Obesity is associated with a higher incidence of rejection in patients on belatacept: A pooled analysis from the BENEFIT/BENEFIT-EXT clinical trials.

Though belatacept is administered with a weight-based dosing schema, there has been higher clearance reported in obese patients. Therefore, we evaluated the association between body mass index (BMI) and transplant outcomes in kidney transplant recipients who were randomized to cyclosporine- or belatacept-based immunosuppression in the BENEFIT and BENEFIT-EXT randomized clinical trials. A total of 666 and 543 patients underwent randomization and transplantation in BENEFIT and BENEFIT-EXT, respectively, of which 1056 had complete data and were included in this analysis. Patients were grouped categorically according to BMI: <25, 25 to <30, and ≥30 kg/m2. BMI did influence both the incidence and severity of acute rejection. Obese patients with BMI >30 kg/m2 in the low intensity belatacept group experienced significantly more rejection at 12 months than did patients with BMI <25 kg/m2 or BMI 25 to <30 kg/m2. In both the moderate intensity belatacept and low intensity belatacept groups, obese patients with BMI >30 kg/m2 experienced significantly more severe acute rejection than did patients with BMI < 25 kg/m2 or BMI 25 to <30 kg/m2. These results suggest that obese kidney transplant recipients are at an increased risk for acute rejection when under belatacept-based immunosuppression when compared to nonobese patients.

Elevated posaconazole trough concentrations are not associated with increased risk for posaconazole toxicity in lung transplant recipients.

OBJECTIVE: Posaconazole is used for prophylaxis and treatment of invasive fungal infections in lung transplant recipients (LTR). Previous studies have not described the relationship between elevated posaconazole trough concentrations and adverse drug reactions in this population. METHODS: This IRB-approved, retrospective cohort study at NewYork-Presbyterian Hospital included LTR who had posaconazole trough concentrations measured. The primary aim of this study was to evaluate elevated posaconazole trough concentrations and changes in liver function tests as well as QTc interval. A secondary aim of this study was to identify patient factors associated with elevated posaconazole trough levels. RESULTS: A total of 109 LTR were included. The average age was 58.1 years (IQR, 48-65), the majority were male (56%). A total of 932 trough levels were assessed with a median number of 8 (IQR, 5-15) levels per patient. The median posaconazole trough concentration was 1.7 mg/L (IQR, 1.1-2.5). Hepatotoxicity, as defined by common terminology criteria for adverse events (CTCAE), was observed in 73.4% of subjects, with the majority classified as grade 1 (67.5%). However, there was no correlation between elevated posaconazole levels and aspartate aminotransferase (r = .03), alanine aminotransferase (r = .04), alkaline phosphatase (r = .04), and total bilirubin (r = .02). There was also no correlation between posaconazole trough concentrations and QTc interval (r = .03). CONCLUSION: This analysis demonstrates that no correlation exists between whole blood posaconazole levels and hepatotoxicity or QTc prolongation. Based on these results, posaconazole dose reductions may not be warranted for posaconazole levels that are significantly above the therapeutic target to avert risk for hepatotoxicity or QTc prolongation.

Early clinical experience with nirmatrelvir/ritonavir for the treatment of COVID-19 in solid organ transplant recipients.

Nirmatrelvir/ritonavir (NR) use has not yet been described in solid organ transplant recipients (SOTRs) with mild COVID-19. The objective was to evaluate outcomes among SOTR and describe the drug-drug interaction of NR. This is an IRB-approved, retrospective study of all adult SOTR on a calcineurin inhibitor (CNI) or mammalian target of rapamycin inhibitor who were prescribed NR between December 28, 2021 and January 6, 2022. A total of 25 adult SOTR were included (n = 21 tacrolimus, n = 4 cyclosporine, n = 3 everolimus, n = 1 sirolimus). All patients were instructed to follow the following standardized protocol during treatment with 5 days of NR: hold tacrolimus or mTOR inhibitor or reduce cyclosporine dose to 20% of baseline daily dose. Four patients (16%) were hospitalized by day 30; one for infectious diarrhea and three for symptoms related to COVID-19. No patients died within 30 days of receipt of NR. Median tacrolimus level pre- and post-NR were 7.4 ng/ml (IQR, 6.6-8.6) and 5.2 (IQR, 3.6-8.7), respectively. Four patients experienced a supratherapeutic tacrolimus concentration after restarting tacrolimus post-NR. Our results show the clinically significant interaction between NR and immunosuppressive agents can be reasonably managed with a standardized dosing protocol. Prescribers should carefully re-introduce CNI after the NR course is complete.

COVID-19 therapeutics and outcomes among solid organ transplant recipients during the Omicron BA.1 era.

Treatment outcomes associated with the use of novel COVID-19 therapeutics in solid organ transplant recipients (SOTR) are not well described in the literature. The objective of this analysis was to characterize 30-day hospitalization and other key secondary endpoints experienced by outpatient SOTR with mild-moderate COVID-19 treated with nirmatrelvir/ritonavir (NR), sotrovimab, or no SARS-CoV-2 specific treatment. This IRB-approved, retrospective study included 154 SOTR with a documented positive SARS-CoV-2 infection between December 16, 2021 and January 19, 2022 (a predominant Omicron BA.1 period in New York City). Patients who received NR (N = 28) or sotrovimab (N = 51) experienced a lower rate of 30-day hospitalization or death as compared to those who received no specific treatment (N = 75) (p = .009). A total of three deaths occurred, all among patients who initially received no specific treatment prior to hospitalization. These results suggest a role for SARS-CoV-2 specific agents in the treatment of SOTR with COVID-19, and that there does not appear to be any difference in effectiveness when comparing NR versus sotrovimab.

Comparing weight-based dosing of tacrolimus XR in obese and non-obese renal transplant recipients.

The recommended initial weight-based dose of extended-release (XR) tacrolimus (Envarsus XR) in kidney transplant recipients (KTR) is 0.14 mg/kg/day. However, no data exist regarding dosing recommendations for obese patients specifically. The aim of this study was to evaluate weight-based dosing requirements in a cohort of obese KTR who were initiated on de novo tacrolimus XR post-transplantation. The primary outcome was weight-based dosing requirements (mg/kg/day) on post-operative day (POD) 7 and 14. Of the 254 KTR, 81 (31%) were obese. The median therapeutic dose on POD7 was 0.1 versus 0.12 vs. 0.14 mg/kg/day in the BMI > 30 kg/m2 , BMI 25-30 kg/m2 , and BMI < 25 kg/m2 , respectively, (p = .0001). This result was similar on POD14; median therapeutic dose was 0.09 versus 0.11 versus 0.15 mg/kg/day in the BMI > 30 kg/m2 , BMI 25-30 kg/m2 , and BMI < 25 kg/m2 , respectively, (p < .001). Therapeutic dose on POD7 and POD14 based on ideal body was similar in all cohorts (p = .238, p = .923, respectively). This finding was supported by a strong linear relationship between ideal body weight (IBW) and therapeutic dose (r = .929). In both obese and non-obese KTR, IBW had a stronger correlation with the therapeutic dose for tacrolimus XR.

A 16-year study of longitudinal volumetric brain development in males with autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with unknown brain etiology. Our knowledge to date about structural brain development across the lifespan in ASD comes mainly from cross-sectional studies, thereby limiting our understanding of true age effects within individuals with the disorder that can only be gained through longitudinal research. The present study describes FreeSurfer-derived volumetric findings from a longitudinal dataset consisting of 607 T1-weighted magnetic resonance imaging (MRI) scans collected from 105 male individuals with ASD (349 MRIs) and 125 typically developing male controls (258 MRIs). Participants were six to forty-five years of age at their first scan, and were scanned up to 5 times over a period of 16 years (average inter-scan interval of 3.7 years). Atypical age-related volumetric trajectories in ASD included enlarged gray matter volume in early childhood that approached levels of the control group by late childhood, an age-related increase in ventricle volume resulting in enlarged ventricles by early adulthood and reduced corpus callosum age-related volumetric increase resulting in smaller corpus callosum volume in adulthood. Larger corpus callosum volume was related to a lower (better) ADOS score at the most recent study visit for the participants with ASD. These longitudinal findings expand our knowledge of volumetric brain-based abnormalities in males with ASD, and highlight the need to continue to examine brain structure across the lifespan and well into adulthood.

Evidence for normal extra-axial cerebrospinal fluid volume in autistic males from middle childhood to adulthood.

Autism spectrum disorder has long been associated with a variety of organizational and developmental abnormalities in the brain. An increase in extra-axial cerebrospinal fluid volume in autistic individuals between the ages of 6 months and 4 years has been reported in recent studies. Increased extra-axial cerebrospinal fluid volume was predictive of the diagnosis and severity of the autistic symptoms in all of them, irrespective of genetic risk for developing the disorder. In the present study, we explored the trajectory of extra-axial cerebrospinal fluid volume from childhood to adulthood in both autism and typical development. We hypothesized that an elevated extra-axial cerebrospinal fluid volume would be found in autism persisting throughout the age range studied. We tested the hypothesis by employing an accelerated, multi-cohort longitudinal data set of 189 individuals (97 autistic, 92 typically developing). Each individual had been scanned between 1 and 5 times, with scanning sessions separated by 2-3 years, for a total of 439 T1-weighted MRI scans. A linear mixed-effects model was used to compare developmental, age-related changes in extra-axial cerebrospinal fluid volume between groups. Inconsistent with our hypothesis, we found no group differences in extra-axial cerebrospinal fluid volume in this cohort of individuals 3 to 42 years of age. Our results suggest that extra-axial cerebrospinal fluid volume in autistic individuals is not increased compared with controls beyond four years of age.

Less bleeding associated with apixaban versus other direct acting oral anticoagulation in solid organ transplant recipients.

BACKGROUND: The purpose of this study was to evaluate outcomes of bleeding and thrombosis resulting from the use of direct oral anticoagulants (DOACs) in a large cohort of solid organ transplant (SOT) recipients. METHODS: This was a single center, retrospective cohort study of adult kidney, heart, lung, and liver transplant recipients transplanted between August 2009 and May 2018. Patients were stratified into two groups: those who received apixaban (apixaban group) or those patients receiving either rivaroxaban or dabigatran (non-apixaban group). The primary endpoint was the cumulative incidence of bleeding while receiving DOAC therapy. The secondary endpoints were incidence of major bleeding and thrombosis at any time while receiving DOAC therapy. RESULTS: A total of 106 patients were included; 70 patients received apixaban and 36 patients received non-apixaban anticoagulation. Cumulative incidence of any bleeding was lower in the apixaban group compared to the non-apixaban group at both 90 days (4.9% vs. 16.1%) and 180 days (11.4% vs. 24.9%, P = .034). Cumulative incidence of major bleeding (P = .686) and thrombosis (P = .515) were similar between groups. DOAC dosing congruent with the package insert(s) was associated with a lower risk of thrombosis. CONCLUSION: Apixaban-based anticoagulation was associated with a lower cumulative incidence of any bleeding compared to non-apixaban DOACs.

An evaluation of PJP prophylaxis and anemia among renal transplant recipients.

BACKGROUND: Dapone and atovaquone are therapeutic options for PJP prophylaxis in renal transplant recipients. The objective of this study was to evaluate the incidence of anemia in renal transplant recipients receiving these agents. METHODS: This is an IRB-approved, retrospective analysis of adult renal transplant recipients who received either dapsone or atovaquone. The primary endpoint was the change in hemoglobin within 90 days of drug initiation. Other endpoints of interest included incidence and management of anemia at multiple time points post-transplant. Categorical variables were compared with Pearson's chi-squared or Fischer's exact test and continuous data were compared utilizing Wilcoxon rank-sum test. Statistical analyses were performed using Stata 14.2. RESULTS: A total of 478 patients were screened for inclusion; 50 patients were evaluated in both the dapsone and atovaquone groups. In the dapsone and atovaquone groups, the median age was 52 and 50.5 years, 44% and 42% were Caucasian, and median time to treatment initiation was 27 and 39 days post-transplant, respectively. All patients receiving dapsone had normal G6PD function. There was no difference in baseline hemoglobin between groups (9.7 g/dL vs 9.8 g/dL, P = .83). The median nadir hemoglobin values were 8.6 g/dL and 9.6 g/dL in the dapsone and atovaquone groups, respectively (P = .047). The median decrease in hemoglobin from baseline to nadir was 1.3 g/dL in dapsone patients and 0.2 g/dL in atovaquone patients (P = .001). Dapsone was discontinued in 46% of patients, whereas atovaquone was discontinued in 18% (P = .001). CONCLUSION: Among renal transplant recipients with normal G6PD activity, dapsone is associated with greater hemoglobin reductions and rates of drug discontinuation as compared to atovaquone.

Management of Hepatic Coagulopathy in Bleeding and Nonbleeding Patients: An Evidence-Based Review.

Patients with varying degrees of hepatic dysfunction often present with presumed bleeding diathesis based on interpretation of routine measures of coagulation (prothrombin time [PT], international normalized ratio [INR], and activated partial thromboplastin time). However, standard markers of coagulation do not reflect the actual bleeding risk in this population and may lead to inappropriate administration of hemostatic agents and blood products. The concept of "rebalanced hemostasis" explains both the risk of bleeding and clotting seen in patients with liver dysfunction. The role of pharmacologic agents and blood products for prevention of bleeding during high-risk procedures and treatment of clinically significant bleeding remains unclear. Viscoelastic measurements of the clotting cascade provide information about platelets, fibrinogen/fibrin polymerization, coagulation factors, and fibrinolysis that might better represent hemostasis in vivo and may better inform management strategies. Due to the paucity of available data, firm recommendations for the use of blood products and pharmacologic agents in patients with hepatic coagulopathies are lacking, and thus, these products should not be routinely administered. Traditional laboratory tests such as PT/INR should not be the sole determinant of potential interventions. Rather, clinicians should assess factors such as the severity of bleed or bleeding risk of the procedure, the patient's risk of thromboembolism, and the strength of available evidence for specific agents and blood products to guide decision-making.

Delayed calcineurin inhibitor introduction and renal outcomes in liver transplant recipients receiving basiliximab induction.

BACKGROUND: To investigate the impact of delayed calcineurin inhibitor (CNI) initiation in liver transplant recipients (LTR) with peri-operative renal insufficiency receiving basiliximab induction, we compared renal outcomes of LTR stratified by the degree of achieved post-operative renal recovery (RR) prior to CNI initiation. METHODS: All adult LTR transplanted between 01/2007 and 12/2015 who received basiliximab were included. Patients who received multi-organ transplantations, were repeat transplant recipients, or expired prior to post-operative day (POD) 90 were excluded. The primary outcome of our retrospective analysis was renal function at POD 90. RESULTS: A total of 210 patients were included in our final analysis. Most patients were Caucasian males undergoing liver transplantation for liver disease secondary to hepatitis C virus. Baseline characteristics were similar among the evaluable population. Estimated GFR was significantly higher among patients with the greatest degree of post-operative renal recovery at POD 90; however, this difference did not persist at POD 180. There was no significant difference in incidence or severity of biopsy-proven acute rejection (BPAR) at any measured time point. CONCLUSIONS: Delayed CNI initiation following liver transplantation in patients with post-operative renal insufficiency who receive basiliximab induction does not adversely affect the incidence of BPAR or long-term renal outcomes.

Using known drug interactions to manage supratherapeutic calcineurin inhibitor concentrations.

OBJECTIVES: To summarize the available body of evidence guiding the management of supratherapeutic concentrations of calcineurin inhibitors (CNI) using cytochrome P450 (CYP450) enzyme inducers. METHODS: A nondate restricted literature search within MEDLINE, Embase, and Scopus was performed using the terms "cyclosporine," "tacrolimus," "calcineurin inhibitor," "toxicity," "pharmacokinetics," "carbamazepine," "rifampin," "phenytoin," and "phenobarbital." Additional references were identified from a review of all included citations. All English-language reports that describe the management of supratherapeutic CNI concentrations with interventions targeting metabolic induction using CYP450 enzyme inducers were evaluated. RESULTS: A total of 10 publications were identified in which a CYP450 enzyme inducer was utilized intentionally to enhance CNI clearance in the setting of supratherapeutic concentrations; 7 case reports describe the use of phenytoin and 3 case reports describe the use of phenobarbital. Patient demographics, dosing strategies employed, and reported efficacy across this series of publications are heterogeneous; however, both agents appear to be well-tolerated when used in this setting. CONCLUSIONS: There is a paucity of published data on the use of CYP450 enzyme inducers for the management of supratherapeutic CNI concentrations. While routine use of this approach cannot be recommended, thorough risk-benefit analyses should be performed in the management of each such clinical scenario.

Longitudinal development of manual motor ability in autism spectrum disorder from childhood to mid-adulthood relates to adaptive daily living skills.

Many individuals with autism spectrum disorder (ASD) exhibit motor difficulties, but it is unknown whether manual motor skills improve, plateau, or decline in ASD in the transition from childhood into adulthood. Atypical development of manual motor skills could impact the ability to learn and perform daily activities across the life span. This study examined longitudinal grip strength and finger tapping development in individuals with ASD (n = 90) compared to individuals with typical development (n = 56), ages 5 to 40 years old. We further examined manual motor performance as a possible correlate of current and future daily living skills. The group with ASD demonstrated atypical motor development, characterized by similar performance during childhood but increasingly poorer performance from adolescence into adulthood. Grip strength was correlated with current adaptive daily living skills, and Time 1 grip strength predicted daily living skills eight years into the future. These results suggest that individuals with ASD may experience increasingly more pronounced motor difficulties from adolescence into adulthood and that manual motor performance in ASD is related to adaptive daily living skills.

Metabolic costs and evolutionary implications of human brain development.

The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.