Faculty Bibliography

BACKGROUND AND AIMS/OBJECTIVE:Frailty is a well-established risk factor for poor outcomes in patients with cirrhosis awaiting liver transplantation (LT), but whether it predicts outcomes among those who have undergone LT is unknown. APPROACH AND RESULTS/UNASSIGNED:Adult LT recipients from 8 US centers (2012-2019) were included. Pre-LT frailty was assessed in the ambulatory setting using the Liver Frailty Index (LFI). "Frail" was defined by an optimal cut point of LFI ≥ 4.5. We used the 75th percentile to define "prolonged" post-LT length of stay (LOS; ≥12 days), intensive care unit (ICU) days (≥4 days), and inpatient days within 90 post-LT days (≥17 days). Of 1166 LT recipients, 21% were frail pre-LT. Cumulative incidence of death at 1 and 5 years was 6% and 16% for frail and 4% and 10% for nonfrail patients (overall log-rank p = 0.02). Pre-LT frailty was associated with an unadjusted 62% increased risk of post-LT mortality (95% CI, 1.08-2.44); after adjustment for body mass index, HCC, donor age, and donation after cardiac death status, the HR was 2.13 (95% CI, 1.39-3.26). Patients who were frail versus nonfrail experienced a higher adjusted odds of prolonged LT LOS (OR, 2.00; 95% CI, 1.47-2.73), ICU stay (OR, 1.56; 95% CI, 1.12-2.14), inpatient days within 90 post-LT days (OR, 1.72; 95% CI, 1.25-2.37), and nonhome discharge (OR, 2.50; 95% CI, 1.58-3.97). CONCLUSIONS:Compared with nonfrail patients, frail LT recipients had a higher risk of post-LT death and greater post-LT health care utilization, although overall post-LT survival was acceptable. These data lay the foundation to investigate whether targeting pre-LT frailty will improve post-LT outcomes and reduce resource utilization.

RATIONALE & OBJECTIVE/UNASSIGNED:Disorders of bone and mineral metabolism frequently develop with advanced kidney disease, may be exacerbated by immunosuppression after kidney transplantation, and increase the risk of fractures. STUDY DESIGN/UNASSIGNED:Retrospective database study. SETTING & PARTICIPANTS/UNASSIGNED:Kidney-only transplant recipients aged ≥18 years from 2005 to 2016 in the United States captured in US Renal Data System records, which integrate Organ Procurement and Transplantation Network/United Network for Organ Sharing records with Medicare billing claims. EXPOSURES/UNASSIGNED:Various immunosuppression regimens in the first 3 months after kidney transplantation. OUTCOMES/UNASSIGNED:The development of fractures, as ascertained using diagnostic codes on Medicare billing claims. ANALYTICAL APPROACH/UNASSIGNED:We used multivariable Cox regression with inverse propensity weighting to compare the incidence of fractures >3 months-to-3 years after kidney transplantation associated with various immunosuppression regimens compared to a reference regimen of antithymocyte globulin (TMG) or alemtuzumab (ALEM) with tacrolimus + mycophenolic acid + prednisone using inverse probability treatment weighting. RESULTS/UNASSIGNED: < 0.001]). Induction with TMG or ALEM and the avoidance or early withdrawal of steroids significantly reduced the risk of fractures in younger (aHR, 0.63; 95% CI, 0.54-0.73) and older (aHR, 0.83; 95% CI, 0.74-0.94) patients. The avoidance or early withdrawal of steroids with any induction was associated with a reduced risk of fractures in women. LIMITATIONS/UNASSIGNED:This was a retrospective study which lacked data on immunosuppression levels. CONCLUSIONS/UNASSIGNED:Fractures after kidney transplantation are associated with significantly increased mortality risk and costs. The early avoidance or early withdrawal of steroids after induction with TMG or ALEM reduces the risk of fractures after kidney transplantation and should be considered for patients at high-risk of this complication, including older adults and women.

BACKGROUND:In older adults (≥65) access to and outcomes following kidney transplantation (KT) have improved over the past three decades. It is unknown if there were parallel trends in re-KT. We characterized the trends, changing landscape, and outcomes of re-KT in older adults. METHODS:Among the 44,149 older kidney-only recipients (1995-2016) in the Scientific Registry of Transplant Recipients, we identified 1,743 who underwent re-KT. We analyzed trends and outcomes (mortality, death-censored graft failure [DCGF]) by eras (1995-2002, 2003-2014 and 2015-2016) that were defined by changes to the ECD and KDPI policies. RESULTS:Among all older kidney-only recipients during 1995-2002, 2003-2014, 2015-2016 the proportion that were re-KTs increased from 2.7%-4.2%-5.7% p<0.001, respectively. Median age at re-KT (67-68-68, p=0.04), years on dialysis after graft failure (1.4-1.5-2.2, p=0.003), donor age (40.0-43.0-43.5, p=0.04), proportion with PRA 80-100 (22.0%-32.7%-48.7%, p<0.001) and donations after circulatory death (1.1%-13.4%-19.5%, p<0.001) have increased. Despite this, the 3-year cumulative incidence for mortality (22.3%-19.1%-11.5%, p=0.002) and DCGF (13.3%-10.0%-5.1%, p=0.01) decreased over time. Compared with deceased donor re-transplant recipients during 1995-2002, those during 2003-2014 and 2015-2016 had lower mortality hazard (aHR=0.78, 95%CI:0.63-0.86 and aHR=0.55, 95%CI:0.35-0.86, respectively). These declines were noted but not significant for DCGF and in living donor re-KTs. CONCLUSIONS:In older re-transplant recipients, outcomes have improved significantly over time despite higher risk profiles; yet they represent a fraction of the KTs performed. Our results support increasing access to re-KT in older adults; however, approaches to guide the selection and management in those with graft failure need to be explored.

BACKGROUND:Air pollution is associated with cardiopulmonary disease and death in the general population. Fine particulate matter (PM2.5) is particularly harmful due to its ability to penetrate into areas of gas exchange within the lungs. Persons with advanced lung disease are believed to be particularly susceptible to PM2.5 exposure but few studies have examined the effect of exposure on this population. Here we investigate the association between PM2.5 exposure and adverse waitlist events among lung transplant (LT) candidates. METHODS:US registry data were used to identify LT candidates listed between 1/1/2010-12/31/2016. Annual PM2.5 concentration at year of listing was estimated for each candidate's ZIP Code using NASA's SEDAC Global Annual PM2.5 Grids. We estimated crude and adjusted hazard ratios for adverse waitlist events, defined as death or removal, using Cox proportional hazards regression. RESULTS:Of the 15,075 included candidates, median age at listing was 60, 43.8% were female and 81.7% were non-Hispanic white. Median ZIP Code PM2.5 concentration was 9.06µg/m3. When compared to those living in ZIP Codes with lower PM2.5 exposure (PM2.5 <10.53µg/m3), candidates in ZIP Codes in the highest quartile of PM2.5 exposure (≥10.53µg/m3) had 1.14-fold (95%CI 1.04-1.25) risk of adverse waitlist events. The result remained significant after adjusting for demographics, education, insurance, smoking, lung allocation score, BMI, and blood type (HR=1.17; 95%CI 1.07-1.29). CONCLUSIONS:Elevated ambient PM2.5 concentration was associated with adverse waitlist events among LT candidates. These findings highlight the impact of air pollution on clinical outcomes in this critically ill population.

Acute kidney injury (AKI) and frailty are major drivers of outcomes among patients with cirrhosis. What is unknown is the impact of physical frailty on the development of AKI. We included adults with cirrhosis without hepatocellular carcinoma listed for liver transplantation at nine US centers (n = 1,033). Frailty was assessed using the Liver Frailty Index (LFI); "frail" was defined by LFI ≥ 4.2. Chronic kidney disease as a baseline estimated glomerular filtration rate <60 mL/min/1.73 m² . Our primary outcome, AKI, was defined as an increase in serum creatinine ≥0.3 mg/dL or a serum creatinine ≥1.5-fold increase. Wait-list mortality was defined as either a death on the wait list or removal for being too sick. We performed Cox regression analyses to estimate the hazard ratios (HRs) for AKI and wait-list mortality. Of 1,033 participants, 41% were frail and 23% had CKD. Twenty-one percent had an episode of AKI during follow-up. Frail versus nonfrail patients were more likely to develop AKI (25% vs. 19%) and wait-list mortality (21% vs. 13%) (P < 0.01 for each). In multivariable Cox regression, each of the following groups was associated with a higher risk of AKI as compared with not frail/no CKD: frail/no CKD (adjusted HR [aHR] = 1.87, 95% confidence interval [CI] = 1.29-2.72); not frail/CKD (aHR = 4.30, CI = 2.88-6.42); and frail/CKD (aHR = 4.85, CI = 3.33-7.07). We use a readily available metric, LFI, to identify those patients with cirrhosis most at risk for AKI. We highlight that serum creatinine and creatinine-based estimations of glomerular filtration rate may not fully capture a patient's vulnerability to AKI among the frail phenotype. Conclusion: Our work lays the foundation for implementing physical frailty in clinical practice to identify AKI earlier, implement reno-protective strategies, and expedite liver transplantation.

Kidney transplantation (KT) experts did not support the use of subjective unintentional weight loss to measure shrinking in the physical frailty phenotype (PFP); a clinically feasible and predictive measure of shrinking is needed. To test whether unintentional weight loss could be replaced by an assessment of sarcopenia using existing CT scans, we performed a prospective cohort study of adult KT recipients with original PFP (oPFP) measured at admission (December 2008-February 2020). We ascertained sarcopenia by calculating skeletal muscle index from available, clinically obtained CTs within 1-year pre-KT (male < 50 cm² /m² ; female < 39 cm² /m² ) and combined it with the original four components to determine new PFP (nPFP) scores. Frailty was classified by frailty score: 0: non-frail; 1-2: pre-frail; ≥3: frail. Mortality and graft loss hazard ratios (HRs) were estimated using adjusted Cox proportional hazard models. Model discrimination was quantified using Harrell's C-statistic. Among 1113 recipients, 18.6% and 17.1% were frail by oPFP and nPFP, respectively. Compared to non-frail recipients, frail patients by either PFP had higher risks of mortality (oPFP HR = 1.67, 95% CI: 1.07-2.62, C = 0.710; nPFP HR = 1.68, 95% CI: 1.06-2.66, C = 0.710) and graft loss (oPFP HR = 1.67, 95% CI: 1.17-2.40, C = 0.631; nPFP HR = 1.66, 95% CI: 1.15-2.40, C = 0.634) with similar discriminations. oPFP and nPFP are equally useful in risk prediction for KT recipients; oPFP may aid in screening patients for pre-KT interventions, while nPFP may assist in nuanced clinical decision-making.

BACKGROUND:Early steroid withdrawal (ESW) is a viable maintenance immunosuppression strategy in low-risk kidney transplant recipients. A low panel reactive antibody (PRA) may indicate low-risk condition amenable to ESW. We aimed to identify the threshold value of PRA above which ESW may pose additional risk, and to compare the association of ESW with transplant outcomes across PRA strata. METHODS:We studied 121,699 deceased-donor kidney-only recipients in 2002-2017 from SRTR. Using natural splines and ESW-PRA interaction terms, we explored how the associations of ESW with transplant outcomes change with increasing PRA values, and identified a threshold value for PRA. Then, we assessed whether PRA exceeding the threshold modified the associations of ESW with 1-year acute rejection, death-censored graft failure, and death. RESULTS:The association of ESW with acute rejection exacerbated rapidly when PRA exceeded 60. Among PRA≤60 recipients, ESW was associated with a minor increase in rejection (aOR=1.001.051.10) and with a tendency of decreased graft failure (aHR=0.910.971.03). However, among PRA>60 recipients, ESW was associated with a substantial increase in rejection (aOR=1.191.271.36; interaction p<0.001) and with a tendency of increased graft failure (aHR=0.981.081.20; interaction p=0.028). The association of ESW with death was similar between PRA strata (PRA≤60, aHR=0.910.961.01; and PRA>60, aHR=0.900.991.09; interaction p=0.5). CONCLUSIONS:Our findings show that the association of ESW with transplant outcomes is less favorable in recipients with higher PRA, especially those with PRA>60, suggesting a possible role of PRA in the risk assessment for ESW.

BACKGROUND/UNASSIGNED:To characterize the use of nephrotoxic medications in patients with chronic kidney disease (CKD) Stages G3-5 in routine care. METHODS/UNASSIGNED: = 16 255)]. We evaluated the proportion of patients receiving nephrotoxic medications within 1 year overall and by baseline kidney function, ranked main contributors and examined the association between receipt of nephrotoxic medication and age, sex, CKD G-stages comorbidities and provider awareness of the patient's CKD using multivariable logistic regression. RESULTS/UNASSIGNED:During a 1-year period, 20% (SCREAM) and 17% (Geisinger) of patients with CKD received at least one nephrotoxic medication. Among the top nephrotoxic medications identified in both cohorts were non-steroidal anti-inflammatory drugs (given to 11% and 9% of patients in SCREAM and Geisinger, respectively), antivirals (2.5% and 2.0%) and immunosuppressants (2.7% and 1.5%). Bisphosphonate use was common in SCREAM (3.3%) and fenofibrates in Geisinger (3.6%). Patients <65 years of age, women and those with CKD G3 were at higher risk of receiving nephrotoxic medications in both cohorts. Notably, provider awareness of a patient's CKD was associated with lower odds of nephrotoxic medication use {odds ratios [OR] 0.85[95% confidence interval (CI) 0.80-0.90] in SCREAM and OR 0.80 [95% CI 0.72-0.89] in Geisinger}. CONCLUSIONS/UNASSIGNED:One in five patients with CKD received nephrotoxic medications in two distinct health systems. Strategies to increase physician's awareness of patients' CKD and knowledge of drug nephrotoxicity may reduce prescribing nephrotoxic medications and prevent iatrogenic kidney injury.

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.

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.