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BACKGROUND: Eculizumab is approved for the treatment of atypical hemolytic uremic syndrome (aHUS). Its use off-label is frequently reported. The aim of this study was to describe the broader use and outcomes of a cohort of pediatric patients exposed to eculizumab. METHODS: A retrospective, cohort analysis was performed on the clinical and biomarker characteristics of eculizumab-exposed patients < 25 years of age seen across 21 centers of the Pediatric Nephrology Research Consortium. Patients were included if they received at least one dose of eculizumab between 2008 and 2015. Traditional summary statistics were applied to demographic and clinical data. RESULTS: A total of 152 patients were identified, mean age 9.1 (+/-6.8) years. Eculizumab was used off-label in 44% of cases. The most common diagnoses were aHUS (47.4%), Shiga toxin-producing Escherichia coli HUS (12%), unspecified thrombotic microangiopathies (9%), and glomerulonephritis (9%). Genetic testing was available for 60% of patients; 20% had gene variants. Dosing regimens were variable. Kidney outcomes tended to vary according to diagnosis. Infectious adverse events were the most common adverse event (33.5%). No cases of meningitis were reported. Nine patients died of noninfectious causes while on therapy. CONCLUSIONS: This multi-center retrospective cohort analysis indicates that a significant number of children and young adults are being exposed to C5 blockade for off-label indications. Dosing schedules were highly variable, limiting outcome conclusions. Attributable adverse events appeared to be low. Cohort mortality (6.6%) was not insignificant. Prospective studies in homogenous disease cohorts are needed to support the role of C5 blockade in kidney outcomes.

B‐cell maturation antigen (BCMA)‐targeting immunotherapies (e.g., chimeric antigen receptor T cells (CAR‐T) and bispecific antibodies (BsAbs)) have achieved remarkable clinical responses in patients with relapsed and/or refractory multiple myeloma (RRMM). Their use is accompanied by exaggerated immune responses related to T‐cell activation and cytokine elevations leading to cytokine release syndrome (CRS) in some patients, which can be potentially life‐threatening. However, systematic evaluation of the risk of CRS with BCMA‐targeting BsAb and CAR‐T therapies, and comparisons across different routes of BsAb administration (intravenous (i.v.) vs. subcutaneous (s.c.)) have not previously been conducted. This study utilized a meta‐analysis approach to compare the CRS profile in BCMA‐targeting CAR‐T vs. BsAb immunotherapies administered either i.v. or s.c. in patients with RRMM. A total of 36 studies including 1,560 patients with RRMM treated with BCMA‐targeting CAR‐T and BsAb therapies were included in the analysis. The current analysis suggests that compared with BsAbs, CAR‐T therapies were associated with higher CRS incidences (88% vs. 59%), higher rates of grade ≥ 3 CRS (7% vs. 2%), longer CRS duration (5 vs. 2 days), and more prevalent tocilizumab use (44% vs. 25%). The proportion of CRS grade ≥ 3 may also be lower (0% vs. 4%) for BsAb therapies administered via the s.c. (3 studies, n = 311) vs. i.v. (5 studies, n = 338) route. This meta‐analysis suggests that different types of BCMA‐targeting immunotherapies and administration routes could result in a range of CRS incidence and severity that should be considered while evaluating the benefit–risk profiles of these therapies. [ABSTRACT FROM AUTHOR]

Background Children with chronic kidney disease (CKD) have a high prevalence of cardiovascular disease (CVD) risk factors which may contribute to the development of cardiovascular events in adulthood. Among adults with CKD, cystatin C-based estimates of glomerular filtration rate (eGFR) demonstrate a stronger predictive value for cardiovascular events than creatinine-based eGFR. The PDAY (Pathobiological Determinants of Atherosclerosis in Youth) risk score is a validated tool used to estimate the probability of advanced coronary atherosclerotic lesions in young adults. Objective To assess the association between cystatin C-based versus creatinine-based eGFR (eGFR cystatin C and eGFR creatinine, respectively) and cardiovascular risk using a modified PDAY risk score as a proxy for CVD in children and young adults. Methods We performed a cross-sectional study of 71 participants with CKD [median age 15.5 years; inter-quartile range (IQR) 13, 17], and 33 healthy controls (median age 15.1 years; IQR 13, 17). eGFR was calculated using age-appropriate creatinine- and cystatin C-based formulas. Median eGFR creatinine and eGFR cystatin C for CKD participants were 50 (IQR 30, 75) and 53 (32, 74) mL/min/1.73 m.sup.2, respectively. For the healthy controls, median eGFR creatinine and eGFR cystatin were 112 (IQR 85, 128) and 106 mL/min/1.73m.sup.2 (95, 123) mL/min/1.73 m.sup.2, respectively. A modified PDAY risk score was calculated based on sex, age, serum lipoprotein concentrations, obesity, smoking status, hypertension, and hyperglycemia. Results Modified PDAY scores ranged from -2 to 20. The Spearman's correlations of eGFR creatinine and eGFR cystatin C with coronary artery PDAY scores were -0.23 (p = 0.02) and -0.28 (p = 0.004), respectively. Ordinal logistic regression also showed a similar association of higher eGFR creatinine and higher eGFR cystatin C with lower PDAY scores. When stratified by age Conclusions Overall, the correlation between cystatin C- or creatinine-based eGFR with PDAY risk score was similar in children. Further studies in children with CKD should explore the association between cystatin C and cardiovascular risk., Author(s): Sheena Sharma [sup.1] , Michelle R. Denburg [sup.2] [sup.3] , Susan L. Furth [sup.2] [sup.3] Author Affiliations: (1) 0000 0001 0381 0779grid.417276.1Division of Nephrology, Phoenix Children's Hospital, 1919 E [...]

Byline: Isha. Sharma, Shelly. Rana, Bharti. Choudhary, Tanvi. Dhiman, Sheena. Sharma, Mahesh. Kumar Background and Aim: Intrathecal and intravenous dexmedetomidine has been used as adjuvant in subarachnoid block [SAB]. The [...]

Recent work has suggested that inflammation is a common component of a number of age-related diseases. The hypothesis of the present study was that normal aging of the retina and choroid would increase levels of inducible nitric oxide synthase (iNOS), prostaglandin E2 (PGE2), and tumor necrosis factor alpha (TNF-[alpha]). To investigate this hypothesis, gene expression and protein analyses were completed on retinal and choroidal samples from Fischer 344 x Brown Norway F1 hybrid rats at 8, 22, and 32 months of age. Aging of the choroid produced significant increases in PGE2, with decreased TNF-[alpha] protein. Protein levels and messenger RNA of iNOS and TNF-[alpha] protein levels were significantly decreased in the aging retina in contrast to PGE2 protein activity, which was increased with age in the retina. These results suggest that PGE2 is likely involved in the aging process in both the retina and choroid, whereas iNOS plays a role predominantly in the retina. Key Words: Inflammatory markers--Retina--Choroid--Aging.

Normal aging of the choroid results in morphological and physiological changes. The growth factors that mediate these changes are unclear. Vascular endothelial growth factor (VEGF) binds its receptor 2, VEGFR2, to mediate vascular remodeling. Pigment epithelium-derived factor (PEDF) is an inhibitor of angiogenesis produced by retinal pigmented epithelial (RPE) cells. Angiopoietinl (Ang-1) binds its receptor Tie-2 to recruit mural cells to stabilize vessels. To investigate age-related changes in growth factor activities in aged choroidal vasculature, real-time polymerase chain reaction and protein analysis of VEGF, VEGFR2, PEDF, Ang-1, and Tie-2 were completed on rat choroid/RPE complexes at 8, 22, and 32 months. VEGF messenger RNA (mRNA) peaked at 22 months, whereas protein levels were significantly decreased by 32 months. Both mRNA and protein levels of PEDF were significantly decreased with age. Ang-1 protein levels were not altered, whereas Tie-2 had increased protein levels with age. These results indicate that normal aging involves temporal changes in many of the growth factors common in age-related disease. Key Words: Aging--Choroid--Growth factors.