Faculty Bibliography

BACKGROUND:Prescription opioid and benzodiazepine use have been associated with morbidity and mortality among some groups of solid organ transplant recipients, but implications for outcomes among lung transplant patients are not well described. METHODS:). RESULTS:). These effects were independent, and interactions were not detected. CONCLUSIONS:Benzodiazepine prescription fills before and after lung transplant, and opioid fills after transplant, are independently associated with posttransplant mortality. Review of benzodiazepine and opioid use history is relevant to risk-stratifying patients before and after lung transplant.

BACKGROUND:Fine particulate matter (particulate matter with diameter <2.5 µm [PM2.5]) is associated with CKD progression and may impact the health of patients living with kidney failure. While older (aged ≥65 years) adults are most vulnerable to the impact of PM2.5, it is unclear whether older patients on dialysis are at elevated risk of mortality when exposed to fine particulate matter. METHODS:Older adults initiating dialysis (2010-2016) were identified from US Renal Data System (USRDS). PM2.5 concentrations were obtained from NASA's Socioeconomic Data and Application Center (SEDAC) Global Annual PM2.5 Grids. We investigated the association between PM2.5 and all-cause mortality using Cox proportional hazard models with linear splines [knot at the current Environmental Protection Agency (EPA) National Ambient Air Quality Standard for PM2.5 of 12 μg/m3] and robust variance. RESULTS:For older dialysis patients who resided in areas with high PM2.5, a 10 μg/m3 increase in PM2.5 was associated with 1.16-fold (95% CI: 1.08-1.25) increased risk of mortality; furthermore, those who were female (aHR = 1.26, 95% CI: 1.13-1.42), Black (aHR = 1.31, 95% CI: 1.09-1.59), or had diabetes as a primary cause of kidney failure (aHR = 1.25, 95% CI: 1.13-1.38) were most vulnerable to high PM2.5. While the mortality risk associated with PM2.5 was stronger at higher levels (aHR = 1.19, 95% CI: 1.08-1.32), at lower levels (≤12 μg/m3), PM2.5 was significantly associated with mortality risk (aHR = 1.04, 95% CI: 1.00-1.07) among patients aged ≥75 years (Pslope difference = 0.006). CONCLUSIONS:Older adults initiating dialysis who resided in ZIP codes with PM2.5 levels >12 μg/m3 are at increased risk of mortality. Those aged >75 were at elevated risk even at levels below the EPA Standard for PM2.5.

BACKGROUND:Individuals undergoing hemodialysis in the United States frequently report pain and receive three-fold more opioid prescriptions than the general population. While opioid use is appropriate for select patients, high-dose utilization may contribute to an increased risk of death due to possible accumulation of opioid metabolites. METHODS:We studied high-dose opioid utilization (≥120 morphine milligram equivalents [MME] per day) among adults initiating hemodialysis in the United States between 2007 and 2014 using national registry data. We calculated the cumulative incidence (%) of high-dose utilization and depicted trends in the average percentage of days individuals were exposed to opioids. We used adjusted Cox proportional hazards models to identify which opioid doses were associated with mortality. RESULTS:Among 327,344 adults undergoing hemodialysis, the cumulative incidence of high-dose utilization was 14.9% at 2 years after initiating hemodialysis. Among patients with ≥1 opioid prescription during follow-up, the average percentage of days exposed to high-dose utilization increased from 13.9% in 2007 to 26.1% in 2014. Compared to 0MME per day, doses < 60MME were not associated with an increased risk of mortality, but high-dose utilization was associated with a 1.63-fold (95% CI, 1.57, 1.69) increased risk of mortality. The risk of mortality associated with opioid dose was highest in the first year after hemodialysis initiation. CONCLUSIONS:The risk of mortality associated with opioid utilization among individuals on hemodialysis increases as doses exceed 60MME per day and is greatest during periods of high-dose utilization. Patients and clinicians should carefully weigh the risks and benefits of opioid doses exceeding 60MME per day.

BACKGROUND:With stressors of dialysis prekidney transplantation (KT) and restoration of kidney function post-KT, it is likely that KT recipients experience a decline in functional status while on the waitlist and improvements post-KT. METHODS:We leveraged 224 832 KT recipients from the national registry (SRTR, February 1990-May 2019) with measured Karnofsky Performance Status (KPS, 0%-100%) at listing, KT admission, and post-KT. We quantified the change in KPS from listing to KT using generalized linear models. We described post-KT KPS trajectories using adjusted mixed-effects models and tested whether those trajectories differed by age, sex, race, and diabetes status using a Wald test among all KT recipients. We then quantified risk adverse post-KT outcomes (mortality and all-cause graft loss [ACGL]) by preoperative KPS and time-varying KPS. RESULTS:Mean KPS declined from listing (83.7%) to admission (78.9%) (mean = 4.76%, 95% confidence interval [CI]: -4.82, -4.70). After adjustment, mean KPS improved post-KT (slope = 0.89%/y, 95% CI: 0.87, 0.91); younger, female, non-Black, and diabetic recipients experienced greater post-KT improvements (Pinteractions < 0.001). Lower KPS (per 10% decrease) at admission was associated with greater mortality (adjusted hazard ratio [aHR] = 1.11, 95% CI: 1.10, 1.11) and ACGL (aHR = 1.08, 95% CI: 1.08, 1.09) risk. Lower post-KT KPS (per 10% decrease; time-varying) were more strongly associated with mortality (aHR = 1.93, 95% CI: 1.92, 1.94) and ACGL (aHR = 1.84, 95% CI: 1.83, 1.85). CONCLUSIONS:Functional status declines pre-KT and improves post-KT in the national registry. Despite post-KT improvements, poorer functional status at KT and post-KT are associated with greater mortality and ACGL risk. Because of its dynamic nature, clinicians should repeatedly screen for lower functional status pre-KT to refer vulnerable patients to prehabilitation in hopes of reducing risk of adverse post-KT outcomes.

Importance:Female liver transplant candidates experience higher rates of wait list mortality than male candidates. Frailty is a critical determinant of mortality in patients with cirrhosis, but how frailty differs between women and men is unknown. Objective:To determine whether frailty is associated with the gap between women and men in mortality among patients with cirrhosis awaiting liver transplantation. Design, Setting, and Participants:This prospective cohort study enrolled 1405 adults with cirrhosis awaiting liver transplant without hepatocellular carcinoma seen during 3436 ambulatory clinic visits at 9 US liver transplant centers. Data were collected from January 1, 2012, to October 1, 2019, and analyzed from August 30, 2019, to October 30, 2020. Exposures:At outpatient evaluation, the Liver Frailty Index (LFI) score was calculated (grip strength, chair stands, and balance). Main Outcomes and Measures:The risk of wait list mortality was quantified using Cox proportional hazards regression by frailty. Mediation analysis was used to quantify the contribution of frailty to the gap in wait list mortality between women and men. Results:Of 1405 participants, 578 (41%) were women and 827 (59%) were men (median age, 58 [interquartile range (IQR), 50-63] years). Women and men had similar median scores on the laboratory-based Model for End-stage Liver Disease incorporating sodium levels (MELDNa) (women, 18 [IQR, 14-23]; men, 18 [IQR, 15-22]), but baseline LFI was higher in women (mean [SD], 4.12 [0.85] vs 4.00 [0.82]; P = .005). Women displayed worse balance of less than 30 seconds (145 [25%] vs 149 [18%]; P = .003), worse sex-adjusted grip (mean [SD], -0.31 [1.08] vs -0.16 [1.08] kg; P = .01), and fewer chair stands per second (median, 0.35 [IQR, 0.23-0.46] vs 0.37 [IQR, 0.25-0.49]; P = .04). In unadjusted mixed-effects models, LFI was 0.15 (95% CI, 0.06-0.23) units higher in women than men (P = .001). After adjustment for other variables associated with frailty, LFI was 0.16 (95% CI, 0.08-0.23) units higher in women than men (P < .001). In unadjusted regression, women experienced a 34% (95% CI, 3%-74%) increased risk of wait list mortality than men (P = .03). Sequential covariable adjustment did not alter the association between sex and wait list mortality; however, adjustment for LFI attenuated the mortality gap between women and men. In mediation analysis, an estimated 13.0% (IQR, 0.5%-132.0%) of the gender gap in wait list mortality was mediated by frailty. Conclusions and Relevance:These findings demonstrate that women with cirrhosis display worse frailty scores than men despite similar MELDNa scores. The higher risk of wait list mortality that women experienced appeared to be explained in part by frailty.

BACKGROUND:Approximately 30% of kidney transplant recipients undergo early steroid withdrawal (ESW) for maintenance immunosuppression. However, there is no consensus on which patients are suitable for ESW, and transplant centers may disagree on how various clinical factors characterize individual recipients' suitability for ESW. METHODS:To examine center-level variation in the association of clinical factors with the choice of ESW, we studied 206 544 kidney transplant recipients from 278 centers in 2002-2017 using SRTR data. We conducted multi-level logistic regressions to characterize the association of clinical factors with the choice of ESW at each transplant center. RESULTS:). When estimated at each center, this odds ratio was significantly lower than the population odds ratio at 48 (17.3%) centers and significantly higher at 28 (10.1%) centers. CONCLUSIONS:We have observed apparent inconsistencies across transplant centers in the practice of tailoring ESW to the recipient's risk profile. Standardized guidelines for ESW tailoring are needed.

BACKGROUND:Although the population of older transplant recipients has increased dramatically, there are limited data describing the impact of immunosuppression regimen choice on outcomes in this recipient group. METHODS:National data for US Medicare-insured adult kidney recipients (N = 67 362; 2005-2016) were examined to determine early immunosuppression regimen and associations with acute rejection, death-censored graft failure, and mortality using multivariable regression analysis in younger (18-64 y) and older (>65 y) adults. RESULTS:The use of antithymocyte globulin (TMG) or alemtuzumab (ALEM) induction with triple maintenance immunosuppression (reference) was less common in older compared with younger (36.9% versus 47.0%) recipients, as was TMG/ALEM + steroid avoidance (19.2% versus 20.1%) and mammalian target of rapamycin inhibitor (mTORi)-based (6.7% versus 7.7%) treatments. Conversely, older patients were more likely to receive interleukin (IL)-2-receptor antibody (IL2rAb) + triple maintenance (21.1% versus 14.7%), IL2rAb + steroid avoidance (4.1% versus 1.8%), and cyclosporine-based (8.3% versus 6.6%) immunosuppression. Compared with older recipients treated with TMG/ALEM + triple maintenance (reference regimen), those managed with TMG/ALEM + steroid avoidance (adjusted odds ratio [aOR], 0.440.520.61) and IL2rAb + steroid avoidance (aOR, 0.390.550.79) had lower risk of acute rejection. Older patients experienced more death-censored graft failure when managed with Tac + antimetabolite avoidance (adjusted hazard [aHR], 1.411.782.25), mTORi-based (aHR, 1.702.142.71), and cyclosporine-based (aHR, 1.411.782.25) regimens, versus the reference regimen. mTORi-based and cyclosporine-based regimens were associated with increased mortality in both older and younger patients. CONCLUSIONS:Lower-intensity immunosuppression regimens (eg, steroid-sparing) appear beneficial for older kidney transplant recipients, while mTORi and cyclosporine-based maintenance immunosuppression are associated with higher risk of adverse outcomes.

BACKGROUND:Kidney transplant recipients have higher risk of infectious diseases due to their reliance on immunosuppression. During the current COVID-19 pandemic, some clinicians might have opted for less potent immunosuppressive agents to counterbalance the novel infectious risk. We conducted a nationwide study to characterize immunosuppression use and subsequent clinical outcomes during the first 5 months of COVID-19 pandemic in the United States. METHODS:Using data from the Scientific Registry of Transplant Recipients, we studied all kidney-only recipients in the United States from January 1, 2017, to March 12, 2020 ("prepandemic" era; n = 64 849) and from March 13, 2020, to July 31, 2020 ("pandemic" era; n = 5035). We compared the use of lymphocyte-depleting agents (versus basiliximab or no induction) and maintenance steroids (versus steroid avoidance/withdrawal) in the pandemic era compared with the prepandemic era. Then, we compared early posttransplant outcomes by immunosuppression regimen during the pandemic era. RESULTS:Recipients in the pandemic era were substantially less likely to receive lymphocyte-depleting induction agents compared with their prepandemic counterparts (aOR = 0.400.530.69); similar trends were found across subgroups of state-level COVID-19 incidence, donor type, and recipient age. However, lymphocyte-depleting induction agents were associated with decreased rejection during admission (aOR = 0.110.230.47) but not with increased mortality in the pandemic era (aHR = 0.130.471.66). On the other hand, the use of maintenance steroids versus early steroid withdrawal remained similar (aOR = 0.711.071.62). CONCLUSIONS:The use of lymphocyte-depleting induction agents has decreased in favor of basiliximab and no induction during the COVID-19 pandemic. However, this shift might have resulted in increases in rejection with no clear reductions in posttransplant mortality.

BACKGROUND:Physical frailty phenotype is characterized by decreased physiologic reserve to stressors and associated with poor outcomes, such as delirium and mortality, that may result from post-kidney transplant (KT) inflammation. Despite a hypothesized underlying pro-inflammatory state, conventional measures of frailty typically do not incorporate inflammatory biomarkers directly. Among KT candidates and recipients, we evaluated the inclusion of inflammatory biomarkers with traditional physical frailty phenotype components. METHODS:Among 1154 KT candidates and recipients with measures of physical frailty phenotype and inflammation (interleukin 6 [IL6], tumor necrosis factor alpha [TNFα], C-reactive protein [CRP]) at 2 transplant centers (2009-2017), we evaluated construct validity of inflammatory-frailty using latent class analysis. Inflammatory-frailty measures combined 5 physical frailty phenotype components plus the addition of an individual inflammatory biomarkers, separately (highest tertiles) as a sixth component. We then used Kaplan-Meier methods and adjusted Cox proportional hazards to assess post-KT mortality risk by inflammatory-frailty (n = 378); Harrell's C-statistics assessed risk prediction (discrimination). RESULTS:Based on fit criteria, a 2-class solution (frail vs nonfrail) for inflammatory-frailty was the best-fitting model. Five-year survival (frail vs nonfrail) was: 81% versus 93% (IL6-frailty), 87% versus 89% (CRP-frailty), and 83% versus 91% (TNFα-frailty). Mortality was 2.07-fold higher for IL6-frail recipients (95% CI: 1.03-4.19, p = .04); there were no associations between the mortality and the other inflammatory-frailty indices (TNFα-frail: 1.88, 95% CI: 0.95-3.74, p = .07; CRP-frail: 1.02, 95% CI: 0.52-2.03, p = .95). However, none of the frailty-inflammatory indices (all C-statistics = 0.71) improved post-KT mortality risk prediction over the physical frailty phenotype (C-statistics = 0.70). CONCLUSIONS:Measurement of IL6-frailty at transplantation can inform which patients should be targeted for pre-KT interventions. However, the traditional physical frailty phenotype is sufficient for post-KT mortality risk prediction.