De novo donor‐specific antibodies (dnDSAs) have been associated with reduced graft survival. Tacrolimus (TAC)–based regimens are the most common among immunosuppressive approaches used in in clinical ...practice today, yet an optimal therapeutic dose to prevent dnDSAs has not been established. We evaluated mean TAC C0 (tacrolimus trough concentration) and TAC time in therapeutic range for the risk of dnDSAs in a cohort of 538 patients in the first year after kidney transplantation. A mean TAC C0 < 8 ng/mL was associated with dnDSAs by 6 months (odds ratio OR 2.51, 95% confidence interval CI 1.32–4.79, P = .005) and by 12 months (OR 2.32, 95% CI 1.30–4.15, P = .004), and there was a graded increase in risk with lower mean TAC C0. TAC time in the therapeutic range of <60% was associated with dnDSAs (OR 2.05, 95% CI 1.28‐3.30, P = .003) and acute rejection (hazard ratio HR 4.18, 95% CI 2.31–7.58, P < .001) by 12 months and death‐censored graft loss by 5 years (HR 3.12, 95% CI 1.53–6.37, P = .002). TAC minimization may come at a cost of higher rates of dnDSAs, and TAC time in therapeutic range may be a valuable strategy to stratify patients at increased risk of adverse outcomes.
Minimizing tacrolimus exposure may increase the risk of de novo donor‐specific antibodies, and calculating the time tacrolimus is in therapeutic range may be a useful method to identify patients at risk for adverse clinical outcomes.
Tacrolimus (TAC) is the most important agent for maintenance immunosuppression and prevention of immunologic injury to the renal allograft, yet there remains no consensus on how best to monitor drug ...therapy. Both high TAC intrapatient variability and low TAC time in therapeutic range (TTR) have been associated with risk of de novo donor-specific antibodies (dnDSA). In this study, we hypothesized that the risk associated with high TAC coefficient of variation (CV) is a result of low TAC TTR rather than the variability itself.
We analyzed the risk of dnDSA, acute rejection, or death-censored graft loss by non-dosed-corrected TAC CV and TAC TTR during the first posttransplant year in a cohort of 538 patients with a median follow-up period of 4.1 years.
Patients with CV >44.2% and TTR <40% (high intrapatient variability and low TTR) had a high risk of dnDSA (adjusted OR = 4.93, 95% confidence interval = 2.02-12.06, P < 0.001) and death-censored graft loss by 5 years (adjusted HR = 4.00, 95% confidence interval = 1.31-12.24, P = 0.015) when compared with patients with CV >44.2% and TTR ≥40% (high intrapatient variability and optimal TTR), while the latter patients had similar risk to patients with CV <44.2% (lower intrapatient variability).
These data suggest that previously reported immunologic risk associated with high TAC intrapatient variability is due to time outside of therapeutic range rather than variability in and of itself when evaluating absolute non-dose-corrected TAC levels irrespective of reason or indication.
Current organ allocation policy prioritizes placement of kidneys (with pancreas) to patients listed for simultaneous pancreas-kidney transplantation (SPK). Patients with type 2 diabetes mellitus ...(T2DM) may undergo SPK, but it is unknown whether these patients enjoy a survival advantage with SPK versus deceased-donor kidney transplantation alone (DDKA) or living-donor kidney transplantation alone (LDKA).
Using the Scientific Registry of Transplant Recipients database, patients with T2DM, age 18-59 years, body mass index 18-30 kg/m(2), who underwent SPK, DDKA, or LDKA from 2000 through 2008 were identified. Five-year patient and kidney graft survival rates were compared, and multivariable analysis was performed to determine donor, recipient, and transplant factors influencing these outcomes.
Of 6416 patients identified, 4005, 1987, and 424 underwent DDKA, LDKA, and SPK, respectively. On unadjusted analysis, patient and kidney graft survival rates were superior for LDKA versus SPK, whereas patient but not graft survival was higher for SPK versus DDKA. On multivariable analysis, survival advantage for SPK versus DDKA was related not to pancreas transplantation but younger donor and recipient ages in the SPK cohort.
Good outcomes can occur with SPK in selected patients with T2DM, but no patient or graft survival advantage is provided by added pancreas transplantation compared with DDKA; outcomes were superior with LDKA. These results support cautious use of SPK in T2DM when LDKA is not an option, with close oversight of the effect of kidney (with pancreas) allocation priority over other transplant candidates.
Current assays and tests that are used to determine the degree of immunosuppression in renal transplant recipients are suboptimal. The ImmuKnow assay (Cylex), a measure of intracellular CD4+ T cell ...ATP release proposed as a means to quantify cell-mediated immunity in transplant recipients, could be considered as a potential tool to identify patients at risk for opportunistic infections (OI) or acute rejection (AR).
We retrospectively analyzed 1330 ImmuKnow assay values in 583 renal transplant recipients at a single center from 2004 to 2009 and correlated these values with episodes of OI and AR in the subsequent 90 days. Assay values were compared with a control population matched for age, gender, and time post-transplantation.
In patients with OI (n=94), there were no differences in prior mean assay values compared with matched controls (386 versus 417 ng/ml, P=0.24). In 47 patients with AR, again no differences were detected in prior assay results (390 versus 432 ng/ml, P=0.25) when compared with controls. "Low" values (≤225 ng/ml) lacked sensitivity and specificity as a predictive test for subsequent OI, as did "strong" (≥525 ng/ml) values as a predictive test for subsequent AR.
Our results fail to show an association between single time point ImmuKnow assay values and the subsequent development of an adverse event in the subsequent 90 days. The optimal use of the ImmuKnow assay in kidney transplantation has yet to be determined.
Tacrolimus (TAC) is an immunosuppressant drug given to kidney transplant recipients post-transplant to prevent antibody formation and kidney rejection. The optimal therapeutic dose for TAC is poorly ...defined and therapy requires frequent monitoring of drug trough levels. Analyzing the association between TAC levels over time and the development of potentially harmful de novo donor specific antibodies (dnDSA) is complex because TAC levels are subject to measurement error and dnDSA is assessed at discrete times, so it is an interval censored time-to-event outcome.
Using data from the University of Colorado Transplant Center, we investigated the association between TAC and dnDSA using a shared random effects (intercept and slope) model with longitudinal and interval censored survival sub-models (JM) and compared it with the more traditional interval censored survival model with a time-varying covariate (TVC). We carried out simulations to compare bias, level and power for the association parameter in the TVC and JM under varying conditions of measurement error and interval censoring. In addition, using Markov Chain Monte Carlo (MCMC) methods allowed us to calculate clinically relevant quantities along with credible intervals (CrI).
The shared random effects model was a better fit and showed both the average TAC and the slope of TAC were associated with risk of dnDSA. The simulation studies demonstrated that, in the presence of heavy interval censoring and high measurement error, the TVC survival model underestimates the association between the survival and longitudinal measurement and has inflated type I error and considerably less power to detect associations.
To avoid underestimating associations, shared random effects models should be used in analyses of data with interval censoring and measurement error.
The purpose of this double-blind, placebo-controlled exploratory pilot study was to evaluate the safety and efficacy of risperidone for the treatment of anorexia nervosa.
Forty female subjects 12 to ...21 years of age (mean, 16 years) with primary anorexia nervosa in an eating disorders program were randomized to receive risperidone (n = 18) or placebo (n = 22). Subjects completed the Eating Disorder Inventory 2, Color-A-Person Test, Body Image Software, and Multidimensional Anxiety Scale for Children at baseline and regular intervals. Weight, laboratory values, and electrocardiograms were monitored. Study medication was started at 0.5 mg daily and titrated upward weekly in 0.5-mg increments to a maximum dose of 4 mg until the subject reached a study endpoint.
The mean dose for the risperidone group was 2.5 mg and for the placebo group was 3 mg for a mean duration of 9 weeks. Subjects taking risperidone had a significant decrease on the Eating Disorder Inventory 2 Drive for Thinness subscale over the first 7 weeks (effect size, 0.88; p = .002), but this difference was not sustained to the end of the study (p = .13). The Eating Disorder Inventory 2 Interpersonal Distrust subscale decreased significantly more in subjects taking risperidone (effect size, 0.60; p = .03). Subjects taking risperidone had increased prolactin levels (week 7; p = .001). There were no significant differences between groups at baseline or the end of the study for the other rating scales, change in weight, or laboratory measurements.
This study does not demonstrate a benefit for the addition of risperidone in adolescents with anorexia nervosa during the weight-restoration phase of care. Clinical trial registration information-A Double-Blind, Placebo-Controlled Study of Risperidone for the Treatment of Anorexia Nervosa, http://www.clinicaltrials.gov, NCT00140426.
Purpose To describe a novel retinopathy of prematurity (ROP) screening model incorporating birth weight, gestational age, and postnatal weight gain that maintains sensitivity but improves specificity ...in detecting all grades of ROP compared to current 2013 screening guidelines. Methods The medical records of 499 neonates from a single tertiary referral center who met the 2013 screening guidelines for ROP were retrospectively reviewed. Weekly weights were analyzed using standard logistic regression to determine the age at which the weekly net weight gain best predicted the development of ROP, which was designated as the postnatal weight gain criterion. The 2013 birth weight and gestational age criteria were included in an “and” fashion to form the CO-ROP model. Sensitivities and specificities in detecting high grade (type 1 and 2) and all grades of ROP were calculated. Results The CO-ROP model screens infants with a gestational age at birth of ≤30 weeks and birth weight of ≤1500 g and net weight gain of ≤650 g between birth and 1 month of age. In our cohort, CO-ROP had a sensitivity of 100% (95% CI, 92.1%-100.0%) for high-grade (type 1 and 2) ROP and 96.4% (95% CI, 92.3%-98.7%) for all grades of ROP. It would reduce the number of infants screened by 23.7% compared to 2013 guidelines. Calibrating the model to detect only high-grade ROP would result in a 45.9% reduction in the total number of infants screened. Conclusions CO-ROP is a simple model that maintains a statistically similar sensitivity in detecting all grades of ROP while significantly reducing the total number of required ROP screenings compared to 2013 guidelines. The study had a small sample size but shows promise for future research and clinical efforts.
Objective To evaluate the efficacy and safety of a carbohydrate restricted versus a low fat diet on weight loss, metabolic markers, body composition, and cardiac function tests in severely obese ...adolescents. Study design Subjects were randomly assigned to 1 of 2 diets: a high protein, low carbohydrate (20 g/d) diet (high protein, low carbohydrate, HPLC) or low fat (30% of calories) regimen for 13 weeks; close monitoring was maintained to evaluate safety. After the intervention, no clinical contact was made until follow-up measurements were obtained at 24 and 36 weeks from baseline. The primary outcome was change in body mass index Z -score for age and sex (BMI-Z) at 13, 24, and 36 weeks. Results Forty-six subjects (24 HPLC, 22 in low fat) initiated and 33 subjects completed the intervention; follow-up data were available on approximately half of the subjects. Significant reduction in (BMI-Z) was achieved in both groups during intervention and was significantly greater for the HPLC group ( P = .03). Both groups maintained significant BMI-Z reduction at follow-up; changes were not significantly different between groups. Loss of lean body mass was not spared in the HPLC group. No serious adverse effects were observed related to metabolic profiles, cardiac function, or subjective complaints. Conclusions The HPLC diet is a safe and effective option for medically supervised weight loss in severely obese adolescents.
Femoroacetabular impingement (FAI) is a recently recognized hip disorder resulting from an abnormal morphology of the proximal femur and acetabulum. This morphology results in increased hip contact ...forces with hip motion, specifically flexion. This may lead to labral-cartilage injury and pain. The purpose of this study is to describe the clinical presentation and diagnosis of FAI as a cause of hip pain in adolescents.Thirty-five patients with FAI as the etiology of chronic hip pain from one institution were reviewed. The common symptoms, physical examination, and radiographic findings were analyzed.The age range was 13 to 18 years. There were 30 girls and 5 boys. All patients complained of anterior groin pain. All patients performed a sport/activity that contributed to the symptoms such as dancing. Patients had decreased flexion and limited internal rotation on physical examination. All patients had a positive impingement test. Fifteen patients (43%) had primarily pincer impingement with a crossover sign or acetabular retroversion. Cam impingement was the primary type in 2 patients (6%). There were findings of cam and pincer in 18 patients (51%). Sixteen of 28 patients had a positive labral tear on magnetic resonance imaging (57%). Femoroacetabular impingement is a cause of hip pain in the adolescent population. The diagnosis can be derived from reproducible history, physical examination, and radiographic findings. It is more common in female adolescents, and pincer type is more prevalent.
Maintenance steroid (MS) use in pediatric heart transplantation (HT) varies across centers. The purpose of this study was to evaluate the impact of steroid-free maintenance immunosuppression (SF) on ...graft outcomes in pediatric HT.
Patients younger than 18 years in the United States undergoing a first HT during 1990 to 2010 were analyzed for conditional 30-day graft loss (death or repeat HT) and death based on MS use by multivariable analysis. A propensity score was then given to each patient using a logistic model, and propensity matching was performed using pre-HT risk factors, induction therapy, and nonsteroid maintenance immunosuppression. Kaplan-Meier graft and patient survival probabilities by MS use were then calculated.
Of 4894 patients, 3962 (81%) were taking MS and 932 (19%) SF. Of the 4530 alive at 30 days after HT, 3694 (82%) and 836 (18%) were in the MS and SF groups, respectively. Unmatched multivariable analysis showed no difference in 30-day conditional graft survival between MS and SF groups (hazard ratio=1.08, 95% confidence interval=0.93-1.24; P=0.33). Propensity matching resulted in 462 patients in each MS and SF group. Propensity-matched Kaplan-Meier survival analysis showed no difference in graft or patient survival between groups (P=0.3 and P=0.16, respectively).
We found no difference in graft survival between SF patients and those taking MS. An SF regimen in pediatric HT avoids potential complications of steroid use without compromising graft survival, even after accounting for pre-HT risk factors.
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