Forty-Year Survival of Simultaneous Kidney and Duct-Injected Segmental Pancreas Transplants in a Recipient Maintained on Low-Dose Azathioprine and Prednisone.

Here, we report on the remarkable survival of a simultaneous kidney-pancreas transplant recipient who has received minimal immunosuppression, has had normal kidney function, and has been insulin-free for 40 years since her transplant surgery.

TAK-101 Nanoparticles Induce Gluten-Specific Tolerance in Celiac Disease: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND & AIMS: In celiac disease (CeD), gluten induces immune activation, leading to enteropathy. TAK-101, gluten protein (gliadin) encapsulated in negatively charged poly(dl-lactide-co-glycolic acid) nanoparticles, is designed to induce gluten-specific tolerance. METHODS: TAK-101 was evaluated in phase 1 dose escalation safety and phase 2a double-blind, randomized, placebo-controlled studies. Primary endpoints included pharmacokinetics, safety, and tolerability of TAK-101 (phase 1) and change from baseline in circulating gliadin-specific interferon-γ-producing cells at day 6 of gluten challenge, in patients with CeD (phase 2a). Secondary endpoints in the phase 2a study included changes from baseline in enteropathy (villus height to crypt depth ratio [Vh:Cd]), and frequency of intestinal intraepithelial lymphocytes and peripheral gut-homing T cells. RESULTS: In phase 2a, 33 randomized patients completed the 14-day gluten challenge. TAK-101 induced an 88% reduction in change from baseline in interferon-γ spot-forming units vs placebo (2.01 vs 17.58, P = .006). Vh:Cd deteriorated in the placebo group (-0.63, P = .002), but not in the TAK-101 group (-0.18, P = .110), although the intergroup change from baseline was not significant (P = .08). Intraepithelial lymphocyte numbers remained equal. TAK-101 reduced changes in circulating α4ß7+CD4+ (0.26 vs 1.05, P = .032), αEß7+CD8+ (0.69 vs 3.64, P = .003), and γδ (0.15 vs 1.59, P = .010) effector memory T cells. TAK-101 (up to 8 mg/kg) induced no clinically meaningful changes in vital signs or routine clinical laboratory evaluations. No serious adverse events occurred. CONCLUSIONS: TAK-101 was well tolerated and prevented gluten-induced immune activation in CeD. The findings from the present clinical trial suggest that antigen-specific tolerance was induced and represent a novel approach translatable to other immune-mediated diseases. ClinicalTrials.gov identifiers: NCT03486990 and NCT03738475.

Avoiding surveillance biopsy: Use of a noninvasive biomarker assay in a real-life scenario.

PURPOSE: TruGraf™ blood test measures a specific gene expression signature in peripheral blood mononuclear cells for noninvasive assessment of kidney transplant recipients (KTRs) with stable renal function, excluding subclinical acute rejection (subAR) with high degree of confidence. Study objective was to correlate TruGraf™ test with 6-month surveillance biopsy (SBx). METHODS: Prospective, single-center study of 116 consecutive KTRs with SBx performed at 6 months post-transplant..TruGraf™ done at time of SBx; results compared with histology (Banff 2017) for concordance. RESULTS: Of 116 enrollees, 26 excluded, absent biopsy (n = 17), test quality control issues (n = 9), leaving 90 KTRs-66% deceased donor kidneys, 58% African American, and 59% male. TruGraf™ result negative in 67 subjects; 54 had normal biopsy, indicating SBx could have been avoided. Eight subjects had true positive result where biopsy justified. Unnecessary biopsy would have been performed in 15 subjects with false-positive TruGraf™, and subAR missed in 13 subjects with false-negative test. In overall population of 90 patients, SBx would have been avoided in 54 (60%). CONCLUSIONS: Implementation of TruGraf™ testing in a "real-world" cohort at the time of SBx identified a significant proportion of KTRs that could have avoided SBx.

Kidney Graft Surveillance Biopsy Utilization and Trends: Results From a Survey of High-Volume Transplant Centers.

An e-mail-based market research survey focused on high-volume US adult transplant centers was developed and implemented to assess surveillance based on United Network for Organ Sharing/Scientific Registry of Transplant Recipients data: 51 to 100 transplants, 101 to 200 transplants, and more than 200 transplants. Eighty-three centers responded to the survey. Respondent centers represented 13,837/21,167 (65%) of the total kidney transplants in 2018. In total, 38/83 (46%) centers reported the use of surveillance biopsies-20 centers in all patients and 18 in select patients. Surveillance biopsies were performed in 37% (7/19) of centers performing 51 to 100 transplants annually, in 44% (15/34) doing 101 to 200 transplants, and in 53% (16/30) of centers doing more than 200 transplants. Of the 20 centers doing surveillance biopsies in all patients, 17/20 (85%) perform more than 100 annual transplants, and 3/20 (15%) perform less than 100 annual transplants. Of the 45 centers not currently doing surveillance biopsies, 13 (29%) used surveillance biopsies in the past; discontinuation was primarily due to patient inconvenience, adverse events, and cost. Using survey percentages, it is estimated that surveillance biopsies are performed in approximately 34% of kidney transplant recipients and that 74% of all surveillance biopsies occur in centers performing more than 100 kidney transplants per year.

Serial Peripheral Blood Gene Expression Profiling to Assess Immune Quiescence in Kidney Transplant Recipients with Stable Renal Function.

BACKGROUND TruGraf is a blood-based biomarker test that measures differential expression of a collection of genes that have been shown to correlate with surveillance biopsy results. However, in the majority of U.S. transplant centers, surveillance biopsies are not performed. The objectives of this study were to evaluate the clinical validity of TruGraf in stable kidney transplant recipients and to demonstrate the potential clinical utility of serial TruGraf testing in a center not utilizing surveillance biopsies. MATERIAL AND METHODS Serum creatinine levels, TruGraf testing at multiple time points, and subsequent clinical follow-up were obtained for 28 patients. RESULTS Overall concordance of TruGraf results, when compared with independent clinical assessment of testing, was 77% (54/70) for all tests; 79% (22/28) for test 1, 75% (21/28) for test 2, and 79% (11/14) for test 3. The negative predictive value (NPV) was 98.0%. Analysis of clinical utility indicated that 77% of TruGraf results would have been useful in patient management. CONCLUSIONS Our results indicate the value of serial TruGraf testing in those transplant centers that do not perform surveillance biopsies as part of their standard of care. The high negative predictive value indicates the ability of TruGraf to confirm immune quiescence with a high degree of probability in patients with a Transplant eXcellence (TX) result, without the need to perform a surveillance biopsy.

Application of TruGraf v1: A Novel Molecular Biomarker for Managing Kidney Transplant Recipients With Stable Renal Function.

TruGraf v1 is a laboratory-developed DNA microarray-based gene expression blood test to enable proactive noninvasive serial assessment of kidney transplant recipients with stable renal function. It has been previously validated in patients identified as Transplant eXcellence (TX: stable serum creatinine, normal biopsy results, indicative of immune quiescence), and not-TX (renal dysfunction and/or rejection on biopsy results). TruGraf v1 is intended for use in subjects with stable renal function to measure the immune status as an alternative to invasive, expensive, and risky surveillance biopsies. MATERIALS AND METHODS: In this study, simultaneous blood tests and clinical assessments were performed in 192 patients from 7 transplant centers to evaluate TruGraf v1. The molecular testing laboratory was blinded to renal function and biopsy results. RESULTS: Overall, TruGraf v1 accuracy (concordance between TruGraf v1 result and clinical and/or histologic assessment) was 74% (142/192), and a result of TX was accurate in 116 of 125 (93%). The negative predictive value for TruGraf v1 was 90%, with a sensitivity 74% and specificity of 73%. Results did not significantly differ in patients with a biopsy-confirmed diagnosis vs those without a biopsy. CONCLUSIONS: TruGraf v1 can potentially support a clinical decision enabling unnecessary surveillance biopsies with high confidence, making it an invaluable addition to the transplant physician's tool kit for managing patients. TruGraf v1 testing can potentially avoid painful and risky invasive biopsies, reduce health care costs, and enable frequent assessment of patients with stable renal function to confirm the presence of immune quiescence in the peripheral blood.

Investigator Assessment of the Utility of the TruGraf Molecular Diagnostic Test in Clinical Practice.

BACKGROUND: TruGraf v1 is a well-validated DNA microarray-based test that analyzes blood gene expression profiles as an indicator of immune status in kidney transplant recipients with stable renal function. METHODS: In this study, investigators assessed clinical utility of the TruGraf test in patient management. In a retrospective study, simultaneous blood tests and clinical assessments were performed in 192 patients at 7 transplant centers, and in a prospective observational study they were performed in 45 subjects at 5 transplant centers. RESULTS: When queried regarding whether or not the TruGraf test result impacted their decision regarding patient management, in 168 of 192 (87.5%) cases the investigator responded affirmatively. The prospective study indicated that TruGraf results supported physicians' decisions on patient management 87% (39/45) of the time, and in 93% of cases physicians indicated that they would use serial TruGraf testing in future patient management. A total of 21 of 39 (54%) reported results confirmed their decision that no intervention was needed, and 17 of 39 (44%) reported that results specifically informed them that a decision not to perform a surveillance biopsy was correct. CONCLUSIONS: TruGraf is the first and only noninvasive test to be evaluated for clinical utility in determining rejection status of patients with stable renal function and shows promise of providing support for clinical decisions to avoid unnecessary surveillance biopsies with a high degree of confidence. TruGraf is an invaluable addition to the transplant physician's tool kit for managing patient health by avoiding painful and invasive biopsies, reducing health care costs, and enabling frequent assessment of patients with stable renal function to confirm immune quiescence.

The importance of drug safety and tolerability in the development of new immunosuppressive therapy for transplant recipients: The Transplant Therapeutics Consortium's position statement.

The Transplant Therapeutics Consortium (TTC) is a public-private partnership between the US Food and Drug Administration and the transplantation community including the transplantation societies and members of the biopharmaceutical industry. The TTC was formed to accelerate the process of developing new medical products for transplant patients. The initial goals of this collaboration are the following: (a) To define which aspects of the kidney transplant drug-development process have clear needs for improvement from an industry and regulatory perspective; (b) to define which of the unmet needs in the process could be positively impacted through the development of specific drug-development tools based on available data; and (c) to determine the most appropriate pathway to achieve regulatory acceptance of the proposed process-accelerating tools. The TTC has identified 2 major areas of emphasis: new biomarkers or endpoints for determining the efficacy of new therapies and new tools to assess the safety or tolerability of new therapies. This article presents the rationale and planned approach to develop new tools to assess safety and tolerability of therapies for transplant patients. We also discuss how similar efforts might support the continued development of patient-reported outcome measures in the future.

The Early Psychosis Screener (EPS): Item development and qualitative validation.

A panel of experts assembled and analyzed a comprehensive item bank from which a highly sensitive and specific early psychosis screener could be developed. Twenty well-established assessments relating to the prodromal stage, early psychosis, and psychosis were identified. Using DSM-5 criteria, we identified the core concepts represented by each of the items in each of the assessments. These granular core concepts were converted into a uniform set of 490 self-report items using a Likert scale and a 'past 30days' time frame. Partial redundancy was allowed to assure adequate concept coverage. A panel of experts and TeleSage staff rated these items and eliminated 189 items, resulting in 301 items. The items were subjected to five rounds of cognitive interviewing with 16 individuals at clinically high risk for psychosis and 26 community mental health center patients. After each round, the expert panel iteratively reviewed, rated, revised, added, or deleted items to maximize clarity and centrality to the concept. As a result of the interviews, 36 items were revised, 52 items were added, and 205 items were deleted. By the last round of cognitive interviewing, all of the items were clearly understood by all participants. In future work, responses to the final set of 148 items and machine learning techniques will be used to quantitatively identify the subset of items that will best predict clinical high-risk status and conversion.

Orthogonal Comparison of Molecular Signatures of Kidney Transplants With Subclinical and Clinical Acute Rejection: Equivalent Performance Is Agnostic to Both Technology and Platform.

We performed orthogonal technology comparisons of concurrent peripheral blood and biopsy tissue samples from 69 kidney transplant recipients who underwent comprehensive algorithm-driven clinical phenotyping. The sample cohort included patients with normal protocol biopsies and stable transplant (sTx) function (n = 25), subclinical acute rejection (subAR, n = 23), and clinical acute rejection (cAR, n = 21). Comparisons between microarray and RNA sequencing (RNA-seq) signatures were performed and demonstrated a strong correlation between the blood and tissue compartments for both technology platforms. A number of shared differentially expressed genes and pathways between subAR and cAR in both platforms strongly suggest that these two clinical phenotypes form a continuum of alloimmune activation. SubAR is associated with fewer or less expressed genes than cAR in blood, whereas in biopsy tissues, this clinical phenotype demonstrates a more robust molecular signature for both platforms. The discovery work done in this study confirms a clear ability to detect gene expression profiles for sTx, subAR, and cAR in both blood and biopsy tissue, yielding equivalent predictive performance that is agnostic to both technology and platform. Our data also provide strong biological insights into the molecular mechanisms underlying these signatures, underscoring their logistical potential as molecular diagnostics to improve clinical outcomes following kidney transplantation.

The DSM revision process: needing to keep an eye on the empirical ball.

From DSM-III onward, successive DSM editions have strived to ground the diagnostic definitions in empirical evidence. DSM-IV established a three-stage process of empirical review, consisting of comprehensive and systematic literature reviews, secondary analyses of datasets, and field trials to provide reliability and validity data for the most substantial or controversial proposals. DSM-IV Work Group members were required to review the empirical literature to document explicitly the evidence supporting the text and criteria published in DSM-IV. As noted by Kendler and Solomon (2016), in contrast to the emphasis on systematic reviews in medicine which is a manifestation of the evidence-based medicine movement, such systematic evidence-based reviews have not been consistently integrated into the development of DSM-5, raising questions about empirical rigor underlying the DSM-5 revision. It is likely that this regression in terms of anchoring the revision process in a comprehensive review of empirical data stemmed from the emphasis during the DSM-5 revision process on trying to move DSM-5 from its categorical descriptive approach towards a more etiological dimensional approach. Although such a shift ultimately did not occur, the effort spent on trying to achieve a paradigm shift likely came at the expense of the hard work of conducting systematic empirical reviews. For the DSM to continue to remain credible in the current era of evidence-based medicine, it is essential that the developers of future editions of the DSM avoid taking their eye off the empirical ball and insure that the manual remains grounded in solid empirical evidence.

Performance characteristics and clinical utility of diagnostic criteria proposals in bereaved treatment-seeking patients.

BACKGROUND: Persistent complex bereavement disorder (PCBD) is a protracted form of grief included in DSM Section 3 indicating a need for more research. Two other criteria sets [prolonged grief disorder (PGD) and complicated grief (CG) disorder] are also currently in use by researchers. This study evaluates rates of diagnosis of each proposed criteria set in a clinical sample of bereaved individuals participating in clinical research. METHOD: Two groups in which persistent grief was judged to be present or absent completed an assessment instrument that included items needed to diagnose PCBD as well as PGD and CG. One group included grief treatment-seeking participants in our multicenter National Institute of Mental Health (NIMH)-sponsored study who scored ⩾30 on the Inventory of Complicated Grief (ICG) and the other comprised bereaved adults enrolled in clinical research studies who scored <20 on the ICG. Rates of diagnosis were determined for proposed PCBD, PGD and CG criteria. RESULTS: PCBD criteria diagnosed 70 [95% confidence interval (CI) 64.2-75.8] % of the grief treatment-seeking group, PGD criteria identified 59.6 (95% CI 53.4-65.8) % of these individuals and CG criteria identified 99.6 (95% CI 98.8-100.0) %. None of the three proposed criteria identified any cases in the bereaved comparison group. CONCLUSIONS: Both proposed DSM-5 criteria for PCBD and criteria for PGD appear to be too restrictive as they failed to identify substantial numbers of treatment-seeking individuals with clinically significant levels of grief-related distress and impairment. Use of CG criteria or a similar algorithm appears to be warranted.

Pharmacokinetics of prolonged-release tacrolimus and implications for use in solid organ transplant recipients.

Prolonged-release tacrolimus was developed as a once-daily formulation with ethylcellulose as the excipient, resulting in slower release and reduction in peak concentration (Cmax ) for a given dose compared with immediate-release tacrolimus, which is administered twice daily. This manuscript reviews pharmacokinetic information on prolonged-release tacrolimus in healthy subjects, in transplant recipients converted from immediate-release tacrolimus, and in de novo kidney and liver transplant recipients. As with the immediate-release formulation, prolonged-release tacrolimus shows a strong correlation between trough concentration (Cmin ) and area under the 24-hour time-concentration curve (AUC24 ), indicating that trough whole blood concentrations provide an accurate measure of drug exposure. We present the pharmacokinetic similarities and differences between the two formulations, so that prescribing physicians will have a better understanding of therapeutic drug monitoring in patients receiving prolonged-release tacrolimus.

New-Onset Diabetes After Transplantation: Results From a Double-Blind Early Corticosteroid Withdrawal Trial.

New-onset diabetes after transplantation (NODAT) is an important complication following kidney transplantation. Data from the 5-year early steroid withdrawal double-blind randomized trial were analyzed to determine if steroid avoidance reduced the NODAT risk. Incidence, timing and risk factors for NODAT were evaluated using eight definitions. By American Diabetes Association definition, 36.3% of patients on chronic corticosteroids (CCS) and 35.9% on early corticosteroid withdrawal (CSWD) were diagnosed with NODAT by 5 years. The definition combining fasting blood glucose ≥126 mg/dL on two occasions or treatment identified slightly more cases of NODAT: CCS (39.3%) and CSWD (39.4%). Through 5 years posttransplant, the proportion of NODAT patients requiring treatment were similar (CSWD 22.5% vs. CCS 21.5%); however, insulin therapy was lower with CSWD (3.7% vs. 11.6%; p = 0.049). By multivariate analysis, only age, but not corticosteroid use, was a significant risk factor for NODAT for more than one definition. Numerical, but not statistically significant trends toward lower NODAT rates with CSWD were observed through 5 years for insulin use, HbA1c ≥6.0% and ≥6.5% on two occasions. This prospective, randomized trial of CSWD indicates that CSWD has a limited impact in reducing NODAT when compared to low-dose prednisone (5 mg/day from month 6 to 5 years).

Interleukin-2 receptor antagonist therapy leads to increased tacrolimus levels after kidney transplantation.

BACKGROUND: Tacrolimus (TAC) is a known substrate for cytochrome P450 (CYP) enzyme. CYP enzyme activity can be modulated by activation of IL-2 receptors (IL-2R) expressed on hepatocytes and intestinal cells. IL-2R antagonists (IL-2RA) may promote preferential binding of circulating IL-2 to IL-2Rs on these cells by blocking IL-2Rs on activated T cells. This downregulates CYP enzymes, leading to increased calcineurin inhibitor levels. This analysis evaluates the significance of this drug-drug interaction in kidney transplant recipients. METHODS: Data were used from a previous 5-year randomized, controlled study comparing outcomes associated with maintenance immunosuppression using 2 corticosteroid regimens: long-term therapy versus early withdrawal. Patients received either IL-2RAs or rabbit anti-thymocyte globulin (rATG) for induction. Serial TAC trough levels and doses were compared between induction agents within each corticosteroid arm. Rejection rates, patient/graft survival, and TAC adverse effects were also evaluated. RESULTS: In the first week, IL-2RA-treated patients achieved significantly higher trough levels and required lower doses (in milligram per kilogram) to achieve target levels than rATG-treated patients. No significant differences in rejection rates, patient/graft survival, or rate of adverse effects were observed through 1 year.

Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients.

BACKGROUND: In a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported. METHODS: Evaluations included patient and graft survival, study drug discontinuations, laboratory values including renal function and development of new-onset diabetes after transplantation, concomitant medications, and adverse events. RESULTS: At study termination, 129 Astagraf XL, 113 Prograf, and 79 CsA patients had continued follow-up. Demographic and baseline characteristics were similar in all arms. Four-year Kaplan-Meier estimates of patient survival in the Astagraf XL, Prograf, and CsA groups were 93.2, 91.2, and 91.7%, respectively, while graft survival was 84.7, 82.7, and 83.9%, respectively. At least one serious adverse event was reported in the majority of patients in each group during the study (65.9% Astagraf XL, 69.8% Prograf, and 65.6% CsA). Renal function was not significantly different between Astagraf XL and Prograf. HgbA1c levels were collected every 6 months; the 4-year Kaplan-Meier estimate for incidence of HgbA1c levels ≥ 6.5% was significantly higher for both tacrolimus formulations compared to CsA; 41.1% (Astagraf XL), 33.6% (Prograf), and 21.3% (CsA). CONCLUSIONS: In this 4-year follow-up report, patients receiving Astagraf XL and Prograf showed comparable efficacy and safety profiles, with a higher incidence of new-onset diabetes after transplantation but superior renal function compared to patients receiving CsA.

New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials.

BACKGROUND: New-onset diabetes after transplantation (NODAT) occurs commonly. Prior NODAT definitions have been inconsistent. Based on the American Diabetic Association criteria, we propose a new approach to defining NODAT. METHODS: Analysis of 1416 at-risk transplant recipients was performed. Data from three de novo Astellas registration transplant studies (two kidney and one liver) evaluated NODAT in 634 at-risk patients receiving tacrolimus, 630 at-risk patients receiving tacrolimus extended release, and 152 at-risk patients receiving cyclosporine. NODAT was defined as a composite endpoint consisting of first occurrence of one of four parameters: (i) two fasting plasma glucose levels ≥ 126 mg/dL (≥ 7.0 mmol/L) ≥ 30 days apart, (ii) oral hypoglycemic agent use for ≥ 30 consecutive days, (iii) insulin therapy for ≥ 30 consecutive days, and (iv) hemoglobin A1c ≥ 6.5%. We evaluated each of the above parameters, as well as the composite endpoint, in an attempt to establish an appropriate clinical approach to the diagnosis of NODAT. RESULTS: The composite definition results in a 1-year NODAT incidence of 30% to 37% in kidney and 44% to 45% in liver transplant recipients treated with tacrolimus. NODAT incidence was significantly higher with tacrolimus than cyclosporine; there was no difference between the two tacrolimus formulations. CONCLUSIONS: Based on these analyses, the proposed composite definition for NODAT, incorporating broader criteria, is recommended for clinical trials. Appropriate definitions of NODAT allow for a better understanding of the incidence of this complication and may result in earlier initiation of therapy with improved long-term outcomes.

Acute rejection characteristics from a prospective, randomized, double-blind, placebo-controlled multicenter trial of early corticosteroid withdrawal.

BACKGROUND: This report characterizes acute rejection and rejection outcomes in subjects randomized to continuous corticosteroid therapy (CCS) or early corticosteroid withdrawal (CSWD; 7 days after transplantation) in the Astellas Blinded CSWD Trial. METHODS: The Astellas Blinded CSWD Trial was a 5-year, prospective, multicenter, randomized, double-blind trial of early CCS withdrawal in 386 kidney transplant recipients (195 CCS and 191 CSWD). Tacrolimus and mycophenolate mofetil were required as well as either rabbit antithymocyte globulin or interleukin-2 receptor antibody induction. Biopsy-confirmed acute rejection (BCAR) was grade 1A or higher by Banff criteria. This report also provides borderline changes (BL) that did not meet Banff grade 1A included with BCAR (BCAR+BL). RESULTS: BCAR+BL was 25 (12.8%) in CCS group and 42 (22.0%) in CSWD group (P=0.022). Early BCAR+BL (first 90 days after transplantation) was less frequent in CCS (n=5 [2.6%]) than in CSWD (n=22 [11.5%]; P<0.001). Among non-African-American subjects, early BCAR+BL occurred more often in CSWD (n=20 [12.7%]) versus CCS (n=2 [1.3%]; P<0.001). Late acute rejection (>2 years) occurred more often in African-American subjects in CCS (n=5 [13.9%]) than in CSWD (n=0; P=0.056). Risk factors were CSWD (hazard ratio [HR], 4.72; P<0.002) and human leukocyte antigen mismatch (HR, 1.48; P<0.005) for early BCAR+BL and CSWD (HR, 1.9; P<0.02), human leukocyte antigen mismatch (HR, 1.2; P<0.01), and age (HR, 0.97; P<0.002) for 5-year rejection. The HR for graft loss associated with BCAR+BL was 8.8. CONCLUSIONS: BCAR+BL may occur more frequently during the early period after transplantation under an early CSWD regimen with tacrolimus plus induction compared with CCS, particularly among non-African-Americans.

Alemtuzumab induction in renal transplantation.

BACKGROUND: There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS: In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups. CONCLUSIONS: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.).

Assessment of efficacy and safety of FK778 in comparison with standard care in renal transplant recipients with untreated BK nephropathy.

BACKGROUND: BK polyomavirus infection has been reported in 10% to 60% of renal transplant recipients with progression to BK nephropathy (BKN) occurring in 1% to 5% of patients. Graft loss occurs in up to 60% of renal transplant recipients with BKN. Because BK polyomavirus infection is believed, in part, to be a manifestation of overimmunosuppression, the current standard of care involves the reduction of immunosuppressants. This strategy has been associated with clearance of viral load, preservation of renal function, and improvement in graft survival; however, this may come at a risk of rejection. A safe and effective immunosuppressive agent that does not predispose to viral infection is needed in transplantation. METHODS: In a phase 2, proof-of-concept, randomized, open-label, parallel-group, 6-month study in renal transplant patients, FK778 (an investigational immunosuppressant from the malononitrilamides class) was compared with the current standard of care (reduction of immunosuppression) for treatment of newly diagnosed or untreated BKN, which was confirmed by renal biopsy. RESULTS: Demographic characteristics were similar between the two groups, except there were numerically more females in the FK778 group than in the standard care group. Although the treatment with FK778 decreased BK viral load in this study, it was associated with a less favorable rejection profile and renal function and a higher incidence of serious adverse events compared with reduction of immunosuppression. CONCLUSIONS: Data from this study are consistent with the findings of previous studies that found no benefit of drug therapy in the treatment of BKN in kidney transplant recipients.