Faculty Bibliography

BACKGROUND:Recommendations for apixaban dosing on the basis of kidney function are inconsistent between the US Food and Drug Administration and European Medicines Agency for patients with atrial fibrillation. Optimal apixaban dosing in chronic kidney disease remains unknown. METHODS:With the use of deidentified electronic health record data from the Optum Labs Data Warehouse, patients with atrial fibrillation and chronic kidney disease stage 4/5 initiating apixaban between 2013 and 2021 were identified. Risks of bleeding and stroke/systemic embolism were compared by apixaban dose (5 versus 2.5 mg), adjusted for baseline characteristics by the inverse probability of treatment weighting. The Fine-Gray subdistribution hazard model was used to account for the competing risk of death. Cox regression was used to examine risk of death by apixaban dose. RESULTS:). In inverse probability of treatment weighting analysis, apixaban 5 mg was associated with a higher risk of bleeding (incidence rate 4.9 versus 2.9 events per 100 person-years; incidence rate difference, 2.0 [95% CI, 0.6-3.4] events per 100 person-years; subdistribution hazard ratio, 1.63 [95% CI, 1.04-2.54]). There was no difference between apixaban 5 mg and 2.5 mg groups in the risk of stroke/systemic embolism (3.3 versus 3.0 events per 100 person-years; incidence rate difference, 0.2 [95% CI, -1.0 to 1.4] events per 100 person-years; subdistribution hazard ratio, 1.01 [95% CI, 0.59-1.73]), or death (9.9 versus 9.4 events per 100 person-years; incidence rate difference, 0.5 [95% CI, -1.6 to 2.6] events per 100 person-years; hazard ratio, 1.03 [95% CI, 0.77-1.38]). CONCLUSIONS:Compared with 2.5 mg, use of 5 mg apixaban was associated with a higher risk of bleeding in patients with atrial fibrillation and severe chronic kidney disease, with no difference in the risk of stroke/systemic embolism or death, supporting the apixaban dosing recommendations on the basis of kidney function by the European Medicines Agency, which differ from those issued by the US Food and Drug Administration.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Older adults initiating dialysis have a high risk of mortality and that risk may be related to potentially inappropriate medications (PIMs). Our objective was to identify and validate mortality risk associated with American Geriatrics Society Beers Criteria PIM classes and concomitant PIM use. METHODS:We used US Renal Data System data to establish a cohort of adults aged ≥ 65 years initiating dialysis (2013-2014) and had no PIM prescriptions in the 6 months prior to dialysis initiation. In a development cohort (40% sample), adjusted Cox proportional hazards models were performed to determine which of 30 PIM classes were associated with mortality (or "high-risk" PIMs). Adjusted Cox models were performed to assess the association of the number of "high-risk" PIM fills/month with mortality. All models were repeated in the validation cohort (60% sample). RESULTS:In the development cohort (n = 15,570), only 13 of 30 PIM classes were associated with a higher mortality risk. Compared with those with no "high-risk" PIM fills/month, patients having one "high-risk" PIM fill/month had a 1.29-fold (95% confidence interval 1.21-1.38) increased risk of death; those with two or more "high-risk" PIM fills/month had a 1.40-fold (95% confidence interval 1.24-1.58) increased risk. These findings were similar in the validation cohort (n = 23,569). CONCLUSIONS:Only a minority of Beers Criteria PIM classes may be associated with mortality in the older dialysis population; however, mortality risk increases with concomitant use of "high-risk" PIMs. Additional studies are needed to confirm these associations and their underlying mechanisms.

Understanding the physiological basis of physical resilience to clinical stressors is crucial for the well-being of older adults. This article presents a novel framework to discover the biological underpinnings of physical resilience in older adults as part of the "Characterizing Resiliencies to Physical Stressors in Older Adults: A Dynamical Physiological Systems Approach" study, also known as The Study of Physical Resilience and Aging (SPRING). Physical resilience, defined as the capacity of a person to withstand clinical stressors and quickly recover or improve upon a baseline functional level, is examined in adults aged 55 years and older by studying the dynamics of stress response systems. The hypothesis is that well-regulated stress response systems promote physical resilience. The study employs dynamic stimulation tests to assess energy metabolism, the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and the innate immune system. Baseline characteristics influencing resilience outcomes are identified through deep phenotyping of physical and cognitive function, as well as of biological, environmental, and psychosocial characteristics. SPRING aims to study participants undergoing knee replacement surgery (n = 100), bone and marrow transplantation (n = 100), or anticipating dialysis initiation (n = 60). Phenotypic and functional measures are collected pre-stressor and at multiple times after stressor for up to 12 months to examine resilience trajectories. By improving our understanding of physical resilience in older adults, SPRING has the potential to enhance resilient outcomes to major clinical stressors. The article provides an overview of the study's background, rationale, design, pilot phase, implementation, and implications for improving the health and well-being of older adults.

BACKGROUND:Short and long sleep durations are associated with cognitive dysfunction. Given the increased prevalence of sleep abnormalities in the CKD population, we tested whether the association between sleep duration and cognitive function differed between older adults with and without CKD. METHODS:This was a study of 3215 older adults (aged ≥ 60years) enrolled in the National Health and Nutrition Examination Survey (2011-2014) evaluating sleep duration, cognitive function (immediate recall, delayed recall, verbal fluency, executive function and processing speed, and global cognition), and kidney function. We quantified the association between sleep duration and cognitive function using linear regression and tested whether the associations differed among those with CKD and without using a Wald test for interaction. RESULTS:Among 3215 participants, 13.3% reported 2-5 hours of sleep per day, 75.2% reported 6-8 hours, and 11.5% reported ≥ 9 hours. Persons with CKD were more likely to sleep ≥ 9 hours (OR = 1.73, 95% CI: 1.22-2.46). Among participants with CKD, those with sleep duration ≥ 9 hours demonstrated worse global cognitive function (p for interaction = 0.01), immediate recall (p for interaction = 0.01), and verbal fluency (p for interaction = 0.004) than those with 6-8 hours sleep duration; no differences were observed for participants with CKD who slept 2-5 hours. Among participants without CKD, sleep was not associated with any measures of cognitive function. CONCLUSIONS:Longer sleep duration is associated with worse cognitive function only among persons with CKD and global cognition, delayed recall, and verbal fluency are particularly affected. Studies should identify interventions to improve sleep patterns and quality in this population.

SIGNIFICANCE STATEMENT:Cardiovascular diseases account for 32% of deaths among kidney transplant recipients. Statin therapy is common in this population. However, its effect on mortality prevention remains unclear among kidney transplant recipients, whose clinical risk profile might be unique because of concomitant immunosuppressive therapy. In this national study of 58,264 single-kidney transplant recipients, statin use was associated with a 5% decrease in mortality. More importantly, this protective association was stronger among those who used a mammalian target of rapamycin (mTOR) inhibitor for immunosuppression (27% decrease in mTOR inhibitor users versus 5% in nonusers). Our results suggest that statin therapy may reduce mortality in kidney transplant recipients and that the strength of this protective association may vary by immunosuppression regimen. BACKGROUND:Cardiovascular diseases are the leading cause of mortality in kidney transplant (KT) recipients, accounting for 32% of deaths. Statins are widely used in KT recipients, but effectiveness for preventing mortality remains unclear in this population, especially because of interaction between statins and immunosuppressive agents. We analyzed a national cohort to assess the real-world effectiveness of statins for reducing all-cause mortality in KT recipients. METHODS:We studied statin use and mortality among 58,264 adults (18 years or older) who received single kidneys between 2006 and 2016 and had Medicare part A/B/D. Statin use was ascertained from Medicare prescription drug claims and deaths from Center for Medicare and Medicaid Services records. We estimated the association of statin use with mortality using multivariable Cox models, with statin use as a time-varying exposure and immunosuppression regimen as effect modifiers. RESULTS:Statin use increased from 45.5% at KT to 58.2% at 1-year post-KT to 70.9% at 5-year post-KT. We observed 9785 deaths over 236,944 person-years. Overall, statin use was significantly associated with lower mortality (adjusted hazard ratio [aHR], 0.95; 95% confidence interval [CI], 0.90 to 0.99). The strength of this protective association varied by calcineurin inhibitor use (among tacrolimus users, aHR, 0.97; 95% CI, 0.92 to 1.03 versus among calcineurin nonusers, aHR, 0.72; 95% CI, 0.60 to 0.87; interaction P =0.002), mammalian target of rapamycin (mTOR) inhibitor use (among mTOR inhibitor users, aHR, 0.73; 95% CI, 0.57 to 0.92 versus among nonusers, aHR, 0.95; 95% CI, 0.91 to 1.00; interaction P =0.03), and mycophenolate use (among mycophenolate users, aHR, 0.96; 95% CI, 0.91 to 1.02 versus among nonusers, aHR, 0.76; 95% CI, 0.64 to 0.89; interaction P =0.002). CONCLUSION:Real-world evidence supports statin therapy for reducing all-cause mortality in KT recipients. Effectiveness might be greater when combined with mTOR inhibitor-based immunosuppression.

Repeat kidney transplantation (re-KT) is the preferred treatment for patients with graft failure. Changing allocation policies, widening the risk profile of recipients, and improving dialysis care may have altered the survival benefit of a re-KT. We characterized trends in re-KT survival benefit over 3 decades and tested whether it differed by age, race/ethnicity, sex, and panel reactive assay (PRA). By using the Scientific Registry of Transplant Recipient data, we identified 25 419 patients who underwent a re-KT from 1990 to 2019 and 25 419 waitlisted counterfactuals from the same year with the same waitlisted time following graft failure. In the adjusted analysis, a re-KT was associated with a lower risk of death (adjusted hazard ratio [aHR] = 0.63; 95% confidence interval [CI], 0.61-0.65). By using the 1990-1994 era as a reference (aHR = 0.77; 95% CI, 0.69-0.85), incremental improvements in the survival benefit were noted (1995-1999: aHR = 0.72; 95% CI, 0.67-0.78: 2000-2004: aHR = 0.59; 95% CI, 0.55-0.63: 2005-2009: aHR = 0.59; 95% CI, 0.56-0.63: 2010-2014: aHR = 0.57; 95% CI, 0.53-0.62: 2015-2019: aHR = 0.64; 95% CI, 0.57-0.73). The survival benefit of a re-KT was noted in both younger (age = 18-64 years: aHR = 0.63; 95% CI, 0.61-0.65) and older patients (age ≥65 years: aHR = 0.66; 95% CI, 0.58-0.74; P_interaction = .45). Patients of all races/ethnicities demonstrated similar benefits with a re-KT. However, it varied by the sex of the recipient (female patients: aHR = 0.60; 95% CI, 0.56-0.63: male patients: aHR = 0.66; 95% CI, 0.63-0.68; P_interaction = .004) and PRA (0-20: aHR = 0.69; 95% CI, 0.65-0.74: 21-80: aHR = 0.61; 95% CI, 0.57-0.66; P_interaction = .02; >80: aHR = 0.57; 95% CI, 0.53-0.61; P_interaction< .001). Our findings support the continued practice of a re-KT and efforts to overcome the medical, immunologic, and surgical challenges of a re-KT.

Frailty, characterized by a decreased physiological reserve and an increased vulnerability to stressors, is common among kidney transplant (KT) candidates and recipients. In this review, we present and summarize the key arguments for and against the assessment of frailty as part of KT evaluation. The key arguments for including frailty were: (i) sheer prevalence and far-reaching consequences of frailty on KT, and (ii) the ability to conduct a more holistic and objective evaluation of candidates, removing the inaccuracy associated with 'eye-ball' assessments of transplant fitness. The key argument against were: (i) lack of agreement on the definition of frailty and which tools should be used in renal populations, (ii) a lack of clarity on how, by whom and how often frailty assessments should be performed, and (iii) a poor understanding of how acute stressors affect frailty. However, it is the overwhelming opinion that the time has come for frailty assessments to be incorporated into KT listing. Although ongoing areas of uncertainty exist and further evidence development is needed, the well-established impact of frailty on clinical and experiential outcomes, the invaluable information obtained from frailty assessments, and the potential for intervention outweigh these limitations. Proactive and early identification of frailty allows for individualized and improved risk assessment, communication and optimization of candidates.

BACKGROUND:Kidney transplant recipients with graft failure are a rapidly rising cohort of patients who experience high morbidity, mortality, and fragmented transitions of care between transplant and dialysis teams. Current approaches to improving care focus on medical and surgical interventions, increasing re-transplantation, and improving coordination between treating teams with little understanding of patient needs and perspectives. METHODS:We undertook a systematic literature review of personal experiences of patients with graft failure. Six electronic and five grey literature databases were searched systematically. Of 4664 records screened 43 met the inclusion criteria. Six empirical qualitative studies and case studies were included in the final analysis. Thematic synthesis was used to combine data that included the perspectives of 31 patients with graft failure and 9 caregivers. RESULTS:Using the Transition Model, we isolated three interconnected phases as patients transition through graft failure: shattering of lifestyle and plans associated with a successful transplant; physical and psychological turbulence; and re-alignment by learning adaptive strategies to move forward. Critical factors affecting coping included multi-disciplinary healthcare approaches, social support, and individual-level factors. While clinical transplant care was evaluated positively, participants identified gaps in the provision of information and psychosocial support related to graft failure. Graft failure had a profound impact on caregivers especially when they were living donors. CONCLUSIONS:Our review reports patient-identified priorities for improving care and can help inform research and guideline development that strives to improve the care of patients with graft failure.

Purpose of Review: Irreversible cognitive impairment is a contraindication to liver transplantation, but growing evidence suggests many etiologies of liver disease have cognitive manifestations independent of hepatic encephalopathy and with variable reversibilities. Recent Findings: While cognitive sequelae of chronic alcohol use have long been recognized, cognitive dysfunction associated with other liver disease etiologies such as chronic hepatitis C infection, non-alcoholic fatty liver disease, and primary biliary cirrhosis has been recognized. While mechanisms vary and are incompletely understood, inflammation appears to play a central role in causing cognitive dysfunction associated with these diseases. Summary: Further research is needed to determine optimal cognitive assessment tools for patients with liver disease, identify patients at greatest risk for cognitive impairment, determine which elements of cognitive impairment are reversible, and identify effective therapies. This information will inform neurologic evaluation at time of liver transplant evaluation as well as expectations for neurologic recovery post-transplant.

Purpose of Review: This review presents an overview of the clinical syndrome of frailty and its association with kidney transplantation outcomes, recent developments in refining frailty assessment, and considerations for its implementation into kidney transplant evaluation. Recent Findings: Recent studies show that frailty is associated with adverse clinical outcomes before and after kidney transplantation, including decreased likelihood of listing and increased risks of mortality. However, frailty assessment has yet to be fully adopted by transplant centers; a study found that 40.9% of centers reported never assessing frailty at evaluation of kidney transplant candidates. Geriatric transplant experts and kidney transplant candidates agree that frailty is a valid consideration for evaluating candidacy. Summary: While frailty is an important consideration for treatment of patients with end-stage renal disease, its use in kidney transplant evaluation remains under-utilized. Future research is necessary to refine the frailty phenotype for effective integration into a kidney transplant context.