Efficacy and Safety of Bleselumab in Preventing the Recurrence of Primary Focal Segmental Glomerulosclerosis in Kidney Transplant Recipients: A Phase 2a, Randomized, Multicenter Study.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease and frequently recurs after kidney transplantation. Recurrent FSGS (rFSGS) is associated with poor allograft and patient outcomes. Bleselumab, a fully human immunoglobulin G4 anti-CD40 antagonistic monoclonal antibody, disrupts CD40-related processes in FSGS, potentially preventing rFSGS. METHODS: A phase 2a, randomized, multicenter, open-label study of adult recipients (aged ≥18 y) of a living or deceased donor kidney transplant with a history of biopsy-proven primary FSGS. The study assessed the efficacy of bleselumab combined with tacrolimus and corticosteroids as maintenance immunosuppression in the prevention of rFSGS >12 mo posttransplantation, versus standard of care (SOC) comprising tacrolimus, mycophenolate mofetil, and corticosteroids. All patients received basiliximab induction. The primary endpoint was rFSGS, defined as proteinuria (protein-creatinine ratio ≥3.0 g/g) with death, graft loss, or loss to follow-up imputed as rFSGS, through 3 mo posttransplant. RESULTS: Sixty-three patients were followed for 12 mo posttransplantation. Relative decrease in rFSGS occurrence through 3 mo with bleselumab versus SOC was 40.7% (95% confidence interval, -89.8 to 26.8; P = 0.37; absolute decrease 12.7% [95% confidence interval, -34.5 to 9.0]). Central-blinded biopsy review found relative (absolute) decreases in rFSGS of 10.9% (3.9%), 17.0% (6.2%), and 20.5% (7.5%) at 3, 6, and 12 mo posttransplant, respectively; these differences were not statistically significant. Adverse events were similar for both treatments. No deaths occurred during the study. CONCLUSIONS: In at-risk kidney transplant recipients, bleselumab numerically reduced proteinuria occurrence versus SOC, but no notable difference in occurrence of biopsy-proven rFSGS was observed.

The ICD-9 to ICD-10 transition has not improved identification of rapidly progressing stage 3 and stage 4 chronic kidney disease patients: a diagnostic test study.

BACKGROUND: The International Classification of Diseases (ICD) coding system is the industry standard tool for billing, disease classification, and epidemiology purposes. Prior research has demonstrated ICD codes to have poor accuracy, particularly in relation to rapidly progressing chronic kidney disease (CKD) patients. In 2016, the ICD system moved to revision 10. This study examines subjects in a large insurer database to determine the accuracy of ICD-10 CKD-staging codes to diagnose patients rapidly progressing towards end-stage kidney disease (ESKD). PATIENTS AND METHODS: Serial observations of outpatient serum creatinine measurements from 2016 to 2021 of 315,903 patients were transformed to estimated glomerular filtration rate (eGFR) to identify CKD stage-3 and advanced patients diagnosed clinically (eGFR-CKD). CKD-staging codes from the same time period of 59,386 patients and used to identify stage-3 and advanced patients diagnosed by ICD-code (ICD-CKD). eGFR-CKD and ICD-CKD diagnostic accuracy was compared between a total of 334,610 patients. RESULTS: 5,618 patients qualified for the progression analysis; 72 were identified as eGFR rapid progressors; 718 had multiple codes to qualify as ICD rapid progressors. Sensitivity was 5.56%, with positive predictive value (PPV) 5.6%. 34,858 patients were diagnosed as eGFR-CKD stage-3 patients; 17,549 were also diagnosed as ICD-CKD stage-3 patients, for a sensitivity of 50.34%, with PPV of 58.71%. 4,069 patients reached eGFR-CKD stage-4 with 2,750 ICD-CKD stage-4 patients, giving a sensitivity of 67.58%, PPV of 42.43%. 959 patients reached eGFR-CKD stage-5 with 566 ICD-CKD stage-5 patients, giving a sensitivity of 59.02%, PPV of 35.85%. CONCLUSION: This research shows that recent ICD revisions have not improved identification of rapid progressors in diagnostic accuracy, although marked increases in sensitivity for stage-3 (50.34% vs. 24.68%), and PPV in stage-3 (58.71% vs. 40.08%), stage-4 (42.43% vs. 18.52%), and stage-5 (35.85% vs. 4.51%) were observed. However, sensitivity in stage-5 compares poorly (59.02% vs. 91.05%).

Bayesian optimization of tacrolimus exposure in stable kidney transplant patients.

STUDY OBJECTIVE: The objective was to compare tacrolimus AUC0-12 determined by Non-Compartmental Analysis (NCA) using intensive sampling to Maximum a Posteriori-Bayesian (MAP-Bayesian) estimates from robust (n = 9 samples/subject) and sparse (n = 2 samples/subject) sampling in 67 stable KTRs and a validation group of similar patients. DESIGN: This open-label, prospective, single center 12-h PK study included nine serial samples collected in KTRs to determine steady-state NCA tacrolimus AUC0-12 . SETTING: This study was conducted at a single site within a large, urban hospital in the western New York area. PATIENTS: This study described tacrolimus pharmacokinetics in stable kidney transplant recipients on maintenance tacrolimus therapy. INTERVENTION: Robust and sparse AUC0-12 estimates by a MAP-Bayesian approach were obtained using the Advanced Dosing Solutions (AdDS) and ADAPT5 freeware. Limited sampling strategies were evaluated using the original population PK model (n = 67), which was also assessed using a validation group (n = 15). AUC0-12 agreement was tested by paired t-tests with intraclass correlation coefficient (ICC) and Bland Altman analysis. MEASUREMENTS AND MAIN RESULTS: A total of 35 Black and 32 White stable KTRs (estimated glomerular filtration rate [eGFR] = 55.2 ± 15.7 mL/min/1.73m2 ) received the tacrolimus dose of 3.4 ± 1.7 mg/study with troughs of 6.8 ± 1.8 ng/mL. The NCA-AUC0-12 was 123.8 ± 33.6 µg·h/L compared to MAP-Bayesian estimates for Robust-AUC0-12 of 124.7 ± 33.3 µg·h/L and optimal 2-specimen Sparse-AUC0-12 of 119.7 ± 32.7 µg·h/L for the training group. Comparison of Robust-AUC0-12 to NCA-AUC0-12 had an ICC of 0.96 (p = 0.99) while comparison of Robust-AUC0-12 to Sparse-AUC0-12 using Pre-dose trough [C(t0h )] and 1 h [C(t1h )] resulted in an ICC of 0.93 (p = 0.014). In the validation group, 5 Black and 10 White KTRs (eGFR = 56.4 ± 16.8 mL/min/1.73m2 ) received a mean tacrolimus dose of 1.9 ± 1.2 mg/study with a trough of 6.0 ± 1.7 ng/mL. The validation group's NCA-AUC0-12 (88.4 ± 33.1 µg·h/L) was comparable to Robust-AUC0-12 (85.1 ± 33.8 µg·h/L, ICC = 0.93; p = 0.12) and Sparse-AUC0-12 determined from C(t0h ) and C(t4h ) (86.7 ± 33.9 µg·h/L, ICC = 0.91; p = 0.61). CONCLUSION: MAP-Bayesian estimation for patient-specific AUC0-12 using sparse, two-specimen sampling is comparable to NCA and may enhance tacrolimus TDM in stable KTRs.

Broad organ acceptance and equitable access to early kidney transplantation.

BACKGROUND: Broad organ acceptance can increase early kidney transplantation (KTX) within <1-year of dialysis initiation while improving access inequity. METHODS: Single-center data of adult isolated deceased-donor KTX recipients between 2013 and 2020 were stratified into three 2.5-year periods before-, early after-, and late after our center's deceased-donor organ acceptance practice change, excluding a 6-month implementation period. Outcomes were assessed within five recipient subgroups based on demographic and clinical characteristics. RESULTS: Of 704 recipients, the frequency of early KTX was 22% pre-change, 36% early post-change, and 34% late post-change. Given similar post-change frequencies of early KTX, post-change eras were combined to improve analytic power of subgroup analyses. After the organ acceptance practice change (vs. pre-change), the likelihood of early KTX increased variably within historically underserved groups, including recipients who were older (37%-39%, p = .859), Black (10%-21%, p = .136), female (21%-37%, p = .034), diabetic (13%-32%, p = .010), and BMI≥35 kg/m2 (20%-34%, p = .007). Despite the practice change, Black recipients continued to experience less early KTX compared to non-Black recipients. The likelihood of delayed graft function was significantly increased (p < .001), and 1-year creatinine was significantly higher (p < .001) post-practice change, but between-era risk-adjusted death-censored graft survival was similar. CONCLUSIONS: Transition to broader donor acceptance was associated with more early KTXs among historically underserved patient subgroups. However, the effect was non-significant among Black recipients, suggesting the need for additional strategies to impact early transplant access for this population. Studies of broad organ acceptance are needed to examine both access and outcomes.

Comparison of P-glycoprotein function in peripheral blood mononuclear cells ex vivo in stable Black and White male and female kidney transplant recipients.

Kidney allograft survival remains poorer in Black compared to White recipients due to racial differences in calcineurin inhibitor (CNI) pharmacology. P-glycoprotein (P-gp), an ABC efflux transporter expressed in peripheral blood mononuclear cells (PBMCs), modulates CNI pharmacokinetics and intracellular pharmacology. This study investigated P-gp function in PBMC ex vivo at 0 (trough), 4, 8, and 12 h in stable Black and White male and female kidney transplant recipients (n = 67) receiving tacrolimus and mycophenolic acid. Tacrolimus doses were adjusted to troughs of 4-10 ng/ml. P-gp function was quantified with flow cytometric measurement of cyclosporine (CYA; 2.5 µM)-reversible efflux of P-gp substrate, 3,3'-Diethyloxacarbocyanine iodide by determining the percentage change of mean fluorescent intensity (MFI) with CYA (% ΔMFI). The composite parameter of area under the concentration versus time (AUC)0-12h % ΔMFI estimated P-gp function. Data analysis examined race, sex, and race-sex associations to P-gp function. A secondary aim analyzed ABCB1 genotypes: 1236C>T (rs1128503), 2677G>T/A (rs2032582), 3435C>T (rs1045642), and P-gp function. P-gp function (% ΔMFI) was higher in White patients at troughs (p = 0.031) compared to Black counterparts with similar trends at 4 and 8 h. Reduced AUC0-12h % ΔMFI was noted in Black recipients (N = 32) compared with Whites (N = 35, p = 0.029) with notable pairwise adjusted differences between Black and White women (p = 0.021). Higher AUC0-12h % ΔMFI was associated with ABCB1 2677 TT compared to GG variants (p = 0.035). The AUC0-12h % ΔMFI was greater in White than Black subjects. P-gp function was higher at troughs in White subjects and differed between race-sex groups. P-gp function in PBMC may influence intracellular tacrolimus exposure and inter-relating pharmacodynamic responses which may support race and sex pharmacologic differences.

Leukotriene inhibitors with dexamethasone show promise in the prevention of death in COVID-19 patients with low oxygen saturations.

Introduction: COVID-19 is a major health threat around the world causing hundreds of millions of infections and millions of deaths. There is a pressing global need for effective therapies. We hypothesized that leukotriene inhibitors (LTIs), that have been shown to lower IL6 and IL8 levels, may have a protective effect in patients with COVID-19. Methods: In this retrospective controlled cohort study, we compared death rates in COVID-19 patients who were taking a LTI with those who were not taking an LTI. We used the Department of Veterans Affairs (VA) Corporate Data Warehouse (CDW) to create a cohort of COVID-19-positive patients and tracked their use of LTIs between November 1, 2019 and November 11, 2021. Results: Of the 1,677,595 cohort of patients tested for COVID-19, 189,195 patients tested positive for COVID-19. Forty thousand seven hundred one were admitted. 38,184 had an oxygen requirement and 1214 were taking an LTI. The use of dexamethasone plus a LTI in hospital showed a survival advantage of 13.5% (CI: 0.23%-26.7%; p < 0.01) in patients presenting with a minimal O2Sat of 50% or less. For patients with an O2Sat of <60 and <50% if they were on LTIs as outpatients, continuing the LTI led to a 14.4% and 22.25 survival advantage if they were continued on the medication as inpatients. Conclusions: When combined dexamethasone and LTIs provided a mortality benefit in COVID-19 patients presenting with an O2 saturations <50%. The LTI cohort had lower markers of inflammation and cytokine storm.

Race and sex associations with tacrolimus pharmacokinetics in stable kidney transplant recipients.

STUDY OBJECTIVE: This study investigated race and sex differences in tacrolimus pharmacokinetics and pharmacodynamics in stable kidney transplant recipients. DESIGN AND SETTING: A cross-sectional, open-label, single center, 12-h pharmacokinetic-pharmacodynamic study was conducted. Tacrolimus pharmacokinetic parameters included area under the concentration-time curve (AUC0-12 ), AUC0-4 , 12-h troughs (C12 h ), maximum concentrations (Cmax ), oral clearance (Cl), with dose-normalized AUC0-12 , troughs, and Cmax with standardized adverse effect scores. Statistical models were used to analyze end points with individual covariate-adjustment including clinical factors, genotypic variants CYP3A5*3, CYP3A5*6, CYP3A5*7(CYP3A5*3*6*7) metabolic composite, and ATP binding cassette gene subfamily B member 1 (ABCB1) polymorphisms. PATIENTS: 65 stable, female and male, Black and White kidney transplant recipients receiving tacrolimus and mycophenolic acid ≥6 months post-transplant were evaluated. MEASUREMENTS AND MAIN RESULTS: Black recipients exhibited higher tacrolimus AUC0-12 (Race: p = 0.005), lower AUC* (Race: p < 0.001; Race × Sex: p = 0.068), and higher Cl (Race: p < 0.001; Sex: p = 0.066). Greater cumulative (Sex: p < 0.001; Race × Sex: p = 0.014), neurologic (Sex: p = 0.021; Race × Sex: p = 0.005), and aesthetic (Sex: p = 0.002) adverse effects were found in females, with highest scores in Black women. In 84.8% of Black and 68.8% of White patients, the target AUC0-12 was achieved (p = 0.027). In 31.3% of White and 9.1% of Black recipients, AUC0-12 was <100 ng‧h/ml despite tacrolimus troughs in the target range (p = 0.027). The novel CYP3A5*3*6*7 metabolic composite was the significant covariate accounting for 15%-19% of tacrolimus variability in dose (p = 0.002); AUC0-12 h * (p < 0.001), and Cl (p < 0.001). CONCLUSIONS: Tacrolimus pharmacokinetics and adverse effects were different among stable kidney transplant recipient groups based upon race and sex with interpatient variability associated with the CYP3A5*3*6*7 metabolic composite. More cumulative, neurologic, and aesthetic adverse effects were noted among females. Tacrolimus regimens that consider race and sex may reduce adverse effects and enhance allograft outcomes by facilitating more patients to achieve the targeted AUC0-12 h .

Insight Into Disorder, Stress and Strain of Radiation Damaged Pyrochlores: A Possible Mechanism for the Appearance of Defect Fluorite.

We have examined the irradiation response of a titanate and zirconate pyrochlore-both of which are well studied in the literature individually-in an attempt to define the appearance of defect fluorite in zirconate pyrochlores. To our knowledge this study is unique in that it attempts to discover the mechanism of formation by a comparison of the different systems exposed to the same conditions and then examined via a range of techniques that cover a wide length scale. The conditions of approximately 1 displacement per atom via He2+ ions were used to simulate long term waste storage conditions as outlined by previous results from Ewing in a large enough sample volume to allow for neutron diffraction, as not attempted previously. The titanate sample, used as a baseline comparison since it readily becomes amorphous under these conditions behaved as expected. In contrast, the zirconate sample accumulates tensile stress in the absence of detectable strain. We propose this is analogous to the lanthanide zirconate pyrochlores examined by Simeone et al. where they reported the appearance of defect fluorite diffraction patterns due to a reduction in grain size. Radiation damage and stress results in the grains breaking into even smaller crystallites, thus creating even smaller coherent diffraction domains. An (ErNd)2(ZrTi)2O7 pyrochlore was synthesized to examine which mechanism might dominate, amorphization or stress/strain build up. Although strain was detected in the pristine sample via Synchrotron X-ray diffraction it was not of sufficient quality to perform a full analysis on.

Evaluating for a correlation between osteopathic examination and ultrasonography on thoracic spine asymmetry.

CONTEXT: The thoracic spine is a common area of focus in osteopathic manipulative medicine (OMM) for a variety of conditions. Thoracic spine somatic dysfunction diagnosis is achieved by palpating for asymmetry at the tips of the transverse processes (TPs). Previous studies reveal that instead of following the rule of threes, the TPs of a given thoracic vertebra generally align with the spinous process (SP) of the vertebra above. Ultrasonography has been widely utilized as a diagnostic tool to monitor musculoskeletal conditions; it does not utilize ionizing radiation, and it has comparable results to gold-standard modalities. In the case of thoracic somatic dysfunction, ultrasound (US) can be utilized to determine the location of each vertebral TP and its relationship with the SP. Previous studies have investigated the correlation between OMM and ultrasonography of the cervical, lumbar, and sacral regions. However, there has been no study yet that has compared osteopathic structural examination with ultrasonographic examination of the thoracic vertebral region. OBJECTIVES: To examine the relationship between osteopathic palpation and ultrasonographic measurements of the thoracic spine by creating a study design that utilizes interexaminer agreement and correlation. METHODS: The ClinicalTrials.gov study identifier is NCT04823637. Subjects were student volunteers recruited from the Midwestern University (MWU)-Glendale campus. A nontoxic, nonpermanent marker was utilized to mark bony landmarks on the skin. Two neuromusculoskeletal board-certified physicians (OMM1, OMM2) separately performed structural exams by palpating T2-T5 TPs to determine vertebral rotation. Two sonographers (US1, US2) separately scanned and measured the distance from the tip of the SP to the adjacent TPs of the vertebral segment below. Demographic variables were summarized with mean and standard deviation. Interexaminer agreement was assessed with percent agreement, Cohen's Kappa, and Fleiss' Kappa. Correlation was measured by Spearman's rank correlation coefficient. Recruitment and protocols were approved by the MWU Institutional Review Board (IRB). RESULTS: US had fair interexaminer agreement for the overall most prominent segmental rotation of the T3-T5 thoracic spine, with Cohen's Kappa at 0.27 (0.09, 0.45), and a total agreement percentage at 51.5%. Osteopathic palpation revealed low interexaminer agreement for the overall most prominent vertebral rotation, with Cohen's Kappa at 0.05 (0.0, 0.27), and 31.8%. Segment-specific vertebral analysis revealed slight agreement between US examiners, with a correlation coefficient of 0.23, whereas all other pairwise comparisons showed low agreement and correlation. At T4, US had slight interexaminer agreement with 0.24 correlation coefficient, and osteopathic palpation showed low interexaminer (OMM1 vs. OMM2) agreement (0.17 correlation coefficient). At T5, there was moderate agreement between the two sonographers with 0.44 (0.27, 0.60) and 63.6%, with a correlation coefficient of 0.57, and slight agreement between OMM1 and OMM2 with 0.12 (0.0, 0.28) and 42.4%, with 0.23 correlation coefficient. CONCLUSIONS: This preliminary study of an asymptomatic population revealed that there is a low-to-moderate interexaminer reliability between sonographers, low-to-slight interexaminer reliability between osteopathic physicians, and low interexaminer reliability between OMM palpatory examination and ultrasonographic evaluation of the thoracic spine.

Beyond Single Nucleotide Polymorphisms: CYP3A5∗3∗6∗7 Composite and ABCB1 Haplotype Associations to Tacrolimus Pharmacokinetics in Black and White Renal Transplant Recipients.

Interpatient variability in tacrolimus pharmacokinetics is attributed to metabolism by cytochrome P-450 3A5 (CYP3A5) isoenzymes and membrane transport by P-glycoprotein. Interpatient pharmacokinetic variability has been associated with genotypic variants for both CYP3A5 or ABCB1. Tacrolimus pharmacokinetics was investigated in 65 stable Black and Caucasian post-renal transplant patients by assessing the effects of multiple alleles in both CYP3A5 and ABCB1. A metabolic composite based upon the CYP3A5 polymorphisms: ∗3(rs776746), ∗6(10264272), and ∗7(41303343), each independently responsible for loss of protein expression was used to classify patients as extensive, intermediate and poor metabolizers. In addition, the role of ABCB1 on tacrolimus pharmacokinetics was assessed using haplotype analysis encompassing the single nucleotide polymorphisms: 1236C > T (rs1128503), 2677G > T/A(rs2032582), and 3435C > T(rs1045642). Finally, a combined analysis using both CYP3A5 and ABCB1 polymorphisms was developed to assess their inter-related influence on tacrolimus pharmacokinetics. Extensive metabolizers identified as homozygous wild type at all three CYP3A5 loci were found in 7 Blacks and required twice the tacrolimus dose (5.6 ± 1.6 mg) compared to Poor metabolizers [2.5 ± 1.1 mg (P < 0.001)]; who were primarily Whites. These extensive metabolizers had 2-fold faster clearance (P < 0.001) with 50% lower AUC∗ (P < 0.001) than Poor metabolizers. No differences in C12 h were found due to therapeutic drug monitoring. The majority of blacks (81%) were classified as either Extensive or Intermediate Metabolizers requiring higher tacrolimus doses to accommodate the more rapid clearance. Blacks who were homozygous for one or more loss of function SNPS were associated with lower tacrolimus doses and slower clearance. These values are comparable to Whites, 82% of who were in the Poor metabolic composite group. The ABCB1 haplotype analysis detected significant associations of the wildtype 1236T-2677T-3435T haplotype to tacrolimus dose (P = 0.03), CL (P = 0.023), CL/LBW (P = 0.022), and AUC∗ (P = 0.078). Finally, analysis combining CYP3A5 and ABCB1 genotypes indicated that the presence of the ABCB1 3435 T allele significantly reduced tacrolimus clearance for all three CPY3A5 metabolic composite groups. Genotypic associations of tacrolimus pharmacokinetics can be improved by using the novel composite CYP3A5∗3∗4∗5 and ABCB1 haplotypes. Consideration of multiple alleles using CYP3A5 metabolic composites and drug transporter ABCB1 haplotypes provides a more comprehensive appraisal of genetic factors contributing to interpatient variability in tacrolimus pharmacokinetics among Whites and Blacks.

Correlation between structural progression in glaucoma and obstructive sleep apnea.

BACKGROUND/OBJECTIVES: To investigate the correlation between obstructive sleep apnea (OSA) severity and the structural and functional progression in patients with glaucoma. SUBJECTS/METHODS: This retrospective comparative cohort study included subjects from the polysomnography database in Chang Gung Memorial Hospital between June 1, 2009, and June 1, 2017, by identifying patients who had received diagnoses of primary open-angle glaucoma (POAG), normal-tension glaucoma (NTG), or glaucoma suspect. Patients with follow-up time of <3 years and/or <3 consecutive reliable optical coherence tomography (OCT) or visual field (VF) tests were excluded. Progression of overall peripapillary retinal nerve fiber layer (RNFL) thickness on OCT scans and VF mean deviation (MD) or VF index (VFI) were determined through linear regression trend analysis. RESULTS: Thirty-two patients were included. There was a trend to higher percentage of progression on RNFL thickness and VF in higher OSAS severity. After stratifying patients to no OSA/mild OSA (group 1) and moderate/severe OSA (group 2), group 2 exhibited a significantly higher percentage of RNFL thickness progression than did group 1 (64.7% vs 26.7%, P = 0.042). Multivariate Cox regression analysis showed that severe OSA had an 8.448-fold higher risk of RNFL thickness progression after age, sex, diabetes mellitus, hypertension, hyperlipidemia, and body mass index adjustment (95% confidence interval, 1.464-48.752, P = 0.017). CONCLUSIONS: Severe OSA is significantly correlated with a higher risk of structural deterioration in patients with glaucoma.

Utility of Serial Protocol Biopsies Performed After 1 Year in Predicting Long-Term Kidney Allograft Function According to Histologic Phenotype.

OBJECTIVES: Prognostic implications of early protocol biopsies have been studied; however, the value of late protocol biopsy in predicting graft outcome has not been well defined. Here, we compared the effects of early and late protocol biopsy histologic findings in stable kidney allografts and aimed to understand the significance of "borderline" rejection on allograft function. MATERIALS AND METHODS: We studied 261 biopsies from 159 renal transplant recipients who were on a steroid-free, calcineurin inhibitor and mycophenolate mofetil regimen and who received transplants between 2004 and 2012 with mean follow-up of 5 years. Early (between 3 and 9 mo) and subsequent late (between 12 and 24 mo) protocol biopsies were performed. Biopsies were classified as normal, interstitial fibrosis and/or tubular atrophy, subclinical acute rejection with interstitial fibrosis and/or tubular atrophy, and borderline rejection with interstitial fibrosis and/or tubular atrophy. A linear mixed-effects model was used to determine the effects of early and late protocol biopsies on estimated glomerular filtration rate changes, with baseline time for estimated glomerular filtration rate fixed at 12 months. RESULTS: The adjusted model showed that estimated glomerular filtration rate at 3 months, donor age, delayed graft function, and early protocol biopsies were associated with baseline estimated glomerular filtration rate at 12 months. Estimated glomerular filtration rate changes over time were associated with findings of interstitial fibrosis and/or tubular atrophy at early biopsy and subclinical acute rejection and borderline rejection at late biopsy. At last follow-up, final estimated glomerular filtration rate was significantly associated with interstitial fibrosis and/or tubular atrophy at early biopsy and with subclinical acute rejection at late biopsy. CONCLUSIONS: Although early protocol biopsy predicted baseline estimated glomerular filtration rate, late biopsy was important for predicting changes in function over time. In addition, a diagnosis of "borderline" rejection on protocol biopsies predicted long-term graft function.

Anterior Chamber Angle and Anterior Segment Structure of Eyes in Children With Early Stages of Retinopathy of Prematurity.

PURPOSE: To compare structural differences in the anterior chamber angle (ACA) and related optic components in children with or without retinopathy of prematurity (ROP). DESIGN: Prospective cross-sectional study. METHODS: Setting: A referred medical center in Taiwan. STUDY POPULATION: The patients included preterm children with a history of ROP who had undergone laser therapy. The controls included age-matched healthy full-term children. OBSERVATION PROCEDURE: The ACA structures were evaluated using gonioscopy. MAIN OUTCOME MEASURES: The angularity of the anterior chamber and associated anatomic changes. RESULTS: We examined 54 eyes of 29 preterm children with ROP and 134 eyes of 67 children born at term. The eyes of the ROP children exhibited a narrower ACA, steeper iris curvature, and more anteriorly inserted iris than those of the full-term children (P < .001, P = .002, and P = .08, respectively). The eyes of the ROP children also exhibited steeper corneas, shallower anterior chamber depths, thicker lenses, and higher degrees of refractive errors (all P < .001) than those of the full-term children. The axial lengths did not differ between the 2 groups (P = .15). CONCLUSIONS: The eyes of the ROP children presented a narrower ACA and a more anteriorly curved and inserted iris than those of the full-term children. A steeper cornea, shallower anterior chamber, and greater lens thickness were the main structural changes in the anterior segment components of these patients. Further research is needed to investigate the association between these structural changes and the development of certain ocular diseases, such as glaucoma, in these patients.

Regional Relationship between Macular Retinal Thickness and Corresponding Central Visual Field Sensitivity in Glaucoma Patients.

Purpose. To investigate the relationship between macular retinal thickness (MRT) and central visual field sensitivity (VFS) in patients with glaucoma. Methods. This retrospective study enrolled patients diagnosed with open-angle glaucoma. All study patients underwent Humphrey 10-2 visual field (VF) test and Spectralis spectral-domain optical coherence tomography (SD-OCT) exam for MRT measurement. Results. Sixty-eight eyes of 68 patients were examined. The correlation coefficients between VFS and MRT were 0.331 (P = 0.006) and 0.491 (P = 0.000) in the superior and inferior hemispheres, respectively. The average MRT in the eyes with abnormal 10-2 VF hemifields was significantly thinner than that in the eyes without abnormal hemifields in both hemispheres (P = 0.005 and 0.000 in the superior and inferior hemisphere, resp.). The average MRT values with an optimal sensitivity-specificity balance for discriminating the abnormal VF hemifield from the normal hemifield were 273.5 µm and 255.5 µm in the superior and inferior hemisphere, respectively. The area under the receiver operating characteristic curve was 0.701 in the superior hemisphere and 0.784 in the inferior hemisphere (both P < 0.05). Conclusions. MRT measured through SD-OCT was significantly correlated with central VFS. Lower MRT values might be a warning sign for central VF defects in glaucoma patients.

A method to preserve limbus during penetrating keratoplasty for a case of presumed PHACES syndrome with sclerocornea: A case report.

BACKGROUND: Sclerocornea, a congenital corneal pathology characterized by bilateral scleralization of the cornea, which can be found in few cases with posterior fossa malformationshemangiomas-arterial anomalies-cardiac defects-eye abnormalities-sternal cleft and supraumbilical raphe (PHACES) syndrome. Presence of vascularization in peripheral cornea and smaller diameter of recipient cornea correlate to poor outcome of penetrating keratoplasty (PKP) in sclerocornea. Here we report a method to preserve limbus during PKP for small, irregular, and scleralized cornea. METHODS: A 12-year-old boy with multiple congenital anomalies diagnosed as PHACES syndrome suffered from bilateral total sclerocornea and poor visual acuity. Due to the fact that the left eye cornea was small (6.5 mm × 10 mm), lamellar dissection and posterior recession of inferior limbus was first performed and followed by a 6 mm trephination and PKP with a 6.5 mm graft for left eye. At the same time, lens aspiration and release of peripheral anterior synechia were performed. RESULTS: After 6 years of follow-up, the cornea remained clear, and there has been no sign of inflammation and conjunctivalization. The patient maintained useful vision of 20/400 in left eye. CONCLUSION: The stabilization of corneal surface is possible after PKP for sclerocornea if the limbus can be preserved during the operation, and epithelium can remain corneal in phenotype preventing pannas growth.

The relationship of bleb morphology and the outcome of needle revision with 5-fluorouracil in failing filtering bleb.

To investigate the risk factors for failure of needling revision with 5-fluorouracil (5-FU) and to identify the correlation of outcomes of needling revision and the morphological features of dysfunctional filtration blebs using Moorfields bleb grading system.This retrospective, nonrandomized, comparative case-control study included 41 consecutive patients (41 eyes) who underwent 5-FU needling revision for failed or failing filtration blebs between July 2012 and August 2014 in Chang Gung Memorial Hospital, a referral center in Taiwan. The main outcome measures were the bleb survival and the correlation factors of bleb morphology before revision. The secondary outcome measure was the identification of any study factor associated with bleb failure.Forty-one eyes of 41 patients were included in this study. The most frequent glaucoma diagnoses were 10 cases (24%) of neovascular glaucoma and 8 cases (19%) of chronic open-angle glaucoma. Survival of bleb at 6, 12, and 24 months was 42%, 39%, and 23%. Fourteen cases (34%) maintained overall success at the last follow-up, with an average follow-up of 22.7 ±â€Š9.4 months (range: 12-48 months). The central bleb area and height were significantly different between the successful needling group and the failed needling group (P = 0.03 and 0.04, respectively). Further trend test confirmed that smaller central bleb extension and flatter height were associated with a higher chance of failure (P = 0.02 and 0.02, respectively). Time from initial trabeculectomy to needling of less than 4 months and higher intraocular pressure (IOP) in the first postoperative week also led to significantly higher risk for failure (P = 0.01 and 0.03, respectively).A small central area and the flat height of dysfunctional blebs were more likely to fail after the needle revision. Cautious case selections, taking account of the time from the initial filtering surgery and postoperative IOP, may improve the surgical outcome.

Anterior chamber depth and angle-closure glaucoma after central retinal vein occlusion.

BACKGROUND: The purpose of this study was to report the anterior chamber (AC) depth and the attack of angle-closure glaucoma (ACG) in eyes with the recent onset of central retinal vein occlusion (CRVO). METHODS: This retrospective case series included 24 patients with recent onset of CRVO (within one month of attack) from July 2001 to December 2002. The mean follow-up period of the patients was 46 months (range: 3 to 92 months). AC depth was measured using an ultrasound biomicroscopy. Clinical data, including systemic disorders, intraocular pressure, and visual outcomes were recorded. The main outcome measures were AC depth in the diseased eye and the fellow eye of the same patient and the attack of ACG after CRVO. RESULTS: The mean AC depth in the diseased eyes was significantly shallower than in the unaffected fellow eyes (2.43 ± 0.45 mm vs. 2.55 ± 0.46 mm; p < 0.001). Four patients (17 %) developed ACG after the onset of CRVO within one month of the CRVO attack. In these four patients, the mean AC depth in the diseased eyes was 1.91 ± 0.21 mm, which was much shallower than the eyes without ACG attack (2.53 ± 0.40 mm). CONCLUSIONS: AC depth is significantly shallower following the onset of CRVO. ACG can occur in patients after the onset of CRVO.

Association of Extrarenal Adverse Effects of Posttransplant Immunosuppression With Sex and ABCB1 Haplotypes.

Extrarenal adverse effects (AEs) associated with calcineurin inhibitor (CNI) and mycophenolic acid (MPA) occur frequently but are unpredictable posttransplant complications. AEs may result from intracellular CNI accumulation and low activity of P-glycoprotein, encoded by the ABCB1 gene. Since ABCB1 single nucleotide polymorphisms (SNPs) and sex influence P-glycoprotein, we investigated haplotypes and extrarenal AEs. A prospective, cross-sectional study evaluated 149 patients receiving tacrolimus and enteric coated mycophenolate sodium or cyclosporine and mycophenolate mofetil. Immunosuppressive AE assessment determined individual and composite gastrointestinal, neurologic, aesthetic, and cumulative AEs. Lipids were quantitated after 12-hour fast. ABCB1 SNPs: c.1236C>T (rs1128503), c.2677G>T/A (rs2032582), and c.3435C>T (rs1045642) were determined with haplotype associations computed using the THESIAS program, and evaluated by immunosuppression, sex and race using multivariate general linear models. Tacrolimus patients exhibited more frequent and higher gastrointestinal AE scores compared with cyclosporine with association to CTT (P = 0.018) and sex (P = 0.01). Aesthetic AE score was 3 times greater for cyclosporine with TTC haplotype (P = 0.005). Females had higher gastrointestinal (P = 0.022), aesthetic (P < 0.001), neurologic (P = 0.022), and cumulative AE ratios (P < 0.001). Total cholesterol (TCHOL), low-density lipoproteins (LDL), and triglycerides were higher with cyclosporine. The TTC haplotype had higher TCHOL (P < 0.001) and LDL (P = 0.005). Higher triglyceride (P = 0.034) and lower high-density lipoproteins (P = 0.057) were associated with TTT with sex-adjusted analysis. ABCB1 haplotypes and sex were associated with extrarenal AEs. Using haplotypes, certain female patients manifested more AEs regardless of CNI. Haplotype testing may identify patients with greater susceptibility to AEs and facilitate CNI individualization.

Acute angle-closure glaucoma in retinopathy of prematurity following pupil dilation.

BACKGROUND: Pupil dilation is a known risk factor for acute angle-closure glaucoma. Regular retinal evaluation is necessary for retinopathy of prematurity (ROP) cases. An acute attack of angle-closure glaucoma following pupil dilation in regressed ROP has never been reported. CASE PRESENTATION: A five-year-old girl presented to the hospital for a routine retina check-up. The patient was born prematurely with a gestation age of 27 weeks and a body weight of 980 grams. She had a history of stage 4A ROP in the right eye and received scleral buckling. After pupil dilation with 1 % tropicamide and 10 % phenylephrine for retinal examination, acute elevation of intraocular pressure (IOP) was observed in the right eye. Her IOP remained over 50 mmHg in the right eye even under treatment with oral acetazolamide and maximal tolerated doses of topical anti-glaucoma medications. Ultrasound biomicroscopy (UBM) showed that the angle in the right eye was closed 360 degrees circumferentially. In order to lower IOP, trabeculectomy with mitomycin C (0.2 mg/cc) was performed under general anesthesia. Postoperatively, the cornea became clear, the filtering bleb functioned well, and IOP returned to normal values. In the two-year follow-up, IOP was kept around 15 mmHg without anti-glaucoma medications. Although mild lens opacity was noted, her postoperative VA remained 20/200 in the right eye. CONCLUSION: Regular retinal evaluation will be necessary for the increasing number of ROP cases to be seen in the future. Ophthalmologists should bear in mind that pupil dilation for a retina check-up could result in acute angle-closure glaucoma in ROP patients.

Influence of sex and race on mycophenolic acid pharmacokinetics in stable African American and Caucasian renal transplant recipients.

BACKGROUND AND OBJECTIVES: No evaluation of sex and race influences on mycophenolic acid (MPA) pharmacokinetics and adverse effects (AEs) during enteric-coated mycophenolate sodium (ECMPS) and tacrolimus immunosuppression are available. The primary objective of this study was to investigate the influence of sex and race on MPA and MPA glucuronide (MPAG) pharmacokinetics in stable renal transplant recipients receiving ECMPS and tacrolimus METHODS: The pharmacokinetics of MPA and MPAG and their associated gastrointestinal AEs were investigated in 67 stable renal transplant recipients: 22 African American males (AAMs), 13 African American females (AAFs), 16 Caucasian males (CMs), and 16 Caucasian females (CFs) receiving ECMPS and tacrolimus. A validated gastrointestinal AE rating included diarrhea, dyspepsia, vomiting, and acid-suppressive therapy was completed. Apparent clearance, clearance normalized to body mass index (BMI), area under the concentration-time curve from time zero to 12 h (AUC12) and dose-normalized AUC12 (AUC*) were determined using a statistical model that incorporated gastrointestinal AE and clinical covariates. RESULTS: Males had more rapid apparent MPA clearance (CMs 13.8 ± 6.27 L/h vs. AAMs 10.2 ± 3.73 L/h) than females (CFs 8.70 ± 3.33 L/h and AAFs 9.71 ± 3.94 L/h; p = 0.014) with a race-sex interaction (p = 0.043). Sex differences were observed in MPA clearance/BMI (p = 0.033) and AUC* (p = 0.033). MPA AUC12 was greater than 60 mg·h/L in 57 % of renal transplant recipients (RTR) with 71 % of patients demonstrating gastrointestinal AEs and a higher score noted in females. In all patients, females exhibited 1.40-fold increased gastrointestinal AE scores compared with males (p = 0.024). Race (p = 0.044) and sex (p = 0.005) differences were evident with greater MPAG AUC12 in AAFs and CFs. CONCLUSION: Sex and race differences were evident, with females having slower MPA clearance, higher MPAG AUC12, and more severe gastrointestinal AEs. These findings suggest sex and race should be considered during MPA immunosuppression.