Association of early steroid withdrawal with kidney transplant outcomes in first-transplant and retransplant recipients.

BACKGROUND AND HYPOTHESIS: Early steroid withdrawal (ESW) is often preferred over conventional steroid maintenance (CSM) therapy for kidney transplant recipients with low immunological risks because it may minimize immunosuppression-related adverse events while achieving similar transplant outcomes. However, the risk-benefit balance of ESW could be less favorable in retransplant recipients given their unique immunological risk profile. We hypothesized that the association of ESW with transplant outcomes would differ between first-transplant and retransplant recipients. METHODS: To assess whether the impact of ESW differs between first and retransplant recipients, we studied 210 086 adult deceased-donor kidney transplant recipients using the Scientific Registry of Transplant Recipients. Recipients who discontinued maintenance steroids before discharge from transplant admission were classified with ESW; all others were classified with CSM. We quantified the association of ESW (vs. CSM) with acute rejection, death-censored graft failure, and death, addressing retransplant as an effect modifier, using logistic/Cox regression with inverse probability weights to control for confounders. RESULTS: In our cohort, 26 248 (12%) were retransplant recipients. ESW was used in 30% of first-transplant and 20% of retransplant recipients. Among first-transplant recipients, ESW was associated with no significant difference in acute rejection (aOR = 1.04 [95% CI = 1.00-1.09]), slightly higher hazard of graft failure (HR = 1.09 [95% CI = 1.05-1.12]), and slightly lower mortality (HR = 0.93 [95% CI = 0.91-0.95]) compared to CSM. Nonetheless, among retransplant recipients, ESW was associated with notably higher risk of acute rejection (OR = 1.42 [95% CI = 1.29-1.57]; interaction p < 0.001) and graft failure (HR = 1.24 [95% CI = 1.14-1.34]; interaction p = 0.003), and similar mortality (HR = 1.01 [95% CI = 0.94-1.08]; interaction p = 0.04). CONCLUSIONS: In retransplant recipients, the negative impacts of ESW on transplant outcomes appear to be non-negligible. A more conservatively tailored approach to ESW might be necessary for retransplant recipients.

ChatGPT Solving Complex Kidney Transplant Cases: A Comparative Study With Human Respondents.

INTRODUCTION: ChatGPT has shown the ability to answer clinical questions in general medicine but may be constrained by the specialized nature of kidney transplantation. Thus, it is important to explore how ChatGPT can be used in kidney transplantation and how its knowledge compares to human respondents. METHODS: We prompted ChatGPT versions 3.5, 4, and 4 Visual (4 V) with 12 multiple-choice questions related to six kidney transplant cases from 2013 to 2015 American Society of Nephrology (ASN) fellowship program quizzes. We compared the performance of ChatGPT with US nephrology fellowship program directors, nephrology fellows, and the audience of the ASN's annual Kidney Week meeting. RESULTS: Overall, ChatGPT 4 V correctly answered 10 out of 12 questions, showing a performance level comparable to nephrology fellows (group majority correctly answered 9 of 12 questions) and training program directors (11 of 12). This surpassed ChatGPT 4 (7 of 12 correct) and 3.5 (5 of 12). All three ChatGPT versions failed to correctly answer questions where the consensus among human respondents was low. CONCLUSION: Each iterative version of ChatGPT performed better than the prior version, with version 4 V achieving performance on par with nephrology fellows and training program directors. While it shows promise in understanding and answering kidney transplantation questions, ChatGPT should be seen as a complementary tool to human expertise rather than a replacement.

Obesogenic Medication Use in End-Stage Kidney Disease and Association With Transplant Listing.

OBJECTIVES: Obesogenic medications are a putative contributor to the obesity epidemic. While 20% of adults take ≥1 obesogenic medication, the proportion in the end-stage kidney disease (ESKD) population-a group enriched for cardiometabolic complications-is unknown. Obesogenic medications may contribute to obesity and hamper weight loss efforts to achieve transplant listing. METHODS: Using 2017-2020 USRDS and Medicare claims, patients were identified as taking obesogenic medications if prescribed anticonvulsants, antidepressants, antidiabetics, anti-inflammatories, antipsychotics, and/or antihypertensives known to cause weight gain for ≥30 days in their first hemodialysis year. Ordinal logistic and Cox regression with inverse probability of treatment weighting were used to quantify obesogenic medications' association with body mass index (BMI) and listing, respectively. RESULTS: Among 271 401 hemodialysis initiates, 63.5% took ≥1 obesogenic medication. For those in underweight, normal weight, overweight, and class I, II, and III categories, 54.3%, 58.4%, 63.1%, 66.5%, 68.6%, and 68.8% took ≥1, respectively. Number of obesogenic medications was associated with increased BMI; use of one was associated with 13% increased odds of higher BMI (aOR [adjusted odds ratio] 1.14; 95%CI: 1.13-1.16; p < 0.001), use of three was associated with a 55% increase (aOR 1.55; 95%CI: 1.53-1.57; p < 0.001). Any use was associated with 6% lower odds of transplant listing (aHR [adjusted hazard ratio] 0.94; 95%CI: 0.92-0.96; p < 0.001). Within each BMI category, obesogenic medication use was associated with lower listing likelihood. CONCLUSIONS: Obesogenic medication use is common in ESKD patients-particularly those with obesity-and is associated with lower listing likelihood. Whenever possible, non-obesogenic alternatives should be chosen for ESKD patients attempting weight loss to achieve transplant listing.

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.

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.

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.

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.

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.

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.

Early steroid withdrawal in HIV-infected kidney transplant recipients: Utilization and outcomes.

Kidney transplant (KT) outcomes for HIV-infected (HIV+) persons are excellent, yet acute rejection (AR) is common and optimal immunosuppressive regimens remain unclear. Early steroid withdrawal (ESW) is associated with AR in other populations, but its utilization and impact are unknown in HIV+ KT. Using SRTR, we identified 1225 HIV+ KT recipients between January 1, 2000, and December 31, 2017, without AR, graft failure, or mortality during KT admission, and compared those with ESW with those with steroid continuation (SC). We quantified associations between ESW and AR using multivariable logistic regression and interval-censored survival analysis, as well as with graft failure and mortality using Cox regression, adjusting for donor, recipient, and immunologic factors. ESW utilization was 20.4%, with more zero HLA mismatch (8% vs 4%), living donors (26% vs 20%), and lymphodepleting induction (64% vs 46%) compared to the SC group. ESW utilization varied widely across 129 centers, with less use at high- versus moderate-volume centers (6% vs 21%, P < .001). AR was more common with ESW by 1 year (18.4% vs 12.3%; aOR: 1.08 1.612.41 , P = .04) and over the study period (aHR: 1.02 1.391.90 , P = .03), without difference in death-censored graft failure (aHR 0.60 0.911.36 , P = .33) or mortality (aHR: 0.75 1.151.77 , P = .45). To reduce AR after HIV+ KT, tailoring of ESW utilization is reasonable.

Characterizing the landscape and impact of infections following kidney transplantation.

Infections remain a major threat to successful kidney transplantation (KT). To characterize the landscape and impact of post-KT infections in the modern era, we used United States Renal Data System (USRDS) data linked to the Scientific Registry of Transplant Recipients (SRTR) to study 141 661 Medicare-primary kidney transplant recipients from January 1, 1999 to December 31, 2014. Infection diagnoses were ascertained by International Classification of Diseases, Ninth Revision (ICD-9) codes. The cumulative incidence of a post-KT infection was 36.9% at 3 months, 53.7% at 1 year, and 78.0% at 5 years. The most common infections were urinary tract infection (UTI; 46.8%) and pneumonia (28.2%). Five-year mortality for kidney transplant recipients who developed an infection was 24.9% vs 7.9% for those who did not, and 5-year death-censored graft failure (DCGF) was 20.6% vs 10.1% (P < .001). This translated to a 2.22-fold higher mortality risk (adjusted hazard ratio [aHR]: 2.15 2.222.29 , P < .001) and 1.92-fold higher DCGF risk (aHR: 1.84 1.911.98 , P < .001) for kidney transplant recipients who developed an infection, although the magnitude of this higher risk varied across infection types (for example, 3.11-fold higher mortality risk for sepsis vs 1.62-fold for a UTI). Post-KT infections are common and substantially impact mortality and DCGF, even in the modern era. Kidney transplant recipients at high risk for infections might benefit from enhanced surveillance or follow-up to mitigate these risks.

Inconsistencies in the association of clinical factors with the choice of early steroid withdrawal across kidney transplant centers: A national registry study.

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: The association of clinical factors with the choice of ESW varied substantially across centers. We found particularly greater inconsistency in recipient age, PRA, re-transplantation, living/deceased donor, post-transplant length of stay, and delayed graft function. For example, across the entire population, re-transplantation was associated with lower odds of ESW (population odds ratio = 0.35 0.400.46 ). 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.

Early Steroid Withdrawal in Deceased-Donor Kidney Transplant Recipients with Delayed Graft Function.

BACKGROUND: Early steroid withdrawal (ESW) is associated with acceptable outcomes in kidney transplant (KT) recipients. Recipients with delayed graft function (DGF), however, often have a suboptimal allograft milieu, which may alter the risk/benefit equation for ESW. This may contribute to varying practices across transplant centers. METHODS: Using the Scientific Registry of Transplant Recipients, we studied 110,019 adult deceased-donor KT recipients between 2005 and 2017. We characterized the association of DGF with the use of ESW versus continued steroid maintenance across KT centers, and quantified the association of ESW with acute rejection, graft failure, and mortality using multivariable logistic and Cox regression with DGF-ESW interaction terms. RESULTS: Overall 29.2% of KT recipients underwent ESW. Recipients with DGF had lower odds of ESW (aOR=0.600.670.75). The strength of this association varied across 261 KT centers, with center-specific aOR of <0.5 at 31 (11.9%) and >1.0 at 22 (8.4%) centers. ESW was associated with benefits and harms among recipients with immediate graft function (IGF), but only with harms among recipients with DGF. ESW was associated with increased acute rejection (aOR=1.091.161.23), slightly increased graft failure (aHR=1.011.061.12), but decreased mortality (aHR=0.860.890.93) among recipients with IGF. Among recipients with DGF, ESW was associated with a similar increase in rejection (aOR=1.12; 95% CI, 1.02 to 1.23), a more pronounced increase in graft failure (aHR=1.16; 95% CI, 1.08 to 1.26), and no improvement in mortality (aHR=1.00; 95% CI, 0.94 to 1.07). DGF-ESW interaction was statistically significant for graft failure (P=0.04) and mortality (P=0.003), but not for rejection (P=0.6). CONCLUSIONS: KT centers in the United States use ESW inconsistently in recipients with DGF. Our findings suggest ESW may lead to worse KT outcomes in recipients with DGF.

Identifying scenarios of benefit or harm from kidney transplantation during the COVID-19 pandemic: A stochastic simulation and machine learning study.

Clinical decision-making in kidney transplant (KT) during the coronavirus disease 2019 (COVID-19) pandemic is understandably a conundrum: both candidates and recipients may face increased acquisition risks and case fatality rates (CFRs). Given our poor understanding of these risks, many centers have paused or reduced KT activity, yet data to inform such decisions are lacking. To quantify the benefit/harm of KT in this context, we conducted a simulation study of immediate-KT vs delay-until-after-pandemic for different patient phenotypes under a variety of potential COVID-19 scenarios. A calculator was implemented (http://www.transplantmodels.com/covid_sim), and machine learning approaches were used to evaluate the important aspects of our modeling. Characteristics of the pandemic (acquisition risk, CFR) and length of delay (length of pandemic, waitlist priority when modeling deceased donor KT) had greatest influence on benefit/harm. In most scenarios of COVID-19 dynamics and patient characteristics, immediate KT provided survival benefit; KT only began showing evidence of harm in scenarios where CFRs were substantially higher for KT recipients (eg, ≥50% fatality) than for waitlist registrants. Our simulations suggest that KT could be beneficial in many centers if local resources allow, and our calculator can help identify patients who would benefit most. Furthermore, as the pandemic evolves, our calculator can update these predictions.

Induction immunosuppression and the risk of incident malignancies among older and younger kidney transplant recipients: A prospective cohort study.

BACKGROUND: Older (≥65) KT recipients differ from their younger counterparts in their immune response to immunosuppression (IS) and may have a different risk of malignancy after receiving induction. METHODS: We identified 66 700 adult KT recipients treated with anti-thymocyte globulin (ATG) (n = 40 443) or interleukin-2 receptor antagonist (IL-2RA) (n = 26 327) induction (1/1/1999-12/31/2014) using USRDS/Medicare data. We estimated the risk of first-diagnosed post-KT malignancy associated with induction (ATG vs. IL-2RA) using Cox proportional hazard models. We then tested whether these risks differed between older and younger recipients (Wald test for interaction). Models incorporated inverse probability of treatment weights to adjust for confounders. RESULTS: The 3-year cumulative incidences of any diagnosed malignancy were 11.5%. ATG was associated with a higher malignancy risk (HR = 1.12, 95%CI:1.06-1.18). This association differed (pinteraction  = 0.04) between younger (HR = 1.12, 95%CI:1.06-1.18) and older recipients (HR = 1.03, 95%CI:0.96-1.09). ATG was also associated with higher risk of skin (HR = 1.18, 95%CI:1.08-1.29), lung (HR = 1.24, 95%CI:1.05-1.47), and ovary malignancies (HR = 1.94, 95%CI:1.08-3.48). However, only the association of ATG with post-KT skin malignancy differed (pinteraction  = 0.01) between younger (HR = 1.18; 95%CI:1.08-1.29) and older (HR = 1.01; 95%CI:0.93-1.09) recipients. CONCLUSIONS: Compared with IL-2RA induction, ATG was associated with elevated post-KT malignancy risk but only among younger recipients. Transplant centers may need to tailor induction IS for younger recipients to mitigate malignancy risk.

Machine learning to predict transplant outcomes: helpful or hype? A national cohort study.

An increasing number of studies claim machine learning (ML) predicts transplant outcomes more accurately. However, these claims were possibly confounded by other factors, namely, supplying new variables to ML models. To better understand the prospects of ML in transplantation, we compared ML to conventional regression in a "common" analytic task: predicting kidney transplant outcomes using national registry data. We studied 133 431 adult deceased-donor kidney transplant recipients between 2005 and 2017. Transplant centers were randomly divided into 70% training set (190 centers/97 787 recipients) and 30% validation set (82 centers/35 644 recipients). Using the training set, we performed regression and ML procedures [gradient boosting (GB) and random forests (RF)] to predict delayed graft function, one-year acute rejection, death-censored graft failure C, all-cause graft failure, and death. Their performances were compared on the validation set using -statistics. In predicting rejection, regression (C = 0.601 0.6110.621 ) actually outperformed GB (C = 0.581 0.5910.601 ) and RF (C = 0.569 0.5790.589 ). For all other outcomes, the C-statistics were nearly identical across methods (delayed graft function, 0.717-0.723; death-censored graft failure, 0.637-0.642; all-cause graft failure, 0.633-0.635; and death, 0.705-0.708). Given its shortcomings in model interpretability and hypothesis testing, ML is advantageous only when it clearly outperforms conventional regression; in the case of transplant outcomes prediction, ML seems more hype than helpful.

Projected 20- and 30-Year Outcomes for Pediatric Liver Transplant Recipients in the United States.

BACKGROUND: Observed long-term outcomes no longer reflect the survival trajectory facing pediatric liver transplant (LT) recipients today. We aimed to use national registry data and parametric models to project 20- and 30-year post-transplant outcomes for recently transplanted pediatric LT recipients. METHODS: We conducted a retrospective cohort study of 13,442 first-time pediatric (age <18) LT recipients using 1987 to 2018 Scientific Registry of Transplant Recipients data. We validated the proposed method (ie, to project long-term patient and graft survival using parametric survival models and short-term data) in 2 historic cohorts (1987-1996 and 1997-2006) and estimated long-term projections among patients transplanted between 2007 and 2018. Projections were stratified by raft type, recipient age, and indication for transplant. RESULTS: Parsimonious parametric models with Weibull distribution can be applied to post-transplant data and used to project long-term outcomes for pediatric LT recipients beyond observed data. Projected 20-year patient survival for pediatric LT recipients transplanted in 2007 to 2018 was 84.0% (95% confidence interval 81.5-85.8), compared to observed 20-year survival of 72.8% and 63.6% among those transplanted in 1997 to 2006 and 1987 to 1996, respectively. Projected 30-year survival for pediatric LT recipients in 2007 to 2018 was 80.1% (75.2-82.7), compared to projected 30-year survival of 68.6% (66.1-70.9) in the 1997 to 2006 cohort and observed 30-year survival of 57.5% in the 1987 to 1996 cohort. Twenty- and 30-year patient and graft survival varied slightly by recipient age, graft type, and indication for transplant. CONCLUSIONS: Projected long-term outcomes for recently transplanted pediatric LT recipients are excellent, reflective of substantial improvements in medical care, and informative for physician-patient education and decision making in the current era.

Induction immunosuppression agents as risk factors for incident cardiovascular events and mortality after kidney transplantation.

Low T cell counts and acute rejection are associated with increased cardiovascular events (CVEs); T cell-depleting agents decrease both. Thus, we aimed to characterize the risk of CVEs by using an induction agent used in kidney transplant recipients. We conducted a secondary data analysis of patients who received a kidney transplant and used Medicare as their primary insurance from 1999 to 2010. Outcomes of interest were incident CVE, all-cause mortality, CVE-related mortality, and a composite outcome of mortality and CVE. Of 47 258 recipients, 29.3% received IL-2 receptor antagonist (IL-2RA), 33.3% received anti-thymocyte globulin (ATG), 7.3% received alemtuzumab, and 30.0% received no induction. Compared with IL-2RA, there was no difference in the risk of CVE in the ATG (adjusted hazard ratio [aHR] 0.98, 95% confidence interval [CI] 0.92-1.05) and alemtuzumab group (aHR 1.01, 95% CI 0.89-1.16), but slightly higher in the no induction group (aHR 1.06, 95% CI 1.00-1.14). Acute rejection did not modify this association in the latter group but did increase CVE by 46% in the alemtuzumab group. There was no difference in the hazard of all-cause or CVE-related mortality. Only in the ATG group, a 7% lower hazard of the composite outcome of mortality and CVE was noted. Induction agents are not associated with incident CVE, although prospective trials are needed to determine a personalized approach to prevention.

Better graft outcomes from offspring donor kidneys among living donor kidney transplant recipients in the United States.

A recent study reported that kidney transplant recipients of offspring living donors had higher graft loss and mortality. This seemed counterintuitive, given the excellent HLA matching and younger age of offspring donors; we were concerned about residual confounding and other study design issues. We used Scientific Registry of Transplant Recipients data 2001-2016 to evaluate death-censored graft failure (DCGF) and mortality for recipients of offspring versus nonoffspring living donor kidneys, using Cox regression models with interaction terms. Recipients of offspring kidneys had lower DCGF than recipients of nonoffspring kidneys (15-year cumulative incidence 21.2% vs 26.1%, P < .001). This association remained after adjustment for recipient and transplant factors (adjusted hazard ratio [aHR] = 0.73 0.770.82 , P < .001), and was attenuated among African American donors (aHR 0.77 0.850.95 ; interaction: P = .01) and female recipients (aHR 0.77 0.840.91 , P < .001). Although offspring kidney recipients had higher mortality (15-year mortality 56.4% vs 37.2%, P < .001), this largely disappeared with adjustment for recipient age alone (aHR = 1.02 1.061.10 , P = .002) and was nonsignificant after further adjustment for other recipient characteristics (aHR = 0.93 0.971.01 , P = .1). Kidneys from offspring donors provided lower graft failure and comparable mortality. An otherwise eligible donor should not be dismissed because they are the offspring of the recipient, and we encourage continued individualized counseling for potential donors.