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Donor/recipient incompatibility in kidney transplantation classically refers to ABO/HLA-incompatibility. Kidney paired donation (KPD) was historically established to circumvent ABO/HLA-incompatibility, with the goal of identifying ABO/HLA-compatible matches. However, there is a broad range of donor factors known to impact recipient outcomes beyond ABO/HLA-incompatibility, such as age and weight, and quantitative tools are now available to empirically compare potential living donors across many of these factors, such as the living donor kidney donor profile index (LKDPI). Moreover, the detrimental impact of mismatch at other HLA antigens (such as DQ) and epitope mismatching on post-transplant outcomes has become increasingly recognized. Thus, it is time for a new paradigm of incompatibility that considers all of these risks factors together in assessing donor/recipient compatibility and the potential utility for KPD. Under this new paradigm of incompatibility, we show how the LKDPI and other tools can be used to identify donor/recipient incompatibilities that could be improved through KPD, even for those with a traditionally 'compatible' living donor.

COVID-19 has profoundly affected the American health care system; its effect on the liver transplant (LT) waitlist based on COVID-19 incidence has not been characterized. Using SRTR data, we compared observed LT waitlist registrations, waitlist mortality, deceased donor LTs (DDLT), and living donor LTs (LDLT) 3/15/2020-8/31/2020 to expected values based on historical trends 1/2016-1/2020, stratified by statewide COVID-19 incidence. Overall, from 3/15 to 4/30, new listings were 11% fewer than expected (IRR = 0.84 0.890.93 ), LDLTs were 49% fewer (IRR = 0.37 0.510.72 ), and DDLTs were 9% fewer (IRR = 0.85 0.910.97 ). In May, new listings were 21% fewer (IRR = 0.74 0.790.84 ), LDLTs were 42% fewer (IRR = 0.39 0.580.85 ) and DDLTs were 13% more (IRR = 1.07 1.151.23 ). Centers in states with the highest incidence 3/15-4/30 had 59% more waitlist deaths (IRR = 1.09 1.592.32 ) and 34% fewer DDLTs (IRR = 0.50 0.660.86 ). By August, waitlist outcomes were occurring at expected rates, except for DDLT (13% more across all incidences). While the early COVID-affected states endured major transplant practice changes, later in the pandemic the newly COVID-affected areas were not impacted to the same extent. These results speak to the adaptability of the transplant community in addressing the pandemic and applying new knowledge to patient care.

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0‐4 plasmaphereses, n = 47), moderate (5‐9, n = 74), and high (≥10, n = 94). The 1‐year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high‐intensity desensitization (P, Among living donor kidney transplant recipients, infections are most common in patients who receive high‐intensity desensitization, and patients with more than 4 infections in the first year posttransplant are at increased risk of adverse outcomes.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

Cytotoxic T lymphocyte (CTL)-based cancer immunotherapies have shown great promise for inducing clinical regressions by targeting tumor-associated antigens (TAA). To expand the TAA landscape of pancreatic ductal adenocarcinoma (PDAC), we performed tandem mass spectrometry analysis of HLA class I-bound peptides from 35 PDAC patient tumors. This identified a shared HLA-A*0101 restricted peptide derived from co-transcriptional activator Vestigial-like 1 (VGLL1) as a putative TAA demonstrating overexpression in multiple tumor types and low or absent expression in essential normal tissues. Here we show that VGLL1-specific CTLs expanded from the blood of a PDAC patient could recognize and kill in an antigen-specific manner a majority of HLA-A*0101 allogeneic tumor cell lines derived not only from PDAC, but also bladder, ovarian, gastric, lung, and basal-like breast cancers. Gene expression profiling reveals VGLL1 as a member of a unique group of cancer-placenta antigens (CPA) that may constitute immunotherapeutic targets for patients with multiple cancer types., Cytotoxic T lymphocyte (CTL)-based immunotherapies can induce tumor regressions by targeting HLA class I-bound tumor-associated peptides. Here, the authors identified a peptide derived from Vestigial-like 1 (VGLL1) as a shared, potentially therapeutic CTL target expressed by multiple cancer types.

Organs from uncontrolled DCD donors (uDCDs) have expanded donation in Europe since the 1980s, but are seldom used in the United States. Cited barriers include lack of knowledge about the potential donor pool, lack of robust outcomes data, lack of standard donor eligibility criteria and preservation methods, and logistical and ethical challenges. To determine whether it would be appropriate to invest in addressing these barriers and building this practice, we sought to enumerate the potential pool of uDCD donors. Using data from the Nationwide Emergency Department Sample, the largest all-payer emergency department (ED) database, between 2013 and 2016, we identified patients who had refractory cardiac arrest in the ED. We excluded patients with contraindications to both deceased donation (including infection, malignancy, cardiopulmonary disease) and uDCD (including hemorrhage, major polytrauma, burns, and poisoning). We identified 9828 (range: 9454-10 202) potential uDCDs/y; average age was 32 years, and all were free of major comorbidity. Of these, 91.1% had traumatic deaths, with major causes including nonhead blunt injuries (43.2%) and head injuries (40.1%). In the current era, uDCD donors represent a significant potential source of unused organs. Efforts to address barriers to uDCD in the United States should be encouraged.

Stakeholders have expressed concerns regarding decreased deceased donor kidney transplant (DDKT) rates for pediatric candidates under the Kidney Allocation System (KAS). To better understand what might be driving this, we studied Scientific Registry of Transplant Recipients kidney offer data for 3642 pediatric (age

BACKGROUND. Steatotic donor livers (SDLs, ≥30% macrosteatosis on biopsy) are often declined, as they are associated with a higher risk of graft loss, even though candidates may wait an indefinite time for a subsequent organ offer. We sought to quantify outcomes for transplant candidates who declined or accepted an SDL offer. METHODS. We used Scientific Registry of Transplant Recipients offer data from 2009 to 2015 to compare outcomes of 759 candidates who accepted an SDL to 13 362 matched controls who declined and followed candidates from the date of decision (decline or accept) until death or end of study period. We used a competing risk framework to understand the natural history of candidates who declined and Cox regression to compare postdecision survival after declining versus accepting (ie, what could have happened if candidates who declined had instead accepted). RESULTS. Among those who declined an SDL, only 53.1% of candidates were subsequently transplanted, 23.8% died, and 19.4% were removed from the waitlist. Candidates who accepted had a brief perioperative risk period within the first month posttransplant (adjusted hazard ratio [aHR]: (2.49)3.49(4.89’) P < 0.001), but a 62% lower mortality risk (aHR: (0.31)0.38(0.46’) P < 0.001) beyond this. Although the long-term survival benefit of acceptance did not vary by candidate model for end-stage liver disease (MELD), the short-term risk period did. MELD 6–21 candidates who accepted an SDL had a 7.88-fold higher mortality risk (aHR: (4.80)7.88(12.93’) P < 0.001) in the first month posttransplant, whereas MELD 35–40 candidates had a 68% lower mortality risk (aHR: (0.11)0.32(0.90’) P = 0.03). CONCLUSIONS. Appropriately selected SDLs can decrease wait time and provide substantial long-term survival benefit for liver transplant candidates.

It has been hypothesized that transplanting simultaneous pancreas kidney (SPK) grafts from donors with a history of cardiac arrest and cardiopulmonary resuscitation (CACPR) leads to inferior posttransplant outcomes due to organ hypoperfusion during cardiac arrest and mechanical trauma during resuscitation. Using Scientific Registry of Transplant Recipients data, we identified 13 095 SPK transplants from 2000-2018, of which 810 (6.2%) were from donors with a history of CACPR. After inverse probability of treatment weighting on donor and recipient characteristics, we found that 1-, 5-, and 10-year patient (CACPR: 96.4%, 89.9%, and 78.9%; non-CACPR: 96.3%, 88.9%, and 76.0%; P = .3), death-censored pancreas graft survival (CACPR: 89.3%, 82.7%, 75.0%; non-CACPR: 89.9%, 82.7%, 76.3%; P = .7), and death-censored kidney graft survival (CACPR: 97.0%, 89.5%, 78.2%; non-CACPR: 96.9.9%, 88.7%, 80.0%; P = .4) were comparable between the two groups. There were no differences in the risk of pancreatitis (CACPR: 2.9%, non-CACPR: 2.4%; weighted OR = 0.74 1.22 2.02 ; P = .4), anastomotic leak (CACPR: 1.6%, non-CACPR: 2.0%; weighted OR = 0.54 1.02 1.93 ; P > .9), or median length of hospital stay (CACPR: 8 days, non-CACPR: 9 days; P = .6) for recipients of CACPR vs non-CACPR donors. Our findings suggest that CACPR donors could be used to expand the SPK donor pool without compromising short- or long-term outcomes.

BACKGROUND Desensitization protocols for HLA-incompatible living donor kidney transplantation (ILDKT) vary across centers. The impact of these, as well as other practice variations, on ILDKT outcomes remains unknown. METHODS We sought to quantify center-level variation in mortality and graft loss following ILDKT using a 25-center cohort of 1358 ILDKT recipients with linkage to Scientific Registry of Transplant Recipients for accurate outcome ascertainment. We used multilevel Cox regression with shared frailty to determine the variation in post-ILDKT outcomes attributable to between-center differences and to identify any center-level characteristics associated with improved post-ILDKT outcomes. RESULTS After adjusting for patient-level characteristics, only 6 centers (24%) had lower mortality and 1 (4%) had higher mortality than average. Similarly, only 5 centers (20%) had higher graft loss and 2 had lower graft loss than average. Only 4.7% of the differences in mortality (P < 0.01) and 4.4% of the differences in graft loss (P < 0.01) were attributable to between-center variation. These translated to a median hazard ratio of 1.36 for mortality and 1.34 of graft loss for similar candidates at different centers. Post-ILDKT outcomes were not associated with the following center-level characteristics: ILDKT volume and transplanting a higher proportion of highly sensitized, prior transplant, preemptive, or minority candidates. CONCLUSIONS Unlike most aspects of transplantation in which center-level variation and volume impact outcomes, we did not find substantial evidence for this in ILDKT. Our findings support the continued practice of ILDKT across these diverse centers.

Steatotic donor livers (SDLs) (macrosteatosis ≥30%) represent a possible donor pool expansion, but are frequently discarded due to a historical association with mortality and graft loss. However, changes in recipient/donor demographics, allocation policy, and clinical protocols might have altered utilization and outcomes of SDLs. We used Scientific Registry of Transplant Recipients data from 2005 to 2017 and adjusted multilevel regression to quantify temporal trends in discard rates (logistic) and posttransplant outcomes (Cox) of SDLs, accounting for Organ Procurement Organization-level variation. Of 4346 recovered SDLs, 58.0% were discarded in 2005, versus only 43.1% in 2017 (P

With implementation of the Kidney Allocation System, the growth of kidney paired donation programs, and advances in desensitization and immunosuppression, the outlook for "untransplantable" kidney transplantation candidates has never been more promising. The Kidney Allocation System prioritized compatible matches for candidates with calculated panel-reactive antibody levels of 98%, 99%, or 100% and broadened allocation of non-A1 and non-A1-B subgroup kidneys to blood group type B candidates. Concurrently, the growth of kidney paired donation programs and use of incompatible transplantation as part of kidney paired donation to achieve "more compatible" kidney transplantation has improved options for candidates with an incompatible living donor. Finally, advances in desensitization and immunosuppression have strengthened the ability to manage donor-specific antibodies and antibody-mediated rejection. Although no patient should be labeled "untransplantable" due to blood group type or donor-specific antibody, all candidates should be provided with individualized and realistic counseling regarding their anticipated wait times for deceased donor or kidney paired donation matching, with early referral to expert centers when needed. In this Perspective, we consider blood group type ABO incompatibility, HLA antigen incompatibility, antibody-mediated rejection, kidney paired donation, and recent developments in incompatible transplantation in more depth and recommend an approach to the sensitized candidate.

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=(0.60)0.67(0.75)). The strength of this association varied across 261 KT centers, with center-specific aOR of 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=(1.09)1.16(1.23)), slightly increased graft failure (aHR=(1.01)1.06(1.12)), but decreased mortality (aHR=(0.86)0.89(0.93)) 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.

The Kidney Allocation System (KAS) has resulted in fewer pediatric kidneys being allocated to pediatric deceased donor kidney transplant (pDDKT) recipients. This had prompted concerns that post-pDDKT outcomes may worsen. To study this, we used SRTR data to compare the outcomes of 953 pre-KAS pDDKT (age

Despite a documented survival benefit, older liver donor (OLD, age ≥70) graft offers are frequently declined, with utilization worsening over the last decade. To understand how offer acceptance varies by center, we studied 1113 eventually transplanted OLD grafts from 2009 to 2017 using Scientific Registry of Transplant Recipients (SRTR) data and random-intercept multilevel logistic regression. To understand how center-level acceptance of OLD graft offers might be associated with waitlist and posttransplant outcomes, we studied all adult, actively listed, liver-only candidates and recipients during the study period using Poisson regression (transplant rate), competing risks regression (waitlist mortality), and Cox regression (posttransplant mortality). Among 117 centers, OLD offer acceptance ranged from 0 (23 centers) to 95 acceptances, with a median odds ratio of 2.88. Thus, a candidate may be three times as likely to receive an OLD graft simply by listing at a different center. Centers in the highest quartile (Q4) of OLD acceptance (accepted 39% of OLD offers) accepted more nationally shared organs (Q4 versus Q1: 14.1% versus 0.0%, P

Historically, donation after circulatory death (DCD) livers were frequently discarded because of higher mortality and graft loss after liver transplantation (LT). However, the demand for LT continues to outstrip the supply of "acceptable" organs. Additionally, changes in the donor pool, organ allocation, and clinical management of donors and recipients, and improved clinical protocols might have altered post-DCD-LT outcomes.We studied 5975 recovered DCD livers using US Scientific Registry of Transplant Recipients data from 2005 to 2017, with a comparison group of 78 235 adult donation after brain death (DBD) livers recovered during the same time period. We quantified temporal trends in discard using adjusted multilevel logistic regression and temporal trends in post-LT mortality and graft loss for DCD LT recipients using adjusted Cox regression.DCD livers were more likely to be discarded than DBD livers across the entire study period, and the relative likelihood of discard increased over time (adjusted odds ratio [aOR] of discard DCD versus DBD 3.854.455.14 2005-2007, 5.225.876.59 2015-2017) despite improving outcomes after DCD LT. Mortality risk for DCD LTs decreased in each time period (compared with 2005-2007, aHR 2008-2011 0.720.840.97, aHR 2012-2014 0.480.580.70, aHR 2015-2017 0.340.430.55), as did risk of graft loss (compared with 2005-2007, aHR 2008-2011 0.690.810.94, aHR 2012-2014 0.450.550.67, aHR 2015-2017 0.360.450.56).Despite dramatic improvements in outcomes of DCD LT recipients, DCD livers remain substantially more likely to be discarded than DBD livers, and this discrepancy has actually increased over time. DCD livers are underutilized and have the potential to expand the donor pool.

Recently, model for end-stage liver disease (MELD)-based liver allocation in the United States has been questioned based on concerns that waitlist mortality for a given biologic MELD (bMELD), calculated using laboratory values alone, might be higher at certain centers in certain locations across the country. Therefore, we aimed to quantify the center-level variation in bMELD-predicted mortality risk. Using Scientific Registry of Transplant Recipients (SRTR) data from January 2015 to December 2019, we modeled mortality risk in 33 260 adult, first-time waitlisted candidates from 120 centers using multilevel Poisson regression, adjusting for sex, and time-varying age and bMELD. We calculated a "MELD correction factor" using each center's random intercept and bMELD coefficient. A MELD correction factor of +1 means that center's candidates have a higher-than-average bMELD-predicted mortality risk equivalent to 1 bMELD point. We found that the "MELD correction factor" median (IQR) was 0.03 (-0.47, 0.52), indicating almost no center-level variation. The number of centers with "MELD correction factors" within ±0.5 points, and between ±0.5-± 1, ±1.0-±1.5, and ±1.5-±2.0 points was 62, 41, 13, and 4, respectively. No centers had waitlisted candidates with a higher-than-average bMELD-predicted mortality risk beyond ±2 bMELD points. Given that bMELD similarly predicts waitlist mortality at centers across the country, our results support continued MELD-based prioritization of waitlisted candidates irrespective of center.

The impact of donor quality on post-kidney transplant (KT) survival may vary by candidate condition. Characterizing this variation would increase access to KT without sacrificing outcomes. We developed a tool to estimate post-KT survival for combinations of donor quality and candidate condition. We studied deceased donor KT recipients (n = 120 818) and waitlisted candidates (n = 376 272) between 2005 and 2016 by using the Scientific Registry of Transplant Recipients. Donor quality and candidate condition were measured by using the Kidney Donor Profile Index (KDPI) and the Estimated Post Transplant Survival (EPTS) score. We estimated 5-year post-KT survival based on combinations of KDPI and EPTS score using random forest algorithms and waitlist survival by EPTS score using Weibull regressions. Survival benefit was defined as absolute reduction in mortality risk with KT. For candidates with an EPTS score of 80, 5-year waitlist survival was 47.6%, and 5-year post-KT survival was 78.9% after receiving kidneys with a KDPI of 20 and was 70.7% after receiving kidneys with a KDPI of 80. The impact of KDPI on survival benefit varied greatly by EPTS score. For candidates with low EPTS scores (eg,40), the KDPI had limited impact on survival benefit. For candidates with middle or high EPTS scores (eg,40), survival benefit decreased with higher KDPI but was still substantial even with a KDPI of 100 (16 percentage points). Our prediction tool (www.transplantmodels.com/kdpi-epts) can support individualized decision-making on kidney offers in clinical practice.

In our first survey of transplant centers in March 2020, >75% of kidney and liver programs were either suspended or operating under restrictions. To safely resume transplantation, we must understand the evolving impact of COVID-19 on transplant recipients and center-level practices. We therefore conducted a six-week follow-up survey May 7-15, 2020, and linked responses to the COVID-19 incidence map, with a response rate of 84%. Suspension of live donor transplantation decreased from 72% in March to 30% in May for kidneys and from 68% to 52% for livers. Restrictions/suspension of deceased donor transplantation decreased from 84% to 58% for kidneys and from 73% to 42% for livers. Resuming transplantation at normal capacity was envisioned by 83% of programs by August 2020. Exclusively using local recovery teams for deceased donor procurement was reported by 28%. Respondents reported caring for a total of 1166 COVID-19-positive transplant recipients; 25% were critically ill. Telemedicine challenges were reported by 81%. There was a lack of consensus regarding management of potential living donors or candidates with SARS-CoV-2. Our findings demonstrate persistent heterogeneity in center-level response to COVID-19 even as transplant activity resumes, making ongoing national data collection and real-time analysis critical to inform best practices.

In March 2020, coronavirus disease 2019 (COVID-19) spread rapidly nationally, causing widespread emergent changes to the health system. Our goal was to understand the impact of the epidemic on kidney transplantation (KT), at both the national and center levels, accounting statistically for waitlist composition. Using Scientific Registry of Transplant Recipients data, we compared data on observed waitlist registrations, waitlist mortality, and living-donor and deceased-donor kidney transplants (LDKT/DDKT) March 15-April 30, 2020 to expected events calculated from preepidemic data January 2016-February 2020. There were few changes before March 15, at which point the number of new listings/DDKT/LDKT dropped to 18%/24%/87% below the expected value (all P&nbsp

COVID‐19 is a novel, rapidly changing pandemic: consequently, evidence‐based recommendations in solid organ transplantation (SOT) remain challenging and unclear. To understand the impact on transplant activity across the United States, and center‐level variation in testing, clinical practice, and policies, we conducted a national survey between March 24, 2020 and March 31, 2020 and linked responses to the COVID‐19 incidence map. Response rate was a very high 79.3%, reflecting a strong national priority to better understand COVID‐19. Complete suspension of live donor kidney transplantation was reported by 71.8% and live donor liver by 67.7%. While complete suspension of deceased donor transplantation was less frequent, some restrictions to deceased donor kidney transplantation were reported by 84.0% and deceased donor liver by 73.3%; more stringent restrictions were associated with higher regional incidence of COVID‐19. Shortage of COVID‐19 tests was reported by 42.5%. Respondents reported a total of 148 COVID‐19 recipients from 10 years posttransplant: 69.6% were kidney recipients, and 25.0% were critically ill. Hydroxychloroquine (HCQ) was used by 78.1% of respondents; azithromycin by 46.9%; tocilizumab by 31.3%, and remdesivir by 25.0%. There is wide heterogeneity in center‐level response across the United States; ongoing national data collection, expert discussion, and clinical studies are critical to informing evidence‐based practices.

BACKGROUND A number of deceased donor kidney scoring systems have been developed to predict post-transplant graft failure. However, studies comparing the predictive ability of these scoring systems to each other are lacking. METHODS We used single-center histopathologic and UNOS data from 140 marginal deceased donor kidneys and transplant recipients to compare the predictive accuracy of the Maryland Aggregate Pathology Index (MAPI), Kidney Donor Risk Index (KDRI), Remuzzi, and Nyberg scoring systems for 2-year graft survival using time-dependent receiver operating curves and Kaplan-Meier analysis. RESULTS MAPI had the highest predictive accuracy (area under curve [AUC] = 0.81) compared to KDRI (AUC = 0.45), Remuzzi (AUC = 0.59), and Nyberg (AUC = 0.63) for 2-year graft survival. Furthermore, when analyzing each score according to its pre-defined risk strata, MAPI was the only scoring system for which 2-year graft survival was significantly different across strata (84.3% for low risk, 56.5% for intermediate risk, and 50% for high risk, P

BACKGROUND Recipients of kidneys from living donors who subsequently develop end-stage renal disease (ESRD) also have higher graft failure, suggesting the 2 donor kidneys share risk factors that could inform recipient outcomes. Given that donor ESRD is rare, an earlier and more common postdonation outcome could serve as a surrogate to individualize counseling and management for recipients. Hypertension is a frequent event before donor ESRD; thus, early postdonation hypertension might indicate higher risk of graft failure. METHODS We studied Scientific Registry of Transplant Recipients data to quantify the association between early postdonation hypertension and recipient graft failure using propensity score-weighted Cox proportional hazards regression. We also examined the association between postdonation systolic blood pressure and graft failure. RESULTS Of 37 901 recipients, 2.4% had a donor who developed hypertension within 2 years postdonation. Controlling for donor and recipient characteristics, recipients whose donors developed hypertension had no higher risk for graft failure (adjusted hazard ratio [aHR] 1.03, 95% confidence interval [CI] 0.85-1.25, P = 0.72). This was consistent among subgroups of recipients at higher risk for adverse outcomes due to hyperfiltration: African American recipients (aHR 1.10, 95% CI 0.70-1.73, P = 0.68) and those with ESRD caused by hypertension (aHR 1.10, 95% CI 0.65-1.85, P = 0.73) or diabetes (aHR 0.80, 95% CI 0.56-1.13, P = 0.20). However, graft failure was associated with postdonation systolic blood pressure (per 10 mm Hg, aHR 1.05, 95% CI 1.03-1.08, P < 0.001). CONCLUSIONS Although postdonation systolic blood pressure is associated with graft failure, the reported diagnosis of hypertension as determined by the requirement for blood pressure treatment early postdonation did not portend a higher risk of recipient graft failure in the same way as eventual postdonation ESRD.

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.

In light of changes in donor/recipient case-mix and increased cold ischemia times under the Kidney Allocation System (KAS), there is some concern that cPRA 100% recipients might be doing poorly under KAS. We used granular, single-center data on 109 cPRA 100% deceased donor kidney transplant (DDKT) recipients to study post-KAS posttransplant outcomes not readily available in national registry data. We found that 3-year patient (96.4%) and death-censored graft survival (96.8%) was excellent. We also found that cPRA 100% recipients had a relatively low incidence of T cell-mediated rejection (9.2%) and antibody-mediated rejection (AMR) (13.8%). T cell-mediated rejection episodes tended to be relatively mild-50% (5 episodes) were grade 1, 50% (5 episodes) were grade 2, and none were grade 3. Only 1 episode was associated with graft loss, but this was in the context of a mixed rejection. Although only 15 recipients (13.8%) developed an AMR episode, 2 of these were associated with a graft loss. Despite the rejection episodes, the vast majority of recipients had excellent graft function 3 years posttransplant (median serum creatinine 1.5 mg/dL). In conclusion, cPRA 100% DDKT recipients are doing well under KAS, although every effort should be made to prevent AMR to ensure long-term outcomes remain excellent.

There is concern in the transplant community that outcomes for the most highly sensitized recipients might be poor under Kidney Allocation System (KAS) high prioritization.To study this, we compared posttransplant outcomes of 525 pre-KAS (December 4, 2009, to December 3, 2014) calculated panel-reactive antibodies (cPRA)-100% recipients to 3026 post-KAS (December 4, 2014, to December 3, 2017) cPRA-100% recipients using SRTR data. We compared mortality and death-censored graft survival using Cox regression, acute rejection, and delayed graft function (DGF) using logistic regression, and length of stay (LOS) using negative binomial regression.Compared with pre-KAS recipients, post-KAS recipients were allocated kidneys with lower Kidney Donor Profile Index (median 30% versus 35%, P0.001) but longer cold ischemic time (CIT) (median 21.0 h versus 18.6 h, P0.001). Compared with pre-KAS cPRA-100% recipients, those post-KAS had higher 3-year patient survival (93.6% versus 91.4%, P = 0.04) and 3-year death-censored graft survival (93.7% versus 90.6%, P = 0.005). The incidence of DGF (29.3% versus 29.2%, P = 0.9), acute rejection (11.2% versus 11.7%, P = 0.8), and median LOS (5 d versus 5d, P = 0.2) were similar between pre-KAS and post-KAS recipients. After accounting for secular trends and adjusting for recipient characteristics, post-KAS recipients had no difference in mortality (adjusted hazard ratio [aHR]: 0.861.623.06, P = 0.1), death-censored graft failure (aHR: 0.521.001.91, P0.9), DGF (adjusted odds ratio [aOR]: 0.580.861.27, P = 0.4), acute rejection (aOR: 0.610.941.43, P = 0.8), and LOS (adjusted LOS ratio: 0.981.161.36, P = 0.08).We did not find any statistically significant worsening of outcomes for cPRA-100% recipients under KAS, although longer-term monitoring of posttransplant mortality is warranted.

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.

IMPORTANCE: Historically, deceased organ donation was lower among Black compared with White populations, motivating efforts to reduce racial disparities. The overarching effect of these efforts in Black and other racial/ethnic groups remains unclear. OBJECTIVE: To examine changes in deceased organ donation over time. DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study used data from January 1, 1999, through December 31, 2017, from the Scientific Registry of Transplant Recipients to quantify the number of actual deceased organ donors, and from the Centers for Disease Control and Prevention Wide-ranging Online Data for Epidemiologic Research Detailed Mortality File to quantify the number of potential donors (individuals who died under conditions consistent with organ donation). Data were analyzed from December 2, 2019, to May 14, 2020. EXPOSURES: Race and ethnicity of deceased and potential donors. MAIN OUTCOMES AND MEASURES: For each racial/ethnic group and year, a donation ratio was calculated as the number of actual deceased donors divided by the number of potential donors. Direct age and sex standardization was used to allow for group comparisons, and Poisson regression was used to quantify changes in donation ratio over time. RESULTS: A total of 141 534 deceased donors and 5 268 200 potential donors were included in the analysis. Among Black individuals, the donation ratio increased 2.58-fold from 1999 to 2017 (yearly change in adjusted incidence rate ratio [aIRR], 1.05; 95% CI, 1.05-1.05; P

Cytotoxic T lymphocyte (CTL)–based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma. Although the melanocyte differentiation antigens (MDA) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets. Using a tandem mass spectrometry (MS) approach to analyze the immunopeptidomes of 55 melanoma patient–derived cell lines, we identified a number of shared HLA class I–bound peptides derived from the melanocyte-specific transporter protein SLC45A2. Antigen-specific CTLs generated against HLA-A*0201- and HLA-A*2402–restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25). CTLs specific for SLC45A2 showed significantly reduced recognition of HLA-matched primary melanocytes that were, conversely, robustly killed by MART1- and PMEL-specific T cells. Transcriptome analysis revealed that SLC45A2 mRNA expression in normal melanocytes was less than 2% that of other MDAs, therefore providing a more favorable melanoma-to-melanocyte expression ratio. Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs. Taken together, our study demonstrates the feasibility of using tandem MS as a means of discovering shared immunogenic tumor-associated epitopes and identifies SLC45A2 as a promising immunotherapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity. Cancer Immunol Res; 5(8); 618–29. ©2017 AACR.

Prioritization of highly sensitized (HS) candidates under the kidney allocation system (KAS) and growth of large, multicenter kidney-paired donation (KPD) clearinghouses have broadened the transplant modalities available to HS candidates. To quantify temporal trends in utilization of these modalities, we used SRTR data from 2009 to 2017 to study 39 907 adult HS (cPRA ≥ 80%) waitlisted candidates and 19 003 recipients. We used competing risks regression to quantify temporal trends in likelihood of DDKT, KPD, and non-KPD LDKT for HS candidates (Era 1: January 1, 2009-December 31, 2011; Era 2: January 1, 2012-December 3, 2014; Era 3: December 4, 2014-December 31, 2017). Although the likelihood of DDKT and KPD increased over time for all HS candidates (adjusted subhazard ratio [aSHR] Era 3 vs 1 for DDKT: (1.74)1.85(1.97), P < .001 and for KPD: (1.70)2.20(2.84), P < .001), the likelihood of non-KPD LDKT decreased (aSHR: (0.69)0.82(0.97), P = .02). However, these changes affected HS recipients differently based on cPRA. Among recipients, more cPRA 98%−99.9% and 99.9%+ recipients underwent DDKT (96.2% in Era 3% vs 59.1% in Era 1 for cPRA 99.9%+), whereas fewer underwent non-KPD LDKT (1.9% vs 30.9%) or KPD (2.0% vs 10.0%). Although KAS increased DDKT likelihood for the most HS candidates, it also decreased the use of non-KPD LDKT to transplant cPRA 98%+ candidates.

BACKGROUND Kidneys from infectious risk donors (IRD) confer substantial survival benefit in adults, yet the benefit of IRD kidneys to pediatric candidates remains unclear in the context of high waitlist prioritization. METHODS Using 2010-2016 Scientific Registry of Transplant Recipients data, we studied 2417 pediatric candidates (age

Livers from older donors (OLDs; age ≥70) are risky and often declined; however, it is likely that some candidates will benefit from OLDs versus waiting for younger ones. To characterize the survival benefit of accepting OLD grafts, we used 2009-2017 SRTR data to identify 24 431 adult liver transplant (LT) candidates who were offered OLD grafts eventually accepted by someone. Outcomes from the time-of-offer were compared between candidates who accepted an OLD graft and matched controls within MELD ± 2 who declined the same offer. Candidates who accepted OLD grafts (n = 1311) were older (60.5 vs. 57.8 years, P < .001), had a higher median MELD score (25 vs. 22, P < .001), and were less likely to have hepatitis C cirrhosis (14.9% vs. 31.2%, P < .001). Five-year cumulative mortality among those who accepted versus declined the same OLD offer was 23.4% versus 41.2% (P < .001). Candidates who accepted OLDs experienced an almost twofold reduction in mortality (aHR:0.45 0.520.59 , P < .001) compared to those who declined the same offer, especially among the highest MELD (35-40) candidates (aHR:0.10 0.240.55 , P = .001). Accepting an OLD offer provided substantial long-term survival benefit compared to waiting for a better organ offer, notably among candidates with MELD 35-40. Providers should consider these benefits as they evaluate OLD graft offers.

Background Previous studies have reported a wide range of prevalence of post-donation anxiety, depression, and regret in living kidney donors (LKDs). It is also unclear what risk factors are associated with these outcomes. Methods We screened 825 LKDs for anxiety and depression using 2-item GAD-2 and PHQ-2 scales and asked about regret. Results Overall, 5.5% screened positive for anxiety, 4.2% for depression, and 2.1% reported regretting their donation. While there was moderate correlation between positive anxiety and depression screens (r = 0.52), there was no correlation between regret and positive screens (r

Development of end-stage renal disease (ESRD) in living kidney donors is associated with increased graft loss in the recipients of their kidneys. Our goal was to investigate if this relationship was reflected at an earlier stage postdonation, possibly early enough for recipient risk prediction based on donor response to nephrectomy. Using national registry data, we studied 29 464 recipients and their donors from 2008-2016 to determine the association between donor 6-month postnephrectomy estimated GFR (eGFR) and recipient death-censored graft failure (DCGF). We explored donor BMI as an effect modifier, given the association between obesity and hyperfiltration. On average, risk of DCGF increased with each 10 mL/min decrement in postdonation eGFR (adjusted hazard ratio [aHR] 1.06, 95% confidence interval [CI] 1.02-1.10, P = .007). The association was attenuated with higher donor BMI (interaction P = .049): recipients from donors with BMI = 20 (aHR 1.12, 95% CI 1.04-1.19, P = .002) and BMI = 25 (aHR 1.07, 95% CI 1.03-1.12, P = .001) had a higher risk of DCGF with each 10 mL/min decrement in postdonation eGFR, whereas recipients from donors with BMI = 30 and BMI = 35 did not have a higher risk. The relationship between postdonation eGFR, donor BMI, and recipient graft loss can inform counseling and management of living donor kidney transplant recipients.

Deceased donor kidney transplantation (DDKT) rates for highly sensitized (HS) candidates increased early after implementation of the Kidney Allocation System (KAS) in 2014. However, this may represent a bolus effect, and a granular investigation of the current state of DDKT for HS candidates remains lacking. We studied 270,722 DDKT candidates from the SRTR from 12/4/2011-12/3/2014 (‘pre-KAS’) and 12/4/2014-12/3/2017 (‘post-KAS’), analyzing DDKT rates for HS candidates using adjusted negative binomial regression. Post-KAS, candidates with the highest levels of sensitization had an increased DDKT rate compared to pre-KAS (cPRA 98% adjusted incidence rate ratio [aIRR]:(1.27)1.77(2.46) p=0.001, cPRA 99% aIRR:(3.18)4.36(5.98) p

One criticism of kidney paired donation (KPD) is that easy-to-match candidates leave the registry quickly, thus concentrating the pool with hard-to-match sensitized and blood type O candidates. We studied candidate/donor pairs who registered with the National Kidney Registry (NKR), the largest US KPD clearinghouse, from January 2012-June 2016. There were no changes in age, gender, BMI, race, ABO blood type, or panel-reactive antibody (PRA) of newly registering candidates over time, with consistent registration of hard-to-match candidates (59% type O and 38% PRA ≥97%). However, there was no accumulation of type O candidates over time, presumably due to increasing numbers of nondirected type O donors. Although there was an initial accumulation of candidates with PRA ≥97% (from 33% of the pool in 2012% to 43% in 2014, P = .03), the proportion decreased to 17% by June 2016 (P

Kidney paired donation (KPD) can facilitate living donor transplantation for candidates with an incompatible donor, but requires waiting for a match while experiencing the morbidity of dialysis. The balance between waiting for KPD vs desensitization or deceased donor transplantation relies on the ability to estimate KPD wait times. We studied donor/candidate pairs in the National Kidney Registry (NKR), a large multicenter KPD clearinghouse, between October 2011 and September 2015 using a competing-risk framework. Among 1894 candidates, 52% were male, median age was 50 years, 66% were white, 59% had blood type O, 42% had panel reactive antibody (PRA)>80, and 50% obtained KPD through NKR. Median times to KPD ranged from 2 months for candidates with ABO-A and PRA 0, to over a year for candidates with ABO-O or PRA 98+. Candidates with PRA 80-97 and 98+ were 23% (95% confidence interval , 6%-37%) and 83% (78%-87%) less likely to be matched than PRA 0 candidates. ABO-O candidates were 67% (61%-73%) less likely to be matched than ABO-A candidates. Candidates with ABO-B or ABO-O donors were 31% (10%-56%) and 118% (82%-162%) more likely to match than those with ABO-A donors. Providers should counsel candidates about realistic, individualized expectations for KPD, especially in the context of their alternative treatment options.

Molecular docking is a standard computational approach to predict binding modes of protein–ligand complexes by exploring alternative orientations and conformations of the ligand (i.e., by exploring ligand flexibility). Docking tools are largely used for virtual screening of small drug-like molecules, but their accuracy and efficiency greatly decays for ligands with more than 10 flexible bonds. This prevents a broader use of these tools to dock larger ligands, such as peptides, which are molecules of growing interest in cancer research. To overcome this limitation, our group has previously proposed a meta-docking strategy, called DINC, to predict binding modes of large ligands. By incrementally docking overlapping fragments of a ligand, DINC allowed predicting binding modes of peptide-based inhibitors of transcription factors involved in cancer. Here, we describe DINC 2.0, a revamped version of the DINC webserver with enhanced capabilities and a more user-friendly interface. DINC 2.0 allows docking ligands that were previously too challenging for DINC, such as peptides with more than 25 flexible bonds. The webserver is freely accessible at http://dinc.kavrakilab.org, together with additional documentation and video tutorials. Our team will provide continuous support for this tool and is working on extending its applicability to other challenging fields, such as personalized immunotherapy against cancer. Cancer Res; 77(21); e55–57. ©2017 AACR.