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BACKGROUND There is great interest in reducing exposure of renal transplant recipients to the nephrotoxic effects of calcineurin inhibitors. OBJECTIVE To establish whether minimization or withdrawal of ciclosporin improves outcome after renal transplantation in patients receiving daclizumab, mycophenolate mofetil and corticosteroids. DESIGN Recipients of a first renal transplant were prospectively recruited from sites in Australia, Europe and North America for the randomized, open-label Cyclosporine Avoidance Eliminates Serious Adverse Renal Toxicity (CAESAR) trial. Exclusion criteria included receipt of an HLA-identical living related graft, a panel-reactive antibody value >20% in the previous 6 months, and an expected need for antilymphocyte treatment for delayed graft function. INTERVENTION In addition to mycophenolate and corticosteroids, participants were randomly allocated (1:1:1) to receive standard-dose ciclosporin; daclizumab induction plus low-dose ciclosporin; or daclizumab induction plus a maximum of 6 months' treatment with low-dose ciclosporin. In the third group, ciclosporin withdrawal began at month 4. Target ciclosporin trough levels were 50-100 ng/ml for low-dose treatment and 150-300ng/ml for the first 4 months of standard-dose treatment (100-200 ng/ml subsequently). Follow-up continued for 12 months OUTCOME MEASURES Glomerular filtration rate (GFR) 12 months after transplantation, as determined by clearance of an exogenous substrate, was the primary end point. Secondary end points included biopsy-proven acute rejection, graft failure and patient mortality. RESULTS Between 12 January 2001 and 24 October 2002, the investigators recruited 536 patients. In the intention to treat analysis, mean GFR at 12 months after transplantation was 50.9 ml/min/1.73 m² in both the ciclosporin withdrawal group (n = 128) and low-dose ciclosporin group (n = 138); mean GFR was 48.6ml/min/1.73m² in the standard- dose ciclosporin group (n = 119). There was no significant difference between these values. In addition, GFR at 3 months after transplantation, and creatinine clearance at 12 months after transplantation (calculated using the Cockcroft-Gault equation), did not differ significantly between the groups. Compared with the low-dose and standard-dose ciclosporin groups, a higher proportion of patients in the ciclosporin withdrawal group experienced a first episode of biopsy-proven acute rejection during the 12 months of follow-up (38% vs 25.4% and 27.5%; P=0.027 and P=0.040, respectively). There were 12 graft losses in the ciclosporin withdrawal group, 6 in the low-dose ciclosporin group and 9 in the standard-dose ciclosporin group (P= NS); 8, 4 and 5 patients died, respectively. The incidences of serious and ciclosporin-related adverse events did not differ significantly between the three groups. CONCLUSION In renal transplant patients receiving daclizumab, mycophenolate and corticosteroids, low-dose ciclosporin (target trough levels 50-100 ng/ml) produces 1-year outcomes similar to those obtained with standard-dose ciclosporin. [ABSTRACT FROM AUTHOR]

Deals with a study which aimed to determine the effects of anti-HBc AB(+) donor status on viral transmission and graft and patient survival. Methodology used in the study; Results and conclusion.

Introduction: Living liver donation improves survival of end-stage liver disease (ESLD) patients. Yet, it continues to represent a small proportion of United States (U.S.) liver transplantation with existing racial disparities. We investigated the interplay of donor-recipient relationship and donor race to understand donor subgroups with no significant increase., Methods: We studied 4407 living liver donors in the U.S. from January 1, 2012, to December 31, 2022 (median age = 36 years, and 59% were biologically related to the recipient). We quantified the change in the number of donors per 3-year increment using negative binomial regression (incidence rate ratio [IRR]), stratified by donor-recipient relationship and race/ethnicity., Results: Among biologically related donors, the observed annual number of White donors increased from 146 to 253, Hispanic donors from 18 to 53, and Black donors decreased from 11 to 10. Among unrelated donors, White donors increased from 65 to 221, Hispanic donors from 4 to 25, and Black donors from 3 to 11. For the IRR of biologically related donors aged <40 and ≥40 years, White donors increased by 18% and 22%; Hispanic donors increased by 25% and 54%; and Black donors did not change. Likewise, the IRR of unrelated donors aged <40 and ≥40 years, White donors increased by 48% and 55%; Hispanic donors increased by 52% and 65%; and Black donors did not change., Conclusions: While biologically related donors represent the majority of donors, unrelated donors have substantially risen in recent years, primarily driven by White donors. Although the rate of unrelated donations increased among Hispanic donors, the absolute number remains very small (≤25 donors/year). Interventions are needed to increase education among Hispanic and Black communities to grow unrelated living liver donations across race/ethnicity., (© 2024 The Author(s). Clinical Transplantation published by Wiley Periodicals LLC.)

Background: Delayed graft function (DGF) is a common early complication after kidney transplantation (KT) and is associated with various long-term adverse outcomes. Despite numerous studies on hemodynamic management, the optimal hemodynamic goals during KT remain unclear. In this retrospective study, we aimed to investigate if three mean artery pressure (MAP) thresholds (≤75, 80, and 85 mmHg) that were commonly used in clinical practice were associated with DGF in adult patients undergoing KT., Methods: We extracted de-identified data on adult patients who underwent deceased donor KT from our Discovery Data Repository. DGF was defined as the requirement for dialysis within the first 7 days after transplantation. Three MAP thresholds (≤75, 80, and 85 mmHg) and the duration of pressure below the three thresholds were recorded. Multivariable logistic analysis was used to identify risk factors for DGF., Results: We included 2301 adult KT patients. The mean age was 52.5±12.9 years and 59% were male. DGF occurred in 1066 patients (46.3%). Patients frequently experienced MAP ≤75, 80, and 85 mmHg (approximately 70%, 80%, and 90% of patients experienced 10 min of MAP ≤75, 80, and 85 mmHg, respectively). Patients with DGF spent significantly longer durations below the three MAP thresholds during surgery compared with those without DGF. Further analysis revealed that the minimal time spent on MAP ≤75, 80, and 85 mmHg that were significantly associated with DGF were 6, 23, and 37 min, respectively. After adjusting for non-hemodynamic risk factors (age, basiliximab administration, and urine output), prolonged exposure to the three MAP thresholds remained significant predictors for DGF (for MAP ≤75 mmHg, OR 1.257, 95% CI 1.017-1.554, p = 0.034; MAP ≤80 mmHg, OR 1.220, 95% CI 1.018-1.463, p = 0.031; MAP ≤85 mmHg, OR 1.253, 95% CI 1.048-1.498, p = 0.013)., Conclusion: Prolonged exposure to the three common MAP thresholds (≤75, 80, and 85 mmHg) occurred frequently during adult deceased donor KT and was associated with DGF., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Rationale & Objective: The option for A2/A2B deceased donor kidney transplantation was integrated into the kidney allocation system in 2014 to improve access for B blood group waitlist candidates. Despite excellent reported outcomes, center uptake has remained low across the United States. Here, we examined the effect of implementing an A2/A2B protocol using a cutoff titer of ≤1:8 for IgG and ≤1:16 for IgM on blood group B kidney transplant recipients at a single center., Study Design: Retrospective observational study., Setting & Participants: Blood group B recipients of deceased donor kidney transplants at a single center from January 1, 2019, to December 2022., Exposure: Recipients of deceased donor kidney transplants were analyzed based on donor blood type with comparisons of A2/A2B versus blood group compatible., Outcomes: One-year patient survival, death-censored allograft function, primary nonfunction, delayed graft function, allograft function as measured using serum creatinine levels and estimated glomerular filtration rate at 1 year, biopsy-proven rejection, and need for plasmapheresis., Analytical Approach: Comparison between the A2/A2B and compatible groups were performed using the Fisher test or the χ 2 test for categorical variables and the nonparametric Wilcoxon rank-sum test for continuous variables., Results: A total of 104 blood type B patients received a deceased donor kidney transplant at our center during the study period, 49 (47.1%) of whom received an A2/A2B transplant. Waiting time was lower in A2/A2B recipients compared with blood group compatible recipients (57.9 months vs 74.7 months, P  = 0.01). A2/A2B recipients were more likely to receive a donor after cardiac death (24.5% vs 1.8%, P  < 0.05) and experience delayed graft function (65.3% vs 41.8%). There were no observed differences in the average serum creatinine level or estimated glomerular filtration rate at 1 month, 3 months, and 1 year post kidney transplantation, acute rejection, or primary nonfunction., Limitations: Single-center study. Small cohort size limiting outcome analysis., Conclusions: Implementation of an A2/A2B protocol increased transplant volumes of blood group B waitlisted patients by 83.6% and decreased the waiting time for transplantation by 22.5% with similar transplant outcomes., (© 2024 The Authors.)

Purpose of Review: Kidney dysfunction is challenging in liver transplant candidates to determine whether it is reversible or not. This review focuses on the pertinent data on how to best approach liver transplant candidates with kidney dysfunction in the current era after implementing the simultaneous liver kidney (SLK) allocation policy and safety net., Recent Findings: The implementation of the SLK policy inverted the steady rise in SLK transplants and improved the utilization of high-quality kidneys. Access to kidney transplantation following liver transplant alone (LTA) increased with favorable outcomes. Estimating GFR in liver transplant candidates remains challenging, and innovative methods are needed. SLK provided superior patient and graft survival compared to LTA only for patients with advanced CKD and dialysis at least 3 months. SLK can provide immunological protection against kidney rejection in highly sensitized candidates. Post-SLK transplant care is complex, with an increased risk of complications and hospitalization., Summary: The SLK policy improved kidney access and utilization. Transplant centers are encouraged, under the safety net, to reserve SLK for liver transplant candidates with advanced CKD or dialysis at least 3 months while allowing lower thresholds for highly sensitized patients. Herein, we propose a practical approach to liver transplant candidates with kidney dysfunction., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

BACKGROUND LCPT (Envarsus XR®) is a common once-daily, extended-release oral tacrolimus formulation used in kidney transplantation. However, there are minimal evidence-based recommendations regarding optimal dosing and treatment in the de novo and conversion settings. MATERIAL AND METHODS Using Delphi methodology, 12 kidney transplantation experts with LCPT experience reviewed available data to determine potential consensus topics. Key statements regarding LCPT use were generated and disseminated to the panel in an online Delphi survey. Statements were either accepted, revised, or rejected based on the level of consensus, perceived strength of evidence, and alignment with clinical practice. Consensus was defined a priori as ≥75% agreement. RESULTS Twenty-three statements were generated: 14 focused on de novo LCPT use and 9 on general administration or LCPT conversion use. After 2 rounds, consensus was achieved for 11/14 of the former and 7/9 of the latter statements. In a de novo setting, LCPT was recognized as a first-line option based on its safety and efficacy compared to immediate-release tacrolimus. In particular, African Americans and rapid metabolizer populations were identified as preferred for first-line LCPT therapy. In a conversion setting, full consensus was achieved for converting to LCPT to address neurological adverse effects related to immediate-release tacrolimus and for the time required (approximately 7 days) for steady-state LCPT trough levels to be reached. CONCLUSIONS When randomized clinical trials do not replicate current utilization patterns, the Delphi process can successfully generate consensus statements by expert clinicians to inform clinical decision-making for the use of LCPT in kidney transplant recipients.

Introduction: An increasing number of older patients are undergoing evaluation for kidney transplantation; however, older patients experience increased rates of complications compared with younger patients, leading to the study of frailty assessments. Although many centers have evaluated the Fried Frailty Phenotype (FFP), less is known about the ability of the Short Performance Physical Battery (SPPB) to predict outcomes., Methods: Frailty assessment by FFP and SPPB was introduced into routine outpatient evaluation for patients aged 55 years and older referred for transplantation. Transplant rate, length of stay, readmission up to 3 months posttransplant, and death were reviewed. Patients were evaluated in an initial cohort followed by a validation cohort by FFP and SPPB. Multivariate analysis correcting for demographic characteristics was applied., Results: Patient cohorts reflected the racial and ethnic diversity of our population, including approximately 40% Hispanic patients. The first cohort of 514 patients demonstrated a significant association between frailty as measured by SPPB and transplantation (odds ratio [OR], 2.27; 95% CI, 1.38-3.83; p = .002). The second cohort of 1408 patients validated the association between frailty measured by SPPB and transplantation (OR, 2.81; 95% CI, 1.83-4.48; p < .001). In addition, there was a significant association between nonfrail status measured by SPPB and death (OR, 0.16; 95% CI, 0.04-0.62; p = .006)., Conclusions: Frailty assessment is a potentially useful approach for the assessment of transplant candidates. Our real-world study examined the performance of 2 methods of frailty evaluation methods in a diverse population, demonstrating that SPPB but not FFP was predictive of clinical outcomes. Incorporation of frailty assessments into transplant evaluation may improve risk stratification and optimize outcomes for older patients., Competing Interests: Declaration of Competing Interest All the authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A large number of procured kidneys continue not to be transplanted, while the waiting list remains high., Methods: We analyzed donor characteristics for unutilized kidneys in our large organ procurement organization (OPO) service area in a single year to determine the reasonableness of their nonuse and to identify how we might increase the transplant rate of these kidneys. Five experienced local transplant physicians independently reviewed unutilized kidneys to identify which kidneys they would consider transplanting in the future. Biopsy results, donor age, kidney donor profile index, positive serologies, diabetes, and hypertension were risk factors for nonuse., Results: Two-thirds of nonused kidneys had biopsies with high degree of glomerulosclerosis and interstitial fibrosis. Reviewers identified 33 kidneys as potentially transplantable (12%)., Conclusions: Reducing the rate of unutilized kidneys in this OPO service area will be achieved by setting acceptable expanded donor characteristics, identifying suitable well-informed recipients, defining acceptable outcomes, and systematically evaluating the results of these transplants. Because the improvement opportunity will vary by region, to achieve a significant impact on improving the national nonuse rate, it would be useful for all OPOs, in collaboration with their transplant centers, to conduct a similar analysis., Competing Interests: T.S. and A.C. are employees of OneLegacy. The other authors declare no conflicts of interest. The authors declare no funding., (Copyright © 2023 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Background: Cytomegalovirus (CMV) infection, either de novo or as reactivation after allotransplantation and chronic immunosuppression, is recognized to cause detrimental alloimmune effects, inclusive of higher susceptibility to graft rejection and substantive impact on chronic graft injury and reduced transplant survival. To obtain further insights into the evolution and pathogenesis of CMV infection in an immunocompromised host we evaluated changes in the circulating host proteome serially, before and after transplantation, and during and after CMV DNA replication (DNAemia), as measured by quantitative polymerase chain reaction (QPCR)., Methods: LC-MS-based proteomics was conducted on 168 serially banked plasma samples, from 62 propensity score-matched kidney transplant recipients. Patients were stratified by CMV replication status into 31 with CMV DNAemia and 31 without CMV DNAemia. Patients had blood samples drawn at protocol times of 3- and 12-months post-transplant. Additionally, blood samples were also drawn before and 1 week and 1 month after detection of CMV DNAemia. Plasma proteins were analyzed using an LCMS 8060 triple quadrupole mass spectrometer. Further, public transcriptomic data on time matched PBMCs samples from the same patients was utilized to evaluate integrative pathways. Data analysis was conducted using R and Limma., Results: Samples were segregated based on their proteomic profiles with respect to their CMV Dnaemia status. A subset of 17 plasma proteins was observed to predict the onset of CMV at 3 months post-transplant enriching platelet degranulation (FDR, 4.83E-06), acute inflammatory response (FDR, 0.0018), blood coagulation (FDR, 0.0018) pathways. An increase in many immune complex proteins were observed at CMV infection. Prior to DNAemia the plasma proteome showed changes in the anti-inflammatory adipokine vaspin (SERPINA12), copper binding protein ceruloplasmin (CP), complement activation (FDR = 0.03), and proteins enriched in the humoral (FDR = 0.01) and innate immune responses (FDR = 0.01)., Conclusion: Plasma proteomic and transcriptional perturbations impacting humoral and innate immune pathways are observed during CMV infection and provide biomarkers for CMV disease prediction and resolution. Further studies to understand the clinical impact of these pathways can help in the formulation of different types and duration of anti-viral therapies for the management of CMV infection in the immunocompromised host., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Sigdel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose of Review: There has been a decline in living kidney donation over the last two decades. Donors from low-income families or racial/ethnic minorities face greater disproportionate geographic, financial, and logistical barriers to completing lengthy and complex evaluations. This has contributed to the decreased proportion of these subgroups. The authors view telemedicine as a potential solution to this problem., Recent Findings: Since the initial decline of donors in 2005, biologically related donors have experienced a lack of growth across race/ethnicity. Conversely, unrelated donors have emerged as the majority of donors in recent years across race/ethnicity, except for unrelated black donors. Disparities in access to living kidney donation persist. Telemedicine using live-video visits can overcome barriers to access transplant centers and facilitate care coordination. In a U.S. survey, nephrologists, surgeons, coordinators, social workers, and psychologists/psychologists across transplant centers are favorably disposed to use telemedicine for donor evaluation/follow-up beyond the coronavirus disease 2019 pandemic. However, with the waning of relaxed telemedicine regulations under the Public Health Emergency, providers perceive payor policy and out-of-state licensing as major factors hindering telemedicine growth prospects., Summary: Permanent federal and state policies that support telemedicine services for living kidney donation can enhance access to transplant centers and help overcome barriers to donor evaluation., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Ischemia-reperfusion (IR) of a kidney transplant (KTx) upregulates TNF α production that amplifies allograft inflammation and may negatively affect transplant outcomes., Methods: We tested the effects of blocking TNF peri-KTx via a randomized, double-blind, placebo-controlled, 15-center, phase 2 clinical trial. A total of 225 primary transplant recipients of deceased-donor kidneys (KTx; 38.2% Black/African American, 44% White) were randomized to receive intravenous infliximab (IFX) 3 mg/kg or saline placebo (PLBO) initiated before kidney reperfusion. All patients received rabbit anti-thymocyte globulin induction and maintenance immunosuppression (IS) with tacrolimus, mycophenolate mofetil, and prednisone. The primary end point was the difference between groups in mean 24-month eGFR., Results: There was no difference in the primary end point of 24-month eGFR between IFX (52.45 ml/min per 1.73 m 2 ; 95% CI, 48.38 to 56.52) versus PLBO (57.35 ml/min per 1.73 m 2 ; 95% CI, 53.18 to 61.52; P =0.1). There were no significant differences between groups in rates of delayed graft function, biopsy-proven acute rejection (BPAR), development of de novo donor-specific antibodies, or graft loss/death. Immunosuppression did not differ, and day 7 post-KTx plasma analyses showed approximately ten-fold lower TNF ( P <0.001) in IFX versus PLBO. BK viremia requiring IS change occurred more frequently in IFX (28.9%) versus PLBO (13.4%; P =0.004), with a strong trend toward higher rates of BKV nephropathy in IFX (13.3%) versus PLBO (4.9%; P =0.06)., Conclusions: IFX induction therapy does not benefit recipients of kidney transplants from deceased donors on this IS regimen. Because the intervention unexpectedly increased rates of BK virus infections, our findings underscore the complexities of targeting peritransplant inflammation as a strategy to improve KTx outcomes.Clinical Trial registry name and registration number:clinicaltrials.gov (NCT02495077)., (Copyright © 2022 by the American Society of Nephrology.)

Personalization of maintenance immunosuppression in kidney transplant recipients has long remained a goal in the transplant community. The recent addition of donor-derived cell-free DNA assays to detect allograft rejection and monitor allograft health may permit for reductions in maintenance immunosuppression in recipients with stable levels. Herein, we described 5 patients with stable donor-derived cell-free DNA levels who underwent reduction in maintenance immunosuppression without precipitation of clinical rejection, proteinuria, or de novo donor specific antibody formation., Competing Interests: DISCLOSURE S.B. receives grant funding from Natera, CareDx. E.L. received grant funding from Natera., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Rationale & Objective: An average of 3,280 recovered deceased donor kidneys are discarded annually in the United States. Increased cold ischemia time is associated with an increased rate of organ decline and subsequent discard. Here we examined the effect of prolonged cold ischemia time on kidney transplant outcomes., Study Design: Retrospective observational study., Setting & Participants: Recipients of deceased donor kidney transplants in the United States from 2000 to 2018., Exposure: Recipients of deceased donor kidneys were divided based on documented cold ischemia time: ≤16, 16-24, 24-32, 32-40, and >40 hours., Outcomes: The incidence of delayed graft function, primary nonfunction, and 10-year death-censored graft survival., Analytical Approach: The Kaplan-Meier method was used to generate survival curves, and the log rank test was used to compare graft survival., Results: The rate of observed delayed graft function increased with cold ischemia time (20.9%, 28.1%, 32.4%, 37.5%, and 35.8%). Primary nonfunction also showed a similar increase with cold ischemia time (0.6%, 0.9%, 1.3%, 2.1%, and 2.3%), During a median follow-up time of 4.6 years, 37,301 recipients experienced death-censored graft failure. Analysis based on kidney donor profile index (KDPI) demonstrated significant differences in 10-year death-censored graft survival, with a death-censored graft survival in recipients of a kidney with a KDPI <85% of 71.0% (95% CI, 70.5%-71.5%), 70.5% (95% CI, 69.9%-71.0%), 69.6% (95% CI, 68.7%-70.4%), 65.5% (95% CI, 63.7%-67.3%), and 67.2% (95% CI, 64.6%-69.6%), compared to 53.5% (95% CI, 51.1%-55.8%), 50.7% (95% CI, 48.3%-53.1%), 50.3% (95% CI, 46.6%-53.8%), 50.7% (95% CI, 45.1%-56.1%), and 48.3% (95% CI, 40.0%-56.1%), for recipients of a kidney with a KDPI >85%., Limitations: Heterogeneity of acceptance patterns among transplant centers, presence of confounding variables leading to acceptance of kidneys with prolonged cold ischemia times., Conclusions: Cold ischemia time was associated with an increased risk of delayed graft function and primary nonfunction. However, the effect of increased cold ischemia time is modest and has less impact than the KDPI. Transplant programs should not consider prolonged cold ischemia time alone as a predominant reason to decline an organ, especially with a KDPI <85%., (© 2022 The Authors.)

Introduction: Belatacept has shown potential for prevention of rejection after kidney transplantation, given its demonstration of reduced nephrotoxicity in combination with absence of significant incidence of rejection. However, concerns have been raised regarding increased risk of viral infection., Methods: We set out to explore the impact of the switch to belatacept on alloimmune and antiviral immunity through the study of patients switched from calcineurin inhibitor (CNI) to belatacept within 3 months of kidney transplantation compared with a matched cohort of control patients on a CNI-based regimen., Results: After the switch to belatacept, immune phenotyping demonstrated a decrease in naive and an increase in terminally differentiated effector memory (TMRA) T cells, with no significant difference compared with control patients. Donor-specific immune response, measured by intracellular cytokine staining (ICS), did not change significantly either by single or double cytokine secretion, but it was associated with the appearance of donor-specific antibody (DSA) in the control but not the belatacept cohort ( P  = 0.039 for naive and P  = 0.002 for TMRA subtypes). Increased incidence of de novo DSA development was observed in the control group ( P  = 0.035). Virus-specific immune response, as measured by ICS in response to cytomegalovirus (CMV) or Epstein-Barr virus (EBV), was similar in both groups and stable over time., Conclusion: We found that belatacept use was associated with an absence of alloreactivity without impact on immune phenotype, while preserving the antiviral immune response, for patients switched from a CNI-based regimen. In parallel, the antiviral immune response against CMV and EBV was preserved after the belatacept switch (clinicaltrials.gov: NCT01953120)., (© 2022 Published by Elsevier Inc. on behalf of the International Society of Nephrology.)

Older kidney transplant recipients demonstrate increased rates of infection, and lower rates of rejection, compared with younger kidney transplant recipients. However, the mechanism behind this observation remains unknown. To develop a multifaceted view of age-associated immune dysfunction, we determined the function and phenotype of T cells predisposing to vulnerability to infection on a molecular level. Overlapping peptide pools representing the dominant CMV antigens were used to stimulate PBMC collected from 51 kidney transplant recipients, using cytokine secretion to determine specificity and intensity of response. Staphylococcal endotoxin B (SEB) was analyzed in parallel. To define immune cell subsets, we used single cell RNA sequencing (scRNAseq) to evaluate cellular surface markers and gene expression. We found increased frequency of SEB- and CMV-specific T cells was associated with freedom from infection, especially in older patients. Spatialized t-SNE analysis revealed decreased frequency of naïve T cells, increased frequency of TEMRA cells, and decreased frequency of IFNγ secreting T cells in patients with infection. Application of scRNAseq analysis revealed increased frequency of terminally differentiated T cells expressing NK-associated receptors and inhibitory markers. These findings offer unique insight into the mechanism behind vulnerability to infection in the kidney transplant recipient, revealing a specific T cell subtype of impaired antigen response and terminal effector phenotype as markers of T cell senescence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

In 2017, United Network for Organ Sharing (UNOS) established the safety net policy with set criteria for offering kidney transplantation (KT) for patients who developed end-stage renal disease between 60 and 365 days after liver transplant (LT). We provide an update on the impact of the policy. We analyzed UNOS data of liver recipients transplanted between 1987 and 2020 who developed acute kidney injury requiring dialysis within 60 days before or after LT and subsequently listed for KT. We identified 407 patients who were listed for kidney after LT before policy and 248 patients after policy. Median waiting time to KT was shorter after policy (324 days vs. 2827 days). There was a higher proportion of candidates who were listed for subsequent KT within 1-year after policy (94.8% vs. 63.6%). KT rate was also higher after policy (87.7 vs. 30.7 per 100 patient-years at risk). Most importantly, we started to observe a net negative kidney utilization in end-stage liver disease setting (i.e., summation of simultaneous liver kidney and kidney after liver transplant in the first-year after LT has decreased from 1086 to 876 transplants in 2019). Such findings are consistent with a more efficient system and more appropriate allocation of organs., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Cytomegalovirus (CMV) viremia continues to cause significant morbidity and mortality in kidney transplant patients with clinical complications including organ rejection and death. Whole blood gene expression dynamics in CMV viremic patients from onset of DNAemia through convalescence has not been well studied to date in humans. To evaluate how CMV infection impacts whole blood leukocyte gene expression over time, we evaluated a matched cohort of 62 kidney transplant recipients with and without CMV DNAemia using blood samples collected at multiple time points during the 12-month period after transplant. While transcriptomic differences were minimal at baseline between DNAemic and non-DNAemic patients, hundreds of genes were differentially expressed at the long-term timepoint, including genes enriching for pathways important for macrophages, interferon, and IL-8 signaling. Amongst patients with CMV DNAemia, the greatest amount of transcriptomic change occurred between baseline and 1-week post-DNAemia, with increase in pathways for interferon signaling and cytotoxic T cell function. Time-course gene set analysis of these differentially expressed genes revealed that most of the enriched pathways had a significant time-trend. While many pathways that were significantly down- or upregulated at 1 week returned to baseline-like levels, we noted that several pathways important in adaptive and innate cell function remained upregulated at the long-term timepoint after resolution of CMV DNAemia. Differential expression analysis and time-course gene set analysis revealed the dynamics of genes and pathways involved in the immune response to CMV DNAemia in kidney transplant patients. Understanding transcriptional changes caused by CMV DNAemia may identify the mechanism behind patient vulnerability to CMV reactivation and increased risk of rejection in transplant recipients and suggest protective strategies to counter the negative immunologic impact of CMV. These findings provide a framework to identify immune correlates for risk assessment and guiding need for extending antiviral prophylaxis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Ahn, Schaenman, Qian, Pickering, Groysberg, Rossetti, Llamas, Hoffmann, Gjertson, Deng, Bunnapradist, Reed and CMV Systems Immunobiology Group.)

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28-CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28-CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.

A small pediatric deceased donor (SPD) weight cutoff whether to transplant as en bloc (EB) or single pediatric (SP) kidney is uncertain. Using UNOS/OPTN data (2000-2019), 27 875 SPDs were divided by (i) EB (11.4%) or SP (88.6%) and (ii) donor weight [≤10 (5.4%), >10-15 (8.3%), >15-18 (3.7%), >18-20 (2.9%), and >20 kg (79.7%)]. SP >20 kg and adult deceased donors (grouped by Kidney Donor Profile Index, KDPI, <30, 30-85, and >85) were used as references. The primary outcome was 10-year graft failure. In SP <10 kg, the hazard ratio (HR) for overall graft failure was 1.64 (1.38-2.20) compared with EB <10 kg, and 1.45 (1.18-1.80) compared with SP >20 kg. In SP >10-15 kg, HR was 1.31 (1.12-1.54) compared with EB >10-15 kg, and 1.04 (0.91-1.18) compared with SP >20 kg. In SP >15 kg, the risk was the same as SP >20 kg. Ten-year overall graft survival of SP 12 kg was comparable to SP >20 kg (62% vs. 57%). Ten-year death censored graft failure of SP >10-15 kg (70%) and SP >15-18 kg (70%) was like the adult donors with KDPI 30-85 (67%). In conclusion, we recommend single kidney transplants from SPDs with weight >12 kg to adult recipients in centers with experience in SPD transplants to optimize organ utilization., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Rationale & Objective: Posttransplant diabetes mellitus (DM) after kidney transplantation increases morbidity and mortality, particularly in older and obese recipients. We aimed to examine the impact of immunosuppression selection on the risk of posttransplant DM among both older and obese kidney transplant recipients., Study Design: Retrospective database study., Setting & Participants: Kidney-only transplant recipients aged ≥18 years from 2005 to 2016 in the United States from US Renal Data System records, which integrate Organ Procurement and Transplantation Network/United Network for Organ Sharing records with Medicare billing claims., Exposures: Various immunosuppression regimens in the first 3 months after transplant., Outcomes: Development of DM >3 months-to-1 year posttransplant., Analytical Approach: We used multivariable Cox regression to compare the incidence of posttransplant DM by immunosuppression regimen with the reference regimen of thymoglobulin (TMG) or alemtuzumab (ALEM) with tacrolimus + mycophenolic acid + prednisone using inverse propensity weighting., Results: 12.7% of kidney transplant recipients developed posttransplant DM with higher incidences in older (≥55 years vs <55 years: 16.7% vs 10.1%) and obese (body mass index [BMI] ≥ 30 kg/m 2 vs BMI < 30 kg/m 2 : 17.1% vs 10.9%) patients. The incidence of posttransplant DM was lower with steroid avoidance [TMG/ALEM + no prednisone (8.4%) and IL2rAb + no prednisone (9.7%)] than TMG/ALEM with triple therapy (13.1%). After adjustment for donor and recipient characteristics, TMG/ALEM with steroid avoidance was beneficial for all groups [age < 55 years: adjusted HR (aHR), 0.63 (95% confidence interval [CI], 0.54-0.72); age ≥ 55 years: aHR, 0.69 (95% CI, 0.60-0.79); BMI < 30 kg/m 2 : aHR, 0.69 (95% CI, 0.60-0.78); BMI ≥ 30 kg/m 2 : aHR, 0.67 (95% CI, 0.57-0.79)]. However, IL2rAb with steroid avoidance was beneficial only for older patients (aHR, 0.76; 95% CI, 0.58-0.99) and for those with BMI < 30 kg/m 2 (aHR, 0.63; 95% CI, 0.46-0.87)., Limitations: Retrospective study and lacked data on immunosuppression levels., Conclusions: The beneficial impact of steroid avoidance using tacrolimus on posttransplant DM appears to differ by patient age and induction regimen., (© 2021 Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc.)

Introduction: One of the most commonly used immunosuppressants in organ transplant, tacrolimus exhibits wide interpatient and intrapatient variability and narrow therapeutic index that necessitates routine concentration monitoring and dosage adjustments. Availability of modified -release tacrolimus products offer once-daily dosing options. The objective of this review is to highlight and compare available pharmacokinetic (PK) data of extended-release tacrolimus tablets (LCP-TAC) to immediate-release tacrolimus (IR-TAC) in kidney transplant recipients., Areas Covered: A review of the literature was performed using PubMed and Embase search to identify relevant articles evaluating PK data for LCP-TAC compared to IR-TAC in kidney transplant patients including special populations., Expert Opinion: LCP-TAC's unique PK profile may be more favorable than IR-TAC. While the clinical impact of these PK differences have not been established, several outcomes are being evaluated in ongoing studies. Results of these studies will add information incrementally to care for kidney transplant patients. Larger prospective studies evaluating kidney and patient survival differences are needed but it is unlikely that they will be conducted. Given that the patent exclusivity of LCP-TAC for the next several years and imminent loss of exclusivity of PR-TAC, our opinion is the use of LCP-TAC will be increasing, especially in Europe.

White kidney transplant candidates have the highest pre-transplant mortality rate compared to other ethnicities. The reason for a higher mortality rate is not well-understood. Estimated post-transplant survival (EPTS) score has been used to predict patient survival after transplant and may be associated with pre-transplant survival. First-time kidney transplant candidates listed between 2015 and 2018 were identified from the Organ Procurement Transplantation Network database. Individuals listed for multiple organs, at multiple centers, and age <18 years were excluded. We examined the impact of ethnicity on waitlist mortality and delisting. A total of 114 806 candidates were included. The study population was categorized into four groups which were 43% white, 28% Black, 19.2% Hispanic, and 9.8% "other ethnicities." At 5.2 years, the cumulative incidences of death and delist were 32%, 31%, 29%, and 26%, respectively. Compared to whites, adjusted subdistribution hazard ratio (aSHR) for death and delist among Black, Hispanics, and "other ethnicities" were 0.92 (95% CI 0.89-0.95), 0.89 (95% CI 0.85-0.91), and 0.76 (95% CI 0.72-0.80) after adjustment by EPTS along with other factors, respectively. After adjusting for EPTS score along with additional confounding factors and functional status at initial listing, white ethnicity was independently associated with an increased risk for death and delist., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Despite advances in immune suppression, kidney allograft rejection and other injuries remain a significant clinical concern, particularly with regards to long-term allograft survival. Evaluation of immune activity can provide information about rejection status and help guide interventions to extend allograft life. Here, we describe the validation of a blood gene expression classifier developed to differentiate immune quiescence from both T cell-mediated rejection (TCMR) and antibody-mediated rejection (ABMR)., Methods: A five-gene classifier (DCAF12, MARCH8, FLT3, IL1R2, and PDCD1) was developed on 56 peripheral blood samples and validated on two sample sets independent of the training cohort. The primary validation set comprised 98 quiescence samples and 18 rejection samples: seven TCMR, ten ABMR, and one mixed rejection. The second validation set included eight quiescence and 11 rejection samples: seven TCMR, two ABMR, and two mixed rejection. AlloSure donor-derived cell-free DNA (dd-cfDNA) was also evaluated., Results: AlloMap Kidney classifier scores in the primary validation set differed significantly between quiescence (median, 9.49; IQR, 7.68-11.53) and rejection (median, 13.09; IQR, 11.25-15.28), with P <0.001. In the second validation set, the cohorts were statistically different ( P =0.03) and the medians were similar to the primary validation set. The AUC for discriminating rejection from quiescence was 0.786 for the primary validation and 0.800 for the second validation. AlloMap Kidney results were not significantly correlated with AlloSure, although both were elevated in rejection. The ability to discriminate rejection from quiescence was improved when AlloSure and AlloMap Kidney were used together (AUC, 0.894)., Conclusion: Validation of AlloMap Kidney demonstrated the ability to differentiate between rejection and immune quiescence using a range of scores. The diagnostic performance suggests that assessment of the mechanisms of immunologic activity is complementary to allograft injury information derived from AlloSure dd-cfDNA. Together, these biomarkers offer a more comprehensive assessment of allograft health and immune quiescence., Competing Interests: E. Akalin reports receiving research funding from Angion, Astellas, CareDx, and National Institutes of Health (NIH); and having consultancy agreements with, receiving honoraria from, and serving as a scientific advisor for or member of CareDx and Immucor. D.C. Brennan reports having consultancy agreements with CareDx, Medeor, Sanofi, and Veloxis; receiving research funding from CareDx and Natera; receiving honoraria from CareDx, Sanofi, and Veloxis; and serving as a scientific advisor for or member of the editorial boards of Transplantation and UpToDate. D.C. Brennan, J.S. Bromberg, R. Weir, S. Bunnapradist, R. Delos Santos, and A. Langone report being DART investigators. J.S. Bromberg reports receiving research funding from Angion, Astellas, CareDx, Natera, Novartis, and Quark; having consultancy agreements with Eurofins; and serving as a scientific advisor for, or member of, NIH and Transplantation. S. Bunnapradist reports receiving research funding from Alexion, Angion, Astellas, CareDx, and Merck; receiving honoraria from Bristol Myers Squibb (BMS), CareDx, Sanofi, and Veloxis; serving on speakers bureau for BMS, CareDx, Natera, Veloxis, and Vitaeris; and having consultancy agreements with CareDx. R. Delos Santos reports having other interests/relationships with the American Society of Transplantation (AST) Conflict of Interest Committee and AST Transplant Nephrology Fellowship Training Accreditation Program Review Committee; receiving research funding from CareDx, Merck, and Veloxis; having ownership interest in Pfizer; and receiving honoraria from UpToDate. S. Dholakia reports having ownership interest in CareDx. S. Dholakia, X. Jin, H. Xu, and R.N. Woodward report being employees of CareDx. A. Djamali reports having consultancy agreements with, receiving honoraria from, and serving as a scientific advisor for or member of CareDx and CSL; and receiving research funding from CareDx and Takeda. X. Jin reports having ownership interest in CareDx. M.R. Weir reports having consultancy agreements (all are modest, <$10,000) with, receiving honoraria from, and serving as a scientific advisor for or member of AstraZeneca, Boehringer-Ingelheim, Bayer, CareDx, Janssen, Merck, Novo Nordisk, and Vifor Pharma. R.N. Woodward reports having ownership interest in CareDx. H. Xu reports having ownership interest in CareDx and Proxim Diagnostics, and having consultancy agreements with Proxim Diagnostics., (Copyright © 2021 by the American Society of Nephrology.)

Purpose of Review: While kidney transplantation improves the long-term survival of the majority of patients with end-stage kidney disease (ESKD), age-related immune dysfunction and associated comorbidities make older transplant recipients more susceptible to complications related to immunosuppression. In this review, we discuss appropriate management of immunosuppressive agents in older adults to minimize adverse events, avoid acute rejection, and maximize patient and graft survival., Recent Findings: Physiological changes associated with senescence can impact drug metabolism and increase the risk of posttransplant infection and malignancy. Clinical trials assessing the safety and efficacy of immunosuppressive agents in older adults are lacking. Recent findings from U.S. transplant registry-based studies suggest that risk-adjusted death-censored graft failure is higher among older patients who received antimetabolite avoidance, mammalian target of rapamycin inhibitor (mTORi)-based, and cyclosporine-based regimens. Observational data suggest that risk-adjusted mortality may be increased in older patients who receive mTORi-based and cyclosporine-based regimens but lower in those managed with T-cell induction and maintenance steroid avoidance/withdrawal., Summary: Tailored immunosuppression management to improve patient and graft survival in older transplant recipients is an important goal of personalized medicine. Lower intensity immunosuppression, such as steroid-sparing regimens, appear beneficial whereas mTORi- and cyclosporine-based maintenance are associated with greater potential for adverse effects. Prospective clinical trials to assess the safety and efficacy of immunosuppression agents in older recipients are urgently needed., Competing Interests: Conflict of Interest The authors of this manuscript have no conflicts of interest to disclose.

Beyond its widely recognized morbidity and mortality, coronavirus disease 2019 poses an additional health risk to renal allograft recipients. Detection and measurement of donor-derived cell-free DNA (dd-cfDNA), expressed as a fraction of the total cell-free DNA (cfDNA), has emerged as a noninvasive biomarker for allograft rejection. Here, we present a case report of a patient who was infected with severe acute respiratory syndrome coronavirus 2, 11 mo post-kidney transplant. The patient was serially monitored using an analytically and clinically validated massively multiplex PCR-based dd-cfDNA assay to assess allograft injury and risk for rejection. Over the course of infection, low dd-cfDNA fractions were observed (below the 1% cutoff) and were accompanied by unusually highly elevated levels of total cfDNA, which gradually declined as the infection resolved. The case study highlights the variability in total cfDNA levels during and after viral infection, and the need to consider both total and dd-cfDNA levels when clinically interpreting the results for allograft rejection. Furthermore, the study highlights the importance of serial testing, wherein an interplay between total cfDNA and dd-cfDNA can inform the optimization of a patient's immunosuppressive treatment regimen in response to infection., Competing Interests: S.B. has received support from FDA, NIDDK, NIAID, NIH, Astellas, Mallinckrodt, BMS, CareDx, Natera, Merck, Sanofi, Veloxis, Vitaeris, and OneLegacy Foundation. N.D., J.S., and E.L. declare no conflicts of interest. N.I., M.S.B., M.M., H.T., P.G., E.A., and P.R.B. are employees and equity holders at Natera, Inc. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions., (Copyright © 2021 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

BACKGROUND The pharmacokinetics and metabolism of tacrolimus, an immunosuppressant commonly used to prevent transplant rejection, can differ in specific subpopulations. This analysis examined treatment outcomes and safety of immediate-release tacrolimus (IR-Tac) and LCP-tacrolimus (LCPT) in stable Hispanic kidney transplant recipients. MATERIAL AND METHODS This was a post hoc analysis of clinical trial data from Hispanic adult stable kidney transplant recipients randomized to remain on IR-Tac or convert from IR-Tac to a reduced dose of LCPT (NCT00817206). Composite treatment failure was evaluated at 12 months. Estimated glomerular filtration rate and tacrolimus trough concentrations were evaluated over 12 months. RESULTS Fifty-five stable (LCPT n=26, IR-Tac n=29) kidney transplant recipients who self-identified as Hispanic or Latino were included in this analysis. Composite treatment failure occurred in 1 patient (4%) who converted to LCPT and 1 (3%) who remained on IR-Tac. The estimated glomerular filtration rate was stable over time and similar in the 2 treatment groups (P=0.08). Tacrolimus trough levels for both groups were similar over time in the 2 treatment groups (P=0.98). Treatment-emergent adverse events were similar in patients who converted to LCPT and in those who remained on IR-Tac. CONCLUSIONS Efficacy and safety were similar in Hispanic kidney transplant recipients who converted from IR-Tac to LCPT and in those remaining on IR-Tac.

After kidney transplantation, infection and death are important clinical complications, especially for the growing numbers of older patients with limited resilience to withstand adverse events. Evaluation of changes in gene expression in immune cells can reveal the underlying mechanisms behind vulnerability to infection. A cohort of 60 kidney transplant recipients was evaluated. Gene expression in peripheral blood mononuclear cells 3 months after kidney transplantation was analyzed to compare differences between patients with infection and those who were infection-free in the first-year post-transplant. Pro-inflammatory genes such as IL1B, CCL4, and TNF were found to be downregulated in post-transplant PBMC from patients who developed infection. In contrast, genes involved in metabolism, HLA genes, and transcripts involved in type I interferon innate antiviral responses were found to be upregulated. Promoter-based bioinformatic analyses implicated increased activity of interferon regulatory factors, erythroid nuclear factor (E2), and CCAAT-enhancer-binding protein (C/EBP) in patients who developed infections. Differential patterns of gene expression were observed in patients who developed infection after kidney transplantation, with patterns distinct from changes associated with patient age, suggesting possible mechanisms behind vulnerability to infection. Assessment of gene expression in blood may offer an approach for patient risk stratification and monitoring after transplantation., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Obesity in deceased kidney donors is a known risk factor for poor allograft outcomes. The Kidney Donor Profile Index (KDPI) has been introduced to predict graft survival in deceased donor kidney transplantation (DDKT). Obesity, however, is not included in KDPI. We study the impact of donor obesity on DDKT outcomes after adjusting for organ quality by KDPI. The Organ Procurement Transplantation Network/United Network for Organ Sharing (OPTN/UNOS) data of DDKT from 2005 to 2017, with donor BMI ≥ 18.5 kg/m 2 and weight >80 kg were included. There was a total of 66 382 DDKTs with 10 917 death-censored graft failures. For KDPI ≤ 30%, the 10-year death-censored graft survival (DCGS) rates among donor BMI < 30, 30-35, 35-40, 40-45 and ≥45 kg/m 2 groups were 75.9%, 75.4%, 76.1%, 74.9% and 79.6%, respectively. For KDPI > 30%, 10-year DCGS rates were 67.5%, 66.1%, 65.9%, 62.6% and 63.2%, respectively. After adjusting for known confounding factors including KDPI, donor obesity was not independently associated with an increased risk for graft failure. In DDKT with donor weight >80 kg, donor obesity was not associated with a lower long term DCGS compared to non-obesity when KDPI ≤ 30%., (© 2021 Steunstichting ESOT. Published by John Wiley & Sons Ltd.)

Background: Cytomegalovirus (CMV) infection continues to negatively affect outcomes for solid organ transplant recipients, despite the advent of strategies for preemptive surveillance and prophylaxis. The impact is especially great for CMV seronegative recipients of donor seropositive organs, who typically lack the ability to control CMV infection at the time of transplantation., Methods: We reviewed episodes of CMV DNAemia in a modern cohort of kidney transplant recipients over a 3-year period at a high-volume transplant center to investigate the frequency of DNAemia during antiviral prophylaxis., Results: Despite receipt of antiviral prophylaxis per current guidelines, 75 cases of CMV DNAemia were observed in the first 100 days after transplantation. For high risk patients, median time to DNAemia was 75 days after transplantation, and the majority of patients had experienced dose-reduction of valganciclovir due to renal insufficiency. Review of CMV seropositive intermediate risk patients demonstrated DNAemia occurring earlier after transplantation compared with high risk patients with a median time of 64 days (P = .029). The impact of valganciclovir dose adjustment was less notable in the intermediate risk group., Conclusions: Guidelines recommend beginning routine surveillance for CMV after the completion of antiviral prophylaxis. Our findings suggest that closer monitoring may be beneficial, especially for high risk patients at risk for DNAemia. Patients requiring dose adjustment of valganciclovir due to renal insufficiency may be at increased risk for CMV DNAemia. Improved methods for CMV prophylaxis and evaluation of immunologic risk for CMV DNAemia and disease are needed to improve patient outcomes after kidney transplantation., (© 2020 Wiley Periodicals LLC.)

Background: Melanoma is an immune responsive malignancy and the need for immunosuppression for successful transplantation may lead to recurrent disease. The recommended waiting time is unknown with various groups recommending anywhere from no wait to 5 years., Methods: In this single-center, retrospective observational study all kidney transplant recipients' charts from 1991 to 2015 were reviewed for a diagnosis of melanoma before transplantation. The charts were reviewed for the clinical characteristics of melanoma pre transplantation, induction immunosuppression, maintenance immunosuppression, graft function, death, and recurrence of melanoma., Results: Thirteen patients with a history of melanoma underwent kidney transplantation during this period. Recipients had been in remission for an average of 7.0 years (range, 10 months to 20 years, median 6 years). Approximately 61.5% received a living donor transplant, antithymocyte globulin was administered in 23.1% of recipients, and the remaining 76.9% received basiliximab. Melanoma recurred in 1 patient (7.7%). Maintenance immunosuppression varied, but only 2 patients remained on standard triple therapy with prednisone, calcineurin inhibitor, and antimetabolite therapy. Average follow-up time since transplant was 7.5 years, with 1 patient death 9 years post transplant from sepsis., Conclusion: In conclusion, with our center demonstrates safety of kidney transplantation in patients with a prior history of localized melanoma and shorter waiting time. In malignant melanoma stage 0 and 1, waiting the recommended 5 years from the time of remission to kidney transplantation should be reconsidered., (Published by Elsevier Inc.)

Background: Under the current kidney allocation system, pediatric candidates listed prior to age 18 receive priority for high-quality deceased donor organs. This has resulted in a decline in living donor transplantation in pediatrics, despite superior outcomes of living donor transplantation. Due to a young age at transplantation, most pediatric kidney transplant recipients require re-transplantation. The effects of a previously failed deceased donor vs a previously failed living donor on re-transplant candidates are unknown., Methods: Using the United Network for Organ Sharing database, we examined 2772 re-transplant recipients aged 18-30 years at time of relisting for second KT from 2000 to 2018 with history of prior pediatric KT (age ≤ 18 years)., Results: PFLDKT recipients compared to those with PFDDKT had shorter median waiting times and dialysis time regardless of their second donor type (14.0 vs 20.3 months, and 19.1 vs 34.5 months, respectively). PFLDKT recipients had higher re-transplant rates (adjusted HR 1.17, 95% CI 1.09-1.27, and adjusted HR 1.05, 95% CI 0.95-1.15 when calculating from time of relisting and time of returning to dialysis, respectively). PFDDKT recipients were more likely to have higher median PRA levels (90% vs 73%)., Conclusions: Re-transplant candidates who received a previous deceased donor as a child had a higher level of sensitization, longer waiting time, and dialysis exposure compared to those with PFLDKT. Among primary pediatric kidney transplant candidates, consideration should be considered for living donor transplantation, despite the priority for deceased donor organs, to avoid increased sensitization and longer waiting times for with re-transplantation., (© 2020 Wiley Periodicals LLC.)

Purpose: We reviewed the clinical experience of kidney transplant recipients diagnosed with severe acute respiratory syndrome coronavirus 2 infection in order to understand the impact of the current coronavirus disease 2019 (COVID-19) pandemic infection on transplant recipients. Given that early reports from heavily affected areas demonstrated a very high mortality rate amongst kidney transplant recipients, ranging between 30% and 40%, we sought to evaluate outcomes at a center with a high burden of cases but not experiencing acute crisis due to COVID-19., Procedures: In this single center retrospective observational study, medical records of all kidney transplant recipients at the UCLA Medical Center were reviewed for a diagnosis of COVID-19 by polymerase chain reaction, followed by chart review to determine kidney transplant characteristics and clinical course., Main Findings: A total of 41 kidney transplant recipients were identified with COVID-19 positive polymerase chain reaction. Recipients had been transplanted for a median of 47 months before diagnosis. The large proportion of infected individuals were minorities (Hispanic 65.9%, black 14.6%), on prednisone, tacrolimus, and mycophenolate mofetil (95.1%, 87.8%, and 87.8%, respectively), and had excellent allograft function (median 1.25 mg/dL). The most common presenting symptoms were fever, dyspnea, or cough. Most patients were hospitalized (63.4%); mortality was 9.8% and occurred only in patients in the intensive care unit. The most common treatment was reduction or removal of antimetabolite (77.8%). Approximately 26.9% presented with AKI., Conclusions: COVID-19 infection in kidney transplant recipients results in a higher rate of hospitalization and mortality than in the general population. In an area with a high number of infections, the mortality rate was lower compared with earlier reports from areas experiencing early surge and strain on the medical system. Minorities were disproportionately affected. Future studies are needed to determine optimal approach to treatment and management of immunosuppression in kidney transplant recipients with COVID-19 infection., (Copyright © 2020 Elsevier Inc. All rights reserved.)

BACKGROUND A previous phase 3 clinical trial in de novo adult kidney transplant recipients (NCT01187953) compared the efficacy and safety of once-daily LCP-tacrolimus (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac). However, whether the rate of tacrolimus metabolism affects outcomes between LCPT and IR-Tac was not examined. MATERIAL AND METHODS Patients were initiated on 0.17 mg/kg/day LCPT or 0.1 mg/kg/day IR-Tac, with doses adjusted over time to maintain target therapeutic trough concentrations. This post hoc analysis examined dosing trends, relative efficacy, and safety of LCPT (n=247) and IR-Tac (n=249) in slow, intermediate, and rapid metabolizers as defined by concentration/dose ratios at day 30. RESULTS For all metabolizer subgroups, minimum target tacrolimus trough concentrations were obtained more rapidly with LCPT than with IR-Tac. Slow metabolizers were more likely to exceed target trough concentrations with LCPT, while rapid metabolizers were more likely to fall below target trough concentrations with IR-Tac. Regardless of metabolizer status, significant differences were not detected between LCPT and IR-Tac for treatment failure, death, graft failure, biopsy-proven acute rejection, estimated glomerular filtration rate, or other clinical outcomes. CONCLUSIONS Although within metabolizer subgroups, attainment of target trough concentrations in the first week differed between LCPT and IR-Tac, these results suggest that, regardless of metabolizer phenotype, clinical outcomes do not differ between these formulations when dose adjustments are made.

Older kidney transplant recipients demonstrate increased rates of infection but decreased rates of rejection compared with younger recipients, suggesting that older transplant patients are functionally overimmunosuppressed. We hypothesized that this is a consequence of reduction in immunological activity due to biological aging and that an immune biological age, as determined by DNA methylation (DNAm), would be associated more strongly with incidence of infection than chronological age., Methods: DNAm analysis was performed on peripheral blood mononuclear cell collected from 60 kidney transplant recipients representing older (≥age 60 y) and younger (aged 30-59 y) patients 3 months after transplantation. DNAm age was calculated based on methylation status of a panel of CpG sites, which have been previously identified as indicative of biological age., Results: Correlation was seen between chronological and DNAm age; however, there were many patients with significant differences (either acceleration or slowing) between DNAm age and chronological age. A statistically significant association was seen between increased DNAm age and incidence of infection in the first year after kidney transplantation, whereas no significant association was seen between chronological age and infection., Conclusions: Assessment of DNAm age holds promise as an approach for patient evaluation and individualization of immune suppression regimens. This analysis may provide insights into the immunological mechanism behind increased incidence of infection observed in older transplant patients. The ability to measure biological age would allow for patient risk stratification and individualization of immunosuppression, improving outcomes for the growing numbers of older patients undergoing kidney transplantation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 The Author(s). Transplantation Direct. Published by Wolters Kluwer Health, Inc.)

Competing Interests: The authors declare no funding or conflicts of interest.

Renal dysfunction in cirrhosis is common and is associated with increased mortality. Identifying and treating reversible causes of renal disease can significantly improve outcomes. The etiology, approach, and evaluation of renal disease in this group of patients is similar to the noncirrhosis patient, with a few specific caveats. Renal disease may be unrelated to the cause of cirrhosis (eg, prerenal acute kidney injury, acute tubular necrosis), occur as a manifestation of the same systemic disease responsible for the liver disease (eg, chronic viral hepatitis B and C infection) or as a consequence of cirrhosis (hepatorenal syndrome). Kidney impairment may be underrecognized in patients with cirrhosis due to over-reliance on creatinine-based glomerular filtration rate equations used in clinical practice. The first steps of evaluation for the renal disease include a thorough medical history to identify the underlying cause of cirrhosis and any potential trigger for renal dysfunction, physical examination, and review of prior laboratory records for baseline renal function. Renal imaging and urinalysis should be performed on all cirrhotic patients with renal dysfunction to establish the presence of urinary obstruction, chronicity and intrinsic renal disease.

Fungus account for ∼ 5% of all cases infections following solid organ transplant. Fungal infections in the setting of immunosuppression may progress rapidly and present in an atypical pattern. Herein we describe 4 cases of environmental fungal infections acquired decades prior to transplant that developed into localized atypical cutaneous masses following kidney transplant., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose of Review: Plasma cell dyscrasias encompass a group of hematological disorders characterized by increased production of immunoglobulins by clonal B cells. Kidney involvement is common. Significant advances in the treatment of plasma cell dyscrasias have resulted in improved survival and may permit kidney transplantation in candidates previously denied transplantation. Treatments may also have effects on kidney transplant recipients who develop plasma cell dyscrasias post transplantation., Recent Finding: The available evidence suggests that transplantation of candidates with nonmultiple myeloma plasma cell dyscrasias provides good outcome with low recurrence rates, so long as the disease has been treated with a complete or good partial response prior to transplantation. Candidates with a history untreated MGRS or a history of multiple myeloma have a high rate of recurrence posttransplant. Kidney transplant recipients who develop plasma cell dyscrasias post transplantation have an increased risk of death and thalidomide-based regimens may increase the risk of rejection., Summary: Transplant candidates with a history of plasma cell dyscrasia who are in remission should not be excluded from transplantation. Individuals with multiple myeloma have a high rate of recurrence and myeloma post kidney transplant must be managed carefully.

Background: Kidney delayed graft function (kDGF) remains a challenging problem following simultaneous liver and kidney transplantation (SLKT) with a reported incidence up to 40%. Given the scarcity of renal allografts, it is crucial to minimize the development of kDGF among SLKT recipients to improve patient and graft outcomes. We sought to assess the role of preoperative recipient and donor/graft factors on developing kDGF among recipients of SLKT., Methods: A retrospective review of 194 patients who received SLKT in the period from January 2004 to March 2017 in a single center was performed to assess the effect of preoperative factors on the development of kDGF., Results: Kidney delayed graft function was observed in 95 patients (49%). Multivariate analysis revealed that donor history of hypertension, cold static preservation of kidney grafts [versus using hypothermic pulsatile machine perfusion (HPMP)], donor final creatinine, physiologic MELD, and duration of delay of kidney transplantation after liver transplantation were significant independent predictors for kDGF. kDGF is associated with worse graft function and patient and graft survival., Conclusions: Kidney delayed graft function has detrimental effects on graft function and graft survival. Understanding the risks and combining careful perioperative patient management, proper recipient selection and donor matching, and graft preservation using HPMP would decrease kDGF among SLKT recipients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)