Faculty Bibliography

Kidney transplant (KT) recipients with delirium, a preventable surgical complication, are likely to reap cognitive benefits from restored kidney function, but may be more vulnerable to longer-term neurotoxic stressors post-KT (i.e., aging, immunosuppression). In this prospective cohort study, we measured delirium (chart-based), global cognitive function (3MS), and executive function (Trail Making Test Part B minus Part A) in 894 recipients (2009-2021) at KT, 1/3/6-months, 1-year, and annually post-KT. Dementia was ascertained using linked Medicare claims. We described repeated measures of cognitive performance (mixed effects model) and quantified dementia risk (Fine & Gray competing risk) by post-KT delirium. Of 894 recipients, 43(4.8%) had post-KT delirium. Delirium was not associated with global cognitive function at KT (difference = -3.2 points, 95%CI: -6.7, 0.4) or trajectories post-KT (0.03 points/month, 95%CI: -0.27, 0.33). Delirium was associated with worse executive function at KT (55.1 s, 95%CI: 25.6, 84.5), greater improvements in executive function <2 years post-KT (-2.73 s/month, 95%CI: -4.46,-0.99), and greater decline in executive function >2 years post-KT (1.72 s/month, 95%CI: 0.22, 3.21). Post-KT delirium was associated with over 7-fold greater risk of dementia post-KT (adjusted subdistribution hazard ratio = 7.84, 95%CI: 1.22, 50.40). Transplant centers should be aware of cognitive risks associated with post-KT delirium and implement available preventative interventions to reduce delirium risk.

A recent study concluded that SARS-CoV-2 mRNA vaccine responses were improved among transplant patients taking mTOR inhibitors (mTORi). This could have profound implications for vaccine strategies in transplant patients; however, limitations in the study design raise concerns about the conclusions. To address this issue more robustly, in a large cohort with appropriate adjustment for confounders, we conducted various regression- and machine learning-based analyses to compare antibody responses by immunosuppressive agents in a national cohort (n = 1037). MMF was associated with significantly lower odds of positive antibody response (aOR = _0.09 0.13_0.18 ). Consistent with the recent mTORi study, the odds tended to be higher with mTORi (aOR = _1.00 1.45_2.13 ); however, importantly, this seemingly protective tendency disappeared (aOR = _0.47 0.73_1.12 ) after adjusting for MMF. We repeated this comparison by combinations of immunosuppression agents. Compared to MMF + tacrolimus, MMF-free regimens were associated with higher odds of positive antibody response (aOR = _2.39 4.26_7.92 for mTORi+tacrolimus; _2.34 5.54_15.32 for mTORi-only; and _6.78 10.25_15.93 for tacrolimus-only), whereas MMF-including regimens were not, regardless of mTORi use (aOR = _0.81 1.54_2.98 for MMF + mTORi; and _0.81 1.51_2.87 for MMF-only). We repeated these analyses in an independent cohort (n = 512) and found similar results. Our study demonstrates that the recently reported findings were confounded by MMF, and that mTORi is not independently associated with improved vaccine responses.

BACKGROUND:Hurricanes are severe weather events that can disrupt power, water, and transportation systems. These disruptions may be deadly for patients requiring maintenance dialysis. We hypothesized that the mortality risk among patients requiring maintenance dialysis would be increased in the 30 days after a hurricane. METHODS:Patients registered as requiring maintenance dialysis in the United States Renal Data System who initiated treatment between January 1, 1997 and December 31, 2017 in one of 108 hurricane-afflicted counties were followed from dialysis initiation until transplantation, dialysis discontinuation, a move to a nonafflicted county, or death. Hurricane exposure was determined as a tropical cyclone event with peak local wind speeds ≥64 knots in the county of a patient's residence. The risk of death after the hurricane was estimated using time-varying Cox proportional hazards models. RESULTS:The median age of the 187,388 patients was 65 years (IQR, 53-75) and 43.7% were female. There were 27 hurricanes and 105,398 deaths in 529,339 person-years of follow-up on dialysis. In total, 29,849 patients were exposed to at least one hurricane. Hurricane exposure was associated with a significantly higher mortality after adjusting for demographic and socioeconomic covariates (hazard ratio, 1.13; 95% confidence interval, 1.05-1.22). The association persisted when adjusting for seasonality. CONCLUSIONS:Patients requiring maintenance dialysis have a higher mortality risk in the 30 days after a hurricane.

Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P-glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m². At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow-up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding-related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6-4.2 events per 100 person-years; adjusted hazard ratio, 1.56, 95% CI, 1.15-2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1-2.6 events per 100 person-years]; adjusted hazard ratio, 1.84 [95% CI, 1.18-2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate <60 mL/min per 1.73 m²) (P for interaction=0.524 and 0.629, respectively). Among 13 179 warfarin users (the negative control), concomitant diltiazem use was not associated with bleeding. Conclusions Concomitant use of diltiazem with DOACs was associated with a higher bleeding risk in patients with atrial fibrillation, consistently in both subgroups of chronic kidney disease and non-chronic kidney disease. For DOAC users, concomitant diltiazem should be prescribed only when the benefit outweighs the risk, with close monitoring for signs of bleeding.

Introduction/UNASSIGNED:Depressive symptoms, even without a clinical diagnosis of depression, are common in kidney failure patients and may be a barrier to completing the complex process of kidney transplant (KT) evaluation. We assessed depressive symptom burden and association between depressive symptoms and access to KT waitlist by age. Methods/UNASSIGNED:In a prospective cohort of 3728 KT patients (aged 18-88 years), the Center for Epidemiologic Studies-Depression (CES-D) scale was used to measure depressive symptoms at evaluation. Depressive symptom severity was defined as follows: none: 0; minimal: 1 to 15; mild: 16 to 20; moderate: 21 to 25; severe: 26 to 60. Hazard ratios (HRs) of active listing within 1 year after evaluation were estimated using Cox proportional hazards models, adjusted for clinical and social factors. Results/UNASSIGNED: < 0.001). After adjustment, every 5-point higher CES-D score (more depressive symptoms) was associated with a 13% lower chance of listing (HR = 0.87, 95% CI: 0.85-0.90); the strongest association was found among patients aged ≥70 years (adjusted HR [aHR] = 0.73, 95% CI: 0.62-0.86). Furthermore, minimal (HR = 0.69, 95% CI: 0.60-0.79), mild (HR = 0.57, 95% CI: 0.44-0.72), moderate (HR = 0.53, 95% CI: 0.39-0.71), and severe (HR = 0.44, 95% CI: 0.34-0.57) depressive symptoms were all associated with a lower chance of listing. Conclusion/UNASSIGNED:Older candidates were less likely to report depressive symptoms at KT evaluation. Regardless of age, candidates who did report depressive symptoms, and even minimal symptoms, had a lower chance of listing. Transplant centers should routinely screen patients for depressive symptoms and refer the affected patients to mental health services to improve access to KT.

BACKGROUND:Elevated parathyroid hormone (PTH) levels have been reported as a potential risk factor for cognitive impairment. Compared to the general population, older adults with end-stage renal disease (ESRD) who are frequently affected by secondary hyperparathyroidism (SHPT) are at increased risk of developing dementia. The main objective of our study was to evaluate if the risk of dementia in older (age ≥ 65) ESRD patients differed if they were treated for SHPT. METHODS:Using the United States Renal Data System (USRDS) and Medicare claims, we identified 189 433 older adults without a diagnosis of dementia, who initiated dialysis between 2006-2016. SHPT treatment was defined as use of vitamin D analogs, phosphate binders, calcimimetics, or parathyroidectomy. We quantified the association between treated SHPT and incident dementia during dialysis using a multivariable Cox proportional hazards model with inverse probability weighting, considering SHPT treatment as a time varying exposure. RESULTS:Of 189 433 older ESRD adults, 92% had a claims diagnosis of SHPT, and 123 388 (65%) were treated for SHPT. The rate of incident dementia was 6 cases per 100 person-years among SHPT treated patients compared to 11 cases per 100 person-years among untreated patients. Compared to untreated SHPT patients, the risk of dementia was 42% lower (aHR = 0.58, 95% CI: 0.56-0.59) among SHPT treated patients. The magnitude of the beneficial effect of SHPT treatment differed by sex (pinteraction = 0.02) and race (pinteraction ≤ 0.01) with females (aHR = 0.56, 95% CI: 0.54-0.58) and those of Asian (aHR = 0.51, 95% CI: 0.46-0.57) or Black race (aHR = 0.51, 95% CI: 0.48-0.53) having greatest reduction in dementia risk. CONCLUSION/CONCLUSIONS:Receiving treatment for SHPT was associated with a lower risk of incident dementia among older patients with ESRD. This work provides additional support for treatment of SHPT in older ESRD patients.

OBJECTIVE:We compared methods used with current recommendations for synthesizing harms in systematic reviews and meta-analyses (SRMAs) of gabapentin. STUDY DESIGN & SETTING/METHODS:We followed recommended systematic review practices. We selected reliable SRMAs of gabapentin (i.e., met a pre-defined list of methodological criteria) that assessed at least one harm. We extracted and compared methods in four areas: pre-specification, searching, analysis, and reporting. Whereas our focus in this paper is on the methods used, Part 2 examines the results for harms across reviews. RESULTS:We screened 4320 records and identified 157 SRMAs of gabapentin, 70 of which were reliable. Most reliable reviews (51/70; 73%) reported following a general guideline for SRMA conduct or reporting, but none reported following recommendations specifically for synthesizing harms. Across all domains assessed, review methods were designed to address questions of benefit and rarely included the additional methods that are recommended for evaluating harms. CONCLUSION/CONCLUSIONS:Approaches to assessing harms in SRMAs we examined are tokenistic and unlikely to produce valid summaries of harms to guide decisions. A paradigm shift is needed. At a minimal, reviewers should describe any limitations to their assessment of harms and provide clearer descriptions of methods for synthesizing harms.

BACKGROUND:Frailty predicts adverse post-kidney transplant (KT) outcomes, yet the impact of frailty assessment on center-level outcomes remains unclear. We sought to test whether transplant centers assessing frailty as part of clinical practice have better pre- and post-KT outcomes in all adult patients (≥18 years) and older patients (≥65 years). METHODS:In a survey of US transplant centers (11/2017-4/2018), 132 (response rate = 65.3%) centers reported their frailty assessment practices (frequency and specific tool) at KT evaluation and admission. Assessment frequency was categorized as never, sometime, and always; type of assessment tool was categorized as none, validated (for post-KT risk prediction), and any other tool. Center characteristics and clinical outcomes for adult patients during 2017-2019 were gleaned from the transplant national registry (Scientific Registry of Transplant Recipients). Poisson regression was used to estimate incidence rate ratios (IRRs) of waitlist outcomes (waitlist mortality, transplantation) in candidates and IRRs of post-KT outcomes (all-cause mortality, death-censored graft loss) in recipients by frailty assessment frequency. We also estimated IRRs of waitlist outcomes by type of assessment tool at evaluation. All models were adjusted for case mix and center characteristics. RESULTS:Assessing frailty at evaluation was associated with lower waitlist mortality rate (always IRR = 0.91,95%CI:0.84-0.99; sometimes = 0.89,95%CI:0.83-0.96) and KT rate (always = 0.94,95%CI:0.91-0.97; sometimes = 0.88,95%CI:0.85-0.90); the associations with waitlist mortality rate (always = 0.86,95%CI:0.74-0.99; sometimes = 0.83,95%CI:0.73-0.94) and KT rate (always = 0.82,95%CI:0.77-0.88; sometimes = 0.92,95%CI:0.87-0.98) were stronger in older patients. Furthermore, using validated (IRR = 0.90,95%CI:0.88-0.92) or any other tool (IRR = 0.90,95%CI:0.87-0.93) at evaluation was associated lower KT rate, while only using a validated tool was associated with lower waitlist mortality rate (IRR = 0.89,95%CI:0.83-0.96), especially in older patients (IRR = 0.82,95%CI:0.72-0.93). At admission for KT, always assessing frailty was associated with a lower graft loss rate (IRR = 0.71,95%CI:0.54-0.92) but not with mortality (IRR = 0.93,95%CI:0.76-1.13). CONCLUSIONS:Assessing frailty at evaluation is associated with lower KT rate, while only using a validated frailty assessment tool is associated with better survival, particularly in older candidates. Centers always assessing frailty at admission are likely to have better graft survival rates. Transplant centers may utilize validated frailty assessment tools to secure KT access for appropriate candidates and to better allocate health care resources for patients identified as frail, particularly for older patients.

OBJECTIVE:In this methodologic study (Part 2 of 2), we examined the overlap in sources of evidence and the corresponding results for harms in systematic reviews for gabapentin. STUDY DESIGN & SETTING/METHODS:We extracted all citations referenced as sources of evidence for harms of gabapentin from 70 systematic reviews, as well as the harms assessed and numerical results. We assessed consistency of harms between pairs of reviews with a high degree of overlap in sources of evidence (>50%) as determined by corrected covered area (CCA). RESULTS:We found 514 reports cited across 70 included reviews. Most reports (244/514, 48%) were not cited in more than one review. Among 18 pairs of reviews, we found reviews had differences in which harms were assessed and their choice to meta-analyze estimates or present descriptive summaries. When a specific harm was meta-analyzed in a pair of reviews, we found similar effect estimates. CONCLUSION/CONCLUSIONS:Differences in harms results across reviews can occur because the choice of harms is driven by reviewer preferences, rather than standardized approaches to selecting harms for assessment. A paradigm shift is needed in the current approach to synthesizing harms.