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Eplet mismatch load, both overall and at the single molecule level, correlates with transplant recipient outcomes. However, precise eplet assessment requires high-resolution HLA typing of both the donor and recipient. Anything less than high-resolution typing requires imputation of HLA types. The currently available methods to identify eplet mismatch are both tedious and demanding. Therefore, we developed a software package and user-friendly web application (hlaR), that simplifies the workflow of eplet analysis, provides functions to impute high-resolution from low-resolution data and calculates both overall and single molecule eplet mismatch for single or multiple donor recipient pairs. Compared to manual assessments using currently available tools (namely, HLAMatchMaker), hlaR resulted in only minimal discrepancy in eplet mismatches (mean absolute difference of 0.56 for class I and 0.86 for class II for unique sum across loci). Additionally, output of the single molecule eplet function compared well to manual calculation, with an average single antigen count increase of 0.19. Importantly, the hlaR tool permits rapid and reproducible imputation and eplet mismatch including comparison between eplet reference tables (e.g. HLAMatchMaker version 2 or 3). Users can import data from a spreadsheet rather than relying on keystroke entry of individual donor and recipient data, thus reducing the risk of data entry errors. The resulting improved scalability of the hlaR tool is highlighted by plotting analysis time against the size of the input dataset. The new hlaR tool can provide eplet mismatch data with a streamlined workflow. With decreased effort from the end user, eplet matching and mismatch load data can be further incorporated into both research and clinical use.

The effectiveness of T cell-mediated rejection (TCMR) therapy for achieving histological remission remains undefined in patients on modern immunosuppression. We systematically identified, critically appraised and summarized the incidence and histological outcomes after TCMR treatment in patients on tacrolimus (Tac) and mycophenolic acid (MPA). English-language publications were searched in MEDLINE (Ovid), Embase (Ovid), Cochrane Central (Ovid), CINAHL (EBSCO), Clinicaltrials.gov (NLM) up to January 2021. Study quality was assessed with National Institutes of Health Study Quality Tool. We pooled results using an inverse variance, random-effects model and report the binomial proportions with associated 95% confidence intervals (95% CI). Statistical heterogeneity was explored using the I2 statistic. From 2,875 screened citations, we included 12 studies (1,255 participants). Fifty-eight percent were good/high quality while the rest were moderate quality. Thirty-nine percent of patients (95%CI 0.26-0.53, I2 77%) had persistent ≥Banff Borderline TCMR 2-9 months after anti-rejection therapy. Pulse steroids and augmented maintenance immunosuppression were mainstays of therapy, but considerable practice heterogeneity was present. A high proportion of biopsy-proven rejection exists after treatment emphasizing the importance of histology to characterize remission. Anti-rejection therapy is foundational to transplant management but well-designed clinical trials in patients on Tac/MPA immunosuppression are lacking to define the optimal therapeutic approach.

Malaltia renal en fase terminal; Trasplantament de ronyó Enfermedad renal en etapa terminal; Transplante de riñón End-stage renal disease; Kidney Transplant Background. There are challenges in designing adequate, well-controlled studies of patients with active antibody-mediated rejection (AMR) after kidney transplantation (KTx). Methods. We assessed the functional relationship between change in estimated glomerular filtration rate (eGFR) following the diagnosis of AMR and the risk of subsequent death-censored graft failure using the joint modeling framework. We included recipients of solitary KTx between 1995 and 2013 at 4 transplant centers diagnosed with biopsy-proven active AMR at least 1 year post-KTx, who had a minimum of 3-year follow-up. Results. A total of 91 patients across participating centers were included in the analysis. Of the 91 patients, n = 54 patients (59%) met the death-censored graft failure endpoint and n = 62 patients (68%) met the all-cause graft failure composite endpoint. Kaplan-Meier death-censored graft survival rates at 12, 36, and 60 months postdiagnosis of AMR pooled across centers were 88.9%, 58.9%, and 36.4%, respectively. Spaghetti plots indicated a linear trend in the change in eGFR, especially in the first 12 months postdiagnosis of active AMR. A significant change in eGFR was observed within the first 12 months postdiagnosis of active AMR, getting worse by a factor of −0.757 mL/min/1.73 m2 per month during the 12-month analysis period (a delta of −9.084 mL/min/1.73 m2 at 1 y). Notably, an extrapolated 30% improvement in the slope of eGFR in the first 12 months was associated with a 10% improvement in death-censored graft failure at 5 years. Conclusions. If prospectively validated, this study may inform the design of pivotal clinical trials for therapies for late AMR.

Clinicians have few tools to predict the risk of alloimmune injury that would guide immunosuppression management in renal transplant patients. We evaluated human leukocyte antigen (HLA)-DR/DQ molecular mismatch to predict de novo donor-specific antibodies (DSAs) during the first year of transplant and explored how differences in tacrolimus exposure may modulate this risk. HLA-DR and -DQ eplet mismatches were determined between 444 donor-recipient pairs in Denver, Colorado between 2007 and 2013. Previously defined mismatch thresholds stratified recipients into low- (N = 119), intermediate- (N = 153), and high- (N = 172) risk categories. The area under the curve for DSA at 1 year was 0.84 and 0.82 for HLA-DR and HLA-DQ eplet mismatches, respectively. Compared to low-risk patients, there was a graded increase in risk of DR/DQ DSA in intermediate (HR 15.39, 95% CI 2.01-118.09, p = .009) and high-risk (HR 23.81, 95% CI 3.17-178.66, p = 0.002) categories. Intermediate- and high-risk patients with a mean tacrolimus6 ng/ml versus8 ng/ml had increased risk of DR/DQ DSA at 1 year (HR 2.34, 95% CI 1.05-5.22, p = .04). HLA molecular mismatch represents a reproducible, objective, and clinically relevant tool to stratify patients by alloimmune risk and may help guide personalized immunosuppression management.

We describe the structural and magnetic properties of a tetranuclear [2 × 2] Co4 grid complex containing a ditopic arylazo ligand. At low temperatures and in solution the complex is comprised of Co3+ and singly reduced trianion-radical ligands. In the solid state we demonstrate the presence of valence tautomerization via variable temperature magnetic susceptibility experiments and powder-pattern EPR spectroscopy. Valence tautomerism in polynuclear complexes is very rare and to our knowledge is unprecedented in [2 × 2] grid complexes.

BACKGROUND: Post-transplant diabetes mellitus (PTDM) occurs in 10%–40% of liver and renal transplant recipients. Whether the risk factors for PTDM in liver and renal transplant recipients are similar and whether Indigenous Canadians, who have a high underlying prevalence of diabetes mellitus (DM), are at increased risk of developing PTDM have yet to be determined. OBJECTIVE: To describe and compare those variables associated with PTDM in adult Canadian liver and renal transplant recipients. METHODS: A retrospective chart review of adult liver and renal transplant recipients attending four transplant follow-up clinics in three Canadian provinces was undertaken. RESULTS: De novo PTDM was diagnosed in 184/905 (20.3%) of liver and 179/390 (45.9%) of renal transplant recipients. Older age, higher pre-transplant BMI, underlying immune-mediated liver disease, lower trough tacrolimus levels and longer duration of follow-up were independently associated with PTDM in liver transplant recipients and non-Caucasian race, higher pre-transplant body mass index (BMI), and incidence of organ rejection in renal transplant recipients. Compared with Caucasians, Indigenous Canadians who had undergone renal transplantation had a significantly increased prevalence of PTDM (56.5% vs 40.0%, p = 0.035). The prevalence of PTDM in liver transplant recipients was similar in Indigenous Canadians and Caucasians (27.9% vs 20.1%, p = 0.215). CONCLUSIONS: The variables associated with PTDM differ in liver and renal transplant recipients. Compared with Caucasians, Indigenous Canadians undergoing renal transplantation are at increased risk of developing PTDM.

Improving long‐term kidney transplant outcomes requires novel treatment strategies, including delayed calcineurin inhibitor (CNI) substitution, tested using informative trial designs. An alternative approach to the usual superiority‐based trial is a noninferiority trial design that tests whether an investigational agent is not unacceptably worse than standard of care. An informative noninferiority design, with biopsy‐proven acute rejection (BPAR) as the endpoint, requires determination of a prespecified, evidence‐based noninferiority margin for BPAR. No such information is available for delayed CNI substitution in kidney transplantation. Herein we analyzed data from recent kidney transplant trials of CNI withdrawal and “real world” CNI‐ based standard of care, containing subjects with well‐documented evidence of immune quiescence at 6 months posttransplant—ideal candidates for delayed CNI substitution. Our analysis indicates an evidence‐based noninferiority margin of 13.8% for the United States Food and Drug Administration's composite definition of BPAR between 6 and 24 months posttransplant. Sample size estimation determined that ~225 randomized subjects would be required to evaluate noninferiority for this primary clinical efficacy endpoint, and superiority for a renal function safety endpoint. Our findings provide the basis for future delayed CNI substitution noninferiority trials, thereby increasing the likelihood they will provide clinically implementable results and achieve regulatory approval., This meta‐analysis defines a noninferiority margin to use in the design of a phase II/III delayed calcineurin inhibitor substitution trial in kidney transplantation.

Purpose of review A precise understanding of the alloimmune risk faced by individual recipients at the time of transplant is an unmet need in transplantation. Although conventional HLA donor-recipient mismatch is too imprecise to fulfil this need, HLA molecular mismatch increases the precision in alloimmune risk assessment by quantifying the difference between donors and recipients at the molecular level. Recent findings Within each conventional HLA mismatch the number, type, and position of mismatched amino acids create a wide range of HLA molecular mismatches between recipients and donors. Multiple different solid organ transplant groups from across the world have correlated HLA molecular mismatch with transplant outcomes including de novo donor-specific antibody development, antibody-mediated rejection, T-cell-mediated rejection, and allograft survival. Summary All alloimmunity is driven by differences between donors and recipients at the molecular level. HLA molecular mismatch may represent an advancement compared to traditional HLA antigen mismatch as a fast, reproducible, cost-effective way to improve alloimmune risk assessment at the time of transplantation to move the field towards precision medicine.

Prognostic biomarkers of T cell–mediated rejection (TCMR) have not been adequately studied in the modern era. We evaluated 803 renal transplant recipients and correlated HLA‐DR/DQ molecular mismatch alloimmune risk categories (low, intermediate, high) with the severity, frequency, and persistence of TCMR. Allograft survival was reduced in recipients with Banff Borderline (hazard ratio [HR] 2.4, P = .003) and Banff ≥ IA TCMR (HR 4.3, P, Alloimmune risk categorization using HLA‐DR/DQ molecular mismatch risk correlates with the severity, frequency, and persistence of T cell–mediated rejection and with graft survival, independent of de novo DSA.

Improving precision in predicting alloreactivity is an important unmet need and may require individualized consideration of non-HLA antibodies. We report a 21-year-old man with kidney failure from immunoglobulin A nephropathy who met all traditional criteria for a "low-risk" transplant for immune memory. He was unsensitized and received a haplotype-matched living donor kidney transplant from his mother. There were no anti-HLA donor-specific antibodies and flow cross-match was negative. After immediate function, he developed delayed graft function on postoperative day 2. The transplant biopsy specimen was suggestive of antibody-mediated rejection and acute tubular injury with increased vimentin proximal tubular expression compared to the implantation biopsy specimen. He had a history of juvenile idiopathic arthritis, and non-HLA antibody screening demonstrated preformed anti-vimentin antibody. He was successfully treated with plasmapheresis, intravenous immunoglobulin, antithymocyte globulin, and methylprednisolone, with renal recovery. The follow-up biopsy specimen demonstrated decreased vimentin expression with decreased alloinflammation, and graft function remains stable at 1 year posttransplantation (estimated glomerular filtration rate, 62mL/min/1.73m2). We postulate that preformed anti-vimentin autoantibodies bound to vimentin expressed on apoptotic tubular epithelial cells induced by ischemia-reperfusion injury and to constitutively expressed vimentin on peritubular capillaries and podocytes. Our case is suggestive of the involvement of anti-vimentin antibody, for which the pathogenic epitopes may be exposed during ischemia-reperfusion injury.

To date, traditional pre-transplant risk factors have failed to provide accurate risk stratification in transplantation. As a result, the practice of precision medicine remains elusive, resulting in a one-size-fits-all therapeutic approach for most patients. However, recent advancements in the understanding of HLA molecules at the molecular level have revitalized interest in HLA mismatch assessment. This review discusses HLA molecular mismatch as a potential prognostic and predictive biomarker available at the time of transplantation and answers some of the common questions and critiques of this approach. We highlight the retrospective data that supports single molecule risk categorization and explore the next steps required to evaluate its potential in clinical practice.

Innate immune cells remember Immunological memory is a phenomenon by which immune cells can quickly recognize an antigen that the host has previously encountered. Certain cells of the innate immune system exhibit memory-like responses know as trained immunity. Rapid, antigen-specific secondary (anamnestic) responses were long thought to be the domain of B and T cells. However, Dai et al. report that monocytes and macrophages can acquire memory specific for particular major histocompatibility complex I antigens using paired A-type immunoglobulin-like receptors (PIR-As) (see the Perspective by Dominguez-Andrés and Netea). This pathway contributes to recognition and rejection of allograft-transplanted tissue from a donor of the same species. Genetic depletion or blockade of PIR-As in mice diminished the rejection of kidney and heart allografts. This work, which expands immunological memory to include myeloid cells, points to targets that may improve organ transplantation outcomes in the future. Science , this issue p. 1122 ; see also p. 1052

Situated in an understanding of contemporary US education as heavily influenced by a neoliberal technocracy we conducted a Critical Discourse Analysis of the 2010 and 2016 National Education Techno...

Introduction Pneumocystis jirovecii pneumonia (PJP) is a significant cause of morbidity and mortality in transplant patients yet little is known about their adherence to prophylaxis. The goal of this study was to evaluate patient uptake and long-term adherence after implementing universal, lifelong PJP prophylaxis. Materials and methods This retrospective cohort study evaluated an adult kidney transplant program 18-months after initiating trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 mg thrice-weekly following a cluster of PJP cases. The protocol incorporated multi-modal patient education and drug tolerability strategies to improve adherence, including a modified re-challenge strategy for TMP-SMX intolerance. Adherence was independently confirmed by the transplant pharmacist and nurse for each patient, with an a priori target ≥ 75% population on prophylaxis. Results Initial uptake was high with 237/250 (94.8%) patients starting prophylaxis. Long-term maintenance was high with 192/237 (81.0%) patients remaining on prophylaxis at 18-months. Of the remaining 45 patients who initiated prophylaxis, 36/237 (15.2%) were non-adherent and 9/237 (3.8%) discontinued prophylaxis by 18-months. Reasons for non-adherence included gastrointestinal upset, fear of drug reactions and cost; but the majority of reasons were not delineated by the patients (31/36, 86.1%). There was a statistically significant increase in serum creatinine 3.3 µmol/L (0.3-6.3 µmol/L 95% CI) and potassium 0.08 mmol/L (0.03-0.15 mmol/L 95% CI) in those prescribed TMP-SMX with only 3/237 (1.3%) patients discontinuing TMP-SMX for an increase in creatinine. Conclusion High rates of patient uptake (94.8%) and long-term adherence (81.0%) were observed after implementing universal lifelong PJP prophylaxis. This may be due in part to the in-depth patient education and drug tolerability strategies employed.

Purpose of review There is tremendous interest in understanding when, if, and how non-HLA antibodies contribute to allograft injury. Numerous non-HLA target antigens have been identified and sensitization to these targets have been associated with delayed allograft function, rejection, and allograft failure. This review focuses on the clinical utility of HLA antibody testing, highlighting the strengths and limitations of current clinical studies, and the need for defining characteristics to inform non-HLA antibody pathogenicity. Recent findings Clinical studies continue to show associations between non-HLA antibodies and rejection and reduced allograft survival across multiple transplanted organ types. The worst clinical outcomes continue to be observed among recipients testing positive for both non-HLA and donor-specific HLA antibodies. Mechanistic insights from both animal and clinical studies support a model in which tissue injury accompanied by an inflammatory environment influence non-HLA antibody formation and pathogenicity. Summary Immune triggers that lead to non-HLA antibody formation and pathogenicity are complex and poorly understood. The ability of non-HLA antibodies to mediate allograft injury may depend upon their affinity and strength (titer), target specificity, density of the target antigen, and synergy with donor-specific HLA antibodies.

The purpose of the STAR 2019 Working Group was to build on findings from the initial STAR report to further clarify the expectations, limitations, perceptions, and utility of alloimmune assays that are currently in use or in development for risk assessment in the setting of organ transplantation. The goal was to determine the precision and clinical feasibility/utility of such assays in evaluating both memory and primary alloimmune risks. The process included a critical review of biologically driven, state‐of‐the‐art, clinical diagnostics literature by experts in the field and an open public forum in a face‐to‐face meeting to promote broader engagement of the American Society of Transplantation and American Society of Histocompatibility and Immunogenetics membership. This report summarizes the literature review and the workshop discussions. Specifically, it highlights (1) available assays to evaluate the attributes of HLA antibodies and their utility both as clinical diagnostics and as research tools to evaluate the effector mechanisms driving rejection; (2) potential assays to assess the presence of alloimmune T and B cell memory; and (3) progress in the development of HLA molecular mismatch computational scores as a potential prognostic biomarker for primary alloimmunity and its application in research trial design., This meeting report from an AST‐ASHI expert workgroup provides recommendations on the utility and “clinical‐grade” qualification of assays and biomarkers to evaluate alloimmune risk.

BACKGROUND: In kidney transplantation, evaluating mismatches of HLA eplets—small patches of surface-exposed amino acids of the HLA molecule—instead of antigen mismatches might offer a better approach to assessing donor-recipient HLA incompatibility and improve risk assessment and prediction of transplant outcomes. METHODS: To evaluate the effect of number of eplet mismatches (mismatch load) on de novo formation of donor-specific HLA antibodies (DSAs) and transplant outcomes, we conducted a cohort study that included consecutive adult kidney recipients transplanted at a single center from March 2004 to February 2013. We performed retrospective high-resolution genotyping of HLA loci of 926 transplant pairs and used the HLAMatchmaker computer algorithm to count HLA eplet mismatches. RESULTS: De novo DSAs occurred in 43 (4.6%) patients. Multivariable analysis showed a significant independent association between antibody-verified eplet mismatch load and de novo DSA occurrence and graft failure, mainly explained by DQ antibody-verified eplet effects. The association with DQ antibody-verified eplet mismatches was linear, without a safe threshold at which de novo DSA did not occur. Odds for T cell– or antibody-mediated rejection increased by 5% and 12%, respectively, per antibody-verified DQ eplet mismatch. CONCLUSIONS: Eplet mismatches in HLA-DQ confer substantial risk for de novo DSA formation, graft rejection, and graft failure after kidney transplantation. Mismatches in other loci seem to have less effect. The results suggest that antibody-verified HLA-DQ eplet mismatch load could be used to guide personalized post-transplant immunosuppression. Adoption of molecular matching for DQA(1) and DQB(1) alleles could also help to minimize de novo DSA formation and potentially improve transplant outcomes.

Pretransplant and posttransplant alloimmune risk assessment needs to evolve towards a precision medicine model already used in other areas of medicine. Although this has not been possible with traditional risk factors available at the time of transplant, new methods of human leukocyte antigen (HLA) molecular mismatch have generated hope that alloimmune risk assessment may be precise enough for personalized treatment strategies.This review describes the various HLA molecular mismatch methods and some of the recent publications for each method. These include studies that have evaluated HLA molecular mismatch in the context of lung, pancreas and kidney transplant as a correlate with short and long-term outcomes. The limitations of traditional alloimmune risk assessment strategies are highlighted in the context of individualized patient care.Recent studies that have evaluated HLA molecular mismatch in the context of immunosuppression minimization are examples of how more precise measurements of alloimmune risk can lead to novel insights that may help personalize immunosuppression protocols.

Studies investigating the potential pathogenic effects of non-HLA antibodies (Ab) have identified Ab against the angiotensin II type 1 receptor (AT1R-Ab) as a risk factor for rejection and kidney graft loss. This study sought to validate the risk of AT1R-Ab for acute rejection and to explore the role of other non-HLA Abs in this capacity. Pre- and post-transplant sera from a cohort of 101 patients (n = 453 samples total) were tested for AT1R-Ab and other non-HLA Ab using a commercially available ELISA kit and the Luminex platform, respectively. Patients positive for pre-transplant AT1R-Ab were more likely to develop de novo donor-specific Ab (dnDSA) compared to patients that were negative for AT1R-Ab (28% vs 10%, p = 0.027). Pre-transplant positivity for AT1R-Ab was associated with TCMR in the first year post-transplant (p = 0.034), but did not predict graft loss independent of dnDSA (p = 0.063). AT1R-Ab positivity was significantly associated with positivity for Ab against the endothelin A type 1 receptor (ETAR-Ab) inclusive of all study time points (p = 0.0021). Given the high prevalence of AT1R-Ab pre-transplant (20%) and its association with dnDSA and early TCMR, a prospective study to determine if more intense immunosuppression and/or AT1R blockade has an impact on outcomes in these patients is warranted.

De novo donor-specific antibodies (dnDSAs) that develop after renal transplantation are independent predictors of allograft loss. However, it is unknown if dnDSA C1q status or titer at the time of first detection can independently predict allograft loss. In a consecutive cohort of 508 renal transplant recipients, 70 developed dnDSAs. Histologic and clinical outcomes were correlated with the C1q assay or dnDSA titer. C1q positivity correlated with dnDSA titer (p < 0.01) and mean fluorescence intensity (p < 0.01) and was more common in class II versus class I dnDSAs (p < 0.01). C1q status correlated with tubulitis (p = 0.02) and C4d status (p = 0.03) in biopsies at the time of dnDSA development, but not T cell-mediated rejection (TCMR) or antibody-mediated rejection (ABMR). De novo DSA titer correlated with Banff g, i, t, ptc, C4d scores, TCMR (p < 0.01) and ABMR (p < 0.01). Post-dnDSA graft loss was observed more frequently in recipients with C1q-positve dnDSA (p < 0.01) or dnDSA titer ≥ 1:1024 (p ≤ 0.01). However, after adjustment for clinical phenotype and nonadherence in multivariate models, neither C1q status nor dnDSA titer were independently associated with allograft loss, questioning the utility of these assays at the time of dnDSA development.

Purpose of review Stalled drug development and the lack of improvement in long-term graft survival reflect the unmet need for prognostic and predictive biomarkers in transplantation. Although conventional human leukocyte antigen (HLA) mismatch is too imprecise to fulfill this need, HLA molecular mismatch increases the precision in alloimmune risk assessment by quantifying the difference between donors and recipients at the molecular level. Recent findings Within each conventional HLA mismatch, recipients exhibit a wide range of HLA molecular mismatches with their donors. Quantifying HLA molecular mismatch improves the precision of alloimmune risk assessment for de novo donor-specific antibody development (dnDSA). Alloimmune risk categories developed analyzing dnDSA development were also found to correlate with T-cell-mediated rejection, antibody-mediated rejection, and all cause graft loss in adjusted and unadjusted models. Summary All alloimmunity is driven by differences between donors and recipients at the molecular level. HLA molecular mismatch may represent a fast, reproducible, cost-effective, way to improve alloimmune risk assessment at the time of transplantation to move the field towards precision medicine.

Alloimmune risk stratification in renal transplantation has lacked the necessary prognostic biomarkers to personalize recipient care or optimize clinical trials. HLA molecular mismatch improves precision compared to traditional antigen mismatch but has not been studied in detail at the individual molecule level. This study evaluated 664 renal transplant recipients and correlated HLA‐DR/DQ single molecule eplet mismatch with serologic, histologic, and clinical outcomes. Compared to traditional HLA‐DR/DQ whole antigen mismatch, HLA‐DR/DQ single molecule eplet mismatch improved the correlation with de novo donor‐specific antibody development (area under the curve 0.54 vs 0.84) and allowed recipients to be stratified into low, intermediate, and high alloimmune risk categories. These risk categories were significantly correlated with primary alloimmune events including Banff ≥1A T cell–mediated rejection (P = .0006), HLA‐DR/DQ de novo donor‐specific antibody development (P, Primary alloimmune risk precisely determined using HLA class II molecular mismatch may facilitate personalized treatment and monitoring strategies for kidney transplant recipients.

IntroductionSubclinical inflammation is an important predictor of death-censored graft loss, and its treatment has been shown to improve graft outcomes. Urine CXCL10 outperforms standard post-transplant surveillance in observational studies, by detecting subclinical rejection and early clinical rejection before graft functional decline in kidney transplant recipients.Methods and analysisThis is a phase ii/iii multicentre, international randomised controlled parallel group trial to determine if the early treatment of rejection, as detected by urine CXCL10, will improve kidney allograft outcomes. Incident adult kidney transplant patients (n~420) will be enrolled to undergo routine urine CXCL10 monitoring postkidney transplant. Patients at high risk of rejection, defined as confirmed elevated urine CXCL10 level, will be randomised 1:1 stratified by centre (n=250). The intervention arm (n=125) will undergo a study biopsy to check for subclinical rejection and biopsy-proven rejection will be treated per protocol. The control arm (n=125) will undergo routine post-transplant monitoring. The primary outcome at 12 months is a composite of death-censored graft loss, clinical biopsy-proven acute rejection, de novo donor-specific antibody, inflammation in areas of interstitial fibrosis and tubular atrophy (Banff i-IFTA, chronic active T-cell mediated rejection) and subclinical tubulitis on 12-month surveillance biopsy. The secondary outcomes include decline of graft function, microvascular inflammation at 12 months, development of IFTA at 12 months, days from transplantation to clinical biopsy-proven rejection, albuminuria, EuroQol five-dimension five-level instrument, cost-effectiveness analysis of the urine CXCL10 monitoring strategy and the urine CXCL10 kinetics in response to rejection therapy.Ethics and disseminationThe study has been approved by the University of Manitoba Health Research Ethics Board (HS20861, B2017:076) and the local research ethics boards of participating centres. Recruitment commenced in March 2018 and results are expected to be published in 2023. De-identified data may be shared with other researchers according to international guidelines (International Committee of Medical Journal Editors [ICJME]).Trial registration numberNCT03206801; Pre-results.

Transition metal oxides of the $4d$ and $5d$ block have recently become the targets of materials discovery, largely due to their strong spin-orbit coupling that can generate exotic magnetic and electronic states. Here we report the high pressure synthesis of Lu$_2$Rh$_2$O$_7$, a new cubic pyrochlore oxide based on $4d^5$ Rh$^{4+}$ and characterizations via thermodynamic, electrical transport, and muon spin relaxation measurements. Magnetic susceptibility measurements reveal a large temperature-independent Pauli paramagnetic contribution, while heat capacity shows an enhanced Sommerfeld coefficient, $\gamma$ = 21.8(1) mJ/mol-Rh K$^2$. Muon spin relaxation measurements confirm that Lu$_2$Rh$_2$O$_7$ remains paramagnetic down to 2 K. Taken in combination, these three measurements suggest that Lu$_2$Rh$_2$O$_7$ is a correlated paramagnetic metal with a Wilson ratio of $R_W = 2.5$. However, electric transport measurements present a striking contradiction as the resistivity of Lu$_2$Rh$_2$O$_7$ is observed to monotonically increase with decreasing temperature, indicative of a nonmetallic state. Furthermore, although the magnitude of the resistivity is that of a semiconductor, the temperature dependence does not obey any conventional form. Thus, we propose that Lu$_2$Rh$_2$O$_7$ may belong to the same novel class of non-Fermi liquids as the nonmetallic metal FeCrAs., Comment: 11 pages, 5 figures

Women scientists are less likely to obtain Assistant Professorship and achieve promotion, and obtain less grant funding than men. Scientist/clinician-scientist training programs which provide salary awards as well as training and mentorship are a potential intervention to improve outcomes among women scientists. We hypothesized whether a programmatic approach to scientist/clinician-scientist training is associated with improved outcomes for women scientists in Canada when compared with salary awards alone. Trainees within the Kidney Research Scientist Core Education and National Training Program (KRESCENT), Canadian Child Health Clinician Scientist Program (CCHCSP), and the Canadian Institutes of Health Research (CIHR) salary award programs were evaluated.To examine whether the structured KRESCENT training program with salary support improves academic success for women scientists relative to salary awards alone.Retrospective cohort study.Canadian national research scientist and clinician-scientist training programs and salary awards.KRESCENT cohort (n = 59, 2005-2017), CCHCSP cohort (n = 58, 2002-2015), and CIHR (n = 571, 2005-2015) Salary Awardees for postdoctoral fellows (PDF) and new investigators (NI).National operating grant funding success, achieving an academic position as an Assistant Professor for PDF, or achieving promotion to Associate Professor for NI.The gender distribution of each cohort was determined using first name and NamepediA and was examined for PDF and NI, followed by a description of trainee outcomes by gender and training level.KRESCENT and CIHR PDF were balanced (12/27, 44% men and 55/116, 47% women) while CCHCSP had a higher proportion of women (13/20, 65%). KRESCENT and CCHCSP NI retained women scientists (19/32, 59% and 22/38, 58% women), whereas CIHR NI had fewer women (165/455, 36% women vs 290/455, 64% men,KRESCENT and CCHCSP training program cohort size and heterogeneity; assigning gender by first name may result in misclassification; lack of data on the respective applicant pools; and inability to examine intersectionality with gender, ethnicity, and sexual orientation.Overall trainee performance across programs is remarkable by community standards regardless of gender. KRESCENT and CCHCSP training programs demonstrated balanced success in their PDF and NI, whereas the CIHR awardees had reduced representation of women scientists from PDF to NI. This exploratory study highlights the utility of programmatic training approaches like the KRESCENT program as potential tools to support and retain women scientists in the academic pipeline during the challenging PDF to NI transition period.Les chercheuses sont moins susceptibles que les hommes d’obtenir une promotion ou un poste de professeur adjoint, en plus d’obtenir moins de subventions. Des programmes de formation pour les chercheurs et chercheurs cliniciens offrant des bourses salariales ainsi que de la formation et du mentorat pourraient s’avérer pertinents pour améliorer la situation des femmes en sciences. Nous avons émis l’hypothèse qu’une approche programmatique de la formation des chercheurs et chercheurs cliniciens pourrait améliorer les résultats pour les chercheuses canadiennes comparativement aux bourses salariales seules. Pour ce faire, les stagiaires du Programme national de formation scientifique et d’encadrement des chercheurs spécialisés dans le domaine rénal (KRESCENT), du Programme canadien des cliniciens-chercheurs en santé de l’enfant (PCCCSE) et des programmes de bourses salariales des Instituts de recherche en santé du Canada (IRSC) ont été évalués.Vérifier si le programme de formation structuré KRESCENT avec soutien salarial favorise le succès académique des scientifiques féminines par rapport aux bourses salariales uniquement.Étude de cohorte rétrospective.Programmes nationaux de formation et de bourses salariales pour les chercheurs et les chercheurs cliniciens du Canada.La cohorte KRESCENT (n = 59; 2005-2017), la cohorte PCCCSE (n = 58; 2002-2015) et les récipiendaires d’une bourse salariale des IRSC (n = 571; 2005-2015) destinées aux boursiers postdoctoraux (BPD) et aux nouveaux chercheurs (NC).Le succès du financement des subventions de fonctionnement nationales, l’obtention d’un poste de professeur adjoint à l’université pour les BPD ou l’obtention d’une promotion au poste de professeur agrégé pour les NC.La répartition des genres dans chaque cohorte a été déterminée à l’aide du prénom et de Namepedia, et a été examinée en fonction du statut (BPD ou NC). Les résultats des stagiaires ont été décrits selon le genre et le niveau de formation.Dans le cas des BPD, les cohortes KRESCENT et IRSC étaient plutôt équilibrées (44 % d’hommes [12/27] pour KRESCENT et 47 % [55/116] de femmes pour IRSC). Les femmes BPD étaient plus nombreuses dans la cohorte PCCCSE (13/20 [65 %]). Du côté des NC, les femmes étaient majoritaires dans les cohortes KRESCENT et PCCCSE (respectivement 59 % [19/32] et 58 % [22/38] de femmes) et les hommes étaient plus nombreux dans la cohorte IRSC (64 % d’hommes [290/455]; 36 % de femmes [165/455] [p = 0,01]). Nous avons observé un taux élevé de réussite des subventions de fonctionnement chez les NC (91 à 95 %) dans toutes les cohortes, sans égard au genre. Une forte proportion de BPD du PCCCSE avaient obtenu un poste de professeur adjoint (18/20 [90 %]); ceci pourrait s’expliquer en partie par le plus long suivi (9,3 ± 3 ans) comparativement aux BPD du KRESCENT (7/27 [26 %]; 0,88 ± 4,5 ans). Ces données n’étaient pas disponibles pour les BPD des IRSC. On a vu une augmentation des promotions à des postes de professeurs agrégés pour les nouvelles chercheuses de la cohorte KRESCENT (p = 0,02, pour 0,25 ± 3,2 ans de suivi). Les NC du PCCCSE présentaient un taux élevé de promotions (37/38 [97 %]; 6,9 ± 3,6 ans de suivi), indépendamment du genre. Une tendance globale pour un plus grand nombre d’hommes poursuivant des recherches biomédicales a été observée.Parmi les limites, on compte la taille et l’hétérogénéité des cohortes KRESCENT et PCCCSE; de possibles erreurs de classification dues à l’attribution du genre par le prénom; le manque de données sur les bassins respectifs de candidats; l’incapacité d’examiner l’intersectionnalité avec le genre, l’origine ethnique et l’orientation sexuelle.Le rendement global des stagiaires dans l’ensemble des programmes est remarquable, quel que soit leur genre, par rapport aux normes communautaires. Les programmes de formation de KRESCENT et PCCCSE ont démontré un succès équilibré chez leurs BPD et NC, tandis que les récipiendaires d’une bourse des IRSC ont montré une plus faible représentation de chercheuses tant chez les BPD et les NC. Cette étude exploratoire met en lumière la pertinence d’approches de formation programmatique comme le KRESCENT pour soutenir et retenir les scientifiques féminines dans le domaine académique pendant la difficile période de transition entre le statut de boursière postdoctorale et celui de nouvelle chercheuse.

Understanding the events leading to allorecognition and the subsequent effector pathways engaged is key for the development of strategies to prolong graft survival. Optimizing patient outcomes will require 2 major advancements: (1) minimizing premature death with a functioning graft in the patients with stable graft function, and (2) maximizing graft survival by avoiding the aforementioned allorecognition. This necessitates personalized immunosuppression to avoid known metabolic side effects, risk for infection, and malignancy, while holding the alloimmune system in check. Since the beginning of transplant a key strategy to achieve this goal is to minimize HLA mismatching between donor and recipient. What has not evolved is any refinement in our evaluation of HLA relatedness between donor and recipient when HLA mismatch exists. Donor-recipient HLA mismatch at the amino acid level can now be determined. These mismatches serve as potential epitopes for de novo donor specific antibody development and correlate with late rejection and graft loss. It is in this context that HLA epitope analysis is considered as a strategy to permit safe immunosuppression minimization to improve patient outcomes through: (1) improved allocation schemes that favor donor-recipient pairs with a low HLA epitope mismatch load (especially at the class II loci) or avoiding specific epitope mismatches known to be highly immunogenic and (2) immunosuppressive minimization in patients with low epitope mismatch loads or without highly immunogenic epitope mismatches.

The urinary CXC chemokine ligand (CXCL)10 detects renal transplant inflammation noninvasively, but has limited sensitivity and specificity. In this study, we performed urinary proteomic analysis to identify novel biomarkers that may improve the diagnostic performance of urinary CXCL10 for detecting alloimmune inflammation in renal transplant patients.In preliminary studies, adult renal transplant patients with normal histology (n = 5), interstitial fibrosis and tubular atrophy (n = 6), subclinical (n = 6) and clinical rejection (n = 6), underwent in-depth urine protein compositional analysis with LC-MS/MS, and matrix metalloproteinase-7 (MMP7) were identified as a potential candidate for the diagnosis of renal allograft inflammation. Urine MMP7 performance was then studied in a larger, prospective adult renal transplant population (n = 148 urines from n = 133 patients) with matched surveillance/indication biopsies. The diagnostic performance of urinary MMP7 and CXCL10 in combination was next evaluated using concordance (C-) statistics, net reclassification improvement and integrated discrimination improvement indices, to determine whether it was better than CXCL10 alone.Urinary MMP7:creatinine (Cr) was lower in normal transplants compared to those with inflammation: glomerulonephritis (P = 0.009), viral nephropathies (P = 0.002), interstitial fibrosis and tubular atrophy and inflammation (P = 0.04), borderline (P = 0.08), subclinical (P = 0.01) and clinical rejection (P = 0.0006), and acute tubular necrosis (P0.0001). Urinary MMP7:Cr and CXCL10:Cr significantly distinguished noninflamed from inflamed biopsies (area under the curve, 0.74 and 0.70, respectively). The addition of urinary MMP7:Cr to CXCL10:Cr improved the diagnostic performance for subclinical and clinical inflammation/injury by integrated discrimination improvement (P = 0.002) and net reclassification improvement (P = 0.006) analyses.Urinary MMP7:Cr improves the overall diagnostic performance of urinary CXCL10:Cr for distinguishing normal histology from subclinical and clinical inflammation/injury, but not subclinical inflammation alone.

Langasites have been studied extensively in past for their functional properties and use in telecommunication. A thorough understanding of their ground state is limited by the difficulty in synthesizing new members belonging to this series due to the formation of competing phases such as the garnets. Three magnetic langasites A3Ga3Ge2BeO14 (A=Pr, Nd, and Sm) and a non-magnetic lattice standard La3Ga3Ge2BeO14 were synthesized using the ceramic method. These were further characterized by X-ray diffraction, magnetization, magnetic susceptibility and heat capacity measurements. All three langasites exhibit net antiferromagnetic interactions at low temperatures and no evidence of long range magnetic ordering was observed down to 0.350 K.

Predicting allograft failure in kidney transplant recipients can help plan renal replacement therapy and guide patient-provider communication. The kidney failure risk equation (KFRE) accurately predicts the need for dialysis in patients with chronic kidney disease (CKD), but has not been validated in kidney transplant recipients.We sought to validate the 4-variable KFRE (age, sex, estimated glomerular filtration rate [eGFR], and urine albumin-to-creatinine ratio [ACR]) for prediction of 2- and 5-year death-censored allograft failure.Retrospective cohort study.Four independent North American Cohorts from Ontario, Canada; Alberta, Canada; Manitoba, Canada; and Wisconsin, United States, between January 1999 and December 2017.Adult kidney transplant patients at 1-year posttransplantation.Kidney failure risk as measured by the KFRE (eGFR, urine ACR, age, and sex).We included all adult patients who had at least 1 serum creatinine and at least 1 urine ACR measurement approximately 1 year following kidney transplantation. The performance of the KFRE was evaluated using the area under the receiver operating characteristic curve (C-statistic). C-statistics from the 4 cohorts were meta-analyzed using random-effects models.A total of 3659 patients were included. Pooled C-statistics were good in the entire population, at 0.81 (95% confidence interval: 0.72-0.91) for the 2-year KFRE and 0.73 (0.67-0.80) for the 5-year KFRE. Discrimination improved among patients with poorer kidney function (eGFR45 mL/min/1.73 mThe KFRE does not predict episodes of acute rejection and there was heterogeneity between cohorts.The KFRE accurately predicts kidney failure in kidney transplant recipients at 1-year posttransplantation. Further validation in larger cohorts with longer follow-up times can strengthen the case for clinical implementation.En transplantation rénale, la capacité de prévoir la défaillance du greffon permet de planifier une thérapie de remplacement rénal et de guider la communication entre le patient et son soignant. L’équation KFRE (Nous souhaitions valider le pouvoir prédictif de l’équation KFRE à 4 variables (âge, sexe, débit de filtration glomérulaire estimé [DFGe] et rapport albumine-créatine urinaire [RAC]) quant à la défaillance du greffon après deux ans et cinq ans.Étude de cohorte rétrospective.Quatre cohortes indépendantes d’Amérique du Nord : trois provinces canadiennes (Ontario, Alberta et Manitoba) et un état américain (Wisconsin) entre janvier 1999 et décembre 2017.Des adultes receveurs d’une greffe rénale, un an après l’intervention.Le risque d’évolution vers l’insuffisance rénale, tel que mesuré par l’équation KFRE (DFGe, RAC urinaire, âge et sexe).Ont été inclus tous les patients adultes ayant eu au moins une mesure de la créatinine sérique et du RAC urinaire environ un an après la greffe. La performance de la KFRE a été évaluée par la surface sous la courbe ROC (statistique C). Des modèles à effets aléatoires ont été employés pour la méta-analyse des statistiques C pour les quatre cohortes.Un total de 3 659 patients a été inclus. Les statistiques C regroupées ont été bonnes dans l’ensemble de la population étudiée, avec des valeurs de 0,81 (intervalle de confiance à 95 % : 0,72-0,91) pour la prédiction sur deux ans et de 0,73 (0,67-0,80) pour la prédiction sur cinq ans. La discrimination s’est avérée encore meilleure pour les patients qui présentaient une plus faible fonction rénale (DFGe45 ml/min/1,73 mLa KFRE ne peut prédire les épisodes de rejet aigu et les cohortes étudiées comportaient une grande hétérogénéité.L’équation KFRE prédit avec exactitude le risque de défaillance du greffon dans notre population de receveurs d’une greffe rénale, un an après l’intervention. Poursuivre la validation dans de plus vastes cohortes et pour des temps de suivi prolongés viendrait appuyer le cas en vue de son application clinique.

The XY pyrochlore Yb$_2$Ti$_2$O$_7$, with pseudo spin 1/2 at the Yb$^{3+}$ site, has been celebrated as potential host for the quantum spin ice state. The substitution of non-magnetic Ti with Pt gives Yb$_2$Pt$_2$O$_7$, a system with remarkably similar magnetic properties. The large nuclear gyromagnetic ratio ($\gamma_{n}/2 \pi = 9.15$~MHz/T) of $^{195}$Pt makes Yb$_2$Pt$_2$O$_7$ an ideal material for NMR investigation of its unconventional magnetic properties. Based on the $^{195}$Pt nuclear spin-lattice relaxation rate $1/T_1$ and the magnetic specific heat $C_{p}$ measured in a broad range of magnetic field $B_{ext}$, we demonstrate that the field-induced magnon gap linearly decreases with $B_{ext}$ but additional low energy mode of spin excitations emerge below $\sim 0.5$~T.

Over the past two decades, the magnetic ground states of all rare-earth titanate pyrochlores have been extensively studied, with the exception of ${\mathrm{Sm}}_{2}{\mathrm{Ti}}_{2}{\mathrm{O}}_{7}$. This is, in large part, due to the very high absorption cross section of naturally occurring samarium, which renders neutron scattering infeasible. To combat this, we have grown a large, isotopically enriched single crystal of ${\mathrm{Sm}}_{2}{\mathrm{Ti}}_{2}{\mathrm{O}}_{7}$. Using inelastic neutron scattering, we determine that the crystal field ground state for ${\mathrm{Sm}}^{3+}$ is a dipolar-octupolar doublet with Ising anisotropy. Neutron diffraction experiments reveal that ${\mathrm{Sm}}_{2}{\mathrm{Ti}}_{2}{\mathrm{O}}_{7}$ orders into the all-in, all-out magnetic structure with an ordered moment of $0.44(7){\ensuremath{\mu}}_{B}$ below ${T}_{N}=0.35$ K, consistent with expectations for antiferromagnetically coupled Ising spins on the pyrochlore lattice. Zero-field muon spin relaxation measurements reveal an absence of spontaneous oscillations and persistent spin fluctuations down to 0.03 K. The combination of the dipolar-octupolar nature of the ${\mathrm{Sm}}^{3+}$ moment, the all-in, all-out ordered state, and the low-temperature persistent spin dynamics make this material an intriguing candidate for moment fragmentation physics.

Background Antibody-mediated rejection is a major cause of premature graft loss in kidney transplantation. Multiple scoring systems are available to assess the HLA mismatch between donors and recipients at the molecular level; however, their correlation with the development of de novo donor-specific antibody (dnDSA) has not been compared in recipients on active immunosuppression. Methods HLA-DRβ1/3/4/5/DQα1β1 molecular mismatch was determined using eplet analysis, amino acid mismatch, and electrostatic mismatch for 596 renal transplant recipients and correlated with HLA-DR/DQ dnDSA development. The molecular mismatch scores were evaluated in multivariate models of posttransplant dnDSA-free survival. Results Eplet mismatch correlated with amino acid mismatch and electrostatic mismatch (R2 = 0.85-0.96). HLA-DR dnDSA-free survival correlated with HLA-DR eplet mismatch (hazards ratio [HR], 2.50 per 10 eplets mismatched; P < 0.0001), amino acid mismatch (HR, 1.49 per 10 amino acids mismatched; P < 0.0001), and electrostatic mismatch (HR, 1.23 per 10 units mismatched; P < 0.0001). HLA-DQ dnDSA-free survival correlated with HLA-DQ eplet mismatch (HR, 1.98 per 10 eplets mismatched; P < 0.0001), amino acid mismatch (HR, 1.24 per 10 amino acids mismatched; P < 0.0001), and electrostatic mismatch (HR, 1.14 per 10 units mismatched; P < 0.0001). All 3 methods were significant multivariate correlates of dnDSA development after adjustment for recipient age, baseline immunosuppression, and nonadherence. Conclusions HLA molecular mismatch represents a precise method of alloimmune risk assessment for renal transplant patients. The method used to determine the molecular mismatch is likely to be driven by familiarity and ease of use as highly correlated results are produced by each method., In order to assess alloimmune risk in kidney transplant recipiennts, the authors compare 3 methods evaluating HLA molecular mismatch (HLA-DG eplet, amino acid and electrostatic) which all correlate with adjusted dnDSA development. Supplemental digital content is available in the text.

Although $S=1/2$ kagom\'e systems have been intensely studied theoretically, and within the past decade been realized experimentally, much less is known about the $S=1$ analogs. While the theoretical ground state is still under debate, it has been found experimentally that $S=1$ kagom\'e systems either order at low temperatures or enter a spin glass state. In this work, ${\mathrm{YCa}}_{3}{(\mathrm{VO})}_{3}{({\mathrm{BO}}_{3})}_{4}$ (YCVBO) is presented, with trivalent vanadium. Owing to its unusual crystal structure, the metal-metal bonding is highly connected along all three crystallographic directions, atypical of other kagom\'e materials. Using neutron scattering it is shown that YCVBO fails to order down to at least 50 mK and exhibits broad and dispersionless excitations. $^{11}\mathrm{B}$ NMR provides evidence of fluctuating spins at low temperatures while dc magnetization shows critical scaling that is also observed in systems near a quantum critical point such as Herbertsmithite, despite its insulating nature and $S=1$ magnetism. The evidence shown indicates that YCVBO is naturally tuned to be a quantum disordered magnet in the limit of $T=0$ K.

Urinary CXCL10 and metabolites are biomarkers independently associated with TCMR. We sought to test whether these biomarkers fluctuate in association with histological severity of TCMR over short time frames. Forty-nine pairs of renal biopsies obtained 1-3 months apart from 40 pediatric renal transplant recipients were each scored for TCMR acuity score (i + t; Banff criteria). Urinary CXCL10:Cr and TCMR MDS were obtained at each biopsy and were tested for association with changes between biopsies in acuity, estimated GFR (ΔeGFR), and 12-month ΔeGFR. Sequential biopsies were obtained 1.8 ± 0.8 months apart. Biopsy 1 was usually obtained under protocol (75%), and 62% percent had evidence of TCMR. Using each biopsy pair for comparison, ΔeGFR did not predict change in acuity. By contrast, change in acuity was significantly correlated with change in urinary CXCL10:Cr (ρ 0.45, P = .003) and MDS (ρ 0.29, P = .04) between biopsies. The 12-month ΔeGFR was not predicted by TCMR acuity or CXCL10:Cr at Biopsy 2; however, an inverse correlation was seen with urinary MDS (ρ -0.35; P = .02). Changes in eGFR correlate poorly with evolving TCMR acuity on histology. Urinary biomarkers may be superior for non-invasive monitoring of rejection, including histological response to therapy, and may be prognostic for medium-term function.

This chapter explores the programmatic components of a successful strength-based school serving twice exceptional (2e) students in grades 4 through 12. The chapter first provides a brief overview of the school’s background to shed light on the unique learning needs of 2e students and discusses the institutional foundations and beliefs that best support student growth. An overview of the school’s Multiple Perspectives Model shows how faculty members focus on several factors—including students’ gifts and talents, learning differences, and family contexts—to make decisions about learning strategies in a dynamic educational environment. The school stresses the importance of a culture of appreciation of students’ strengths while differentiating and dual differentiating their curricula to move students forward to appropriate levels of depth and complexity in their learning. Finally, the chapter underscores the need for flexible school policies that embrace creative problem-solving and put the needs of the student above external rules and regulations.

The current immunosuppressive pipeline in kidney transplantation is limited. In part, this is due to excellent one-year allograft outcomes with the current standard of care (ie, calcineurin inhibitor in combination with anti-proliferative agents). Despite this success, a recent Federal government-sponsored systematic review has identified gaps/limits in the evidence of what constitutes optimal calcineurin inhibitor use in the short- and long-term. Moreover, recent empiric approaches to minimize/withdraw/convert from calcineurin inhibitors have come with the price of increased alloreactivity. As the time horizon to replace calcineurin inhibitors on a global scale may be distant, the transplant community should seize the opportunity to develop ways to personalize calcineurin inhibitor immunosuppression to the individual-transitioning from empiricism to precision. The authors argue in this viewpoint that the path to precision will require measures capable of detecting subclinical alloreactivity to define adequacy of immunosuppression, as well as novel genetic analytics to accurately define alloimmune risk at the individual level-both approaches will require validation in clinical trials.

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.