines. It is increasingly recognized yet poorly studied that crosstalk between the brain and immune system is highly complex but also bidirectional in response to injury.8 Perhaps ischemia reperfusion injury and localized inflammatory response of organ transplantation initiating systemic innate immunity responses is a trigger for delirium, and its persistence and early immune activation act against long-term graft function (Figure 1). Although not the primary focus of this study, the interplay of DGF and delirium requires additional study to better characterize cause and effect. Similarly, no data on rejection was available to evaluate if a delirium/DGF nexus might be linked to increased rejection or other immune or nonimmune injury pathways.Figure 1.: Hypothetical model incorporating inter-relationships between delirium, KT outcomes, and DGF across the time course of kidney transplantation. A, Prior to transplant vulnerable brain risk identified. B, KT surgery “unmasks” vulnerability and in a minority delirium occurs, triggering a range of neuroinflammatory processes. C, Posttransplant neuroinflammation accelerates neurocognitive decline, associated with increased graft loss and risk of death. DGF is incorporated as a potential mediator in this construct. AD, Alzheimer’s dementia; DGF, delayed graft function; ESKD, end-stage kidney disease; KT, kidney transplant. Adapted from reference 3.The increase in all-cause death is not further explored in this study, but it would be valuable to understand whether accelerated vascular disease, withdrawal from progressive neurological disease or other causes are identified. The findings here alert clinicians that an episode of delirium is of great clinical significance and not just an isolated adverse event. As suggested by the authors, greater attention to preservation of neurocognitive function and reduction in vascular risk in follow-up is needed. Additionally, it seems closer attention to graft function and modification of immunosuppression may be required, although in the absence of clear signals about what drives graft loss this is speculative. Like most conditions, prevention of delirium is optimal and this begins with early interventions to reduce cerebrovascular disease.9 The low incidence of delirium reported here (likely an underestimate) suggests that risk stratification by identifying high risk for delirium might include greater intensity of screening prelisting using established processes at regular intervals, for example, Montreal Cognitive Assessment, but noting that there is no perfect nor single estimate of cognitive function, and when admitted, utilizing well-established preventative measures for delirium.3,10 Age >65, diabetes, hypertension, and cerebrovascular disease identify those at higher risk. Much research awaits to understand how delirium and/or its triggers cause such a significant downstream effect on KT patient and graft outcomes.

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