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BACKGROUND: Standard-of-care biomarkers for renal allograft rejection are lagging indicators, signaling existing organ injury. This precludes early intervention, when immunological cascades leading to rejection are most susceptible. Donor-derived cell-free DNA (dd-cfDNA) shows promise as an early indicator of rejection, allowing earlier and possibly more effective treatment. This analysis was designed to assess this promise using real-world dd-cfDNA testing evidence. METHODS: This retrospective analysis of the prospective, observational ProActive registry study (NCT04091984) assessed dd-cfDNA and serum creatinine levels before biopsy in 424 patients with ≥1 dd-cfDNA test (n = 1013) in the 6 mo before biopsy. RESULTS: Of 4667 enrolled patients, 1631 patients had ≥18 mo of follow-up data, of which 424 had a biopsy and were included in this analysis. Twenty-six biopsies showed antibody-mediated rejection (ABMR), 62 showed T cell-mediated rejection, and 336 showed nonrejection; each from a unique patient. dd-cfDNA fractions were significantly elevated 5 mo before ABMR biopsies, and 2 mo before T cell-mediated rejection biopsies, compared with nonrejection biopsies. In contrast, serum creatinine did not discriminate between rejection and nonrejection in advance, or concurrent with biopsy. Among patients with nonrejection biopsies, estimated glomerular filtration rate was significantly lower in cases with ≥2 increased dd-cfDNA results (≥1%), compared with those with 0 or 1 increased dd-cfDNA result. CONCLUSIONS: These data indicate that dd-cfDNA is an early indicator of biopsy-proven rejection, especially ABMR, suggesting a greater role for dd-cfDNA in surveillance to identify patients at high risk of ongoing or future rejection, thus requiring closer monitoring, biopsy, or other management changes.

Despite the continued improvements in pancreas transplant outcomes in recent decades, a subset of recipients experience graft failure and can experience substantial morbidity and mortality. Here, we summarize what is known about the failed pancreas allograft and what factors are important for consideration of retransplantation. The current definition of pancreas allograft failure and its challenges for the transplant community are explored. The impacts of a failed pancreas allograft are presented, including patient survival and resultant morbidities. The signs, symptoms, and medical and surgical management of a failed pancreas allograft are described, whereas the options and consequences of immunosuppression withdrawal are reviewed. Medical and surgical factors necessary for successful retransplant candidacy are detailed with emphasis on how well-selected patients may achieve excellent retransplant outcomes. To achieve substantial medical mitigation and even pancreas retransplantation, patients with a failed pancreas allograft warrant special attention to their residual renal, cardiovascular, and pulmonary function. Future studies of the failed pancreas allograft will require improved reporting of graft failure from transplant centers and continued investigation from experienced centers.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

There are currently fewer than 10 antifungal drugs in clinical development, but new fungal strains that are resistant to most current antifungals are spreading rapidly across the world. To prevent a second resistance crisis, new classes of antifungal drugs are urgently needed. Metal complexes have proven to be promising candidates for novel antibiotics, but so far, few compounds have been explored for their potential application as antifungal agents. In this work, we report the evaluation of 1039 metal-containing compounds that were screened by the Community for Open Antimicrobial Drug Discovery (CO-ADD). We show that 20.9% of all metal compounds tested have antimicrobial activity against two representative Candida and Cryptococcus strains compared with only 1.1% of the >300,000 purely organic molecules tested through CO-ADD. We identified 90 metal compounds (8.7%) that show antifungal activity while not displaying any cytotoxicity against mammalian cell lines or hemolytic properties at similar concentrations. The structures of 21 metal complexes that display high antifungal activity (MIC ≤1.25 μM) are discussed and evaluated further against a broad panel of yeasts. Most of these have not been previously tested for antifungal activity. Eleven of these metal complexes were tested for toxicity in the Galleria mellonella moth larva model, revealing that only one compound showed signs of toxicity at the highest injected concentration. Lastly, we demonstrated that the organo-Pt(II) cyclooctadiene complex Pt1 significantly reduces fungal load in an in vivo G. mellonella infection model. These findings showcase that the structural and chemical diversity of metal-based compounds can be an invaluable tool in the development of new drugs against infectious diseases.

This retrospective review of the largest United States kidney exchange reports characteristics, utilization, and recipient outcomes of kidneys with simple compared to complex anatomy and extrapolates reluctance to accept these kidneys. Of 3105 transplants performed, only 12.8% were right kidneys and 23.1% had multiple renal arteries. 59.3% of centers used fewer right kidneys than expected and 12.1% transplanted zero right kidneys or kidneys with more than 1 artery. Five centers transplanted a third of these kidneys (35.8% of right kidneys and 36.7% of kidneys with multiple renal arteries). 22.5% and 25.5% of centers currently will not entertain a match offer for a left or right kidney with more than one artery, respectively. There were no significant differences in all-cause graft failure or death-censored graft loss for kidneys with multiple arteries, and a very small increased risk of graft failure for right kidneys versus left of limited clinical relevance for most recipients. Kidneys with complex anatomy can be used with excellent outcomes at many centers. Variation in use (lack of demand) for these kidneys reduces the number of transplants, so systems to facilitate use could increase demand. We cannot know how many donors are turned away because perceived demand is limited.

Increasing numbers of compatible pairs are choosing to enter paired exchange programs, but motivations, outcomes, and system-level effects of participation are not well described. Using a linkage of the Scientific Registry of Transplant Recipients and National Kidney Registry, we compared outcomes of traditional (originally incompatible) recipients to originally compatible recipients using the Kaplan-Meier method. We identified 154 compatible pairs. Most pairs sought to improve HLA matching. Compared to the original donor, actual donors were younger (39 vs. 50 years, p

BackgroundDespite the institution of a new Kidney Allocation System in 2014, A2/A2B to B transplantation has not increased as expected. The current Organ Procurement and Transplantation Network policy requires subtyping on two separate occasions, and in the setting of discrepant results, defaulting to the A1 subtype. However, there is significant inherent variability in the serologic assays used for blood group subtyping and genotyping is rarely done.MethodsThe National Kidney Registry, a kidney paired donation (KPD) program, performs serological typing on all A/AB donors, and in cases of non-A1/non-A1B donors, confirmatory genotyping is performed.ResultsBetween 2/18/2018 and 9/15/2020, 13.0% (145) of 1,111 type A donors registered with the NKR were ultimately subtyped as A2 via genotyping. Notably, 49.6% (72) of these were subtyped as A1 at their donor center, and in accordance with OPTN policy, ineligible for allocation as A2.ConclusionInaccurate A2 subtyping represents a significant lost opportunity in transplantation, especially in KPD where A2 donors can not only facilitate living donor transplantation for O and highly sensitized candidates, but can also facilitate additional living donor transplants. This study highlights the need for improved accuracy of subtyping technique, and the need for policy changes encouraging optimal utilization of A2 donor kidneys.

ImportancePolicy makers, transplant professionals, and patient organizations agree that there is a need to increase the number of kidney transplants by facilitating living donation. Vouchers for future transplant provide a means of overcoming the chronological incompatibility that occurs when the ideal time for living donation differs from the time at which the intended recipient actually needs a transplant. However, uncertainty remains regarding the actual change in the number of living kidney donors associated with voucher programs and the capability of voucher redemptions to produce timely transplants.ObjectiveTo examine the consequences of voucher-based kidney donation and the capability of voucher redemptions to provide timely kidney allografts.Design, setting, and participantsThis multicenter cohort study of 79 transplant centers across the US used data from the National Kidney Registry from January 1, 2014, to January 31, 2021, to identify all family vouchers and patterns in downstream kidney-paired donations. The analysis included living kidney donors and recipients participating in the National Kidney Registry family voucher program.ExposuresA voucher was provided to the intended recipient at the time of donation. Vouchers had no cash value and could not be sold, bartered, or transferred to another person. When a voucher was redeemed, a living donation chain was used to return a kidney to the voucher holder.Main outcomes and measuresDeidentified demographic and clinical data from each kidney donation were evaluated, including the downstream patterns in kidney-paired donation. Voucher redemptions were separately evaluated and analyzed.ResultsBetween 2014 and 2021, 250 family voucher-based donations were facilitated. Each donation precipitated a transplant chain with a mean (SD) length of 2.3 (1.6) downstream kidney transplants, facilitating 573 total transplants. Of those, 111 transplants (19.4%) were performed in highly sensitized recipients. Among 250 voucher donors, the median age was 46 years (range, 19-78 years), and 157 donors (62.8%) were female, 241 (96.4%) were White, and 104 (41.6%) had blood type O. Over a 7-year period, the waiting time for those in the National Kidney Registry exchange pool decreased by more than 3 months. Six vouchers were redeemed, and 3 of those redemptions were among individuals with blood type O. The time from voucher redemption to kidney transplant ranged from 36 to 155 days.Conclusions and relevanceIn this study, the family voucher program appeared to mitigate a major disincentive to living kidney donation, namely the reluctance to donate a kidney in the present that could be redeemed in the future if needed. The program facilitated kidney donations that may not otherwise have occurred. All 6 of the redeemed vouchers produced timely kidney transplants, indicating the capability of the voucher program.

The year 2020 brought unimaginable challenges in public health, with the confluence of the COVID-19 pandemic and wildfires across the western United States. Wildfires produce high levels of fine particulate matter (PM2.5). Recent studies reported that short-term exposure to PM2.5 is associated with increased risk of COVID-19 cases and deaths. We acquired and linked publicly available daily data on PM2.5, the number of COVID-19 cases and deaths, and other confounders for 92 western U.S. counties that were affected by the 2020 wildfires. We estimated the association between short-term exposure to PM2.5 during the wildfires and the epidemiological dynamics of COVID-19 cases and deaths. We adjusted for several time-varying confounding factors (e.g., weather, seasonality, long-term trends, mobility, and population size). We found strong evidence that wildfires amplified the effect of short-term exposure to PM2.5 on COVID-19 cases and deaths, although with substantial heterogeneity across counties.

Background: The association between socioeconomic status (SES) and outcomes after abdominal aortic aneurysm (AAA) repair in publicly funded health care systems is poorly described. The purpose of this study was to determine the effect of SES on postoperative outcomes in patients who underwent AAA repair in Nova Scotia, Canada. Methods: We performed a retrospective analysis of all elective AAA repairs in Nova Scotia between November 2005 and March 2015 using administrative data sources. We compared postoperative 30-day outcomes and long-term survival across socioeconomic quintiles, defined as the Pampalon Material Deprivation Index (MDI) and Social Deprivation Index (SDI). We also compared the relation between baseline characteristics, MDI quintile, SDI quintile and 30-day mortality. We used multivariable logistic regression and survival analysis to calculate adjusted 30-day mortality and long-term survival, respectively. Results: A total of 1913 patients underwent AAA repair during the study period. The overall 30-day mortality rate was 2.6% (50 patients). Thirty-day outcomes including death (p = 0.8), stroke (p = 0.7), myocardial infarction (p = 0.06), length of stay (p = 0.3) and discharge disposition other than home (p = 0.8) were similar across MDI quintiles. Similarly, there was no statistically significant association between SDI quintile and postoperative outcomes. Multivariable analysis showed that age greater than 70 years (odds ratio [OR] 3.06, 95% confidence interval [CI] 1.55-6.06) and open repair (OR 3.22, 95% CI 1.59-6.52) but not MDI quintile (p = NS) or SDI quintile (p = NS) were associated with increased 30-day mortality. There was no effect of MDI or SDI quintile on long-term survival on univariable or multivariable analysis. Conclusion: Socioeconomic status does not appear to affect short- or long-term mortality after AAA repair in a publicly funded health care system. Further research is needed to address any existing gaps in screening and referral before repair. Contexte : Le lien entre le statut socioeconomique (SSE) et les issues suivant la reparation d'un anevrisme aortique abdominal (AAA) realisee dans un systeme de sante public est mal defini. Cette etude avait pour but de determiner l'effet du SSE sur les issues postoperatoires chez les patients ayant subi la reparation d'un AAA en Nouvelle-Ecosse, au Canada. Methodes : Nous avons mene une analyse retrospective de toutes les reparations electives d'un AAA realisees entre novembre 2005 et mars 2015 en Nouvelle-Ecosse a partir de bases de donnees administratives. Nous avons compare les issues postoperatoires sur 30 jours et la survie a long terme pour tous les quintiles socioeconomiques, etablis selon l'indice de defavorisation materielle et sociale de Pampalon (IDMS) et l'indice de defavorisation sociale (IDS). Nous avons aussi compare les relations entre les caracteristiques de base, les quintiles d'IDMS et d'IDS et la mortalite dans les 30 jours. Nous nous sommes servis d'une regression logistique multivariee et d'analyses de survie pour calculer respectivement la mortalite ajustee dans les 30 jours et la survie a long terme. Resultats : Au total, 1913 patients ont subi une reparation d'un AAA pendant la pe riode de l'etude. Le taux de mortalite global dans les 30 jours etait de 2,6 % (50 patients). Les issues sur 30 jours, soit les deces (p = 0,8), les AVC (p = 0,7), les infarctus du myocarde (p = 0,06), la duree de sejour (p = 0,3) et un etat a la sortie autre que le domicile (p = 0,8), etaient similaires pour tous les quintiles d'IDMS. De mame, il n'y avait pas d'association statistiquement significative entre le quintile d'IDS et les issues postoperatoires. L'analyse multivariee a montre qu'un age supe rieur a 70 ans (rapport de cotes [RC] 3,06, intervalle de confance [IC] a 95 % 1,55-6,06) et les reparations ouvertes (RC 3,22, IC a 95 % 1,59-6,52) etaient associes a une mortalite accrue dans les 30 jours, mais ni le quintile d'IDMS (p = NS) ni le quintile d'IDS (p = NS) ne l'etaient. Ces 2 variables n'avaient aucun effet sur l'analyse univa riee ou multivariee de la survie a long terme. Conclusion : Le SSE ne semble pas influencer la mortalite a court ni a long terme suivant la reparation d'un AAA realisee dans un systeme de sante public. D'autres etudes seront cependant necessaires pour examiner la presence de lacunes dans le depistage et l'orientation du patient avant la reparation., The incidence of abdominal aortic aneurysms (AAAs) in people older than 65 years in Canada ranges from 1% to 5%. (1,2) Surgical management is the most common form of management, [...]

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.

The National Kidney Registry (NKR) Advanced Donation Program enables living donors the opportunity to donate altruistically, or in advance of a potential recipient's transplant, and to receive a voucher that can be redeemed for a future transplant facilitated by the NKR. Family vouchers allow a donor to identify multiple individuals within their immediate family, with the first person in that group in need of a transplant being prioritized to receive a kidney. An increase in vouchers introduces concerns that demand for future voucher redemptions could exceed the supply of available donors and kidneys. A Monte Carlo simulation model was constructed to estimate the annual number of voucher redemptions relative to the number of kidneys available over a 50-year time horizon under several projected scenarios for growth of the program. In all simulated scenarios, the number of available kidneys exceeded voucher redemptions every year. While not able to account for all real-life scenarios, this simulation study found that the NKR should be able to satisfy the likely redemption of increasing numbers of vouchers under a range of possible scenarios over a 50-year time horizon. This modeling exercise suggests that a donor family's future needs can be satisfied through the voucher program.

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.