Sociodemographic disparities in sodium-glucose cotransporter-2 inhibitor use among US kidney transplant recipients: An observational study of real-world pharmacy records.

BACKGROUND: Recent clinical trials demonstrate benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in patients with chronic kidney disease, but data on use in kidney transplant (KTx) recipients are limited. METHODS: We examined a novel database linking SRTR registry data for KTx recipients (2000-2021) with outpatient fill records from a large pharmaceutical claims warehouse (2015-2021). Adult (≥18 years) KTx recipients treated with SGLT2i were compared to those who received other noninsulin diabetes medications without SGLT2i. Characteristics associated with SGLT2i use were quantified by multivariable logistic regression (adjusted odds ratio, 95%LCLaOR95%UCL). RESULTS: Among 18 988 KTx recipients treated with noninsulin diabetes agents in the study period, 2224 filled an SGLT2i. Mean time from KTx to prescription was 6.7 years for SGLT2i versus 4.7 years for non-SGLT2i medications. SGLT2i use was more common in Asian adults (aOR, 1.091.311.58) and those aged > 30-59 years (compared with 18-30 years) or with BMI > 35 kg/m2 (aOR, 1.191.411.67), and trended higher with self-pay status. SGLT2i use was lower among KTx recipients who were women (aOR, .79.87.96), Black (aOR, .77.881.00) and other (aOR, .52.751.07) race, publicly insured (aOR, .82.921.03), or with less than college education (aOR, .78.87.96), and trended lower in those age 75 years and older. SGLT2i use in KTx patients increased dramatically in 2019-2021 (aOR, 5.015.636.33 vs. prior years). CONCLUSION: SGLT2i use is increasing in KTx recipients but varies with factors including race, education, and insurance. While ongoing study is needed to define risks and benefits of SGLT2i use in KTx patients, attention should also focus on reducing treatment disparities related to sociodemographic traits.

Neighborhood Segregation and Access to Live Donor Kidney Transplantation.

Importance: Identifying the mechanisms of structural racism, such as racial and ethnic segregation, is a crucial first step in addressing the persistent disparities in access to live donor kidney transplantation (LDKT). Objective: To assess whether segregation at the candidate's residential neighborhood and transplant center neighborhood is associated with access to LDKT. Design, Setting, and Participants: In this cohort study spanning January 1995 to December 2021, participants included non-Hispanic Black or White adult candidates for first-time LDKT reported in the US national transplant registry. The median (IQR) follow-up time for each participant was 1.9 (0.6-3.0) years. Main Outcome and Measures: Segregation, measured using the Theil H method to calculate segregation tertiles in zip code tabulation areas based on the American Community Survey 5-year estimates, reflects the heterogeneity in neighborhood racial and ethnic composition. To quantify the likelihood of LDKT by neighborhood segregation, cause-specific hazard models were adjusted for individual-level and neighborhood-level factors and included an interaction between segregation tertiles and race. Results: Among 162 587 candidates for kidney transplant, the mean (SD) age was 51.6 (13.2) years, 65 141 (40.1%) were female, 80 023 (49.2%) were Black, and 82 564 (50.8%) were White. Among Black candidates, living in a high-segregation neighborhood was associated with 10% (adjusted hazard ratio [AHR], 0.90 [95% CI, 0.84-0.97]) lower access to LDKT relative to residence in low-segregation neighborhoods; no such association was observed among White candidates (P for interaction = .01). Both Black candidates (AHR, 0.94 [95% CI, 0.89-1.00]) and White candidates (AHR, 0.92 [95% CI, 0.88-0.97]) listed at transplant centers in high-segregation neighborhoods had lower access to LDKT relative to their counterparts listed at centers in low-segregation neighborhoods (P for interaction = .64). Within high-segregation transplant center neighborhoods, candidates listed at predominantly minority neighborhoods had 17% lower access to LDKT relative to candidates listed at predominantly White neighborhoods (AHR, 0.83 [95% CI, 0.75-0.92]). Black candidates residing in or listed at transplant centers in predominantly minority neighborhoods had significantly lower likelihood of LDKT relative to White candidates residing in or listed at transplant centers located in predominantly White neighborhoods (65% and 64%, respectively). Conclusions: Segregated residential and transplant center neighborhoods likely serve as a mechanism of structural racism, contributing to persistent racial disparities in access to LDKT. To promote equitable access, studies should assess targeted interventions (eg, community outreach clinics) to improve support for potential candidates and donors and ultimately mitigate the effects of segregation.

Evaluating Cost-Effectiveness in Using High-Kidney Donor Profile Index Organs.

A more granular donor kidney grading scale, the kidney donor profile index (KDPI), has recently emerged in contradistinction to the standard criteria donor/expanded criteria donor framework. In this paper, we built a Markov decision process model to evaluate the survival, quality-adjusted life years (QALY), and cost advantages of using high-KDPI kidneys based on multiple KDPI strata over a 60-month time horizon as opposed to remaining on the waiting list waiting for a lower-KDPI kidney. Data for the model were gathered from the Scientific Registry of Transplant Recipients and the United States Renal Data System Medicare parts A, B, and D databases. Of the 129,024 phenotypes delineated in this model, 65% of them would experience a survival benefit, 81% would experience an increase in QALYs, 87% would see cost-savings, and 76% would experience cost-savings per QALY from accepting a high-KDPI kidney rather than remaining on the waiting list waiting for a kidney of lower-KDPI. Classification and regression tree analysis (CART) revealed the main drivers of increased survival in accepting high-KDPI kidneys were wait time ≥30 months, panel reactive antibody (PRA) <90, age ≥45 to 65, diagnosis leading to renal failure, and prior transplantation. The CART analysis showed the main drivers of increased QALYs in accepting high-kidneys were wait time ≥30 months, PRA <90, and age ≥55 to 65.

Association of Potentially Inappropriate Medication Classes with Mortality Risk Among Older Adults Initiating Hemodialysis.

BACKGROUND AND 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.

Trajectories of eGFR after kidney transplantation according to trajectories of eGFR prior to kidney replacement therapies in children with chronic kidney disease.

BACKGROUND: In children with chronic kidney disease (CKD), certain risk factors are associated with faster eGFR decline and earlier kidney failure. Whether these factors have lingering effects on post-transplant eGFR trajectory remains unclear. We characterized pre- and post-transplant eGFR trajectories in pediatric kidney transplant recipients by their pre-kidney replacement therapy (KRT) risk factors. METHODS: We studied eGFR trajectories before KRT initiation and after transplantation among Chronic Kidney Disease in Children (CKiD) Study participants. We used mixed-effects models to compare pre-KRT versus post-transplant eGFR trajectories within individual participants by 7 pre-KRT risk factors: glomerular/non-glomerular etiology, race, preemptive transplant, proteinuria, albuminuria, and systolic/diastolic blood pressure (SBP/DBP). RESULTS: We analyzed 1602 pre-KRT and 592 post-transplant eGFR measurements from 246 transplant recipients. Mean annual eGFR decline was decreased from 18.0% pre-KRT (95%CI, 16.1-19.8) to 5.0% post-transplant (95%CI, 3.3-6.7). All 7 pre-KRT risk factors showed strong associations with faster pre-KRT eGFR decline, but not with post-transplant eGFR decline; only albuminuria, high SBP, and high DBP reached statistical significance with notably attenuated associations. In our multivariable model of the pre-KRT risk factors, post-transplant eGFR decline was more rapid only when albuminuria and high SBP were both present. CONCLUSIONS: eGFR decline substantially slows down after transplant even among children with rapidly progressing forms of CKD. Nonetheless, those who had albuminuria and high SBP before KRT might continue to show faster eGFR decline after transplant, specifically when both risk factors were present. This subgroup might benefit from intensive pre-transplant management for at least one of the two risk factors. A higher resolution version of the Graphical abstract is available as Supplementary information.

Statins in Kidney Transplant Recipients: Usage, All-Cause Mortality, and Interactions with Maintenance Immunosuppressive Agents.

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.

Incidence of Statin-Associated Adverse Events in Kidney Transplant Recipients.

BACKGROUND: Statins are the third most prescribed drug class in kidney transplant recipients as cardiovascular diseases is the leading cause of death in this population. However, statins' safety profile remains unclear in kidney transplant recipients who are uniquely burdened by concomitant immunosuppression and comorbidities. We conducted a national study to characterize the association of statin use with adverse events in kidney transplant recipients. METHODS: We studied adult (≥18) single-organ kidney transplant recipients in 2006-2016 with Medicare as primary payer (n=57,699). We used prescription drug claims to capture statin use, and ICD-9/10 diagnosis codes to capture statin-related adverse events (post-transplant diabetes mellitus, hemorrhagic stroke, cataract, liver injury, and rhabdomyolysis). We conducted multivariable Cox regression for each outcome with statin use as a time-varying exposure. RESULTS: Post-transplant diabetes mellitus was the most common outcome (5-year Kaplan-Meier incidence; 43% in statin users vs. 35% in non-users), followed by cataract (22% vs. 12%), liver injury (2% vs. 3%), hemorrhagic stroke (1.9% vs. 1.4%), and rhabdomyolysis (1.5% vs. 0.9%). In our multivariable analysis, statin use was associated with higher hazard of post-transplant diabetes mellitus (aHR=1.12 [95% CI, 1.07-1.18]), cataract (aHR=1.22 [1.14-1.31]), and rhabdomyolysis (aHR=1.37 [1.10-1.71]), but lower hazard of liver injury (aHR=0.82 [0.71-0.95]). Statin use was not associated with hemorrhagic stroke (aHR=1.04 [0.86-1.26]). CONCLUSIONS: Statins appear to be generally well-tolerated in kidney transplant recipients. However, statin use might be associated with slightly higher risk of post-transplant diabetes mellitus, cataract, and rhabdomyolysis.

Gabapentin, Concomitant Prescription of Opioids, and Benzodiazepines among Kidney Transplant Recipients.

BACKGROUND: Gabapentinoids, commonly used for treating neuropathic pain, may be misused and coprescribed with opioid and benzodiazepine, increasing the risk of mortality and dependency among kidney transplant recipients. METHODS: We identified adult kidney transplant recipients who enrolled in Medicare Part D in 2006-2017 using the United States Renal Data System/Medicare claims database. We characterized recipients' post-transplant concomitant prescription of gabapentinoids, opioids, and benzodiazepine stratified by transplant year and recipient factors (age, sex, race, and diabetes). We investigated whether concomitant prescriptions were associated with postkidney transplant mortality using Cox regression. Models incorporated inverse probability weighting to adjust for confounders. RESULTS: Among 63,359 eligible recipients, 13% of recipients filled at least one gabapentinoid prescription within 1 year after kidney transplant. The prevalence of gabapentinoid prescriptions increased by 70% over the study period (16% in 2017 versus 10% in 2006). Compared with nonusers, gabapentinoids users were more likely to have diabetes (55% versus 37%) and obesity (46% versus 34%). Of the 8509 recipients with gabapentinoid prescriptions, 45% were coprescribed opioids, 7% were coprescribed benzodiazepines, and 3% were coprescribed both opioids and benzodiazepines. Compared with no study prescriptions, gabapentinoid monotherapy (adjusted hazard ratio [aHR]=1.25; 95% confidence interval [CI], 1.16 to 1.32) and combination therapy (gabapentinoids and opioids [aHR=1.49; 95% CI, 1.39 to 1.60], gabapentinoids and benzodiazepines [aHR=1.46; 95% CI, 1.03 to 2.08], and coprescribing all three [aHR=1.88; 95% CI, 1.18 to 2.98]) were all associated with a higher risk of postkidney transplant mortality. CONCLUSIONS: Gabapentinoid coprescription with both benzodiazepines and opioids among kidney transplant recipients increased over time. Kidney transplant recipients prescribed gabapentinoids had a higher risk of post-transplant mortality, and the risk was higher with opioids or benzodiazepine coprescription.

Delirium, changes in cognitive function, and risk of diagnosed dementia after kidney transplantation.

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.

Machine Learning-Based Prediction of Masked Hypertension Among Children With Chronic Kidney Disease.

BACKGROUND: Ambulatory blood pressure monitoring (ABPM) is routinely performed in children with chronic kidney disease to identify masked hypertension, a risk factor for accelerated chronic kidney disease progression. However, ABPM is burdensome, and developing an accurate prediction of masked hypertension may allow using ABPM selectively rather than routinely. METHODS: To create a prediction model for masked hypertension using clinic blood pressure (BP) and other clinical characteristics, we analyzed 809 ABPM studies with nonhypertensive clinic BP among the participants of the Chronic Kidney Disease in Children study. RESULTS: Masked hypertension was identified in 170 (21.0%) observations. We created prediction models for masked hypertension via gradient boosting, random forests, and logistic regression using 109 candidate predictors and evaluated its performance using bootstrap validation. The models showed C statistics from 0.660 (95% CI, 0.595-0.707) to 0.732 (95% CI, 0.695-0.786) and Brier scores from 0.148 (95% CI, 0.141-0.154) to 0.167 (95% CI, 0.152-0.183). Using the possible thresholds identified from this model, we stratified the dataset by clinic systolic/diastolic BP percentiles. The prevalence of masked hypertension was the lowest (4.8%) when clinic systolic/diastolic BP were both <20th percentile, and relatively low (9.0%) with clinic systolic BP<20th and diastolic BP<80th percentiles. Above these thresholds, the prevalence was higher with no discernable pattern. CONCLUSIONS: ABPM could be used selectively in those with low clinic BP, for example, systolic BP<20th and diastolic BP<80th percentiles, although careful assessment is warranted as masked hypertension was not completely absent even in this subgroup. Above these clinic BP levels, routine ABPM remains recommended.

mTOR inhibitors, mycophenolates, and other immunosuppression regimens on antibody response to SARS-CoV-2 mRNA vaccines in solid organ transplant recipients.

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 0.130.18 ). Consistent with the recent mTORi study, the odds tended to be higher with mTORi (aOR = 1.00 1.452.13 ); however, importantly, this seemingly protective tendency disappeared (aOR = 0.47 0.731.12 ) 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 4.267.92 for mTORi+tacrolimus; 2.34 5.5415.32 for mTORi-only; and 6.78 10.2515.93 for tacrolimus-only), whereas MMF-including regimens were not, regardless of mTORi use (aOR = 0.81 1.542.98 for MMF + mTORi; and 0.81 1.512.87 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.

Predicting a Positive Antibody Response After 2 SARS-CoV-2 mRNA Vaccines in Transplant Recipients: A Machine Learning Approach With External Validation.

BACKGROUND: Solid organ transplant recipients (SOTRs) are less likely to mount an antibody response to SARS-CoV-2 mRNA vaccines. Understanding risk factors for impaired vaccine response can guide strategies for antibody testing and additional vaccine dose recommendations. METHODS: Using a nationwide observational cohort of 1031 SOTRs, we created a machine learning model to explore, identify, rank, and quantify the association of 19 clinical factors with antibody responses to 2 doses of SARS-CoV-2 mRNA vaccines. External validation of the model was performed using a cohort of 512 SOTRs at Houston Methodist Hospital. RESULTS: Mycophenolate mofetil use, a shorter time since transplant, and older age were the strongest predictors of a negative antibody response, collectively contributing to 76% of the model's prediction performance. Other clinical factors, including transplanted organ, vaccine type (mRNA-1273 versus BNT162b2), sex, race, and other immunosuppressants, showed comparatively weaker associations with an antibody response. This model showed moderate prediction performance, with an area under the receiver operating characteristic curve of 0.79 in our cohort and 0.67 in the external validation cohort. An online calculator based on our prediction model is available at http://transplantmodels.com/covidvaccine/ . CONCLUSIONS: Our machine learning model helps understand which transplant patients need closer follow-up and additional doses of vaccine to achieve protective immunity. The online calculator based on this model can be incorporated into transplant providers' practice to facilitate patient-centric, precision risk stratification and inform vaccination strategies among SOTRs.

Kidney Transplantation, Immunosuppression and the Risk of Fracture: Clinical and Economic Implications.

Rationale & Objective: 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: Retrospective database study. Setting & Participants: 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: Various immunosuppression regimens in the first 3 months after kidney transplantation. Outcomes: The development of fractures, as ascertained using diagnostic codes on Medicare billing claims. Analytical Approach: 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: Overall, fractures were identified in 7.5% of kidney transplant recipients (women, 8.8%; men, 6.7%; age < 55 years, 5.9%; age ≥ 55 years, 9.3%). In time-varying regression, experiencing a fracture was associated with a substantially increased risk of subsequent death within 3 months (adjusted hazard ratio [aHR], 3.06; 95% confidence interval [CI], 2.45-3.81). Fractures were also associated with increased Medicare spending (first year: $5,122; second year: $10,890; third year: $11,083; [P < 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: This was a retrospective study which lacked data on immunosuppression levels. Conclusions: 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.

Entry inhibition of hepatitis B virus using cyclosporin O derivatives with peptoid side chain incorporation.

Hepatitis B virus (HBV) infection is a serious worldwide health problem causing liver cirrhosis and hepatocellular carcinoma. The development of novel therapeutics targeting distinct steps of the HBV life cycle and combination therapy with approved drugs (i.e., nucleot(s)ides, interferon-α) are considered effective strategies for curing HBV. Among these strategies is the development of entry inhibitors that interfere with the host entry step of HBV to prevent viral infection and transmission. Herein, we generated a novel library of cyclosporin O (CsO) derivatives that incorporate peptoid side chains. Twenty-two CsO derivatives were evaluated for membrane permeability, cytotoxicity, and in vitro HBV entry inhibitory activity. The lead compound (i.e., compound 21) showed the greatest potency in the in vitro HBV entry inhibition assay (IC50 = 0.36 ± 0.01 µM) with minimal cytotoxicity. Our peptide-peptoid hybrid CsO scaffold can readily expand chemical diversity and is applicable for screening various targets requiring macrocyclic chemical entities.

Posttransplant Diabetes Mellitus and Immunosuppression Selection in Older and Obese Kidney Recipients.

RATIONALE & OBJECTIVE: Posttransplant diabetes mellitus (DM) after kidney transplantation increases morbidity and mortality, particularly in older and obese recipients. We aimed to examine the impact of immunosuppression selection on the risk of posttransplant DM among both older and obese kidney transplant recipients. STUDY DESIGN: Retrospective database study. SETTING & PARTICIPANTS: Kidney-only transplant recipients aged ≥18 years from 2005 to 2016 in the United States from US Renal Data System records, which integrate Organ Procurement and Transplantation Network/United Network for Organ Sharing records with Medicare billing claims. EXPOSURES: Various immunosuppression regimens in the first 3 months after transplant. OUTCOMES: Development of DM >3 months-to-1 year posttransplant. ANALYTICAL APPROACH: We used multivariable Cox regression to compare the incidence of posttransplant DM by immunosuppression regimen with the reference regimen of thymoglobulin (TMG) or alemtuzumab (ALEM) with tacrolimus + mycophenolic acid + prednisone using inverse propensity weighting. RESULTS: 12.7% of kidney transplant recipients developed posttransplant DM with higher incidences in older (≥55 years vs <55 years: 16.7% vs 10.1%) and obese (body mass index [BMI] ≥ 30 kg/m2 vs BMI < 30 kg/m2: 17.1% vs 10.9%) patients. The incidence of posttransplant DM was lower with steroid avoidance [TMG/ALEM + no prednisone (8.4%) and IL2rAb + no prednisone (9.7%)] than TMG/ALEM with triple therapy (13.1%). After adjustment for donor and recipient characteristics, TMG/ALEM with steroid avoidance was beneficial for all groups [age < 55 years: adjusted HR (aHR), 0.63 (95% confidence interval [CI], 0.54-0.72); age ≥ 55 years: aHR, 0.69 (95% CI, 0.60-0.79); BMI < 30 kg/m2: aHR, 0.69 (95% CI, 0.60-0.78); BMI ≥ 30 kg/m2: aHR, 0.67 (95% CI, 0.57-0.79)]. However, IL2rAb with steroid avoidance was beneficial only for older patients (aHR, 0.76; 95% CI, 0.58-0.99) and for those with BMI < 30 kg/m2 (aHR, 0.63; 95% CI, 0.46-0.87). LIMITATIONS: Retrospective study and lacked data on immunosuppression levels. CONCLUSIONS: The beneficial impact of steroid avoidance using tacrolimus on posttransplant DM appears to differ by patient age and induction regimen.

Panel-reactive Antibody and the Association of Early Steroid Withdrawal With Kidney Transplant Outcomes.

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 Scientific Registry of Transplant Recipients. 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-y 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 (adjusted odds ratio [aOR], 1.001.051.10) and with a tendency of decreased graft failure (adjusted hazard ratio [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.

Effect of Early Steroid Withdrawal on Posttransplant Diabetes Among Kidney Transplant Recipients Differs by Recipient Age.

BACKGROUND: Posttransplant diabetes (PTD), a major complication after kidney transplantation (KT), is often attributable to immunosuppression. The risk of PTD may increase with more potent steroid maintenance and older recipient age. METHODS: Using United States Renal Data System data, we studied 12 488 adult first-time KT recipients (2010-2015) with no known pre-KT diabetes. We compared the risk of PTD among recipients who underwent early steroid withdrawal (ESW) versus continued steroid maintenance (CSM) using Cox regression with inverse probability weighting to adjust for confounding. We tested whether the risk of PTD resulting from ESW differed by recipient age (18-29, 30-54, and ≥55 y). RESULTS: Of 12 488, 28.3% recipients received ESW. The incidence rate for PTD was 13 per 100 person-y and lower among recipients who received ESW (11 per 100 person-y in ESW; 14 per 100 person-y in CSM). Overall, ESW was associated with lower risk of PTD compared with CSM (adjusted hazard ratio [aHR] = 0.720.790.86), but the risk differed by recipient age (P interaction = 0.09 for comparison between recipients aged 18-29 and those aged 30-54; P interaction = 0.01 for comparison between recipients aged 18-29 and those aged ≥55). ESW was associated with lower risk of PTD among recipients aged ≥55 (aHR = 0.620.710.81) and those aged 30-54 (aHR = 0.730.830.95), but not among recipients aged 18-29 (aHR = 0.811.181.72). Although recipients who received ESW had a higher risk of acute rejection across the age groups (adjusted odds ratio = 1.011.171.34), recipients with no PTD had a lower risk of mortality (aHR = 0.580.660.74). CONCLUSIONS: The beneficial association of ESW with decreased PTD was more pronounced among recipients aged ≥55, supporting an age-specific assessment of the risk-benefit balance regarding ESW.

The Risk of Postkidney Transplant Outcomes by Induction Choice Differs by Recipient Age.

BACKGROUND: Among adult kidney transplant (KT) recipients, the risk of post-KT adverse outcomes differs by type of induction immunosuppression. Immune response to induction differs as recipients age; yet, choice of induction is barely tailored by age likely due to a lack of evidence of the risks and benefits. METHODS: Using Scientific Registry of Transplant Recipients data, we identified 39336 first-time KT recipients (2010-2016). We estimated the length of stay (LOS), acute rejection (AR), graft failure, and death by induction type using logistic and Cox regression weighted by propensity score to adjust for confounders. We tested whether these estimates differed by age (65+ versus 18-64 y) using a Wald test. RESULTS: Overall, rabbit antithymocyte globulin (rATG) was associated with a decreased risk of AR (odds ratio = 0.79, 95% confidence interval [CI], 0.72-0.85) compared with basiliximab. The effect of induction on LOS and death (interaction P = 0.03 and 0.003) differed by recipient age. Discharge was on average 11% shorter in rATG among younger recipients (relative time = 0.89; 95% confidence interval [CI], 0.81-0.99) but not among older recipients (relative time = 1.01; 95% CI, 0.95-1.08). rATG was not associated with mortality among older (hazard ratio = 1.05; 95% CI, 0.96-1.15), but among younger recipients (hazard ratio = 0.87; 95% CI, 0.80-0.95), it was associated with reduced mortality risk. CONCLUSIONS: rATG should be considered to prevent AR, especially among recipients with high-immunologic risk regardless of age; however, choice of induction should be tailored to reduce LOS and risk of mortality, particularly among younger recipients.

SARS-CoV-2 messenger RNA vaccine antibody response and reactogenicity in heart and lung transplant recipients.

BACKGROUND: While several studies have observed that solid organ transplant recipients experience diminished antibody responses to SARS-CoV-2 mRNA vaccination, data specific to heart and lung transplant (HT/LT) recipients remains sparse. METHODS: US adult HT and LT recipients completed their vaccine series between January 7 and April 10, 2021. Reactogencity and SARS-CoV-2 anti-spike antibody were assessed after a priming dose (D1) and booster dose (D2). Modified Poisson regression with robust variance estimator was used to evaluate associations between participant characteristics and antibody development. RESULTS: Of 134 heart recipients, there were 38% non-responders (D1-/D2-), 48% booster responders (D1-/D2+), and 14% priming dose responders (D1+/D2+). Of 103 lung recipients, 64% were non-responders, 27% were booster responders, and 9% were priming dose responders. Lung recipients were less likely to develop antibodies (p < .001). Priming dose antibody response was associated with younger recipient age (p = .04), transplant-to-vaccination time ≥6 years (p < .01), and lack of anti-metabolite maintenance immunosuppression (p < .001). Pain at injection site was the most commonly reported reaction (85% after D1, 76% after D2). Serious reactions were rare, the most common being fatigue (2% after D1 and 3% after D2). No serious adverse events were reported. CONCLUSIONS: HT and LT recipients experienced diminished antibody response following vaccination; reactogenicity was comparable to that of the general population. LT recipients may exhibit a more impaired antibody response than HT recipients. While current recommendations are to vaccinate eligible candidates and recipients, further studies characterizing the cell-mediated immune response and clinical efficacy of these vaccines in this population are needed.